WO2020245291A1

WO2020245291A1 - Pyrrole derivatives as acc inhibitors

Info

Publication number: WO2020245291A1
Application number: PCT/EP2020/065518
Authority: WO
Inventors: Jordi Bach Taña; Cristina Esteve Trias
Original assignee: Almirall, S.A.
Priority date: 2019-06-06
Filing date: 2020-06-04
Publication date: 2020-12-10

Abstract

Novel pyrrole derivatives of Formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Acetyl-CoA carboxylase (ACC).

Description

PYRROLE DERIVATIVES AS ACC INHIBITORS

FIELD OF THE INVENTION

The present invention relates to novel compounds having ACC inhibitory activity. This invention also relates to pharmaceutical compositions containing them, processes for their preparation and their use in the treatment of several disorders.

BACKGROUND OF THE INVENTION

Acetyl-CoA carboxylase (ACC) is the rate-limiting enzyme in de novo synthesis of fatty acids (Strable MS and Ntambi JM. Crit Rev Biochem Mol Biol. 2010;45: 199-214) and in the translocation of fatty acids to the mitochondria for b-oxidation (Schreurs M et at. Obes Rev. 2010; 11 :380-8). ACC is also key for the elongation of fatty acids including essential fatty acids (Kim CW et al. Cell Metab. 2017;26:394-406). ACC catalyzes the ATP-dependent carboxylation of acetyl-CoA to malonyl-CoA (Barber MC et al. Biochim Biophys Acta. 2005 Mar; 1733: 1-28). In mammals, ACC activity is produced by two isoenzymes, namely ACC1 (also known as ACCa) and ACC2 (also known as Aΰΰb) encoded by two different genes (Acd and Acc2 respectively) (Barber MC et al. Biochim Biophys Acta. 2005 Mar; 1733: 1-28). ACC1 is located in the cytosol and is involved in the synthesis and elongation of fatty acids. ACC2 is located in cytosolic face of the external mitochondrial membrane and is involved in the inhibition of the carnitine palmitolyltransferase I (CPT-I), which is the crucial enzyme for the transport of long-chain fatty acids to mitochondria for b-oxidation (Tong L. Cell Mol Life Sci. 2013; 70: 863-91). The activity of both ACC1 and ACC2 in mammals is stimulated by citrate, inhibited by long chain saturated acyl- CoA and inactivated by phosphorylation, especially by AMP-activated protein kinase (AMPK) and cAMP-dependent protein kinase (PKA) (Brownsey RW et al. Biochem Soc Trans. 2006; 34: 223- 7). ACC activity is also key for the survival of several organisms, some of them related to human pathologies such as bacteria, virus and parasites (Tong L. Cell Mol Life Sci. 2013; 70: 863-91). In several immune cells types, including T cells and macrophages ACC activity is required for the differentiation, survival and production of cytokines such as IL-17 (Buck M. et al. Cell. 2017; 169: 570-86). The crucial role of ACC enzymes in several (patho)physiological processes make them attractive pharmaceutical targets for diseases related to fatty acid metabolism alterations, dermatological diseases such as acne or psoriasis, diabetes, obesity, non-alcoholic steatohepatitis (NASH), cancer, atherosclerosis, inflammation, autoimmunity, infection, and infestation among others (Luo D. et al. Recent Pat Anticancer Drug Discov 2012; 7: 168-84). Indeed, several dermatological diseases are linked to ACC activity, for instance acne is characterized for an increase in sebum production (Pappas A. et al. Dermatoendocrinol. 2009; 1 : 157-61 ; Williams H et. al. Lancet. 2012; 379: 361-72) and both T cells and IL-17 are increased in acne and psoriatic lesions (Agak G. et al. J. Invest. Dermatol. 2014; 134: 366-73; Greb J. et al. Nat Rev Dis Primers. 2016; 2: 1-17). In acne overactivation of the sebaceous glands leading to the increase in sebum production is a well-known feature of this disease. Sebum is formed mainly from lipids such as triglycerides (TAG), free fatty acids, wax esters, squalene, cholesterol and cholesterol esters. Human sebum is formed mainly from lipids derived from fatty acids such as TAGs and wax esters (Pappas A. Dermatoendocrinol. 2009; 1 : 72-6) and it has been shown that in humans most of the sebum is produced from de novo synthesis of fatty acids, process that is dependent of ACC activity (Esler W. P et al. WO2015/036892). Both T cells and IL-17 are increased in acne lesions and Th17 cells depend of ACC-mediated fatty acid synthesis for several functions such as the activity of the Th17 master gene RORyt and the production of pro- inflammatory cytokines such as IL-17 (Stokinger B. and Omenetti S. Nat. Rev. Immunol. 2017; 17: 535-44). Current acne treatments can be classified between topical and systemic. Topical therapies include retinoids such as adapalene, tretinoin and tazarotene, benzoyl peroxide (BPO) and antibiotics. BPO and retinoids induce skin irritation which can compromise both treatment adherence and efficacy. Topical antibiotics have limited efficacy and are associated to antibiotic resistance. The most efficacious systemic treatments are oral isotretinoin and oral antibiotics (Savage L. and Layton A. Expert Rev Clin Pharmacol. 2010; 13: 563-80). Oral isotretinoin treatment is linked to severe side effects including teratogenesis and alteration of blood lipids among others (Layton A. Dermatoendocrinol. 2009; 1 : 162-9) and oral antibiotics can induce antibiotic resistance. Genetic and pharmacological evidences have shown that ACC inhibitors are useful to reduce sebum production and block IL-17 expression. However no ACC inhibitor has been approved for dermatological indications yet and the only ACC inhibitor that has progressed into clinical trials for the treatment of a dermatologic indication (Olumacostat Glasaretil for acne) has been discontinued due to lack of efficacy in a phase III study with acne patients.

In view of the numerous conditions that are contemplated to benefit from treatment involving modulation of the ACC pathway or of the AC carboxylase it is immediately apparent that new compounds that modulate ACC pathways and use of these compounds should provide substantial therapeutic benefits to a wide variety of patients. Provided herein are novel pyrrole derivatives for use in the treatment of conditions in which targeting of the ACC pathway or inhibition of AC carboxylase can be therapeutically useful.

It has now been found that certain pyrrole derivatives are novel and potent ACC inhibitors and can therefore be used in the treatment or prevention of these diseases.

SUM MARY OF THE INVENTION

Thus, the present invention is directed to new compounds that possess ACC inhibitory activity. Accordingly, there is provided a pyrrole derivative, which pyrrole derivative is a compound of Formula (I), or a pharmaceutically acceptable salt, or a solvate, or a /V-oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof:

Formula (I)

wherein:

• R¹ is selected from the group consisting of a hydrogen atom, a linear or branched C1-4 haloalkyl group, a linear or branched Ci-4 hydroxyalkyl group, a -[(CH₂)₂0]i-₂-R^a group and a -(CR^bR^c)-0C(0)0-R⁵ group,

• R² represents a hydrogen atom or a halogen atom,

• R³ is selected from the group consisting of a hydrogen atom, a halogen atom and a

phenyl group,

• R⁴ is selected from the group consisting of a linear or branched C10-17 alkyl group, a

linear or branched C9-17 haloalkyl group, a -(CH₂)_n-L-(CH₂)_m-CH₃ group, a -(CH2)3-9-L- (C3-6 monocyclic cycloalkyl group) and a phenyl ring which is substituted by a linear or branched Ce-io alkyl group,

• n is an integer >2, m is an integer >3 and the addition of n+m results in an integer >10,

• L represents -O- or -S-,

• R⁵ is selected from the group consisting of a linear or branched C1-3 alkyl group and a - [(CH₂)i-2-0]i-₂-R^d group, • R^a, R^b, R^c and R^d are each independently selected from the group consisting of a hydrogen atom and a linear or branched C_1-4 alkyl group, and

characterized in that when R⁴ is a linear C_10-17 alkyl group at least one of R² or R³ is not a hydrogen atom.

The invention further provides synthetic processes and intermediates described herein, which are useful for preparing said pyrrole derivatives.

The invention is also directed to a pyrrole derivative of the invention as described herein for use in the treatment of the human or animal body by therapy.

The invention also provides a pharmaceutical composition comprising the pyrrole derivatives of the invention and a pharmaceutically-acceptable diluent or carrier.

The invention is also directed to the pyrrole derivatives of the invention as described herein, for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Acetyl-CoA carboxylase (ACC), in particular wherein the pathological condition or disease is selected from a dermatological disease, an inflammatory or autoimmune-mediated disease and a metabolism/endocrine function disorder. More in particular wherein the pathological condition or disease is selected from acne vulgaris, acne conglobata, inflammatory acne, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, oily skin, plaque psoriasis, guttate psoriasis, inverse psoriasis, erythrodermic psoriasis, scalp psoriasis, nail psoriasis, postular psoriasis and palmoplantar pustulosis; preferably in the treatment of acne vulgaris, acne conglobata, inflammatory acne, choracne, plaque psoriasis, guttate psoriasis, inverse psoriasis, erythrodermic psoriasis, scalp psoriasis, nail psoriasis and postular psoriasis.

The invention is also directed to use of the pyrrole derivatives of the invention as described herein, in the manufacture of a medicament for treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Acetyl-CoA carboxylase (ACC), in particular wherein the pathological condition or disease is selected from a dermatological disease, an inflammatory or autoimmune-mediated disease and a metabolism/endocrine function disorder. More in particular wherein the pathological condition or disease is selected from acne vulgaris, acne conglobata, inflammatory acne, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, oily skin, plaque psoriasis, guttate psoriasis, inverse psoriasis, erythrodermic psoriasis, scalp psoriasis, nail psoriasis, postular psoriasis and palmoplantar pustulosis; preferably in the treatment of acne vulgaris, acne conglobata, inflammatory acne, choracne, plaque psoriasis, guttate psoriasis, inverse psoriasis, erythrodermic psoriasis, scalp psoriasis, nail psoriasis and postular psoriasis.

The invention also provides a method of treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Acetyl-CoA carboxylase (ACC), in particular wherein the pathological condition or disease is selected from a dermatological disease, an inflammatory or autoimmune-mediated disease and a metabolism/endocrine function disorder. More in particular wherein the pathological condition or disease is selected from acne vulgaris, acne conglobata, inflammatory acne, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, oily skin, plaque psoriasis, guttate psoriasis, inverse psoriasis, erythrodermic psoriasis, scalp psoriasis, nail psoriasis, postular psoriasis and palmoplantar pustulosis; preferably in the treatment of acne vulgaris, acne conglobata, inflammatory acne, choracne, plaque psoriasis, guttate psoriasis, inverse psoriasis, erythrodermic psoriasis, scalp psoriasis, nail psoriasis and postular psoriasis.

The invention also provides a combination product comprising (i) the pyrrole derivatives of the invention as described herein; and (ii) one or more additional active substances.

DETAILED DESCRIPTION OF THE INVENTION

When describing the pyrrole derivatives, compositions, combinations and methods of the invention, the following terms have the following meanings, unless otherwise indicated.

As used herein the term C1-4 alkyl embraces linear or branched radicals having 1 to 4 carbon atoms. Analogously, the term C1-3 alkyl embraces unsubstituted linear or branched radicals having 1 to 3 carbon atoms. Examples of C1-4 alkyl include methyl, ethyl, n-propyl, /.propyl, n-butyl, /-butyl, sec-butyl and f-butyl.

As used herein, the term Ce-io alkyl embraces linear or branched radicals having 6 to 10 carbon atoms. Examples of Ce-io alkyl include n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, 1-ethylbutyl, 4- ethyl-2-methylhexyl and 4-ethyl-3,3-dimethylheptyl. As used herein the term C_10-17 alkyl embraces linear or branched radicals having 10 to 17 carbon atoms. Examples of C_10-17 alkyl include decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, 1-methyltetradecyl, 2,2-dimethyltridecyl, 2-methyltetradecyl, 2,2- dimethyltetradecyl, 2,2-dimethyldodecyl, 3,3-dimethylpentadecyl, 2,2-dimethylpentadecyl, and

3.3-dimethyltridecyl radicals.

As used herein the term C_1-4 haloalkyl is a linear or branched alkyl group, which is substituted by one or more, preferably 1 ,2 or 3 halogen atoms. Examples of haloalkyl groups include CC , CF₃, CHF₂, CH2CF3 and CH₂CHF₂.

As used herein the term C_9-17 haloalkyl is a linear or branched alkyl group, which is substituted by one or more, preferably 1 or 2, halogen atoms. Analogously, the term Ci₂-is embraces linear or branched haloalkyl radicals, which are substituted by one or more, preferable 1 or 2, halogen atoms. Examples of haloalkyl groups include (CH₂)i₃CH₂F, CH₂CHCI₂H₂₅, CH₂CF₂C9Hi9 and CH₂CF₂C₁₂H₁₅.

As used herein, the term Ci-4 hydroxyalkyl embraces linear or branched alkyl radicals having 1 to 4 carbon atoms, any one of which may be substituted with one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl,

2.3-dihydroxypropyl and 1 ,3-dihydroxypropan-2-yl.

As used herein, the term halogen atom embraces fluorine, chlorine, bromine and iodine. A halogen atom is typically a fluorine, chlorine or bromine atom. The term halo when used as a prefix has the same meaning.

As used herein, the term C_3-6 cycloalkyl group embraces saturated monocyclic carbocyclic radicals having from 3 to 6 carbon atoms. Examples of C_3-6 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

As used herein, some of the atoms, radicals, moieties, chains and cycles present in the general structures of the invention are“unsubstituted or substituted”. This means that these atoms, radicals, moieties, chains and cycles can be either unsubstituted or substituted in any position by one or more, for example 1 , 2, 3, or 4, substituents, whereby the hydrogen atoms bound to the unsubstituted atoms, radicals, moieties, chains and cycles are replaces by chemically acceptable atoms, radicals, moieties, chains and cycles. Compounds containing one or more chiral center may be used in enantiomerically or diastereomerically pure form, in the form of a racemic mixtures and in the form of mixtures enriched in one or more stereoisomer. The scope of the invention as described and claimed encompasses the racemic forms of the compounds as well as the individual enantiomers, diastereomers and stereoisomer-enriched mixtures.

Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenethylamine. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art. Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20% and from 0 to 5% of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture. Stereoisomer conglomerates may be separated by conventional techniques known to those skilled in the art. See, e.g.“Stereochemistry of Organic Compounds” by Ernest L. Eliel (Wiley, New York, 1994).

The term "therapeutically effective amount" refers to an amount sufficient to effect treatment when administered to a patient in need of treatment.

The term "treatment" as used herein refers to the treatment of a disease or medical condition in a human patient which includes:

(a) preventing the disease or medical condition from occurring, i.e., prophylactic treatment of a patient;

(b) ameliorating the disease or medical condition, i.e., causing regression of the disease or medical condition in a patient;

(c) suppressing the disease or medical condition, i.e., slowing the development of the disease or medical condition in a patient; or

(d) alleviating the symptoms of the disease or medical condition in a patient. The phrase“pathological condition or disease susceptible to amelioration by inhibiton of ACC" includes all disease states and/or conditions that are acknowledged now, or that are found in the future, to be associated with an increased ACC activity. Such disease states include, but are not limited to, dermatological diseases, inflammatory or autoimmune-mediated diseases and a metabolism/endocrine function disorders.

As used herein, the term“pharmaceutically acceptable salt” refers to a salt prepared from a base or acid which is acceptable for administration to a patient, such as a mammal. Such salts can be derived from pharmaceutically-acceptable inorganic or organic bases and from pharmaceutically- acceptable inorganic or organic acids.

As used herein, a N-oxide is formed from the tertiary basic amines or imines present in the molecule, using a convenient oxidising agent.

The pyrrole derivatives of the invention may exist in both unsolvated and solvated forms. The term solvate is used herein to describe a molecular complex comprising a compound of the invention and an amount of one or more pharmaceutically acceptable solvent molecules. The term hydrate is employed when said solvent is water. Examples of solvate forms include, but are not limited to, compounds of the invention in association with water, acetone, dichloromethane, 2-propanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof.

The invention also includes isotopically-labelled pyrrole derivatives of the invention, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as ²H and ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶CI , fluorine, such as ¹⁸F, iodine, such as ¹²³l and ¹²⁵l, nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ¹⁵0, ¹⁷0 and ¹⁸0, phosphorus, such as ³²P, and sulfur, such as ³⁵S. Preferred isotopically-labelled compounds include deuterated derivatives of the compounds of the invention. As used herein, the term deuterated derivative embraces compounds of the invention where in a particular position at least one hydrogen atom is replaced by deuterium. Deuterium (D or ²H) is a stable isotope of hydrogen which is present at a natural abundance of 0.015 molar %.

Isotopically-labelled pyrrole derivatives of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labelled reagent in place of the non-labelled reagent otherwise employed.

As used in the present invention, the term tautomer means two or more forms or isomers of an organic compound that readily could be interconverted into each other via a common chemical reaction called tautomerization. This reaction commonly results in the formal migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond. The concept of tautomerizations is called tautomerism. Because of the rapid interconversion, tautomers are generally considered to be the same chemical compound. In solutions in which tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH.

Hydrogen deuterium exchange (deuterium incorporation)- is a chemical reaction in which a covalently bonded hydrogen atom is replaced by a deuterium atom. Said exchange (incorporation) reaction can be total or partial.

Prodrugs of the pyrrole derivatives described herein are also within the scope of the invention. Thus certain derivatives of the pyrrole derivatives of the present invention, which derivatives may have little or no pharmacological activity themselves, when administered into or onto the body may be converted into compounds of the present invention having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association).

Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of the present invention with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).

In the case of pyrrole derivatives that are solids, it is understood by those skilled in the art that the inventive compounds and salts may exist in different crystalline or polymorphic forms, or in an amorphous form, all of which are intended to be within the scope of the present invention.

R¹ may be selected from the group consisting of a hydrogen atom, a C2fluoroalkyl group, a linear or branched C3 hydroxyalkyl group , a -[(CH2)20]2-CH2CH3 group and a -(CR^bR^c)-0C(0)0-R⁵ group. Typically, R¹ is selected from the group consisting of a hydrogen atom, a C2 fluoroalkyl group, a -[(CH₂)₂0]₂-CH₂CH₃ group and a -(CR^bR^c)-0C(0)0-R⁵ group.

Preferably, R¹ represents a hydrogen atom.

Typically, R² represents a hydrogen atom or a fluorine atom Preferably, R² represents a hydrogen atom.

Typically, R^a, R^b and R^d each independently represent a methyl group or an ethyl group.

Preferably, R^a and R^d each represent a methyl group or an ethyl and R^b represents a methyl group.

Typically, R^c represents a hydrogen atom or a linear or branched C1-3 alkyl group.

Preferably, R^c represents a hydrogen atom.

Typically, R³ is a hydrogen atom or a fluorine atom.

Preferably, R³ is a hydrogen atom.

R⁴ may be linear or branched C10-17 alkyl group, a linear or branched C12-15 haloalkyl group, a - (CH₂)n-0-(CH₂)m-CH₃ group or a -(CH₂)n-S-(CH₂)m-CH₃ group, for example, R⁴ may be a linear or branched C10-17 alkyl group, a linear or branched C12-15 haloalkyl group or a -(CH₂)n-0-(CH₂)m-CH₃ group.

Typically, R⁴ represents a linear or branched C10-17 alkyl group, a linear or branched C12-15 haloalkyl group or a -(CH₂)n-0-(CH₂)m-CH₃ group.

Preferably, R⁴ represents a linear or branched C10-17 alkyl group.

Typically, n is an integer >2, m is an integer >3 and the addition of n+m results in an integer >10.

Preferably, n is an integer from 2 to 9, m represents an integer from 3 to 11 and the addition of n+m results in an integer from 11 to 14.

Typically, R⁵ represents a linear or branched C1 -3 alkyl group or a [(CH₂)₂0]i-₂-R^d. Preferably, R⁵ represents an isopropyl group, a [(0H₂)₂0]₂0H₃ group and a [(CH₂)₂0]₂CH₂CH₃ group.

Typically, L represents -O- or -S-.

Preferably, L represents a -0-.

In a particular preferred embodiment,

• R¹ is selected from the group consisting of a hydrogen atom, a C2 fluoroalkyl group, a - [(CH₂)₂0]₂-CH₂CH₃ group and a -(CH(CH₃))-0C(0)0-R⁵ group,

• R² is a hydrogen atom or a fluorine atom,

• R³ is selected from the group consisting of a hydrogen atom and a fluorine atom,

• R⁴ is selected from the group consisting of a linear or branched C10-17 alkyl group, a linear or branched C12-15 haloalkyl group and a -(CH₂)n-0-(CH₂)m-CH₃ group,

• R⁵ is selected from the group consisting of a linear or branched C1-3 alkyl group and a [(CH₂)₂C>]i-2-R^d group,

• R^a, R^b and R^d each independently represent a methyl group or an ethyl group,

• R^c represents a hydrogen atom, and

• n is an integer from 2 to 9, m is an integer from 3 to 11 and n+m results in an integer from 11 to 14,

characterized in that when R⁴ is a linear C_10-17 alkyl group, at least one of R² or R³ is not a hydrogen atom.

In another particular preferred embodiment:

• R¹ is selected from the group consisting of a hydrogen atom, a CH2CF3 group, a

-CH₂CH(OH)CH₂OH group, a -[(Ch^ObChhCHs group, a -CH(CH₃)-0C(0)- 0(CH₂)₂0CH₃ group, a -CH(CH₃)-0C(0)-0[(CH2)20]2CH₂CH3 group and a -CH(CH₃)- 0C(0)0CH(CH₃)₂ group.

• R² represents a hydrogen or a fluorine atom,

• R³ represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or a phenyl group,

• R⁴ is selected from the group consisting of a -CH(CH3)-(CH₂)i₂CH3 group, a -(CH₂)- CH(CH₃)-(CH₂)I ICH₃ group, a -(CH₂)-C(CH3)2-(CH₂)9CH3 group, a -(CH₂)-C(CH₃)₂- (CH₂)IOCH₃ group, a -(CH₂)-C(CH3)2-(CH₂)II CH3 group, a -(CH₂)-C(CH3)2-(CH₂)i2CH3 group, a -(CH₂)₂-C(CH₃)₂-(CH₂)₉CH₃ group, a -(CH₂)i3CH₂F group, a - (CH₂)CHF(CH₂)II CH3 group, a -(CH₂)CF2(CH₂)iiCH3 group, a -(CH₂)9-0-(CH₂)3CH₃, a - (CH₂)₉-0-cyclohexyl group, an n-decyl group, a n-tridecyl group, a n-tetradecyl group, a n-pentadecyl group, a -(CH₂)2-0-(CH₂)IO-CH3 group, a -(CH₂)9-0-(CH₂)3-CH3 group, a - (CH₂)2-S-(CH₂)₁₁CH3 group and a phenyl group substituted by a n-decyl group, and

• R⁵ represents a -CH(CH3)2 group, a -(CFh^OCF group or a -[(CH2)2]C>2CH2CH3 group

• characterized in that when R⁴ is a linear C_10-17 alkyl group, at least one of R² or R³ is not a hydrogen atom.

In a more preferred embodiment:

• R¹ represents a hydrogen atom.

• R² represents a hydrogen atom,

• R³ represents a hydrogen atom or a fluorine atom, and

• R⁴ is selected from the group consisting of a -CH(CH₃)-(CH₂)i₂CH₃ group, a -(CH2)- CH(CH₃)-(CH₂)I ICH3 group, a -(CH2)-C(CH₃)2-(CH₂)9CH3 group, a -(CH₂)-C(CH₃)2- (CH₂)IOCH₃ group, a -(CH₂)-C(CH3)2-(CH₂)iiCH3 group, a -(CH2)-C(CH₃)2-(CH₂)i2CH3 group, a -(CH₂)₂-C(CH₃)₂-(CH₂)₉CH₃ group, a n-tridecyl group, a n-tetradecyl group, a n- pentadecyl group,

• characterized in that at least one of R² or R³ is not a hydrogen atom.

Particular individual compounds of the invention include:

1-(2-(Undecyloxy)ethyl)-1 H-pyrrole- 3-carboxyl ic acid;

1-(9-Butoxynonyl)-1 H-pyrrole-3-carboxylic acid;

2,2,2-T rifluoroethyl 1-(9-butoxynonyl)-1 H-pyrrole-3-carboxylate;

2-(2-Ethoxyethoxy)ethyl 1-(9-butoxynonyl)-1 H-pyrrole-3-carboxylate;

1-(9-(Cyclohexyloxy)nonyl)-1 H-pyrrole-3-carboxylic acid;

1-(2-(Dodecylthio)ethyl)-1 H-pyrrole-3-carboxylic acid;

1-(Pentadecan-2-yl)-1 H-pyrrole-3-carboxylic acid;

1-(2-Methyltetradecyl)-1 H-pyrrole-3-carboxylic acid;

1-(2,2-Dimethyldodecyl)-1 H-pyrrole-3-carboxylic acid;

1-(2,2-Dimethyltridecyl)-1 H-pyrrole-3-carboxylic acid;

1-(2,2-Dimethyltetradecyl)-1 H-pyrrole-3-carboxylic acid;

2,2,2-T rifluoroethyl 1-(2,2-dimethyltetradecyl)-1 H-pyrrole-3-carboxylate; 2-(2-Ethoxyethoxy)ethyl 1-(2,2-dimethyltetradecyl)-1 H-pyrrole-3-carboxylate;

2,3-Dihydroxypropyl 1-(2,2-dimethyltetradecyl)-1 H-pyrrole-3-carboxylate;

1-(((2-Methoxyethoxy)carbonyl)oxy)ethyl 1-(2,2-dimethyltetradecyl)-1 H-pyrrole-3-carboxylate; 1-((lsopropoxycarbonyl)oxy)ethyl 1-(2,2-dimethyltetradecyl)-1 H-pyrrole-3-carboxylate;

4-Oxo-3,5,8,11-tetraoxatridecan-2-yl 1-(2,2-dimethyltetradecyl)-1 H-pyrrole-3-carboxylate; 1-(2,2-Dimethylpentadecyl)-1 H-pyrrole-3-carboxylic acid;

1-(3,3-dimethyltridecyl)-1 H-pyrrole- 3-carboxyl ic acid;

1-(3,3-Dimethylpentadecyl)-1 H-pyrrole- 3-carboxylic acid;

1-(14-Fluorotetradecyl)-1 H-pyrrole-3-carboxylic acid;

(R)-1-(2-Fluorotetradecyl)-1 H-pyrrole-3-carboxylic acid;

(S)-1-(2-Fluorotetradecyl)-1 H-pyrrole-3-carboxylic acid;

1-(2,2-difluoroundecyl)-1 H-pyrrole-3-carboxylic acid;

1-(2,2-Difluorotetradecyl)-1 H-pyrrole- 3-carboxylic acid;

4- Phenyl- 1-tetradecyl-1 H-pyrrole-3-carboxylic acid;

1-(4-Decylphenyl)-1 H-pyrrole-3-carboxylic acid;

1-Decyl-4-fluoro-1 H-pyrrole-3-carboxylic acid;

4-Fluoro-1-tridecyl-1 H-pyrrole-3-carboxylic acid;

4-Fluoro-1-tetradecyl-1 H-pyrrole-3-carboxylic acid;

4-Fluoro-1-pentadecyl-1 H-pyrrole- 3-carboxylic acid;

1-(9-Butoxynonyl)-4-fluoro-1 H-pyrrole-3-carboxylic acid;

2-Fluoro-1-tetradecyl-1 H-pyrrole- 3-carboxylic acid;

4-Chloro-1-tetradecyl-1 H-pyrrole-3-carboxylic acid;

4-Bromo-1-tetradecyl-1 H-pyrrole-3-carboxylic acid;

1-(2,2-Dimethyltetradecyl)-4-fluoro-1 H-pyrrole-3-carboxylic acid;

1-(3,3-Dimethylpentadecyl)-4-fluoro-1 H-pyrrole-3-carboxylic acid;

4-Fluoro-1-(2-fluorotetradecyl)-1 H-pyrrole- 3-carboxylic acid;

1-(2,2-Difluorotetradecyl)-4-fluoro-1 H-pyrrole-3-carboxylic acid;

1-(((2-Methoxyethoxy)carbonyl)oxy)ethyl 1-(9-butoxynonyl)-1 H-pyrrole-3-carboxylate;

1-((lsopropoxycarbonyl)oxy)ethyl 1-(9-butoxynonyl)-1 H-pyrrole-3-carboxylate;

4-Oxo-3,5,8,11-tetraoxatridecan-2-yl 1-(9-butoxynonyl)-1 H-pyrrole-3-carboxylate;

2,2,2-T rifluoroethyl 4-fluoro-1-tridecyl-1 H-pyrrole-3-carboxylate;

2-(2-Ethoxyethoxy)ethyl 4-fluoro-1-tridecyl-1 H-pyrrole-3-carboxylate;

1-(((2-Methoxyethoxy)carbonyl)oxy)ethyl 4-fluoro-1-tridecyl-1 H-pyrrole-3-carboxylate;

1-((lsopropoxycarbonyl)oxy)ethyl 4-fluoro-1-tridecyl-1 H-pyrrole-3-carboxylate; and 4-Oxo-3,5,8, 1 1-tetraoxatridecan-2-yl 4-fluoro-1-tridecyl-1 H-pyrrole-3-carboxylate; or a pharmaceutically acceptable salt, or solvate, or N-oxide, or stereoisomer, or tautomer, or isotopically labelled derivative thereof.

Of particular interest are the compounds:

1-(9-Butoxynonyl)-1 H-pyrrole-3-carboxylic acid;

1-(2,2-Dimethyltridecyl)-1 H-pyrrole-3-carboxylic acid;

1-(2,2-Dimethyltetradecyl)-1 H-pyrrole-3-carboxylic acid;

1-(((2-methoxyethoxy)carbonyl)oxy)ethyl 1-(2,2-Dimethyltetradecyl)-1 H-pyrrole-3-carboxylate; 4-Fluoro-1-tridecyl-1 H-pyrrole-3-carboxylic acid; and

1-(2,2-Dimethyltetradecyl)-4-fluoro-1 H-pyrrole-3-carboxylic acid

or a pharmaceutically acceptable salt, or solvate, or N-oxide, or stereoisomer, or tautomer, or isotopically labelled derivative thereof.

GENERAL SYNTHETIC PROCEDURES

The compounds of the invention can be prepared using the methods and procedures described herein, or using similar methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e. , reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

Starting compounds are commercially available or may be obtained following the conventional synthetic methods already known in the art.

Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group, as well as suitable conditions for protection and deprotection, are well known in the art. For example, numerous protecting groups, and their introduction and removal are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.

Processes for preparing compounds of the invention are provided as further embodiments of the invention and are illustrated by the procedures below.

Specific synthetic processes not covered by Schemes 1-6 are described in detail in the experimental section. According to one embodiment of the present invention, compounds of general formula (la) and (lb), subsets of general formula (I), wherein R¹-R⁴ are as defined in the claims, may be prepared by the following synthetic route as illustrated in Scheme 1 :

Scheme 1

Compounds of general formula (lb), a subset of general formula (I) wherein R¹ is other than a hydrogen atom, may be obtained from acids of general formula (la), a subset of general formula (I) wherein R¹ is a hydrogen atom, by reaction with alcohols of formula (V) in the presence of a base such as 4-dimethylaminopyridine and a coupling reagent such as 3-

((ethylimino)methyleneamino)-/\/,/\/-dimethylpropan-1-aminium chloride (EDCI-HCI), in a solvent such as methylene chloride or dimethylsulfoxide at room temperature. Alternatively, compounds of formula (lb) may also be obtained by reaction of acids of formula (la) with haloderivatives of formula (VI), wherein X represents an halogen atom, in the presence of a base such as potassium carbonate or triethylamine, in a solvent such as acetonitrile or A/,/\/-dimethylformamide at temperatures ranging from room temperature to reflux.

Acids of formula (la) may be obtained by treatment of esters of formula (IV), wherein R⁶ represents an alkyl group such as methyl or ethyl group, with a suitable base such as lithium hydroxide, sodium hydroxide or potassium hydroxide, in a solvent such as methanol, ethanol or tetrahydrofuran, with or without the presence of water as co-solvent, at temperatures ranging from room temperature to reflux. Esters of formula (IV) may be prepared by treatment of compounds of formula (II) with a suitable base such as sodium hydride in a solvent such as N,N- dimethylformamide followed by addition of an haloderivative or trifluoromethanesulfonate of formula (III), wherein X represents an halogen atom or a trifluoromethanesulfonate group, at temperatures ranging from 0 °C to room temperature. In the particular case where R⁴ is an aromatic group, esters of formula (IV) may be prepared by reaction of compounds of general formula (II) with bromoaryl derivatives of general formula (III), wherein X is a bromine atom, using a suitable catalyst such as copper(l) iodide, in the presence of a ligand such as L/1 ,L/2- dimethylethane-1 , 2-diamine and a base such as potassium phosphate tribasic, in a solvent such as toluene at 100 °C.

In a particular case, compounds of general formula (lla), a subset of general formula (II) wherein R² is a hydrogen atom and R³ is a fluorine atom, may be prepared by the following synthetic route as illustrated in Scheme 2:

Reaction of 3-fluoro- 1 -(triisopropylsilyl)- 1 H-pyrrole (VII) with 2,2,2-trichloroacetyl chloride in the presence of a Lewis acid such as aluminium(lll) chloride, in a solvent such as methylene chloride at temperatures ranging from 0 °C to room temperature, provides trichloroketone (VIII) which may be converted into fluoroderivatives of formula (I la) by treatment with sodium alcoxides of formula (IX), such as sodium methoxide or sodium ethoxide, in a solvent such as methanol or ethanol at room temperature.

In another particular case, compounds of general formula (lib), a subset of general formula (II) wherein R² is a hydrogen atom and R³ is a chlorine atom, may be prepared by the following synthetic route as illustrated in Scheme 3:

Scheme 3 1-(T riisopropylsilyl)-1 H-pyrrole (X) may be transformed into bromoderivative (XI) by reaction with a brominating reagent such as /V-bromosuccinimide, in a solvent such as tetrahydrofuran at -78 °C. Bromopyrrole (XI) may be converted into chloropyrrole (XII) by treatment with te/f-butyllithium followed by the addition of a chlorinating agent such as perchloroethane, in a solvent such as tetrahydrofuran at -78 °C. Reaction of chloropyrrole (XII) with 2,2,2-trichloroacetyl chloride in the presence of a Lewis acid such as aluminium(lll) chloride, in a solvent such as methylene chloride at temperatures ranging from 0 °C to room temperature, provides trichloroketone (XIII) which may be converted into esters of formula (lib) by treatment with sodium alcoxides of formula (IX), such as sodium methoxide or sodium ethoxide, in a solvent such as methanol or ethanol at room temperature.

In a particular case, compounds of general formula (IVb), a subset of general formula (IV) wherein R² is a fluorine atom and R³ is a hydrogen atom, may be obtained from compounds of general formula (IVa), a subset of general formula (IV) wherein both R² and R³ are hydrogen atoms, by treatment with a fluorinating agent such as Selectfluor^®, in a solvent such as acetonitrile at 70 °C, as illustrated in Scheme 4:

(IVa) (IVb)

Scheme 4

In another particular case, compounds of general formula (IVc), a subset of general formula (IV) wherein R³ is a bromine atom, may be reacted with arylboronic acids of general formula (XIV) under Suzuki-Miyaura reaction conditions (Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457) to give compounds of formula (IVd), wherein R³ is an aromatic group, as illustrated in Scheme 5. Such reactions may be catalyzed by a suitable palladium catalyst such as tetrakis(triphenylphospino)palladium (0), in a mixture of A/,/\/-dimethylformamide and water as solvents, in the presence of a base such as sodium carbonate at 100 °C, with or without the use of microwave irradiation.

(IVc) (IVd)

Scheme 5

In another particular case, compounds of general formula (IVe) and (IVf), wherein R⁴ is a - (CH2)nOR⁷ and -(ChynSR⁷ group respectively, may be prepared by the following synthetic route as illustrated in Scheme 6:

(XX) (IVf)

Scheme 6

Treatment of compounds of formula (II) with a suitable base such as sodium hydride, in a solvent such as A/,/\/-dimethylformamide, followed by addition at room temperature of an haloderivative of formula (XV), wherein X represents an halogen, gives rise to compounds of formula (XVI). Alcohols of formula (XVII) may be obtained by reaction of compounds of formula (XVI) with tetrabutylammonium fluoride in a solvent such as tetrahydrofuran at room temperature. T reatment of alcohols of formula (XVII) with a suitable base such as sodium hydride in a solvent such as A/,/\/-dimethylformamide, followed by addition at room temperature of an haloderivative of formula (XVI II), wherein X represents an halogen, provides compounds of formula (IVe). Alternatively, compounds of formula (IVe) may also be obtained by a different synthetic approach. Reaction of alcohols of formula (XVII) with sulfonyl chlorides of formula (XIX) in the presence of a base such as trimethylamine, in a solvent such as methylene chloride at temperatures ranging from 0 °C to room temperature furnishes sulfonates of formula (XX). Treatment of alcohols of formula (XXI) with a suitable base such as sodium hydride, followed by the addition of sulfonates of formula (XX), in a solvent such as tetrahydrofuran, at temperatures ranging from 0 °C to reflux provides compounds of formula (IVe). Similarly, treatment of thiols of formula (XXII) with a suitable base such as sodium hydride, followed by the addition of sulfonates of formula (XX), in a solvent such as tetrahydrofuran, at temperatures ranging from 0 °C to reflux gives rise to thioethers of formula (IVf).

EXAMPLES

The syntheses of the compounds of the invention are illustrated by the following Examples (1 to 39) including Intermediates (1 to 32) which do not limit the scope of the invention in any way.

General

Reagents, starting materials, and solvents were purchased from commercial suppliers and used as received. Commercial intermediates are referred to in the experimental section by their lUPAC name. Concentration or evaporation refer to evaporation under vacuum using a Buchi rotatory evaporator.

Reaction products were purified, when necessary, by flash chromatography on silica gel (40-63 pm) with the solvent system indicated. Purifications in reverse phase were made in a Biotage Isolera® automated purification system equipped with a C18 column and using a gradient, unless otherwise stated, of water-acetonitrile/MeOH (1 :1) (0.1 % v/v ammonium formate both phases) from 0% to 100% acetonitrile/MeOH (1 : 1) in 40 column volumes. The conditions“formic acid buffer” refer to the use of 0.1 % v/v formic acid in both phases. The appropriate fractions were collected and the solvents evaporated under reduced pressure and/or liofilized.

Purifications in reverse phase were also made in a Biotage SP1® automated purification system equipped with a C18 column and using a gradient of, unless otherwise stated, water- acetonitrile/MeOH (1 : 1) (0.1 % v/v ammonium formate both phases) from 0% to 100% acetonitrile/MeOH (1 : 1) in 80 column volumes. The conditions“formic acid buffer” refer to the use of 0.1 % v/v formic acid in both phases. The appropriate fractions were collected and freeze dried. Preparative HPLC-MS were performed on a Waters instrument equipped with a 2767 injector/collector, a 2525 binary gradient pump, a 2996 PDA detector, a 515 pump as a make-up pump and a ZQ4000 Mass spectrometer detector or on a Agilent 1200 Series coupled to an Agilent 6120 Mass spectrometer detector. Both systems were equipped with a Symmetry Prep C18 (19 x 300 mm, 7 pm) column or a XBridge Prep C18 (19 x 100 mm, 5 pm) column. The mobile phase was formic acid (0.4 ml_), ammonia (0.1 ml_), methanol (500 ml_) and acetonitrile (500 ml_) (B) and formic acid (0.5 ml_), ammonia (0.125 ml_) and water (1000 ml_) (A), the specific gradients used are specified in each particular case. The flow rate was 20 ml/min.

The UPLC chromatographic separations were obtained using a Waters Acquity UPLC system coupled to a SQD mass spectrometer detector. The system was equipped with an ACQUITY UPLC BEH C-18 (2.1x50mm, 1.7 mm) column. The mobile phase was formic acid (0.4 ml), ammonia (0.1 ml), methanol (500 ml) and acetonitrile (500 ml) (B) and formic acid (0.5 ml), ammonia (0.125 ml) and water (1000 ml) (A). A gradient between 0 to 95% of B was used. The run time was 3 or 6 minutes. The injection volume was 0.5 microliter. Chromatograms were processed at 210 nM or 254 nM. Mass spectra of the chromatograms were acquired using positive and negative electrospray ionization.

¹ H Nuclear Magnetic Resonance Spectra were recorded on a Varian Mercury plus operating at a frequency of 400MHz or a Varian VNMRS operating at 600MHz and equipped with a cold probe for the ¹ H spectra. Samples were dissolved in the specified deuterated solvent. Tetramethylsilane was used as reference.

Standard synthetic methods are described the first time they are used. Compounds synthesized with similar methods are referred to only by their starting materials, without full experimental detail. Slight modifications to the general experimental methods used are permitted in these cases. Specific synthetic transformations already described in the literature are referred to only by their bibliographical reference. Other specific methods are also described in full.

Abbreviations:

ACN Acetonitrile

br Broad

CDCIs Deuterated chloroform

CDsOD Deuterated methanol

Celite^® Diatomaceous earth

d Doublet

DAST (Diethylamino)sulfur trifluoride

DCM Dichloromethane, methylene chloride

dd Doublet of doublets

DIEA Diisopropylethyamine

DMAP Dimethylaminopyridine

DMF A/./V-Dimethylformamide

DMSO Dimethylsulfoxide

DMSO-des Deuterated Dimethylsulfoxide

EDC HCI 3-((Ethylimino)methyleneamino)-/\/,/\/-dimethylpropan-1-aminium chloride

EtOAc Ethyl acetate

h Hour

hept Heptuplet

HPLC High-performance liquid chromatography

m Multiplet

min Minutes M Molar

MS Mass spectrometry

NBS /V-Bromosuccinimide

NCS /V-Chlorosuccinimide

NMR Nuclear magnetic resonance q Quartet s Singlet t Triplet td Triple doublet

TEA Triethylamine

TFA Trifluoroacetic acid

THF T etrahydrofuran

INTERMEDIATE 1

Methyl 1 -(2-(undecyloxy)ethyl)-1 H-pyrrole-3-carboxylate a) Methyl 1 -(2-((fert-butyldimethylsilyl)oxy)ethyl)-1 H-pyrrole-3-carboxylate

To a cooled (0 °C) suspension of sodium hydride (60% dispersion in paraffin oil, 53 mg, 1.32 mmol) in DMF (6 ml_) was added methyl 1 H-pyrrole-3-carboxylate (150 mg, 1.20 mmol) and the resulting mixture was stirred at room temperature for 15 min. The solution was cooled to 0 °C and (2-bromoethoxy)(te/f-butyl)dimethylsilane (0.31 ml_, 1.43 mmol) was added. The reaction mixture was stirred at room temperature for 2 h before being partitioned between water and EtOAc. The aqueous layer was separated and washed with EtOAc (x3). The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and the solvent was evaporated to dryness. The residue was purified by flash chromatography (hexanes/diethyl ether) to yield the title compound (290 mg, 85%) as a colourless oil.

MS (m/z): 284 [M+1] ¹ H-NMR d (400 MHz, CDCIs): 0.00 (s, 6H), 0.91 (s, 9H), 3.84 (s, 3H), 3.88 (t, J=5.3 Hz, 2H), 4.01 (t, J=5.3 Hz, 2H), 6.61 (dd, J=2.9, 1.8 Hz, 1 H), 6.66-6.68 (m, 1 H), 7.36 (t, J=1.8 Hz, 1 H). b) Methyl 1-(2-hydroxyethyl)-1H-pyrrole-3-carboxylate

To a solution of methyl 1-(2-((te/Y-butyldimethylsilyl)oxy)ethyl)-1 H-pyrrole-3-carboxylate (Intermediate 1 a, 290 mg, 1.02 mmol) in THF (10 ml_) was added a solution of tetrabutylammonium fluoride (1 M in THF, 1.02 ml_, 1.02 mmol) and the reaction mixture was stirred at room temperature for 2.5 h. The solvent was evaporated to dryness and the residue was purified by flash chromatography (hexanes/EtOAc) to yield the title compound (150 mg, 89%) as a colourless oil.

MS (m/z): 170 [M+1]⁺ ¹ H-NMR d (400 MHz, CDCIs): 1.71 (t, J=5.8 Hz, 1 H), 3.80 (s, 3H), 3.90 (q, J=5.3 Hz, 2H), 4.03 (t, J=5.3 Hz, 2H), 6.60 (dd, J=2.9, 1.8 Hz, 1 H), 6.64-6.67 (m, 1 H), 7.35 (t, J=1.8 Hz, 1 H). c) Methyl 1-(2-(undecyloxy)ethyl)-1H-pyrrole-3-carboxylate

To a cooled (0 °C) solution of methyl 1-(2-hydroxyethyl)-1 H-pyrrole-3-carboxylate (Intermediate 1 b, 45 mg, 0.27 mmol) in anhydrous DMF (1 ml_) was added sodium hydride (60% in mineral oil dispersion, 15.96 mg, 0.39 mmol) and the reaction mixture was stirred at room temperature for 30 min. A solution of 1-bromoundecane (0.06 ml_, 0.28 mmol) in anhydrous DMF (0.5 ml_) was then added dropwise at 0 °C and the resulting mixture was stirred at room temperature for 16 h. Additional sodium hydride (3.19 mg, 0.08 mmol) and 1-bromoundecane (0.01 ml_, 0.07 mmol) were then added in order to complete the reaction. After stirring at room temperature for 3 additional hours, water and toluene were added to the reaction mixture. The phases were separated and the aqueous fraction was further extracted with toluene (x2). The combined organic fractions were washed with brine, dried over magnesium sulfate, filtered and the solvent was evaporated to dryness. The residue was purified by flash chromatography (hexanes/EtOAc) to yield the title compound (32 mg, 37%) as an oil.

MS (m/z): 324 [M+1] ¹ H-NMR d (400 MHz, CDCIs): 0.88 (t, J=7 Hz, 3H), 1.26 (s, 16H), 1.57-1.46 (m, 2H), 3.38 (t, J=7 Hz, 2H), 3.66 (t, J=5 Hz, 2H), 3.79 (s, 3H), 4.02 (t, J=5 Hz, 2H), 6.56 (d, J=4 Hz, 1 H), 6.64 (d, J=5 Hz, 1 H), 7.39-7.29 (m, 1 H).

INTERMEDIATE 2

Methyl 1 -(9-butoxynonyl)-1 H-pyrrole-3-carboxylate a) 1-Bromo-9-butoxynonane

To a cooled (0 °C) suspension of sodium hydride (60% dispersion in paraffin oil, 143 g, 3.57 mmol) in DMF (14 ml_) was added butan-1-ol (0.3 ml_, 3.27 mmol) and the resulting mixture was stirred at 0 °C for 30 min. 1 ,9-Dibromononane (2.66 ml_, 13.28 mmol) was then added and the reaction mixture was stirred at room temperature for 2 h, poured into water and extracted with diethyl ether (x2). The combined organic layers were washed with water and 2N hydrochloric acid solution, dried over magnesium sulfate, filtered and the solvent was evaporated. The residue was purified by flash chromatography (hexanes/diethyl ether) to yield the title compound (730 mg, 40%) as a colourless oil.

¹ H-NMR d (400 MHz, CDCh): 0.92 (t, J=7.4 Hz, 3H), 1.24-1.46 (m, 12H), 1.51-1.61 (m, 4H), 1.79-1.91 (m, 2H), 3.35-3.44 (m, 6H). b) Methyl 1-(9-butoxynonyl)-1 H-pyrrole-3-carboxylate

To a cooled (0 °C) suspension of sodium hydride (60% dispersion in paraffin oil, 105 mg, 2.62 mmol) in DMF (1.5 ml_) was added portionwise methyl 1 H-pyrrole-3-carboxylate (300 mg, 2.40 mmol) and the resulting mixture was stirred at room temperature for 25 min. After cooling to 0 °C, a solution of 1-bromo-9-butoxynonane (Intermediate 2a, 736 mg, 2.63 mmol) in DMF (1 ml_) was added and the resulting solution was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with EtOAc (x2). The combined organic layers were washed with water (x2) and brine, dried over magnesium sulfate, filtered and the solvent was evaporated. The residue was purified by flash chromatography (hexanes/diethyl ether) to yield the title compound (630 mg, 81 %) as a colourless oil.

MS (m/z): 324 [M+1]⁺. ¹ H-NMR d (400 MHz, CDCIs): 0.92 (t, J=7.4 Hz, 3H), 1.23-1.42 (m, 12H), 1.51-1.59 (m, 4H), 1.76 (q, J=7.1 Hz, 2H), 3.39 (td, J=6.7, 5.3 Hz, 4H), 3.79 (s, 3H), 3.85 (t, J=7.1 Hz, 2H), 6.55-6.58 (m, 2H), 7.27 (s, 1 H).

INTERMEDIATE S

Cyclohexyl 1 -(9-(cyclohexyloxy)nonyl)-1 H-pyrrole-3-carboxylate a) ((9-Bromononyl)oxy)(fert-butyl)dimethylsilane

To a cooled (0 °C) solution of 9-bromononan-1-ol (1.0 g, 4.48 mmol), imidazole (458 mg, 6.72 mmol) and DMAP (55 mg, 0.448 mmol) in DCM (20 ml_) was added te/f-butylchlorodimethylsilane (709 mg, 4.71 mmol) and the resulting mixture was stirred at room temperature for 4h. The reaction mixture was partitioned between water and DCM and phases were separated. The organic phase was washed with brine (2x), dried over magnesium sulfate, filtered and the solvent evaporated to yield the title compound (1.5 g, 99%) which was used in the next synthetic step without further purification.

¹ H-NMR d (400 MHz, CDCIs): 0.04 (s, 6H), 0.89 (s, 9H), 1.27-1.35 (m, 8H), 1.37-1.46 (m, 2H), 1.46-1.52 (m, 2H), 1.81-1.88 (m, 2H), 3.40 (t, J= 7 Hz, 2H), 3.59 (t, J = 7 Hz, 2H). b) Methyl 1-(9-((fert-butyldimethylsilyl)oxy)nonyl)-1 H-pyrrole-3-carboxylate

To a cooled (0 °C) suspension of sodium hydride (60% dispersion in paraffin oil, 192 mg, 4 mmol) in DMF (2 ml_) was added methyl 1 H-pyrrole-3-carboxylate (500 mg, 4 mmol) and the resulting mixture was stirred for 30 min at room temperature. ((9-Bromononyl)oxy)(te/f-butyl)dimethylsilane (Intermediate 3a, 1.48 g, 4.4 mmol) was then added and the mixture was stirred for 18 h. The reaction mixture was partitioned between water and diethyl ether and phases were separated. The organic phase was washed with brine (3x), dried over magnesium sulfate, filtered and the solvent was evaporated. Purification of the resulting residue by flash chromatography (Hexanes/EtOAc) gave the title compound (1.09 g, 71 %) as a clear oil.

MS (m/z): 382 [M+1]⁺.

¹ H-NMR 5 (400 MHz, CDCIs): 0.04 (s, 6H), 0.89 (s, 9H), 1.24-1.31 (m, 10H), 1.45-1.53 (m, 2H), 1.71-1.79 (m, 2H), 3.59 (t, J=7 Hz, 2H), 3.79 (s, 3H), 3.85 (t, J=7 Hz, 2H), 6.54-6.58 (m, 2H), 7.27 (t, J=2 Hz, 1 H). c) Methyl 1-(9-hydroxynonyl)-1 H-pyrrole-3-carboxylate

To a solution of methyl 1-(9-((te/f-butyldimethylsilyl)oxy)nonyl)-1 H-pyrrole-3-carboxylate (Intermediate 3b, 1.09 g, 2.84 mmol) in THF (20 ml_) was added tetrabutylammonium fluoride (1 M solution in THF, 2.84 ml_, 2.84 mmol) and the resulting mixture was stirred at room temperature for 3 h. The solvent was evaporated to dryness and the residue was purified by flash chromatography (hexanes/EtOAc) to give the title compound (600 mg, 79%) as a clear oil.

MS (m/z): 268 [M+1]⁺. d) Methyl 1 -(9-((methylsulfonyl)oxy)nonyl)-1 H-pyrrole-3-carboxylate

To a cooled (0 °C) solution of methyl 1-(9-hydroxynonyl)-1 H-pyrrole-3-carboxylate (Intermediate 3c, 600 mg, 2.24 mmol) and TEA (407 mI_, 2.92 mmol) in DCM (10 ml_) was added methanesulfonyl chloride (210 mI_, 2.69 mmol) and the mixture was stirred at room temperature for 18 h. The reaction mixture was partitioned between 1 N hydrochloric acid solution and DCM and the phases were separated. The organic phase was washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried over magnesium sulfate and the solvent was evaporated to dryness. Purification of the residue by flash chromatography (Hexanes/EtOAc) gave the title compound (450 mg, 58%) as a clear oil.

MS (m/z): 346 [M+1]⁺.

¹ H-NMR d (400 MHz, CDCh): 1.22-1.42 (m, 10H), 1.69-1.79 (m, 4H), 2.99 (s, 3H), 3.79 (s, 3H), 3.85 (t, J=7 Hz, 2H), 4.21 (t, J=7 Hz, 2H), 6.54-6.58 (m, 2H), 7.27 (t, J=2 Hz, 1 H). e) Cyclohexyl 1 -(9-(cyclohexyloxy)nonyl)-1 H-pyrrole-3-carboxylate

To a cooled (0 °C) suspension of sodium hydride (60% dispersion in paraffin oil, 36 mg, 0.9 mmol) in THF (1 ml_) was added cyclohexanol (92 mI_, 0.9 mmol) and the mixture was stirred at 0 °C for 30 min. Then, a solution of methyl 1-(9-((methylsulfonyl)oxy)nonyl)-1 H-pyrrole-3-carboxylate (Intermediate 3d, 100 mg, 0.29 mmol) in THF (1 ml_) was added and the mixture was heated at 70 °C overnight. After cooling to room temperature, the reaction mixture was partitioned between saturated aqueous ammonium chloride solution and diethyl ether. Phases were separated and the aqueous phase was further extracted with diethyl ether (x2). The combined organic phases were dried over magnesium sulfate, filtered and solvent was evaporated to dryness. Purification of the residue by flash chromatography (Hexanes/EtOAc) gave the title compound (65 mg, 54%) as a clear oil. MS (m/z): 418 [M+1]⁺.

¹ H-NMR d (400 MHz, CDCIs): 1.18-1.58 (m, 24H), 1.68-1.81 (m, 6H), 1.85-1.94 (m, 4H), 3.15-3.22 (m, 1 H), 3.41 (t, J=7 Hz, 2H), 3.84 (t, J=7 Hz, 2H), 4.95-4.88 (m, 1 H), 6.56 (d, J=2 Hz, 2H), 7.26-7.25 (m, 1 H).

INTERMEDIATE 4

Methyl 1 -(2-(dodecylthio)ethyl)-1 H-pyrrole-3-carboxylate a) Methyl 1 -(2-((methylsulfonyl)oxy)ethyl)-1 H-pyrrole-3-carboxylate

To a cooled (0 °C) solution of methyl 1-(2-hydroxyethyl)-1 H-pyrrole-3-carboxylate (Intermediate 1 b, 150 mg, 0.88 mmol) and TEA (0.16 ml_, 1.15 mmol) in DCM (5 ml_) was added methansulfonyl chloride (83 mI_, 1.07 mmol) and the reaction mixture was stirred at room temperature for 2 h before being partitioned between DCM and saturated aqueous ammonium chloride solution. The organic layer was separated, washed with 4% aqueous sodium hydrogencarbonate solution and brine, dried over magnesium sulfate and the solvent was evaporated to dryness. The resulting residue was purified by flash chromatography (hexanes/diethyl ether) to give the title compound (130 mg, 55%) as a colourless oil.

MS (m/z): 248 [M+1]⁺.

¹ H-NMR d (400 MHz, CDCIs): 2.84 (s, 3H), 3.80 (s, 3H), 4.23 (t, J=5.2 Hz, 2H), 4.43-4.47 (m, 2H), 6.62 (dd, J=2.9, 1.6 Hz, 1 H), 6.65-6.67 (m, 1 H), 7.32-7.35 (m, 1 H).

b) Methyl 1-(2-(dodecylthio)ethyl)-1H-pyrrole-3-carboxylate

Obtained as a colourless oil (82%) from methyl 1-(2-((methylsulfonyl)oxy)ethyl)-1 H-pyrrole-3- carboxylate (Intermediate 4a) and dodecane-1 -thiol following the experimental procedure described in Intermediate 3e followed by purification of the crude product by flash chromatography.

MS (m/z): 354 [M+1]⁺.

¹ H-NMR d (400 MHz, CDCIs): 0.87 (t, J=7.0 Hz, 3H), 1.23-1.37 (m, 18H), 1.48-1.55 (m, 2H), 2.36-2.42 (m, 2H), 2.81-2.87 (m, 2H), 3.80 (s, 3H), 4.06 (t, J=7.0 Hz, 2H), 6.58 (dd, J=2.9, 1.7 Hz, 1 H), 6.62-6.64 (m, 1 H), 7.31-7.34 (m, 1 H). INTERMEDIATE S

Methyl 1-(pentadecan-2-yl)-1H-pyrrole-3-carboxylate a) 2-lodopentadecane

To a cooled (0 °C) solution of pentadecan-2-ol (187 mg, 0.82 mmol), 1 /-/-imidazole (78 mg, 1.15 mmol) and triphenylphosphine (301 mg, 1.15 mmol) in DCM (8 ml_) was added portionwise diiodine (291 mg, 1.15 mmol) and the mixture was stirred at room temperature for 1 h. Hexane was then added and the suspension was filtered through a silica gel pad (10 g). The filtrate was concentrated under reduced pressure to give the title compound (273 mg, 98%) as an oil which was used in the next synthetic step without further purification.

¹ H-NMR d (600 MHz, CDCIs): 0.88 (t, J=7.0 Hz, 3H), 1.24-1.35 (m, 22H), 1.57-1.63 (m, 1 H), 1.80-1.87 (m, 1 H), 1.92 (d, J=6.8 Hz, 3H), 4.16-4.23 (m, 1 H). b) Methyl 1-(pentadecan-2-yl)-1H-pyrrole-3-carboxylate

To a cooled (0 °C) solution of methyl 1 H-pyrrole-3-carboxylate (55 mg, 0.44 mmol) in DMF (1 ml_) was added sodium hydride (60% suspension in paraffin oil, 24 mg, 0.6 mmol) and the reaction mixture was stirred at room temperature for 30 min. 2-lodopentadecane (Intermediate 5a, 273 mg, 0.81 mmol) was added and the reaction mixture was stirred overnight at room temperature, poured into water and extracted with EtOAc (x3). The combined organic layers were washed with water (x3) and brine, dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (hexanes to ethyl acetate) to give the title compound (42 mg, 29%).

MS (m/z): 336 [M+1]⁺.

¹ H-NMR d (600 MHz, CDCIs): 0.87 (t, J=7.1 Hz, 3H), 1.21-1.27 (m, 22H), 1.43 (d, J=6.8 Hz, 3H), 1.66-1.74 (m, 2H), 3.79 (s, 3H), 3.95-4.01 (m, 1 H), 6.56 (dd, J=2.87 and 1.71 Hz, 1 H), 6.61-6.62 (m, 1 H), 7.39 (t, J=1.92 Hz, 1 H).

INTERMEDIATE 6

Methyl 1 -(2-methyltetradecyl)-1 H-pyrrole-3-carboxylate a) Ethyl (£)-2-methyltetradec-2-enoate

To a cooled (0 °C) suspension of sodium hydride (60% in mineral oil dispersion, 130 mg, 3.26 mmol) in THF (10 ml_) was added dropwise ethyl 2-(diethoxyphosphoryl)propanoate (698 mI_, 3.26 mmol) and the mixture was stirred for 1 h at 0 °C. Then, a solution of dodecanal (500 mg, 2.71 mmol) in THF (5 ml_) was added dropwise. The reaction mixture was allowed to slowly warm to room temperature and stirred for additional 16 h. Water (3.75 ml_) was added, the phases were separated and the aqueous layer was extracted with diethyl ether (x2). The combined organic layers were dried over magnesium sulfate, filtered and the solvents were evaporated to give the title compound (622 mg, 85%) which was used in the next synthetic step without further purification. b) Ethyl 2-methyltetradecanoate

To a solution of ethyl (E)-2-methyltetradec-2-enoate (Intermediate 6a, 622 mg, 2.323 mmol) in methanol (1 1 ml_) was added 10% Pd/C (25 mg) and the resulting mixture was stirred under an hydrogen atmosphere for 18 h. The reaction mixture was filtered through a Celite^® pad and the solvent was evaporated to yield the title compound (600 mg, 96%) as a clear oil which was used in the next synthetic step without further purifiication. c) 2-Methyltetradecan-1-ol

To a cooled (0 °C) solution of lithium aluminium hydride (1 M in THF, 2.17 ml_, 2.17 mmol) was added dropwise a solution of ethyl 2-methyltetradecanoate (Intermediate 6b, 588 mg, 2.17 mmol) in THF (8 ml_) and the resulting mixture was stirred at room temperature for 20 h. After cooling to 0 °C, diethyl ether (4.3 ml_), water (0.1 ml_), aqueous 3N sodium hydroxide solution (0.52 ml_) and water (0.52 ml_) were successively added in this order and temperature was allowed to warm to 20 °C. After stirring for 15 minutes, the reaction mixture was filtered through a Celite^® pad and the solids were washed with DCM. The combined filtrates were concentrated under reduced pressure to afford the title compound (430 mg, 87%) as a colourless oil which was used in the next synthetic step without further purification.

¹ H-NMR d (400 MHz, CDCh): 0.88 (t, J=7 Hz, 3H), 0.91 (d, J=7 Hz, 3H), 1.05-1.43 (m, 22H), 1.56-1.65 (m, 1 H), 3.41 (dd, J=10 and 7 Hz, 1 H), 3.51 (dd, J=10 and 6 Hz, 1 H). d) 2-Methyltetradecyl trifluoromethanesulfonate

To a cooled (0 °C) solution of 2-methyltetradecan-1-ol (Intermediate 6c, 100 g, 0.44 mmol) and pyridine (39 mI_, 0.482 mmol) in DCM (5 ml_) was added triflic anhydride (81 mI_, 0.482 mmol) and the mixture was stirred at room temperature for 4 h. The mixture was cooled down to 0° C and water was added. Phases were separated and the aqueous phase was further extracted with DCM. The combined organic phases were dried over magnesium sulfate, filtered and the solvent was evaporated to give the title compound (150 mg, 95%) which was used in the next synthetic step without further purification. e) Methyl 1-(2-methyltetradecyl)-1H-pyrrole-3-carboxylate

To a cooled (0 °C) suspension of sodium hydride (60% in mineral oil dispersion, 15 mg, 0.37 mmol) in DMF (2 ml_) was added methyl 1 H-pyrrole-3-carboxylate (46 mg, 0.37 mmol) and the mixture was stirred at 0 °C for 30 minutes. A solution of 2-methyltetradecyl trifluoromethanesulfonate (Intermediate 6d, 133 mg, 0.37 mmol) in DMF (1 ml_) was then added. The reaction mixture was allowed to slowly warm to room temperature and stirred for additional 4 h. The mixture was cooled down to 0 °C and water and diethyl ether were added. Phases were separated and the aqueous phase was further extracted with additional diethyl ether. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and the solvent was evaporated to dryness. Purification of the residue by flash chromatography (hexanes/diethyl ether) gave the title compound (15 mg, 10%) as an orange oil.

MS (m/z): 336 [M+1]⁺.

¹ H-NMR d (400 MHz, CDCh): 0.84 (d, J=7 Hz, 3H), 0.88 (t, J =7 Hz, 3H), 1.05-1.15 (m, 1 H), 1.18-1.39 (m, 22H), 1.83-1.88 (m, 1 H), 3.59 (dd, J=14 and 8 Hz, 1 H), 3.75-3.80 (m, 4H), 6.53-6.56 (m, 2H), 7.24 (t, J=2 Hz, 1 H).

INTERMEDIATE 7

Methyl 1-(2,2-dimethyldodecyl)-1 H-pyrrole-3-carboxylate a) 2,2-Dimethyldodecan-1-ol

To a suspension of lithium aluminium hydride (332 mg, 8.75 mmol) in THF (5 ml_) under argon atmosphere was added dropwise a solution of 2,2-dimethyldodecanoic acid (500 mg, 2.19 mmol) in THF (5 ml_) and the mixture was heated at 60 °C for 2 h. The reaction was cooled to room temperature and water (0.33 ml_), aqueous 4N sodium hydroxide solution (0.33 ml_) and water (1 ml_) were successively added in this order. The reaction mixture was diluted with EtOAc and solids were filtered. The organic layer was separated and the aqueous phase was extracted with EtOAc (x2). The combined organic layers were washed with brine, dried over magnesium sulfate and the solvent was removed under reduced pressure to give the title compound (445 mg, 95%) as a colourless oil.

¹ H-NMR d (400 MHz, CDCh): 0.86-0.90 (m, 9H), 1.22-1.26 (m, 18H), 3.31 (s, 2H). b) 2,2-Dimethyldodecyl trifluoromethanesulfonate

To a cooled (0 °C) solution of 2,2-dimethyldodecan-1-ol (Intermediate 7a, 120 mg, 0.56 mmol) and pyridine (50 mI_, 0.62 mmol) in DCM (3 ml_) under argon atmosphere was added trifluoromethylsulfonyl trifluoromethanesulfonate (0.10 ml_, 0.62 mmol) and the resulting mixture was stirred at room temperature for 45 min. After cooling to 0 °C, water was added and the reaction mixture was partitioned between water and DCM. The aqueous layer was separated and washed with additional DCM (x3). The combined organic layers were filtered through a Phase Separator and the solvent was removed under reduced pressure to give the title compound (170 mg, 87%) as a yellow oil.

¹ H-NMR d (400 MHz, CDCh): 0.85-0.91 (m, 3H), 0.98 (s, 6H), 1.27 (s, 20H), 4.20 (s, 2H). c) Methyl 1-(2,2-dimethyldodecyl)-1 H-pyrrole-3-carboxylate

To a cooled (0 °C) suspension of sodium hydride (60% suspension in paraffin oil, 25 mg, 0.62 mmol) in DMF (2.5 ml_) was added methyl 1 H-pyrrole-3-carboxylate (60 mg, 0.48 mmol) and the resulting solution was stirred at 0 °C for 20 min. 2,2-Dimethyldodecyl trifluoromethanesulfonate (Intermediate 7b, 200 mg, 0.58 mmol) was then added and the solution was stirred at room temperature for 1 h, poured into water and extracted with EtOAc (x3). The combined organic extracts were washed with water and brine, dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (hexanes to dietyl ether) to give the title compound (65 mg, 42%) as a colourless oil.

MS (m/z): 322 [M+1]⁺.

¹ H-NMR d (400 MHz, CDCh): 0.87-0.90 (m, 9H), 1.27 (s, 18H), 3.64 (s, 2H), 3.79 (s, 3H), 6.48-6.57 (m, 2H), 7.21 (s, 1 H).

INTERMEDIATE S

Methyl 1 -(2,2-dimethyltridecyl)-1 H-pyrrole-3-carboxylate a) Ethyl 2,2-dimethyltridecanoate

To a solution of diisopropylamine (2.6 ml_) in THF (14 ml_) at -78 °C was added n-butyl lithium (2.5 M solution in hexanes, 7.2 ml_, 18.00 mmol). The temperature was allowed to rise to 0 °C and the reaction mixture was stirred at this temperature for 30 min. The solution was cooled to - 78 °C and ethyl isobutyrate (2.00 g, 17.13 mmol) was added dropwise. Stirring was continued for 1 h at -78 °C and then 1-bromoundecane (4.17 g, 17.72 mmol) was added. After stirring overnight at room temperature, the reaction mixture was poured into ice/water containing 20 mL of saturated aqueous solution of ammonium chloride and then extracted with diethyl ether (x3). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to give the title compound (4.65 g, 100%) as a yellow oil which was used in the next synthetic step without further purification. b) 2,2-Dimethyltridecanoic acid

To a solution of ethyl 2,2-dimethyltridecanoate (Intermediate 8a, 2.00 g, 7.39 mmol) in ethanol (20 mL) was added a solution of potassium hydroxide (2.06 g, 36.71 mmol) in water (4 mL) and the reaction mixture was stirred at 70 °C overnight. The solvent was evaporated under reduced pressure, water was added and the aqueous solution was washed with diethyl ether (x2). The organic layer was discarded and the aqueous phase was acidified until pH=5 by addition of 5N hydrochloric acid solution. The aqueous phase was extracted with diethyl ether (x3). The combined organic extracts were washed with brine, dried over magnesium sulfate and the solvent was evaporated under reduced pressure to give the title compound (1.09 g, 4.50 mmol) as a yellow semisolid.

¹ H-NMR d (400 MHz, CDCh): 0.88 (t, J=6.9 Hz, 3H), 1.19 (s, 6H), 1.26-1.29 (m, 20H). c) 2,2-Dimethyltridecan-1-ol

Obtained as a colourless oil (82%) from 2,2-dimethyltridecanoic acid (Intermediate 8b) following the experimental procedure described in Intermediate 7a.

¹ H-NMR d (400 MHz, CDCh): 0.86 (s, 6H), 0.88 (t, J=6.9 Hz, 3H), 1.24-1.29 (m, 20H), 3.31 (s, 2H). d) 2,2-Dimethyltridecyl trifluoromethanesulfonate

Obtained as a light yellow oil (97%) from 2,2-dimethyltridecan-1-ol (Intermediate 8c) following the experimental procedure described in Intermediate 7b. ¹ H-NMR d (400 MHz, CDCh): 0.88 (t, J=6.8 Hz, 3H), 0.98 (s, 6H), 1.25-1.30 (m, 20H), 4.20 (s, 2H). e) Methyl 1-(2,2-dimethyltridecyl)-1 H-pyrrole-3-carboxylate

Obtained as a colourless oil (51 %) from 2,2-dimethyltridecyl trifluoromethane sulfonate (Intermediate 8d) and methyl 1 H-pyrrole-3-carboxylate following the experimental procedure described in Intermediate 7c.

MS (m/z): 336 [M+1]⁺.

¹ H-NMR d (400 MHz, CDCh): 0.88 (t, J=6.8 Hz, 3H), 1.22-1.30 (m, 20H), 3.64 (s, 2H), 3.79 (s, 3H), 6.49-6.52 (m, 1 H), 6.52-6.56 (m, 1 H), 7.21 (t, J=1.9 Hz, 1 H).

INTERMEDIATE 9

Methyl 1-(2,2-dimethyltetradecyl)-1 H-pyrrole-3-carboxylate a) 2,2-Dimethyltetradecan-1-ol

Obtained as a colourless oil (99%) from 2,2-dimethyltetradecanoic acid following the experimental procedure described in Intermediate 7a.

¹ H-NMR d (400 MHz, CDCh): 0.86 (s, 6H), 0.88 (t, J=6.8 Hz, 4H), 1.22-1.30 (m, 22H), 3.31 (d, J=4.6 Hz, 2H). b) 2,2-Dimethyltetradecyl trifluoromethanesulfonate

Obtained as a yellow oil (100%) from 2,2-dimethyltetradecan-1-ol (Intermediate 9a) following the experimental procedure described in Intermediate 7b.

¹ H-NMR d (400 MHz, CDCh): 0.88 (t, J=6.8 Hz, 3H), 0.98 (s, 6H), 1.22-1.30 (m, 22H), 4.20 (s, 2H). c) Methyl 1-(2,2-dimethyltetradecyl)-1H-pyrrole-3-carboxylate

Obtained as a colourless oil (68%) from 2,2-dimethyltetradecyl trifluoromethane sulfonate (Intermediate 9b) and methyl 1 H-pyrrole-3-carboxylate following the experimental procedure described in Intermediate 7c.

MS (m/z): 350 [M+1]⁺. ¹ H-NMR d (300 MHz, CDCIs): 0.88 (m, 9H), 1.26 (s, 22H), 3.64 (s, 2H), 3.79 (s, 3H), 6.48- 6.56 (m, 2H), 7.21 (t, J=1.9 Hz, 1 H).

INTERMEDIATE 10

1-Chloroethyl (2-methoxyethyl) carbonate

To a cooled (0 °C) solution of 1-chloroethyl carbonochloridate (250 mg, 1.75 mmol) and 2- methoxyethan-1-ol (121 mg, 1.59 mmol) in DCM (2 ml_) pyridine (141 mI_, 1.75 mmol) was added dropwise and the resulting mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with DCM and washed with 1 N hydrochloric acid solution, water and saturated sodium hydrogen carbonate solution. The organic phase was dried over magnesium sulfate, filtered and solvent was evaporated to dryness to yield the title compound (250 mg, 86%) as a clear oil which was used in the next synthetic step without further purification.

¹ H-NMR d (400 MHz, CDCIs): 1.83 (d, J=6 Hz, 3H), 3.39 (s, 3H), 3.65-3.61 (m, 2H), 4.34 (ddd, J=7.5 and 4 Hz, 2H), 6.42 (q, J=6 Hz, 1 H).

INTERMEDIATE 1 1

1-Chloroethyl (2-(2-ethoxyethoxy)ethyl) carbonate

To a cooled (-78 °C) solution of 2-(2-ethoxyethoxy)ethanol (0.49 ml_, 3.5 mmol) and pyridine (0.32 ml_, 4.02 mmol) in DCM (5 ml_) was slowly added 1-chloroethyl carbonochloridate (0.38 ml_, 3.5 mmol) and the reaction mixture was stirred at -78 °C for 3 h. After warming to room temperature, the reaction mixture was filtered and the solid was washed with DCM. The combined organic fractions were washed with water and brine, dried over magnesium sulfate, filtered and the solvent was evaporated to yield the title compound (750 mg, 89%) as a colourless oil which was used in the next synthetic step without further purification.

¹ H-NMR d (400 MHz, CDCIs): 1.21 (t, J=7 Hz, 3H), 1.83 (d, J=6 Hz, 3H), 3.53 (q, J=7 Hz, 2H), 3.61-3.57 (m, 2H), 3.67-3.63 (m, 2H), 3.77-3.73 (m, 2H), 4.39-4.31 (m, 2H), 6.42 (q, J=6 Hz, 1 H).

INTERMEDIATE 12

Methyl 1-(2,2-dimethylpentadecyl)-1 H-pyrrole-3-carboxylate a) Ethyl 2,2-dimethylpentadecanoate Obtained as a yellow oil (78%) from ethyl isobutyrate and 1-bromotridecane following the experimental procedure described in Intermediate 8a. b) 2,2-Dimethylpentadecanoic acid

Obtained as a yellow solid (66%) from ethyl 2,2-dimethylpentadecanoate (Intermediate 12a) following the experimental procedure described in Intermediate 8b.

¹H-NMR d (400 MHz, CDCIs): 0.87 (t, J=6.8 Hz, 3H), 1.19 (s, 6H), 1.22-1.33 (m, 22H), 1.49-1.57 (m, 2H). c) 2,2-Dimethylpentadecan-1 -ol

Obtained as a colourless oil (88%) from 2,2-dimethylpentadecanoic acid (Intermediate 12b) following the experimental procedure described in Intermediate 8c.

¹H-NMR d (400 MHz, CDCIs): 0.86 (s, 6H), 0.88 (t, J=6.8 Hz, 3H), 1.23-1.32 (m, 24H), 3.28-3.36 (m, 2H). d) 2,2-Dimethylpentadecyl trifluoromethanesulfonate

Obtained as a deep yellow oil (98%) from 2,2-dimethylpentadecan-1 -ol (Intermediate 12c) following the experimental procedure described in Intermediate 7b.

¹H-NMR d (400 MHz, CDCIs): 0.88 (t, J=6.8 Hz, 3H), 0.98 (s, 6H), 1.24- 1.33 (m, 24H),

4.20 (s, 2H). e) Methyl 1 -(2,2-dimethylpentadecyl)-1 H-pyrrole-3-carboxylate

Obtained as a colourless oil (69%) from 2,2-dimethylpentadecyl trifluoromethanesulfonate (Intermediate 12d) and methyl 1 H-pyrrole-3-carboxylate following the experimental procedure described in Intermediate 7c.

MS (m/z): 365 [M+1]⁺.

¹H-NMR d (400 MHz, CDCIs): 0.86-0.90 (m, 9H), 1.20-1.30 (m, 24H), 3.64 (s, 2H), 3.79 (s, 3H), 6.49-6.52 (m, 1 H), 6.54 (dd, J=2.8, 1.8 Hz, 1 H), 7.21 (t, J=1.8 Hz, 1 H).

INTERMEDIATE 13

Methyl 1 -(3,3-dimethyltridecyl)-1 H-pyrrole-3-carboxylate a) Methyl 3,3-dimethyltridecanoate

To a suspension of copper (I) iodide (125 mg, 0.65 mmol) in THF (20 ml_) under an argon atmosphere was added methyl 3-methylbut-2-enoate (748 mg, 6.55 mmol) and chlorotrimethylsilane (1 .00 ml_, 7.88 mmol) and the reaction mixture was cooled to -15 °C. A solution of decylmagnesium bromide (1 M in 2-methyltetrahydrofuran, 7.80 ml_, 7.80 mmol) was added over a period of 1 hour and the reaction was stirred at room temperature overnight. Saturated aqueous solution of ammonium chloride was added and the mixture was stirred for 10 min. The solvent was evaporated under reduced pressure and the residue was partitioned between water and hexanes. The organic layer was separated and the aqueous layer was extracted with hexanes (x2). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure to give the title compound (1 .70 g, 96%) as a green oil which was used in the next synthetic step without any further purification.

b) 3,3-Dimethyltridecanoic acid

To a solution of methyl 3,3-dimethyltridecanoate (Intermediate 13a, 1.70 g, 6.29 mmol) in ethanol (15 ml_) was added a solution of potassium hydroxide (2.78 g, 49.54 mmol) in water (3 ml_) and the reaction mixture was stirred under reflux for 5 h. After cooling to room temperature, the organic solvent was evaporated under reduced pressure, water was added and the aqueous solution was washed with hexanes. Then, the aqueous solution was acidified until pH=2 by addition of 5N hydrochloric acid solution and extracted with diethyl ether (x3). The combined organic layers were dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure to give the title compound (1.17 g, 77%) as a brown oil which was used in the next synthetic step without further purification. c) 3,3-Dimethyltridecan-1-ol

Obtained as a yellow oil (83%) from 3,3-dimethyltridecanoic acid (Intermediate 13b) following the experimental procedure described in Intermediate 7a.

¹ H-NMR d (400 MHz, CDCIs): 0.88-0.96 ( , 9H), 1.18-1.36 ( , 18H), 1.60-1.67 ( , 3H), 3.65-3.74 (m, 2H). d) 3,3-Dimethyltridecyl trifluoromethanesulfonate Obtained as brown oil (87%) from 3,3-dimethyltridecan-1-ol (Intermediate 13c) following the experimental procedure described in Intermediate 7b.

¹H-NMR d (400 MHz, CDCIs): 0.88-0.98 (m, 9H), 1.21-1.36 (m, 18H), 1.77-1.90 (m, 2H), 4.59 (dt, J= 14.6, 7.1 Hz, 2H). e) Methyl 1-(3,3-dimethyltridecyl)-1 H-pyrrole-3-carboxylate

Obtained as a light yellow oil (38%) from 3,3-dimethyltridecyl trifluoromethanesulfonate (Intermediate 13d) and methyl 1 H-pyrrole-3-carboxylate following the experimental procedure described in Intermediate 7c.

MS ( /z): 336 [M+1]⁺.

¹H-NMR d (400 MHz, CDCIs): 0.85-0.93 (m, 9H), 1.19-1.33 (m, 18H), 1.66-1.73 (m, 2H), 3.79 (s, 3H), 3.81-3.87 (m, 2H), 6.55 (dd, J=2.9, 1.8 Hz, 1 H), 6.57-6.59 (m, 1 H), 7.29 (t, J=1.8 Hz, 1 H).

INTERMEDIATE 14

Methyl 1-(3,3-dimethylpentadecyl)-1 H-pyrrole-3-carboxylate a) Methyl 3,3-dimethylpentadecanoate

Obtained as a green oil (100%) from 3-methylbut-2-enoate and dodecylmagnesium bromide following the experimental procedure described in Intermediate 13a.

b) 3,3-Dimethylpentadecanoic acid

Obtained as a light yellow oil (32%) from methyl 3,3-dimethylpentadecanoate (Intermediate 14a) following the experimental procedure described in Intermediate 13b. c) 3,3-Dimethylpentadecan-1-ol

Obtained as an orange oil (100%) from 3,3-dimethylpentadecanoic acid (Intermediate 14b) following the experimental procedure described in Intermediate 7a.

¹H-NMR d (400 MHz, CDCIs): 0.90-0.95 ( , 9H), 1.22-1.35 ( , 22H), 1.52-1.56 ( , 2H), 3.67-3.74 (m, 2H). d) 3,3-Dimethylpentadecyl trifluoromethanesulfonate Obtained as an orange oil (83%) from 3,3-dimethylpentadecan-1-ol (Intermediate 14c) following the experimental procedure described in Intermediate 7b.

¹ H-NMR d (400 MHz, CDCIs): 0.88 (t, J=6.8 Hz, 3H), 0.93 (s, 6H), 1.17-1.35 (m, 22H), 1.73-1.82 (m, 2H), 4.49-4.64 (m, 2H). e) Methyl 1-(3,3-dimethylpentadecyl)-1 H-pyrrole-3-carboxylate

Obtained as a colourless oil (14%) from 3,3-dimethylpentadecyl trifluoromethanesulfonate (Intermediate 14d) and methyl 1 H-pyrrole-3-carboxylate following the experimental procedure described in Intermediate 7c.

MS (m/z): 364 [M+1]⁺.

INTERMEDIATE 15

Methyl 1-(14-fluorotetradecyl)-1 H-pyrrole-3-carboxylate a) 1-Bromo-14-fluorotetradecane

A mixture of 14-bromotetradecan-1-ol (300 g, 1.02 mmol) and diethylaminosulfur trifluoride (0.27 ml_, 2.04 mmol) was stirred at 35 °C for 4 h. The mixture was poured into cooled (0 °C) water and extracted with DCM (x3). The combined organic layers were washed with brine, dried over magnesium sulfate and the solvent was evaporated to dryness to yield the title compound (302 mg, 100%) as an orange oil.

¹ H-NMR 5 (400 MHz, CDCIs): 1.23-1.33 (m, 16H), 1.40 (dt, J=13.6, 7.5 Hz, 4H), 1.61-1.76 (m, 2H), 1.80-1.90 (m, 2H), 3.41 (t, J=6.9 Hz, 2H), 4.38 (t, J=6.2 Hz, 1 H), 4.50 (t, J=6.2 Hz, 1 H). b) Methyl 1-(14-fluorotetradecyl)-1H-pyrrole-3-carboxylate

Obtained as a colourless oil (63%) from 1-bromo-14-fluorotetradecane (Intermediate 15a) and methyl 1 H-pyrrole-3-carboxylate following the experimental procedure described in Intermediate 7c.

MS (m/z): 340 [M+1]⁺. ¹ H-NMR d (400 MHz, CDCIs): 1.19-1.44 (m, 20H), 1.61-1.81 (m, 4H), 3.79 (s, 3H), 3.85 (t, J=7.1 Hz, 2H), 4.38 (t, J=6.2 Hz, 1 H), 4.49 (t, J=6.2 Hz, 1 H), 6.55-6.59 (m, 2H), 7.27 (t, J=1.9 Hz, 1 H).

INTERMEDIATE 16

Methyl 1-(2-fluorotetradecyl)-1H-pyrrole-3-carboxylate a) 1 -Bromo-2-fluorotetradecane

To a solution of tetradec-1 -ene (5.00 g, 25.45 mmol) in DCM (55 ml_) was added a solution of triethylamine hydrofluoride (12.31 g, 76.36 mmol) in DCM (5 ml_) and the resulting solution was cooled to 0 °C and protected from the light. /V-bromosuccinimide (4.98 g, 27.98 mmol) was then added in portions and the reaction mixture was stirred at room temperature for 6 h, poured into a mixture of ice and water and extracted with DCM (x3). The combined organic layers were washed with 0.5N hydrochloric acid solution, 4% aqueous sodium hydrogencarbonate solution and brine and dried over magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (7.50 g, 100%) as a colourless oil.

¹ H-NMR d (400 MHz, CDCIs): 0.84-0.92 ( , 3H), 1.23-1.29 ( , 18H), 1.36-1.52 ( , 2H), 1.69-1.81 (m, 2H), 3.48 (m, 2H), 4.50-4.78 (m, 1 H). b) Methyl 1 -(2-fluorotetradecyl)-1 H-pyrrole-3-carboxylate

Obtained as a white solid (36%) from methyl 1 H-pyrrole-3-carboxylate and 1 -bromo-2- fluorotetradecane (Intermediate 16a) following the experimental procedure described in Intermediate 7c.

MS (m/z): 340 [M+1 ]⁺.

¹ H-NMR d (400 MHz, CDCIs): 0.84-0.94 (m, 3H), 1.22-1.33 (m, 22H), 3.80 (s, 3H), 3.92- 4.14 (m, 2H), 4.55-4.79 (m, 1 H), 6.59 (dd, J=2.9 and 1.7 Hz, 1 H), 6.61-6.63 (m, 1 H), 7.31 (t, J= 1.7 Hz, 1 H).

INTERMEDIATE 17

Methyl 1-(2,2-difluoroundecyl)-1 H-pyrrole-3-carboxylate a) 2,2-difluoroundecan-1 -ol To a solution of undecanal (0,97 ml_, 4.70 mmol) in THF (40 ml_) were added pyrrolidine- 2-carboxylic acid (1 .08 g, 9.38 mmol) and N-fluoro-N- (phenylsulfonyl)benzenesulfonamide (3.70 g, 1 1 .77 mmol) and the mixture was stirred at room temperature for 20 h. Saturated aqueous solution of potassium hydrogencarbonate (40 ml_) was then added and the resulting mixture was stirred vigorously for 10 min. The resulting precipitate was filtered, washed with water and the filtrate was extracted with EtOAc (x3). The combined organic layers were washed with saturated aqueous solution of potassium carbonate, dried over magnesium sulfate and the solvent was removed under reduced pressure. The resulting oil was dissolved in a mixture of DCM/methanol (28 mL/18 ml_) and sodium borohydride (533 mg, 14.09 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 2 h. After cooling to 0 °C, saturated aqueous solution of sodium potassium tartrate was added (20 ml_) and the mixture was vigorously stirred for 20 min before being extracted with DCM (x3). The combined organic extracts were washed with brine, dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (hexanes to diethyl ether) to yield the title compound (515 mg, 53%) as a colourless oil.

¹ H-NMR d (400 MHz, CDCIs): 0.85-0.91 (m, 3H), 1.23-1.37 (m, 12H), 1.44-1.54 (m, 2H),

1.81-1.98 (m, 2H), 3.73 (td, J=12.8, 6.9 Hz, 1 H).

b) 2,2-Difluoroundecyl trifluoromethanesulfonate

Obtained as a brown oil (93%) from 2,2-difluoroundecan-1 -ol (Intermediate 17a) following the experimental procedure described in Intermediate 7b.

¹ H-NMR d (400 MHz, CDCIs): 0.85-0.92 ( , 3H), 1.23-1.40 ( , 12H), 1.46-1.56 ( , 2H), 1.87-2.02 (m, 2H), 4.51 (t, J=1 1.3 Hz, 2H).

c) Methyl 1-(2,2-difluoroundecyl)-1H-pyrrole-3-carboxylate Obtained as an orange oil (69%) from 2,2-difluoroundecyl trifluoromethanesulfonate (Intermediate 17b) and methyl 1 H-pyrrole-3-carboxylate following the experimental procedure described in Intermediate 7c.

MS (m/z): 316 [M+1]⁺.

¹ H-NMR d (400 MHz, CDCIs): 0.85-0.91 (m, 3H), 1.21-1.34 (m, 12H), 1.43-1.53 (m, 2H), 1.62-1.79 (m, 2H), 3.81 (s, 3H), 4.15 (t, J=12.9 Hz, 2H), 6.60-6.64 (m, 2H), 7.30 (s, 1 H).

INTERMEDIATE 18

Methyl 1 -(2,2-difluorotetradecyl)-1 H-pyrrole-3-carboxylate

a) 2,2-Difluorotetradecan-1-ol

Obtained as a colourless oil (53%) from tetradecanal following the experimental procedure described in Intermediate 17a followed by purification of the crude product by flash chromatography (hexanes to diethyl ether).

¹ H-NMR d (400 MHz, CDCIs): 0.88 (t, J=6.9 Hz, 3H), 1.23-1.35 (m, 18H), 1.42-1.54 (m, 1 H), 1.76-1.99 (m, 3H), 3.67-3.79 (m, 2H).

b) 2,2-Difluorotetradecyl trifluoromethanesulfonate

Obtained as a yellow oil (100%) from 2,2-difluorotetradecan-1-ol (Intermediate 18a) following the experimental procedure described in Intermediate 7b.

¹ H-NMR d (400 MHz, CDCIs): 0.87 (t, J=6.9 Hz, 3H), 1.22-1.40 (m, 18H), 1.45-1.55 (m, 2H), 1.80-2.08 (m, 2H), 4.51 (t, J=11.2 Hz, 2H).

c) Methyl 1-(2,2-difluorotetradecyl)-1 H-pyrrole-3-carboxylate

Obtained as a white solid (44%) from methyl 1 H-pyrrole-3-carboxylate and 2,2-difluorotetradecyl trifluoromethanesulfonate (Intermediate 18b) following the experimental procedure described in Intermediate 7c.

MS (m/z): 358 [M+1]⁺. ¹ H-NMR d (400 MHz, CDCh): 0.87 (t, J=6.8 Hz, 3H), 1.23-1.31 (m, 18H), 1.41-1.53 (m, 2H), 1.64-1.79 (m, 2H), 3.81 (s, 3H), 4.15 (t, J=12.9 Hz, 2H), 6.60-6.64 (m, 2H), 7.30 (s, 1 H).

INTERMEDIATE 19

Methyl 4-phenyl-1 -tetradecyl-1 H-pyrrole-3-carboxylate a) 4-Bromo-1 -tetradecyl-1 H-pyrrole-3-carboxylate

Obtained as a colorless oil (68%) from methyl 4-bromo-1 H-pyrrole-3-carboxylate and 1- bromotetradecane following the experimental procedure described in Intermediate 7c.

MS (m/z): 400, 402 [M+1]⁺.

¹ H NMR d (400 MHz, CDCIs): 0.95-0.81 (m, 3H), 1.27 (m, 22H), 1.75 (m, 2H), 3.81 (s, 3H), 3.82 (t, J=7.1 Hz, 2H), 6.66 (d, J=2.6 Hz, 1 H), 7.25 (s, 1 H).

b) Methyl 4-phenyl-1-tetradecyl-1 H-pyrrole-3-carboxylate

To a solution of 4-bromo-1-tetradecyl-1 H-pyrrole-3-carboxylate (Intermediate 19a, 135 g, 0.33 mmol) in DMF (5 ml_) under an argon atmosphere were added phenylboronic acid (85 mg, 0.69 mmol) and a solution of sodium carbonate (320 mg, 3.3 mmol) in water (1.5 ml_). Tetrakis(triphenylphosphine) palladium(O) (20 mg, 0.017 mmol) was then added and the mixture was heated at 100 °C overnight under an argon atmosphere. After cooling to room temperature, the reaction mixture was filtered through a celite® pad and the filtrate was partitioned between water and EtOAc. The organic phase was separated and washed with brine (x2), dried over magnesium sulfate and the solvent was evaporated to dryness. The residue was purified using SP1^® Purification System (hexanes-diethyl ether) to yield the title compound (100 mg, 75%) as an oil.

MS (m/z): 398 [M+1]⁺.

INTERMEDIATE 20 Methyl 1-(4-decylphenyl)-1 H-pyrrole-3-carboxylate

A Schlenk flask was charged with methyl 1 H-pyrrole-3-carboxylate (100 g, 0.80 mmol), copper(l) iodide (7.6 mg, 0.04 mmol), potassium phosphate tribasic (356 mg, 1.67 mmol), 1- bromo-4-decylbenzene (0.26 ml_, 0.96 mmol), A/1 ,/\/2-dimethylethane-1 , 2-diamine (0.017 ml_, 0.16 mmol) and toluene (1 ml_). The mixture was subjected to three cycles of evacuation- backfilling with argon and stirred at 100 °C overnight under an argon atmosphere. After cooling to room temperature, the reaction mixture was filtered through a Celite^® pad. The filtrate was evaporated to dryness and the resulting residue was purified by flash chromatography (hexanes/diethyl ether) to yield the title compound (67 mg, 24%) as a white solid.

MS (m/z): 342 [M+1]⁺ ¹ H-NMR d (400 MHz, CDCIs): 0.81-0.88 (m, 3H), 1.20-1.32 (m, 14H), 1.52-1.62 (m, 2H), 2.57-2.63 (m, 2H), 3.74 (s, 3H), 6.63 (dd, J=3.0, 2.0 Hz, 1 H), 7.29 (d, J=8.6 Hz, 2H), 7.40 (dd, J=3.0, 2.0 Hz, 1 H), 7.54-7.58 (m, 2H), 7.94-7.96 (m, 1 H).

INTERMEDIATE 21

Ethyl 4-fluoro-1 H-pyrrole-3-carboxylate a) 2,2,2-Trichloro-1-(4-fluoro-1-(triisopropylsilyl)-1 H-pyrrol-3-yl)ethan-1-one

To a cooled (0 °C) suspension of aluminium (III) chloride (304 mg, 2.28 mmol) in DCM (8 ml_) was slowly added trichloroacetyl chloride (0.35 ml_, 3.1 1 mmol) and the mixture was stirred at 0 °C for 15 min. A solution of 3-fluoro-1-(triisopropylsilyl)-1 H-pyrrole (500 mg, 2.07 mmol) in DCM (7 ml_) was then added dropwise and the reaction mixture was stirred at 0 °C for 30 min and at room temperature for 30 min. The crude was poured into an ice-water mixture, the organic phase was separated and the aqueous layer was washed with DCM. The combined organic extracts were dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc) to yield the title compound (285 mg, 36%) as a brown solid.

MS (m/z): 386/388/390 [M+1/M+3/M+5] 1 H NMR 5 (400 MHz, CDCb): 1.12 (d, J=7 Hz, 18H), 1.45 (dt, J=15 and 7 Hz, 3H), 6.54- 6.46 (m, 1 H), 7.53-7.45 (m, 1 H). b) Ethyl 4-fluoro-1H-pyrrole-3-carboxylate

To a solution of sodium (20.9 g, 0.91 mmol) in anhydrous ethanol (2 ml_) was added dropwise a solution of 2,2,2-trichloro-1-(4-fluoro-1-(triisopropylsilyl)-1 H-pyrrol-3-yl)ethan-1-one (Intermediate 21a, 293 g, 0.76 mmol) in ethanol (3 ml_) and the mixture was stirred at room temperature for 40 min. The volatiles were partially removed under reduced pressure. 3N Hydrochloric acid solution was added at 0 °C and the reaction mixture was extracted with DCM (x3). The combined organic extracts were washed with aqueous 10% sodium hydrogencarbonate solution, water and brine, dried over magnesium sulfate and the solvent was evaporated to dryness. The residue was purified by flash chromatography (hexanes/EtOAc) to yield the title compound (77 g, 65%) as a white solid.

MS ( /z): 158 [M+1]⁺ ¹ H-NMR 5 (400 MHz, CDCb) 1.35 (t, J=7 Hz, 3H), 4.31 (q, J=7 Hz, 2H), 6.53 (q, J=3 Hz, 1 H), 7.16 (td, J=3 and 3 Hz, 1 H).

INTERMEDIATE 22

Ethyl 1 -decyl-4-fluoro-1 H-pyrrole-3-carboxylate

Obtained as an off-white solid (66%) from ethyl 4-fluoro-1 H-pyrrole-3-carboxylate (Intermediate 21 b) and 1 -bromodecane following the experimental procedure described in Intermediate 7c.

MS ( /z): 198 [M+1]⁺.

¹ H-NMR 5 (400 MHz, CDCb): 0.88 (t, J=6.9 Hz, 4H), 1.20-1.30 ( , 14H), 1.34 (t, J=7.1 Hz, 3H), 1.67-1.77 ( , 2H), 3.76 (t, J=7.1 Hz, 2H), 4.29 (q, J=7.1 Hz, 2H), 6.36-6.39 ( , 1 H), 6.98-7.01 (m, 1 H).

INTERMEDIATE 23 Ethyl 4-fluoro-1-tridecyl-1 H-pyrrole-3-carboxylate

Obtained as an off-white solid (76%) from ethyl 4-fluoro-1 H-pyrrole-3-carboxylate (Intermediate 21 b) and 1 -bromotridecane following the experimental procedure described in Intermediate 7c followed by purification of the crude product by flash chromatography (hexanes/EtOAc).

MS ( /z): 340 [M+1]⁺ ¹H-NMR d (400 MHz, CDCIs): 0.95-0.79 ( , 3H), 1.39-1.17 ( , 23H), 1.74 (q, J=7 Hz, 2H), 3.75 (t, J=7 Hz, 2H), 4.29 (q, J=7 Hz, 2H), 6.41-6.35 (m, 1 H), 7.05-6.95 (m, 1 H).

INTERMEDIATE 24

Ethyl 4-fluoro-1 -tetradecyl-1 H-pyrrole-3-carboxylate

Obtained as a colourless oil (44%) from ethyl 4-fluoro-1 H-pyrrole-3-carboxylate (Intermediate 21 b) and 1 -bromotetradecane following the experimental procedure described in Intermediate 7c followed by purification of the crude product by flash chromatography (hexanes/EtOAc).

MS ( /z): 354 [M+1]⁺ ¹H-NMR d (400 MHz, CDCIs): 0.92-0.81 (m, 3H), 1.38-1.20 (m, 25H), 1.80-1.66 (m, 2H), 3.75 (t, J=7 Hz, 2H), 4.28 (q, J=7 Hz, 2H), 6.43-6.31 (m, 1 H), 7.04-6.93 (m, 1 H).

INTERMEDIATE 25

Ethyl 4-fluoro-1 -pentadecyl-1 H-pyrrole-3-carboxylate

Obtained as a colourless oil (77%) from ethyl 4-fluoro-1 H-pyrrole-3-carboxylate (Intermediate 21 b) and 1 -bromopentadecane following the experimental procedure described in Intermediate 7c followed by purification of the crude product by flash chromatography (hexanes/EtOAc).

MS (m/z): 368 [M+1]⁺ ¹ H-NMR d (400 MHz, CDCIs): 0.94-0.80 (m, 3H), 1.38-1.13 (m, 27H), 1.79-1.68 (m, 2H), 3.75 (t, J=7 Hz, 2H), 4.29 (q, J=7 Hz, 2H), 6.40-6.35 (m, 1 H), 7.02-6.96 (m, 1 H).

INTERMEDIATE 26

Ethyl 1-(9-butoxynonyl)-4-fluoro-1H-pyrrole-3-carboxylate

Obtained as an orange oil (72%) from ethyl 4-fluoro-1 H-pyrrole-3-carboxylate (Intermediate 21 b) and 1-bromo-9-butoxynonane (Intermediate 2a) following the experimental procedure described in Intermediate 7c.

MS (m/z): 356 [M+1]⁺ ¹ H-NMR d (400 MHz, CDCIs): 0.92 (t, J=7.4 Hz, 3H), 1.22-1.42 (m, 14H), 1.51-1.60 (m, 2H), 1.73 (p, J=7.1 Hz, 2H), 3.39 (td, J=6.7, 4.8 Hz, 4H), 3.75 (t, J=7.1 Hz, 2H), 4.29 (q, J=7.1 Hz, 2H), 6.38 (t, J=3.1 Hz, 1 H), 6.98-7.01 (m, 1 H).

INTERMEDIATE 27

Methyl 5-fluoro-1-tetradecyl-1 H-pyrrole-3-carboxylate a) Methyl 1 -tetradecyl-1 H-pyrrole-3-carboxylate

To a cooled (0 °C) solution of methyl 1 H-pyrrole-3-carboxylate (215 g, 1.71 mmol) in DMF (10 ml_) was added sodium hydride (60% dispersion in mineral oil, 82 mg, 2.06 mmol) and the mixture was stirred at room temperature for 10 min. 1-Bromotetradecane (0.46 ml_, 1.71 mmol) was then added dropwise at 0 °C and the mixture was stirred at room temperature for 24 h. Water was carefully added and the reaction mixture was partitioned between water and toluene. The organic layer was separated and the aqueous layer was washed with toluene (x3). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and the solvent was evaporated to dryness. The residue was purified by flash chromatography (hexanes/EtOAc) to yield the title compound (320 mg, 58%).

MS (m/z): 322 [M+1]⁺ ¹ H NMR d (400 MHz, CDCIs): 0.80-0.99 (m, 4H), 1.26 (d, J=9 Hz, 23H), 1.68-1.86 (m, 2H),

3.79 (s, 3H), 3.81-3.96 (m, 2H), 6.57 (dd, J=4 and 2 Hz, 2H), 7.27 (d, J=5 Hz, 1 H). b) Methyl 5-fluoro-1-tetradecyl-1 H-pyrrole-3-carboxylate and methyl 2-fluoro-1- tetradecyl-1 H-pyrrole-3-carboxylate

A mixture of methyl 1-tetradecyl-1 H-pyrrole-3-carboxylate (Intermediate 27a, 1.15 g, 3.58 mmol) and Selectfluor^® (1.26 g, 3.58 mmol) in ACN (10 ml_) was heated at 70 °C for 1 h. Aqueous saturated sodium hydrogencarbonate solution was added and the reaction mixture was extracted with EtOAc (x2). The combined organic extracts were washed with water and brine, dried over magnesium sulfate, filtered and the solvent evaporated to dryness. The residue was purified by flash chromatography (hexanes/DCM) to yield methyl 5-fluoro-1-tetradecyl-1 H-pyrrole-3- carboxylate (238 mg, 18%):

MS (m/z): 340 [M+1]⁺ ¹H NMR d (400 MHz, CDCIs): 0.85-0.97 (m, 3H), 1.21-1.34 (m, 22H), 1.68-1.78 (m, 2H),

3.76-3.81 (m, 5H), 5.88 (dd, J=4 and 2 Hz, 1 H), 6.88 (d, J=2Hz, 1 H)

and methyl 2-fluoro-1-tetradecyl-1 H-pyrrole-3-carboxylate (54 g, 4%):

MS (m/z): 340 [M+1]⁺ ¹H NMR d (400 MHz, CDCIs): 0.74-1.06 (m, 3H), 1.15-1.40 (m, 22H), 1.63-1.82 (m, 2H), 3.78 (t, J=7 Hz, 2H), 3.81 (s, 3H), 6.06-6.19 (m, 1 H), 6.36 (dd, J=4 and 3 Hz, 1 H).

INTERMEDIATE 28

Ethyl 4-chloro-1-tetradecyl-1 H-pyrrole-3-carboxylate a) 1-(Triisopropylsilyl)-1 H-pyrrole

To a cooled (0 °C) solution of 1 H-pyrrole (2.5 g, 37.3 mmol) in DMF (80 ml_) was added portionwise sodium hydride (60% dispersion in mineral oil, 1.64 g, 41 mmol) and the mixture was stirred for 45 min. Chlorotriisopropylsilane (7.89 ml_, 37.3 mmol) was then added dropwise and the mixture was stirred at room temperature overnight. After cooling to 0 °C, water (30 ml_) was added and the reaction mixture was extracted with toluene (x3). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and the solvent was evaporated to dryness. The residue was purifed by flash chromatography (hexanes/diethyl ether) to yield the title compound (3.82 g, 46%) as a clear oil.

MS (m/z): 224 [M+1]⁺ ¹ H-NMR d (400 MHz, CDCIs): 1.10 (d, J=7 Hz, 18H), 1.46 (dt, J=15 and 7 Hz, 3H), 6.32 (d, J=2 Hz, 1 H), 6.80 (d, J=2 Hz, 1 H). b) 3-Bromo-1-(triisopropylsilyl)-1 H-pyrrole

To a solution of 1 -(triisopropylsilyl)-l H-pyrrole (Intermediate 28a, 3.8 g, 17.01 mmol) in THF (40 ml_) at -78 °C was added portionwise /V-bromosuccinimide (3.03 g, 17.01 mmol) and the mixture was stirred at -78 °C for 3 h. After warming to room temperature, aqueous saturated sodium hydrogencarbonate solution was added and the reaction mixture was extracted with diethyl ether (x3). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and the solvent was evaporated to dryness. The residue was purified by flash chromatography (2% EtOAc in hexanes) to yield the title product (4.71 g, 92%) as a clear oil.

MS (m/z): 302/304 [M+1/M+3]⁺ ¹ H-NMR d (400 MHz, CDCIs): 1.09 (d, J=7 Hz, 18H), 1.50-1.34 (m, 3H), 6.29 (d, J=4 Hz, 1 H), 6.67 (d, J=3 Hz, 1 H), 6.73 (d, J=1 Hz, 1 H). c) 3-Chloro-1 -(triisopropylsilyl)-l H-pyrrole

To a solution of 3-bromo-1-(triisopropylsilyl)-1 H-pyrrole (Intermediate 28b, 1.0 g, 3.31 mmol) in THF (6.5 ml_) at -78 °C was added dropwise te/f-butyllithium (1.7M solution in pentane, 3.99 ml_, 6.8 mmol) and the mixture was stirred at -78 °C for 30 min. A solution of perchloroethane (1.57 g, 6.62 mmol) in THF (10 ml_) was added dropwise and the reaction mixture was stirred for 30 min at -78 °C and then allowed to warm to room temperature. Aqueous saturated ammonium chloride solution was added, phases were separated and the aqueous phase was extracted with EtOAc (x2). The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and the solvent was evaporated to dryness. The residue was purified by flash chromatography (hexanes/diethyl ether) to yield the title compound (654 mg, 77%) as a slightly yellow oil.

MS (m/z): 258/260 [M+1/M+3] ¹ H-NMR d (400 MHz, CDCIs): 1.09 (d, J=7 Hz, 18H), 1.41 (dt, J=15 and 7 Hz, 3H), 6.23 (d, J=4 Hz, 1 H), 6.67 (d, J=9 Hz, 2H). d) 2,2,2-Trichloro-1-(4-chloro-1-(triisopropylsilyl)-1H-pyrrol-3-yl)ethan-1-one

To a cooled (0 °C) solution of aluminium(lll) chloride (370 mg, 2.77 mmol) in DCM (15 ml_) was added trichloroacetyl chloride (0.42 ml_, 3.78 mmol) and the mixture was stirred at 0 °C for 15 min. A solution of 3-chloro- 1 -(triisopropylsilyl)-l H-pyrrole (Intermediate 28c, 650 mg, 2.52 mmol) in DCM (10 ml_) was added dropwise and the mixture was stirred at 0 °C for 30 min and then allowed to warm to room temperature. The reaction mixture was poured into an ice-water mixture, phases were separated and the aqueous phase was washed with DCM (x3). The combined organic fractions were dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography (hexanes/diethyl ether) to give the title product (316 mg, 31 %) as a white solid.

MS (m/z): 402/404/406/408 [M+1/M+3/M+5/M+7G

¹ H-NMR d (400 MHz, CDCIs): 1.12 (d, J=7 Hz, 18H), 1.46 (dt, J=15 and 7 Hz, 3H), 6.74 (d, J=2 Hz, 1 H), 7.75 (d, J=2 Hz, 1 H). e) Ethyl 4-chloro-1H-pyrrole-3-carboxylate

To a solution of sodium (21.55 mg, 0.94 mmol) in ethanol (2 ml_) was added dropwise a solution of 2,2,2-trichloro-1-(4-chloro-1-(triisopropylsilyl)-1 H-pyrrol-3-yl)ethan-1-one (Intermediate 28d, 315 mg, 0.78 mmol) in ethanol (7 ml_) and the mixture was stirred for 1 h. The volatiles were partially removed under reduced pressure and temperature was lowered to 0 °C. 3N hydrochloric acid solution was added and the mixture was extracted with DCM (x3). The combined organic extracts were washed with aqueous 10% sodium hydrogencarbonate solution, water and brine, dried over magnesium sulfate, filtered and the solvent was evaporated. The residue was purified by flash chromatography (hexanes/diethyl ether) to yield the title product (1 11 mg, 82%) as a white solid.

MS (m/z): 174/176 [M+1/M+3]⁺ ¹ H-NMR d (400 MHz, CDCIs): 1.35 (t, J=7 Hz, 3H), 4.30 (t, J=7 Hz, 2H), 6.70-6.81 (m, 1 H), 7.29-7.43 (m, 1 H), 8.57 (s, 1 H). f) Ethyl 4-chloro-1-tetradecyl-1H-pyrrole-3-carboxylate To a cooled (0 °C) solution of ethyl 4-chloro-1 H-pyrrole-3-carboxylate (Intermediate 28e, 30 mg, 0.17 mmol) in DMF (1 ml_) was added sodium hydride (60% dispersion in mineral oil, 8.29 mg, 0.21 mmol) and the mixture was stirred at room temperature for 15 min. A solution of 1- bromotetradecane (50 mI_, 0.17 mmol) in DMF (0.5 ml_) was added dropwise and the reaction mixture was stirred at room temperature for 48 h. Water was added and the reaction mixture was extracted with toluene (x3). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and the solvent was evaporated. The residue was purified by flash chromatography (hexanes/diethyl ether) to yield the title compound (41 mg, 64%) as a colourless oil.

MS (m/z): 370/372 [M+1/M+3]⁺ ¹ H-NMR 5 (400 MHz, CDCh): 0.88 (t, J=7 Hz, 3H), 1.16-1.40 (m, 25H), 1.63-1.81 (m, 2H), 3.79 (t, J=7 Hz, 2H), 4.28 (q, J=7 Hz, 2H), 6.60 (d, J=3 Hz, 1 H), 7.21 (d, J=3 Hz, 1 H).

INTERMEDIATE 29

Ethyl 1-(2,2-dimethyltetradecyl)-4-fluoro-1H-pyrrole-3-carboxylate

Obtained as a colourless oil (58%) from ethyl 4-fluoro-1 H-pyrrole-3-carboxylate (Intermediate 21 b) and 2,2-dimethyltetradecyl trifluoromethanesulfonate (Intermediate 9b) following the experimental procedure described in Intermediate 7c.

MS (m/z): 382 [M+1]⁺.

¹ H-NMR d (300 MHz, CDCh): 0.86-0.91 (m, 9H), 1.22-1.31 (m, 22H), 1.34 (t, J=7.1 Hz, 2H), 3.54 (s, 2H), 4.29 (q, J=7.1 Hz, 2H), 6.32 (t, J= 3.0 Hz, 1 H), 6.91-6.93 (m, 1 H).

INTERMEDIATE 30

Ethyl 1-(3,3-dimethylpentadecyl)-4-fluoro-1H-pyrrole-3-carboxylate

Obtained as a colourless oil (58%) from ethyl 4-fluoro-1 H-pyrrole-3-carboxylate (Intermediate 21 b) and 3,3-dimethylpentadecyl trifluoromethanesulfonate (Intermediate 14d) following the experimental procedure described in Intermediate 7c.

MS (m/z): 382 [M+1]⁺. ¹ H-NMR 5 (400 MHz, CDCIs): 0.86-0.91 (m, 9H), 1.17-1.31 (m, 22H), 1.34 (t, J=7.1 Hz, 3H), 3.54 (s, 2H), 4.29 (q, J=7.1 Hz, 2H), 6.32 (t, J=3.0 Hz, 1 H), 6.90-6.94 (m, 1 H).

INTERMEDIATE 31

Methyl 4-fluoro-1-(2-fluorotetradecyl)-1 H-pyrrole-3-carboxylate

Obtained as a colourless oil (18%) from ethyl 4-fluoro-1 H-pyrrole-3-carboxylate (Intermediate 21 b) and 1-bromo-2-fluorotetradecane (Intermediate 16a) following the experimental procedure described in Intermediate 7c.

MS (m/z): 397 [M+1]⁺.

INTERMEDIATE 32

Ethyl 1-(2,2-difluorotetradecyl)-4-fluoro-1 H-pyrrole-3-carboxylate

Obtained as a white solid (59%) from ethyl 4-fluoro-1 H-pyrrole-3-carboxylate (Intermediate 21 b) and 2,2-difluorotetradecyl trifluoromethanesulfonate (Intermediate 18b) following the experimental procedure as described in Intermediate 7c.

MS (m/z): 390 [M+1]⁺.

¹ H-NMR 5 (400 MHz, CDCIs): 0.85-0.91 (m, 3H), 1.23-1.31 (m, 18H), 1.34 (t, J=7.1 Hz, 3H), 1.43-1.51 (m, 2H), 1.65-1.81 (m, 2H), 4.04 (t, J=12.8 Hz, 2H), 4.30 (q, J=7.1 Hz, 2H), 6.46 (t, J=3.1 Hz, 1 H), 7.03 (t, J=3.1 Hz, 1 H).

EXAMPLE 1

1-(2-(Undecyloxy)ethyl)-1 H-pyrrole-3-carboxylic acid

To a solution of methyl 1-(2-(undecyloxy)ethyl)-1 H-pyrrole-3-carboxylate (Intermediate 1 c, 32 mg, 0.09 mmol) in methanol (1 ml_) was added a 4M aqueous sodium hydroxide solution (0.36 ml_, 1.38 mmol) and the mixture was heated to reflux for 1 h. After cooling to room temperature, methanol was removed under reduced pressure. Water was added and the pH was lowered to 2- 3 by the addition of 1 N hydrochloric acid solution. The mixture was then extracted with EtOAc (x3) and the combined organic fractions were washed with brine, dried over magnesium sulfate, filtered and the solvent was evaporated to yield the title compound (27 mg, 87%) as a white solid.

MS (m/z): 310 [M+1]⁺ ¹ H-NMR d (400 MHz, CDCIs): 0.88 (t, J=7 Hz, 3H), 1.26 (s, 16H), 1.59-1.45 (m, 2H), 3.39 (t, J=7 Hz, 2H), 3.67 (t, J=5 Hz, 2H), 4.04 (t, J=5 Hz, 2H), 6.61 (dd, J=3 and 2 Hz, 1 H), 6.67 (t, J=3 Hz, 1 H), 7.40 (t, J=2 Hz, 1 H).

EXAMPLE 2

1-(9-Butoxynonyl)-1 H-pyrrole-3-carboxylic acid

To a solution of methyl 1-(9-butoxynonyl)-1 H-pyrrole-3-carboxylate (Intermediate 2b, 625 mg, 1.93 mmol) in ethanol (7.7 ml_) was added a 2N aqueous sodium hydroxide solution (7.70 ml_, 15.40 mmol) and the reaction mixture was stirred at 70 °C for 3 h. The solvent was removed in vacuo, water was added and the pH of the solution was adjusted to 2-3 by addition of 1 N hydrochloric acid solution. The reaction mixture was then extracted with EtOAc (x3). The combined organic extracts were washed with water and brine, dried over magnesium sulfate, filtered and the solvent evaporated to dryness. The residue was purified by flash chromatography (hexanes/diethyl ether) to yield the title compound (379 mg, 63%) as a solid.

MS (m/z): 310 [M+1]⁺ ¹ H-NMR d (400 MHz, CDCh): 0.91 (t, J=7.1 Hz, 3H), 1.21-1.41 (m, 10H), 1.50-1.60 (m, 4H), 1.71-1.80 (m, 2H), 3.38 (t, J=7.1 Hz, 2H), 3.40 (t, J=7.1 Hz, 2H), 3.86 (t, J=7.1 Hz, 2H), 6.58-6.62 (m, 2H), 7.35 (t, J=2 Hz, 1 H).

EXAMPLE 3

2,2,2-Trifluoroethyl 1-(9-butoxynonyl)-1 H-pyrrole-3-carboxylate

To a solution of 1-(9-butoxynonyl)-1 H-pyrrole-3-carboxylic acid (Example 2, 50 mg, 0.16 mmol) in DCM (1 mL) were added EDC HCI (37 mg, 0.19 mmol) and 4-DMAP (24 mg, 0.19 mmol) followed by 2,2,2-trifluoroethanol (18 mg, 0.18 mmol) and the mixture was stirred at room temperature for 16 h. The reaction mixture was then partitioned between DCM and water, the organic layer was separated and the aqueous layer was washed with DCM. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and the solvent evaporated to dryness. The residue was purified by flash chromatography (hexanes/diethyl ether) to yield the title compound (27 mg, 43%) as a white solid. ¹ H-NMR d (400 MHz, CDCh): 0.92 (t, J=7.4 Hz, 3H), 1.24-1.42 (m, 12H), 1.51-1.59 (m, 4H), 1.78 (q, J=7.1 Hz, 2H), 3.39 (td, J=6.7, 4.9 Hz, 4H), 3.87 (t, J=7.2 Hz, 2H), 4.59 (q, J=8.6 Hz, 2H), 6.59-6.62 (m, 2H), 7.34 (t, J=1.9 Hz, 1 H).

EXAMPLE 4

2-(2-Ethoxyethoxy)ethyl 1-(9-butoxynonyl)-1H-pyrrole-3-carboxylate

Obtained (27%) from 1-(9-butoxynonyl)-1 H-pyrrole-3-carboxylic acid (Example 2) and 2-(2- ethoxyethoxy)ethanol following the experimental procedure described in Example 3 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 426 [M+1]⁺ ¹ H-NMR d (400 MHz, CDCh): 0.92 (t, J=7.4 Hz, 3H), 1.21 (t, J=7.1 Hz, 3H), 1.25-1.40 (m, 12H), 1.51-1.58 (m, 4H), 1.76 (q, J=7.0 Hz, 2H), 3.39 (td, J=6.7, 4.9 Hz, 4H), 3.54 (q, J=7.0 Hz, 2H), 3.58-3.62 (m, 2H), 3.67-3.71 (m, 2H), 3.79 (dd, J=5.5, 4.5 Hz, 2H), 3.85 (t, J=7.1 Hz, 2H), 4.38 (dd, J=5.5, 4.5 Hz, 2H), 6.56-6.58 (m, 2H), 7.29 (t, J=1.9 Hz, 1 H).

EXAMPLE 5

1-(9-(Cyclohexyloxy)nonyl)-1 H-pyrrole-3-carboxylic acid

Obtained as a yellow oil (31 %) from cyclohexyl 1-(9-(cyclohexyloxy)nonyl)-1 H-pyrrole-3- carboxylate (Intermediate 3e) following the experimental procedure described in Example 2.

MS (m/z): 336 [M+1]⁺ ¹ H-NMR d (400 MHz, CDCh): 1.12-1.38 (m, 16H), 1.50-1.55 (m, 2H), 1.67-1.81 (m, 4H), 1.84-1.94 (m, 2H), 3.15-3.22 (m, 1 H), 3.42 (t, J=7 Hz, 2H), 3.86 (t, J=7 Hz, 2H), 6.58-6.62 (m, 2H), 7.35 (t, J=2 Hz, 1 H).

EXAMPLE 6

1-(2-(Dodecylthio)ethyl)-1 H-pyrrole-3-carboxylic acid

To a solution of methyl 1-(2-(dodecylthio)ethyl)-1 H-pyrrole-3-carboxylate (Intermediate 4b, 30 mg, 0.08 mmol) in ethanol (0.34 mL) was added a 2N aqueous sodium hydroxide solution (0.34 mL, 0.68 mmol) and the reaction mixture was stirred at 70 °C for 4 h. The solvent was removed in vacuo , water was added and the pH of the solution was adjusted to 2-3 by addition of 1 N hydrochloric acid solution. The precipitate was filtered, rinsed with water and dried to yield the title compound (24 mg, 83%) as a white solid.

MS (m/z): 340 [M+1]⁺ ¹ H-NMR d (400 MHz, CDCIs): 0.88 (t, J=7.0 Hz, 3H), 1.22-1.37 (m, 18H), 1.48-1.64 (m, 2H), 2.37-2.43 (m, 2H), 2.85 (t, J=7.0 Hz, 2H), 4.07 (t, J=7.0 Hz, 2H), 6.63 (dd, J=2.9, 1.8 Hz, 1 H), 6.64-6.66 (m, 1 H), 7.39 (t, J=1.8 Hz, 1 H).

EXAMPLE 7

1-(Pentadecan-2-yl)-1 H-pyrrole-3-carboxylic acid

Obtained (86%) from methyl 1-(pentadecan-2-yl)-1 H-pyrrole-3-carboxylate (Intermediate 5b) following the experimental procedure described in Example 2.

MS (m/z): 322 [M+1]⁺.

¹ H-NMR d (600 MHz, CDCIs): 0.87 (t, J=7.1 Hz, 3H), 1.22-1.29 (m, 22H), 1.44 (d, J=6.8 Hz, 3H), 1.66-1.74 (m, 2H), 3.97-4.03 (m, 1 H), 6.61-6.64 (m, 2H), 7.32 (t, J=2.0 Hz, 1 H).

EXAMPLE 8

1-(2-Methyltetradecyl)-1H-pyrrole-3-carboxylic acid

Obtained as a clear oil (72%) from methyl 1-(2-methyltetradecyl)-1 H-pyrrole-3-carboxylate (Intermediate 6e) following the experimental procedure as described in Example 2.

MS (m/z): 322 [M+1]⁺.

¹ H-NMR d (400 MHz, CDCIs): 0.84-0.90 (m, 6H), 1.05-1.15 (m, 1 H), 1.18-1.39 (m, 22H), 1.83-1.91 (m, 1 H), 3.61 (dd, J=14 and 8 Hz, 1 H), 3.79 (dd, J=14 and 6 Hz, 1 H), 6.56 (t, J=3 Hz, 1 H), 6.61 (dd, J=3 and 2 Hz, 1 H), 7.32 (t, J=2 Hz, 1 H).

EXAMPLE 9

1-(2,2-Dimethyldodecyl)-1H-pyrrole-3-carboxylic acid Obtained as a colourless oil (55%) from methyl 1-(2,2-dimethyldodecyl)-1 H-pyrrole-3-carboxylate (Intermediate 7c) following the experimental procedure as described in Example 2 followed by purification of the crude product by flash chromatography (DCM to ethanol).

MS (m/z): 308 [M+1]⁺.

¹ H-NMR d (400 MHz, CDCIs): 0.87-0.89 (m, 9H), 1.24-1.28 (m, 18H), 3.65 (s, 2H), 6.51- 6.55 (m, 1 H), 6.59 (dd, J=2.9, 1.8 Hz, 1 H), 7.28 (t, J=1.8 Hz, 1 H).

EXAMPLE 10

1-(2,2-Dimethyltridecyl)-1 H-pyrrole-3-carboxylic acid

Obtained as an off-white solid (78%) from methyl 1-(2,2-dimethyltridecyl)-1 H-pyrrole-3- carboxylate (Intermediate 8e) following the experimental procedure described in Example 2.

MS (m/z): 322 [M+1]⁺.

¹ H-NMR d (400 MHz, CDCIs): 0.88 (t, J=6.8 Hz, 3H), 0.89 (s, 6H), 1.23-1.30 (m, 20H), 3.65 (s, 2H), 6.52-6.55 (m, 1 H), 6.59 (dd, J=2.9, 1.8 Hz, 1 H), 7.28 (t, J=1.8 Hz, 1 H).

EXAMPLE 11

1-(2,2-Dimethyltetradecyl)-1 H-pyrrole-3-carboxylic acid

Obtained as an off-white solid (43%) from methyl 1-(2,2-dimethyltetradecyl)-1 H-pyrrole-3- carboxylate (Intermediate 9c) following the experimental procedure described in Example 2.

MS (m/z): 336 [M+1]⁺.

¹ H-NMR d (300 MHz, CDCIs): 0.84-0.92 (m, 9H), 1.23-1.29 (m, 22H), 3.65 (s, 2H), 6.51- 6.55 (m, 1 H), 6.56-6.62 (m, 1 H), 7.28 (t, J=1.8 Hz, 1 H).

EXAMPLE 12

2,2,2-Trifluoroethyl 1-(2,2-dimethyltetradecyl)-1H-pyrrole-3-carboxylate

Obtained as a colourless oil (29%) from 1-(2,2-dimethyltetradecyl)-1 H-pyrrole-3-carboxylic acid (Example 1 1) and 2,2,2-trifluoroethanol following the experimental procedure described in Example 3. MS (m/z): 418 [M+1]⁺.

¹ H-NMR d (400 MHz, CDCh): 0.88 (t, J=6.8 Hz, 3H), 0.89 (s, 6H), 1.23-1.30 (m, 20H), 3.65 (s, 2H), 6.52-6.55 (m, 1 H), 6.59 (dd, J=2.9, 1.8 Hz, 1 H), 7.28 (t, J=1.8 Hz, 1 H).

EXAMPLE 13

2-(2-Ethoxyethoxy)ethyl 1-(2,2-dimethyltetradecyl)-1 H-pyrrole-3-carboxylate

A mixture of 1-(2,2-dimethyltetradecyl)pyrrole-3-carboxylic acid (Example 11 , 80 mg, 0.2 4 mmol), 2-(2-ethoxyethoxy)ethanol (38 mg, 0.28 mmol), EDC HCI (44 mg, 0.28 mmol) and DMAP (35 mg, 0.28 mmol) was stirred in DCM (1 mL) at room temperature for 20 h. The reaction mixture was partitioned between water and DCM and the aqueous layer was separated and extracted with DCM (x2). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and the solvent was evaporated to dryness. The residue was purified by flash chromatography (DCM/methanol) to give the title compound (73 mg, 68%).

MS (m/z) 452 [M+1]⁺

1 H NMR d (400 MHz, CDCIs): 0.84-0.92 (m, 9H), 1.21 (t, J=7.0 Hz, 3H), 1.24-1.31 (m, 22H), 3.53 (q, J=7.0 Hz, 2H), 3.58-3.62 (m, 2H), 3.63 (s, 2H), 3.67-3.72 (m, 2H), 3.77-3.82 (m, 2H), 4.35-4.40 (m, 2H), 6.49-6.51 (m, 1 H), 6.55 (dd, J=2.8, 1.7 Hz, 1 H), 7.22 (t, J=1.9 Hz, 1 H).

EXAMPLE 14

2,3-Dihydroxypropyl 1-(2,2-dimethyltetradecyl)-1 H-pyrrole-3-carboxylate

To a solution of 1-(2,2-dimethyltetradecyl)pyrrole-3-carboxylic acid (Example 11 , 80 g, 0.238 mmol) and propane-1 , 2, 3-triol (205 mg, 2.23 mmol) in a mixture of DCM (2 mL) and DMSO (1 mL) were added EDCTHCI (55 mg, 0.287 mmol) and DMAP (35 mg, 0.287 mmol) and the mixture was stirred at room temperature for 18 h. The reaction mixture was partitioned between water and DCM and phases were separated. The organic phase was washed with 1 N hydrochloric acid solution and brine, dried over magnesium sulfate, filtered and solvent was evaporated. Purification of the residue by flash chromatography (DCM/methanol) gave the title compound (33 mg, 34%) as a clear oil.

MS (m/z): 410 [M+1]⁺. ¹ H-NMR d (400 MHz, CDCIs): 0.83-0.92 (m, 9H), 1.15-1.33 (m, 22H), 3.64 (s, 2H), 3.65 (dd, J=11.5 and 5.5 Hz, 1 H), 3.72 (dd, J=11.5 and 4 Hz, 1 H), 3.99 (p, J=5.2 Hz, 1 H), 4.31 (dd, J=11.8 and 6 Hz, 1 H), 4.36 (dd, J=11.8 and 5 Hz, 1 H), 6.51-6.55 (m, 2H), 7.24 (t, J=2 Hz, 1 H).

EXAMPLE 15

1-(((2-Methoxyethoxy)carbonyl)oxy)ethyl 1-(2,2-dimethyltetradecyl)-1H-pyrrole-3- carboxylate

To a solution of 1-(2,2-dimethyltetradecyl)pyrrole-3-carboxylic acid (Example 11 , 80 g, 0.238 mmol) and TEA (100 mI_, 0.717 mmol) in ACN (2 ml_) was added 1-chloroethyl 2-methoxyethyl carbonate (Intermediate 10, 65 mg, 0.356 mmol) and the mixture was heated at 100 °C for 20 h. Solvent was evaporated and purification of the resulting residue by flash chromatography (hexanes/diethyl ether) gave the title compound (43 mg, 37%) as clear oil.

MS (m/z): 499 [M+17]⁺.

¹ H-NMR d (400 MHz, CDCIs): 0.84-0.91 (m, 9H), 1.15-1.33 (m, 22H), 1.59 (d, J=5.5 Hz, 3H), 3.37 (s, 3H), 3.61 (t, J=5 Hz, 2H), 3.63 (s, 2H), 4.23-4.35 (m, 1 H), 6.49-6.51 (m, 1 H), 6.56 (dd, J=3 and 1.6 Hz, 1 H), 6.98 (q, J=5.4 Hz, 1 H), 7.23 (t, J=2 Hz, 1 H).

EXAMPLE 16

1-((lsopropoxycarbonyl)oxy)ethyl 1-(2,2-dimethyltetradecyl)-1H-pyrrole-3-carboxylate

Obtained as a clear oil (70%) from 1-(2,2-dimethyltetradecyl)pyrrole-3-carboxylic acid (Example 11) and 1-chloroethyl isopropyl carbonate following the experimental procedure described in Example 15 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 483 [M+17]⁺.

¹ H-NMR d (400 MHz, CDCIs): 0.83-0.91 (m, 9H), 1.15-1.32 (m, 28H), 1.59 (d, J=5.5 Hz, 3H), 3.63 (s, 2H), 4.89 (hept, J=6 Hz, 1 H), 6.49-6.51 (m, 1 H), 6.56 (dd, J=3 and 1.6 Hz, 1 H), 6.97 (q, J=5.4 Hz, 1 H), 7.23 (t, J=2 Hz, 1 H).

EXAMPLE 17 4-Oxo-3,5,8,11-tetraoxatridecan-2-yl 1-(2,2-dimethyltetradecyl)-1H-pyrrole-3-carboxylate

To a solution of 1-(2,2-dimethyltetradecyl)pyrrole-3-carboxylic acid (Example 11 , 80 mg, 0.24 mmol) in ACN (1.6 mL) was added 1-chloroethyl 2-(2-ethoxyethoxy)ethyl carbonate (Intermediate 11 , 58 mg, 0.24 mmol) and triethylamine (83 mί, 0.598 mmol) and the mixture was heated at 100 °C for 24 h. The solvent was removed under reduced pressure, EtOAc was added and the resulting solution was washed with water and brine, dried over magnesium sulfate, filtered and the solvent was evaporated. The residue was purified by flash chromatography (hexanes/diethyl ether) and by reverse phase chromatography to yield the title compound (24 mg, 18%) as a yellow oil.

MS (m/z): 540 [M+1]⁺

1 H NMR d (400 MHz, CDCIs): 0.85-0.92 (m, 9H), 1.20 (t, J=7.0 Hz, 3H), 1.26 (s, 22H), 1.59 (d, J=5.4 Hz, 3H), 3.52 (q, J=7.0 Hz, 2H), 3.56-3.60 (m, 2H), 3.64 (q, J=3.7, 3.1 Hz, 4H), 3.73 (t, J=4.8 Hz, 2H), 4.24-4.37 (m, 2H), 6.49-6.52 (m, 1 H), 6.56 (dd, J=2.9, 1.7 Hz, 1 H), 6.98 (q, J=5.4 Hz, 1 H), 7.24 (t, J=1.9 Hz, 1 H).

EXAMPLE 18

1-(2,2-Dimethylpentadecyl)-1H-pyrrole-3-carboxylic acid

Obtained as a white solid (78%) from methyl 1-(2,2-dimethylpentadecyl)-1 H-pyrrole-3-carboxylate (Intermediate 12e) following the experimental procedure described in Example 2.

MS (m/z): 350 [M+1]⁺.

¹ H-NMR d (400 MHz, CDCIs): 0.86-0.90 (m, 9H), 1.15-1.33 (m, 24H), 3.65 (s, 2H), 6.52- 6.54 (m, 1 H), 6.59 (dd, J=2.9, 1.8 Hz, 1 H), 7.28 (t, J=1.8 Hz, 1 H).

EXAMPLE 19

1-(3,3-Dimethyltridecyl)-1 H-pyrrole-3-carboxylic acid

Obtained as a beige solid (83%) from methyl 1-(3,3-dimethyltridecyl)-1 H-pyrrole-3-carboxylate (Intermediate 13e) following the experimental procedure described in Example 6.

MS (m/z): 350 [M+1]⁺. ¹ H-NMR d (400 MHz, CDCIs): 0.87 (t, J=7.0 Hz, 3H), 0.91 (s, 6H), 1.20-1.29 (m, 22H), 1.67-1.73 (m, 2H), 3.82-3.87 (m, 2H), 6.58-6.61 (m, 2H), 7.34 (t, J=1.8 Hz, 1 H).

EXAMPLE 20

1-(3,3-Dimethylpentadecyl)-1H-pyrrole-3-carboxylic acid

Obtained (73%) as a white solid from methyl 1-(3,3-dimethylpentadecyl)-1 H-pyrrole-3-carboxylate (Intermediate 14e) following the experimental procedure described in Example 6.

MS (m/z): 322 [M+1]⁺.

¹ H-NMR d (400 MHz, CDCIs): 0.86-0.93 (m, 9H), 1.19-1.33 (m, 18H), 1.68-1.75 (m, 2H), 3.83-3.89 (m, 2H), 6.59-6.62 (m, 2H), 7.36 (t, J=1.9 Hz, 1 H).

EXAMPLE 21

1-(14-Fluorotetradecyl)-1H-pyrrole-3-carboxylic acid

Obtained as a white solid (64%) from methyl 1-(14-fluorotetradecyl)-1 H-pyrrole-3-carboxylate (Intermediate 15b) following the experimental procedure described in Example 6.

MS (m/z): 326 [M+1]⁺.

¹ H-NMR d (400 MHz, CDCIs): 1.19-1.42 (m, 18H), 1.61-1.81 (m, 4H), 3.87 (t, J=7.1 Hz, 2H), 4.38 (t, J=6.2 Hz, 1 H), 4.49 (t, J=6.2 Hz, 1 H), 6.59-6.62 (m, 2H), 7.34 (t, J=1.9 Hz, 1 H).

EXAMPLES 22 and 23

( R )- and (S)-1-(2-Fluorotetradecyl)-1H-pyrrole-3-carboxylic acid

To a solution of methyl 1-(2-fluorotetradecyl)-1 H-pyrrole-3-carboxylate (Intermediate 16b, 98 mg, 0.29 mmol) in ethanol (1 mL) was added 2N aqueous solution of sodium hydroxide (1.2 mL, 2.4 mmol) and the mixture was stirred at 70 °C overnight. Ethanol was removed under reduced pressure, water was added and pH was adjusted to 2 by addition of 2N hydrochloric acid solution. The precipitate was filtered, washed with water and dried under vacuum to give the title compounds (80 mg, 85%) as a white solid.

MS (m/z): 326 [M+1]⁺. ¹ H-NMR d (400 MHz, CDCh): 0.81 (t, J=6.8 Hz, 3H), 1.16-1.26 (m, 20H), 3.89-4.10 (m, 2H), 4.48-4.73 (m, 1 H), 6.53-6.61 (m, 2H), 7.30 (s, 1 H).

Pure samples of both enantiomers:

23 mg of the first eluting enantiomer (Example 22)

17 mg of the second eluting enantiomer (Example 23)

were obtained after a chiral chromatographic separation of a sample of 48 mg of the racemic mixture under the following conditions:

Column: CHIRALPAK^® IC 5 mGP - 250 x 30 mm

Mobile phase: Acetonitrile + 0.1 % Formic Acid

Flow rate: 42.5 mL/min

Detection: UV 270 nm

Temperature: 25°C

Optical purity was assessed to be >98.5% (for Example 22) and >99.5% (for Example 23) using the following chromatographic condicions:

Column: CHIRALPAK^® IC 5 Im - 250 x 4.6 mm

Mobile phase: Acetonitrile + 0.1 % Formic Acid

Flow rate: 1 mL/min

EXAMPLE 24

1-(2,2-difluoroundecyl)-1H-pyrrole-3-carboxylic acid

Obtained as a white solid (88%) from methyl 1-(2,2-difluoroundecyl)-1 H-pyrrole-3-carboxylate (Intermediate 17c) following the experimental procedure described in Example 6.

MS (m/z): 302 [M+1]⁺.

¹ H-NMR d (400 MHz, CDCh): 0.88 (t, J=6.7 Hz, 3H), 1.22-1.32 (m, 12H), 1.44-1.53 (m, 2H), 1.66-1.80 (m, 2H), 4.17 (t, J=12.9 Hz, 2H), 6.64-6.67 (m, 2H), 7.38 (s, 1 H).

EXAMPLE 25

1-(2,2-Difluorotetradecyl)-1H-pyrrole-3-carboxylic acid Obtained as a white solid (84%) from methyl 1-(2,2-difluorotetradecyl)-1 H-pyrrole-3-carboxylate (Intermediate18c) following the experimental procedure described in Example 6.

MS (m/z): 344 [M+1]⁺.

¹ H-NMR d (400 MHz, CDCb): 0.88 (t, J=6.8 Hz, 3H), 1.20-1.35 (m, 18H), 1.49 (s, 2H), 1.65-1.81 (m, 2H), 4.17 (t, J=12.8 Hz, 2H), 6.64-6.67 (m, 1 H), 7.37 (s, 1 H).

EXAMPLE 26

4-Phenyl-1 -tetradecyl-1 H-pyrrole-3-carboxylic acid

Obtained as an oil (37%) from methyl 4-phenyl-1-tetradecyl-1 H-pyrrole-3-carboxylate (Intermediate 19b) following the procedure described in Example 2.

MS (m/z): 384 [M+1]⁺.

¹ H NMR d (400 MHz, CDCb): 0.88 (t, J=6.8 Hz, 3H), 1.25 (s, 22H), 1.84-1.76 (m, 2H), 3.87 (t, J=7.1 Hz, 2H), 6.64 (d, J=2.5 Hz, 1 H), 7.38-7.29 (m, 3H), 7.43 (d, J=2.5 Hz, 1 H), 7.50 (dd, J=8.2, 1.2 Hz, 2H).

EXAMPLE 27

1-(4-Decylphenyl)-1 H-pyrrole-3-carboxylic acid

Obtained as a white solid (59%) from methyl 1-(4-decylphenyl)-1 H-pyrrole-3-carboxylate (Intermediate 20) following the experimental procedure described in Example 6.

MS (m/z): 328 [M+1]⁺.

¹ H NMR d (400 MHz, CDCb): 0.88 (t, J=6.8 Hz, 3H), 1.24-1.36 (m, 14H), 1.58-1.68 (m, 2H), 2.61-2.67 (m, 2H), 6.79 (dd, J=2.9, 1.6 Hz, 1 H), 7.00-7.02 (m, 1 H), 7.24-7.28 (m, 2H), 7.32 (d, J=8.5 Hz, 2H), 7.74 (t, J=1.9 Hz, 1 H).

EXAMPLE 28

1-Decyl-4-fluoro-1 H-pyrrole-3-carboxylic acid

To a suspension of ethyl 1-decyl-4-fluoro-1 H-pyrrole-3-carboxylate (Intermediate 22, 61 mg, 0.20 mmol) in ethanol (1 mL) was added a solution of potassium hydroxide (75 mg, 1.33 mmol) in water (0.4 mL) and the resulting mixture was stirred at 60 °C for 2 h. The solvent was evaporated under reduced pressure, water was added and the pH was adjusted to 2 by addition of 2N hydrochloric acid solution. The aqueous solution was extracted with DCM (x3) and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. The resulting solid was triturated with hexanes, filtered and dried to give the title compound (32 mg, 58%) as a white solid.

MS (m/z): 269 [M+1]⁺.

¹ H-NMR d (400 MHz, CDCIs): 0.88 (t, J=6.8 Hz, 3H), 1.26 (s, 14H), 1.69-1.79 (m, 2H), 3.78 (t, J=7.1 Hz, 2H), 6.41 (t, J=3.1 Hz, 1 H), 7.07 (t, J=3.1 Hz, 1 H).

EXAMPLE 29

4-Fluoro-1 -tridecyl-1 H-pyrrole-3-carboxylic acid

Obtained as a light yellow solid (78%) from ethyl 4-fluoro-1-tridecyl-1 H-pyrrole-3-carboxylate (Intermediate 23) following the experimental procedure described in Example 28.

MS (m/z): 312 [M+1]⁺ ¹ H-NMR d (400 MHz, CDCIs): 0.93-0.82 (m, 3H), 1.25 (s, 20H), 1.80-1.67 (m, 2H), 3.83- 3.72 (m, 2H), 6.44-6.37 (m, 1 H), 7.12-7.04 (m, 1 H).

EXAMPLE 30

4-Fluoro-1 -tetradecyl-1 H-pyrrole-3-carboxylic acid

Obtained as a sligthly yellow solid (94%) from ethyl 4-fluoro-1-tetradecyl-1 H-pyrrole-3-carboxylate (Intermediate 24) following the experimental procedure described in Example 28.

MS (m/z): 326 [M+1]⁺ ¹ H-NMR d (400 MHz, CDCIs): 0.94-0.85 (m, 3H), 1.25 (s, 22H), 1.81-1.68 (m, 2H), 3.78 (t, J=7 Hz, 2H), 6.41 (t, J=3 Hz, 1 H), 7.06 (t, J=3 Hz, 1 H).

EXAMPLE 31

4-Fluoro-1 -pentadecyl-1 H-pyrrole-3-carboxylic acid

Obtained as a white solid (80%) from ethyl 4-fluoro-1-pentadecyl-1 H-pyrrole-3-carboxylate (Intermediate 25) following the experimental procedure described in Example 28.

MS (m/z): 340 [M+1]⁺ ¹ H-NMR d (400 MHz, CDCh): 0.98-0.81 (m, 3H), 1.25 (s, 24H), 1.80-1.66 (m, 2H), 3.78 (t, J=7 Hz, 2H), 6.41 (t, J=3 Hz, 1 H), 7.07 (t, J=3 Hz, 1 H).

EXAMPLE 32

1-(9-Butoxynonyl)-4-fluoro-1 H-pyrrole-3-carboxylic acid

Obtained as a beige solid (61 %) from ethyl 1-(9-butoxynonyl)-4-fluoro-1 H-pyrrole-3-carboxylate (Intermediate 26) following the experimental procedure described in Example 2.

MS (m/z): 326 [M-1]

¹ H-NMR d (400 MHz, CDCh): 0.92 (t, J=7.4 Hz, 3H), 1.23-1.43 (m, 12H), 1.51-1.59 (m, 4H), 1.69-1.78 (m, 2H), 3.39 (td, J=6.7, 4.4 Hz, 4H), 3.78 (t, J=7.1 Hz, 2H), 6.41 (t, J=3.1 Hz, 1 H), 7.06 (t, J=3.1 Hz, 1 H).

EXAMPLE 33

2-Fluoro-1 -tetradecyl-1 H-pyrrole-3-carboxylic acid

Obtained (79%) from methyl 2-fluoro-1 -tetradecyl-1 H-pyrrole-3-carboxylate (Intermediate 27b) following the experimental procedure described in Example 1 using potassium hydroxide as base.

MS (m/z): 326 [M+1]⁺ ¹ H NMR d (400 MHz, CDCh): 0.77-0.95 (m, 3H), 1.12-1.41 (m, 22H), 1.73 (p, J=8 and 7 Hz, 2H), 3.79 (t, J=7 Hz, 2H), 6.17 (dd, J=3 and 2 Hz, 1 H), 6.40 (dd, J=4 and 3 Hz, 1 H).

EXAMPLE 34

4-Chloro-1 -tetradecyl-1 H-pyrrole-3-carboxylic acid

Obtained as a white solid (79%) from ethyl 4-chloro-1-tetradecyl-1 H-pyrrole-3-carboxylate (Intermediate 28f) following the the experimental procedure as described Example 2 using potassium hydroxide as base.

MS (m/z): 342/344 [M+1/M+3] ¹ H-NMR d (400 MHz, CDCh): 0.88 (t, J=7 Hz, 3H), 1.27 (d, J=10 Hz, 22H), 1.75 (d, J=11 Hz, 2H), 3.82 (t, J=7 Hz, 2H), 6.63 (d, J=3 Hz, 1 H), 7.30 (d, J=3 Hz, 1 H).

EXAMPLE 35

4-Bromo-1-tetradecyl-1 H-pyrrole-3-carboxylic acid

Obtained as white solid (26%) from methyl 4-bromo-1-tetradecyl-1 H-pyrrole-3-carboxylate (Intermediate 19a) following the procedure described in Example 6.

MS (m/z): 386, 388 [M+1]⁺.

¹ H NMR d (400 MHz, CDCI3): 0.88 (t, J=6.8 Hz, 3H), 1.25 (m, 22H), 1.69 (m, 2H), 3.79 (m, 2H), 6.54 (s, 1 H), 7.29 (s, 1 H).

EXAMPLE 36

1-(2,2-Dimethyltetradecyl)-4-fluoro-1H-pyrrole-3-carboxylic acid

Obtained as a beige solid (24%) from ethyl 1-(2,2-dimethyltetradecyl)-4-fluoro-1 H-pyrrole-3- carboxylate (Intermediate 29b) following the experimental procedure as described in Example 2.

MS (m/z): 354 [M+1]⁺.

¹ H-NMR d (400 MHz, CDCh): 0.82-0.91 (m, 9H), 1.16-1.33 (m, 22H), 3.56 (s, 2H), 6.36 (t, J=3.0 Hz, 1 H), 6.98-7.01 (m, 1 H).

EXAMPLE 37

1-(3,3-Dimethylpentadecyl)-4-fluoro-1H-pyrrole-3-carboxylic acid

Obtained as a beige solid (24%) from ethyl 1-(3,3-dimethylpentadecyl)-4-fluoro-1 H-pyrrole-3- carboxylate (Intermediate 30b) following the experimental procedure as described in Example 2 followed by purification by reverse phase chromatography (water/ACN both with 0.5% of formic acid).

MS (m/z): 368 [M+1]⁺.

¹ H-NMR d (400 MHz, CDCh): 0.85-0.91 (m, 9H), 1.16-1.35 (m, 22H), 3.56 (s, 2H), 6.36 (t, J=3.0 Hz, 1 H), 6.97-7.01 (m, 1 H). EXAMPLE 38

4-Fluoro-1 -(2-fluorotetradecyl)-1 H-pyrrole-3-carboxylic acid

Obtained as white solid (79%) from methyl 4-fluoro-1-(2-fluorotetradecyl)-1 H-pyrrole-3- carboxylate (Intermediate 31) following the experimental procedure described in Example 6.

MS (m/z): 368 [M+1]⁺.

¹ H-NMR d (400 MHz, CDCIs): 0.88 (t, J=6.9 Hz, 3H), 0.91 (s, 6H), 1.18-1.32 (m, 20H), 1.65-1.71 (m, 2H), 3.71-3.81 (m, 2H), 6.40-6.43 (m, 1 H), 7.06-7.09 (m, 1 H).

EXAMPLE 39

1-(2,2-Difluorotetradecyl)-4-fluoro-1 H-pyrrole-3-carboxylic acid

Obtained as a white solid (78%) from ethyl 1-(2,2-difluorotetradecyl)-4-fluoro-1 H-pyrrole-3- carboxylate (Intermediate 32b) following the experimental procedure as described in Example 6.

MS (m/z): 362 [M+1]⁺.

¹ H-NMR d (300 MHz, CDCIs): 0.88 (t, J=6.8 Hz, 3H), 1.23-1.32 (m, 18H), 1.44-1.53 (m, 2H), 1.67-1.82 (m, 2H), 4.07 (t, J=12.8 Hz, 2H), 6.50 (t, J=3.0 Hz, 1 H), 7.1 1 (t, J=3.0 Hz, 1 H).

EXAMPLE 40

1 -(((2-methoxyethoxy)carbonyl)oxy)ethyl 1 -(9-butoxynonyl)-1 H-pyrrole-3-carboxylate

EXAMPLE 41

1-((lsopropoxycarbonyl)oxy)ethyl 1 -(9-butoxynonyl)-1 H-pyrrole-3-carboxylate

EXAMPLE 42

4-Oxo-3,5,8,11-tetraoxatridecan-2-yl 1-(9-butoxynonyl)-1 H-pyrrole-3-carboxylate

EXAMPLE 43

2,2,2-Trifluoroethyl 4-fluoro-1-tridecyl-1 H-pyrrole-3-carboxylate

EXAMPLE 44

2-(2-Ethoxyethoxy)ethyl 4-fluoro-1-tridecyl-1 H-pyrrole-3-carboxylate EXAMPLE 45

1-(((2-Methoxyethoxy)carbonyl)oxy)ethyl 4-fluoro-1-tridecyl-1H-pyrrole-3-carboxylate

EXAMPLE 46

1-((lsopropoxycarbonyl)oxy)ethyl 4-fluoro-1-tridecyl-1 H-pyrrole-3-carboxylate

EXAMPLE 47

4-oxo-3,5,8,11-tetraoxatridecan-2-yl 4-fluoro-1-tridecyl-1H-pyrrole-3-carboxylate

PHARMACOLOGICAL ACTIVITY

In vitro assay of inhibition of Lipid Synthesis

To evaluate the inhibition of lipid synthesis, the immortalized human sebocyte cell line, SZ95 (stablished by Zouboulis, C.C. et al J Invest Dermatol 1999; 113: 1011-20), was treated with arachidonic acid (AA) in presence or absence of compound. Lipids were detected by using a lipid sensing fluorophore.

10k cells were plated in 384 well microtiter plates and incubated at 37°C and 5% C02 in DMEM/F12 supplemented with 10% FBS, 1.25ng/ml of rhEGF and GA-1000, using the

MicroClime Lids from Labcyte to reduce the edge effect, before of compound and stimulus addition.

After 24h, compounds were dissolved in DMSO 100%. Then the stocks were serial diluted 1/3 in DMSO 100%, and this battery of solutions were diluted 1/10 in culture medium. Later, compounds dissolved in culture media were added over cells, diluting the solutions prepared 1/40 in the final volume of the assay. Then, cells and compounds were preincubated for 30 min at 37°C and 5% C02. After this prior incubation, the lipid synthesis was induced by 75mM of AA final solution, preparing a solution 10x in culture media containing a 1.25% of DMSO. Finally, SZ95 treated were incubated for 48h at 37°C and 5% C02.

Neutral lipids were measured using AdipoRedTM, purchased from Lonza. To do that, cells were washed with PBS and incubated with a solution of AdipoRedTM (final dilution 1/80 in PBS) for 30 min at room temperature. After the staining process, the fluorescence intensity (FI) was quantified using a fluorescence plate reader (excitation 485 nm; emission 535). Activity of compounds were calculated as % of inhibition considering the maximal fluorescence for AA-stimulated cells and the minimum fluorescence for unstimulated cells as controls.

Some of the acronyms used above have the following meaning:

AA: Arachidoin Acid

DMSO: dimethylsulfoxide

DMEM/F12: Dulbecco's Modified Eagle's Medium/F12

FBS: Fetal Bovine Serum

rhEGF: recombinant human Epidermal Growth Factor

GA-1000: Gentamicin/Amphotericin

PBS: Phosphate-buffered saline

FI: Fluorescece intensity

In the following table, I C50 values are represented by letters according to the value:

A: < 200 nM B: 200 - 1000 nM

C: > 1000 nM

It can be seen from Table 1 , that the pyrrole derivatives of the present invention are potent inhibitors of lipid synthesis. Preferred pyrrole derivatives of the invention possess an I C50 value for the inhibition of lipid synthesis (determined as defined above) of less than 1 mM (1000 nM), preferably of less than 0.20 pM (200 nM).

The invention is also directed to a compound of the invention as described herein for use in the treatment of the human or animal body by therapy. Compound of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products, or mixtures thereof. They may be obtained, for example, as solid plugs, powders or films by methods such as precipitation, crystallization, freeze drying, spray drying or evaporative drying. Microwave or radio frequency drying may be used for this purpose. COMBINATIONS

The pyrrole derivatives of the present invention may also be combined with other active compounds in the treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Acetyl-CoA carboxylase (ACC).

The combinations of the invention can optionally comprise one or more additional active substances which are known to be useful in the treatment of a dermatological disease, an inflammatory or autoimmune-mediated disease and a metabolism/endocrine function disorder; more in particular wherein the pathological condition or disease is selected from acne vulgaris, acne conglobata, inflammatory acne, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, oily skin, plaque psoriasis, guttate psoriasis, inverse psoriasis, erythrodermic psoriasis, scalp psoriasis, nail psoriasis, postular psoriasis and palmoplantar pustulosis, such as, a) Corticoids and glucocorticoids, such as beclomethasone, betamethasone, betamethasone dipropionate, budesonide, dexamethasone, fluticasone furoate, fluticasone propionate, hydrocortisone, methylprednisolone, mometasone furoate, prednicarbate, prednisolone or prednisone;

b) Dihydrofolate reductase inhibitors, such as methotrexate or pralatrexate;

c) Dihydroo rotate dehydrogenase (DHODH) inhibitors such as leflunomide, teriflunomide or ASLAN-003 or LAS186323;

d) Purine antagonists, such as azathioprine, mercaptopurine or tioguanine;

e) Antimalarials, such as hydroxichloroquine, chloroquine or quinacrine;

f) Calcineurin inhibitors, such as cyclosporine A, tacrolimus, pimecrolimus or voclosporin; g) Inosine-monophosphate dehydrogenase (IMPDH) inhibitors, such as mycophenolate mophetyl, ribavirin or mizoribine;

h) Fumaric acid esters, such as dimethyl fumarate;

i) Vitamine D3 derivatives such as calcipotriol, calcitriol or tacalcitol;

j) Retinoids, such as tazarotene, adapalene, tretinoin alitretinoin, acitretin or isotretinoin; k) Anti-tumor necrosis factor-alpha (Anti-TNF-alpha) monoclonal antibodies, such as infliximab, adalimumab, certolizumab pegol or golimumab;

L) Soluble Tumor necrosis factor-alpha (TNF-alpha) receptors such as etanercept or CC- 11050; m) Anti-Interleukin 6 Receptor (IL-6R) antibody, such as tocilizumab, sarilumab, SA-237 or ALX-0061 ;

n) Anti-Interleukin 12 (IL-12) / Interleukin 23 (IL-23) antibody, such as ustekinumab;

o) Anti-Interleukin 17 Receptor (IL-17R) antibody, such as brodalumab;

p) Anti-CD20 (B lymphocyte protein) antibody, such as rituximab, ofatumumab, obinutuzumab, ocrelizumab, ublituximab, veltuzumab, or ocaratuzumab;

q) Anti-Interleukin 5 (IL-5) antibody, such as mepolizumab;

r) Anti-Interleukin 5 Receptor (IL-5R) antibody, such as benralizumab;

s) Anti-Interleukin 13 (IL-13) antibody, such as lebrikizumab or tralokinumab;

t) Anti-Interleukin 4 Receptor (IL-4R) / Interleukin 13 Receptor (IL-13R) antibody, such as dupilumab;

u) Anti-Interleukin 17 (IL-17) antibody, such as secukinumab, ixekizumab or bimekizumab; v) An anti-IL-23 antibody such as tildrakizumab, guselkumab or risankizumab;

w) Anti-Interleukin 1 Receptor (I L-1 R) antibody;

x) Anti-lnmunoglobuline E (IgE) antibody, such as omalizumab or quilizumab;

y) Anti-B-cell activating factor (BAFF), such as belimumab or atacicept;

z) Anti-CD19 (B lymphocyte protein) monoclonal antibody, such as blinatumomab, MEDI- 551 or MOR-208;

aa) Kappa opioid agonists, such as nalfurafine, nalbuphine, asimadoline or CR-845;

bb) Neurokinin receptor 1 antagonists, such as aprepitant, fosaprepitant, rolapitant, orvepitant, tradipitant or serlopitant;

cc) Dihydropteroate synthase inhibitors, such as dapsone or sulfadoxine;

dd) Histamine 1 (H1) receptor antagonists, such as azelastine, ebastine, desloratadine, promethazine, mizolastine or cetirizine;

ee) Cysteinyl leukotriene (CysLT) receptor antagonists, such as montelukast, zafirlukast, tipelukast or masilukast;

ff) Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTh2)

antagonists, such as OC-459, AZD-1981 , ADC-3680, ARRY-502 or setipripant;

gg) Topical anti-septics, such as Benzoyl peroxide (BPO), triclosan, chlorhexidine, crystal violet 0.3% or sodium hypochlorite water-baths;

hh) Antibiotics such as tetracyclines (doxycycline, minocycline, and tetracycline ) macrolides (azithromycin, clarithromycin, erythromycin) or clindamycin;

ii) Azelaic acid;

jj) a-hydroxy acids such as glycolic acid or lactic acid; kk) b-hydroxy acids such as salycilic acid; and

II) A PDE4 inhibitor such as apremilast.

The pyrrole derivatives of the present invention and the combinations of the invention may be used in the treatment of a dermatological disease, an inflammatory or autoimmune-mediated disease and a metabolism/endocrine function disorder; more in particular wherein the pathological condition or disease is selected from acne vulgaris, acne conglobata, inflammatory acne, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, oily skin, plaque psoriasis, guttate psoriasis, inverse psoriasis, erythrodermic psoriasis, scalp psoriasis, nail psoriasis, postular psoriasis and palmoplantar pustulosis; preferably in the treatment of acne vulgaris, acne conglobata, inflammatory acne, choracne, plaque psoriasis, guttate psoriasis, inverse psoriasis, erythrodermic psoriasis, scalp psoriasis, nail psoriasis and postular psoriasis.

In a preferred embodiment the pyrrole derivatives of the present invention and the combinations of the invention may be used in the treatment of dermatological diseases.

In a more preferred embodiment, the pyrrole derivatives of the present invention and the combinations of the invention may be used in the treatment of acne vulgaris, acne conglobata, inflammatory acne, choracne, plaque psoriasis, guttate psoriasis, inverse psoriasis, erythrodermic psoriasis, scalp psoriasis, nail psoriasis and postular psoriasis.

The active compounds in the combination product may be administered together in the same pharmaceutical composition or in different compositions intended for separate, simultaneous, concomitant or sequential administration by the same or a different route.

It is contemplated that all active agents would be administered at the same time, or very close in time. Alternatively, one or two actives could be administered in the morning and the other(s) later in the day. Or in another scenario, one or two actives could be administered twice daily and the other(s) once daily, either at the same time as one of the twice-a-day dosing occurred, or separately. Preferably at least two, and more preferably all, of the actives would be administered together at the same time. Preferably, at least two, and more preferably all actives would be administered as an admixture.

The invention is also directed to a combination product of the pyrrole derivatives of the invention together with one or more other therapeutic agents for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Acetyl-CoA carboxylase (ACC), in particular wherein the pathological condition or disease is selected from a dermatological disease, an inflammatory or autoimmune-mediated disease and a metabolism/endocrine function disorder. More in particular wherein the pathological condition or disease is selected from acne vulgaris, acne conglobata, inflammatory acne, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, oily skin, plaque psoriasis, guttate psoriasis, inverse psoriasis, erythrodermic psoriasis, scalp psoriasis, nail psoriasis, postular psoriasis and palmoplantar pustulosis; preferably in the treatment of acne vulgaris, acne conglobata, inflammatory acne, choracne, plaque psoriasis, guttate psoriasis, inverse psoriasis, erythrodermic psoriasis, scalp psoriasis, nail psoriasis and postular psoriasis.

The invention also encompasses the use of a combination of the pyrrole derivatives of the invention together with one or more other therapeutic agents for the manufacture of a formulation or medicament for treating these diseases.

The invention also provides a method of treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Acetyl-CoA carboxylase (ACC), in particular wherein the pathological condition or disease is selected from a dermatological disease, an inflammatory or autoimmune-mediated disease and a metabolism/endocrine function disorder. More in particular wherein the pathological condition or disease is selected from acne vulgaris, acne conglobata, inflammatory acne, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, oily skin, plaque psoriasis, guttate psoriasis, inverse psoriasis, erythrodermic psoriasis, scalp psoriasis, nail psoriasis, postular psoriasis and palmoplantar pustulosis; preferably in the treatment of acne vulgaris, acne conglobata, inflammatory acne, choracne, plaque psoriasis, guttate psoriasis, inverse psoriasis, erythrodermic psoriasis, scalp psoriasis, nail psoriasis and postular psoriasis, comprising administering a therapeutically effective amount of a combination of the pyrrole derivatives of the invention together with one or more other therapeutic agents.

The active compounds in the combinations of the invention may be administered by any suitable route, depending on the nature of the disorder to be treated, e.g. orally (as syrups, tablets, capsules, lozenges, controlled-release preparations, fast-dissolving preparations, etc); topically (as creams, ointments, lotions, nasal sprays or aerosols, etc) or by injection (subcutaneous, intradermic, intramuscular, intravenous, etc). The active compounds in the combination, i.e. the pyrrole derivatives of the invention, and the other optional active compounds may be administered together in the same pharmaceutical composition or in different compositions intended for separate, simultaneous, concomitant or sequential administration by the same or a different route.

One execution of the present invention consists of a kit of parts comprising a pyrrole derivative of the invention together with instructions for simultaneous, concurrent, separate or sequential use in combination with another active compound useful in the treatment of acne vulgaris, acne conglobata, inflammatory acne, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, oily skin, plaque psoriasis, guttate psoriasis, inverse psoriasis, erythrodermic psoriasis, scalp psoriasis, nail psoriasis, postular psoriasis and palmoplantar pustulosis; preferably in the treatment of acne vulgaris, acne conglobata, inflammatory acne, choracne, plaque psoriasis, guttate psoriasis, inverse psoriasis, erythrodermic psoriasis, scalp psoriasis, nail psoriasis and postular psoriasis.

Another execution of the present invention consists of a package comprising a pyrrole derivative of the invention and another active compound useful in the treatment of acne vulgaris, acne conglobata, inflammatory acne, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, oily skin, plaque psoriasis, guttate psoriasis, inverse psoriasis, erythrodermic psoriasis, scalp psoriasis, nail psoriasis, postular psoriasis and palmoplantar pustulosis; preferably in the treatment of acne vulgaris, acne conglobata, inflammatory acne, choracne, plaque psoriasis, guttate psoriasis, inverse psoriasis, erythrodermic psoriasis, scalp psoriasis, nail psoriasis and postular psoriasis.

PHARMACEUTICAL COMPOSITIONS

Pharmaceutical compositions according to the present invention comprise the pyrrole derivatives of the invention in association with a pharmaceutically acceptable diluent or carrier.

As used herein, the term pharmaceutical composition refers to a mixture of one or more of the pyrrole derivatives of the invention or prodrugs thereof, with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism. As used herein, a physiologically/pharmaceutically acceptable diluent or carrier refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

The invention further provides pharmaceutical compositions comprising the pyrrole derivatives of the invention in association with a pharmaceutically acceptable diluent or carrier together with one or more other therapeutic agents for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Acetyl-CoA carboxylase (ACC), such as the ones previously described.

The invention is also directed to pharmaceutical compositions of the invention for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Acetyl- CoA carboxylase (ACC), in particular wherein the pathological condition or disease is selected from a dermatological disease, an inflammatory or autoimmune-mediated disease and a metabolism/endocrine function disorder. More in particular wherein the pathological condition or disease is selected from acne vulgaris, acne conglobata, inflammatory acne, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, oily skin, plaque psoriasis, guttate psoriasis, inverse psoriasis, erythrodermic psoriasis, scalp psoriasis, nail psoriasis, postular psoriasis and palmoplantar pustulosis; preferably in the treatment of acne vulgaris, acne conglobata, inflammatory acne, choracne, plaque psoriasis, guttate psoriasis, inverse psoriasis, erythrodermic psoriasis, scalp psoriasis, nail psoriasis and postular psoriasis.

The invention also encompasses the use of a pharmaceutical composition of the invention for the manufacture of a medicament for treating these diseases.

The invention also provides a method of treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Acetyl-CoA carboxylase (ACC), in particular wherein the pathological condition or disease is selected from a dermatological disease, an inflammatory or autoimmune-mediated disease and a metabolism/endocrine function disorder. More in particular wherein the pathological condition or disease is selected from acne vulgaris, acne conglobata, inflammatory acne, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, oily skin, plaque psoriasis, guttate psoriasis, inverse psoriasis, erythrodermic psoriasis, scalp psoriasis, nail psoriasis, postular psoriasis and palmoplantar pustulosis; preferably in the treatment of acne vulgaris, acne conglobata, inflammatory acne, choracne, plaque psoriasis, guttate psoriasis, inverse psoriasis, erythrodermic psoriasis, scalp psoriasis, nail psoriasis and postular psoriasis, comprising administering a therapeutically effective amount of a pharmaceutical composition of the invention.

The present invention also provides pharmaceutical compositions which comprise, as an active ingredient, at least a pyrrole derivative of the invention in association with a pharmaceutically acceptable excipient such as a carrier or diluent. Preferably the compositions are made up in a form suitable for oral, topical, nasal, rectal, percutaneous or injectable administration. The compounds of the present invention show physicochemical properties (such as solubility water and in a range of lipophilic and hydrophilic solvents, melting point and stability), which make them specially suitable for topical or oral administration.

In a preferred embodiment, the compositions are made up in a form suitable for topical administration.

In another preferred embodiment, the compositions are made up in a form suitable for oral administration.

Pharmaceutical compositions suitable for the delivery of pyrrole derivatives of the invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Williams & Wilkins, Philadelphia, Pa., 2001. i) Topical Administration

The pyrrole derivatives of the invention may be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free injection.

Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. ii) Oral Administration The pyrrole derivatives of the invention may be administered orally (peroral administration; per os (latin)). Oral administration involve swallowing, so that the compound is absorbed from the gut and delivered to the liver via the portal circulation (hepatic first pass metabolism) and finally enters the gastrointestinal (Gl) tract.

Compositions for oral administration may take the form of tablets, retard tablets, sublingual tablets, capsules, inhalation aerosols, inhalation solutions, dry powder inhalation, or liquid preparations, such as mixtures, solutions, elixirs, syrups or suspensions, all containing the compound of the invention; such preparations may be made by methods well-known in the art. The active ingredient may also be presented as a bolus, electuary or paste. iii) Oral mucosal administration

The pyrrole derivatives of the invention can also be administered via the oral mucosal. Within the oral mucosal cavity, delivery of drugs is classified into three categories: (a) sublingual delivery, which is systemic delivery of drugs through the mucosal membranes lining the floor of the mouth, (b) buccal delivery, which is drug administration through the mucosal membranes lining the cheeks (buccal mucosa), and (c) local delivery, which is drug delivery into the oral cavity.

Pharmaceutical products to be administered via the oral mucosal can be designed using mucoadhesive, quick dissolve tablets and solid lozenge formulations, which are formulated with one or more mucoadhesive (bioadhesive) polymers and/or oral mucosal permeation enhancers. iv) Inhaled administration

The pyrrole derivatives of the invention can also be administered by inhalation, typically in the form of a dry powder from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant. v) Nasal mucosal administration

The pyrrole derivatives of the invention may also be administered via the nasal mucosal.

Typical compositions for nasal mucosa administration are typically applied by a metering, atomizing spray pump and are in the form of a solution or suspension in an inert vehicle such as water optionally in combination with conventional excipients such as buffers, anti-microbials, tonicity modifying agents and viscosity modifying agents vi) Parenteral Administration

The pyrrole derivatives of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.

The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art. The solubility of compounds of the invention used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents. vii) Rectal/lntravaginal Administration

The pyrrole derivatives of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate. Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

viii) Ocular Administration

The pyrrole derivatives of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH- adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable {e.g. absorbable gel sponges, collagen) and nonbiodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. Such formulations may also be delivered by iontophoresis. Formulations for ocular/aural administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release.

The amount of the active pyrrole derivative of the invention administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is typically in the range of 0.01-3000 mg, more preferably 0.5-1000 mg of active ingredient or the equivalent amount of a pharmaceutically acceptable salt thereof per day. Daily dosage may be administered in one or more treatments, preferably from 1 to 4 treatments, per day.

Preferably, the pharmaceutical compositions of the invention are made up in a form suitable for oral or topical administration.

The amount of each active which is required to achieve a therapeutic effect will, of course, vary with the particular active, the route of administration, the subject under treatment, and the particular disorder or disease being treated.

Claims

1. A pyrrole derivative, which pyrrole derivative is a compound of Formula (I), or a pharmaceutically acceptable salt, or a solvate, or a /V-oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof:

Formula (I)

wherein:

• R¹ is selected from the group consisting of a hydrogen atom, a linear or branched C_1-4 haloalkyl group, a linear or branched C_1-4 hydroxyalkyl group, a -[(CH₂)₂0]i-₂-R^a group and a -(CR^bR^c)-0C(0)0-R⁵ group,

• R² represents a hydrogen atom or a halogen atom,

• R³ is selected from the group consisting of a hydrogen atom, a halogen atom and a phenyl group,

• R⁴ is selected from the group consisting of a linear or branched C_10-17 alkyl group, a linear or branched C9-17 haloalkyl group, a -(CH2)n-L-(CH₂)m-CH3 group, a -(CH₂)3-9-L-(C3-6 monocyclic cycloalkyl group) and a phenyl ring which is substituted by a linear or branched Ce-io alkyl group,

• L represents -O- or -S-,

• R⁵ is selected from the group consisting of a linear or branched C_1-3 alkyl group and a - [(CH₂)i-2-0]i-₂-R^d group,

• R^a, R^b, R^c and R^d are each independently selected from the group consisting of a hydrogen atom and a linear or branched C1-4 alkyl group, and

2. A pyrrole derivative according to claim 1 wherein R¹ represents a hydrogen atom, a C2 fluoroalkyl group, a -[(CH₂)₂0]₂-CH₂CH₃ group and a -(CH(CH₃))-0C(0)0-R⁵ group; preferably R¹ represents a hydrogen atom.

3. A pyrrole derivative according to claims 1 or 2 wherein R² is a hydrogen atom or a fluorine atom, preferably a hydrogen atom.

4. A pyrrole derivative according to claims 1 to 3, wherein R^a, R^b and R^d each independently represent a methyl group or an ethyl group.

5. A pyrrole derivative according to claims 1 to 4, wherein R^c represents a hydrogen atom.

6. A pyrrole derivative according to claims 1 to 5 wherein R³ is selected from the group consisting of a hydrogen atom and a fluorine atom.

7. A pyrrole derivative according to claims 1 to 6 wherein R⁴ is selected from the group consisting of a linear or branched C10-17 alkyl group, a linear or branched C12-15 haloalkyl group and a -(Chh 0-(CH₂)m-CH₃ group.

8. A pyrrole derivative according to claim 7, wherein n is an integer from 2 to 9, m is an integer from 3 to 11 and n+m results in an integer from 11 to 14.

9. A pyrrole derivative according to claim 1 , wherein:

• R¹ is selected from the group consisting of a hydrogen atom, a C2 fluoroalkyl group, a - [(CH₂)₂0]₂-CH₂CH₃ group and a -(CH(CH₃))-0C(0)0-R⁵ group; preferably represents a hydrogen atom,

• R² is a hydrogen atom or a fluorine atom, preferably a hydrogen atom,

• R⁴ is selected from the group consisting of a linear or branched C10-17 alkyl group, a linear or branched C12-15 haloalkyl group and a -(CH₂)_n-0-(CH₂)_m-CH₃ group,

• R⁵ is selected from the group consisting of a linear or branched C1-3 alkyl group and a [(CH₂)20]_1-2-R^d group

• R^a, R^b and R^d independently represent a methyl group or an ethyl group,

• R^c represents a hydrogen atom, and

10. A pyrrole derivative according to claim 1 , wherein:

-CH₂CH(OH)CH₂OH group, a -[(CH₂)₂0]₂CH₂CH₃ group, a -CH(CH₃)-0C(0)- 0(CH₂)₂0CH₃ group, a -CH(CH₃)-0C(0)-0[(CH₂)₂0]₂CH₂CH₃ group and a -CH(CH₃)- 0C(0)0CH(CH₃)₂ group.

• R² represents a hydrogen or a fluorine atom,

• R⁴ is selected from the group consisting of a -CH(CH₃)-(CH₂)I₂CH₃ group, a -(CH₂)- CH(CH₃)-(CH₂)I ICH₃ group, a -(CH₂)-C(CH₃)₂-(CH₂)₉CH₃ group, a -(CH₂)-C(CH₃)₂- (CH₂)₁₀CH₃ group, a -(Chy-CCCHsMCH^nCHs group, a -(CH₂)-C(CH₃)₂-(CH₂)₁₂CH₃ group, a -(CH₂)₂-C(CH₃)₂-(CH₂)9CH₃ group, a -(CH₂)I₃CH₂F group, a - (CH₂)CHF(CH₂)H CH₃ group, a -(CH₂)CF₂(CH₂)nCH₃ group, a -(CH₂)₉-0-(CH₂)₃CH₃, a - (CH₂)₉-0-cyclohexyl group, an n-decyl group, a n-tridecyl group, a n-tetradecyl group, a n-pentadecyl group, a -(CH₂)₂-0-(CH₂)io-CH₃ group, a -(CH₂)₉-0-(CH₂)₃-CH₃ group, a - (CH₂)₂-S-(CH₂)I ICH₃ group and a phenyl group substituted by a n-decyl group, and

• R⁵ represents a -CH(CH₃)₂ group, a -(CH₂)₂OCH₃ group or a -[(CH₂)₂]0₂CH₂CH₃ group, characterized in that when R⁴ is a linear C_10-17 alkyl group, at least one of R² or R³ is not a hydrogen atom.

11. A pyrrole derivative according to claims 1 to 12 wherein the compound of Formula (I) is one of:

1-(2-(Undecyloxy)ethyl)-1 H-pyrrole- 3-carboxyl ic acid;

1-(9-Butoxynonyl)-1 H-pyrrole-3-carboxylic acid;

2,2,2-T rifluoroethyl 1-(9-butoxynonyl)-1 H-pyrrole-3-carboxylate;

2-(2-Ethoxyethoxy)ethyl 1-(9-butoxynonyl)-1 H-pyrrole-3-carboxylate;

1-(9-(Cyclohexyloxy)nonyl)-1 H-pyrrole-3-carboxylic acid;

1-(2-(Dodecylthio)ethyl)-1 H-pyrrole-3-carboxylic acid;

1-(Pentadecan-2-yl)-1 H-pyrrole-3-carboxylic acid;

1-(2-Methyltetradecyl)-1 H-pyrrole-3-carboxylic acid;

1-(2,2-Dimethyldodecyl)-1 H-pyrrole-3-carboxylic acid;

1-(2,2-Dimethyltridecyl)-1 H-pyrrole-3-carboxylic acid;

1-(2,2-Dimethyltetradecyl)-1 H-pyrrole-3-carboxylic acid; 2,2,2-T rifluoroethyl 1-(2,2-dimethyltetradecyl)-1 H-pyrrole-3-carboxylate;

2-(2-Ethoxyethoxy)ethyl 1-(2,2-dimethyltetradecyl)-1 H-pyrrole-3-carboxylate;

2,3-Dihydroxypropyl 1-(2,2-dimethyltetradecyl)-1 H-pyrrole-3-carboxylate;

1-(3,3-dimethyltridecyl)-1 H-pyrrole- 3-carboxyl ic acid;

1-(3,3-Dimethylpentadecyl)-1 H-pyrrole- 3-carboxylic acid;

1-(14-Fluorotetradecyl)-1 H-pyrrole-3-carboxylic acid;

(R)-1-(2-Fluorotetradecyl)-1 H-pyrrole-3-carboxylic acid;

(S)-1-(2-Fluorotetradecyl)-1 H-pyrrole-3-carboxylic acid;

1-(2,2-difluoroundecyl)-1 H-pyrrole-3-carboxylic acid;

1-(2,2-Difluorotetradecyl)-1 H-pyrrole- 3-carboxylic acid;

4- Phenyl- 1-tetradecyl-1 H-pyrrole-3-carboxylic acid;

1-(4-Decylphenyl)-1 H-pyrrole-3-carboxylic acid;

1-Decyl-4-fluoro-1 H-pyrrole-3-carboxylic acid;

4-Fluoro-1-tridecyl-1 H-pyrrole-3-carboxylic acid;

4-Fluoro-1-tetradecyl-1 H-pyrrole-3-carboxylic acid;

4-Fluoro-1-pentadecyl-1 H-pyrrole- 3-carboxylic acid;

1-(9-Butoxynonyl)-4-fluoro-1 H-pyrrole-3-carboxylic acid;

5-Fluoro-1-tetradecyl-1 H-pyrrole-3-carboxylic acid;

2-Fluoro-1-tetradecyl-1 H-pyrrole-3-carboxylic acid;

4-Chloro-1-tetradecyl-1 H-pyrrole-3-carboxylic acid;

4-Bromo-1-tetradecyl-1 H-pyrrole-3-carboxylic acid;

1-(2,2-Dimethyltetradecyl)-4-fluoro-1 H-pyrrole-3-carboxylic acid;

1-(3,3-Dimethylpentadecyl)-4-fluoro-1 H-pyrrole-3-carboxylic acid;

4-Fluoro-1-(2-fluorotetradecyl)-1 H-pyrrole- 3-carboxylic acid;

1-(2,2-Difluorotetradecyl)-4-fluoro-1 H-pyrrole-3-carboxylic acid;

1-((lsopropoxycarbonyl)oxy)ethyl 1-(9-butoxynonyl)-1 H-pyrrole-3-carboxylate;

2,2,2-T rifluoroethyl 4-fluoro-1-tridecyl-1 H-pyrrole-3-carboxylate;

2-(2-Ethoxyethoxy)ethyl 4-fluoro-1-tridecyl-1 H-pyrrole-3-carboxylate; 1-(((2-Methoxyethoxy)carbonyl)oxy)ethyl 4-fluoro-1-tridecyl-1 H-pyrrole-3-carboxylate; 1-((lsopropoxycarbonyl)oxy)ethyl 4-fluoro-1-tridecyl-1 H-pyrrole-3-carboxylate;

4-Oxo-3,5,8, 1 1-tetraoxatridecan-2-yl 4-fluoro-1-tridecyl-1 H-pyrrole-3-carboxylate;

12. A pyrrole derivative as defined in any one of claims 1 to 1 1 , for use in the treatment of the human or animal body by therapy.

13. A pyrrole derivative as defined in any one of claims 1 to 1 1 , for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibition of Acetyl-CoA carboxylase.

14. A pyrrole derivative according to any one of claims 1 to 11 , for use according to claim 13 wherein the treatment is of a pathological condition or disease selected from acne vulgaris, acne conglobate, inflammatory acne, chroacne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, oily skin, plaque psoriasis, guttate psoriasis, inverse psoriasis, erythrodermic psoriasis, scalp psoriasis, nail psoriasis, postular psoriasis and palmoplantar pustulosis.

15. A pyrrole derivative according to any one of claims 1 to 1 1 , for use according to claims 13 and 14 wherein the treatment is of a pathological condition or disease selected from acne vulgaris, acne conglobate, inflammatory acne, chroacne, plaque psoriasis, guttate psoriasis, inverse psoriasis, erythodermic psoriasis, scalp psoriasis, nail psoriasis and postular psoriasis.

16. A pharmaceutical composition comprising a pyrrole derivative as defined in any one of claims 1 to 11 in association with a pharmaceutically acceptable diluent or carrier.

17. Use of a pyrrole derivative as defined in any one of claims 1 to 1 1 , for the manufacture of a medicament for the treatment of a pathological condition or disease as defined in claims 13 to 15.

18. A method for treating a subject afflicted with a pathological condition or disease as defined in claims 13 to 15, which comprises administering to said subject a therapeutically effective amount of a pyrrole derivative as defined in any one of claims 1 to 1 1 , or a pharmaceutical composition as defined in claim 16.

19. A combination product comprising (i) at least one pyrrole derivative as defined in any one of claims 1 to 11 , and (ii) one or more active ingredients selected from:

a) Corticoids and glucocorticoids, such as beclomethasone, betamethasone,

betamethasone dipropionate, budesonide, dexamethasone, fluticasone furoate, fluticasone propionate, hydrocortisone, methylprednisolone, mometasone furoate, prednicarbate, prednisolone or prednisone;

b) Dihydrofolate reductase inhibitors, such as methotrexate or pralatrexate;

d) Purine antagonists, such as azathioprine, mercaptopurine or tioguanine;

e) Antimalarials, such as hydroxichloroquine, chloroquine or quinacrine;

h) Fumaric acid esters, such as dimethyl fumarate;

i) Vitamine D3 derivatives such as calcipotriol, calcitriol or tacalcitol;

j) Retinoids, such as tazarotene, adapalene, tretinoin alitretinoin, acitretin or isotretinoin; k) Anti-tumor necrosis factor-alpha (Anti-TNF-alpha) monoclonal antibodies, such as

infliximab, adalimumab, certolizumab pegol or golimumab;

L) Soluble Tumor necrosis factor-alpha (TNF-alpha) receptors such as etanercept or CC- 11050;

m) Anti-Interleukin 6 Receptor (IL-6R) antibody, such as tocilizumab, sarilumab, SA-237 or ALX-0061 ;

o) Anti-Interleukin 17 Receptor (IL-17R) antibody, such as brodalumab;

p) Anti-CD20 (B lymphocyte protein) antibody, such as rituximab, ofatumumab,

obinutuzumab, ocrelizumab, ublituximab, veltuzumab, or ocaratuzumab;

q) Anti-Interleukin 5 (IL-5) antibody, such as mepolizumab;

r) Anti-Interleukin 5 Receptor (IL-5R) antibody, such as benralizumab;

s) Anti-Interleukin 13 (IL-13) antibody, such as lebrikizumab or tralokinumab;

w) Anti-Interleukin 1 Receptor (I L-1 R) antibody;

x) Anti-lnmunoglobuline E (IgE) antibody, such as omalizumab or quilizumab;

y) Anti-B-cell activating factor (BAFF), such as belimumab or atacicept;

bb) Neurokinin receptor 1 antagonists, such as aprepitant, fosaprepitant, rolapitant,

orvepitant, tradipitant or serlopitant;

cc) Dihydropteroate synthase inhibitors, such as dapsone or sulfadoxine;

ff) Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTh2)

antagonists, such as OC-459, AZD-1981 , ADC-3680, ARRY-502 or setipripant;

ii) Azelaic acid;

jj) a-hydroxy acids such as glycolic acid or lactic acid;

kk) b-hydroxy acids such as salycilic acid; and

II) A PDE4 inhibitor such as apremilast.