Carboxylic derivatives for use in the treatment of cancer

The invention relates to compounds of general formula (I), or pharmaceutically acceptable salts, which possess anti-proliferative activity and are therefore useful in methods of treatment of cancer.

BACKGROUND ART

Cancer is a class of diseases or disorders characterized by uncontrolled division of cells and the ability of these cells to invade other tissues, either by direct growth into adjacent tissue through invasion or by implantation into distant sites by metastasis (in which cancer cells are transported through the blood or lymphatic system).

There are a series of types of cancer and the severity of symptoms depends on the site and character of the malignancy and the presence or absence of metastasis. Most cancers can be treated and some cured, depending on the specific type, location, and stage. The current therapies include surgery, chemotherapy, immunotherapy, hormone therapy, radiation therapy, and other treatment methods such as e.g. bone marrow transplantation, photodynamic therapy, and gene therapy.

The unregulated growth that characterizes cancer is caused primarily by damage to DNA, resulting in mutations of genes that encode proteins controlling cell division, apoptosis, and angiogenesis. Mutations are in general caused upon chemical or physical agents termed carcinogens, by close exposure to radioactive materials, or by certain viruses such as Human Papilloma Virus (HPV) or Epstein-Barr Virus (EBV), amongst others. Mutations occur spontaneously, or are hereditary and passed down generations as a result of germ line mutations.

Many forms of cancer are associated with exposure to environmental factors such as tobacco smoke, radiation, alcohol, and tumour-associated viruses. While some of these can be avoided, there is no known way to entirely avoid the disease.

Hence, cancer is still one of the leading causes of death in developed

countries. In some Western countries, cancer is overtaking cardiovascular disease as the leading cause of death in spite of improved surgery and radiochemotherapy. In the last decades great efforts have been made to understand the molecular basis of cancer and to develop new therapies. As cancer has often a great impact on life quality of the patients and may lead to life threatening, there is still a need for developing new therapeutic agents with improved properties.

SUMMARY OF THE INVENTION

The present inventors have found that the compounds of formula (I) has antiproliferative activity. Owing to this anti-proliferative activity the compounds of the present invention are useful in the treatment of cancer.

Surprisingly, the inventors have found that the compounds of general formula (I) show a good anti-proliferative activity, being efficient in the treatment of cancer.

Thus, in a first aspect the present invention relates to a compound of general formula (I), or a pharmaceutical acceptable salt thereof, or a solvate thereof including a hydrate, or any stereoisomer or mixture of stereoisomers:

wherein:

Ri is a radical derived from one of the known ring systems selected from the group consisting of:

one aromatic ring having 5-6 carbon atoms, being optionally one of said carbon atoms replaced by one N, O, or S atom; and a two fused ring system, wherein one of the rings is aromatic and the other is aromatic or partially

insaturated, each ring has 5-6 carbon atoms, being optionally 1 -3 of said carbon atoms replaced by N, O, or S;

wherein each ring, forming the known ring system, is optionally substituted by at least one radical selected from the group consisting of: (d-C ₈ )alkyl, -OH, halogen, (CrC ₈ )alkoxy, -CN, (CrC ₈ )fluoralkyl, (CrC ₈ )fluoroalkoxy, -CH ₂ -R ₅ , -R ₁₀ , -Q _n -OR ₅ , -Q _n -NR ₄ C(O)R ₅ , -Q _n -C(O)NR ₄ R ₅ , -Q _n -NH ₂ , -Q _n -NR ₄ R ₅ , -Q _n -S-R ₅ , -Q _n -S(O ₂ )-R ₅ , -Q _n -NR ₄ S(O ₂ )R ₅ , -Q _n -S(O ₂ )NR ₄ R ₅ , -Q _n -NR ₄ -CO, -NR ₄ R ₅ , -Q _n -NR ₄ -CO-OR _5, and -Q _n -O-CO-NR ₄ R ₅ ; where Q _n is -(CH ₂ ) _n -, being n= O, 1 , 2 or 3;

R ₂ is a phenyl radical optionally substituted by at least one radical selected from the group consisting of: halogen, -OH, -P _n -OR ₅ , -NR ₄ C(O)R ₆ , -C(O)NR ₄ R ₆ , -NH ₂ , -NR ₄ R ₅ , -R ₁₀ , -R ₆ , -CN, (C _r C ₄ )fluoralkyl, (C ₁ - C ₄ )fluoroalkoxy, (Ci-C ₄ )alkoxy, and (Ci-C ₄ )alkyl; where P _n is -(CH ₂ ) _n - being n= O or 1

X _n represents a birradical selected from the group consisting of: -(CH ₂ J _1-4 -, (C ₂ -C ₄ )-alkenyl, (C ₂ -C ₄ )alkynyl, -S-(CH ₂ ) _1-3 -#, and -(CH ₂ ) _1-3 -O-#; wherein the symbol # indicates the position at which X _n is attached to R ₁ ;

Y _n is a birradical selected from the group consisting of: -(CH ₂ J _2-4 -, -S-(CH ₂ ) _1-3 #, and -O-(CH ₂ ) _1-3 -#,; wherein the symbol # indicates the position at which Y _n is attached to R ₂ ;

R ₃ is a radical selected from the group consisting of: -OR ₄ , -0-CR ₄ R ₄ -O-C(O)-R ₄ ;

R ₄ is a radical selected from: hydrogen and (C-ι-C ₄ )alkyl optionally substituted by at least one radical selected from the group consisting of: -NH ₂ and -OH;

R ₅ is a radical selected from: hydrogen, and -L _n -R ₇ , where

L _n is -(CH ₂ ) _n - with n=0, 1 , 2, 3 or 4;and R ₇ is a known ring systems with 1 ring or 2 fused rings, each one of the rings forming said ring system being partially unsaturated or aromatic, have 5-6 members, each member being independently

selected from C, N, O, S, CH, CH ₂ , and NH; and being each ring forming said ring system optionally substituted by at least one radical selected from the group consisting of: (Ci-C ₄ )-alkyl, -CN, (C ₁ - C ₄ )fluoralkyl, (C _r C ₄ )fluoroalkoxy, halogen, (C _r C ₄ )alkoxy, -NH ₂ , -OH, dialkyl(Ci-C ₄ )amino, and a known aromatic ring of 5-6 members independently selected from N, O, S, CH, and NH which is linked to R ₇ via a (d-C ₄ )alkyl birradical;

R ₆ is a radical selected from the group consisting of: (Ci-C ₄ )alkyl optionally substituted by at least one radical selected from the group consisting of: halogen, cyano, amino, and an aromatic known ring having 5-6 members independently selected from N, O, S, CH, and NH;

R-io is an aromatic known ring having 5-6 members independently selected from N, O, S, CH, and NH;

with the proviso that when R ₁ is phenyl:

R ₂ is a phenyl radical substituted by at least one radical selected from the group consisting of: (Ci-C ₄ )alkoxy, (Ci-C ₄ )alkyl, -NHC(O)CH ₃ , halogen, -0-CH ₂ -R ₈ , -OH, -NH ₂ , -OR ₁₁ , -R ₈ , -NHR ₁₁ , and -NH-CH ₂ -phenyl; R ₈ is a aromatic known ring having 5-6 members independently selected from N, O, S, CH, and NH; R ₁₁ is a phenyl ring optionally substituted with -F, -CF ₃ , -OCH ₃ and -CN; R ₃ is selected from the group consisting of: -OH, (C _r C ₄ )alkoxy and

-0-CH ₂ -O-C(O)-CH ₃ ;

X _n is selected from the group consisting of:-(CH ₂ ) ₃ -; and

Y _n is selected from the group consisting of: -(CH ₂ ) ₂ ;

and with the proviso that R ₁ and R ₂ are not simultaneously a phenyl substituted by one -OMe radical.

It is remarkable that the aromatic nature of both R ₁ and R ₂ enhances the activity of the compounds of the present invention as it is shown below. For this reason, it is important that R ₁ has aromatic nature (in addition to R ₂ which is phenyl optionally substituted), specially when R ₁ is a 2-fused ring system: it is necessary that at least one of the rings forming the system is aromatic in

order to achieve the therapeutic effect. In fact, the inventors of the present invention believe that from the activity data obtained with the compounds of the present invention other useful compounds could be obtained which differed from those provided in the present application in that R ₂ is an aromatic ring having 5-6 carbon atoms (other than phenyl), being optionally one of said carbon atoms replaced by one N, O, or S atom; or a two fused ring system, wherein one of the rings is aromatic and the other is aromatic or partially insaturated, each ring has 5-6 carbon atoms, and being optionally 1 -3 of said carbon atoms replaced by N, O, or S.

In a second aspect the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) as defined in the first aspect of the invention, together with the appropriate amounts of pharmaceutical excipients or carriers.

In a third aspect the present invention relates to a compound of general formula (I) as defined in the first aspect of the invention, or a compound selected from the group consisting of:

2-Methyl-4-phenylbutanoic acid;

2-Ethyl-4-phenylbutanoic acid; 2-(2-Phenylethyl)pentanoic acid; 2-Benzyl-4-phenylbutanoic acid; 5-Phenyl-2-(2-phenylethyl)pentanoic acid; Methyl 2-methyl-4-phenylbutanoate;

Methyl 2-ethyl-4-phenylbutanoate; (Acetyloxy)methyl 2-benzyl-4-phenylbutanoate; (Acetyloxy)methyl 5-phenyl-2-(2-phenylethyl)pentanoate; Sodium 2-(Benzylthio)-5-phenylpentanoate; 2-(Benzyloxy)-5-phenylpentanoic acid;

5-Phenyl-2-propylpentanoic acid; (4E)-5-Phenyl-2-(2-phenylethyl)pent-4-enoic acid; and 6-Phenyl-2-(2-phenylethyl)hexanoic acid;

for use as a medicament.

In a fourth aspect the present invention relates to a compound of general

formula (I) as defined in the first aspect of the invention, or a compound selected from the group consisting of:

2-Methyl-4-phenylbutanoic acid; 2-Ethyl-4-phenylbutanoic acid;

2-(2-Phenylethyl)pentanoic acid;

2-Benzyl-4-phenylbutanoic acid;

5-Phenyl-2-(2-phenylethyl)pentanoic acid;

Methyl 2-methyl-4-phenylbutanoate; Methyl 2-ethyl-4-phenylbutanoate;

(Acetyloxy)methyl 2-benzyl-4-phenylbutanoate;

(Acetyloxy)methyl 5-phenyl-2-(2-phenylethyl)pentanoate;

Sodium 2-(Benzylthio)-5-phenylpentanoate;

2-(Benzyloxy)-5-phenylpentanoic acid; 5-Phenyl-2-propylpentanoic acid;

(4E)-5-Phenyl-2-(2-phenylethyl)pent-4-enoic acid; and

6-Phenyl-2-(2-phenylethyl)hexanoic acid;

for use in the treatment of cancer. This aspect can be also formulated as the use of a compound as defined in the fourth aspect of the invention for the manufacture of a medicament for the treatment of cancer.

In a further aspect, the present invention provides a compound as defined according to the first aspect of the invention for use as a medicine.

In a still further aspect, the present invention provides a compound as defined according to the first aspect of the invention, for use in the treatment of cancer. This aspect can be also formulated as the use of a compound as defined in the first aspect of the invention for the manufacture of a medicament for the treatment of cancer.

Another aspect of the present invention is to provide a method for the treatment of cancer which comprises administering to a mammal, preferably a human, a therapeutically effective amount of the compound, as defined in the first or fourth aspect of the invention, together with one or more pharmaceutically acceptable carriers, excipients, diluents or adjuvants.

Throughout the description and claims the word "comprise" and variations of the word, such as "comprising", is not intended to exclude other technical features, additives, components, or steps. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples are provided by way of illustration, and are not intended to be limiting of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

In the present invention, the term "fluoralkyl" means a hydrocarbon chain wherein one or more hydrogen atoms are replaced by one or more fluorine atoms.

In the same way, the term "fluoroalkoxy" means an alcoxy wherein one or more hydrogen atoms are replaced by one or more fluorine atoms.

Illustrative non-limitative examples of known ring systems consisting of one ring are those derived from: cyclopropenyl, cyclobutenyl, cyclopentenyl, phenyl, aziridinyl, oxirenyl, thiiranyl, azetidinyl, oxetanyl, pyrrolyl, furanyl, and thiophenyl.

Illustrative non-limitative examples of known ring systems consisting of two rings totally fused, are those derived from benzofuran, isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline, benzofurazan, benzothiofuran, , heterocyclic chromene, isochromene, chroman, isochroman, quinoline, isoquinoline, and quinolizine , .

As used herein, the symbols -C(O)-, -S(O)- and -S(O ₂ )- means, respectively:

In one embodiment of the first aspect of the invention, the compound of formula (I) according to the first aspect of the invention is one wherein:

Ri is a radical derived from one of the known ring systems selected from the group consisting of:

one aromatic ring having 5-6 carbon atoms, being optionally one of said carbon atoms replaced by one N, O or S; and a two fused ring system, wherein one of the rings is aromatic and the other is aromatic or partially insaturated, each ring has 5-6 carbon atoms, being optionally 1 -3 carbon atoms replaced by N, O, or S;

being each ring, forming said ring system, optionally substituted by at least one radical selected from the group consisting of: (d-C ₈ )alkyl, -OH, halogen, (Ci-C ₈ )alkoxy, -CN, -(C _r C ₄ )fluoralkyl, -(C _r C ₄ )fluoroalkoxy, -CH ₂ -R ₅ , -Rio, -Q _n -OR ₅ , -Q _n -NR ₄ C(O)R ₅ , -Q _n -C(O)NR ₄ R ₅ , -Q _n -NH ₂ , -Q _n -NR ₄ R ₅ , -Q _n -NR ₄ S(O ₂ )R ₅ , -Q _n -S(O ₂ )NR ₄ R ₅ and -Q _n -NR ₄ -CO-OR ₅ ; where Q _n is -(CH ₂ ) _n -, being n= O or 1 ;

R ₄ is a radical selected from: hydrogen and (d-C ₄ )alkyl; R ₅ is a radical selected from: hydrogen, and -L _n -R ₇ where L _n is -(CH ₂ ) _n - with n=0 or 1 ;and

R ₇ is an aromatic ring with 5-6 members, each member being independently selected from N, O, S, CH, and NH; and being optionally substituted by at least one radical selected from the group consisting of: -(d-C ₄ )-alkyl, -CN, -(C _r C ₄ )fluoralkyl, -(C _r

C ₄ )fluoroalkoxy, halogen, -(Ci-C ₄ )alkoxy, -NH ₂ ,-OH and dialkyl(Ci- C ₄ )amino.

In another embodiment of the first aspect of the invention, the compound of general formula (I) is one wherein:

Ri is a radical derived from naphtyl; phenyl and thiophene, being the phenyl and thiophene radical optionally substituted by at least one radical selected from the group consisting of: (Ci-C ₄ )alkyl, -OH, halogen, (C _r C ₄ )alkoxy, -CN, -CF ₃ , -CHF ₂ , -OCF ₃ , -OCHF ₂ ,

-NH ₂ , -Rio, -NR ₄ C(O)R ₅ , -C(O)NR ₄ R ₅ , -NR ₄ S(O ₂ )R ₅ , and -S(O ₂ )NR ₄ R ₅ ;

R ₂ is a phenyl radical optionally substituted by at least one radical selected from the group consisting of: halogen; -OH, -OR ₅ , -NHC(O)R ₆ , -C(O)NHR ₆ , -NH ₂ , -NHR ₅ , -R ₁₀ , -R ₆ , -CN, -CF ₃ , -CHF ₂ , -OCF ₃ , -OCHF ₂ , (C _r C ₄ )alkoxy and (CrC ₄ )alkyl;

X _n represents a birradical selected from the group consisting of: -(CH ₂ ) _2-4 -, (C ₂ -C ₄ )-alkenyl, (C ₂ -C ₄ )alkynyl, and -S-(CH ₂ )i _-3 -#, wherein the symbol # indicates the position at which X _n is attached to R-i;

Y _n is a birradical selected from the group consisting of: -(CH ₂ J _2-3 -, -S-(CH ₂ ) _1-2 #, and -O-(CH ₂ ) _1-2 -#,; wherein the symbol # indicates the position at which Y _n is attached to R ₂ ;

R ₅ is a radical selected from: hydrogen and -L _n -R ₇ , where L _n is -(CH ₂ ) _n - bein n=0 or 1 ;and

R ₇ is an aromatic known ring system with 5-6 members, each member being independently selected from N, O, S, CH, and NH; and being optionally substituted by at least one radical selected from the group consisting of: (d-C ₄ )-alkyl, -CN, -CF ₃ , -CHF ₂ , -OCF ₃ , -OCHF ₂ , halogen, (C _r C ₄ )alkoxy, -NH ₂ , -OH and dialkyl(C _r C ₄ )amino.

In a more preferred embodiment of the first of the invention,

Ri is a radical derived from naphtyl; phenyl and thiophene, being the phenyl and thiophene radical optionally substituted by at least one radical selected from the group consisting of: -NR ₄ C(O)R ₅ , and -S(O ₂ )NR ₄ R ₅ ;

R ₂ is a phenyl radical optionally substituted by at least one radical selected from the group consisting of: -OH, -OR ₅ , -NHR ₅ , -R ₁₀ , and (Ci-C ₄ )alkyl; and

R ₅ is hydrogen or a phenyl radical optionally substituted by at least one radical selected from the group consisting of: (Ci-C ₄ )-alkyl, -CN, (d- C ₄ )alkoxy, -CH ₂ -phenyl, -CH ₂ -pyridine, and dialkyl(Ci-C ₄ )amino.

In still another preferred embodiment of the first aspect of the invention,

Ri is selected from the group consisting:

wherein the symbol # indicates the position at which R ₁ is attached to X _n ;

wherein R ₉ is -CH ₃ , -R _x or -CH ₂ -R _x

R ₂ is wherein the symbol # indicates the position at which R ₂ is attached to Y _n ;

R" ₂ is selected from the group consisting of: hydrogen, -OCH ₃ , -OH ; and

R' ₂ is selected from the group consisting of: hydrogen, -NH ₂ , (d-

C ₄ )alkyl, -OH, -OCH ₃ , -CN, halogen, -NH-CO-CH ₃ , -0-R ₅ , -0-CH ₂ - phenyl, -O-CH ₂ -pyridine, -NH-CH ₂ -phenyl, and an aromatic known ring having 5-6 members selected from CH, N, NH, O and S;

R ₅ is phenyl optionally substituted by one radical selected from: -CN,

-F, -OCH ₃ , -CF ₃ ;

R _x is phenyl optionally substituted by one radical selected from the group consisting of: (Ci-C ₄ )alkyl, (Ci-C ₄ )alkoxy, and dialkyl(Ci-C ₄ )amino;

X _n represents a birradical selected from the group consisting of: -(CH ₂ ) ₂ - ₄ -, C ₃ - alkenyl, -C ₃ -alkynyl, and -S-(CH ₂ ) ₂ -#; wherein the symbol # indicates the position at which X _n is attached to R-i;

Y _n is a birradical selected from the group consisting of: -(CH ₂ )2-3-, -SCH ₂ -#, and -OCH ₂ -# ; wherein the symbol # indicates the position at which X _n is attached to R ₂ ; and

R ₃ is hydroxyl, methoxy, ethoxy or -0-CH ₂ -O-C(O)-CH ₃ .

In another embodiment of the first aspect of the invention, the compound of general formula (I) is one where:

Ri is selected from the group consisting of:

wherein the symbol indicates the position at which R ₁ is attached to X _n ; R ₂ is selected from the group consisting of:

wherein R' ₂ and R" ₂ are selected from the group consisting of: hydrogen, -NH ₂ , -OH, -OCH ₃ , -Cl, -Br, -CONH ₂ , and phenyl; and the symbol \ indicates the position at which R ₂ is attached to Y _n . X _n is selected from the group consisting of: -(CH ₂ )-, -(CH ₂ ) ₂ -, -(CH ₂ ) ₃ -,

-NH-(CH ₂ ) ₂ -f -CH ₂ -NH-C(O)"! , wherein the symbol \ indicates the position at which X _n is attached to R-i;

Y _n is selected from the group consisting of: -(CH ₂ ) ₂ - and -S-CH ₂ -| ; wherein the symbol \ indicates the position at which Y _n is attached to R ₂ ; and

R ₃ is hydroxyl, methoxy, ethoxy -0-CH ₂ -O-C(O)-CH ₃ , or

wherein the symbol f indicates the position wherein the group C=O is attached to R ₃ .

In another embodiment of the first aspect of the invention,

Ri is phenyl;

R ₂ is a phenyl radical substituted by at least one radical selected from the group consisting of: (Ci-C ₄ )alkoxy, (Ci-C ₄ )alkyl, -NHC(O)CH ₃ , halogen,

-0-CH ₂ -R ₈ , -OH, -NH ₂ , -OR ₁₁ , -R ₈ , -NHR ₁₁ , and -NH-CH ₂ -phenyl;

R ₈ is a aromatic known ring having 5-6 members independently selected from N, O, S, CH, and NH;

R ₁₁ is a phenyl ring optionally substituted with -F, -CF ₃ , -OCH ₃ and -CN;

R ₃ is selected from the group consisting of: -OH, (C-ι-C ₄ )alkoxy and

-0-CH ₂ -O-C(O)-CH ₃ ;

X _n is selected from the group consisting of:-(CH ₂ ) ₃ -; and Y _n is selected from the group consisting of: -(CH ₂ ) ₂

In another embodiment of the first aspect of the invention,

R ₁ is phenyl substituted by at least one radical selected from -S(O ₂ )NR ₄ R ₅ , -NR ₄ S(O ₂ )R ₅ and -NR ₄ C(O)R ₅ ;

R ₂ is phenyl optionally substituted by one (C _r C ₄ )alkyl radical; R ₃ is selected from the group consisting of: -OH, methoxy, and -0-CH ₂ -O-C(O)-CH ₃ ; R ₄ is hydrogen; and R ₅ is -L _n -R ₇ , where

L _n is -(CH ₂ ) _n - being n= O or 1 ;and

R ₇ is phenyl optionally substituted by at least one radical selected

from the group consisting of: (Ci-C ₄ )-alkyl, (Ci-C ₄ )alkoxy, and dialkyl(Ci-C ₄ )amino;

X _n is -(CH ₂ ) ₃ - or -CH ₂ -CE^≡C-#, wherein the symbol # indicates the position at which X _n is attached to R-i; and Y _n is -(CHz) ₂ -.

In another embodiment of the first aspect of the invention,

Ri is naphtyl; R ₂ is phenyl optionally substituted by one radical selected from the group consisting of: (d-C ₄ )alkyl radical, thiophene and pyridine;

R ₃ is -OH;

X _n is -(CH ₂ )S-; and

Y _n is -(CHz) ₂ -.

In another embodiment of the first aspect of the invention,

Ri is thiophene substituted by one -S(O ₂ )NR ₄ R ₅ radical; R ₂ is phenyl; R ₃ is -OH;

R ₄ is hydrogen;

R ₅ is a (Ci-C ₄ )alkyl radical;

X _n is -(CH ₂ )S-; and

Y _n is -(CHz) ₂ -.

Preferably the compound of general formula (I) according to the first aspect of the invention is selected from the group consisting of:

2-{4-[(Methylamino)sulfonyl]benzyl}-4-phenylbutanoic acid; 5-(4-[(Methylamino)sulfonyl]phenyl)-2-(2-phenylethyl)pentano ic acid;

(Acetyloxy)methyl 5-(3-{[(3,4-dimethoxyphenyl)amino]sulfonyl}phenyl)-2-(2- phenylethyl)pentanoate;

(Acetyloxy)methyl 5-(3-[(4-methylanilinosulfonyl]phenyl)-2-(2-phenylethyl) pentanoate; (Acetyloxy)methyl 5-(3-[(methylamino)sulfonyl]phenyl)-2-(2-phenylethyl) pentanoate;

Sodium 5-phenyl-2-(2-phenylethyl)pentanoate;

5-(2-Naphthyl)-2-(2-phenylethyl)pentanoic acid;

5-(1 -Naphthyl)-2-(2-phenylethyl)pentanoic acid;

5-[3-{[4-(Dimethylannino)benzoyl]annino}phenyl]-2-(2-phen ylethyl)pentanoic acid; 5-[3-{[4-(Dimethylannino)benzoyl]annino}phenyl]-2-(2-phenyle thyl)pentanoic acid hydrochloride;

5-(3'-{[(4-Methylphenyl)sulfonyl]amino}phenyl)-2-(2-pheny lethyl)pentanoic acid;

5-{5-[(Methylamino)sulfonyl]thien-2-yl}-2-(2-phenylethyl) pentanoic acid; 5-(3-[(Benzylamino)sulfonyl]phenyl)-2-(2-phenylethyl)pentano ic acid;

5-Phenyl-2-(2-pyridin-2-ylethyl)pentanoic acid;

2-[2-(3-methoxyphenyl)ethyl]-5-phenylpentanoic acid;

2-[2-(3-Hydroxyphenyl)ethyl]-5-phenylpentanoic acid;

2-{2-[4-(Acetylamino)phenyl]ethyl}-5-phenylpentanoic acid; 2-[2-(4-Aminophenyl)ethyl]-5-phenylpentanoic acid;

2-[2-(4-(Benzylamino)phenyl)ethyl]-5-phenylpentanoic acid;

5-(3-[(4-Methylanilinosulfonyl]phenyl)-2-(2-phenylethyl)p entanoic acid;

Sodium 5-(3-[(4-methylanilinosulfonyl]phenyl)-2-(2-phenylethyl)pent anoate;

5-[3-(4-Methylanilinosulfonyl)phenyl]-2-(2-phenylethyl)pe nt-4-ynoic acid; 5-(3-[(Anilinosulfonyl]phenyl)-2-(2-phenylethyl)pentanoic acid;

5-(4-[Anilinosulfonyl]phenyl)-2-(2-phenylethyl)pentanoic acid;

5-(3-[(Methylamino)sulfonyl]phenyl)-2-(2-phenylethyl)pent anoic acid;

Methyl 5-(3-[(methylamino)sulfonyl]phenyl)-2-(2-phenylethyl)pentano ate;

5-(3-{[(3,4-dimethoxyphenyl)amino]sulfonyl}phenyl)-2-(2-p henylethyl) pentanoic acid;

5-[3-(4-methylanilinosulfonyl)phenyl]-2-(3-phenylpropyl)p entanoic acid; 2-[2-(4-Ethylphenyl)ethyl]-5-phenylpentanoic acid; 5-[4-(Anilinosulfonyl)phenyl]-2-[2-(4-ethylphenyl)ethyl]pent anoic acid; Methyl 5-[4-(anilinosulfonyl)phenyl]-2-[2-(4-ethylphenyl)ethyl]pent anoate; 2-[2-(4-Ethylphenyl)ethyl]-6-phenylhexanoic acid;

5-(3-{[4-(Dimethylamino)benzoyl]amino}phenyl)-2-[2-(4-eth ylphenyl)ethyl] pentanoic acid;

5-(1 -Naphthyl)-2-[2-(4-ethylphenyl)ethyl]-pentanoic acid; 2-[2-(4-hydroxyphenyl)ethyl]-5-phenylpentanoic acid; 2-[2-(4-Benzyloxyphenyl)ethyl]-5-phenylpentanoic acid;

(Acetyloxy)methyl 2-[2-(4-benzyloxyphenyl)ethyl]-5-phenylpentanoate; 2-[2-(4-Methoxyphenyl)ethyl]-5-phenylpentanoic acid;

2-{2-[4-(Pyndin-2-ylmethoxy)phenyl]ethyl}-5-phenylpentano ic acid;

2-{2-[4-(Pyridin-4-ylnnethoxy)phenyl]ethyl}-5-phenylpenta noic acid;

2-{2-[4-(2-Cyanophenoxy)phenyl]ethyl}-5-phenylpentanoic acid;

2-{2-[4-(3-cyanophenoxy)phenyl]ethyl}-5-phenylpentanoic acid; 2-{2-[4-(4-cyanophenoxy)phenyl]ethyl}-5-phenylpentanoic acid;

2-{2-[4'-(2-Furyl)phenyl]ethyl}-5-phenylpentanoic acid;

2-{2-[4'-(3-Furyl)phenyl]ethyl}-5-phenylpentanoic acid;

2-{2-[4'-(3-Thienyl)phenyl]ethyl}-5-phenylpentanoic acid;

2-{2-[(4'-Pyridinyl)phenyl-4-yl]ethyl}-5-phenylpentanoic acid; 2-{2-[(4'-Pyridinyl)phenyl-4-yl]ethyl}-5-phenylpentanoic acid hydrochloride;

2-[2-(4-Pyridin-3'-ylphenyl)ethyl]-5-phenylpentanoic acid;

5-Phenyl-2-[2-(4'-thien-2-ylphenyl)ethyl]pentanoic acid;

2-[2-(1 ,1 '-Biphenyl-4-yl)ethyl]-5-phenylpentanoic acid;

5-(1 -Naphthyl)-2-[2-(4'-thien-2-ylphenyl)ethyl]-pentanoic acid; 5-(1 -Naphthyl)-2-[2-(4'-pyridin-3-ylphenyl)ethyl]-pentanoic acid;

2-{2-[4-(Pyridin-3-ylmethoxy)phenyl]ethyl}-5-phenylpentan oic acid;

2-{2-[4-(4-Fluorophenoxy)phenyl]ethyl}-5-phenylpentanoic acid;

2-{2-[4-Phenoxyphenyl]ethyl}-5-phenylpentanoic acid;

2-{2-[4-(4-Trifluoromethylphenoxy)phenyl]ethyl}-5-phenylp entanoic acid; 2-[2-(4-Bromophenyl)ethyl]-5-phenylpentanoic acid;

2-{2-[4-(4-Methoxyphenoxy)phenyl]ethyl}-5-phenylpentanoic acid;

2-[2-(2,3-Dihydro-1 H-indol-3-yl)ethyl]-5-phenylpentanoic acid;

5-(1 -Naphthyl)-2-[2-(4'-pyridin-3-ylphenyl)ethyl]-pentanoic acid; and

2-[2-(4-Anilinophenyl)ethyl]-5-phenylpentanoic acid.

The compounds of the present invention are obtained carrying out the steps summarized in the following scheme 1 :

Scheme 1 :

Step (a) corresponds to the alkylation of a compound of general formula (II) with a compound of general formula (III), wherein Z represents halogen. This reaction is carried out in the presence of a suitable base, for instance LDA, although other bases can be used as it is well-known for those skilled in the art.

When it is used as electrophile of formula (III) an alkenyl or alkenyl halide, the resulting product of the previous step can be subjected to hydrogenation.

Step (b) corresponds to the hydrolysis of the product resulting from the alkylation of step (a) or from the hydrogenation. This step is carried out in a basic medium, such as an alkaline or alkaline earth metal hydroxide.

When the compound of general formula (I) is one wherein R ₃ is different from -OH (for instance an alkoxy or an amine), an additional step, (c), is carried out. This step consists of:

c.1 ) Alkylation in presence of base (such as thethylamine); or c.2) Esterification in the presence of coupling reagents.

Suitable bases and coupling agents are well-known in the state of the art.

When the compound of formula (I) is one wherein R ₂ is phenyl substituted by R-io (i.e. a known ring system as defined above), it can be obtained following the routes summarizes in the following Scheme 2:

Scheme 2:

wherein:

Ar ₁ = corresponds to R1 ;

Ar ₂ = is an aromatic known ring having 5-6 members independently selected from N, O, S, CH, and NH

Ar ₂ B(OR) ₂ = boronic acid based reagent for the introduction Of Ar ₂ ; and

LG= is a leaving group such as halogen

and being X _n and Y _n as defined above.

The active compound or pharmaceutical composition comprising the active compound may be administered to a subject by any convenient route of

administration, whether system ical Iy/ peripherally or at the site of desired action, including but not limited to, oral (e. g. by ingestion); topical (including e. g. transdermal, intranasal, ocular, buccal, and sublingual); pulmonary (e. g. by inhalation or insufflation therapy using, e. g. an aerosol, e. g. through mouth or nose); rectal; vaginal; parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal by implant of a depot, for example, subcutaneously or intramuscularly. The active compound of the present invention can be administered in the form of an acid or in the form of a pharmaceutically acceptable prodrug. "A pharmaceutically acceptable prodrug" is a compound that may be converted under physiological conditions or by solvolysis to the specified compound or to a pharmaceutically acceptable salt of such compound.

The compounds according to the present invention have the ability of binding to the the histone deacetylase (HDAC), inhibiting its activity. Histone deacetylases are a family of enzymes that can deacetylate acetyl lysines. HDACs are primarily involved in regulation of chromatin structure and gene expression via their ability to modulate histone acetylation, although they also play roles in other important cellular functions like microtubule deacetylation. As it is well-known in the state of the art, HDAC inhibitors have shown activity in numerous disease models including, but not limited to, many cancers such as colon cancer, lymphoma, leukemias, lung cancer, breast cancer, prostate cancer; neurogenerative disease like Spinal Muscular Atrophy, Huntington Disease, Alzheimer ^' s disease, immune disorder including graft vs. host disorders, Multiple Sclerosis, renal disease, Nervous system conditions, diabetes, malaria, HIV, and stimulation of stem cells/ reprogramming of somatic cells to induce pluripotent stem cells. Therefore, the compounds of the present invention not only are useful for the treatment of cancer but also for the treatment of a pathology associated with an increase of HDAC activity and/or HDAC protein levels.

In one embodiment of the present invention, it is provided a compound of formula (I) as defined in the first aspect of the invention for the treatment of neurodegenerative diseases. This aspect can be formulated as the use of a

compound of formula (I) for the manufacture of a medicament for the treatment of a neurodegenerative disease. Preferably, the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, and Spinal Muscular Atrophy.

The invention further provides a method for the treatment of a neurodegenerative disease which comprises administering to a mammal, preferably a human, a therapeutically effective amount of the compound, as defined in the first or fourth aspect of the invention, together with one or more pharmaceutically acceptable carriers, excipients, diluents or adjuvants.

The pharmaceutical composition (e. g. formulation) may comprise a therapeutically effective amount of the compound of formula (I), as defined above, together with one or more pharmaceutically acceptable excipients or carriers such as adjuvants, diluents, fillers, buffers, stabilizers, preservatives, lubricants.

The term "pharmaceutically acceptable" as used herein pertains to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e. g. human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each carrier, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

Suitable carriers, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1990.

The term "therapeutically-effective amount," as used herein, pertains to that amount of an active compound, or a material, composition or dosage form comprising an active compound, which is effective for producing some desired therapeutic effect.

In one embodiment of the third aspect of the invention, the compounds can be used as an anti-cancer agent.

The term "anti-cancer agent" as used herein, pertains to a compound which treats a cancer (i.e., a compound which is useful in the treatment of a cancer). The anti- cancer effect may arise through one or more mechanisms, including but not limited to, the regulation of cell proliferation, the inhibition of cell cycle progression, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a turnout from its origin), the inhibition of invasion (the spread of turnout cells into neighboring normal structures), or the promotion of apoptosis (programmed cell death).

In one embodiment of the fourth aspect of the invention, the cancer is selected from breast cancer and colon cancer.

The subject may be a eukaryote, an animal, a vertebrate animal, a mammal, a rodent (e. g. a guinea pig, a hamster, a rat, a mouse), murine (e. g. a mouse), canine (e. g. a dog), feline (e. g. a cat), equine (e. g. a horse), a primate, simian (e. g. a monkey or ape), a monkey (e. g. marmoset, baboon), an ape (e. g. gorilla, chimpanzee, orangutang, gibbon), or a human.

EXAMPLES

Molecule names were generated using IsisDraw version 2.4. For molecules larger than 50 atoms, the molecule was fragmented to generate the name. In the case of a conflict between a name and a drawing of the structure, the drawing is controlling.

Synthesis of Intermediates

R ₁ = Phenyl. Methyl 2-{2-(4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)ethyl}-5- phenylpentanoate (Intermediate A).

a) 4-(4-Hydroxyphenyl)butanoic acid

A suspension of 4-(4-methoxyphenyl)butanoic acid (2.0 g, 9.603 mmol) in HBr (20 ml_, 48% aqueous solution) was refluxed for 2 h. The reaction mixture was allowed to reach room temperature (hereinafter abbreviated as "r.t."), poured into H ₂ O (150 ml_) and extracted with EtOAc (200 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated, to give 1.81 g of 4- (4-hydroxyphenyl)butanoic acid (white solid). The crude residue was submitted to next step without purification.

b) Methyl 4-(4-hydroxyphenyl)butanoate

H ₂ SO ₄ (2 ml_, 37.32 mmol) was added to a solution of A-(A- hydroxyphenyl)butanoic acid (9.603 mmol) in MeOH (40 ml_). The reaction mixture was refluxed for 1 h, allowed to reach r.t., and poured into H ₂ O (150 ml_). It was extracted with CH ₂ CI ₂ (200 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated, to give 1.59 g of crude methyl 4-(4-hydroxyphenyl)butanoate (colourless oil, yield: 85%). The compound was submitted to next step without further purification. 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.02 (d, J = 7.9 Hz, 2H), 6.75 (d, J = 7.9 Hz, 2H), 5.47 (bs, 1 H), 3.67 (s, 3H), 2.57 (t, J = 7.7 Hz, 2H), 2.32 (t, J = 7.7 Hz, 2H), 1.92 (m, 2H).

c) Methyl 4-[4-(benzyloxy)phenyl]butanoate BnBr (2.5 ml_, 21.018 mmol) was added to a suspension of K ₂ CO ₃ (3.0 g, 21.706 mmol) and methyl 4-(4-hydroxyphenyl)butanoate (2.1 O g, 10.812 mmol) in CH ₃ CN (100 ml_). The reaction mixture was stirred at r.t. overnight (18 h). It was poured into H ₂ O (200 ml_) and extracted with EtOAc (150 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂ (0→5%

EtOAc/hexanes), to afford 3.05 g of methyl 4-[4-(benzyloxy)phenyl]butanoate (colourless oil, yield: 99%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.38 (m, 5H), 7.10 (d, J = 8.5 Hz, 2H), 6.90 (d, J = 8.5 Hz, 2H), 5.05 (s, 2H), 3.66 (s, 3H), 2.59 (m, 2H), 2.31 (m, 2H), 1.92 (m, 2H).

d) Methyl (4E)-2-[2-(4-benzyloxyphenyl)ethyl]-5-phenylpent-4-enoate

A solution of methyl 4-[4-(benzyloxy)phenyl]butanoate (3.0 g, 10.550 mmol) in THF (5 ml_) was added to a -78 ⁰ C cooled solution of LDA (13 ml_, 1 M THF solution, 13 mmol) in THF (30 ml_). The reaction mixture was stirred at low temperature for 2 min, and a solution of [(1 E)-3-bromoprop-1 -enyl]benzene (3.30 g, 16.744 mmol) in THF (5 ml_) was added. The reaction was allowed to reach r.t. overnight (18 h). It was poured into H ₂ O (150 ml_), taken up to pH= 2 with HCI and extracted with EtOAc (150 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂ (2→4% EtOAc/hexanes), to give 3.51 g of

methyl (4E)-2-[2-(4-benzyloxyphenyl)ethyl]-5-phenylpent-4-enoate (colourless oil, yield: 83%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.43-7.11 (m, 11 H), 7.04 (d, J = 8.5 Hz, 2H), 6.83 (d, J = 8.5 Hz, 2H), 4.99 (s, 2H), 3.63 (s, 3H), 2.56-2.23 (m, 5H), 1.89 (m, 1 H), 1.75 (m, 1 H).

e) Methyl 2-[2-(4-hydroxyphenyl)ethyl]-5-phenylpentanoate

Methyl (4E)-2-[2-(4-benzyloxyphenyl)ethyl]-5-phenylpent-4-enoate (3.45 g, 8.613 mmol) was added to a suspension of Pd/C (900 mg, 10% Pd/C, 0.845 mmol) in MeOH (60 ml_). The reaction mixture was stirred under H ₂ atmosphere (balloon) for 8 h. It was filtered through Celite (eluted with EtOAc) and solvent was concentrated off. The crude residue was flash chromatographed on SiO ₂ (20% EtOAc/hexanes), to furnish 2.34 g of methyl 2-[2-(4-hydroxyphenyl)ethyl]-5-phenylpentanoate (white solid, yield: 87%). ¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.28-7.07 (m, 5H), 6.96 (d, J = 8.5 Hz, 2H), 6.70 (d, J = 8.5 Hz, 2H), 5.00 (bs, 2H), 3.64 (s, 3H), 2.59-2.32 (m, 5H), 1.88 (m, 1 H), 1.75-1.43 (m, 5H).

f) Methyl 2-{2-(4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)ethyl}-5- phenylpentanoate (Intermediate A)

Thfluoromethanesulfonic anhydride (2.60 g, 9.21 mmol) was added to a -18 ⁰ C cooled solution of methyl 2-[2-(4-hydroxyphenyl)ethyl]-5-phenylpentanoate (2.30 g, 7.361 mmol) and DIPEA (2.6 ml_, 15.187 mmol) in CH ₂ CI ₂ (45 ml_). The reaction mixture was allowed to react at low temperature for 10 min, poured into H ₂ O (150 ml_), taken up to pH= 3 with HCI and extracted with CH ₂ CI ₂ (12O mL).

The crude residue was purified by flash chromatography on SiO ₂ (2 6% EtOAc/hexanes), to give 3.04 g of methyl 2-{2-(4-{[(trifluoromethyl)sulfonyl] oxy}phenyl)ethyl}-5-phenylpentanoate (colourless oil, yield: 93%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.37-7.17 (m, 9H), 3.73 (s, 3H), 2.63 (m, 4H), 2.45 (m, 1 H), 1.99 (m, 1 H), 1.86-1.48 (m, 5H).

Ri = Naphthyl. Methyl 2-[2-(4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)ethyl]-5- (i -naphthyl)pentanoate (Intermediate B).

a) Methyl 2-[2-(4-benzyloxyphenyl)ethyl]-5-(1 -naphthyl)pent-4-ynoate A solution of methyl 4-[4-(benzyloxy)phenyl]butanoate (1.5 g, 5.27 mmol) in THF (5 ml_) was added to a -78 ⁰ C cooled solution of LDA (6 ml_, 1 M THF solution, 6 mmol) in THF (30 ml_). The reaction mixture was stirred at low temperature for 3 min, and a solution of 1 -(3-bromoprop-1 -ynyl)naphthalene (1.68 g, 6.86 mmol) in THF (5 ml_) was added. The reaction was allowed to reach r.t. and stirred for 6 h. It was poured into H ₂ O (100 ml_), taken up to pH= 2 with HCI and extracted with EtOAc (2x100 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂ (5→10% EtOAc/hexanes), to furnish 950 mg of methyl 2-[2-(4-benzyloxyphenyl)ethyl]-5-(1 -naphthyl)pent-4-ynoate (colourless oil, yield: 40%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 8.29 (m, 1 H), 7.80 (m, 3H), 7.62-7.48 (m, 3H), 7.47-7.32 (m, 5H), 7.14 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 5.04 (s, 2H), 3.75 (s, 3H), 2.82 (m, 3H), 2.67 (m, 2H), 2.13 (m, 2H).

b) Methyl 2-[2-(4-hydroxyphenyl)ethyl]-5-(1 -naphthyl)pentanoate

Methyl 2-[2-(4-benzyloxyphenyl)ethyl]-5-(1 -naphthyl)pent-4-ynoate (940 mg, 2.095 mmol) was added to a suspension of Pd/C (220 mg, 10% Pd/C, 0.210 mmol) in MeOH (20 ml_). The reaction mixture was stirred under H ₂ atmosphere (balloon) for 2 h. It was filtered through Celite (eluted with EtOAc) and solvent was concentrated off. The crude residue was flash chromatographed on SiO ₂ (20→30% EtOAc/hexanes), to furnish 579 mg of methyl 2-[2-(4-hydroxyphenyl)ethyl]-5-(1 -naphthyl)pentanoate (colourless oil, yield: 76%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.99 (m, 1 H), 7.84 (m, 1 H), 7.71 (d, J = 7.7 Hz, 1 H), 7.48 (m, 2H), 7.39 (m, 1 H), 7.27 (m, 1 H), 7.01 (d, J = 7.4 Hz, 2H), 6.74 (d, J = 7.4 Hz, 2H), 5.10 (bs, 1 H), 3.67 (s, 3H), 3.04 (m, 2H), 2.49 (m, 3H), 1.93 (m, 1 H), 1.73 (m, 5H).

c) Methyl 2-[2-(4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)ethyl]-5-(1 - naphthyl)pentanoate (Intermediate B)

Thfluoromethanesulfonic anhydride (530 mg, 1.89 mmol) was added to a -18 ⁰ C cooled solution of methyl 2-[2-(4-hydroxyphenyl)ethyl]-5-(1 -naphthyl)

pentanoate (570 mg, 1.57 mmol) and DIPEA (430 mg, 3.37 mmol) in CH ₂ CI ₂ (30 ml_). The reaction mixture was allowed to react at low temperature for 15 min, poured into H ₂ O (150 ml_), taken up to pH= 3 with HCI and extracted with CH ₂ CI ₂ (100 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO ₂ (2→10% EtOAc/hexanes), to give 645 mg of methyl 2-[2-(4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)ethyl]-5-(1 -naphthyl)pentanoate (colourless oil, yield: 83%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.99 (m, 1 H), 7.85 (m, 1 H), 7.71 (d, J = 7.7 Hz, 1 H), 7.48 (m, 2H), 7.38 (t, J = 7.8 Hz, 1 H), 7.28 (m, 1 H), 7.18 (m, 4H), 3.66 (s, 3H), 3.05 (m, 2H), 2.59 (m, 2H), 2.44 (m, 1 H), 1.96 (m, 1 H), 1.74 (m, 5H).

Example 1 : Preparation of methyl 4-phenylbutanoate

H ₂ SO ₄ (7.16 ml, 73.08 mmol) was added to a solution of 4-phenylbutanoic acid (40.0 g, 243.60 mmol) in MeOH (300 ml). The reaction mixture was stirred at room temperature for 1 h, poured into H ₂ O (500 ml) and extracted with CH ₂ CI ₂ (2x400 ml). The organic layer was washed with NaHCO ₃ (300 ml, saturated aqueous solution), dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂ (10→20% EtOAc/hexanes), to furnish methyl 4-phenylbutanoate (41.95 g, colourless oil, yield: 96%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.28 (m, 2H), 7.20 (m, 3H), 3.68 (s, 3H), 2.67 (t, J = 7.4 Hz, 2H), 2.35 (t, J = 7.4 Hz, 2H), 1.99 (m, 2H).

Example 2: methyl 2-methyl-4-phenylbutanoate (Method A: ester alkylation)

A solution of methyl 4-phenylbutanoate (500 mg, 2.80 mmol) in THF (5 ml) was dropwise added to a -78 ⁰ C cooled solution of freshly prepared LDA (1 M in THF, 3.08 ml, 3.08 mmol) in THF (10 ml). The reaction mixture was stirred at low temperature for 10 min, and MeI (0.23 ml, 3.64 mmol) was added. The reaction was allowed to stir at low temperature until full conversion was achieved (30 min, checked by TLC analysis).

The mixture was poured into H ₂ O (50 ml) and extracted with EtOAc (100 ml). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂ (10% EtOAc/hexanes), to afford methyl 2-methyl-4-phenylbutanoate (440 mg, colourless oil, yield: 82%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.28 (m, 2H), 7.18 (m, 3H), 3.69 (2, 3H), 2.61 (t, J = 8.2 Hz, 2H), 2.49 (m, 1 H), 2.10-1.94 (m, 2H), 1.81 -1.62 (m, 2H), 1.20 (d, J = 7.1 Hz, 3H).

Example 3: 2-Methyl-4-phenylbutanoic acid (Method B: ester hydrolysis)

LiOH (5.72 ml, 2M solution in H ₂ O, 11.44 mmol) was added to a solution of methyl-4-phenylbutanoate (440 mg, 2.28 mmol) in a mixture of THF (10 ml) and MeOH (10 ml). The reaction mixture was warmed up to reflux, and stirred until no unreacted ester was detected by TLC analysis (30 min). The reaction mixture was allowed to reach room temperature and poured into H ₂ O (100 ml). It was acidified with HCI (10% aqueous solution) until pH 2-3, and extracted with EtOAc (100 ml). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO ₂ (10°50% EtOAc/hexanes) to furnish 2-methyl- 4-phenylbutanoic acid (225 mg, colourless oil, yield: 55%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.29 (m, 2H), 7.21 (m, 3H), 2.68 (t, J = 8.2 Hz, 2H), 2.52 (m, 1 H), 2.15-1.98 (m, 1 H), 1.83-1.68 (m, 1 H), 1.26 (d, J = 6.8 Hz, 3H).

Example 4: Methyl 2-ethyl-4-phenylbutanoate

This compound was prepared following the same procedure than the one followed in Example 2, using EtI as alkylating reagent instead of MeI. Flash chromatography purification afforded the title compound as a colourless oil (yield: 49%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.23 (m, 5H), 3.69 (2, 3H), 2.60 (m, 2H), 2.32 (m, 1 H), 1.92 (m, 1 H), 1.84-1.47 (m, 4H), 0.89 (t, J = 7.4 Hz, 3H).

Example 5: 2-Ethyl-4-phenylbutanoic acid

This compound was prepared following the same procedure than the one followed in Example 3, using as starting ester the methyl 2-ethyl-4- phenylbutanoate, to furnish the title compound as a colourless oil after flash chromatography purification (yield: 37%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.19 (m, 2H), 7.11 (m, 3H), 2.68-2.48 (m, 2H), 2.30 (m, 1 H), 1.90 (m, 1 H), 1.79-1.45 (m, 2H), 1.19 (m, 1 H), 0.89 (t, J = 7.4 Hz, 3H).

Example 6: Methyl 2-(2-phenylethyl)pentanoate

This compound was prepared following the same procedure than the one followed in Example 2, using PrI as alkylating reagent instead of MeI. Flash chromatography purification afforded the title compound as a colourless oil (yield: 45%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.35 (m, 2H), 7.25 (m, 3H), 3.76 (s, 3H), 2.67 (m, 2H), 2.49 (m, 1 H), 2.03 (m, 1 H), 1.92-1.61 (m, 2H), 1.56 (m, 1 H),

1.36 (m, 2H), 0.96 (t, J = 7.1 Hz, 3H).

Example 7: 2-(2-Phenylethyl)pentanoic acid

This compound was prepared following the same procedure than the one followed in Example 3, using as starting ester the methyl 2-(2- phenylethyl)pentanoate, to furnish the compound as a colourless oil after flash chromatography purification (yield: 43%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.31 -7.15 (m, 5H), 2.65 (m, 2H), 2.43 (m,

1 H), 1.97 (m, 1 H), 1.86-1.58 (m, 2H), 1.55-1.23 (m, 3H), 0.91 (t, J = 7.1 Hz,

3H).

Example 8: Methyl 2-benzyl-4-phenylbutanoate

This compound was prepared following the same procedure than the one followed in Example 2, using BnBr as alkylating reagent instead of MeI. Flash chromatography purification afforded the compound as a colourless oil (yield:

82%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.32-7.07 (m, 10H), 3.61 (s, 3H), 2.97 (m,

1 H), 2.82-2.53 (m, 4H), 1.98 (m, 1 H), 1.81 (m, 1 H).

Example 9: 2-Benzyl-4-phenylbutanoic acid

This compound was prepared following the same procedure than the one described in Example 3, using as starting ester the methyl 2-benzyl-4- phenylbutanoate to furnish the compound as a colourless oil after flash chromatography purification (yield: 56%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.61 -7.36 (m, 10H), 3.30 (m, 1 H), 3.13- 2.79 (m, 4H), 2.27 (m, 1 H), 2.09 (m, 1 H).

Example 10: Methyl 5-phenyl-2-(2-phenylethyl)pentanoate

This compound was prepared following the same procedure than the one followed in Example 2, using PhCH ₂ CH ₂ CH ₂ Br as alkylating reagent instead of MeI. Flash chromatography purification afforded the compound as a colourless oil (yield: 20%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.35-7.10 (m, 10H), 3.67 (s, 3H), 2.57 (m, 3H), 2.24 (m, 2H), 1.93-1.81 (m, 4H), 1.19 (m, 2H).

Example 11 : 5-Phenyl-2-(2-phenylethyl)pentanoic acid

This compound was prepared following the same procedure than the one followed in Example 3, using as starting ester the methyl 5-phenyl-2-(2- phenylethyl)pentanoate, to furnish the compound as a colourless oil after flash chromatography purification (yield: 13%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.52-7.27 (m, 10H), 2.78 (m, 4H), 2.60 (m, 1 H), 2.15 (m, 1 H), 2.04-1.66 (m, 5H).

Example 12: 2-{4-[(methylannino)sulfonvπbenzyl)-4-phenylbutanoic acid

a) Synthesis of N,4-dinnethylbenzenesulfonannide.

MeNH ₂ (8 ml, 8 M solution in EtOH, 64 mmol) was added to a solution of 4- methylbenzenesulfonyl chloride (4.72 g, 24.757 mmol) in THF (100 ml). The reaction mixture was stirred at room temperature for 5 min, poured into H ₂ O (400 ml) and extracted with CH ₂ CI ₂ (500 ml). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated, to furnish N,4- dimethylbenzenesulfon-amide, that was submitted to next step without further purification (4.27 g, white solid, yield: 93%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.74 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 4.66 (c, J = 5.5 Hz, 1 H), 2.63 (d, J = 5.5. Hz, 3H), 2.42 (s, 3H).

b) Synthesis of tert-butyl methyl[(4-methylphenyl)sulfonyl]carbamate. BoC ₂ O (2.82 g, 12.955 mmol) was added to a solution of λ/,4-di methyl benzenesulfonamide (2.0 g, 10.796 mmol), DMAP (197 mg, 1.619 mmol) and DIPEA (5.5 ml, 32.38 mmol) in CH ₃ CN (80 ml). The reaction mixture was stirred at room temperature for 30 min, poured into H ₂ O (200 ml) and extracted with EtOAc (200 ml). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂ (10→20% EtOAc/hexanes), to afford tert-butyl methyl[(4-methylphenyl)sulfonyl]carbamate (3.07 g, white solid, yield: 99%). ¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.77 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H), 3.34 (s, 3H), 2.44 (s, 3H), 1.34 (s, 9H).

c) Synthesis of tert-butyl [4-(bromomethyl)phenyl]sulfonyl(methyl)carbamate. NBS (1.03 g, 5.786 mmol) was added to a solution of tert-butyl [4- (bromomethyl)phenyl]sulfonyl(methyl)carbamate (1.5O g, 5.256 mmol) in CCI ₄ (40 ml). The reaction mixture was warmed up to reflux, and allowed to react for 6 h. Solvent was concentrated off, and the crude residue was flash chromatographed on SiO ₂ (10→30% EtOAc/hexanes), to afford tert-butyl [4- (bromomethyl)phenyl]sulfonyl(methyl)carbamate (2.0 g, pale yellow-coloured

oil, yield: 100%. Purity: 60%). Mixture of starting material and product, which was submitted to next step without further purification. 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.86 (d, J = 8.5 Hz, 2H), 7.53 (d, J = 8.5 Hz, 2H), 4.50 (s, 2H), 3.35 (s, 3H), 1.35 (s, 9H).

d) Synthesis of 2-{4-[tert-butyl(methylamino)sulfonyl]benzyl}-4-phenylbutano ic acid.

The compound was prepared following the same procedure than the one of Example 2, using tert-butyl [4-(bromomethyl)phenyl]sulfonyl(methyl) carbamate as alkylating reagent instead of MeI. Flash chromatography purification afforded the compound as a colourless oil (yield: 36%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.78 (d, J = 8.5 Hz, 2H), 7.30-7.10 (m, 7H), 3.60 (s, 3H), 3.34 (s, 3H), 3.04 (m, 1 H), 2.91 -2.83 (m, 4H), 1.98 (m, 1 H), 1.82 (m, 1 H), 1.32 (s, 9H).

e) Obtaining of the title compound 2-{4-[(methylamino)sulfonyl]benzyl}-4- phenylbutanoic acid.

Starting from the product resulting from step (d), it was followed the same process than the one followed in Example 3, to furnish the compound as a white solid after flash chromatography purification (yield: 62%).

¹ H NMR (CDCI ₃ , 250 MHz) ppm: 7.74 (d, J = 8.2 Hz, 2H), 7.34-7.10 (m, 7H), 5.14 (bs, 1 H), 3.09-2.83 (m, 2H), 2.74-2.48 (m, 6H), 2.03 (m, 1 H), 1.82 (m, 1 H).

Example 13: 5-(4-[(Methylamino)sulfonyliphenyl)-2-(2-phenylethyl) pentanoic acid

a) Synthesis of 4-Bromo-λ/-methylbenzenesulfonamide. MeNH ₂ (7.5 ml, 8 M solution in EtOH, 60 mmol) was added to a solution of 4- bromobenzenesulfonyl chloride (5.0 g, 19.568 mmol) in THF (120 ml). The reaction mixture was stirred at room temperature for 5 min, poured into NH ₄ CI (saturated aqueous solution, 300 ml) and extracted with EtOAc (500 ml). The

organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated, to furnish 4-bromo-W-methylbenzenesulfonamide, which was submitted to next step without further purification (4.60 g, white solid, yield: 94%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.70 (m, 4H), 4.49 (bs, 1 H), 2.67 (d, J = 5.2 Hz, 3H).

b) Synthesis of tert-butyl (4-bromophenyl)sulfonyl(methyl)carbamate. BoC ₂ O (4.711 g, 21.589 mmol) was added to a solution of 4-bromo-/V- methylbenzenesulfonamide (4.5 g, 17.99 mmol), DMAP (329 mg, 2.698 mmol) and DIPEA (9.25 ml, 53.97 mmol) in CH ₃ CN (100 ml). The reaction mixture was stirred at room temperature for 30 min, poured into H ₂ O (200 ml) and extracted with EtOAc (200 ml). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂ (10→20% EtOAc/hexanes), to afford tert-butyl (4- bromophenyl)sulfonyl (methyl)carbamate (6.18 g, white solid, yield: 98%). ¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.77 (d, J = 9.0 Hz, 2H), 7.66 (d, J = 9.0 Hz, 2H), 3.34 (s, 3H), 1.37 (s, 9H).

c) Synthesis of tert-butyl [4-(3-hydroxyprop-1 -ynyl)phenyl]sulfonyl(methyl) carbamate. (Method C: Sonogashira coupling with prop-2-yn-1 -ol)

A solution of prop-2-yn-1 -ol (949 mg, 16.939 mmol) in THF (6 ml) was dropwise added to a refluxing suspension of tert-butyl (4-bromophenyl) sulfonyl(methyl)carbamate (6.18 g, 17.645 mmol), CuI (152 mg, 0.794 mmol) and PdCI ₂ (PPh ₃ ) ₂ (557 mg, 0.794 mmol) in a mixture of Et ₃ N (49 ml) and THF (100 ml). The reaction mixture was refluxed for 3 h, and then allowed to reach room temperature Solvent was concentrated off, and the crude residue was flash chromatographed on SiO ₂ (0→10% EtOAc/hexanes), to afford tert-butyl [4-(3-hydroxyprop-1 -ynyl)phenyl]sulfonyl(methyl)carbamate (4.48 g, pale yellow-coloured oil, yield: 78%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.82 (d, J = 8.8 Hz, 2H), 7.53 (d, J = 8.8 Hz, 2H), 4.53 (s, 2H), 3.35 (s, 3H), 1.99 (bs, 1 H), 1.35 (s, 9H).

d) Synthesis of tert-butyl [4-(3-bromoprop-1 -ynyl)phenyl]sulfonyl(methyl) carbamate. (Method D: alkynol bromination) CBr ₄ (1.172 g, 3.534 mmol) was added to a -18 ⁰ C cooled solution of tert- butyl [4-(3-hydroxyprop-1 -ynyl)phenyl]sulfonyl(methyl)carbamate (1.0 g, 3.073 mmol) and PPh ₃ (967 mg, 3.687 mmol) in CH ₂ CI ₂ (40 ml). The reaction

mixture was allowed to react at low temperature for 30 min, poured into H ₂ O (200 ml), and extracted with CH ₂ CI ₂ (200 ml). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂ (50% EtOAc/hexanes), to afford tert-butyl [4- (3-bromoprop-1 -ynyl)phenyl]sulfonyl(methyl)carbamate (1.03 g, pale coloured solid, yield: 86%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.85 (d, J = 8.5 Hz), 7.55 (d, J = 8.5 Hz), 4.16 (s, 2H), 3.34 (s, 3H), 1.33 (s, 9H).

e) Synthesis of methyl 5-{4-[tert-butyl(methylamino)sulfonyl]phenyl}-2-(2- phenylethyl)pent-4-ynoate.

The resulting product of step (d) was submitted to the procedure described in Example 2, using tert-butyl [4-(3-bromoprop-1 -ynyl)phenyl]sulfonyl(methyl) carbamate as alkylating reagent instead of MeI. Flash chromatography purification afforded the compound as a pale yellow-coloured solid (yield: 26%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.79 (d, J = 8.5 Hz, 2H), 7.47 (d, J = 8.5 Hz, 2H), 7.34-7.16 (m, 5H), 3.75 (s, 3H), 3.35 (s, 3H), 2.70 (m, 5H), 2.08 (m, 2H), 1.36 (s, 9H).

f) Synthesis of 5-(4-[tert-butyl(methylamino)sulfonyl]phenyl)-2-(2-phenyleth yl) pentanoic acid. (Method E: Hydrogenation)

A suspension of methyl 5-{4-[tert-butyl(methylamino)sulfonyl]phenyl}-2-(2- phenylethyl)pent-4-ynoate (211 mg, 0.434 mmol) and Pd/C (69 mg, 10% palladium on activated carbon, 0.065 mmol) in MeOH (15 ml) was stirred under H ₂ atmosphere (balloon) for 1 h. It was filtered through Celite, washed with MeOH, and concentrated, to furnish methyl 5-{4-[tert-butyl(methylamino) sulfonyl]phenyl}-2-(2-phenylethyl)pent-4-ynoate (195 mg, pale yellow- coloured oil, yield: 91 %). The crude residue was submitted to next step without purification.

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.63 (d, J = 8.6 Hz, 2H), 7.14 (m, 5H), 7.00 (d, J = 8.6 Hz, 2H), 3.53 (s, 3H), 3.19 (s, 3H), 2.58-2.11 (m, 5H), 2.02-1.65 (m, 2H), 1.60-1.35 (m, 4H), 1.20 (s, 9H).

g) Obtaining of the title compound 5-(4-[(Methylamino)sulfonyl]phenyl)-2-(2- phenylethyl) pentanoic acid.

Starting from the product resulting in step (f), it was followed the same procedure than the one described in Example 3, to furnish the compound as a colourless oil after flash chromatography purification (yield: 37%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.70 (d, J = 8.2 Hz, 2H), 7.22 (m, 4H), 7.12 (m, 3H), 4.71 /bs, 1 H), 2.58 (s, 3H), 2.68-2.49 (m, 4H), 2.36 (m, 1 H), 1.93 (m, 1 H), 1.78-1.41 (m, 5H).

Example 14: 6-Phenyl-2-(2-phenylethyl)hexanoic acid

a) Methyl 6-phenyl-2-(2-phenylethyl)hexanoate The compound was synthesized from methyl-4-phenylbutanoate and (4- iodobutyl)benzene following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO ₂ (0→4% EtOAc/hexanes) to furnish a colourless oil (yield: 88%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm:7.36-7.09 (m, 10H), 3.67 (s, 3H), 2.58 (m, 4H), 2.39 (m, 1 H), 2.00-1.43 (m, 6H), 1.39 (m, 2H).

b) 6-Phenyl-2-(2-phenylethyl)hexanoic acid

The compound was synthesized from methyl 6-phenyl-2-(2- phenylethyl)hexanoate following the experimental procedure detailed in Method B. The crude residue was purified by flash chromatography on SiO ₂

(5→25% EtOAc/hexanes) to furnish a colourless oil (yield: 70%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.29-7.08 (m, 10H), 2.58 (m, 4H), 2.41 (m,

1 H), 1.96 (m, 1 H), 1.83-1.46 (m, 5H), 1.35 (m, 2H). El MS: m/z = 295 (M-1 ).

Example 15: (Acetyloxy)nnethyl 2-benzyl-4-phenylbutanoate

Bromomethyl acetate (0.125 ml_, 1 ,274 mmol) was added to a solution of 2- benzyl-4-phenylbutanoic acid (Example 9) (300 mg, 1.179 mmol) and DIPEA (0.25 ml_, 1.46 mmol) in CH ₃ CN (15 ml_). The reaction mixture was stirred at r.t. for 30 min, poured into H ₂ O (100 ml_) and extracted with EtOAc (100 ml_). The organic layer was washed with HCI (100 ml_, 1 % aqueous solution), NaHCO ₃ (100 ml_, saturated aqueous solution), dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂ (5→20% EtOAc/hexanes), to afford 200 mg of (acetyloxy)methyl 2-benzyl-4-phenylbutanoate (colourless oil, yield: 52%). ¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.29 (m, 6H), 7.20 (m, 4H), 5.49 (m, 2H), 3.02 (m, 1 H), 2.83 (m, 2H), 2.66 (m, 2H), 1.86 (s, 3H), 1.84-1.56 (m, 2H). El MS: m/z = 327 (M+1 ), 344 (M+18).

Example 16: (Acetyloxy)methyl 5-phenyl-2-(2-phenylethyl)pentanoate

Bromomethyl acetate (0.2 ml_, 2.039 mmol) was added to a solution of 5- phenyl-2-(2-phenylethyl)pentanoic acid (Example 11 ) (514 mg, 1.82 mmol) and DIPEA (0.39 ml_, 2.275 mmol) in CH ₃ CN (25 ml_). The reaction mixture was stirred at r.t. for 1 h and then it was poured into H ₂ O (40 ml_) and extracted with EtOAc (2x50 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂ (5→10% EtOAc/hexanes), to afford 224 mg of

(acetyloxy)methyl 5-phenyl-2-(2-phenylethyl)pentanoate (yellow coloured oil, yield: 35%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.32-7.24 (m, 4H), 7.23-7.11 (m, 6H), 5.77

(s, 2H), 2.68-2.47 (m, 6H), 2.07 (s, 3H), 1.85-1.52 (m, 5H).

El MS: m/z = 355 (M+1 ).

Example 17: (Acetyloxy)methyl 5-(3-{[(3,4-dimethoxy phenvDaminol sulfonyl)phenyl)-2-(2-phenylethyl)pentanoate

Bromomethyl acetate (0.1 ml_, 1.019 mmol) was added to a solution of 5-(3- {[(3,4-dimethoxyphenyl)amino]sulfonyl} phenyl)-2-(2-phenylethyl)pentanoic acid (Example 43) (370 mg, 0.743 mmol) and DIPEA (0.2 ml_, 1.168 mmol) in CH ₃ CN (25 ml_). The reaction mixture was stirred at r.t. for 4 h and solvent was concentrated off. The crude residue was flash chromatographed on SiO ₂ (10 40% EtOAc/hexanes), to afford 374 mg of (acetyloxy)methyl 5-(3-{[(3,4- dimethoxyphenyl)amino]sulfonyl}phenyl)-2-(2-phenylethyl)pent anoate (colourless oil, yield: 88%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.59 (m, 2H), 7.32 (m, 5H), 7.21 (m, 3H), 6.82-6.58 (m, 3H), 5.81 (m, 2H), 3.83 (s, 3H), 3.79 (s, 3H), 2.63 (m, 4H), 2.45 (m, 1 H), 2.15 (s, 3H), 2.00 (m, 1 H), 1.84-1.46 (m, 5H). El MS: m/z = 570 (M+1 ), 587 (M+18).

Example 18: (Acetyloxy)methyl 5-(3-[(4-methylanilino sulfonyliphenyl)-2-(2- phenylethvDpentanoate

Bromomethyl acetate (116 mg, 0.758 mmol) was added to a solution of 5-(3- [(4-methylanilinosulfonyl]phenyl)-2-(2-phenylethyl)pentanoic acid (Example

36) (250 mg, 0.554 mmol) and DIPEA (0.15 mL, 0.869 mmol) in CH ₃ CN (20 ml_). The reaction mixture was stirred at r.t. for 4 h and solvent was concentrated off. The crude residue was flash chromatographed on SiO ₂ (5→20% EtOAc/hexanes), to afford 122 mg of (acetyloxy)methyl 5-(3-[(4- methylanilino sulfonyl]phenyl)-2-(2-phenylethyl)pentanoate (colourless oil, yield: 42%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.57-7.47 (m, 2H), 7.34-7.24 (m, 5H), 7.16 (t, J = 7.1 Hz, 2H), 6.98 (m, 4H), 6.68 (s, 1 H), 5.77 (dd, J = 7.9 Hz, 5.5 Hz, 2H), 2.67-2.30 (m, 5H), 2.25 (s, 3H), 2.11 (s, 3H), 1.63-1.47 (m, 6H). El MS: m/z = 524 (M+1 ), 541 (M+18).

Example 19: (Acetyloxy)methyl 5-(3-[(methylamino) sulfonyliphenyl)-2-(2- phenylethvDpentanoate

Bromomethyl acetate (0.09 mL, 0.917 mmol) was added to a solution of 5-(3- [(methylamino)sulfonyl]phenyl)-2-(2-phenylethyl)pentanoic acid (Example 41 ) (300 mg, 0.789 mmol) and DIPEA (0.2 mL, 1.168 mmol) in CH ₃ CN (20 mL). The reaction mixture was stirred at r.t. for 30 min, it was poured into H ₂ O (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with HCI (60 mL, 2% aqueous solution), NaHCO ₃ (60 mL, saturated aqueous solution), dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂ (20→100% EtOAc/hexanes), to afford 120 mg of (acetyloxy)methyl 5-(3- [(methylamino)sulfonyl]phenyl)-2-(2-phenylethyl)pentanoate (colourless oil, yield: 34%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.70 (m, 2H), 7.52-7.26 (m, 4H), 7.25-7.16 (m, 3H), 5.85 (dd, J = 5.5 Hz, 2.5 Hz, 2H), 4.78 (m, 1 H), 2.90 (d, J = 5.5 Hz, 3H), 2.67-2.41 (m, 5H), 2.19 (s, 3H), 2.01 (m, 1 H), 1.89-1.55 (m, 5H). El MS: m/z = 448 (M+1 ), 465 (M+18).

Example 20: Sodium 5-phenyl-2-(2-phenylethyl)pentanoate

NaH (25 mg, 60%mineral oil suspension, 0.64 mmol) was added to a solution of 5-phenyl-2-(2-phenylethyl)pentanoic acid (Example 11 ) (200 mg, 0.708 mmol) in THF (10 ml_). The reaction mixture was stirred at r.t. for 15 min, and solvent was concentrated off. The crude residue was slurred with Et ₂ O (2x5 ml_) and hexanes (5 ml_), to give 95 mg of sodium 5-phenyl-2-(2-phenylethyl) pentanoate (white solid, yield: 45%).

¹ H NMR (MeOD, 250 MHz) δ ppm: 7.38-7.17 (m, 10H), 2.70 (m, 4H), 2.42 (m, 1 H), 1.95 (m, 1 H), 1.74 (m, 4H), 1.55 (m, 1 H). El MS: m/z = 281 (M-18).

Example 21 : (4E)-5-Phenyl-2-(2-phenylethyl)pent-4-enoic acid

a) Methyl (4E)-5-phenyl-2-(2-phenylethyl)pent-4-enoate

The compound was prepared from methyl 4-phenylbutanoate following the general procedure A, by using [(1 E)-3-bromoprop-1 -enyl]benzene as alkylating reagent. The crude residue was flash chromatographed on SiO ₂

(0→2% EtOAc/hexanes), to afford the compound as a yellow-coloured oil

(yield: 41 %).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.36-7.14 (m, 10H), 6.41 (d, J = 15.6 Hz,

1 H), 6.11 (m, 1 H), 3.69 (s, 3H), 2.74-2.28 (m, 5H), 2.11 -1.75 (m, 2H).

b) (4E)-5-Phenyl-2-(2-phenylethyl)pent-4-enoic acid The compound was synthesized from methyl (4E)-5-phenyl-2-(2- phenylethyl)pent-4-enoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (5 10% EtOAc/hexanes) to furnish a white solid (yield: 79%).

¹ H NMR (CDCI ₃ , 250 MHz) ppm: 7.39-7.12 (m, 10H), 6.44 (d, J = 15.6 Hz, 1 H), 6.14 (m, 1 H), 2.80-2.29 (m, 5H), 2.10-1.78 (m, 2H).

Example 22: 5-(2-Naphthyl)-2-(2-phenylethyl)pentanoic acid

a) 3-(2-Naphthyl)prop-2-yn-1 -ol

The compound was synthesized from 2-bromonaphthalene following the experimental procedure detailed in Method C. It was purified by flash chromatography on SiO ₂ (10→40% EtOAc/hexanes) to furnish a brown coloured solid (yield: 98%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.97 (s, 1 H), 7.80 (m, 3H), 7.50 (m, 3H), 4.56 (s, 2H), 2.15 (bs, 1 H).

b) 2-(3-Bromoprop-1 -ynyl)naphthalene

The compound was synthesized from 3-(2-naphthyl)prop-2-yn-1 -ol following the experimental procedure detailed in Method D. It was purified by flash chromatography on SiO ₂ (0→10% EtOAc/hexanes) to furnish a brown coloured solid (yield: 96%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.99 (s, 1 H), 7.80 (m, 3H), 7.50 (m, 3H), 4.23 (s, 2H).

c) Methyl 5-(2-naphthyl)-2-(2-phenylethyl)pent-4-ynoate The compound was synthesized from 2-(3-bromoprop-1 -ynyl)naphthalene and methyl 4-phenylbutanoate following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO ₂ (10→15% EtOAc/hexanes) to furnish an orange coloured solid (yield: 76%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.91 (s, 1 H), 7.79 (m, 3H), 7.47 (m, 3H), 7.37-7.17 (m, 5H), 3.77 (s, 3H), 2.88-2.61 (m, 5H), 2.14 (m, 2H).

d) Methyl 2-(2-phenylethyl)-5-(2-naphthyl)pentanoate The compound was synthesized from methyl 5-(2-naphthyl)-2-(2- phenylethyl)pent-4-ynoate following the experimental procedure detailed in Method E. It was purified by flash chromatography on SiO ₂ (10→15% EtOAc/hexanes) to furnish a colourless oil (yield: 80%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.80 (m, 3H), 7.61 (s, 1 H), 7.45 (m, 2H), 7.30 (m, 3H), 7.19 (m, 3H), 3.71 (s, 3H), 2.79 (t, J = 7.4 Hz, 2H), 2.66-2.34 (m, 3H), 1.97 (m, 1 H), 1.86-1.53 (m, 5H).

e) 5-(2-Naphthyl)-2-(2-phenylethyl)pentanoic acid

The compound was synthesized from methyl 2-(2-phenylethyl)-5-(2- naphthyl)pentanoate following the experimental procedure detailed in Method

B. It was purified by flash chromatography on SiO ₂ (10→15% EtOAc/hexanes) to furnish a white solid (yield: 35%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.78 (m, 3H), 7.60 (s, 1 H), 7.44 (m, 2H),

7.28 (m, 3H), 7.19 (m, 3H), 2.84-2.39 (m, 5H), 2.01 (m, 1 H), 1.87-1.54 (m, 5H).

El MS: m/z = 350 (M+18).

Example 23: 5-(1 -Naphthyl)-2-(2-phenylethyl)pentanoic acid

a) 3-(1 -Naphthyl)prop-2-yn-1 -ol

The compound was synthesized from 1 -bromonaphthalene following the experimental procedure detailed in Method C. It was purified by flash chromatography on SiO ₂ (10→30% EtOAc/hexanes) to furnish a yellow coloured oil (yield: 55%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 8.33 (d, J = 6.8 Hz, 1 H), 7.85 (m, 3H), 7.68 (d, J = 6.8 Hz, 1 H), 7.54 (m, 3H), 7.42 (m, 1 H), 4.66 (s, 2H), 2.04 (bs, 1 H).

b) 1 -(3-Bromoprop-1 -ynyl)naphthalene

The compound was synthesized from 3-(1 -naphthyl)prop-2-yn-1 -ol following the experimental procedure detailed in Method D. It was purified by flash chromatography on SiO ₂ (0→10% EtOAc/hexanes) to furnish a yellow coloured oil (yield: 82%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 8.31 (dd, J = 1.1 Hz, 8.2 Hz, 1 H), 7.85 (dd, J = 0.8 Hz, 7.1 Hz, 2H), 7.68 (dd, J = 1.1 Hz, 7.1 Hz, 1 H), 7.63-7.49 (m, 2H), 7.43 (dd, J = 7.1 Hz, 8.2 Hz, 1 H), 4.34 (s, 2H).

c) Methyl 5-(1 -naphthyl)-2-(2-phenylethyl)pent-4-ynoate

The compound was synthesized from 1 -(3-bromoprop-1 -ynyl)naphthalene and methyl 4-phenylbutanoate following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO ₂ (5→10% EtOAc/hexanes) to furnish a yellow coloured oil (yield: 60%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 8.34 (m, 1 H), 7.87 (m, 2H), 7.69-7.53 (m, 3H), 7.45 (t, J = 7.1 Hz, 1 H), 7.37-7.21 (m, 5H), 3.81 (s, 3H), 2.94-2.54 (m, 5H), 2.21 (m, 2H).

d) Methyl 5-(1 -naphthyl)-2-(2-phenylethyl)pentanoate The compound was synthesized from methyl 5-(1 -naphthyl)-2-(2- phenylethyl)pent-4-ynoate following the experimental procedure detailed in Method E. It was purified by flash chromatography on SiO ₂ (5→10% EtOAc/hexanes) to furnish a yellow coloured oil (yield: 79%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 8.05 (m, 1 H), 7.89 (m, 1 H), 7.75 (m, 1 H), 7.53 (m, 2H), 7.45 (m, 1 H), 7.36-7.14 (m, 6H), 3.72 (s, 3H), 3.10 (t, J = 6.8 Hz, 2H), 2.70-2.46 (m, 3H), 2.10-1.68 (m, 6H).

e) 5-(1 -Naphthyl)-2-(2-phenylethyl)pentanoic acid

The compound was synthesized from methyl 5-(1 -naphthyl)-2-(2- phenylethyl)pentanoate, following the experimental procedure detailed in

Method B. It was purified by flash chromatography on SiO ₂ (10 15% EtOAc/hexanes) to yield a white solid (yield: 35%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 8.05 (m, 1 H), 7.90 (m, 1 H), 7.76 (m, 1 H), 7.59-7.38 (m, 3H), 7.36-7.15 (m, 6H), 3.12 (t, J = 7.4 Hz, 2H), 2.81 -2.45 (m, 3H), 2.12-1.64 (m, 6H). El MS: m/z = 331 (M-1 ).

Example 24: 5-[3-{[4-(dimethylamino)benzovπamino)phenvπ-2-(2- phenylethvDpentanoic acid hydrochloride

a) λ/,λ/-Dibenzyl-λ/-(3-bronnophenyl)annine

BnBr (7 ml_, 58.524 mmol) was added to a suspension of K ₂ CO ₃ (7 g, 50.647 mmol) and 3-bromoaniline (3.0 g, 17.438 mmol) in CH3CN (100 ml_). The reaction mixture was warmed up to reflux and stirred for 4 h. It was allowed to reach r.t. poured into H ₂ O (300 ml_) and extracted with EtOAc (300 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂ (0→5% EtOAc/hexanes) to furnish 6.0 g of λ/,λ/-Dibenzyl-λ/-(3-bromophenyl)amine (colourless oil, yield: 97%). El MS: m/z = 353 (M+1 ).

b) 3-[3-(Dibenzylamino)phenyl]prop-2-yn-1 -ol

The compound was synthesized from λ/,λ/-Dibenzyl-λ/-(3-bromophenyl)amine following the experimental procedure detailed in Method C. It was purified by flash chromatography on SiO ₂ (10→20% EtOAc/hexanes) to yield a colourless oil (yield: 67%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.88-7.65 (m, 11 H), 7.58 (m, 1 H), 7.30 (m, 2H), 7.18 (dd, J = 8.2 Hz, 2.4 Hz, 1 H), 5.13 (s, 4H), 4.92 (s, 2H).

c) λ/,λ/-Dibenzyl-λ/-[3-(3-bromoprop-1 -ynyl)phenyl]amine The compound was synthesized from 3-[3-(dibenzylamino)phenyl]prop-2-yn-

1 -ol following the experimental procedure detailed in Method D. It was purified by flash chromatography on SiO ₂ (10→20% EtOAc/hexanes) to yield a yellow-coloured oil (yield: 87%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.86-7.65 (m, 11 H), 7.58 (t, J = 7.9 Hz, 1 H), 7.33-7.18 (m, 3H), 5.11 (s, 4H), 4.60 (s, 2H).

d) Methyl 5-(3-N,N-dibenzylaminophenyl)-2-(2-phenylethyl)pent-4-ynoate The compound was synthesized from methyl 4-phenylbutanoate and N, N- dibenzyl-λ/-[3-(3-bromoprop-1 -ynyl)phenyl]amine following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO ₂ (5% EtOAc/hexanes) to yield a yellow-coloured oil (yield: 65%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.41 -7.12 (m, 15H), 7.06 (t, J = 8.2 Hz, 1 H), 6.79-6.61 (m, 3H), 4.62 (s, 4H), 3.64 (s, 3H), 2.64 (m, 5H), 1.89 (m, 1 H).

e) Methyl 5-(3-aminophenyl)-2-(2-phenylethyl)pentanoate The compound was synthesized from methyl 5-(3-N,N-dibenzylaminophenyl)- 2-(2-phenylethyl)pent-4-ynoate following the experimental procedure detailed in Method E. It was purified by flash chromatography on SiO ₂ (20→60% EtOAc/hexanes) to yield an orange-coloured oil (yield: 40%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.32-7.12 (m, 7H), 7.06 (t, J = 7.6 Hz, 1 H), 6.53 (m, 3H), 3.68 (s, 3H), 2.63-2.35 (m, 5H), 2.03-1.43 (m, 6H).

f) Methyl 5-[3-{[4-(dimethylamino)benzoyl]amino}phenyl]-2-(2- phenylethyl)pentanoate

4-(Dimethylamino)benzoyl chloride (320 mg, 1 ,742 mmol) was added to a solution of methyl 5-(3-aminophenyl)-2-(2-phenylethyl)pentanoate (450 mg, 1.444 mmol), DIPEA (0.8 ml_, 4.673 mmol) and DMAP (30 mg, 0.246 mmol) in CH ₂ CI ₂ (30 ml_). The reaction mixture was stirred at r.t. for 1 h, poured into H ₂ O (200 ml_), and extracted with CH ₂ CI ₂ (100 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂ (10→40% EtOAc/hexanes) to furnish 642 mg of methyl 5-[3-{[4-(dimethylamino)benzoyl]amino}phenyl]-2-(2- phenylethyl)pentanoate (orange-coloured oil, yield: 97%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.78 (d, J = 9.0 Hz, 2H), 7.67 (bs, 1 H), 7.44 (m, 2H), 7.31 -7.12 (m, 5H), 6.89 (m, 1 H), 6.71 (d, J = 9.0 Hz, 2H), 3.68 (s, 3H), 3.05 (s, 6H), 2.64-2.35 (m, 5H), 2.02-1.46 (m, 6H).

g) 5-[3-{[4-(Dimethylamino)benzoyl]amino}phenyl]-2-(2-phenyleth yl)pentanoic acid

The compound was synthesized from methyl 5-[3-{[4-(dimethylamino)benzoyl] amino}phenyl]-2-(2-phenylethyl)pentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (10→50% EtOAc/hexanes) to yield a colourless oil (yield: 95%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.78 (m, 3H), 7.44 (m, 2H), 7.30-7.12 (m,

5H), 6.89 (m, 1 H), 6.69 (d, J = 9.0 Hz, 2H), 3.03 (s, 6H), 2.70-2.35 (m, 5H),

2.02-1.59 (m, 6H).

El MS: m/z = 445 (M+1 ).

h) 5-[3-{[4-(dimethylannino)benzoyl]annino}phenyl]-2-(2-phenyle thyl)pentanoic acid hydrochloride

A suspension of 5-[3-{[4-(Dimethylamino)benzoyl]amino}phenyl]-2-(2- phenylethyl)pentanoic acid (1.373 mmol) in HCI-Et ₂ O (2 ml_, 2 M solution, 4 mmol) was stirred at r.t. for 18 h. Solvent was concentrated off, and the crude residue was slurred with Et ₂ O (2x15 ml_), to give 5-[3-{[4-(dimethylamino) benzoyl]amino}phenyl]-2-(2-phenylethyl)pentanoic acid hydrochloride(white solid, yield: 48%).

¹ H NMR (MeOD, 250 MHz) δ ppm: 8.14 (d, J = 9.0 Hz, 2H), 7.69 (d, J = 9.0 Hz, 2H), 7.28 (m, 3H), 7.18 (m, 3H), 7.01 (d, J = 7.6 Hz, 1 H), 2.63 (m, 4H),

2.41 (m, 1 H), 1.93 (m, 1 H), 1.83-1.50 (m, 5H).

El MS: m/z = 445 (M+1 -Cl ^" ).

Example 25: 5-(3'-{r(4-Methylphenyl)sulfonyl1amino)phenyl)-2-(2-phenylet hyl) pentanoic acid

a) Methyl 5-(3'-{[(4-methylphenyl)sulfonyl]amino}phenyl)-2-(2-phenylet hyl) pentanoate p-TsCI ( 223 mg, 1.168 mmol) was added to a solution of methyl 5-(3- aminophenyl)-2-(2-phenylethyl)pentanoate (280 mg, 0.899 mmol), DMAP (27 mg, 0.22 mmol) and Et ₃ N (0.25 ml_, 1.79 mmol) in THF (30 ml_). The reaction was stirred at r.t. overnight. It was poured into H ₂ O (80 ml_) and extracted with EtOAc (100 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂ (0→5% EtOAc/hexanes) to furnish 270 mg of methyl 5-(3'-{[(4-

methylphenyl)sulfonyl]annino}phenyl)-2-(2-phenylethyl)pen tanoate (yellow- coloured oil, yield: 65%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.80 (d, J = 7.7 Hz, 2H), 7.35-7.12 (m, 11 H) , 6.84 (m, 1 H), 6.76 (bs, 1 H), 3.68 (s, 3H), 2.50 (m, 4H), 2.45 (s, 3H), 2.37 (m, 1 H), 1.95 (m, 1 H), 1.80-1.39 (m, 5H).

b) 5-(3'-{[(4-Methylphenyl)sulfonyl]amino}phenyl)-2-(2-phenylet hyl)pentanoic acid

The compound was synthesized from methyl 5-(3'-{[(4-methylphenyl) sulfonyl]amino}phenyl)-2-(2-phenylethyl)pentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (10→40% EtOAc/hexanes) to yield a colourless oil

(yield: 18%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.64 (d, J = 8.5 Hz, 2H), 7.33-7.04 (m, 8H), 6.85 (m, 3H), 6.75 (bs, 1 H), 2.69-2.37 (m, 5H), 2.35 (s, 3H), 1.98 (m, 1 H),

1.81 -1.40 (m, 5H).

El MS: m/z = 452 (M+1 ), 469 (M+18).

Example 26: 5-{5-r(Methylamino)sulfonyl1thien-2-yl)-2-(2-phenylethyl) pentanoic acid

a) /V-methylthiophene-2-sulfonamide

MeNH ₂ (10.3 ml_, 8 M solution in EtOH, 82.12 mmol) was added to a solution of 2-thiophenesulfonyl chloride (5.0 g, 27.37 mmol) in THF (70 ml_). The reaction mixture was stirred at r.t. for 2 h, poured into H ₂ O (100 ml_) and extracted with CH ₂ CI ₂ (2x100 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated, to give 5.05 g of /V-methylthiophene- 2-sulfonamide, that were submitted to next step without purification (brown- coloured solid, yield: quantitative). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.60 (m, 2H), 7.09 (dd, J = 3.7 Hz, 4.0 Hz, 1 H), 4.88 (bs, 1 H), 2.71 (s, 3H).

b) 5-Bromo-/V-methylthiophene-2-sulfonamide

Br ₂ (3 ml_, 51.46 mmol) was added to a solution of λ/-methylthiophene-2- sulfonamide (4.56 g, 25.73 mmol) in CHCI ₃ (70 ml_). The reaction mixture was refluxed for 7 h, allowed to reach r.t., poured into H ₂ O (100 ml_) and extracted with CH ₂ CI ₂ (100 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂ (15→30% EtOAc/hexanes) to furnish 1.23 g of 5-bromo-/V- methylthiophene-2-sulfonamide (off-white solid, yield: 19%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.61 (m, 1 H), 7.10 (dd, J = 3.8 Hz, 4.5 Hz, 1 H), 4.79 (bs, 1 H), 2.73 (d, J = 5.2 Hz, 3H).

c) tert-Butyl (5-bromothien-2-yl)sulfonyl(methyl)carbamate BoC ₂ O (1.17 g, 5.36 mmol) was added to a solution of 5-bromo-/V- methylthiophene-2-sulfonamide (1.23 g, 4.78 mmol), DMAP (55 mg, 0.45 mmol) and DIPEA (2.3 ml_, 13.67 mmol) in CH ₃ CN (50 ml_). The reaction mixture was stirred at r.t. for 1 h, poured into H ₂ O (50 ml_) and extracted with CH ₂ CI ₂ (100 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂ (15% EtOAc/hexanes) to furnish 1.61 g of tert-butyl (5-bromothien-2- yl)sulfonyl(methyl)carbamate (orange-coloured solid, yield: 95%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.49 (d, J = 3.9 Hz, 1 H), 7.07 (d, J = 3.9 Hz, 1 H), 3.28 (s, 3H), 1.48 (s, 9H).

d) tert-Butyl [5-(3-hydroxyprop-1 -ynyl)thien-2-yl]sulfonyl(methyl)carbamate The compound was prepared from tert-butyl (5-bromothien-2- yl)sulfonyl(methyl)carbamate following the general procedure C. Flash chromatography purification on SiO ₂ (20→30% EtOAc/hexanes) afforded the desired product as a yellow-coloured solid (yield: 86%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.57 (d, J = 3.8 Hz, 1 H), 7.11 (d, J = 3.8 Hz, 1 H), 4.52 (s, 2H), 3.29 (s, 3H), 1.83 (bs, 1 H), 1.47 (s, 9H).

e) tert-Butyl [5-(3-bromoprop-1 -ynyl)thien-2-yl]sulfonyl(methyl)carbamate The compound was prepared from tert-Butyl [5-(3-hydroxyprop-1 -ynyl)thien-2- yl]sulfonyl(methyl)carbamate following the general procedure D. Flash chromatography purification on SiO ₂ (15→20% EtOAc/hexanes) afforded the desired product as a white solid (yield: 92%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.58 (d, J = 3.9 Hz, 1 H), 7.16 (d, J = 3.9 Hz, 1 H), 4.16 (s, 2H), 3.29 (s, 3H), 1.47 (s, 9H).

f) Methyl 5-{5-[tertbutoxycarbonylmethylannino)sulfonyl]thien-2-yl}-2- (2- phenylethyl)pent-4-ynoate

The compound was prepared from methyl 4-phenylbutanoate and tert-butyl [5-(3-bromoprop-1 -ynyl)thien-2-yl]sulfonyl(methyl)carbamate following the general procedure A. Flash chromatography purification on SiO ₂ (10→20% EtOAc/hexanes) afforded the desired product as a yellow-coloured oil (yield: 45%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.55 (d, J = 3.8 Hz, 1 H), 7.37-7.12 (m, 5H), 7.02 (d, J = 3.8 Hz, 1 H), 3.73 (s, 3H), 3.29 (s, 3H), 2.72 (m, 5H), 1.99 (m, 2H), 1.46 (s, 9H).

g) Methyl 5-{5-[tertbutoxycarbonylmethylamino)sulfonyl]thien-2-yl}-2-( 2- phenylethyl)pentanoate

The compound was prepared from methyl 5-{5-[tertbutoxycarbonylmethyl amino)sulfonyl]thien-2-yl}-2-(2-phenylethyl)pent-4-ynoate following the general procedure E. The crude residue was submitted to next step without purification (colourless oil, yield: 96%). El MS: m/z = 496 (M+1 ).

h) 5-{5-[(Methylamino)sulfonyl]thien-2-yl}-2-(2-phenylethyl)pen tanoic acid

The compound was synthesized from methyl 5-{5-[tertbutoxycarbonylmethyl amino)sulfonyl]thien-2-yl}-2-(2-phenylethyl)pentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (5→10% MeOH/CH ₂ CI ₂ ) to give a yellow-coloured solid (yield: 37%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.42 (d, J = 3.6 Hz, 1 H), 7.29 (m, 2H), 7.18 (m, 3H), 6.75 (d, J = 3.6 Hz, 1 H), 4.75 (bs, 1 H), 2.83 (m, 2H), 2.70 (bs, 3H),

2.63 (m, 1 H), 2.42 (m, 2H), 1.99 (m, 1 H), 1.85-1.54 (m, 5H).

El MS: m/z = 382 (M+1 ), 380 (M-1 ).

Example 27: 5-(3-[(Benzylannino)sulfonyliphenyl)-2-(2-phenylethyl)pentan oic acid

a) λ/-Benzyl-3-bromobenzenesulfonannide. Benzylamine (2.6 ml_, 23.48 mmol) was added to a solution of 3- bromobenzenesulfonyl chloride (2.0 g, 7.83 mmol) in THF (30 ml_). The reaction mixture was stirred at r.t. for 3 h, poured into H ₂ O (50 ml_) and extracted with CH ₂ CI ₂ (120 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂ (10→50% EtOAc/hexanes) to furnish 2.31 g of N- benzyl-3-bromobenzenesulfonamide (white solid, yield: 90%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.76 (m, 1 H), 7.60-7.46 (m, 2H), 7.22-6.94 (m, 6H), 4.82 (t, J = 5.5. Hz, 1 H), 3.97 (d, J = 6.0 Hz, 2H).

b) tert-Butylbenzyl[(3-bromophenyl)sulfonyl]carbamate.

BoC ₂ O (2.00 g, 9.20 mmol) was added to a solution of /V-benzyl-3- bromobenzenesulfonamide (2.31 g, 7.08 mmol), DMAP (87 mg, 0.71 mmol) and DIPEA (3.6 ml_, 21.24 mmol) in CH ₃ CN (30 ml_). The reaction mixture was stirred at r.t. for 40 min, poured into H ₂ O (80 ml_) and extracted with EtOAc (100 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂ (20→30% EtOAc/hexanes) to furnish 2.93 g of tert-butylbenzyl[(3- bromophenyl)sulfonyl]carbamate (off-white solid, yield: 97%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.83 (m, 1 H), 7.77 (m, 1 H), 7.66 (m, 1 H), 7.58-7.34 (m, 6H), 5.15 (s, 2H), 1.46 (s, 9H).

c) tert-Butylbenzyl[3-(3-hydroxyprop-1 -ynyl)phenyl]sulfonylcarbamate The compound was synthesized from tert-butylbenzyl[(3-bromophenyl) sulfonyl]carbamate following the experimental procedure detailed in Method C. It was purified by flash chromatography on SiO ₂ (10→50% EtOAc/hexanes) to furnish a yellow coloured oil (yield: 72%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.71 (m, 1 H), 7.58 (m, 2H), 7.37 (m, 6H), 5.05 (s, 2H), 4.50 (s, 2H), 1.92 (bs, 1 H), 1.33 (s, 9H).

d) tert-Butylbenzyl{[3-(3-bromoprop-1 -ynyl)phenyl]sulfonyl}carbannate The compound was synthesized from tert-butylbenzyl[3-(3-hydroxyprop-1 - ynyl)phenyl]sulfonylcarbamate following the experimental procedure detailed in Method D. It was purified by flash chromatography on SiO ₂ (10→20% EtOAc/hexanes) to furnish a colourless oil (yield: 85%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.65 (m, 1 H), 7.59 (m, 2H), 7.37 (m, 6H), 5.05 (s, 2H), 4.13 (s, 2H), 1.35 (s, 9H).

e) Methyl 5-(3-{[(tert-butyl benzyl)sulfonyl]carbamate}phenyl)-2-(2- phenylethyl)pent-4-ynoate

The compound was synthesized from tert-butylbenzyl{[3-(3-bromoprop-1 - ynyl)phenyl]sulfonyl}carbamate and methyl 4-phenylbutanoate following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO ₂ (5→20% EtOAc/hexanes) to furnish a colourless oil

(yield: 60%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.68 (m, 1 H), 7.51 (m, 2H), 7.41 -7.23 (m, 8H), 7.19 (m, 3H), 5.03 (s, 2H), 3.74 (s, 3H), 2.66 (m, 5H), 2.62 (m, 2H), 1.31

(s, 9H).

f) Methyl 5-(3-{[(tert-butyl benzyl)sulfonyl]carbamate}phenyl)-2-(2- phenylethyl)pentanoate. The compound was synthesized from methyl 5-(3-{[(tert-butyl benzyl )sulfonyl]carbamate}phenyl)-2-(2-phenylethyl)pent-4-ynoate following the experimental procedure detailed in Method E. It was submitted to next step without purification (colourless oil, 88%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.58 (m, 1 H), 7.47 (m, 2H), 7.45-7.29 (m, 8H), 7.22 (m, 3H), 5.11 (s, 2H), 3.74 /s, 3H), 2.74-2.36 (m, 5H), 2.00 (m, 1 H), 1.85-1.44 (m, 5H), 1.33 (s, 9H).

g) 5-(3-[(Benzylamino)sulfonyl]phenyl)-2-(2-phenylethyl)pentano ic acid The compound was synthesized from methyl 5-(3-{[(tert-butyl benzyl)sulfonyl]carbamate}phenyl)-2-(2-phenylethyl)pentanoat e following the experimental procedure detailed in Method B. It was purified by flash

chromatography on SiO ₂ (25→35% EtOAc/hexanes) to yield a colourless oil (yield: 62%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.71 (m, 2H), 7.49-7.35 (m, 2H), 7.34-7.17 (m, 10H), 4.97 (t, J = 6.0 Hz, 1 H), 4.17 (d, J = 6.0 Hz, 2H), 2.69 (m, 4H), 2.47 (m, 1 H), 2.02 (m, 1 H), 1.88-1.55 (m, 5H). El MS: m/z = 452 (M+1 ).

Example 28: 5-Phenyl-2-(2-pyridin-2-ylethyl)pentanoic acid

a) Ethyl 4-pyridin-2-ylbutanoate

4-Ethoxy-4-oxobutylzinc bromide (3.3 ml_, 0.5M solution in THF, 1.65 mmol) was added to a solution of 2-bromopyhdine (200 mg, 1.265 mmol) and (Ph ₃ P) ₄ Pd (105 mg, 0.09 mmol) in THF (15 ml_). The reaction mixture was stirred at r.t. for 3 h and poured into H ₂ O (50 ml_). It was taken up to pH=2 with HCI (10% aqueous solution) and extracted with EtOAc (100 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂ (10→40%

EtOAc/hexanes) to furnish 180 mg of ethyl 4-pyridin-2-ylbutanoate (yellow oil, yield: 74%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 8.50 (d, J = 4.1 Hz, 1 H), 7.57 (dt, J = 7.6 Hz, 2.3 Hz, 1 H), 7.10 (m, 2H), 4.10 (q, J = 7.0 Hz, 2H), 2.81 (t, J = 8.2 Hz, 2H), 2.34 (t, J = 7.6 Hz, 2H), 2.06 (m, 2H), 1.23 (t, J = 7.0 Hz, 3H).

b) Ethyl 5-phenyl-2-(2-pyridin-2-ylethyl)pentanoate

The compound was synthesized from ethyl 4-pyridin-2-ylbutanoate and PhCH ₂ CH ₂ CH ₂ I as alkylating agent, following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO ₂ (10→20% EtOAc/hexanes) to furnish a yellow coloured oil (yield: 40%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 8.52 (d, J = 4.1 Hz, 1 H), 7.58 (dt, J = 7.6 Hz, 2.3 Hz, 1 H), 7.1 (m, 3H), 7.16 (m, 4H), 4.14 (q, J = 7.0 Hz, 2H), 2.76 (m, 2H), 2.59 (t, J = 7.6 Hz, 2H), 2.41 (m, 1 H), 2.02 (m, 2H), 1.68 (m, 4H), 1.26 (t, J = 7.0 Hz, 3H).

c) 5-Phenyl-2-(2-pyridin-2-ylethyl)pentanoic acid The compound was synthesized from ethyl 5-phenyl-2-(2-pyridin-2- ylethyl)pentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (10→70% EtOAc/hexanes), and slurred with Et ₂ O to furnish a white solid (yield: 31 %). ¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 8.54 (d, J = 4.1 Hz, 1 H), 7.74 (t, J = 7.6 Hz, 1 H), 7.37-7.07 (m, 7H), 2.96 (t, J = 8.2 Hz, 2H), 2.59 (q, J = 8.2 Hz, 2H), 2.41 (m, 1 H), 2.05 (m, 1 H), 1.94-1.49 (m, 4H), 1.41 (m, 1 H). El MS: m/z = 284 (M+1 ).

Example 29: 2-[2-(3-methoxyphenyl)ethvH-5-phenylpentanoic acid

a) Ethyl 4-(3-methoxyphenyl)butanoate

4-Ethoxy-4-oxobutylzinc bromide (13 ml_, 0.5M solution in THF, 6.5 mmol) was added to a solution of 1 -bromo-3-methoxybenzene (1.0 g, 5.35 mmol) and (Ph ₃ P) ₄ Pd (742 mg, 0.642 mmol) in THF (25 ml_). The reaction mixture was refluxed for 2 h, allowed to reach r.t. and poured into H ₂ O (80 ml_). It was taken up to pH= 2 with HCI (10% aqueous solution) and extracted with EtOAc (90 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂ (0→4%

EtOAc/hexanes) to furnish 677 mg of ethyl 4-(3-methoxyphenyl)butanoate (coloureless oil, yield: 57%). El MS: m/z = 223 (M+1 ).

b) Ethyl 2-[2-(3-methoxyphenyl)ethyl]-5-phenylpentanoate

The compound was synthesized from ethyl 4-(3-methoxyphenyl)butanoate and PhCH ₂ CH ₂ CH ₂ I, following the experimental procedure detailed in Method

A. It was purified by flash chromatography on SiO ₂ (0→5% EtOAc/hexanes) to furnish a yellow coloured oil (yield: 64%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.30 (m, 2H), 7.16 (m, 4H), 6.72 (m, 3H), 4.16 (c, J = 7.1 Hz, 2H), 3.81 (s, 3H), 2.57 (m, 4H), 2.37 (m, 1 H), 1.91 (m, 1 H), 1.85-1.43 (m, 6H), 1.27 (t, J = 7.1 Hz, 3H). c) 2-[2-(3-methoxyphenyl)ethyl]-5-phenylpentanoic acid The compound was synthesized from ethyl 2-[2-(3-methoxyphenyl)ethyl]-5- phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (15→20% EtOAc/hexanes) to furnish a colourless oil (yield: 57%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.29-7.12 (m, 6H), 6.74 (m, 3H), 3.79 (s, 3H), 2.61 (m, 4H), 2.44 (m, 1 H), 1.94 (m, 1 H), 1.88-1.53 (m, 5H). El MS: m/z = 311 (M-1 ).

Example 30: 2-r2-(3-Hvdroxyphenyl)ethyl1-5-phenylpentanoic acid

BBr ₃ (2.5 ml_, 1 M solution in CH ₂ CI ₂ , 2.5 mmol) was added to a -78 ⁰ C cooled solution of 2-[2-(3-hydroxyphenyl)ethyl]-5-phenylpentanoic acid (261 mg, 0.83 mmol) in CH ₂ CI ₂ (15 ml_). The reaction mixture was stirred at low temperature for 30 min, and allowed to reach r.t. It was stirred overnight (18 h), poured into H ₂ O (15 ml_) and extracted with CH ₂ CI ₂ (50 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂ (15→30% EtOAc/hexanes) to furnish 85 mg of 2-[2-(3-hydroxyphenyl)ethyl]-5-phenylpentanoic acid (off-white solid, yield: 34%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.96 (d, J = 8.5 Hz, 1 H), 7.31 -7.10 (m, 5H), 6.77 (m, 1 H), 6.67 (m, 1 H), 6.56 (bs, 1 H), 2.90 (m, 2H), 2.63 (m, 2H), 2.45 (m, 1 H), 2.17 (m, 1 H), 2.03-1.49 (m, 5H). El MS: m/z = 281 (M-17).

Example 31 : 2-{2-[4-(Acetylamino)phenyl1ethyl)-5-phenylpentanoic acid

a) Methyl 4-(4-nitrophenyl)butanoate

H ₂ SO ₄ (0.16 ml_, 2.868 mmol) was added to a solution of A-(A- nitrophenyl)butanoic acid (2.0 g, 9.56 mmol) in MeOH (20 ml_). The reaction mixture was stirred at r.t. for 16 h, poured into H ₂ O (50 ml_) and extracted with CH ₂ CI ₂ (2x50 ml_). The organic layer was washed with NaHCO ₃ (300 ml_, saturated aqueous solution), dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂ (10 EtOAc/hexanes), to furnish methyl 4-(4-nitrophenyl)butanoate (2.00 g, colourless oil, yield: 94%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 8.14 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 3.67 (s, 3H), 2.76 (t, J = 7.9 Hz, 2H), 2.33 (t, J = 7.6 Hz, 2H), 1.98 (q, J = 7.7 Hz, 2H).

b) Methyl 4-(4-aminophenyl)butanoate

A suspension of methyl 4-(4-nitrophenyl)butanoate (3.05 g, 13.67 mmol) and Pd/C (1.0 g, 10% Pd on activated C, 1.09 mmol) in MeOH (40 ml_) was stirred under H ₂ atmosphere (balloon) for 3 h. The reaction mixture was filtered through Celite (washing with EtOAc). Solvent was concentrated off, to furnish 2.33 g of methyl 4-(4-aminophenyl)butanoate (brown solid, yield: 88%). It was submitted to next step without purification.

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 6.96 (d, J = 8.5 Hz, 2H), 6.63 (d, J = 8.2 Hz, 2H), 3.66 (s, 3H), 2.55 (t, J = 7.6 Hz, 2H), 2.31 (t, J = 7.7 Hz, 2H), 1.90 (q, J = 7.6 Hz, 2H).

c) Methyl 4-[4-(λ/,λ/-dibenzylamino)phenyl]butanoate

BnBr (4.33 ml_, 36.17 mmol) was added to a suspension of K ₂ CO ₃ (5.0 g, 36.18 mmol) and methyl 4-(4-aminophenyl)butanoate (2.33 g, 12.056 mmol) in CH ₃ CN (60 ml_). The reaction mixture was warmed up to reflux and allowed to react for 12 h. It was poured into H ₂ O (100 ml_) and extracted with EtOAc (2x100 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered

and concentrated. The crude residue was flash chromatographed on SiO ₂ (5 10% EtOAc/hexanes) to furnish 3.61 g of methyl 4-[4-(N,N- dibenzylamino)phenyl]butanoate (brown solid, yield: 80%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.25 (m, 10H), 6.94 (d, J = 8.5 Hz, 2H), 6.62 (d, J = 8.5 Hz, 2H), 4.59 (2, 4H), 3.61 (s, 3H), 2.49 (t, J = 7.4 Hz, 2H), 2.28 (t, J = 7.4 Hz, 2H), 1.86 (q, J = 7.6 Hz, 2H).

d) Methyl 2-{2-[4-(N,N-dibenzylamino)phenyl]ethyl}-5-phenylpentanoate The compound was synthesized from methyl 4-[4-(N, N- dibenzylamino)phenyl]butanoate and PhCH ₂ CH ₂ CH ₂ I as alkylating agent, following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO ₂ (5% EtOAc/hexanes) to furnish a yellow coloured oil (yield: 34%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.07 (m, 15H), 6.83 (d, J = 8.5 Hz, 2H), 6.53 (d, J = 8.5 Hz, 2H), 4.50 (s, 4H), 3.54 (s, 3H), 2.52-2.20 (m, 5H), 1.61 - 1.39 (m, 6H).

e) Methyl 2-[2-(4-aminophenyl)ethyl]-5-phenylpentanoate

A suspension of methyl 2-{2-[4-(N,N-dibenzylamino)phenyl]ethyl}-5- phenylpentanoate (1.60 g, 3.254 mmol) and Pd/C (380 mg, 10% Pd on activated C, 0.36 mmol) in MeOH (30 ml_) was stirred under H ₂ atmosphere (balloon) for 4 h. The reaction mixture was filtered through Celite (washing with EtOAc). Solvent was concentrated off, to furnish 0.927 g of methyl 2-[2- (4-aminophenyl)ethyl]-5-phenylpentanoate (red oil, yield: 92%). It was submitted to next step without purification.

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.12 (m, 2H), 6.95 (m, 3H), 6.75 (d, J = 8.3 Hz, 2H), 6.43 (d, J = 8.3 Hz, 2H), 3.47 (s, 3H), 2.43-2.12 (m, 5H), 1.79-1.25 (m, 6H).

f) Methyl 2-[2-(4-(acetylamino)phenyl)ethyl]-5-phenylpentanoate

Ac ₂ O (0.37 ml_, 3.86 mmol) was added to a solution of methyl 2-[2-(4- aminophenyl)ethyl]-5-phenylpentanoate (926 mg, 2.97 mmol) and Et ₃ N (1.25 ml_, 8.95 mmol) in CH ₂ CI ₂ (30 ml_). The reaction mixture was stirred at r.t. for 4 h, poured into H ₂ O (100 ml_), taken up to pH=2 and extracted with EtOAc (2x150 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂

(10→40% EtOAc/hexanes) to furnish 925 mg of methyl 2-[2-(4- (acetylamino)phenyl)ethyl]-5-phenylpentanoate (red coloured oil, yield: 88%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.32 (m, 2H), 7.24-6.98 (m, 7H), 3.61 (s, 3H), 2.58-2.17 (m, 5H), 2.09 (s, 3H), 1.93-1.34 (m, 6H).

g) 2-{2-[4-(Acetylamino)phenyl]ethyl}-5-phenylpentanoic acid The compound was synthesized from methyl 2-[2-(4- (acetylamino)phenyl)ethyl]-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (10→50% EtOAc/hexanes) to furnish a yellow coloured oil (yield: 35%). ¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.25 (m, 2H), 7.13 (m, 2H), 7.00 (m, 6H), 2.59 (m, 4H), 2.40 (m, 1 H), 2.16 (s, 3H), 1.80 (m, 1 H), 1.52 (m, 5H). El MS: m/z = 340 (M+1 ), 357 (M+18).

Example 32: 2-[2-(4-Aminophenyl)ethvπ-5-phenylpentanoic acid

The compound was synthesized from methyl 2-[2-(4-aminophenyl)ethyl]-5- phenylpentanoate following the experimental procedure detailed in Method B.

The crude residue was slurred with hexanes to furnish a white solid (yield:

63%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.33-7.09 (m, 5H), 6.92 (d, J = 8.2, 2H). 6.70 (d, J = 8.2, 2H), 2.64-2.19 (m, 5H), 1.83 (m, 1 H), 1.90-1.45 (m, 5H).

El MS: m/z = 298 (M+1 ).

Example 33: 2-[2-(4-(Benzylamino)phenyl)ethvπ-5-phenylpentanoic acid

a) Methyl 2-[2-(4-(benzylamino)phenyl)ethyl]-5-phenylpentanoate PhCHO (390 mg, 3.71 mmol) was added to a solution of methyl 2-[2-(4- aminophenyl)ethyl]-5-phenylpentanoate (1.10 g, 3.532 mmol) in CICH ₂ CH ₂ CI (50 ml_).The reaction mixture was stirred at r.t. for 15 min, and NaBH(OAc) ₃ (1.50 g, 7.06 mmol) was added in portions. The mixture was allowed to react for 45 min, and poured into H ₂ O (100 ml_). It was extracted with CH2CI2, and the organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂ (0→10% EtOAc/hexanes) to furnish 833 mg of methyl 2-[2-(4- (benzylamino)phenyl)ethyl]-5-phenylpentanoate (colourless oil, yield: 59%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.41 -7.10 (m, 10H), 6.95 (d, J = 8.0 Hz, 2H), 6.56 (d, J = 8.0 Hz, 2H), 4.30 (s, 2H), 3.94 (bs, 1 H), 3.67 (s, 3H), 2.58 (m, 2H), 2.42 (m, 3H), 1.86 (m, 1 H), 1.59 (m, 6H).

b) 2-[2-(4-(Benzylamino)phenyl)ethyl]-5-phenylpentanoic acid The compound was synthesized from methyl 2-[2-(4-(benzylamino) phenyl)ethyl]-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂

(5 20% EtOAc/hexanes) to furnish a yellow-coloured oil (yield: 72%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.51 -7.19 (m, 10 H), 7.06 (d, J = 8.2 Hz, 2H), 6.66 (d, J = 8.2 Hz, 2H), 4.37 (s, 2H), 2.75-2.43 (m, 5H), 2.05 (m, 1 H), 1.88-1.58 (m, 5H). El MS: m/z = 388 (M+1 ).

Example 34: 5-Phenyl-2-(3-phenylpropyl)pentanoic acid

a) Methyl 5-phenylpentanoate

H ₂ SO ₄ (1.7 ml_, 31.89 mmol) was added to a solution of 5-phenylpentanoic acid (15.0 g, 84.161 mmol) in MeOH (80 ml_). The reaction mixture was stirred at r.t. for 3 h, poured into H ₂ O (400 ml_) and extracted with CH ₂ CI ₂ (2x300 ml_). The organic layer was washed with NaHCO ₃ (300 ml_, saturated aqueous solution), dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated, to furnish methyl 5-phenylpentanoate (16.30 g, colourless oil, yield: 100%). The crude residue was submitted to next step without further purification. 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.45 (m, 2H), 7.35 (m, 3H), 3.84 (s, 3H), 2.81 (t, J = 7.2 Hz, 2H), 2.52 (t, J = 7.2 Hz, 2H), 1.84 (m, 4H).

b) Methyl 5-phenyl-2-(3-phenylpropyl)pentanoate The compound was prepared from methyl 5-phenylpentanoate following the general procedure A, by using PhCH ₂ CH ₂ CH ₂ I as alkylating reagent. Flash chromatography purification afforded the compound as a colourless oil (yield: 16%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.25 (m, 10H), 7.17 (m, 5H), 3.67 (s, 3H), 2.60 (m, 3H), 2.32 (m, 2H), 1.71 -1.51 (m, 8H).

c) 5-Phenyl-2-(3-phenylpropyl)pentanoic acid

It was prepared from methyl 5-phenyl-2-(3-phenylpropyl)pentanoate following the general procedure B, to furnish the compound as a colourless oil after flash chromatography purification (yield: 15%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.31 (m, 5H), 7.22 (m, 5H), 2.65 (m, 3H), 2.45 (m, 1 H), 1.80-1.51 (m, 9H). El MS: m/z = 295 (M-1 ).

Example 35: 5-Phenyl-2-propylpentanoic acid

a) Methyl 5-phenyl-2-propylpentanoate

The compound was prepared from methyl 5-phenylpentanoate following the general procedure A, by using PrI as alkylating reagent. Flash chromatography purification afforded the compound as a yellow coloured oil (yield: 55%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.31 (m, 2H), 7.20 (m, 3H), 3.72 (s, 3H), 2.65 (t, J = 7.4 Hz, 2H), 2.42 (m, 1 H), 1.73-1.55 (m, 4H), 1.50-1.26 (m, 4H), 0.94 (t, J = 7.4 Hz, 3H).

b) 5-Phenyl-2-propylpentanoic acid

It was prepared from methyl 5-phenyl-2-propylpentanoate following the general procedure B, to furnish the compound as a colourless oil after flash chromatography purification (yield: 62%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.29 (m, 2H), 7.20 (m, 3H), 2.66 (t, J = 7.4

Hz, 2H), 2.42 (m, 1 H), 1.77-1.55 (m, 4H), 1.52-1.27 (m, 4H), 0.93 (t, J = 7.4

Hz, 3H).

El MS: m/z = 219 (M-1 ).

Example 36: 5-(3-r(4-Methylanilinosulfonyliphenyl)-2-(2- phenylethvDpentanoic acid

a) 3-Bromo-λ/-(4-methylphenyl)benzenesulfonamide p-Toluidine (1.68 g, 15.655 mmol) was added to a solution of 3- bromobenzenesulfonyl chloride (2.0 g, 7.827 mmol) and Et ₃ N (2.19 ml_, 15.655 mmol) in THF (60 ml_). The reaction mixture was allowed to react for 1 h and poured into H ₂ O (120 ml_). It was taken up to pH = 1 with HCI (15%

aqueous solution) and extracted with EtOAc (2x100 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated, to furnish the product as a waxy solid. The crude residue was submitted to next step without purification. 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.91 (t, J = 1.9 Hz, 1 H), 7.65 (dd, J = 6.3 Hz, 1.6 Hz, 2H), 7.30 (t, J = 7.9 Hz, 1 H), 7.02 (m, 4H), 6.83 (bs, 1 H), 2.28 (s, 3H).

b) tert-Butyl (3-bromophenyl)sulfonyl(4-methylphenyl)carbamate BoC ₂ O (2.22 g, 10.175 mmol) was added to a solution of 3-bromo-λ/-(4- methylphenyl)benzenesulfonamide (7.827 mmol), DMAP (95 mg, 0.782 mmol) and DIPEA (4.0 ml_, 23.48 mmol) in CH ₃ CN (60 ml_). The reaction mixture was stirred at r.t. for 2 h, poured into H ₂ O (200 ml_) and extracted with EtOAc (200 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂ (5 10% EtOAc/hexanes), to afford 2.90 g of tert-butyl (3- bromophenyl)sulfonyl(4-methylphenyl)carbamate (white solid, yield: 87%). ¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 8.15 (t, J = 1.9 Hz, 1 H), 7.90 (m, 1 H), 7.78 (m, 1 H), 7.43 (t, J = 7.9 Hz, 1 H), 7.24 (d, J = 7.4 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H), 2.40 (s, 3H), 1.37 (s, 9H).

c) tert-Butyl [3-(3-hydroxyprop-1 -ynyl)phenyl]sulfonyl(4-methylphenyl) carbamate

The compound was synthesized from tert-butyl (3-bromophenyl)sulfonyl(4- methylphenyl)carbamate following the experimental procedure detailed in Method C. It was purified by flash chromatography on SiO ₂ (10→40% EtOAc/hexanes) to furnish an orange coloured solid (yield: 89%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 8.05 (s, 1 H), 7.92 (d, J = 7.9 Hz, 1 H), 7.66 (d, J = 7.6 Hz, 1 H), 7.48 (t, J = 7.9 Hz, 1 H), 7.24 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 8.2 Hz, 2H), 4.47 (s, 2H), 2.91 (bs, 1 H), 2.38 (s, 3H), 1.34 (s, 9H).

d) tert-Butyl [3-(3-bromoprop-1 -ynyl)phenyl]sulfonyl(4-methylphenyl) carbamate

The compound was synthesized from tert-butyl [3-(3-hydroxyprop-1 - ynyl)phenyl]sulfonyl(phenyl)carbamate following the experimental procedure detailed in Method D. It was purified by flash chromatography on SiO ₂ (5→20% EtOAc/hexanes) to furnish a white solid (yield: 85%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 8.07 (t, J = 1.3 Hz, 1 H), 7.93 (m, 1 H), 7.69 (m, 1 H), 7.51 (t, J = 7.9 Hz, 1 H), 7.25 (d, J = 7.4 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H), 4.15 (s, 2H), 2.40 (s, 3H), 1.36 (s, 9H).

e) Methyl 5-[3-(tert-butoxycarbonyl-4-methylanilinosulfonyl)phenyl]-2- (2- phenylethyl)pent-4-ynoate

The compound was synthesized from tert-butyl [3-(3-bromoprop-1 - ynyl)phenyl]sulfonyl(phenyl)carbamate and methyl 4-phenylbutanoate following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO ₂ (5→30% EtOAc/hexanes) to furnish a white solid (yield: 72%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.99 (m, 1 H), 7.88 (m, 1 H), 7.61 (m, 1 H), 7.46 (t, J = 7.4 Hz, 1 H), 7.35-7.09 (m, 9H), 3.74 (s, 3H), 2.83-2.57 (m, 5H), 2.39 (s, 3H), 2.25-1.94 (m, 2H), 1.34 (s, 9H).

f) Methyl 5-[3-(tert-butoxycarbonyl-4-methylanilinosulfonyl)phenyl]-2- (2- phenylethyl)pentanoate

The compound was synthesized from methyl 5-[3-(tert-butoxycarbonyl anilinosulfonyl)phenyl]-2-(2-phenylethyl)pent-4-ynoate following the experimental procedure detailed in Method E to furnish a waxy solid (yield:

94%). The crude residue was submitted to next step without purification. ¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.77 (m, 2H), 7.43 (m, 2H), 7.34-7.19 (m, 5H), 7.14 (t, J = 7.6 Hz, 4H), 3.69 (s, 3H), 2.74-2.51 (m, 4H), 2.39 (s, 3H), 2.07-1.87 (m, 1 H), 1.83-1.46 (m, 6H), 1.33 (s, 9H).

g) 5-(3-[(4-Methylanilinosulfonyl]phenyl)-2-(2-phenylethyl)pent anoic acid The compound was synthesized from methyl 5-[3-(tert-butoxycarbonyl anilinosulfonyl)phenyl]-2-(2-phenylethyl)pentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (10 30% EtOAc/hexanes) to yield a white solid

(yield: 56%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.59-7.47 (m, 2H), 7.27 (m, 5H), 7.18 (t, J = 8.2 Hz, 2H), 7.01 (d, J = 8.5 Hz, 2H), 6.93 (d, J = 8.5 Hz, 2H), 6.76 (bs, 1 H), 2.79-2.52 (m, 4H), 2.51 -2.34 (m, 1 H), 2.24 (s, 3H), 2.11 -1.87 (m, 1 H), 1.85- 1.42 (m, 5H).

El MS: m/z = 452 (M+1 ).

Example 37: Sodium 5-(3-[(4-methylanilinosulfonvπphenyl)-2-(2-phenylethyl) pentanoate

NaH (16 mg, 60%mineral oil suspension, 0.40 mmol) was added to a solution of 5-(3-[(4-methylanilinosulfonyl]phenyl)-2-(2-phenylethyl)pent anoic acid

(Example 36) (180 mg, 0.398 mmol) in THF (10 ml_). The reaction mixture was stirred at r.t. for 15 min, and solvent was concentrated off. The crude residue was slurred with Et ₂ O (5 ml_) and hexanes (5 ml_), to give 120 mg of sodium 5-(3-[(4-methylanilinosulfonyl]phenyl)-2-(2-phenylethyl)pent anoate

(white solid, yield: 64%).

¹ H NMR (MeOD, 250 MHz) δ ppm: 7.50 (m, 2H), 7.34 (m, 2H), 7.17 (m, 5H),

6.93 (m, 4H), 2.66 (m, 4H), 2.27 (m, 1 H), 2.20 (s, 3H), 1.81 (m, 1 H), 1.59 (m,

4H).

El MS: m/z = 452 (M-Na+1 ).

Example 38: 5-[3-(4-Methylanilinosulfonyl)phenyl1-2-(2-phenylethyl)pent- 4- vnoic acid

The compound was synthesized from methyl 5-[3-(tert-butoxycarbonyl-4- methylanilinosulfonyl)phenyl]-2-(2-phenylethyl)pent-4-ynoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (10→50% EtOAc/hexanes) to yield a colourless oil (yield: 40%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.82 (s, 1 H), 7.58 (d, J = 7.9, 1 H), 7.48 (d, J = 6.7 Hz, 1 H), 7.35-7.15 (m, 6H), 7.04-6.88 (m, 5H), 2.78-2.69 (m, 5H), 2.26 (m, 3H), 2.17-2.01 (m, 2H).

El MS: m/z = 448 (M+1 ), 465 (M+18).

Example 39: 5-(3-[(Anilinosulfonvπphenyl)-2-(2-phenylethyl)pentanoic acid

a) 3-Bromo-λ/-phenylbenzenesulfonannide

Aniline (1.42 g, 15.655 mmol) was added to a solution of 3- bromobenzenesulfonyl chloride (2.0 g, 7.827 mmol) and Et ₃ N (2.19 ml_, 15.655 mmol) in THF (60 ml_). The reaction mixture was allowed to react for 1 h and poured into H ₂ O (120 ml_). It was taken up to pH = 1 with HCI (15% aqueous solution) and extracted with EtOAc (2x100 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated, to furnish the product as a waxy solid. The crude residue was submitted to next step without purification.

b) tert-Butyl (3-bromophenyl)sulfonyl(phenyl)carbamate

BoC ₂ O (2.22 g, 10.175 mmol) was added to a solution of 3-bromo-/V- phenylbenzenesulfonamide (7.827 mmol), DMAP (95 mg, 0.782 mmol) and DIPEA (4.0 ml_, 23.48 mmol) in CH ₃ CN (60 ml_). The reaction mixture was stirred at r.t. for 2 h, poured into H ₂ O (200 ml_) and extracted with EtOAc (200 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂ (5→10% EtOAc/hexanes), to afford 2.55 g of tert-butyl (3- bromophenyl)sulfonyl(phenyl)carbamate (white solid, yield: 79%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 8.21 (t, J = 1.6 Hz, 1 H), 7.96 (m, 1 H), 7.84 (m, 1 H), 7.49 (m, 4H), 7.30 (m, 2H), 1.43 (s, 9H).

c) tert-Butyl [3-(3-hydroxyprop-1 -ynyl)phenyl]sulfonyl(phenyl)carbamate The compound was synthesized from tert-butyl (3- bromophenyl)sulfonyl(phenyl)carbamate following the experimental procedure detailed in Method C. It was purified by flash chromatography on SiO ₂ (10→50% EtOAc/hexanes) to furnish a yellow coloured oil (yield: 75%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.90 (m, 1 H), 7.79 (m, 1 H), 7.53 (m, 1 H), 7.41 -7.24 (m, 4H), 7.10 (m, 2H), 4.38 (s, 2H), 1.43 (bs, 1 H), 1.19 (s, 9H).

d) tert-Butyl [3-(3-bromoprop-1 -ynyl)phenyl]sulfonyl(phenyl)carbamate The compound was synthesized from tert-butyl [3-(3-hydroxyprop-1 - ynyl)phenyl]sulfonyl(phenyl)carbamate following the experimental procedure detailed in Method D. It was purified by flash chromatography on SiO ₂ (0→5% EtOAc/hexanes) to furnish a waxy solid (yield: 88%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 8.13 (s, 1 H), 8.00 (m, 1 H), 7.76 (m, 1 H), 7.67-7.44 (m, 4H), 7.32 (m, 2H), 4.23 (s, 2H), 1.41 (s, 9H). e) Methyl 5-[3-(tert-butoxycarbonylanilinosulfonyl)phenyl]-2-(2- phenylethyl)pent-4-ynoate

The compound was synthesized from tert-butyl [3-(3-bromoprop-1 - ynyl)phenyl]sulfonyl(phenyl)carbamate and methyl 4-phenylbutanoate following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO ₂ (10→20% EtOAc/hexanes) to furnish a colourless oil (yield: 57%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.98 (m, 1 H), 7.88 (m, 1 H), 7.62 (m, 1 H), 7.51 -7.40 (m, 3H), 7.33-7.15 (m, 6H), 3.73 (s, 3H), 2.70 (m, 5H), 2.11 (m, 2H), 1.34 (s, 9H).

f) Methyl 5-[3-(tert-butoxycarbonylanilinosulfonyl)phenyl]-2-(2- phenylethyl)pentanoate

The compound was synthesized from methyl 5-[3-(tert- butoxycarbonylanilinosulfonyl)phenyl]-2-(2-phenylethyl)pent- 4-ynoate following the experimental procedure detailed in Method E to furnish a yellow oil (yield: 92%). The crude residue was submitted to next step without purification.

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.79 (m, 2H), 7.42 (m, 5H), 7.30-7.12 (m, 7H), 3.68 (s, 3H), 2.73-2.50 (m, 4H), 2.42 (m, 1 H), 1.95 (m, 1 H), 1.79-1.49 (m,

5H), 1.32 (s, 9H).

g) 5-(3-[(Anilinosulfonyl]phenyl)-2-(2-phenylethyl)pentanoic acid The compound was synthesized from methyl 5-[3-(tert- butoxycarbonylanilinosulfonyl)phenyl]-2-(2-phenylethyl)penta noate following the experimental procedure detailed in Method B. It was purified by flash

chromatography on SiO ₂ (5→20% EtOAc/hexanes) to yield a yellow coloured oil (yield: 45%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.51 (m, 2H), 7.31 -7.22 (m, 5H), 7.17 (m, 4H), 7.04 (m, 3H), 6.75 (bs, 1 H), 2.58 (m, 4H), 2.37 (m, 1 H), 1.96 (m, 1 H), 1.81 -1.41 (m, 5H).

El MS: m/z = 438 (M+1 ), 455 (M+18).

Example 40: 5-(4-[Anilinosulfonyliphenyl)-2-(2-phenylethyl)pentanoic acid

a) 4-Bromo-λ/-phenylbenzenesulfonamide

Aniline (1.837 g, 19.725 mmol) was added to a solution of 4- bromobenzenesulfonyl chloride (2.5 g, 9.784 mmol) and DIPEA (3 ml_, 17.524 mmol) in THF (50 ml_). The reaction mixture was allowed to react for 30 min and poured into H ₂ O (120 ml_). It was taken up to pH = 1 with HCI (15% aqueous solution) and extracted with EtOAc (2x100 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated, to furnish the product as a yellow coloured oil. The crude residue was submitted to next step without purification.

b) tert-Butyl (4-bromophenyl)sulfonyl(phenyl)carbamate

BoC ₂ O (2.80 g, 12.829 mmol) was added to a solution of 4-bromo-/V- phenylbenzenesulfonamide (9.784 mmol), DMAP (150 mg, 1.227 mmol) and DIPEA (5.0 ml_, 29.207 mmol) in CH ₃ CN (80 ml_). The reaction mixture was stirred at r.t. for 2 h, poured into H ₂ O (200 ml_) and extracted with EtOAc (200 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂ (5→10% EtOAc/hexanes), to afford 3.86 g of tert-butyl (4- bromophenyl)sulfonyl(phenyl)carbamate (white solid, yield: 79%). El MS: m/z = 413 (M+1 ).

c) tert-Butyl [4-(3-hydroxyprop-1 -ynyl)phenyl]sulfonyl(phenyl)carbamate

The compound was synthesized from tert-butyl (4-bromophenyl) sulfonyl(phenyl)carbamate following the experimental procedure detailed in Method C. It was purified by flash chromatography on SiO ₂ (20→80% EtOAc/hexanes) to furnish an orange coloured solid (yield: 73%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.99 (d, J = 8.6 Hz, 2H), 7.64 (d, J = 8.6 Hz, 2H), 7.48 (m, 3H), 7.30 (m, 2H), 4.58 (s, 2H), 1.39 (s, 9H).

d) tert-Butyl [4-(3-bromoprop-1 -ynyl)phenyl]sulfonyl(phenyl)carbamate The compound was synthesized from tert-butyl [4-(3-hydroxyprop-1 - ynyl)phenyl]sulfonyl(phenyl)carbamate following the experimental procedure detailed in Method D. It was purified by flash chromatography on SiO ₂ (10→40% EtOAc/hexanes) to furnish a yellow coloured solid (yield: 99%). ¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.81 (d, J = 8.6 Hz, 2H), 7.47 (d, J = 8.6 Hz, 2H), 7.28 (m, 3H), 7.09 (m, 2H), 4.04 (s, 2H), 1.21 (s, 9H).

e) Methyl 5-[4-(tert-butoxycarbonylanilinosulfonyl)phenyl]-2-(2- phenylethyl)pent-4-ynoate

The compound was synthesized from tert-butyl [4-(3-bromoprop-1 - ynyl)phenyl]sulfonyl(phenyl)carbamate and methyl 4-phenylbutanoate following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO ₂ (5→15% EtOAc/hexanes) to furnish a yellow coloured oil (yield: 80%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.73 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.3 Hz, 2H), 7.24 (m, 3H), 7.15-6.95 (m, 7H), 3.58 (s, 3H), 2.52 (m, 5H), 1.94 (m, 2H), 1.18 (s, 9H).

f) Methyl 5-[4-(tert-butoxycarbonylanilinosulfonyl)phenyl]-2-(2- phenylethyl)pentanoate

The compound was synthesized from methyl 5-[4-(tert-butoxycarbonyl anilinosulfonyl)phenyl]-2-(2-phenylethyl)pent-4-ynoate following the experimental procedure detailed in Method E. It was purified by flash chromatography on SiO ₂ (4→12% EtOAc/hexanes) to furnish a colourless oil (yield: 73%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.87 (d, J = 8.3 Hz, 2H), 7.42 (m, 3H), 7.37-7.11 (m, 9H), 3.70 (s, 3H), 2.69 (m, 2H), 2.57 (m, 2H), 2.41 (m, 1 H), 1.92 (m, 1 H), 1.81 -1.48 (m, 5H), 1.35 (s, 9H).

g) 5-(4-[Anilinosulfonyl]phenyl)-2-(2-phenylethyl)pentanoic acid The compound was synthesized from methyl 5-[4-(tert-butoxycarbonyl anilinosulfonyl)phenyl]-2-(2-phenylethyl)pentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (10→50% EtOAc/hexanes) to yield a white solid (yield: 53%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.93 (d, J = 8.5 Hz, 2H), 7.68 (bs, 1 H), 7.56-7.24 (m, 12H), 2.83 (m, 4H), 2.65 (m, 1 H), 2.24 (m, 1 H), 2.09-1.69 (m, 5H). El MS: m/z = 438 (M+1 ), 455 (M+18).

Example 41 : 5-(3-[(Methylamino)sulfonyliphenyl)-2-(2-phenylethyl)pentano ic acid

a) 3-Bromo-λ/-methylbenzenesulfonamide

MeNH ₂ (6 ml_, 8 M solution in EtOH, 48 mmol) was added to a solution of 3- bromobenzenesulfonyl chloride (3.50 g, 13.698 mmol) in THF (60 ml_). The reaction mixture was allowed to react for 5 min and poured into H ₂ O (200 ml_) and extracted with CH ₂ CI ₂ (2x100 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated, to furnish the product as a yellow coloured solid. The crude residue was submitted to next step without purification.

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 8.01 (t, J = 1.6 Hz, 1 H), 7.82-7.68 (m, 2H), 7.41 (t, J = 8.0 Hz, 1 H), 4.70 (bs, 1 H), 2.68 (d, J = 4.9 Hz, 3H).

b) tert-Butyl (3-bromophenyl)sulfonyl(methyl)carbamate BoC ₂ O (3.41 g, 15.624 mmol) was added to a solution of 3-bromo-/V- methylbenzenesulfonamide (13.698 mmol), DMAP (166 mg, 1.358 mmol) and DIPEA (7.0 ml_, 40.89 mmol) in CH ₃ CN (70 ml_). The reaction mixture was stirred at r.t. for 15 min, poured into H ₂ O (200 ml_) and extracted with EtOAc (200 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂

(2→10% EtOAc/hexanes), to afford 4.72 g of tert-butyl (3- bromophenyl)sulfonyl(methyl)carbannate (white solid, yield: 89%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 8.04 (t, J = 1.9 Hz, 1 H), 7.89-7.71 (m, 2H), 7.40 (t, J = 8.0 Hz, 1 H), 3.35 (s, 3H), 1.37 (s, 9H).

c) tert-Butyl [3-(3-hydroxyprop-1 -ynyl)phenyl]sulfonyl(methyl)carbamate The compound was synthesized from tert-butyl (3-bromophenyl)sulfonyl (methyl)carbamate following the experimental procedure detailed in Method C. It was purified by flash chromatography on SiO ₂ (20 40% EtOAc/hexanes) to furnish a yellow coloured oil (yield: 40%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.93 (t, J = 1.1 Hz, 1 H), 7.83 (m, 1 H), 7.64 (m, 1 H), 7.46 (t, J = 7.6 Hz, 1 H), 4.50 (s, 2H), 3.37 (s, 3H), 1.36 (s, 9H).

d) tert-Butyl [3-(3-bromoprop-1 -ynyl)phenyl]sulfonyl(methyl)carbamate The compound was synthesized from tert-butyl [3-(3-hydroxyprop-1 - ynyl)phenyl]sulfonyl(methyl)carbamate following the experimental procedure detailed in Method D. It was purified by flash chromatography on SiO ₂ (5→20% EtOAc/hexanes) to furnish a colourless oil (yield: 86%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.95 (t, J = 1.7Hz, 1 H), 7.85 (m, 1 H), 7.65 (m, 1 H), 7.48 (t, J = 7.6 Hz, 1 H), 4.14 (s, 2H), 3.36 (s, 3H), 1.36 (s, 9H).

e) Methyl 5-[3-(tert-butoxycarbonylmethylaminosulfonyl)phenyl]-2-(2- phenylethyl)pent-4-ynoate

The compound was synthesized from tert-butyl [3-(3-bromoprop-1 - ynyl)phenyl]sulfonyl(methyl)carbamate and methyl 4-phenylbutanoate following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO ₂ (2→15% EtOAc/hexanes) to furnish a colourless oil (yield: 75%).

El MS: m/z = 486 (M+1 ).

f) Methyl 5-[3-(tert-butoxycarbonylmethylaminosulfonyl)phenyl]-2-(2- phenylethyl)pentanoate

The compound was synthesized from methyl 5-[3-(tert-butoxycarbonyl methylaminosulfonyl)phenyl]-2-(2-phenylethyl)pent-4-ynoate following the experimental procedure detailed in Method E to furnish a colourless oil (yield: 96%). The crude residue was submitted to next step without purification.

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.61 (m, 2H), 7.36 (m, 2H), 7.20 (m, 2H), 7.11 (m, 3H), 3.64 (s, 3H), 3.31 (s, 3H), 2.67-2.42 (m, 4H), 2.35 (m, 1 H), 1.88 (m, 1 H), 1.72-1.39 (m, 5H), 1.26 (s, 9H).

g) 5-(3-[(Methylamino)sulfonyl]phenyl)-2-(2-phenylethyl)pentano ic acid The compound was synthesized from methyl 5-[3-(tert- butoxycarbonylmethylaminosulfonyl)phenyl]-2-(2-phenylethyl)p entanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (10→50% EtOAc/hexanes) to yield a colourless oil (yield: 87%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.70 (m, 2H), 7.41 (m, 2H), 7.30 (m, 2H), 7.20 (m, 3H), 4.69 (c, J = 2.7 Hz, 1 H), 2.76-2.57 (m, 7H), 2.44 (m, 1 H), 1.99 (m, 1 H), 1.84-1.50 (m, 5H). El MS: m/z = 376 (M+1 ), 393 (M+18).

Example 42: Methyl 5-(3-[(methylamino)sulfonyliphenyl)-2-(2-phenylethyl) pentanoate

H ₂ SO ₄ (0.05 ml_) was added to a solution of 5-(3-[(methylamino)sulfonyl] phenyl)-2-(2-phenylethyl)pentanoic acid (Example 41 ) (350 mg, 0.932 mmol) in MeOH (25 ml_). The reaction mixture was warmed up to reflux and allowed to react for 3 h. It was poured into H ₂ O (150 ml_) and extracted with CH ₂ CI ₂ (150 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂ (10→40% EtOAc/hexanes), to afford 264 mg of methyl 5-(3-[(methylamino) sulfonyl]phenyl)-2-(2-phenylethyl)pentanoate (colourless oil, yield: 73%). ¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.67 (m, 2H), 7.39 (m, 2H), 7.26 (m, 2H), 7.18 (m, 3H), 4.42 (c, J = 5.4 Hz, 1 H), 3.70 (s, 3H), 2.65 (d, J = 5.4 Hz, 3H), 2.58 (m, 4H), 2.41 (m, 1 H), 1.92 (m, 1 H), 1.78-1.44 (m, 5H). El MS: m/z = 390 (M+1 ), 407 (M+18).

Example 43: 5-(3-{[(3λ-dimethoxyphenyl)amino1sulfonyl)phenyl)-2-(2- phenylethvDpentanoic acid

a) 3-Bromo-λ/-(3,4-dinnethoxyphenyl)benzenesulfonannide 3,4-Dimethoxyaniline (2.0 g, 13.056 mmol) was added to a solution of 3- bromobenzenesulfonyl chloride (1.75 g, 6.849 mmol) and Et ₃ N (2 ml_, 14.349 mmol) in THF (40 ml_). The reaction mixture was allowed to react for 30 min, poured into H ₂ O (200 ml_) and taken to pH = 2. It was extracted with EtOAc (200 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated, to furnish the product as a brown coloured oil. The crude residue was submitted to next step without purification.

b) tert-Butyl (3-bromophenyl)sulfonyl(3,4-dimethoxyphenyl)carbamate BoC ₂ O (1.85 g, 8.476 mmol) was added to a solution of 3-bromo-λ/-(3,4- dimethoxyphenyl)benzenesulfonamide (6.849 mmol), DMAP (100 mg, 0.818 mmol) and DIPEA (3.0 ml_, 17.524 mmol) in CH ₃ CN (100 ml_). The reaction mixture was stirred at r.t. for 45 min, poured into H ₂ O (200 ml_) and extracted with EtOAc (2x120 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂ (10→30% EtOAc/hexanes), to afford 3.12 g of tert- butyl (3-bromophenyl)sulfonyl(3,4-dimethoxyphenyl)carbamate (white solid, yield: 96%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 8.14 (t, J = 1.9 Hz, 1 H), 7.92 (m, 1 H), 7.79 (m, 1 H), 7.44 (t, J = 8.2 Hz, 1 H), 6.92-6.71 (m, 3H), 3.91 (s, 3H), 3.88 (s, 3H), 1.39 (s, 9H).

c) tert-Butyl [3-(3-hydroxyprop-1 -ynyl)phenyl]sulfonyl(3,4-dimethoxyphenyl) carbamate

The compound was synthesized from tert-butyl (3-bromophenyl)sulfonyl(3,4- dimethoxyphenyl)carbamate following the experimental procedure detailed in

Method C. It was purified by flash chromatography on SiO ₂ (10→60% EtOAc/hexanes) to furnish a red coloured solid (yield: 89%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 8.05 (t, J = 1.6 Hz, 1 H), 7.94 (m, 1 H), 7.69 (m, 1 H), 7.51 (t, J = 7.7 Hz, 1 H), 6.90-6.72 (m, 3H), 4.51 (d, J = 6.2 Hz, 2H), 3.91 (s, 3H), 3.88 (s, 3H), 1.88 (t, J = 6.2 Hz, 1 H), 1.36 (s, 9H).

d) tert-Butyl [3-(3-bromoprop-1 -ynyl)phenyl]sulfonyl(3,4-dimethoxyphenyl) carbamate

The compound was synthesized from tert-butyl [3-(3-hydroxyprop-1 - ynyl)phenyl]sulfonyl(3,4-dimethoxyphenyl)carbamate following the experimental procedure detailed in Method D. It was purified by flash chromatography on SiO ₂ (20→30% EtOAc/hexanes) to furnish a colourless oil

(yield: 97%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 8.03 (bs, 1 H), 7.92 (m, 1 H), 7.66 (m, 1 H), 7.49 (t, J = 7.9 Hz, 1 H), 6.89-6.69 (m, 3H), 4.11 (s, 2H), 3.88 (s, 3H), 3.84 (s,

3H), 1.35 (s, 9H).

e) Methyl 5-[3-(tert-butoxycarbonyl(3,4-dimethoxyanilino)sulfonyl)phen yl]-2- (2-phenylethyl)pent-4-ynoate The compound was synthesized from tert-butyl [3-(3-bromoprop-1 -ynyl) phenyl]sulfonyl(3,4-dimethoxyphenyl)carbamate and methyl 4-phenyl butanoate following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO ₂ (10→40% EtOAc/hexanes) to furnish a colourless oil (yield: 89%). El MS: m/z = 608 (M+1 ).

f) Methyl 5-[3-(tert-butoxycarbonyl(3,4-dimethoxyanilino)sulfonyl)phen yl]-2-(2- phenylethyl)pentanoate

The compound was synthesized from methyl 5-[3-(tert-butoxycarbonyl(3,4- dimethoxyanilino)sulfonyl)phenyl]-2-(2-phenylethyl)pent-4-yn oate following the experimental procedure detailed in Method E. It was purified by flash chromatography on SiO ₂ (10→40% EtOAc/hexanes) to furnish a colourless oil (yield: 85%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.79 (m, 2H), 7.44 (m, 2H), 7.32-7.11 (m, 5H), 6.94-6.72 (m, 3H), 3.91 (s, 3H), 3.86 (s, 3H), 2.73-2.49 (m, 4H), 2.40 (m, 1 H), 1.96 (m, 1 H), 1.78-1.54 (m, 5H), 1.35 (s, 9H).

g) 5-(3-{[(3,4-dimethoxyphenyl)annino]sulfonyl}phenyl)-2-(2-phe nylethyl) pentanoic acid

The compound was synthesized from methyl 5-[3-(tert-butoxycarbonyl(3,4- dimethoxyanilino)sulfonyl)phenyl]-2-(2-phenylethyl)pentanoat e following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (10→60% EtOAc/hexanes) to yield a white solid (yield: 87%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.64 (bs, 1 H), 7.57 (m, 1 H), 7.42-7.31 (m, 4H), 7.29-7.17 (m, 3H), 7.10 (s, 1 H), 6.77 (m, 2H), 6.61 (m, 1 H), 3.86 (s, 3H), 3.82 (s, 3H), 2.69 (m, 4H), 2.50 (m, 1 H), 2.06 (m, 1 H), 1.90-1.49 (m, 5H). El MS: m/z = 498 (M+1 ), 515 (M+18).

Example 44: 5-[3-(4-methylanilinosulfonyl)phenyl1-2-(3-phenylpropyl) pentanoic acid

a) Methyl 5-[3-(tert-butoxycarbonyl-4-methylanilinosulfonyl)phenyl]-2- (3- phenylpropyl)pent-4-ynoate

The compound was synthesized from methyl 5-phenylpentanoate and tert- butyl [3-(3-bromoprop-1 -ynyl)phenyl]sulfonyl(4-methylphenyl)carbamate following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO ₂ (10→15% EtOAc/hexanes) to furnish a yellow- coloured oil (yield: 72%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 8.09 (m, 1 H), 7.97 (m, 1 H), 7.67 (m, 1 H), 7.55 (t, J = 7.7 Hz, 1 H), 7.38-7.21 (m, 9H), 3.81 (s, 3H), 2.74 (m, 5H), 2.47 (s, 3H), 1.79 (m, 4H), 1.44 (s, 9H).

b) Methyl 5-[3-(tert-butoxycarbonyl-4-methylanilinosulfonyl)phenyl]-2- (3- phenylpropyl)pentanoate

The compound was synthesized from methyl 5-[3-(tert-butoxycarbonyl-4- methylanilinosulfonyl)phenyl]-2-(3-phenylpropyl)pent-4-ynoat e following the experimental procedure detailed in Method E. The crude residue was submitted to next step without purification.

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.82 (m, 2H), 7.48 (m, 2H), 7.36-7.14 (m, 9H), 3.70 (s, 3H), 2.71 (m, 2H), 2.62 (m, 2H), 2.43 (s, 3H), 1.76-1.48 (m, 9H), 1.38 (s, 9H).

c) 5-[3-(4-methylanilinosulfonyl)phenyl]-2-(3-phenylpropyl)pent anoic acid The compound was prepared from methyl 5-[3-(tert-butoxycarbonyl-4- methylanilinosulfonyl)phenyl]-2-(3-phenylpropyl)pentanoate following the general procedure B. Flash chromatography purification on SiO ₂ (20→50% EtOAc/hexanes), afforded the desired product as a yellow-coloured oil (yield: 73%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.66 (m, 2H), 7.41 -7.17 (m, 8H), 7.09 (m, 4H), 2.70 (m, 4H), 2.48 (m, 1 H), 2.34 (s, 3H), 1.92-1.36 (m, 8H). El MS: m/z = 466 (M+1 ), 483 (M+18).

Example 45: 2-[2-(4-Ethylphenyl)ethvπ-5-phenylpentanoic acid

a) Ethyl 4-(4-ethylphenyl)-4-hydroxybut-2-ynoate

Ethyl propiolate (470 mg, 4.85 mmol) was added to a -78 ⁰ C cooled solution of LiHMDS (5.2 ml_, 1 M solution in THF, 5.22 mmol) in THF (15 ml_). The reaction mixture was stirred at low temperature for 5 min, and 4- ethylbenzaldehyde (500 mg, 3.73 mmol) was added. It was allowed to reach r.t. and poured into H ₂ O (90 ml_). It was taken up to pH=2 with HCI (10% aqueous solution), and the product was extracted with EtOAc (2x100 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated, to furnish a red oil, that was submitted to next step without purification.

b) Ethyl 4-(4-ethylphenyl)butanoate The compound was prepared from ethyl 4-(4-ethylphenyl)-4-hydroxybut-2- ynoate following the general procedure E. Flash chromatography purification

on SiO ₂ (0→10% EtOAc/hexanes) afforded ethyl 4-(4-ethylphenyl)butanoate as a colourless oil (yield: 75%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.12 (m, 4H), 4.12 (c, J = 7.1 Hz, 2H), 2.60 (m, 4H), 2.34 (t, J = 7.4 Hz, 2H), 1.96 (c, J = 8.2 Hz, 2H), 1 -32.1.20 (m, 6H).

c) Ethyl 2-[2-(4-ethylphenyl)ethyl]-5-phenylpentanoate The compound was prepared from ethyl 4-(4-ethylphenyl)butanoate following the general procedure A, by using PhCH ₂ CH ₂ CH ₂ I as alkylating reagent Flash chromatography purification on SiO ₂ (5→10% EtOAc/hexanes) afforded ethyl 2-[2-(4-ethylphenyl)ethyl]-5-phenylpentanoate as a colourless oil (yield: 53%). ¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.27 (m, 2H), 7.09 (m, 7H), 4.16 (c, J = 7.1 Hz, 2H), 2.59 (m, 6H), 2.37 (m, 1 H), 1.95 (m, 1 H), 1.69-1.48 (m, 5H), 1.25 (m, 6H).

d) 2-[2-(4-Ethylphenyl)ethyl]-5-phenylpentanoic acid

The compound was prepared from ethyl 2-[2-(4-ethylphenyl)ethyl]-5- phenylpentanoate following the general procedure B. Flash chromatography purification on SiO ₂ (5→20% EtOAc/hexanes), afforded 2-[2-(4- ethylphenyl)ethyl]-5-phenylpentanoic acid as a colourless oil (yield: 25%). ¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.47-7.34 (m, 9H), 2.88 (m, 7H), 2.22 (m, 1 H), 2.07-1.73 (m, 5H), 1.47 (t, J = 7.7 Hz, 3H). El MS: m/z = 309 (M-1 ).

Example 46: 5-r4-(Anilinosulfonyl)phenyl1-2-r2-(4-ethylphenyl)ethylipent anoic acid

a) Methyl 5-[4-(tert-butoxycarbonylanilinosulfonyl)phenyl]-2-[2-(4-eth ylphenyl) ethyl]pent-4-ynoate The compound was prepared from methyl 4-(4-ethylphenyl)butanoate following the general procedure A, by using tert-butyl [4-(3-bromoprop-1 - ynyl)phenyl]sulfonyl(phenyl)carbamate as alkylating reagent. Flash

chromatography purification on SiO ₂ (5→15% EtOAc/hexanes) afforded the desired product as a yellow coloured oil (yield: 55%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.90 (d, J = 7.4 Hz, 2H), 7.53 (d, J = 7.4 Hz, 2H), 7.42 (m, 3H), 7.24 (m, 2H), 7.13 (m, 4H), 3.75 (s, 3H), 2.80-2.56 (m, 7H), 2.04 (m, 2H), 1.34 (s, 9H), 1.25 (c, J = 7.1 Hz, 3H).

b) Methyl 5-[4-(tert-butoxycarbonylanilinosulfonyl)phenyl]-2-[2-(4- ethylphenyl)ethyl]pentanoate

The compound was prepared from methyl 5-[4-(tert-butoxycarbonyl anilinosulfonyl)phenyl]-2-[2-(4-ethylphenyl)ethyl]pent-4-yno ate following the general procedure E. Flash chromatography purification on SiO ₂ (20% EtOAc/hexanes) afforded the desired product as a colourless oil (yield: 88%). ¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.88 (d, J = 8.2 Hz, 2H), 7.42 (m, 3H), 7.34-7.22 (m, 4H), 7.09 (m, 4H), 3.68 (s, 3H), 2.73-2.35 (m, 7H), 1.94 (m, 1 H), 1.81 -1.48 (m, 5H), 1.33 (s, 9H), 1.21 (t, J = 7.4 Hz).

c) 5-[4-(Anilinosulfonyl)phenyl]-2-[2-(4-ethylphenyl)ethyl]pent anoic acid The compound was prepared from methyl 5-[4-(tert-butoxycarbonylanilino sulfonyl)phenyl]-2-[2-(4-ethylphenyl)ethyl]pentanoate following the general procedure E. Flash chromatography purification on SiO ₂ (15→70% EtOAc/hexanes) afforded 5-[4-(Anilinosulfonyl)phenyl]-2-[2-(4- ethylphenyl)ethyl]pentanoic acid as a colourless oil (yield: 62%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.62 (d, J = 8.1 Hz, 2H), 7.36 (bs, 1 H), 7.18-6.93 (m, 11 H), 2.52 (m, 6H), 2.34 (m, 1 H), 1.87 (m, 1 H), 1.71 -1.38 (m, 5H), 1.13 (t, J = 7.6 Hz, 3H).

El MS: m/z = 466 (M+1 ), 483 (M+18).

Example 47: Methyl 5-[4-(anilinosulfonyl)phenyl1-2-[2-(4-ethylphenyl)ethvH pentanoate

H ₂ SO ₄ (360 mg, 0.373 mmol) was added to a solution of 5-[4-(anilinosulfonyl) phenyl]-2-[2-(4-ethylphenyl)ethyl]pentanoic acid (200 mg, 0.429 mmol) in MeOH (20 ml_). The reaction mixture was allowed to react at r.t. for 10 h, poured into H ₂ O (150 ml_) and extracted with CH ₂ CI ₂ (2x70 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂ (10→20% EtOAc/hexanes) to furnish 177 mg of methyl 5-[4-(anilinosulfonyl)phenyl]-2-[2-(4- ethylphenyl)ethyl]pentanoate (colourless oil, yield: 86%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.60 (d, J = 8.5 Hz, 2H), 7.45 (bs, 1 H), 7.13-6.88 (m, 11 H), 3.55 (s, 3H), 2.44 (m, 6H), 2.28 (m, 1 H), 1.81 (m, 1 H), 1.65-1.29 (m, 5H), 1.10 (t, J = 7.6 Hz, 3H). El MS: m/z = 480 (M+1 ), 497 (M+18).

Example 48: 2-[2-(4-Ethylphenyl)ethvH-6-phenylhexanoic acid

a) Methyl 2-[2-(4-ethylphenyl)ethyl]-6-phenylhexanoate

The compound was synthesized from methyl 4-(4-ethylphenyl)butanoate and (4-iodobutyl)benzene following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO ₂ (0→2% EtOAc/hexanes) to furnish a colourless oil (yield: 73%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm:7.19 (m, 2H), 7.13-6.91 (m, 7H), 3.60 (s, 3H), 2.51 (m, 6H), 2.32 (m, 1 H), 1.85 (m, 1 H), 1.67-1.39 (m, 5H), 1.15 (m, 5H).

b) 2-[2-(4-Ethylphenyl)ethyl]-6-phenylhexanoic acid

The compound was synthesized from methyl 2-[2-(4-ethylphenyl)ethyl]-6- phenylhexanoate following the experimental procedure detailed in Method B. The crude residue was purified by flash chromatography on SiO ₂ (10→30% EtOAc/hexanes) to furnish a colourless oil (yield: 63%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.25 (m, 2H), 7.207.05 (m, 7H), 2.59 (m, 6H), 2.40 (m, 1 H), 1.94 (m, 1 H), 1.82-1.48 (m, 4H), 1.37 (m, 2H), 1.20 (m, 4H).

El MS: m/z = 342 (M+18).

Example 49: 5-(3-{[4-(Dimethylamino)benzovπamino)phenyl)-2-[2-(4-ethyl phenvDethylipentanoic acid

a) Methyl 5-[3-/V,/V-dibenzylaminophenyl]-2-[2-(4-ethylphenyl)ethyl]pe nt-4- ynoate

The compound was synthesized from methyl 4-(4-ethylphenyl)butanoate and λ/,λ/-dibenzyl-λ/-[3-(3-bromoprop-1 -ynyl)phenyl]amine following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO ₂ (0→5% EtOAc/hexanes) to yield a yellow-coloured oil (yield: 67%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.42 (m, 11 H), 7.22 (m, 4H), 6.91 (m, 3H), 4.79 (s, 4H), 3.81 (s, 3H), 2.79 (m, 8H), 2.15 (m, 1 H), 1.40 (t, J = 7.6 Hz, 3H).

b) Methyl 5-(3-aminophenyl)-2-[2-(4-ethylphenyl)ethyl]pentanoate

The compound was synthesized from methyl 5-[3-λ/,λ/-dibenzylaminophenyl]- 2-[2-(4-ethylphenyl)ethyl]pent-4-ynoate following the experimental procedure detailed in Method E. It was purified by flash chromatography on SiO ₂

(10→30% EtOAc/hexanes) to yield a yellow-coloured oil (yield: 64%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.09 (m, 5H), 6.53 (m, 3H), 3.71 (s, 3H), 3.60 (bs, 2H), 2.51 (m, 6H), 1.94 (m, 1 H), 1.78-1.43 (m, 6H), 1.20 (t, J = 7.6 Hz, 3H).

c) Methyl 5-(3-{[4-(dimethylamino)benzoyl]amino}phenyl)-2-[2-(4- ethylphenyl)ethyl]pentanoate

4-(Dimethylamino)benzoyl chloride (350 mg, 1.89 mmol) was added to a solution of methyl 5-(3-aminophenyl)-2-[2-(4-ethylphenyl)ethyl]pentanoate (630 mg, 1.58 mmol), DIPEA (0.87 ml_, 5.06 mmol) and DMAP (30 mg, 0.246 mmol) in CH ₂ CI ₂ (40 ml_). The reaction mixture was stirred at r.t. for 12 h, poured into H ₂ O (100 ml_), and extracted with CH ₂ CI ₂ (100 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂ (10→30% EtOAc/hexanes) to furnish 615 mg of methyl 5-(3-{[4-(dimethylamino)benzoyl]amino}phenyl)-2- [2-(4-ethylphenyl)ethyl]pentanoate (yellow-coloured oil, yield: 80%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.79 (m, 2H), 7.70 (s, 1 H), 7.46 (m, 2H), 7.23 (m, 1 H), 7.09 (m, 4H), 6.87 (m, 1 H), 6.70 (m, 2H), 3.68 (s, 3H), 3.06 (s, 6H), 2.70-2.35 (m, 7H), 1.91 (m, 1 H), 1.80-1.49 (m, 5H), 1.22 (m, 3H).

d) 5-(3-{[4-(Dimethylamino)benzoyl]amino}phenyl)-2-[2-(4-ethylp henyl)ethyl] pentanoic acid

The compound was synthesized from methyl 5-(3-{[4-(dimethylamino)benzoyl] amino}phenyl)-2-[2-(4-ethylphenyl)ethyl]pentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (10→40% EtOAc/hexanes) to yield a white solid

(yield: 43%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.63 (m, 4H), 7.28 (m, 2H), 7.04 (m, 1 H),

6.92 (m, 4H), 6.70 (m, 1 H), 6.49 (d, J = 8.8 Hz, 2H), 2.84 (s, 6H), 2.42 (m, 6H), 2.24 (m, 1 H), 1.78 (m, 1 H), 1.63-1.34 (m, 5H), 1.03 (t, J = 7.4 Hz, 3H).

El MS: m/z = 473 (M+1 ).

Example 50: 5-(1 -Naphthyl)-2-[2-(4-ethylphenyl)ethvH-pentanoic acid

a) Methyl 5-(1 -naphthyl)-2-[2-(4-ethylphenyl)ethyl]-pent-4-ynoate

The compound was synthesized from methyl 4-(4-ethylphenyl)butanoate and 1 -(3-bromoprop-1 -ynyl)naphthalene following the experimental procedure

detailed in Method A. It was purified by flash chromatography on SiO ₂ (0→10% EtOAc/hexanes) to yield a yellow-coloured oil (yield: 42%). El MS: m/z = 371 (M+1 ).

b) Methyl 5-(1 -naphthyl)-2-[2-(4-ethylphenyl)ethyl]-pentanoate

The compound was synthesized from methyl 5-(1 -naphthyl)-2-[2-(4- ethylphenyl)ethyl]-pent-4-ynoate following the experimental procedure detailed in Method E. It was purified by flash chromatography on SiO ₂ (2→4% EtOAc/hexanes) to yield a colourless oil (yield: 78%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.87 (m, 1 H), 7.70 (m, 1 H), 7.57 (m, 1 H), 7.44-7.12 (m, 3H), 6.97 (m, 5H), 3.56 (s, 3H), 2.93 (m, 1 H), 2.68-2.28 (m, 6H), 1.97-1.36 (m, 6H), 1.11 (t, J = 7.6 Hz, 3H).

c) 5-(1 -Naphthyl)-2-[2-(4-ethylphenyl)ethyl]-pentanoic acid The compound was synthesized from methyl 5-(1 -naphthyl)-2-[2-(4- ethylphenyl)ethyl]-pentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (5→20%

EtOAc/hexanes) to yield a colourless oil (yield: 14%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.90 (m, 1 H), 7.75 (m, 1 H), 7.61 (m, 1 H), 7.43-7.15 (m, 4H), 6.99 (m, 4H), 2.96 (m, 2H), 2.59-2.28 (m, 5H), 1.90 (m,

1 H), 1.81 -1.45 (m, 5H), 1.14 (t, J = 7.6 Hz, 3H).

El MS: m/z = 361 (M+1 ), 378 (M+18).

Example 51 : 4-Phenyl-2-(2-phenylethyl)butanoic acid

a) Dimethyl bis(2-phenylethyl)malonate

NaH (760 mg, 60% mineral oil suspension, 19.0 mmol) was added to a solution of dimethyl malonate (1.0 g, 7.568 mmol) in DMF (40 ml_). The mixture was stirred at r.t. for 15 min, and (2-bromoethyl)benzene (4.3 ml_, 31.78 mmol) was added. The reaction mixture was warmed up to 50 ⁰ C and stirred for 4 h. It was allowed to reach r.t., diluted with NaCI (saturated aqueous solution, 200 ml_) and extracted with Et ₂ O (200 ml_). The organic

layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂ (2→10% EtOAc/hexanes) to furnish 1.023 g of dimethyl bis(2-phenylethyl)malonate (colourless oil, yield: 39%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.34 (m, 4H), 7.23 (m, 6H), 3.79 (s, 6H), 2.59 (m, 4H), 2.34 (m, 4H).

b) bis(2-Phenylethyl)malonic acid

The compound was synthesized from dimethyl bis(2-phenylethyl)malonate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (5 MeOH/CH ₂ CI ₂ ) to yield a white solid (yield: 25%). The compound was directly submitted to next step.

c) 4-Phenyl-2-(2-phenylethyl)butanoic acid H ₂ O (1 ml_, 35.12 mmol) was added to a solution of bis(2-phenylethyl)malonic acid (300 mg, 0.878 mmol) in DMSO (25 ml_), and the mixture was refluxed for 2 h. It was allowed to reach r.t., poured into H ₂ O (20 ml_), taken up to pH= 1 and extracted with EtOAc (20 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂ (10→20% EtOAc/hexanes) to furnish 70 mg of 4- phenyl-2-(2-phenylethyl)butanoic acid (yellow-coloured oil, yield: 30%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.35-7.08 (m, 10H), 2.67 (m, 5H), 2.46 (m, 1 H), 2.01 (m, 2H), 1.80 (m, 2H). El MS: m/z = 267 (M-1 ).

Example 52: 2-[2-(4-Bromophenyl)ethvπ-5-phenylpentanoic acid

a) Methyl 4-(4-bromophenyl)butanoate H ₂ SO ₄ (0.35 ml_, 6.49 mmol) was added to a solution of 4-(4- bromophenyl)butanoic acid (5.26 g, 21.64 mmol) in MeOH (100 ml_). The reaction mixture was stirred at r.t. for 16 h, and poured into H ₂ O (120 ml_). It was extracted with CH ₂ CI ₂ (150 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated, to give 5.50 g of methyl 4-(4-

bromophenyl)butanoate (colourless oil, yield: 98%). The compound was submitted to next step without further purification.

b) Methyl 2-[2-(4-bromophenyl)ethyl]-5-phenylpentanoate The compound was synthesized from methyl 4-(4-bromophenyl)butanoate and (3-iodopropyl)benzene following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO ₂ (0→5% EtOAc/hexanes) to give a colourless oil (yield: 76%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.40 (m, 2H), 7.28 (m, 2H), 7.16 (m, 3H), 7.05 (m, 2H), 3.68 (s, 3H), 2.71 -2.48 (m, 4H), 2.39 (m, 1 H), 1.94 (m, 1 H), 1.76-1.50 (m, 5H).

c) 2-[2-(4-Bromophenyl)ethyl]-5-phenylpentanoic acid

The compound was synthesized from methyl 2-[2-(4-bromophenyl)ethyl]-5- phenylpentanoate following the experimental procedure detailed in Method B.

It was purified by flash chromatography on SiO ₂ (10→30% EtOAc/hexanes) to give a colourless oil (yield: 46%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.39 (m, 2H), 7.26 (m, 2H), 7.16 (m, 3H),

7.04 (m, 2H), 2.72-2.49 (m, 4H), 2.41 (m, 1 H), 1.95 (m,1 H), 1.82-1.51 (m, 5H). El MS: m/z = 359, 361 (M-1 ).

Example 53: 2-[2-(2,3-Dihvdro-1 H-indol-3-yl)ethvH-5-phenylpentanoic acid

a) Methyl 4-(1 H-indol-3-yl)butanoate

H ₂ SO ₄ (3.5 ml_, 64.92 mmol) was added to a solution of indole-3-butyhc acid (4.0 g, 19.68 mmol) in MeOH (100 ml_). The reaction mixture was stirred at r.t. for 5 h, and poured into H ₂ O (150 ml_). It was extracted with CH ₂ CI ₂ (2x100 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated, to give 4.22 g of methyl 4-(1 H-indol-3-yl)butanoate (white solid, yield: 98%). The compound was submitted to next step without further purification.

¹ H NMR (CDCI ₃ , 250 MHz) ppm: 7.97 (bs, 1 H), 7.61 (d, J = 7.7 Hz, 1 H), 7.35 (d, J = 8.0 Hz, 1 H), 7.24-7.07 (m, 2H), 7.23 (bs, 1 H), 3.66 (s, 3H), 2.81 (t, J = 7.4 Hz, 2H), 2.40 (t, J = 7.4 Hz, 2H), 2.06 (q, J = 7.4 Hz, 2H).

b) Methyl 4-(1 -benzyl-1 H-indol-3-yl)butanoate

Cs ₂ CO ₃ (9.0 g, 27.62 mmol) was added to a solution of methyl 4-(1 H-indol-3- yl)butanoate (4.0 g, 18.41 mmol) and BnBr (4.4 ml_, 36.83 mmol) in CH ₃ CN (100 ml_). The reaction mixture was refluxed for 14 h, allowed to reach r.t. and poured into H ₂ O (150 ml_). It was extracted with EtOAc (180 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂ (20→25% EtOAc/hexanes) to furnish 2.94 g of methyl 4-(1 -benzyl-1 H-indol-3-yl)butanoate (colourless oil, yield: 53%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.56 (d, J = 8.0 Hz, 1 H), 7.31 -6.98 (m, 8H), 6.85 (s, 1 H), 5.18 (s, 2H), 3.60 (bs, 3H), 2.76 (t, J = 7.4 Hz, 2H), 2.40 (t, J = 7.4 Hz, 2H), 2.05-1.97 (m, 2H).

c) (E)-Methyl 2-(2-(1 -benzyl-1 H-indol-3-yl)ethyl)-5-phenylpent-4-enoate The compound was synthesized from methyl 4-(1 -benzyl-1 H-indol-3- yl)butanoate and [(1 E)-3-bromoprop-1 -enyl]benzene following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO ₂ (0→5% EtOAc/hexanes) to give a colourless oil (yield: 46%).

d) Methyl 2-(2-(indolin-3-yl)ethyl)-5-phenylpentanoate

The compound was synthesized from (E)-methyl 2-(2-(1 -benzyl-1 H-indol-3- yl)ethyl)-5-phenylpent-4-enoate following the experimental procedure detailed in Method E. It was purified by flash chromatography on SiO ₂ (10→50% EtOAc/hexanes) to give a colourless oil (mixture of isomers, yield: 8%). 1H NMR (CDCI ₃ , 250 MHz, signals of the major isomer) δ ppm: 7.41 -7.11 (m,

8H), 6.76-6.59 (m, 1 H), 3.67 (s, 3H), 3.29 (m, 1 H), 3.27-3.11 (m, 2H), 2.65- 2.53 (m, 2H), 2.46-2.26 (m, 3H), 1.79-1.36 (m, 7H).

e) 2-[2-(2,3-Dihydro-1 H-indol-3-yl)ethyl]-5-phenylpentanoic acid The compound was synthesized from methyl 2-(2-(indolin-3-yl)ethyl)-5- phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (5% MeOH/CH ₂ CI ₂ ) to give a colourless oil (mixture of isomers, yield: 33%).

¹ H NMR (CDCI ₃ , 250 MHz, signals of the major isomer) δ ppm: 7.26-7.03 (m, 5H), 7.03-6.89 (m, 2H), 6.72-6.52 (m, 3H), 3.73 (t, J = 7.7 Hz, 1 H), 3.38-3.17 (m, 2H), 2.69 (t, J = 7.0 Hz, 2H), 2.47 (bs, 1 H), 1.85-1.35 (m, 8H). El MS: m/z = 324 (M+1 ).

Example 54: 2-[2-(4-hvdroxyphenyl)ethvH-5-phenylpentanoic acid

The compound was synthesized from methyl 2-[2-(4-hydroxyphenyl)ethyl]-5- phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (5→20% MeOH/CH ₂ CI ₂ ) to furnish, to afford a white solid (yield: 36%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.33 (m, 5H), 7.03 (d, J = 8.2 Hz, 2H), 6.74 (d, J = 8.2 Hz, 2H), 2.60 (m, 4H), 2.43 (m, 1 H), 1.93 (m, 1 H), 1.80-1.48 (m, 5H). El MS: m/z = 297 (M-1 ), 316 (M+18).

Example 55: 2-[2-(4-Benzyloxyphenyl)ethvπ-5-phenylpentanoic acid

a) Methyl 2-[2-(4-benzyloxyphenyl)ethyl]-5-phenylpentanoate K ₂ CO ₃ (1.40 mmol) was added to a solution of methyl 2-[2-(4- hydroxyphenyl)ethyl]-5-phenylpentanoate (1.60 g, 5.121 mmol) and BnBr (1 ml_, 8.407 mmol) in CH ₃ CN (30 ml_). The reaction mixture was stirred at r.t. for

6 h, poured into H ₂ O (120 ml_) and extracted with EtOAc (150 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO ₂ (10→20% EtOAc/hexanes), to give 1.73 g of methyl 2-[2-(4-benzyloxyphenyl)ethyl]-5- phenylpentanoate (colourless oil, yield: 84%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.44-7.19 (m, 7H), 7.18-7.08 (m, 3H), 7.03 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 5.01 (s, 2H), 3.64 (s, 3H), 2.60- 2.32 (m, 5H), 1.90 (m, 1 H), 1.76-1.44 (m, 5H).

b) 2-[2-(4-Benzyloxyphenyl)ethyl]-5-phenylpentanoic acid.

The compound was synthesized from methyl 2-[2-(4-benzyloxyphenyl)ethyl]- 5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (15→30% EtOAc/hexanes) to furnish a white solid (yield: 58%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.32-7.04 (m, 7H), 7.03-6.88 (m, 5H), 6.72 (m, 2H), 4.86 (s, 2H), 2.42 (m, 4H), 2.24 (m, 1 H), 1.78 (m, 1 H), 1.50 (m, 5H). El MS: m/z = 389 (M+1 ), 406 (M+18).

Example 56: (Acetyloxy)methyl 2-[2-(4-benzyloxyphenyl)ethvπ-5-phenyl pentanoate

Bromomethyl acetate (0.055 ml_, 0.564 mmol) was added to a solution of 2-[2- (4-benzyloxyphenyl)ethyl]-5-phenylpentanoic acid (Example 55) (160 mg, 0.412 mmol) and DIPEA (0.11 ml_, 0.646 mmol) in CH ₃ CN (20 ml_). The reaction mixture was stirred at r.t. for 3 h and solvent was concentrated off. The crude residue was flash chromatographed on SiO ₂ (10→20% EtOAc/hexanes), to afford 134 mg of (acetyloxy)methyl 2-[2-(4- benzyloxyphenyl)ethyl]-5-phenylpentanoate (colourless oil, yield: 71 %). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.47-7.13 (m, 7H), 7.22-7.10 (m, 3H), 7.06 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 5.75 (s, 2H), 5.04 (s, 2H), 2.63- 2.37 (m, 5H), 2.07 (s, 3H), 1.82-1.47 (m, 6H). El MS: m/z = 478 (M+18).

Example 57: 2-r2-(4-Methoxyphenyl)ethyl1-5-phenylpentanoic acid

a) Methyl 2-[2-(4-methoxyphenyl)ethyl]-5-phenylpentanoate K ₂ CO ₃ (1.40 mmol) was added to a solution of methyl 2-[2-(4-hydroxyphenyl) ethyl]-5-phenylpentanoate (1.60 g, 5.121 mmol) and MeI (1.20 g, 8.407 mmol) in CH ₃ CN (30 ml_). The reaction mixture was stirred at r.t. for 6 h, poured into H ₂ O (120 ml_) and extracted with EtOAc (150 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO ₂ (10% EtOAc/hexanes), to give 1.55 g of methyl 2-[2-(4-methoxyphenyl)ethyl]-5-phenylpentanoate (white solid, yield: 93%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.32-7.11 (m, 5H), 7.07 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 3.79 (s, 3H), 3.69 (s, 3H), 2.65-2.34 (m, 5H), 1.91 (m, 1 H), 1.78-1.40 (m, 5H).

b) 2-[2-(4-Methoxyphenyl)ethyl]-5-phenylpentanoic acid

The compound was synthesized from methyl 2-[2-(4-methoxyphenyl)ethyl]-5- phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (0→5% EtOAc/hexanes) to furnish a yellow-coloured oil (yield: 58%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.31 -7.12 (m, 5H), 7.09 (d, J = 8.6 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 3.78 (s, 3H), 2.62 (m, 4H), 2.42 (m, 1 H), 1.96 (m, 1 H), 1.83-1.50 (m, 5H). El MS: m/z = 313 (M+1 ), 330 (M+18).

Example 58: 2-{2-[4-(Pyridin-2-ylmethoxy)phenvπethyl)-5-phenylpentanoic acid

a) Methyl 2-{2-[4-(pyridin-2-ylnnethoxy)phenyl]ethyl}-5-phenylpentanoa te 2-(Bromonnethyl)pyπdine hydrobromide (425 mg, 1.68 mmol) was added to a suspension of methyl 2-[2-(4-hydroxyphenyl)ethyl]-5-phenylpentanoate (400 mg, 1.28 mmol) and Cs ₂ CO ₃ (1.30 g, 3.99 mmol) in DMF (25 ml_). The reaction mixture was warmed up to 60 ⁰ C and stirred for 3 h. It was allowed to reach r.t. and poured into H ₂ O (150 ml_), taken up to pH = 3 with HCI and extracted with Et ₂ O (100 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO ₂ (10→30% EtOAc/hexanes), to give 452 mg of methyl 2-{2-[4-(pyridin-2-ylmethoxy)phenyl]ethyl}-5-phenylpentanoat e

(colourless oil, yield: 88%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 8.69 (d, J = 4.9 Hz, 1 H), 7.80 (m, 1 H), 7.62 (m, 1 H), 7.42-7.21 (m, 6H), 7.17 (m, 2H), 7.00 (m, 2H), 5.29 (s, 2H), 3.77 (s, 3H), 2.72-2.42 (m, 5H), 2.00 (m, 1 H), 1.88-1.53 (m, 5H).

b) 2-{2-[4-(Pyridin-2-ylmethoxy)phenyl]ethyl}-5-phenylpentanoic acid The compound was synthesized from methyl 2-{2-[4-(pyridin-2-ylmethoxy) phenyl]ethyl}-5-phenylpentanoate following the experimental procedure detailed in Method B. The crude residue was slurred with Et ₂ O, to afford a white solid (yield: 76%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 8.62 (d, J = 6.0 Hz, 1 H), 7.75 (m, 1 H), 7.57 (m, 1 H), 7.28-7.00 (m, 8H), 6.89 (d, J = 8.5 Hz, 2H), 5.21 (s, 2H), 2.57 (m, 4H), 2.41 (m, 1 H), 1.91 (m, 1 H), 1.80-1.44 (m, 5H). El MS: m/z = 390 (M+1 ).

Example 59: 2-{2-[4-(Pyridin-3-ylmethoxy)phenvπethyl)-5-phenyl pentanoic acid

a) Methyl 2-{2-[4-(pyridin-3-ylnnethoxy)phenyl]ethyl}-5-phenylpentanoa te

3-(Bromonnethyl)pyπdine hydrobromide (260 mg, 1.027 mmol) was added to a suspension of methyl 2-[2-(4-hydroxyphenyl)ethyl]-5-phenylpentanoate (250 mg, 0.800 mmol) and Cs ₂ CO ₃ (820 mg, 2.516 mmol) in DMF (20 ml_). The reaction mixture was warmed up to 60 ⁰ C and stirred for 6 h. It was allowed to reach r.t. and poured into H ₂ O (150 ml_), taken up to pH= 3 with HCI and extracted with Et ₂ O (120 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO ₂ (10→80% EtOAc/hexanes), to give 85 mg of methyl 2-{2-[4-(pyridin-3-ylmethoxy)phenyl]ethyl}-5-phenylpentanoat e (colourless oil, yield: 26%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 8.66 (bs, 1 H), 8.57 (bs, 1 H), 7.75 (d, J = 7.9 Hz, 1 H), 7.25 (m, 3H), 7.20-7.03 (m, 5H), 6.87 (m, 2H), 5.03 (s, 2H), 3.66 (s, 3H), 2.55 (m, 4H), 2.38 (m, 1 H), 1.90 (m, 1 H), 1.78-1.45 (m, 5H).

b) 2-{2-[4-(Pyridin-3-ylmethoxy)phenyl]ethyl}-5-phenylpentanoic acid The compound was synthesized from methyl 2-{2-[4-(pyridin-3- ylmethoxy)phenyl]ethyl}-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (30→50% MeOH/CH ₂ CI ₂ ) to afford a white solid (yield: 22%). 1H NMR (MeOD, 250 MHz) δ ppm: 8.63 (bs, 1 H), 8.51 (bs, 1 H), 7.94 (d, J = 7.7 Hz, 1 H), 7.45 (m, 1 H), 7.28-7.02 (m, 7H), 6.95 (m, 2H), 5.12 (s, 2H), 2.56 (m, 4H), 2.31 (m, 1 H), 1.87 (m, 1 H), 1.72-1.42 (m, 5H). El MS: m/z = 390 (M+1 ).

Example 60: 2-{2-[4-(Pyridin-4-ylmethoxy)phenvπethyl)-5-phenylpentanoic acid

a) Methyl 2-{2-[4-(pyridin-4-ylnnethoxy)phenyl]ethyl}-5-phenylpentanoa te 4-(Bromonnethyl)pyπdine hydrobromide (500 mg, 1.976 mmol) was added to a suspension of methyl 2-[2-(4-hydroxyphenyl)ethyl]-5-phenylpentanoate (400 mg, 1.28 mmol) and Cs ₂ CO ₃ (1.30 g, 3.98 mmol) in DMF (20 ml_). The reaction mixture was warmed up to 60 ⁰ C and stirred for 3 h. It was allowed to reach r.t. and poured into H ₂ O (150 ml_), taken up to pH = 3 with HCI and extracted with Et ₂ O (100 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO ₂ (10→80% EtOAc/hexanes), to give 245 mg of methyl 2-{2-[4-(pyridin-4-ylmethoxy)phenyl]ethyl}-5-phenylpentanoat e

(colourless oil, yield: 49%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 8.60 (m, 2H), 7.34 (m, 2H), 7.26 (m, 2H), 7.21 -7.03 (m, 5H), 6.85 (m, 2H), 5.07 (s, 2H), 3.67 (s, 3H), 2.61 -2.33 (m, 5H), 1.90 (m, 1 H), 1.75-1.46 (m, 5H).

b) 2-{2-[4-(Pyridin-4-ylmethoxy)phenyl]ethyl}-5-phenylpentanoic acid The compound was synthesized from methyl 2-{2-[4-(pyridin-4-ylmethoxy) phenyl]ethyl}-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (5→20% MeOH/CH ₂ CI ₂ ) to afford a white solid (yield: 36%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 11.23 (m, 2H), 8.85 (m, 2H), 7.67 (m, 2H), 7.57-7.15 (m, 7H), 7.05 (d, J = 8.2 Hz, 2H), 5.27 (s, 2H), 2.81 (m, 4H), 2.63 (m, 1 H), 2.15 (m, 1 H), 2.07-1.63 (m, 5H). El MS: m/z = 390 (M+1 ).

Example 61 : 2-{2-[4-(2-Cvanophenoxy)phenvπethyl)-5-phenylpentanoic acid

a) Methyl 2-{2-[4-(2-cyanophenoxy)phenyl]ethyl}-5-phenylpentanoate K ₂ CO ₃ (200 mg, 1.447 mmol) was added to a solution of methyl 2-[2-(4- hydroxyphenyl)ethyl]-5-phenylpentanoate (200 mg, 0.640 mmol) and 2- fluorobenzonitrile (200 mg, 1.651 mmol) in DMF (20 ml_). The reaction mixture was warmed up to 130 ⁰ C, and allowed to react for 30 min. It was poured into H ₂ O (120 ml_) and extracted with Et ₂ O (100 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO ₂ (4→16% EtOAc/hexanes), to give 232 mg of methyl 2-{2-[4-(2- cyanophenoxy)phenyl]ethyl}-5-phenylpentanoate (colourless oil, yield: 88%). ¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.69 (dd, J = 7.9 Hz, 1.9 Hz, 1 H), 7.50 (m, 1 H), 7.36-7.11 (m, 8H), 7.04 (m, 2H), 6.87 (d, J = 7.9 Hz, 1 H), 3.74 (s, 3H), 2.64 (m, 4H), 2.45 (m, 1 H), 2.00 (m, 1 H), 1.85-1.54 (m, 5H).

b) 2-{2-[4-(2-Cyanophenoxy)phenyl]ethyl}-5-phenylpentanoic acid. The compound was synthesized from methyl 2-{2-[4-(2-cyanophenoxy) phenyl]ethyl}-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (10→40% EtOAc/hexanes) to furnish a colourless oil (yield: 72%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.72 (m, 1 H), 7.51 (m, 1 H), 7.38-7.12 (m, 8H), 7.07 (d, J = 8.5 Hz, 2H), 6.90 (d, J = 8.5 Hz, 1 H), 2.71 (m, 4H), 2.51 (m, 1 H), 2.08 (m, 1 H), 1.95-1.58 (m, 5H). El MS: m/z = 398 (M-1 ), 400 (M+1 ).

Example 62: 2-{2-[4-(3-cvanophenoxy)phenvπethyl)-5-phenylpentanoic acid

a) Methyl 2-{2-[4-(3-cyanophenoxy)phenyl]ethyl}-5-phenylpentanoate K ₂ CO ₃ (250 mg, 1.808 mmol) was added to a solution of methyl 2-[2-(4- hydroxyphenyl)ethyl]-5-phenylpentanoate (250 mg, 0.800 mmol) and 3- fluorobenzonitrile (250 mg, 2.064 mmol) in DMF (25 ml_). The reaction mixture was warmed up to 130 ⁰ C, and allowed to react for 6 h. It was poured into H ₂ O (120 ml_) and extracted with Et ₂ O (100 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO ₂ (5→15% EtOAc/hexanes), to give 142 mg of methyl 2-{2-[4-(3-cyanophenoxy)phenyl]ethyl}-5- phenylpentanoate (colourless oil, yield: 43%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.28-6.91 (m, 11 H), 6.78 (dd, J = 8.2 Hz, 1.3 Hz, 2H), 3.54 (s, 3H), 2.40 (m, 4H), 2.28 (m, 1 H), 1.78 (m, 1 H), 1.69-1.28 (m, 5H).

b) 2-{2-[4-(3-cyanophenoxy)phenyl]ethyl}-5-phenylpentanoic acid. The compound was synthesized from methyl 2-{2-[4-(3-cyanophenoxy) phenyl]ethyl}-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (30→40% EtOAc/hexanes) to furnish a colourless oil (yield: 50%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.59 (m, 1 H), 7.48-6.97 (m, 10H), 6.86 (d, J = 8.5 Hz, 2H), 2.53 (m, 4H), 2.37 (m, 1 H), 1.91 (m, 1 H), 1.78-1.41 (m, 5H). El MS: m/z = 398 (M-1 ), 400 (M+1 ).

Example 63: 2-{2-[4-(4-cvanophenoxy)phenvπethyl)-5-phenylpentanoic acid

a) Methyl 2-{2-[4-(4-cyanophenoxy)phenyl]ethyl}-5-phenylpentanoate K ₂ CO ₃ (100 mg, 0.723 mmol) was added to a solution of methyl 2-[2-(4- hydroxyphenyl)ethyl]-5-phenylpentanoate (100 mg, 0.320 mmol) and 4- fluorobenzonitrile (100 mg, 0.825 mmol) in DMF (15 ml_). The reaction mixture was warmed up to 130 ⁰ C, and allowed to react for 2 h. It was poured into H ₂ O (120 ml_) and extracted with Et ₂ O (100 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO ₂ (5→15% EtOAc/hexanes), to give 133 mg of methyl 2-{2-[4-(4-cyanophenoxy)phenyl]ethyl}-5- phenylpentanoate (colourless oil, yield: 99%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.66 (m, 2H), 7.41 -7.20 (m, 7H), 7.06 (m, 4H), 3.79 (s, 3H), 2.67 (m, 4H), 2.50 (m, 1 H), 2.05 (m, 1 H), 1.97-1.60 (m, 5H).

b) 2-{2-[4-(4-cyanophenoxy)phenyl]ethyl}-5-phenylpentanoic acid. The compound was synthesized from methyl 2-{2-[4-(4-cyanophenoxy) phenyl]ethyl}-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (5→40% EtOAc/hexanes) to furnish a colourless oil (yield: 54%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.48 (m, 2H), 7.23-6.99 (m, 7H), 6.88 (m, 4H), 2.55 (m, 4H), 2.36 (m, 1 H), 1.91 (m, 1 H), 1.77-1.43 (m, 5H). El MS: m/z = 398 (M-1 ), 400 (M+1 ).

Example 64: 2-{2-[4-(4-Fluorophenoxy)phenvπethyl)-5-phenylpentanoic acid

Cu(OAc) ₂ (150 mg, 0.825 mmol) was added to a solution of methyl 2-[2-(4- hydroxyphenyl)ethyl]-5-phenylpentanoate (100 mg, 0.320 mmol), pyridine (0.15 ml_, 1.854 mmol) and 4-fluorophenylboronic acid (90 mg, 0.643 mmol) in CH ₂ CI ₂ (25 ml_). The reaction mixture was stirred at r.t. for 20 h. It was poured into H ₂ O (150 ml_), taken up to pH= 2 and extracted with CH ₂ CI ₂ (100 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO ₂ (2→8% EtOAc/hexanes), to give 122 mg of methyl 2-{2-[4-(4-fluoro phenoxy)phenyl]ethyl}-5-phenylpentanoate (colourless oil, yield: 94%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.39 (m, 2H), 7.34-7.20 (m, 5H), 7.18-6.95 (m, 6H), 3.82 (s, 3H), 2.69 (m, 4H), 2.55 (m, 1 H), 2.08 (m, 1 H), 1.94-1.58 (m, 5H).

b) 2-{2-[4-(4-Fluorophenoxy)phenyl]ethyl}-5-phenylpentanoic acid. The compound was synthesized from methyl 2-{2-[4-(4-fluorophenoxy) phenyl]ethyl}-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (10→80% EtOAc/hexanes) to furnish a colourless oil (yield: 62%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.25 (m, 2H), 7.21 -7.07 (m, 5H), 7.01 -6.83 (m, 6H), 2.60 (m, 4H), 2.40 (m, 1 H), 1.96 (m, 1 H), 1.84-1.47 (m, 5H). El MS: m/z = 391 (M-1 ).

Example 65: 2-{2-[4-Phenoxyphenyl1ethyl)-5-phenylpentanoic acid

a) Methyl 2-{2-[4-phenoxyphenyl]ethyl}-5-phenylpentanoate Cu(OAc) ₂ (232 mg, 1.28 mmol) was added to a solution of methyl 2-[2-(4- hydroxyphenyl)ethyl]-5-phenylpentanoate (160 mg, 0.512 mmol), pyridine (0.21 ml_, 2.56 mmol) and phenylboronic acid (123 mg, 1.02 mmol) in CH ₂ CI ₂ (25 ml_). The reaction mixture was stirred at r.t. for 20 h. It was poured into H ₂ O (150 ml_), taken up to pH= 2 and extracted with CH ₂ CI ₂ (2x20 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO ₂ (0→8% EtOAc/hexanes), to give 119 mg of methyl 2-{2-[4-phenoxyphenyl]ethyl}-5- phenylpentanoate (colourless oil, yield: 60%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.30 (m, 5H), 7.15 (m, 5H), 6.98 (m, 4H), 3.70 (s, 3H), 2.57 (m, 4H), 2.46 (m, 1 H), 1.96 (m, 1 H), 1.83-1.48 (m, 5H).

b) 2-{2-[4-Phenoxyphenyl]ethyl}-5-phenylpentanoic acid.

The compound was synthesized from methyl 2-{2-[4-phenoxyphenyl]ethyl}-5- phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (10→80% EtOAc/hexanes) to furnish a colourless oil (yield: 12%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.40-6.90 (m, 14H), 2.63 (m, 4H), 2.48 (m, 1 H), 2.01 (m, 1 H), 1.87-1.50 (m, 5H). El MS: m/z = 373 (M-1 ).

Example 66: 2-{2-[4-(4-Trifluoromethylphenoxy)phenvnethyl)-5-phenyl pentanoic acid

a) Methyl 2-{2-[4-(4-trifluoronnethylphenoxy)phenyl]ethyl}-5-phenylpen tanoate Cu(OAc) ₂ (232 mg, 1.28 mmol) was added to a solution of methyl 2-[2-(4- hydroxyphenyl)ethyl]-5-phenylpentanoate (160 mg, 0.512 mmol), pyridine (0.21 ml_, 2.56 mmol) and 4-(trifluoromethyl)phenylboronic acid (193 mg, 1.02 mmol) in CH ₂ CI ₂ (25 ml_). The reaction mixture was stirred at r.t. for 20 h. It was poured into H ₂ O (150 ml_), taken up to pH= 2 and extracted with CH ₂ CI ₂ (2x20 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO ₂ (0→8% EtOAc/hexanes), to give 200 mg of methyl 2-{2-[4-(4- trifluoromethylphenoxy)phenyl]ethyl}-5-phenylpentanoate (colourless oil, yield: 60%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm:7.56 (m, 2H), 7.37-6.84 (m, 11 H), 3.71 (s, 3H), 2.66-2.35 (m, 5H), 1.95 (m, 1 H), 1.83-1.42 (m, 5H).

b) 2-{2-[4-(4-Trifluoromethylphenoxy)phenyl]ethyl}-5-phenylpent anoic acid. The compound was synthesized from methyl 2-{2-[4-(4-trifluoromethyl phenoxy)phenyl]ethyl}-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (10→80% EtOAc/hexanes) to furnish a colourless oil (yield: 36%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.56 (d, J = 9.0 Hz, 2H), 7.37-7.13 (m, 8H), 7.00 (m, 3H), 2.67 (m, 4H), 2.47 (m, 1 H), 2.00 (m, 1 H), 1.86-1.53 (m, 5H). El MS: m/z = 441 (M-1 ).

Example 67: 2-{2-[4-(4-Methoxyphenoxy)phenvπethyl)-5-phenylpentanoic acid

a) Methyl 2-{2-[4-(4-methoxyphenoxy)phenyl]ethyl}-5-phenylpentanoate Cu(OAc) ₂ (232 mg, 1.28 mmol) was added to a solution of methyl 2-[2-(4- hydroxyphenyl)ethyl]-5-phenylpentanoate (160 mg, 0.512 mmol), pyridine (0.21 ml_, 2.56 mmol) and 4-(methoxy)phenylboronic acid (155 mg, 1.02 mmol) in CH ₂ CI ₂ (25 ml_). The reaction mixture was stirred at r.t. for 20 h. It was poured into H ₂ O (150 ml_), taken up to pH= 2 and extracted with CH ₂ CI ₂ (2x20 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO ₂ (0→8% EtOAc/hexanes), to give 110 mg of methyl 2-{2-[4-(4- methoxyphenoxy)phenyl]ethyl}-5-phenylpentanoate (colourless oil, yield: 52%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.30-6.99 (m, 9H), 6.98-6.75 (m, 4H), 3.77 (s, 3H), 3.66 (s, 3H), 2.57 (m, 4H), 2.38 (m, 1 H), 1.76-1.47 (m, 5H).

b) 2-{2-[4-(4-Methoxyphenoxy)phenyl]ethyl}-5-phenylpentanoic acid The compound was synthesized from methyl 2-{2-[4-(4- methoxyphenoxy)phenyl]ethyl}-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (0→5% EtOAc/hexanes) to furnish a colourless oil (yield: 69%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.40.7.14 (m, 8H), 7.09-6.90 (m, 5H), 3.88 (s, 3H), 2.70 (m, 4H), 2.52 (m, 1 H), 2.03 (m, 1 H), 1.91 -1.56 (m, 5H). El MS: m/z = 403 (M-1 ).

Example 68: 4-Phenyl-2-[(2-phenylethyl)thio1butanoic acid

a) Ethyl 2-hydroxy-4-phenylbutanoate

NaBH ₄ (625 mg, 16.521 mmol) was added to a -18 ⁰ C cooled solution of ethyl 2-oxo-4-phenylbutyrate in EtOH (70 ml_). The reaction mixture was stirred at low temperature for 5 min, poured into H ₂ O (120 ml_), taken up to pH= 2 with HCI and extracted with CH ₂ CI ₂ (200 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO ₂ (5→15% EtOAc/hexanes), to give 2.85 g of ethyl 2-hydroxy-4-phenylbutanoate (colourless oil, yield: 83%).

b) Ethyl 4-phenyl-2-{[(trifluoromethyl)sulfonyl]oxy}butanoate Thfluoromethanesulfonic anhydride (1.70 g, 6.025 mmol) was added to a -78 ⁰ C cooled solution of ethyl 2-hydroxy-4-phenylbutanoate (1.0 g, 4.801 mmol) and 2,6-luitidine (1.7 ml_, 14.642 mmol) in CH ₂ CI ₂ (40 ml_). The reaction mixture was allowed to react at low temperature for 5 min, poured into H ₂ O (150 ml_), taken up to pH= 3 with HCI and extracted with CH ₂ CI ₂ (150 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO ₂ (4→10% EtOAc/hexanes), to give 1.41 g of ethyl 4-phenyl-2-

{[(trifluoromethyl)sulfonyl]oxy}butanoate (colourless oil, yield: 86%). El MS: m/z = 341 (M+1 ).

c) Ethyl 4-phenyl-2-[(2-phenylethyl)thio]butanoate Benzeneethanethiol (0.45 ml_, 3.33 mmol) was added to a solution of ethyl 4- phenyl-2-{[(thfluoromethyl)sulfonyl]oxy}butanoate (750 mg, 2.20 mmol) and DIPEA (1.5 ml_, 8.76 mmol) in CH ₂ CI ₂ (50 ml_). The reaction mixture stirred at r.t. for 2 h, poured into H ₂ O (200 ml_) and extracted with Et ₂ O (100 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO ₂ (0 4% EtOAc/hexanes), to give 635 mg of ethyl 4-phenyl-2-[(2-phenylethyl)thio] butanoate (colourless oil, yield: 88%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.62-7.34 (m, 10H), 4.46 (c, J = 7.1 Hz, 2H), 3.50 (t, J = 7.1 Hz, 1 H), 3.27-2.93 (m, 6H), 2.48 (m, 1 H), 2.24 (m, 1 H), 1.55 (t, J = 7.1 Hz, 3H).

d) 4-Phenyl-2-[(2-phenylethyl)thio]butanoic acid

The compound was synthesized from ethyl 4-phenyl-2-[(2-phenylethyl)thio] butanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (5→40% EtOAc/hexanes) to afford a colourless oil (yield: 56%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.36-7.09 (m, 10H), 3.22 (t, J = 7.4 Hz, 1 H), 2.90 (m, 4H), 3.22 (t, J = 7.6 Hz, 2H), 2.21 (m, 1 H), 1.99 (m, 1 H). El MS: m/z = 299 (M-1 ).

Example 69: 2-(Benzyloxy)-5-phenylpentanoic acid

a) Ethyl 2-oxo-5-phenylpentanoate

A solution of (3-bromopropyl)benzene (2.O g, 10.045 mmol) in Et ₂ O (10 ml_) was dropwise was added to a refluxing suspension of Mg (powder, 240 mg, 9.872 mmol) and 1 ,2-dibromoethane (drops) in Et ₂ O (20 ml_). After 30 min, the mixture was allowed to reach r.t. and transferred to flask containing a 0 ⁰ C cooled a solution of diethyl oxalate (1.185 g, 8.114 mmol) in Et ₂ O (30 ml_). The reaction mixture was stirred at r.t. overnight. It was poured into H ₂ O (100 ml_) and taken up to pH=2 with HCI (10% aqueous solution). The product was extracted with EtOAc (100 ml_), and the organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂ (5→10% EtOAc/hexanes) to furnish 1.6 g of ethyl 2-oxo-5-phenylpentanoate (colourless oil, yield: 89%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.14 (m, 2H), 7.06 (m, 3H), 4.41 -4.24 (m, 2H), 2.85 (t, J = 7.4 Hz, 2H), 2.66 (t, J = 7.4 Hz, 2H), 1.97 (t, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H).

b) Ethyl 2-hydroxy-5-phenylpentanoate

NaBH ₄ (300 mg, 7.932 mmol) was added to 0 ⁰ C cooled a solution of ethyl 2- oxo-5-phenylpentanoate (1.52 g, 6.90 mmol) in EtOH (40 ml_). After 5 min, the reaction mixture was poured into H ₂ O (150 ml_) and taken up to pH=1 with HCI (10% aqueous solution). The product was extracted with CH ₂ CI ₂ (2x120 ml_), and the organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂ (5→20% EtOAc/hexanes) to furnish 843 mg of ethyl 2-hydroxy-5- phenylpentanoate (colourless oil, yield: 55%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.21 (m, 2H), 7.12 (m, 3H), 4.31 -4.14 (m, 3H), 2.80-2.56 (m, 3H), 1.92-1.59 (m, 4H), 1.29 (t, J = 7.1 Hz, 3H).

c) Ethyl 2-(benzyloxy)-5-phenylpentanoate

BnBr (1.1 ml_) was added to a suspension of ethyl 2-hydroxy-5-phenyl pentanoate (830 mg, 3.733 mmol) and Ag ₂ O (1.2O g, 5.178 mmol) in DMF (30 ml_). The reaction mixture was warmed up to 70 ⁰ C and stirred at that temperature for 7 h. It was allowed to reach r.t., filtered through Celite (washing with EtOAc) and washed with H ₂ O (100 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO ₂ (5→15% EtOAc/hexanes) to furnish 680 mg of ethyl 2-(benzyloxy)-5-phenylpentanoate (yellow coloured oil, yield: 58%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.38 (m, 10H), 5.20 (m, 2H), 4.71 (d, J = 11.5 Hz, 1 H), 4.59-4.08 (m, 2H), 2.59 (m, 2H), 1.84-1.6 (m, 4H), 1.28 (m, 3H).

d) 2-(Benzyloxy)-5-phenylpentanoic acid

The compound was prepared from ethyl 2-(benzyloxy)-5-phenylpentanoate following the general procedure B, to furnish the compound as a yellow coloured oil after flash chromatography purification (yield: 10%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.39-7.05 (m, 10H), 4.69 (d, J = 11.5 Hz, 1 H), 4.35 (d, J = 11.5 Hz, 1 H), 3.80 (m, 1 H), 2.56 (m, 2H), 1.36 (m, 4H). El MS: m/z = 283 (M-1 ).

Example 70: Sodium 2-(benzylthio)-5-phenylpentanoate

a) Methyl (benzylthio)acetate

BnBr (3.5 ml_, 29.425 mmol) was added to a suspension of K ₂ CO ₃ (5.10 g, 36.90 mmol) and methyl mercaptoacetate (2 ml_, 22.366 mmol) in CH ₃ CN (50 ml_). The reaction mixture was stirred at r.t. for 10 min, poured into H ₂ O (150 ml_), and extracted with EtOAc (100 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated, and the crude residue was flash chromatographed on SiO ₂ (0→4% EtOAc/hexanes) to furnish 4.14 g of methyl (benzylthio)acetate (colourless oil, yield: 94%).

b) Methyl 2-(benzylthio)-5-phenylpentanoate

The compound was prepared from methyl (benzylthio)acetate following the general procedure A, by using PhCH ₂ CH ₂ CH ₂ I as alkylating reagent. Flash chromatography purification afforded the compound as a colourless oil (yield:

77%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.06 (n, 10H), 3.64 (s, 2H), 3.54 (s, 3H),

2.36 (t, J = 7.1 Hz, 2H), 1.70 (m, 1 H), 1.48 (m, 4H).

c) 2-(Benzylthio)-5-phenylpentanoic acid

The compound was prepared from methyl 2-(benzylthio)-5-phenylpentanoate following the general procedure B, to furnish the compound as a colourless oil after flash chromatography purification (yield: 11 %). El MS: m/z = 299 (M-1 ).

d) Sodium 2-(benzylthio)-5-phenylpentanoate

NaH (16 mg, 60%mineral oil suspension, 0.40 mmol) was added to a solution of 2-(benzylthio)-5-phenylpentanoic acid (123 mg, 0.409 mmol) in THF (10 ml_). The reaction mixture was stirred at r.t. for 15 min, and solvent was

concentrated off. The crude residue was slurred with Et ₂ O (5 ml_) and hexanes (5 ml_), to give 84 mg of sodium 2-(benzylthio)-5-phenylpentanoate (white solid, yield: 64%).

¹ H NMR (MeOD, 250 MHz) δ ppm: 7.33 (m, 3H), 7.22 (m, 4H), 7.14 (m, 3H), 3.76 (m, 2H), 3.20 (m, 1 H), 2.55 (t, J = 7.4 Hz, 2H), 1.86-1.55 (m, 4H). El MS: m/z = 299 (M-Na-I ).

Example 71 : 2-(Benzylthio)-3-phenylpropanoic acid

a) Methyl 2-(benzylthio)-3-phenylpropanoate

The compound was prepared from methyl (benzylthio)acetate following the general procedure A, by using BnBr as alkylating reagent. Flash chromatography purification on SiO ₂ (0→10% EtOAc/hexanes) afforded methyl 2-(benzylthio)-3-phenylpropanoate as a colourless oil (yield: 95%). ¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.28 (m, 10H), 3.77 (s, 2H), 3.61 (s, 3H), 3.41 (m, 1 H), 3.14 (m, 1 H), 2.86 (m, 1 H).

b) 2-(Benzylthio)-3-phenylpropanoic acid

The compound was prepared from methyl 2-(benzylthio)-3-phenylpropanoate following the general procedure B. Flash chromatography purification on SiO ₂

(5→20% EtOAc/hexanes), followed by slurries with hexanes, afforded 2-

(benzylthio)-3-phenylpropanoic acid as a white solid (yield: 5%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.23 (m, 8H), 7.05 (m, 2H), 3.82 (m, 2H),

3.37 (t, J = 8.5 Hz, 1 H), 3.16 (m, 1 H), 2.85 (m, 1 H).

El MS: m/z = 271 (M-1 ).

Example 72: 2-[2-(1 ,1 '-Biphenyl-4-yl)ethvπ-5-phenylpentanoic acid

a) Methyl 2-[2-(1 ,1 '-biphenyl-4-yl)ethyl]-5-phenylpentanoate. (Method F: Suzuki coupling).

Pd(PPh3)4 (65 mg, 0.056 mmol) was added to a suspension of methyl 2-{2- (4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)ethyl}-5-phenylpen tanoate (Intermediate A) (210 mg, 0.559 mmol), Cs ₂ CO ₃ (375 mg, 1.150 mmol) and phenylboronic acid (110 mg, 0.902 mmol) in DMF (14 ml_). The reaction mixture was stirred at 90 ⁰ C until no unreacted Intermediate A was detected by TLC analysis (5 h). It was allowed to reach r.t., poured into H ₂ O (100 ml_) and extracted with Et ₂ O (100 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO ₂ (0->4% EtOAc/hexanes), to afford 54 mg of methyl 2-[2-(1 ,1 '-biphenyl-4-yl)ethyl]-5-phenylpentanoate (colourless oil, yield: 26%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.56 (m, 3H), 7.43 (m, 2H), 7.36-7.12 (m, 9H), 3.71 (s, 3H), 2.60 (m, 4H), 2.45 (m, 1 H), 2.00 (m, 1 H), 1.88-1.46 (m, 5H).

b) 2-[2-(1 ,1 '-Biphenyl-4-yl)ethyl]-5-phenylpentanoic acid

The compound was synthesized from methyl 2-[2-(1 ,1 '-biphenyl-4-yl)ethyl]-5- phenylpentanoate following the experimental procedure detailed in Method B.

It was purified by flash chromatography on SiO ₂ (10→30% EtOAc/hexanes) to furnish a white solid (yield: 44%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.54-7.01 (m, 14H), 2.55 (m, 4H), 2.38 (m,

1 H), 1.91 (m, 1 H), 1.78-1.38 (m, 5H).

El MS: m/z = 357 (M-1 ).

Example 73: 2-{2-[4'-(2-Furyl)phenvπethyl)-5-phenylpentanoic acid

a) Methyl 2-{2-[4'-(2-furyl)phenyl]ethyl}-5-phenylpentanoate

The compound was synthesized from Intermediate A and furan-2-boronic acid, following the experimental procedure detailed in Method F. It was purified by flash chromatography on SiO ₂ (5→10% EtOAc/hexanes) to give a colourless oil (yield: 47%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.69 (d, J = 7.9 Hz, 2H), 7.56 (m, 1 H), 7.37 (m, 2H), 7.27 (m, 5H), 6.71 (d, J = 3.2 Hz, 1 H), 6.56 (m, 1 H), 3.83- 3.76 (m, 3H), 2.76-2.62 (m, 4H), 2.53 (m, 1 H), 2.07 (m, 1 H), 1.92-1.60 (m, 5H).

b) 2-{2-[4'-(2-Furyl)phenyl]ethyl}-5-phenylpentanoic acid

The compound was synthesized from methyl 2-{2-[4'-(2-furyl)phenyl]ethyl}-5- phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (20→100% EtOAc/hexanes) to give a white solid (yield: 75%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.68 (d, J = 7.9 Hz, 2H), 7.53 (m, 1 H), 7.44-7.20 (m, 7H), 6.69 (d, J = 3.2 Hz, 1 H), 6.55 (m, 1 H), 2.71 (m, 4H), 2.53 (m, 1 H), 2.09 (m, 1 H), 1.98-1.58 (m, 5H). El MS: m/z = 347 (M-1 ).

Example 74: 2-{2-[4'-(3-Furyl)phenvπethyl)-5-phenylpentanoic acid

a) Methyl 2-{2-[4'-(3-furyl)phenyl]ethyl}-5-phenylpentanoate The compound was synthesized from Intermediate A and furan-3-boronic acid, following the experimental procedure detailed in Method F. It was purified by flash chromatography on SiO ₂ (5% EtOAc/hexanes) to give a colourless oil (yield: 27%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.79 (s, 1 H), 7.51 (m, 2H), 7.31 (m, 8H), 6.77 (s, 1 H), 3.78 (s, 3H), 2.67 (m, 4H), 2.52 (m, 1 H), 2.05 (m, 1 H), 1.88-1.60 (m, 5H).

b) 2-{2-[4'-(3-Furyl)phenyl]ethyl}-5-phenylpentanoic acid

The compound was synthesized from methyl 2-{2-[4'-(3-furyl)phenyl]ethyl}-5- phenylpentanoate following the experimental procedure detailed in Method B.

It was purified by flash chromatography on SiO ₂ (20→100% EtOAc/hexanes) to furnish an off-white solid (yield: 75%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.51 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 6.8

Hz, 2H), 7.32-7.11 (m, 8H), 2.61 (m, 4H), 2.45 (m, 1 H), 1.99 (m, 1 H), 1.86-

1.50 (m, 5H).

El MS: m/z = 349 (M+1 ).

Example 75: 2-{2-[4'-(3-Thienyl)phenyl1ethyl)-5-phenylpentanoic acid

a) Methyl 2-{2-[4'-(3-thienyl)phenyl]ethyl}-5-phenylpentanoate

The compound was synthesized from Intermediate A and 3-thiopheneboronic acid, following the experimental procedure detailed in Method F. It was purified by flash chromatography on SiO ₂ (5→10% EtOAc/hexanes) to afford a colourless oil (yield: 43%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.40 (d, J = 8.2 Hz, 2H), 7.31 -7.21 (m, 2H), 7.18-6.99 (m, 8H), 3.57 (s, 3H), 2.54- 2.41 (m, 4H), 2.32 (m, 1 H), 1.83 (m, 1 H), 1.64-1.42 (m, 5H).

b) 2-{2-[4'-(3-Thienyl)phenyl]ethyl}-5-phenylpentanoic acid The compound was synthesized from methyl 2-{2-[4'-(3-thienyl)phenyl]ethyl}- 5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (15→50% EtOAc/hexanes) to give an off-white solid (yield: 80%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.51 (d, J = 8.2 Hz, 2H), 7.44-7.35 (m, 2H), 7.31 -7.12 (m, 8H), 2.62 (m, 4H), 2.46 (m, 1 H), 2.00 (m, 1 H), 1.86-1.53 (m, 5H).

El MS: m/z = 363 (M-1 ).

Example 76: 2-{2-[(4'-Pvndinyl)phenyl-4-vHethyl)-5-phenylpentanoic acid hydrochloride

a) Methyl 2-{2-[(4'-pyridinyl)phenyl-4-yl]ethyl}-5-phenylpentanoate

The compound was synthesized from Intermediate A and 4-pyridineboronic acid, following the experimental procedure detailed in Method F. It was purified by flash chromatography on SiO ₂ (20→40% EtOAc/hexanes) to give a yellow-coloured oil (yield: 52%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 8.64 (m, 2H), 7.52 (m, 5H), 7.28 (m, 4H), 7.16 (m, 2H), 3.70 (s, 3H), 2.59 (m, 4H), 2.45 (m, 1 H), 1.97-1.45 (m, 6H).

b) 2-{2-[(4'-Pyridinyl)phenyl-4-yl]ethyl}-5-phenylpentanoic acid The compound was synthesized from methyl 2-{2-[(4'-pyridinyl)phenyl-4- yl]ethyl}-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (0→10% MeOH/CH ₂ CI ₂ ) to give a colourless oil (yield: 98%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.99 (bs, 1 H), 7.83 (bs, 1 H), 7.70 (d, J = 7.9 Hz, 1 H), 7.54-7.42 (m, 3H), 7.39-7.21 (m, 4H), 7.14 (d, J = 7.9 Hz, 2H), 7.08-7.01 (m, 1 H), 2.93-2.54 (m, 4H), 2.50 (m, 1 H), 2.00 (m, 1 H), 1.87-1.62 (m, 5H).

c) 2-{2-[(4'-Pyridinyl)phenyl-4-yl]ethyl}-5-phenylpentanoic acid hydrochloride

A suspension of 2-{2-[(4'-Pyridinyl)phenyl-4-yl]ethyl}-5-phenylpentanoic acid (0.267 mmol) in HCI-MeOH (0.5 ml_, 1 M solution, 0.5 mmol) was stirred at r.t. for 1 h. Solvent was concentrated off, and the crude residue was precipitated from a mixture of MeOH (2 ml_) and Et ₂ O (15 ml_), to give 40 mg of a white solid (yield: 38%).

¹ H NMR (MeOD, 250 MHz) δ ppm: 8.71 (m, 2H), 8.74 (bs, 2H), 7.83 (m, 2H), 7.36 (bs, 2H), 7.11 (m, 2H), 7.05 (m, 3H), 2.60 (m, 2H), 2.49 (m, 2H), 2.27 (m, 1 H), 1.85 (m, 1 H), 1.69 (m, 1 H), 1.50 (m, 4H). El MS: m/z = 360 (M-Cl ^" ).

Example 77: 2-[2-(4-Pvndin-3'-ylphenyl)ethvH-5-phenylpentanoic acid

a) Methyl 2-[2-(4-pyridin-3'-ylphenyl)ethyl]-5-phenylpentanoate The compound was synthesized from Intermediate A and 3-pyridineboronic acid following the experimental procedure detailed in Method F. It was purified by flash chromatography on SiO ₂ (10→40% EtOAc/hexanes) to give a yellow-coloured oil (yield: 49%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 8.83 (m, 1 H), 8.57 (m, 1 H), 7.50 (d, J = 7.9 Hz, 2H), 7.35 (m, 1 H), 7.31 -7.23 (m, 4H), 7.16 (m, 3H), 3.69 (s, 3H), 2.60 (m, 4H), 2.45 (m, 1 H), 1.99 (m, 1 H), 1.84-1.52 (m, 5H).

b) 2-[2-(4-Pyridin-3'-ylphenyl)ethyl]-5-phenylpentanoic acid

The compound was synthesized from methyl 2-[2-(4-pyridin-3'-ylphenyl)ethyl]- 5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (10→60% EtOAc/hexanes) to give a colourless oil (yield: 38%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 8.86 (bs, 1 H), 8.58 (m, 1 H), 7.89 (d, J = 10.1 Hz, 1 H), 7.56-7.07 (m, 10H), 2.65 (m, 4H), 2.47 (m, 1 H), 2.03 (m, 1 H), 1.90-1.47 (m, 5H).

El MS: m/z = 360 (M+1 ).

Example 78: 5-Phenyl-2-[2-(4'-thien-2-ylphenyl)ethvHpentanoic acid

a) Methyl 2-{2-[4'-(2-thienyl)phenyl]ethyl}-5-phenylpentanoate The compound was synthesized from Intermediate A and 2-thiopheneboronic acid, following the experimental procedure detailed in Method F. It was purified by flash chromatography on SiO ₂ (2→4% EtOAc/hexanes) to give a colourless oil (yield: 56%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.53 (d, J = 7.4 Hz, 2H), 7.32-7.22 (m, 4H), 7.21 -7.04 (m, 6H), 3.68 (s, 3H), 2.58 (m, 4H), 2.41 (m, 1 H), 1.95 (m, 1 H), 1.83-1.46 (m, 5H).

b) 5-Phenyl-2-[2-(4'-thien-2-ylphenyl)ethyl]pentanoic acid

The compound was synthesized from methyl 2-{2-[4'-(2-thienyl)phenyl]ethyl}- 5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (10→60% EtOAc/hexanes) to afford a white solid (yield: 38%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.54 (d, J = 8.2 Hz, 2H), 7.33-7.13 (m, 9H), 7.06 (m, 1 H), 2.63 (m, 4H), 2.45 (m, 1 H), 2.00 (m, 1 H), 1.86-1.49 (m, 5H). El MS: m/z = 363 (M-1 ).

Example 79: 5-(1 -Naphthyl)-2-[2-(4'-thien-2-ylphenyl)ethvπ-pentanoic acid

a) Methyl 5-(1 -naphthyl)-2-[2-(4'-thien-2-ylphenyl)ethyl]-pentanoate

The compound was synthesized from Intermediate B and 2-thiopheneboronic acid, following the experimental procedure detailed in Method F. It was purified by flash chromatography on SiO ₂ (10→20% EtOAc/hexanes) to afford a yellow-coloured oil (yield: 78%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.99 (m, 1 H), 7.83 (m, 1 H), 7.70 (d, J = 7.9 Hz, 1 H), 7.54-7.42 (m, 3H), 7.39-7.21 (m, 5H), 7.14 (d, J =7.9 Hz, 2H), 7.08- 7.01 (m, 1 H), 3.67 (s, 3H), 3.07 (m, 2H), 2..60 (m, 2H), 2.40 (m, 1 H), 1.95 (m, 1 H), 1.86-1.62 (m, 5H).

b) 5-(1 -Naphthyl)-2-[2-(4'-thien-2-ylphenyl)ethyl]-pentanoic acid

The compound was synthesized from methyl 5-(1 -naphthyl)-2-[2-(4'-thien-2- ylphenyl)ethyl]-pentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (10→30% EtOAc/hexanes) to give a white solid (yield: 20%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.99 (m, 1 H), 7.83 (m, 1 H), 7.70 (d, J = 7.9 Hz, 1 H), 7.54-7.42 (m, 3H), 7.39-7.21 (m, 5H), 7.14 (d, J =7.9 Hz, 2H), 7.08- 7.01 (m, 1 H), 3.07 (m, 2H), 2.63 (m, 2H), 2.47 (m, 1 H), 1.95 (m, 1 H), 1.87- 1.62 (m, 5H).

Example 80: 5-(1 -Naphthyl)-2-[2-(4'-pyridin-3-ylphenyl)ethvπ-pentanoic acid

a) Methyl 5-(1 -naphthyl)-2-[2-(4'-pyridin-3-ylphenyl)ethyl]-pentanoate The compound was synthesized from Intermediate B and 3-pyridineboronic acid, following the experimental procedure detailed in Method F. It was purified by flash chromatography on SiO ₂ (20→50% EtOAc/hexanes) to give a colourless oil (yield: 79%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 8.83 (m, 1 H), 8.57 (m, 1 H), 7.99 (m, 1 H), 7.84 (m, 3H), 7.54-7.23 (m, 9H), 3.68 (s, 3H), 3.07 (m, 2H), 2.80-2.20 (m, 4H), 2.00-1.67 (m, 5H).

b) 5-(1 -Naphthyl)-2-[2-(4'-pyridin-3-ylphenyl)ethyl]-pentanoic acid

The compound was synthesized from methyl 5-(1 -naphthyl)-2-[2-(4'-pyridin-3- ylphenyl)ethyl]-pentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (0→30% MeOH/EtOAc) to give a colourless oil (yield: 48%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 8.66 (s, 1 H), 8.38 (d, J = 4.9 Hz, 1 H), 7.94 (m, 2H), 7.74 (d, J = 7.1 Hz, 1 H), 7.60 (d, J = 7.9 Hz, 1 H), 7.48-7.32 (m, 5H), 7.28-7.13 (m, 4H), 2.97 (m, 2H), 2.54 (m, 2H), 2.33 (m, 1 H), 1.86 (m, 1 H), 1.72-1.56 (m, 5H). El MS: m/z = 410 (M+1 ).

Example 81 : 2-[2-(4-Anilinophenyl)ethvH-5-phenylpentanoic acid

a) Methyl 2-[2-(4-anilinophenyl)ethyl]-5-phenylpentanoate Cu(OAc) ₂ (150 mg, 0.825 mmol) was added to a solution of methyl 2-[2-(4- aminophenyl)ethyl]-5-phenylpentanoate (100 mg, 0.320 mmol), pyridine (0.13 ml_, 1.60 mmol) and phenylboronic acid (58 mg, 0.475 mmol) in CH ₂ CI ₂ (20 ml_). The reaction mixture was stirred at r.t. for 14 h. It was poured into H ₂ O (150 ml_), taken up to pH= 6 and extracted with CH ₂ CI ₂ (2x100 ml_). The organic layer was dried over Na ₂ SO ₄ (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO ₂ (0→8% EtOAc/hexanes), to give 60 mg of methyl 2-[2-(4-anilinophenyl)ethyl]-5- phenylpentanoate (colourless oil, yield: 48%). 1H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.36-7.12 (m, 8H), 7.10-6.87 (m, 6H), 5.65 (bs, 1 H), 3.70 (s, 3H), 2.67-2.35 (m, 5H), 1.96 (m, 1 H), 1.82-1.48 (m, 5H).

b) 2-[2-(4-Anilinophenyl)ethyl]-5-phenylpentanoic acid

The compound was synthesized from methyl 2-[2-(4-anilinophenyl)ethyl]-5- phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO ₂ (20→50% EtOAc/hexanes) to furnish a colourless oil (yield: 17%).

¹ H NMR (CDCI ₃ , 250 MHz) δ ppm: 7.33-7.13 (m, 8H), 7.12-6.85 (m, 6H), 2.61

(m, 4H), 2.44 (m, 1 H), 1.93 (m, 1 H), 1.88-1.48 (m, 5H).

El MS: m/z = 372 (M-1 ), 374 (M+1 ).

Example 82: Anti-proliferative activity

Cell Culture

The human colon cancer cell line HCT116 and the human breast cancer cell line MCF-7 were from the American Type Culture Collection (ATCC; CCL-247 and HTB-22, respectively).

Additionally, the following cancer cell lines were used:

The NP-9 cell line from pancreas, was provided by Dr. R.AIemany from Translational Research Laboratory (Institut Catala d'Oncologia). (cf.,

Cascallό, M. et al., "Ras-dependent Oncolysis with an Adenovirus VAI mutant", Cancer Research, 2003, 63, 5544-5550). This cells was maintained in DMEM:F12 (Invitrogen) supplemented with 10% fetal calf serum (Invitrogen), L-glutamine 10M (Invitrogen), pyruvate 5M (Invitrogen).

The HCT116 cell line was maintained in DMEM GlutaMAX (Invitrogen) supplemented with 10% fetal calf serum and the MCF7 cell line was maintained in RPMM 640 GlutaMAX (Invitrogen) containing 1 mM sodium piruvate and 10% fetal calf serum.

Cells were grown in a humidified incubator at 37 ⁰ C in 5% CO ₂ .

AlamarBlue Assay

Cells were plated in 96-well plates at a density of 6000 cells/well in 100 μl medium 24 h before addition of drugs. They were then added in concentrations from 100 μM to 0.45 nM (each concentration in triplicate). To do so, a drugs-dilution plate at twice the screening concentrations was prepared. 72 hours later, alamarBlue (Biosource, Invitrogen) viability assay was performed following manufacturer's protocol. In brief, alamarBlue diluted in media was added to cells to have a 5% solution. Cells were incubated at 37 ⁰ C, 3 hours and at room temperature, 30 min. Cells with no drug and, cells with no drug and lysed with triton X-100 were used as controls. Fluorescence was monitored at 530 nm excitation and 590 nm emission wavelengths. Results were quantified using Infinite F200 Microplate Reader (Tecan Group, Ltd.). EC50 were calculated as the dose of drugs required to inhibit cell growth by 50%, with Origin 7.0 computer program.

The EC50 values (μM) obtained for the compounds of the present invention on HCT-116 and MCF-7cell lines are summarized in Table 1.

Table 1

(All values in μM)

Carboxylate-based compounds have a great solubility which allows administration at the doses required for achiving an effect in-vivo). Carboxylates such as valproic acid showed similar activities in cell-based assays but are progressing in clinical phases for cancer treatments. Moreover, example 12 showed clear inhibition of the target of these

compounds (i.e. HDACs).

Panel of cell lines (EC50's) (Table 2)

Table 2

(All values in μM)

Blank spaces = non tested

Example 83: HDAC inhibition assay

HDAC inhibtion was determined indirectly by measuring the fluorescence generated by deacetylated fluorogenic substrate (KI-104 fluor de Lys™, Biomol®, used at 125 μM) product reacting with a developer solution (KI-105 Fluor de Lys ™ Biomol®). All assays were carried out in the assay buffer: 50 mM Tris/CI, pH 8.0, 137 mM NaCI, 2.7 mM KCI, 1 mM MgCI ₂ ). Reactions were carried out in a 96-wells microplate (Corning 96 well Flat Bottom Non-binding surface (black) ref. 3651 ).

Potential inhibitors were added after five fold serial dilutions in DMSO. Final DMSO concentration in the assay microplate was kept at 2%.

Afterwards, human recombinant HDAC1 , HDAC 2 or HDAC 8 were added up to 125 nM, 33.3 nM, 25 nM and 1850 nM respectively in assay buffer. When necessary, the mixture was incubated at room temperature prior the addition of substrate.

Finally, substrate was added at 125nM. Total reaction volume of 50 μl. Human recombinant HDACs could be acquired from commercial sources (HDAC1 : ref. #50001 , BPS Bioscience ™; HDAC 2: ref. # 50002, BPS Bioscience ™; HDAC 8: ref. # 50008, BPS Bioscience ™). Inhibitor-protein incubation, reaction time and reaction temperature are reported in the following Table 3:

Table 3

(Table.1 Main parameters of activity assay with histone deacetylase protein)

Reactions were stopped with 50 μl Developer (KI-105 Fluor de Lys ™,BIOMOL®) with 2 μmol/L thchostatin A (TSA, final concentration 1 μmol/L). After 20 minutes at 37 ⁰ C, fluorescence (excitation 360 nm, emission 460 nm) was measured using an Infinite F200 fluorimeter (Tecan). Background was determined in reactions using substrate in the absence of enzyme.

IC ₅₀ values are defined as the compound concentration at which the deacetylase activity is 50% inhibited. In these assays the following grading was used ( I: IC ₅₀ ≤ 10μM; II: 10μM < IC ₅₀ ≤ 100μM; III: 100μM < IC ₅₀ ≤ 1 mM) The results obtained are summarized in Table 4.

(All values in μM).

Compounds where R ₃ is -OR ₄ or -OCR ₄ R ₄ -O-C(O)-R ₄ instead of -OH do not show inhibition of HDACs in inhibition assays because the -OH is required for the binding with the protein. In in-vivo or cell-based conditions the -OR ₄ and -OCR ₄ R ₄ -O-C(O)-R ₄ groups are biotransformed to -OH, thus these groups acts as prodrugs of the carboxylate form.