WO2020245297A1

WO2020245297A1 - Pyrrole derivatives as acc inhibitors

Info

Publication number: WO2020245297A1
Application number: PCT/EP2020/065526
Authority: WO
Inventors: Jordi Bach Taña; Cristina Esteve Trias
Original assignee: Almirall SA
Current assignee: Almirall SA
Priority date: 2019-06-06
Filing date: 2020-06-04
Publication date: 2020-12-10
Anticipated expiration: 2021-12-06

Abstract

Novel pyrrole derivatives of Formula (I) are disclosed; as well as processes 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 al. 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, nonalcoholic 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 linear or branched C5-14 alkyl group and a linear or branched C_6-M alkoxy group and a -0-(CH₂)_3-6-0R^e group,

• R² represents a hydrogen atom or a halogen atom,

• L represents a -º- group, a phenyl ring, a monocyclic C3-7 cycloalkyl group, a monocyclic C5-7 cycloalkenyl group or a monocyclic 5- to 6-membered heteroaryl group containing one or more heteroatoms selected from the group consisting of O and N, wherein the phenyl, cycloalkyl, cycloalkenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a linear or branched C1-6 alkyl group, a linear or branched C1-6 alkoxy group, a hydroxyl group, a linear or branched C1-3 haloalkyl group and a halogen atom,

• R³ represents a hydrogen atom or a linear or branched C_1-4 alkyl group,

• R⁴ is selected from the group consisting of a hydrogen atom, a linear or branched C1-2 haloalkyl group, a -[(CH₂)₂0)]i-₂-R^a and a -(CR^bR^c)-0C(0)0-R⁵ group,

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

• R^e represents a hydrogen atom or a linear or branched C_1-4 alkyl group.

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

As used herein the term C5-14 alkyl embraces linear or branched radicals having 5 to 14 carbon atoms. Examples of C5-14 alkyl radicals include pentyl, hexyl, heptyl, 2-ethylhexyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl and tetradecyl.

As used herein, the term C1-6 alkyl embraces linear or branched radicals having 1 to 6 carbon atoms. Analogously, the term C1-4 alkyl embraces unsubstituted linear or branched radicals having 1 to 4 carbon atoms. Examples of C1 -6 alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, sec- butyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, isopentyl, 1-ethylpropyl, 1 , 1 -dimethylpropyl, 1 ,2-dimethylpropyl, n-hexyl, 1-ethylbutyl, 2-ethylbutyl, 1 , 1 -dimethylbutyl, 1 ,2-dimethylbutyl, 1 ,3- dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 2-methylpentyl, 3-methylpentyl and iso-hexyl radicals.

As used herein, the term Ce-14 alcoxy (or alkyloxy) embraces linear or branched oxy-containing radicals each having alkyl portions of 6 to 14 carbon atoms. Examples of C6-i4 alkoxy radicals include hexyloxy, heptyloxyl, octyloxyl, nonyloxyl, decyloxyl, undecyloxyl, dodecyloxyl, tridecyloxyl, 4-methyldodecyloxyl, 5,6-dimethylundecyloxyl and tetradecyloxyl.

As used herein, the term Ci-e alkoxy (or alkyloxy) embraces linear or branched oxy-containing radicals each having alkyl portions of 1 to 6 carbon atoms. Examples of Ci-e alkoxy radicals include methoxy, ethoxy, n-propoxy, /-propoxy, n-butoxy, sec-butoxy, f-butoxy, n- pentoxy and n-hexoxy.

As used herein, the term 5- to 6-membered heteroaryl radical embraces typically a 5- to 6- membered ring system comprising at least one heteroaromatic ring and containing at least one heteroatom selected from O and N. Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, oxadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl or pyrrolyl.

As used herein, the term C_3-7 cycloalkyl embraces saturated monocyclic carbocyclic radicals having from 3 to 7 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cycobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

As used herein, the term C_5-7 cycloalkenyl embraces partially unsaturated monocyclic carbocyclic radicals having from 5 to 7 carbon atom. A C_5-7 cycloalkenyl radical is typically unsubstituted or substituted by 1 , 2 or 3 substituents which might be the same or different. Typically, the substituents on a cycloalkenyl group are themselves unsubtituted. Examples include, cyclopentenyl, cyclohexenyl or cycloheptenyl.

As used herein the term C_1-3 haloalkyl is a linear or branched alkyl group, which is substituted by one or more, preferably 1 , 2 or 3 halogen atoms. Analogously, the term C_1-2 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 CCI₃, CF₃, CHF₂, CH₂CF₃ and CH₂CHF₂.

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, 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 replaced 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.

Typically, the compound of Formula (I) is a compound of Formula (la) or a compound of Formula (lb):

Formula (la) Formula (lb)

Preferably, the compound of Formula (I) is a compound of Formula (la).

Formula (la)

Preferably, the compound of Formula (I) is a compound of Formula (lb).

Formula (lb)

Typically, R¹ represents a linear or branched Cg-_M group and a linear or branched Cs-9 alcoxy group.

Preferably, R¹ represents a linear or branched C9-12 alkyl group.

Typically, R² is selected from the group consisting of a hydrogen atom and a fluorine atom. Preferably, R² represents a fluorine atom.

Typically, R³ is selected from the group consisting of a hydrogen atom and a C1-4 linear or branched alkyl group. For example, R³ may be selected from the group consisting of a hydrogen atom and a methyl group

Preferably, R³ represents a hydrogen atom.

Typically, L represents a -º- group, a phenyl ring, a monocyclic C5-6 cycloalkyl group, a monocyclic C5-6 cycloalkenyl group or a monocyclic 5- to 6- membered heteroaryl group containing at least one heteroatom selected from the group consisting of O and N, wherein the phenyl, cycloalkyl, cycloalkenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a linear or branched C1-3 alkyl group, a Ci-2 alkoxy group, a C1-2 haloalkyl group, a halogen atom.

Preferably, L represents a -º- group or a phenyl ring, wherein the phenyl ring is unsubstituted or substituted by one or more substituents selected from a linear or branched C1-3 alkyl group, a methoxy group and a fluorine atom or chlorine atom.

Even more preferably, L represents a phenyl ring unsubstituted or substituted by one or more substituents selected from the group consisting of a linear or branched C1-3 alkyl group and a fluorine atom or a chlorine atom.

Typically, R⁴ represents a hydrogen atom, a C2 fluoroalkyl group, a -[(Chb^Ok-ChhCF group and a -(CH(CH₃))-0C(0)0-R⁵ group.

Preferably, R⁴ is a hydrogen atom.

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

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

In one embodiment, in the compound of formula (I):

• R¹ is selected from the group consisting of a pentyl group, a heptyl group, an octyl

group, a nonyl group, a decyl group, an undecyl group, a dodecyl group, a tridecyl group, a tetradecyl group, a hexyloxy group, an octyloxy group, a nonyloxy group, a - 0-(CH₂)₆-0H group, a -0-(CH₂)₆-0CH₂CH₃ group and a -0-(CH₂)₃-0CH₂CH₃ group, • R² represents a hydrogen atom, a fluorine atom or a chlorine atom,

• R³ represents a hydrogen atom or a methyl group,

• R⁴ is selected from the group consisting of a hydrogen atom, a CH2CF3 group, a - [(CH₂)20]2-CH₂CH3 group, a -CH(CH₃)0C(0)0CH(CH₃)2 group, a - CH(CH3)0C(0)0CH₂CH₂0CH3 group and a -CH(CH₃)0C(0)0[(CH2)20]2CH₂CH3 group, and

• L is selected from the group consisting of a -º- group, a phenyl group, a pyrazole group, a pyridine group, a cyclohexyl group, a cyclohexenyl group, wherein the phenyl, the pyrazole, the pyridine, the cyclohexyl and the cyclohexenyl group can be unsubstituted or substituted by one or more substituents selected from the group consisting of a methyl group, an ethyl group, an isopropyl group, a hydroxyl group, a fluorine atom, a chlorine atom, a trifluoromethyl group and a methoxy group.

Typically, in the compound of formula (I):

group, a nonyl group, a decyl group, an undecyl group, a dodecyl group, a tridecyl group, a tetradecyl group, a hexyloxy group, an octyloxy group, a nonyloxy group, a - 0-(CH₂)₆-0H group, a -0-(CH₂)₆-0CH₂CH₃ group and a -0-(CH₂)₃-0CH₂CH₃ group,

• R² represents a hydrogen atom, a fluorine atom or a chlorine atom,

• R³ represents a hydrogen atom,

In a particular preferred embodiment, in the compound of formula (I): • R¹ represents a linear or branched Cg alkyl group,

• L represents a phenyl group,

• R² represents a fluorine atom, and

• R³ and R⁴ represent a hydrogen atom.

In one embodiment, the compound of Formula (I) is represented by Formula (la)

Formula (la)

Wherein:

• R¹ is selected from the group consisting of a linear or branched C_9-14 alkyl group or a linear or branched Cs-₉ alkoxy group,

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

• L represents a -º- group, a phenyl ring, a monocyclic C_5-6 cycloalkyl group, a monocyclic C_5-6 cycloalkenyl group or a monocyclic 5- to 6-membered heteroaryl group containing at least one heteroatom selected from the group consisting of O and N, wherein the phenyl, cycloalkyl, cycloalkenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a linear or branched C_1-3 alkyl group, a Ci-₂ alkoxy group, a Ci-₂ haloalkyl group and a halogen atom,

• R³ represents a hydrogen atom,

• R⁴ represents a hydrogen atom, a C₂ fluoroalkyl group, a -[(CFb^Ok-CFbCF group or a -(CH(CH₃))-0C(0)0-R⁵ group; preferably R⁴ represents a hydrogen atom,

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

• R^c represents a hydrogen atom.

In a preferred embodiment, in the compound of formula (la),

• R¹ represents a linear or branched C_9-12 alkyl group,

• R² represents a fluorine atom, • L represents a -º- group or a phenyl ring, wherein the phenyl group is unsubstituted or substituted by one or more substituents selected from the group consisting of a linear or branched C_1-3 alkyl group, a fluorine atom or a chlorine atom, and

• R³ and R⁴ represent a hydrogen atom.

In one embodiment, the compound of Formula (I) is represented by Formula (lb),

Formula (lb)

Wherein:

• R³ represents a hydrogen atom,

• R⁴ represents a hydrogen atom, a C₂fluoroalkyl group, a -[(Chh^Ok-ChhCF group or a -(CH(CH₃))-0C(0)0-R⁵ group; preferably R⁴ represents a hydrogen atom,

• R^c represents a hydrogen atom.

In one embodiment in the compound of formula (lb),

• R¹ represents a linear or branched Cg alkyl group,

• R² represents a fluorine atom, • L represents a phenyl group which is unsubstituted or substituted by one or more substituents selected from the group consisting of a linear or branched C1-3 alkyl group, a chlorine atom and a fluorine atom, or a cyclohexyl group, and

• R³ and R⁴ represents a hydrogen atom.

In a preferred embodiment in the compound of formula (lb),

• R¹ represents a linear or branched Cg alkyl group,

• R² represents a fluorine atom,

• L represents a phenyl group which is unsubstituted or substituted by one or more substituents selected from the group consisting of a linear or branched C1-3 alkyl group, a chlorine atom and a fluorine atom, and

• R³ and R⁴ represents a hydrogen atom.

In some embodiments, where the L group is a phenyl group, a monocyclic C5-6 cycloalkyl group, a monocyclic C5-6 cycloalkenyl group or a monocyclic 5- to 6-membered heteroaryl group, the R¹ group attached to the L group can be present at the ortho, meta or para positions. When the L group is a phenyl group or a 6-membered heteroaryl, it is preferred that the R¹ group is present at the para position.

Particular individual compounds of the invention include: 4-(Dodec-1-yn-1-yl)-1 H-pyrrole-2-carboxylic acid;

3-Chloro-4-(dodec-1-yn-1-yl)-1 H-pyrrole-2-carboxylic acid;

4-(Dodec-1-yn-1-yl)-3-fluoro-1 H-pyrrole-2-carboxylic acid;

5-(Dodec-1-yn-1-yl)-1 H-pyrrole-2-carboxylic acid;

5-(Dodec-1-yn-1-yl)-3-fluoro-1 H-pyrrole-2-carboxylic acid;

3-Fluoro-5-(tridec-1-yn-1-yl)-1 H-pyrrole-2-carboxylic acid;

3-Fluoro-5-(tetradec-1-yn-1-yl)-1 H-pyrrole-2-carboxylic acid;

3-Fluoro-5-(pentadec-1-yn-1-yl)-1 H-pyrrole-2-carboxylic acid;

3-Fluoro-5-(hexadec-1-yn-1-yl)-1 H-pyrrole-2-carboxylic acid; 3-Fluoro-4-(4-nonylphenyl)-1 H-pyrrole-2-carboxylic acid;

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

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

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

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

4-(2-Ethyl-4-heptylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid;

4-(2-Ethyl-4-nonylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid;

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

3-Fluoro-4-(2-methyl-5-nonylphenyl)-1 H-pyrrole-2-carboxylic acid;

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

4-(3-Decyl-2-methylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid;

4-(2-Ethyl-3-nonylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid;

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

4-(2-Chloro-3-nonylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid;

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

3-Fluoro-4-(2-fluoro-5-nonylphenyl)-1 H-pyrrole-2-carboxylic acid;

4-(2-Chloro-4-heptylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid;

4-(2-Chloro-4-nonylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid;

4-(2-Chloro-5-nonylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid;

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

3-Fluoro-4-(4-nonyl-2-(trifluoromethyl)phenyl)-1 H-pyrrole-2-carboxylic acid; 3-fluoro-4-(6-nonylpyridin-3-yl)-1 H-pyrrole-2-carboxylic acid;

3-Fluoro-4-(5-nonylpyridin-2-yl)-1 H-pyrrole-2-carboxylic acid;

4-(1-Decyl-1 H-pyrazol-4-yl)-3-fluoro-1 H-pyrrole-2-carboxylic acid;

3-Fluoro-5-(4-nonylphenyl)-1 H-pyrrole-2-carboxylic acid;

"3-Fluoro-5-(4-(octyloxy)phenyl)-1 H-pyrrole-2-carboxylic acid; -Fluoro-5-(3-nonylphenyl)-1 H-pyrrole-2-carboxylic acid;

-Fluoro-5-(2-methyl-5-nonylphenyl)-1 H-pyrrole-2-carboxylic acid;

-(2-Ethyl-4-nonylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid;

-Fluoro-5-(2-methyl-3-nonylphenyl)-1 H-pyrrole-2-carboxylic acid;

-Fluoro-5-(2-isopropyl-3-nonylphenyl)-1 H-pyrrole-2-carboxylic acid;

-Fluoro-5-(2-fluoro-3-nonylphenyl)-1 H-pyrrole-2-carboxylic acid;

-Fluoro-5-(2-fluoro-4-nonylphenyl)-1 H-pyrrole-2-carboxylic acid;

-Fluoro-5-(2-fluoro-5-nonylphenyl)-1 H-pyrrole-2-carboxylic acid;

-(2-Chloro-4-nonylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid;

-(2-Chloro-5-nonylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid;

-Fluoro-5-(2-methoxy-4-nonylphenyl)-1 H-pyrrole-2-carboxylic acid;

-(1-Decyl-1 H-pyrazol-4-yl)-3-fluoro-1 H-pyrrole-2-carboxylic acid;

-(1-Decyl-3,5-dimethyl-1 H-pyrazol-4-yl)-3-fluoro-1 H-pyrrole-2-carboxylic acid;

-fluoro-4-(4-pentylcyclohex-1-en-1-yl)-1 H-pyrrole-2-carboxylic acid;

-Fluoro-4-(4-pentylcyclohexyl)-1 H-pyrrole-2-carboxylic acid (mixture of regioiso ers);-Fluoro-4-(4-pentylcyclohexyl)-1 H-pyrrole-2-carboxylic acid (1 isomer);

-Fluoro-4-((1 r,4s)-4-octylcyclohexyl)-1 H-pyrrole-2-carboxylic acid;

-Fluoro-4-((1 s,4r)-4-octylcyclohexyl)-1 H-pyrrole-2-carboxylic acid;

-Fluoro-5-(4-pentylcyclohex-1-en-1-yl)-1 H-pyrrole-2-carboxylic acid;

-Fluoro-5-(4-pentylcyclohexyl)-1 H-pyrrole-2-carboxylic acid (mixture of regioisomers) ;-Fluoro-5-(4-pentylcyclohexyl)-1 H-pyrrole-2-carboxylic acid (one regioisomer) ;

-((1s,4r)-4-Decylcyclohexyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid;

-((1r,4s)-4-Decylcyclohexyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid;

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

,2,2-Trifluoroethyl 3-fluoro-5-(tetradec-1-yn-1-yl)-1 H-pyrrole-2-carboxylate;

-(2-Ethoxyethoxy)ethyl 3-fluoro-5-(tetradec-1-yn-1-yl)-1 H-pyrrole-2-carboxylate; 1-((lsopropoxycarbonyl)oxy)ethyl 3-fluoro-5-(tetradec-1-yn-1-yl)-1 H-pyrrole-2-carboxylate;

1-(((2-Methoxyethoxy)carbonyl)oxy)ethyl 3-fluoro-5-(tetradec-1-yn-1-yl)-1 H-pyrrole-2- carboxylate;

4-Oxo-3,5,8,11-tetraoxatridecan-2-yl 3-fluoro-5-(tetradec-1-yn-1-yl)-1 H-pyrrole-2-carboxylate; 2,2,2-T rifluoroethyl 3-fluoro-4-(4-nonylphenyl)-1 H-pyrrole-2-carboxylate;

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

1-((lsopropoxycarbonyl)oxy)ethyl 3-fluoro-4-(4-nonylphenyl)-1 H-pyrrole-2-carboxylate;

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

4-Oxo-3,5,8,11-tetraoxatridecan-2-yl 3-fluoro-4-(4-nonylphenyl)-1 H-pyrrole-2-carboxylate; 4-(2,3-Difluoro-4-heptylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid; 4-(2,5-Difluoro-4-heptylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid; 4-(2,3-Difluoro-4-(hexyloxy)phenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid; 4-(2,5-Difluoro-4-(hexyloxy)phenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid;

3-fluoro-4-(4-((6-hydroxyhexyl)oxy)phenyl)-1 H-pyrrole-2-carboxylic acid;

4-(4-((6-Ethoxyhexyl)oxy)phenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid; 4-(4-(3-Ethoxypropoxy)phenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid; 3-Fluoro-4-(4-hydroxy-4-octylcyclohex-1-en-1-yl)-1 H-pyrrole-2-carboxylic acid; and 3-Fluoro-4-(4-hydroxy-4-octylcyclohexyl)-1 H-pyrrole-2-carboxylic acid

Of particular interest are the compounds:

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

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

4-(2-Ethyl-4-heptylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid; 3-Fluoro-4-(2-fluoro-4-nonylphenyl)-1 H-pyrrole-2-carboxylic acid;

4-(2-Chloro-4-heptylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid; 4-(2-Chloro-4-nonylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid;

3-Fluoro-4-(4-pentylcyclohexyl)-1 H-pyrrole-2-carboxylic acid (mixture of regioisomers)and

4-(2,3-Difluoro-4-heptylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid; 4-(2,5-Difluoro-4-heptylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid;

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 1-10 are described in detail in the experimental section.

According to one embodiment of the present invention, compounds of general formula (G) and (G), subsets of general formula (I), wherein R¹-R⁴ and L are as defined in the claims, may be prepared by the following synthetic route as illustrated in Scheme 1 :

Scheme 1

Compounds of formula (I”), a subset of general formula (I), wherein R⁴ is other than a hydrogen atom, may be obtained from compounds of formula (G), a subset of general formula (I), wherein R⁴ is a hydrogen atom, by reaction with alcohols of formula (VI) in the presence of a base such as 4-dimethylaminopyridine or triethylamine and a coupling reagent such as 3- ((ethylimino)methyleneamino)-/\/,/\/-dimethylpropan-1-aminium chloride (EDCI-HCI) or dicyclohexylcarbodiimide (DCC), in a solvent such as methylene chloride at room temperature. Compounds of formula (I”) may also be prepared from acids of formula (G) and alcohols of formula (VI) following a different synthetic approach. Reaction of acids of formula (G) with a suitable chlorinating reagent such as oxalyl chloride in the presence of a catalytic amount of N,N- dimethylformamide in a solvent such as methylene chloride at room temperature gives rise to intermediate acid chlorides which may be treated with alcohols of formula (VI) without the presence of a base or in the presence of a base such as triethylamine, without the use of a solvent or in a solvent such as methylene chloride at temperatures ranging from 0 °C to room temperature to provide compounds of formula (I”). Alternatively, compounds of formula (I”) may also be obtained by reaction of compounds of formula (G) with haloderivatives of formula (VII), wherein X represents a 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 (G) may be obtained from esters of formulas (II), (IV) and (V), wherein R⁵ represents an alkyl group such as methyl or ethyl group. Esters of formulas (II) and (V) may be treated 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 ambient temperature to reflux, with or without the use of microwave irradiation, to furnish acids of formula (I’), wherein R³ is a hydrogen atom. Pyrroles of formula (IV), wherein R³ is an alkyl group, may be prepared from compounds of formula (II) by treatment with a suitable base such as sodium hydride in a solvent such as N,N- dimethylformamide, followed by addition of an haloderivative of formula (III), wherein X represents a halogen atom, such as iodomethane, at temperatures ranging from 0 °C to room temperature. Treatment of pyrroles of formula (IV) 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 ambient temperature to reflux, provides acids of formula (I’), wherein R³ is an alkyl group.

In a particular case, compounds of general formulas (I la) and (Va), subsets of general formula (II) and (V), wherein L is a triple bond, may be prepared by the following synthetic route as illustrated in Scheme 2:

Scheme 2 Reaction of pyrroles of formula (VIII) with /V-bromosuccinimide in a solvent such as methylene chloride at room temperature, or with diiodine in a solvent such as A/./V-dimethylformamide, at temperatures ranging from 0 °C to room temperature, furnishes halogenated pyrroles of formula (IX), wherein X is a bromine or a iodine atom respectively. Halogenated pyrroles of formula (IX) may be converted into tosyl derivatives of formula (XI) by reaction with 4-methylbenzenesulfonyl chloride, in the presence of a base such as trimethylamine or 4-dimethylaminopyridine, in a solvent such as methylene chloride at room temperature. Reaction of compounds of formula (IX) and (XI) with acetylenic derivatives of formula (X) in the presence of copper and palladium catalysts such as copper (I) iodide and bis(triphenylphosphine)palladium(ll) dichloride, in a solvent such as a mixture of tetrahydrofuran and diisopropylamine, at 80 °C under an argon atmosphere, gives rise to compounds of formulas (I la) and (Va).

In another particular case, compounds of formula (lib), a subset of general formula (II), wherein L is a phenyl ring, may be prepared by the following synthetic route as illustrated in Scheme 3:

(IX) (XII) (Mb)

Scheme 3

Halogenated pyrroles of formula (IX) may be reacted with boronic acids (wherein R⁸ is a hydrogen atom) or boronate esters (wherein R⁸ is an alkyl group) of formula (XII) under Suzuki-Miyaura reaction conditions (Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457) to give compounds of formula (lib). Such reactions may be catalysed by a suitable palladium catalyst such as [1 , 1'- bis(diphenylphosphino)ferrocene]palladium(ll) dichloride dichloromethane complex or tetrakis(triphenylphosphine)palladium(0), in a solvent such as toluene or 1 ,4-dioxane, with or without the use of water as co-solvent, in the presence of a base such as cesium carbonate or sodium carbonate, at temperatures ranging from 80 °C to 1 10 °C, with or without the use of microwave irradiation. Boronate esters of formula (Xlla), a subset of general formula (XII), wherein R¹ is a R⁹-CH2-CH2- group, may be prepared by the following synthetic route as illustrated in Scheme 4:

Scheme 4

Reaction of dihalogenated phenyl derivatives of formula (XIII) with acetylenic derivatives of formula (XIV) in the presence of copper and palladium catalysts such as copper (I) iodide and tetrakis(triphenylphosphine)palladium(0), in a solvent such as a mixture of dichloromethane and trietylamine, at 60 °C under an argon atmosphere, gives rise to compounds of formula (XV). Reduction of compounds of formula (XV) with hydrogen in the presence of platinum (IV) oxide or chloridotris(triphenylphosphane)rhodium(l) as catalysts, in a solvent such as ethanol or toluene, with or without the presence of a base, such as trimethylamine, at a pressure ranging from atmospheric pressure to 50 bar, furnishes bromoderivatives of formula (XVI). Alternatively, compounds of formula (XVI) may be prepared by a different synthetic approach. Reaction of aldehydes of formula (XVII) with Grignard reagents of formula (XVIII) in a solvent such as diethyl ether at temperatures ranging from -20 °C to room temperature, gives rise to alcohols of formula (XIX), which may be treated with triethylsilane and boron trifluoride diethyl etherate in a solvent such as methylene chloride, at temperatures ranging from 0 °C to room temperature, to give compounds of formula (XVI). Bromophenyl derivatives of formula (XVI) may be converted into boronates of formula (XI la) by reaction with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2- dioxaborolane), in the presence of a suitable catalyst such as bis(triphenylphosphine) palladium(ll) dichloride, and a base, such as potassium acetate, in a solvent such as 1 ,4-dioxane, at 90 °C under an argon atmosphere.

Boronate esters of formula (XI I b) , a subset of general formula (XII), wherein R¹ is a R¹⁰-O- group, may be prepared by the following synthetic route as illustrated in Scheme 5:

Scheme 5

Compounds of formula (XXII) may be prepared from phenols of formula (XX) by treatment with a suitable base such as potassium carbonate, in a solvent such as A/,/\/-dimethylformamide, followed by addition of an haloderivative of formula (XXI), wherein X represents a halogen atom, such as bromohexane, at 100 °C. Bromophenyl derivatives of formula (XXII) may be converted into boronates of formula (XI I b) by reaction with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2- dioxaborolane), in the presence of a suitable catalyst such as bis(triphenylphosphine) palladium(ll) dichloride, and a base, such as potassium acetate, in a solvent such as 1 ,4-dioxane, at 90 °C under an argon atmosphere.

In another particular case, compounds of formula (lie) and (lid), subsets of general formula (II), wherein L is a phenyl ring and R¹ is a -0-(CH₂)_n-OH group and a -0-(CH₂)_n-0-R¹¹ group respectively, may be prepared by the following synthetic route as illustrated in Scheme 6:

Scheme 6

Treatment of phenols of formula (XXIII) with a suitable base such as potassium carbonate, in a solvent such as /V,/V-dimethylformamide, followed by addition of a bromoalcohol of formula (XXIV), such as 6-bromohexan-1-ol, at 100 °C provides compounds of formula (XXV), which may be reacted with halogenated pyrroles of formula (IX) under Suzuki-Miyaura reaction conditions to give alcohols of formula (lie). Such reactions may be catalyzed by a suitable palladium catalyst such as [1 , T-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride dichloromethane complex, in a solvent such as 1 ,4-dioxane, with the use of water as co-solvent, in the presence of a base such as cesium carbonate at 100 °C. Reaction of alcohols of formula (l ie) with methanesulfonyl chloride in a solvent such as dichloromethane, in the presence of a base such as trimethylamine, at temperatures ranging from 0 °C to room temperature, gives rise to sulfonates of formula (XXVI). Sulfonates of formula (XXVI) may be converted into compounds of formula (l id) by reaction with sodium alkoxides of formula (XXVII), such as sodium ethoxide, in a solvent such as a mixture of ethanol and dichloromethane, at temperatures ranging from 0 °C to 70 °C.

In another particular case, compounds of formula (lie), a subset of general formula (II), wherein L is a pyridine ring, may be prepared by the following synthetic route as illustrated in Scheme 7:

Scheme 7

Reaction of dihalogenated pyridines of formula (XXVIII) with terminal alkynes of formula (XIV) in the presence of copper and palladium catalysts such as copper (I) iodide and tetrakis(triphenylphosphine)palladium(0), in a solvent such a mixture of dichloromethane and triethylamine, at 60 °C under an argon atmosphere, gives rise to compounds of formula (XXIX). Reduction of acetylenic compounds of formula (XXIX) with hydrogen in the presence of a suitable catalyst such as platinum (IV) oxide or chloridotris(triphenylphosphane)rhodium(l), in a solvent such as ethanol or toluene, at a pressure ranging from atmospheric pressure to 50 bar furnishes bromopyridines of formula (XXX). Bromopyridines of formula (XXX) may be converted into stannanes of formula (XXXI) by treatment with n-butyl lithium in a solvent such as tetrahydrofuran at -78 °C followed by reaction of the corresponding pyridyl lithium intermediates with tributyltin chloride. Stannanes of formula (XXXI) may be transformed into compounds of formula (lie) by reaction with halogenated pyrroles of formula (IX) in the presence of a suitable catalyst such as tetrakis(triphenylphosphine) palladium(O), in a solvent such as xylene at 150 °C under an argon atmosphere. Alternatively, compounds of formula (lie) may be prepared following a different synthetic approach. Bromopyridines of formula (XXX) may be converted into boronates of formula (XXXII) by reaction with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane), in the presence of a suitable catalyst such as bis(triphenylphosphine)palladium(ll) dichloride, and a base, such as potassium acetate, in a solvent such as 1 ,4-dioxane, at 90 °C under an argon atmosphere. Reaction of boronates of formula (XXXII) with halogenated pyrroles of formula (IX) in the presence of a palladium catalyst such as [1 ,1 '-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride dichloromethane complex or tetrakis(triphenylphosphine)palladium(0), in a solvent such as toluene or 1 ,4-dioxane, with or without the use of water as co-solvent, in the presence of a base such as cesium carbonate or sodium carbonate, at temperatures ranging from 80 °C to 110 °C, with or without the use of microwave irradiation, gives rise to compounds of formula (lie).

In another particular case, compounds of formula (Ilf), a subset of general formula (II), wherein L is a pyrazole ring, may be prepared by the following synthetic route as illustrated in Scheme 8:

Scheme 8

Alkylated pyrazoles of formula (XXXV) may be prepared by treatment of compounds of formula (XXXIII) with a suitable base such as cesium carbonate in a solvent such as N,N- dimethylformamide followed by addition of an haloderivative of formula (XXXIV), wherein X represents an halogen atom, at temperatures ranging from room temperature to 90 °C. Reaction of alkylated pyrazoles of formula (XXXV) with halogenated pyrroles of formula (IX) in the presence of a suitable palladium catalyst such as [1 , T-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride dichloromethane complex, in a solvent such as 1 ,4-dioxane, with the use of water as co-solvent, in the presence of a base such as cesium carbonate at 100 °C, provides compounds of formula (Ilf).

In another particular case, compounds of formulas (llg) and (Mh), subsets of general formula (II), wherein L is a cyclohexene and a cyclohexane ring respectively, may be prepared by the following synthetic route as illustrated in Scheme 9:

Trifluoromethanesulfonates of formula (XXXVII) may be prepared from ketones of formula (XXXVI) by treatment with a suitable base such as lithium bis(trimethylsilyl)amide in a solvent such as tetrahydrofuran at -78 °C followed by addition of 1 , 1 , 1-trifluoro-/\/-phenyl-/\/- ((trifluoromethyl)sulfonyl)methanesulfonamide. Trifluoromethanesulfonates of formula (XXXVII) may be converted into boronates of formula (XXXVIII) by reaction with 4, 4, 4', 4', 5, 5,5', 5'- octamethyl-2,2'-bi(1 ,3,2-dioxaborolane), in the presence of a suitable palladium catalyst such as bis(triphenylphosphine)palladium(ll) dichloride, and a base, such as potassium acetate, in a solvent such as 1 ,4-dioxane, at 90 °C under an argon atmosphere. Reaction of boronates of formula (XXXVIII) with halogenated pyrroles of formula (IX) in the presence of a suitable palladium catalyst such as [1 , T-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride dichloromethane complex, in a solvent such as 1 ,4-dioxane, with the use of water as co-solvent, in the presence of a base such as cesium carbonate, at 100 °C, provides compounds of formula (llg). Reduction of compounds of formula (llg) with hydrogen in the presence of palladium on carbon as catalyst, in a solvent such as methanol or ethanol at room temperature, furnishes compounds of formula (llh).

In yet another particular case, alcohols of formulas (IN) and (llj), subsets of general formula (II), wherein L is a cyclohexene and a cyclohexane ring respectively, may be prepared by the following synthetic route as illustrated in Scheme 10:

Scheme 10

Reaction of halogenated pyrroles of formula (IX) with boronate ester (XXXIX) in the presence of a suitable catalyst, such as [1 , 1 '-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with methylene chloride, and a base, such as cesium carbonate, in a solvent such as 1 ,4-dioxane, with water as co-solvent at 100 °C, gives rise to compounds of formula (XL). Treatment of compounds of formula (XL) with hydrogen in the presence of palladium on carbon as catalyst, in a solvent such as ethyl acetate at room temperature, provides compounds of formula (XLIII). Compounds of formula (XL) and (XLIII) may be converted into ketones of formula (XLI) and (XLIV) respectively by treatment with hydrochloric acid solution, in a solvent such as 1 ,4-dioxane or acetone at room temperature. Ketones of formula (XLI) and (XLIV) may be transformed into alcohols of formula (IN) and (llj) respectively by reaction with Grignard reagents of formula (XLI I), such as octylmagnesium bromide, in a solvent such as tetrahydrofuran, at temperatures ranging from 0 °C to room temperature.

EXAMPLES

The syntheses of the compounds of the invention are illustrated by the following Examples (1 to 79) including Intermediates (1 to 67) 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. Ether refers to diethyl ether, unless otherwise specified. 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 mGh) 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 m , 7 mhi) column or a XBridge Prep C18 (19 x 100 m , 5 mhi) 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 (2.1x50 m , 1.7 m ) column. The mobile phase was formic acid (0.4 mL), ammonia (0.1 L), methanol (500 L) and acetonitrile (500 L) (B) and formic acid (0.5 L), ammonia (0.125 L) and water (1000 L) (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

CDCh Deuterated chloroform

CDsOD Deuterated methanol

Celite^® Diatomaceous earth d Doublet

DCM Dichloromethane, methylene chloride dd Doublet of doublets

DIEA Diisopropylethyamine

DMAP Dimethylaminopyridine

DMF L/,/V-Dimethylformamide

DMSO Dimethylsulfoxide

DMSO-cfe Deuterated Dimethylsulfoxide

EtOAc Ethyl acetate

EtOH Ethanol

h Hour

hept Heptuplet

HPLC High-performance liquid chromatography m Multiplet

MeOH Methanol

min Minutes

M Molar

MS Mass spectrometry

NBS /V-Bromosuccinimide

NCS /V-Chlorosuccinimide

NMR Nuclear magnetic resonance

P Quintuplet

q Quartet

s Singlet

t Triplet

td Triple doublet

TEA Triethylamine

TFA Trifluoroacetic acid

THF Tetrahydrofuran INTERMEDIATE 1

Ethyl 4-bromo-3-fluoro-1 H-pyrrole-2-carboxylate and ethyl 5-bromo-3-fluoro-1 H-pyrrole-2- carboxylate

To a solution of ethyl 3-fluoro-1 H-pyrrole-2-carboxylate (4.00 g, 25.45 mmol) in DCM (80 ml_) was added /V-bromosuccinimide (4.53 g, 25.45 mmol) and the resulting mixture was stirred in the absence of light for 1 h. The reaction mixture was diluted with DCM and washed with water (2 x 40 ml_) and brine. The organic layer was dried over magnesium sulfate, filtered and the solvent was evaporated to dryness. The resulting crude was purified by flash chromatography (hexanes/diethyl ether) followed by reverse phase chromatography (water/methanol) to give ethyl 4-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (1.60 g, 19%) as a white solid:

MS (m/z): 236, 234 [M, M-2]\

¹ H NMR d (400 MHz, CDCIs): 1.37 (t, J=7.1 Hz, 3H), 4.36 (q, J=7.1 Hz, 2H), 6.80 (t, J=3.8 Hz, 1 H), 8.91 (s, 1 H)

and ethyl 5-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (3.10 g, 46%) as a white solid:

MS (m/z): 236, 234 [M, M-2]\

¹ H NMR d (400 MHz, CDCIs): 1.36 (t, J=7.1 Hz, 2H), 4.34 (q, J=7.1 Hz, 1 H), 6.03 (dd, J=3.2, 0.8 Hz, 1 H), 8.81 (s, 1 H).

INTERMEDIATE 2

Ethyl 3-fluoro-4-iodo-1 H-pyrrole-2-carboxylate

To a cooled (0 °C) solution of ethyl 3-fluoro-1 H-pyrrole-2-carboxylate (1.00 g, 6.36 mmol) in DMF (16 ml_) was added diiodine (4.84 g, 19.07 mmol) in five portions and the mixture was stirred at room temperature for 2 h. The reaction was poured into a mixture of water (100 ml_) and saturated aqueous sodium thiosulfate solution (10 ml_) and extracted with diethyl ether (x3). The combined organic layers were washed with water and 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 (1.10 g, 61 %) as a white solid.

MS (m/z): 282 [M-1]\

¹ H NMR d (400 MHz, CDCIs): 1.37 (t, J=7.1 Hz, 3H), 4.36 (q, J=7.1 Hz, 2H), 6.82 (t, J=3.7 Hz, 1 H), 8.86 (s, 1 H). INTERMEDIATE S

Ethyl 4-(dodec-1 -yn-1 -yl)-1 -tosyl-1 H-pyrrole-2-carboxylate a) Ethyl 4-bromo-1 -tosyl-1 H-pyrrole-2-carboxylate

To a solution of ethyl 4-bromo-1 H-pyrrole-2-carboxylate (300 mg, 1.37 mmol) in DCM (4 ml_) were added TEA (0.44 ml_, 3.16 mmol), 4-DMAP (25 mg, 0.20 mmol) and 4-methylbenzenesulfonyl chloride (290 mg, 1.51 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM and washed with 1 N hydrochloric acid solution and brine. The organic layer was 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 (400 mg, 82%).

MS (m/z): 373 [M+1]⁺.

¹ H NMR d (400 MHz, CDCIs): 1.26 (t, J=7.1 Hz, 3H), 2.43 (s, 3H), 4.20 (q, J=7.1 Hz, 2H), 6.99 (d, J=2.0 Hz, 1 H), 7.31-7.36 (m, 2H), 7.69 (d, J=2.0 Hz, 1 H), 7.87-7.92 (m, 2H). b) Ethyl 4-(dodec-1 -yn-1 -yl)-1 -tosyl-1 H-pyrrole-2-carboxylate

A Schlenk flask was charged with ethyl 4-bromo-1-tosyl-1 H-pyrrole-2-carboxylate (Intermediate 3a, 420 mg, 1.12 mmol), dodec-1-yne (0.48 ml_, 2.25 mmol), copper (I) iodide (43 mg, 0.22 mmol), bis(triphenylphosphine)palladium(ll) dichloride (158 mg, 0.22 mmol), diisopropylamine (0.40 ml_, 2.82 mmol) and THF (8 ml_). The mixture was subjected to three cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred at 80 °C overnight under an argon atmosphere. After cooling to room temperature, the reaction mixture was filtered through a Celite^® pad washing with EtOAc several times. The filtrate and washings were combined and the solvents were evaporated to dryness. Purification of the residue by flash chromatography (hexanes/diethyl ether) yielded the title compound (190 mg, 37%).

MS (m/z): 458 [M+1]⁺.

¹ H NMR d (400 MHz, CDCIs): 0.85-0.91 (m, 3H), 1.21-1.34 (m, 16H), 1.38-1.46 (m, 2H), 2.36 (t, J=7.1 Hz, 2H), 2.42 (s, 3H), 4.18 (q, J=7.1 Hz, 2H), 7.00 (d, J=2.0 Hz, 1 H), 7.31 (d, J=8.0 Hz, 2H), 7.74 (d, J=2.0 Hz, 1 H), 7.87 (d, J=8.0 Hz, 2H).

INTERMEDIATE 4

Methyl 3-chloro-4-(dodec-1 -yn-1 -yl)-1 -tosyl-1 H-pyrrole-2-carboxylate a) Methyl 4-bromo-3-chloro-1 H-pyrrole-2-carboxylate To a cooled (0 °C) solution of methyl 3-chloro-1 H-pyrrole-2-carboxylate (300 g, 1.88 mmol) in ACN (5 ml_) was added /V-bromosuccinimide (334 mg, 1.87 mmol) and the mixture was stirred at room temperature for 2 h. The mixture was cooled again to 0 °C, /V-bromosuccinimide (167 mg, 0.93 mmol) was added and the mixture was stirred at room temperature for 1 h. Water was added and the resulting suspension was stirred at room temperature for 1 h and filtered. The aqueous filtrate was extracted with EtOAc (x3). 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 reverse phase chromatography (water/methanol) gave the title compound (156 mg, 35%) as a solid.

MS (m/z): 238, 236 [M, M-2]\

¹ H NMR d (400 MHz, CDCIs): 3.92 (s, 3H), 6.96 (d, J=3.4 Hz, 1 H), 9.14 (s, 1 H). b) Methyl 4-bromo-3-chloro-1 -tosyl-1 H-pyrrole-2-carboxylate

Obtained as a white solid (51 %) from methyl 4-bromo-3-chloro-1 H-pyrrole-2-carboxylate (Intermediate 4a) following the experimental procedure described in Intermediate 3a followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 392, 394, 396 [M, M+2, M+4]⁺.

¹ H NMR d (400 MHz, CDCIs): 2.45 (s, 3H), 3.84 (s, 3H), 7.36 (d, J=8.1 Hz, 2H), 7.65 (s, 1 H), 7.84-7.89 (m, 2H). c) Methyl 3-chloro-4-(dodec-1 -yn-1 -yl)-1 -tosyl-1 H-pyrrole-2-carboxylate

Obtained as an oil (100%) from methyl 4-bromo-3-chloro-1-tosyl-1 H-pyrrole-2-carboxylate (Intermediate 4b) and dodec-1-yne following the experimental procedure described in Intermediate 3b followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 478, 476 [M, M-2]\

INTERMEDIATE S

Ethyl 4-(dodec-1 -yn-1 -yl)-3-fluoro-1 -tosyl-1 H-pyrrole-2-carboxylate a) Ethyl 4-bromo-3-fluoro-1 -tosyl-1 H-pyrrole-2-carboxylate Obtained as an oil (72%) from ethyl 4-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) following the experimental procedure described in Intermediate 3a followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 390, 392 [M, M+2]⁺.

¹ H NMR d (400 MHz, CDCh): 1.28 (t, J=7.1 Hz, 3H), 2.44 (s, 3H), 4.25 (q, J=7.1 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 7.62 (d, J=5.0 Hz, 1 H), 7.85-7.90 (m, 2H). b) Ethyl 4-(dodec-1 -yn-1 -yl)-3-fluoro-1 -tosyl-1 H-pyrrole-2-carboxylate

Obtained as an oil (57%) from ethyl 4-bromo-3-fluoro-1-tosyl-1 H-pyrrole-2-carboxylate (Intermediate 5a) and dodec-1-yne following the experimental procedure described in Intermediate 3b followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 476 [M+1]⁺.

¹ H NMR d (400 MHz, CDCh): 0.85-0.91 (m, 3H), 1.23-1.33 (m, 14H), 1.37-1.47 (m, 2H), 1.54-1.63 (m, 2H), 2.39 (t, J=7.1 Hz, 2H), 2.43 (s, 3H), 4.23 (q, J=7.1 Hz, 2H), 7.33 (d, J=8.1 Hz, 2H), 7.62 (d, J=5.4 Hz, 1 H), 7.82-7.87 (m, 2H).

INTERMEDIATE 6

Methyl 5-(dodec-1-yn-1-yl)-1 H-pyrrole-2-carboxylate

Obtained as an orange oil (28%) from methyl 5-bromo-1 H-pyrrole-2-carboxylate and dodec-1-yne following the experimental procedure described in Intermediate 3b followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 290 [M+1]⁺.

INTERMEDIATE 7

Ethyl 5-(dodec-1-yn-1-yl)-3-fluoro-1 H-pyrrole-2-carboxylate

Obtained as an oil (51 %) from ethyl 5-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and dodec-1-yne following the experimental procedure described in Intermediate 3b followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 320 [M-1]\

¹ H NMR d (400 MHz, DMSO-d₆): 0.82-0.88 (m, 3H), 1.21-1.30 (m, 15H), 1.35-1.43 (m, 2H), 1.47-1.57 (m, 2H), 2.41 (t, J=6.9 Hz, 2H), 4.22 (q, J=7.1 Hz, 2H), 6.21 (s, 1 H), 12.17 (s, 1 H). INTERMEDIATE S

Ethyl 3-fluoro-5-(tridec-1-yn-1-yl)-1H-pyrrole-2-carboxylate

Obtained as an oil (29%) from ethyl 5-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and tridec-1-yne following the experimental procedure described in Intermediate 3b followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 335 [M-1]\

INTERMEDIATE 9

Ethyl 3-fluoro-5-(tetradec-1 -yn-1 -yl)-1 H-pyrrole-2-carboxylate

Obtained as an oil (71 %) from ethyl 5-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and tetradec-1-yne following the experimental procedure described in Intermediate 3b followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 349 [M-1]\

¹ H NMR d (400 MHz, CDCh): 0.85-0.91 (m, 3H), 1.23-1.33 (m, 16H), 1.36 (t, J=7.1 Hz, 3H), 1.38-1.45 (m, 2H), 1.52-1.62 (m, 2H), 2.38 (t, J=7.1 Hz, 2H), 4.33 (q, J=7.1 Hz, 2H), 6.05 (d, J=3.1 Hz, 1 H), 8.50 (s, 1 H).

INTERMEDIATE 10

Ethyl 3-fluoro-5-(pentadec-1-yn-1-yl)-1H-pyrrole-2-carboxylate

Obtained as an oil (54%) from ethyl 5-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and pentadec-1-yne following the experimental procedure described in Intermediate 3b followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 362 [M-1]\

¹ H NMR d (400 MHz, CDCh): 0.88 (t, J=6.9 Hz, 3H), 1.23-1.33 (m, 18H), 1.36 (t, J=7.1 Hz, 3H), 1.38-1.45 (m, 2H), 1.53-1.64 (m, 2H), 2.38 (t, J=7.1 Hz, 2H), 4.33 (q, J=7.1 Hz, 2H), 6.05 (d, J=3.1 Hz, 1 H), 8.55 (s, 1 H).

INTERMEDIATE 1 1

Ethyl 3-fluoro-5-(hexadec-1 -yn-1 -yl)-1 H-pyrrole-2-carboxylate Obtained as an oil (54%) from ethyl 5-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and hexadec-1-yne following the experimental procedure described in Intermediate 3b followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 377 [M-1]⁺.

¹ H NMR d (400 MHz, CDCh): 0.88 (t, J=6.8 Hz, 3H), 1.22-1.33 (m, 20H), 1.36 (t, J=7.1 Hz, 3H), 1.38-1.45 (m, 2H), 1.53-1.62 (m, 2H), 2.38 (t, J=7.1 Hz, 2H), 4.33 (q, J=7.1 Hz, 2H), 6.05 (d, J=3.0 Hz, 1 H), 8.54 (s, 1 H).

INTERMEDIATE 12

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

A Schlenk flask was charged with ethyl 4-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1 , 1.40 g, 4.14 mmol), (4-nonylphenyl)boronic acid (1.14 g, 4.59 mmol), dioxane (20 ml_) and 2M aqueous cesium carbonate solution (6.2 ml_, 12.40 mmol). The resulting mixture was subjected to three cycles of evacuation-backfilling with argon and [1 , 1 - bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with methylene chloride (203 mg, 0.25 mmol) was then added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred at 100 °C for 18 h under an argon atmosphere. After cooling to room temperature, the reaction mixture was filtered through a Celite^® pad, washing with EtOAc several times. The filtrate and washings were combined, dried over magnesium sulfate and the solvents were removed in vacuo. Purification of the residue by flash chromatography (hexanes/diethyl ether) and reverse phase chromatography (water/methanol) gave the title compound (0.77 g, 51 %) as a white solid.

MS (m/z): 360 [M+1]⁺.

¹ H NMR d (400 MHz, DMSO-d₆): 0.82-0.87 (m, 3H), 1.22-1.26 (m, 12H), 1.29 (t, J=7.1 Hz, 7H), 1.51-1.60 (m, 2H), 2.52-2.58 (m, 2H), 4.27 (q, J=7.1 Hz, 2H), 7.19 (d, J=8.3 Hz, 2H), 7.33 (d, J=5.0 Hz, 1 H), 7.48 (d, J=8.0 Hz, 2H), 11.92 (s, 1 H).

INTERMEDIATE 13

Ethyl 3-fluoro-4-(4-(octyloxy)phenyl)-1 H-pyrrole-2-carboxylate

A Schlenk flask was charged with ethyl 4-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1 , 250 mg, 1.06 mmol), (4-(octyloxy)phenyl)boronic acid (318 mg, 1.27 mmol), sodium carbonate (224 mg, 2.11 mmol) and toluene (5 ml_). The solution was subjected to three cycles of evacuation-backfilling with argon and tetrakis(triphenylphosphine)palladium(0) (61 mg, 0.052 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred at 110 °C overnight under an argon atmosphere. After cooling to room temperature, the mixture was filtered through a Celite^® pad washing with EtOAc several times. The filtrate and washings were combined, dried over magnesium sulfate, filtered and the solvents were evaporated to dryness. Purification of the residue by reverse phase chromatography (water/methanol) yielded the title compound (89 mg, 23%) as a white solid.

MS (m/z): 362 [M+1]⁺.

¹ H NMR 5 (400 MHz, CDCIs): 0.86-0.91 (m, 3H), 1.25-1.36 (m, 8H), 1.39 (t, J=7.1 Hz, 3H), 1.42-1.49 (m, 2H), 1.74-1.83 (m, 2H), 3.92-4.00 (m, 2H), 4.37 (q, J=7.1 Hz, 2H), 6.88-6.96 (m, 3H), 7.46 (d, J=8.5 Hz, 2H), 8.64 (s, 1 H).

INTERMEDIATE 14

Ethyl 3-fluoro-4-(4-(nonyloxy)phenyl)-1 H-pyrrole-2-carboxylate

Obtained as a white solid (71 %) from ethyl 4-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and (4-(nonyloxy)phenyl)boronic acid following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 376 [M+1]⁺.

¹ H NMR d (400 MHz, CDCIs): 0.86-0.91 (m, 3H), 1.25-1.36 (m, 10H), 1.39 (t, J=7.1 Hz, 3H), 1.42-1.50 (m, 2H), 1.74-1.83 (m, 2H), 3.97 (t, J=6.6 Hz, 2H), 4.37 (q, J=7.1 Hz, 2H), 6.89-6.96 (m, 3H), 7.44-7.48 (m, 2H), 8.61 (s, 1 H).

INTERMEDIATE 15

Ethyl 3-fluoro-4-(3-nonylphenyl)-1 H-pyrrole-2-carboxylate a) 1 -Bromo-3-(non-1 -yn-1 -yl)benzene

A Schlenk tube was charged with 1-bromo-3-iodobenzene (2.00 g, 7.07 mmol), non-1-yne (1.25 ml_, 7.62 mmol), DCM (12 ml_) and TEA (10 ml_). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon and then tetrakis(triphenylphosphine)palladium(0) (408 mg, 0.35 mmol) and copper (I) iodide (94 mg, 0.49 mmol) were added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred at 60 °C for 4 h under an argon atmosphere. After cooling to room temperature, the mixture was filtered through a Celite^® pad washing with EtOAc several times. The filtrate and washings were combined and the solvent was evaporated to dryness. Purification of the residue by flash chromatography (hexanes/diethyl ether) gave the title compound (1.29 g, 65%) as a yellow oil.

¹ H NMR d (400 MHz, CDCIs): 0.87-0.92 (m, 3H), 1.25-1.37 (m, 6H), 1.39-1.48 (m, 2H), 1.56-1.64 (m, 2H), 2.39 (t, J=7.1 Hz, 2H), 7.14 (t, J=7.8 Hz, 1 H), 7.30 (dt, J=7.8, 1.2 Hz, 1 H), 7.37-7.40 (m, 1 H), 7.54 (t, J=1.7 Hz, 1 H). b) 1-Bromo-3-nonylbenzene

To a solution of 1-bromo-3-(non-1-yn-1-yl)benzene (Intermediate 15a, 1.29 g, 4.62 mmol) in ethanol (20 ml_) was added trimethylamine (400 mI_) and platinum (IV) oxide (64 mg, 0.28 mmol) and the mixture was stirred under a hydrogen atmosphere for 4 h. The reaction mixture was then filtered through a Celite^® pad washing with methanol several times. The filtrate and washings were combined and the solvent was evaporated to dryness. Purification of the residue by flash chromatography (hexanes/diethyl ether) yielded the title compound (661 mg, 50%) as a clear oil.

1 H NMR d (400 MHz, CDCIs): 0.85-0.91 (m, 3H), 1.59 (p, J=7.4 Hz, 2H), 2.53-2.62 (m, 2H), 7.07-7.19 (m, 2H), 7.24-7.34 (m, 2H). c) 4,4,5,5-Tetramethyl-2-(3-nonylphenyl)-1 ,3,2-dioxaborolane

A Schlenk tube was charged with 1-bromo-3-nonylbenzene (Intermediate 15b, 785 mg, 2.77 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (775 mg, 3.05 mmol), potassium acetate (816 mg, 8.31 mmol) and dioxane (10 ml_). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon and bis(triphenylphosphine)palladium(ll) dichloride (1 13 mg, 0.14 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred at 90 °C overnight under an argon atmosphere. After cooling to room temperature, the mixture was filtered through a Celite^® pad washing with EtOAc several times. The filtrate and washings were combined and the solvents were removed in vacuo. Purification of the residue by flash chromatography (hexanes/diethyl ether) gave the title compound (682mg, 71 %) as a yellow oil.

¹ H NMR d (400 MHz, CDCIs): 0.85-0.91 (m, 3H), 1.24-1.33 (m, 12H), 1.35 (s, 12H), 1.61 (p, J=7.5 Hz, 2H), 2.57-2.63 (m, 2H), 7.27-7.29 (m, 2H), 7.61-7.64 (m, 2H). d) Ethyl 3-fluoro-4-(3-nonylphenyl)-1H-pyrrole-2-carboxylate Obtained as an off-white solid (94%) from ethyl 4-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and 4,4,5,5-tetramethyl-2-(3-nonylphenyl)-1 ,3,2-dioxaborolane (Intermediate 15c) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 360 [M+1]⁺.

¹ H NMR d (400 MHz, CDCIs): 0.85-0.90 (m, 3H), 1.23-1.35 (m, 12H), 1.39 (t, J=7.1 Hz, 3H), 1.63 (dt, J= 15.2, 7.4 Hz, 2H), 2.59-2.65 (m, 2H), 4.38 (q, J=7.1 Hz, 2H), 7.00-7.03 (m, 1 H), 7.08 (d, J=7.4 Hz, 1 H), 7.29 (t, J=7.9 Hz, 1 H), 7.35-7.39 (m, 2H), 8.65 (s, 1 H).

INTERMEDIATE 16

Ethyl 3-fluoro-4-(4-heptyl-2-methylphenyl)-1H-pyrrole-2-carboxylate a) 1-Bromo-4-(hept-1-yn-1-yl)-2-methylbenzene

Obtained as a yellow oil (63%) from 1-bromo-4-iodo-2-methylbenzene and hept-1-yne following the experimental procedure described in Intermediate 15a followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCIs): 0.92 (t, J=7.2 Hz, 3H), 1.32-1.47 (m, 4H), 1.56-1.64 (m, 2H),

2.35 (s, 3H), 2.37 (t, J=7.1 Hz, 2H), 7.06 (dd, J=8.2, 1.8 Hz, 1 H), 7.26 (d, J=1.8 Hz, 1 H), 7.42 (d, J=8.2 Hz, 1 H). b) 1 -Bromo-4-heptyl-2-methylbenzene

Obtained as an oil (65%) from 1-bromo-4-(hept-1-yn-1-yl)-2-methylbenzene (Intermediate 16a) following the experimental procedure described in Intermediate 15b followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCIs): 0.85-0.90 (m, 3H), 1.25-1.31 (m, 8H), 1.56-1.62 (m, 2H),

2.36 (s, 3H), 2.48-2.55 (m, 2H), 6.85 (dd, J=8.1 , 1.9 Hz, 1 H), 7.04 (d, J=1.8 Hz, 1 H), 7.40 (d, J=8.1 Hz, 1 H). c) 2-(4-Heptyl-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Obtained as an oil (48%) from 1-bromo-4-heptyl-2-methylbenzene (Intermediate 16b) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) following the experimental procedure described in Intermediate 15c followed by purification of the crude product by flash chromatography (hexanes/diethyl ether). ¹ H NMR d (400 MHz, CDCh): 0.85-0.89 (m, 3H), 1.23-1.32 (m, 8H), 1.33 (s, 12H), 1.57- 1.63 (m, 2H), 2.51 (s, 3H), 2.53-2.58 (m, 2H), 6.97-7.00 (m, 2H), 7.68 (d, J=8.0 Hz, 1 H). d) Ethyl 3-fluoro-4-(4-heptyl-2-methylphenyl)-1 H-pyrrole-2-carboxylate

Obtained as a colourless oil (71 %) from ethyl 3-fluoro-4-iodo-1 H-pyrrole-2-carboxylate (Intermediate 2) and 2-(4-heptyl-2-methylphenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (Intermediate 16c) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 344 [M-1]\

¹ H NMR d (400 MHz, CDCh): 0.86-0.91 (m, 3H), 1.26-1.36 (m, 8H), 1.38 (t, J=7.1 Hz, 3H), 1.59-1.66 (m, 2H), 2.31 (s, 3H), 2.54-2.62 (m, 2H), 4.38 (q, J=7.1 Hz, 2H), 6.75-6.78 (m, 1 H), 7.03 (dd, J=7.8, 1.4 Hz, 1 H), 7.08 (s, 1 H), 7.17 (d, J=7.8 Hz, 1 H), 8.84 (s, 1 H).

INTERMEDIATE 17

Ethyl 3-fluoro-4-(2-methyl-4-nonylphenyl)-1H-pyrrole-2-carboxylate

a) 1-(4-Bromo-3-methylphenyl)nonan-1-ol

To a cooled (0 °C) solution of 4-bromo-3-methylbenzaldehyde (2.00 g, 10.05 mmol) in diethyl ether (20 ml_) under an argon atmosphere was slowly added octylmagnesium bromide (2M solution in diethyl ether, 5.3 ml_, 10.5 mmol) and the resulting mixture was stirred at 0 °C for 30 min and then at room temperature overnight. The reaction mixture was cooled to 0 °C and saturated aqueous ammonium chloride solution (10 ml_) and diethyl ether were added. The organic layer was separated and the aqueous layer was extracted with diethyl ether (x2). The combined organic layers 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 (1.82 g, 55%) as a colourless oil.

¹ H NMR d (400 MHz, CDCh): 0.84-0.90 (m, 3H), 1.18-1.44 (m, 12H), 1.63-1.71 (m, 1 H), 1.72-1.82 (m, 2H), 2.40 (s, 3H), 4.60 (t, J=6.4 Hz, 1 H), 7.02 (dd, J=8.2, 2.2 Hz, 1 H), 7.21 (d, J=2.0 Hz, 1 H), 7.49 (d, J=8.2 Hz, 1 H). b) 1-Bromo-2-methyl-4-nonylbenzene To a cooled (0 °C) solution of 1-(4-bromo-3-methylphenyl)nonan-1-ol (Intermediate 17a, 0.90 g, 2.87 mmol) in DCM (20 ml_) were added triethylsilane (0.69 ml_, 4.32 mmol) and boron trifluoride diethyl etherate (0.54 ml_, 4.30 mmol) and the resulting solution was stirred at room temperature overnight. Water (14 ml_) was then added and the reaction mixture was extracted with DCM (x3). The combined organic layers 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) yielded the title compound (783 mg, 89%) as a colourless oil.

¹ H NMR d (400 MHz, CDCh): 0.85-0.90 (m, 3H), 1.23-1.32 (m, 12H), 1.56-1.62 (m, 2H), 2.36 (s, 3H), 2.48-2.54 (m, 2H), 6.85 (dd, J=8.1 , 1.8 Hz, 1 H), 7.04 (d, J=1.8 Hz, 1 H), 7.40 (d, J=8.1 Hz, 1 H). c) 4,4,5,5-Tetramethyl-2-(2-methyl-4-nonylphenyl)-1 ,3,2-dioxaborolane

Obtained as a colourless oil (75%) from 1-bromo-2-methyl-4-nonylbenzene (Intermediate 17b) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) following the experimental procedure described in Intermediate 15c followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCh): 0.88 (t, J=6.9 Hz, 3H), 1.24-1.31 (m, 12H), 1.33 (s, 12H), 1.56-1.62 (m, 2H), 2.51 (s, 3H), 2.53-2.58 (m, 2H), 6.96-7.00 (m, 2H), 7.68 (d, J=8.0 Hz, 1 H). d) Ethyl 3-fluoro-4-(2-methyl-4-nonylphenyl)-1 H-pyrrole-2-carboxylate

Obtained as a colourless oil (45%) from ethyl 4-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and 4,4,5,5-tetramethyl-2-(2-methyl-4-nonylphenyl)-1 ,3,2-dioxaborolane (Intermediate 17c) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography.

MS (m/z): 374 [M+1]⁺.

¹ H NMR d (400 MHz, CDCh): 0.85-0.91 (m, 3H), 1.29 (m, 12H), 1.38 (t, J=7.1 Hz, 3H), 1.58-1.67 (m, 2H), 2.31 (s, 3H), 2.55-2.62 (m, 2H), 4.37 (q, J=7.1 Hz, 2H), 6.75-6.78 (m, 1 H), 7.03 (d, J=7.7 Hz, 1 H), 7.08 (s, 1 H), 7.17 (d, J=7.7 Hz, 1 H), 8.66 (s, 1 H).

INTERMEDIATE 18

Ethyl 4-(2-ethyl-4-heptylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylate a) 2-Ethyl-4-iodoaniline To a solution of 2-ethylaniline (5.00 g, 41.37 mmol) in methanol (35 ml_) was added a solution of sodium bicarbonate (6.00 g, 71.42 mmol) in water (35 ml_). After cooling to 0 °C, diiodine (1 1.51 g, 45.70 mmol) was added portionwise and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then partitioned between DCM and water and phases were separated. The organic layer was washed with saturated aqueous sodium hydrogen sulfite solution, 4% aqueous sodium hydrogen carbonate solution and brine, dried over magnesium sulfate, filtered and the solvents were evaporated to dryness. Purification of the residue by flash chromatography (hexanes/diethyl ether) gave the title compound (8.00 g, 78%) as a yellow oil.

MS (m/z): 248 [M+1]⁺.

¹ H NMR d (400 MHz, CDCh): 1.23 (t, J=7.5 Hz, 3H), 2.45 (q, J=7.5 Hz, 2H), 3.63 (s, 2H), 6.45 (d, J=8.3 Hz, 1 H), 7.29 (dd, J=8.3, 2.1 Hz, 1 H), 7.33 (d, J=2.1 Hz, 1 H). b) 1-Bromo-2-ethyl-4-iodobenzene

To a solution of 2-ethyl-4-iodoaniline (Intermediate 18a, 4.00 g, 16.19 mmol) in ACN (40 ml_) were added tetrabutylammonium bromide (10.44 g, 32.26 mmol), 4-methyl benzenesulfonic acid monohydrate (3.06 g, 16.09 mmol), te/Y-butyl nitrite (2.3 ml_, 19.36 mmol) and copper (II) bromide (3.6 mg, 0.016 mmol). The resulting mixture was stirred at room temperature for 5 h, then poured into water and extracted with EtOAc (x3). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and the solvents were evaporated to dryness. Purification of the residue by flash chromatography (hexanes/diethyl ether) gave the title compound (3.92 g, 78%) as an orange oil.

¹ H NMR d (400 MHz, CDCh): 1.21 (t, J=7.5 Hz, 3H), 2.70 (q, J=7.5 Hz, 2H), 7.24 (d, J=8.3 Hz, 1 H), 7.35 (dd, J=8.3, 2.2 Hz, 1 H), 7.55 (d, J=2.2 Hz, 1 H). c) 1 -Bromo-2-ethyl-4-(hept-1 -yn-1 -yl)benzene

Obtained as a yellow oil (65%) from 1-bromo-2-ethyl-4-iodobenzene (Intermediate 18b) and hept- 1-yne following the experimental procedure described in Intermediate 15a followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCh): 0.92 (t, J=7.1 Hz, 4H), 1.21 (t, J=7.5 Hz, 3H), 1.32-1.47 (m, 4H), 1.56-1.64 (m, 2H), 2.38 (t, J=7.1 Hz, 2H), 2.71 (q, J=7.5 Hz, 2H), 7.06 (dd, J=8.2, 2.1 Hz, 1 H), 7.26 (d, J=2.0 Hz, 1 H), 7.42 (d, J=8.2 Hz, 1 H). d) 1 -Bromo-2-ethyl-4-heptylbenzene Obtained as a colourless oil (74%) from 1-bromo-2-ethyl-4-(hept-1-yn-1-yl)benzene (Intermediate 18c) following the experimental procedure described in Intermediate 15b followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCIs): 0.85-0.90 (m, 3H), 1.19-1.23 (m, 3H), 1.27-1.33 (m, 8H), 1.55-1.62 (m, 2H), 2.50-2.56 (m, 2H), 2.72 (q, J=7.5 Hz, 2H), 6.86 (dd, J=8.1 , 2.2 Hz, 1 H), 7.03 (d, J=2.1 Hz, 1 H), 7.40 (d, J=8.1 Hz, 1 H). e) 2-(2-Ethyl-4-heptylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Obtained as a yellow solid (65%) from 1-bromo-2-ethyl-4-heptylbenzene (Intermediate 18d) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) following the experimental procedure described in Intermediate 15c followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCIs): 0.84-0.91 (m, 3H), 1.19 (t, J=7.5 Hz, 3H), 1.25-1.31 (m, 8H), 1.33 (s, 12H), 1.57-1.64 (m, 2H), 2.54-2.60 (m, 2H), 2.89 (q, J=7.5 Hz, 2H), 6.98-7.01 (m, 2H), 7.69 (d, J=8.1 Hz, 1 H). f) Ethyl 4-(2-ethyl-4-heptylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylate

Obtained as a colourless oil (53%) from ethyl 4-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and 2-(2-ethyl-4-heptylphenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (Intermediate 18e) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 358 [M-1]\

¹ H NMR d (400 MHz, CDCIs): 0.87-0.91 (m, 3H), 1.15 (t, J=7.5 Hz, 3H), 1.25-1.36 (m, 8H), 1.38 (t, J=7.1 Hz, 3H), 1.59-1.69 (m, 2H), 2.57-2.69 (m, 4H), 4.37 (q, J=7.1 Hz, 2H), 6.75 (dd, J=4.4, 3.7 Hz, 1 H), 7.03 (dd, J=7.7, 1.8 Hz, 1 H), 7.11-7.16 (m, 2H), 8.67 (s, 1 H).

INTERMEDIATE 19

Ethyl 4-(2-ethyl-4-nonylphenyl)-3-fluoro-1H-pyrrole-2-carboxylate a) 1 -Bromo-2-ethyl-4-(non-1 -yn-1 -yl)benzene

Obtained as a colourless oil (57%) from 1-bromo-2-ethyl-4-iodobenzene (Intermediate 18b) and non-1-yne following the experimental procedure described in Intermediate 15a followed by purification of the crude product by reverse phase chromatography (water/methanol). ¹ H NMR d (400 MHz, CDCIs): 0.85-0.92 (m, 3H), 1.21 (t, J=7.5 Hz, 3H), 1.26-1.38 (m, 6H), 1.39-1.49 (m, 2H), 1.60 (p, J=7.1 Hz, 2H), 2.38 (t, J=7.1 Hz, 2H), 2.71 (q, J=7.5 Hz, 2H), 7.06 (dd, J=8.2, 2.1 Hz, 1 H), 7.26 (d, J=2.1 Hz, 1 H), 7.42 (d, J=8.2 Hz, 1 H). b) 1 -Bromo-2-ethyl-4-nonylbenzene

Obtained as a colourless oil (48%) from 1-bromo-2-ethyl-4-(non-1-yn-1-yl)benzene (Intermediate 19a) following the experimental procedure described in Intermediate 15b followed by purification of the crude product by reverse phase chromatography (water/methanol).

¹ H NMR d (400 MHz, CDCIs): 0.85-0.90 (m, 3H), 1.22 (t, J=7.5 Hz, 3H), 1.24-1.34 (m, 12H), 1.55-1.62 (m, 2H), 2.50-2.56 (m, 2H), 2.72 (q, J=7.5 Hz, 2H), 6.86 (dd, J=8.1 , 2.2 Hz, 1 H), 7.03 (d, J=2.2 Hz, 1 H), 7.40 (d, J=8.1 Hz, 1 H). c) 2-(2-Ethyl-4-nonylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Obtained as a colourless oil (80%) from 1-bromo-2-ethyl-4-nonylbenzene (Intermediate 19b) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) following the experimental procedure described in Intermediate 15c followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCIs): 0.88 (t, J=6.9 Hz, 3H), 1.19 (t, J=7.5 Hz, 3H), 1.24-1.31 (m, 12H), 1.33 (s, 12H), 1.56-1.64 (m, 2H), 2.54-2.59 (m, 2H), 2.89 (q, J=7.5 Hz, 2H), 6.98- 7.01 (m, 2H), 7.69 (d, J=8.0 Hz, 1 H). d) Ethyl 4-(2-ethyl-4-nonylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylate

Obtained as a white solid (13%) from ethyl 4-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and 2-(2-ethyl-4-nonylphenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (Intermediate 19c) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 388 [M+1]⁺.

¹ H NMR d (400 MHz, CDCIs): 0.85-0.91 (m, 3H), 1.15 (t, J=7.1 Hz, 3H), 1.25-1.36 (m, 10H), 1.38 (t, J=7.1 Hz, 3H), 1.58-1.68 (m, 2H), 2.58-2.68 (m, 4H), 4.37 (q, J=7.1 Hz, 2H), 6.73-6.76 (m, 1 H), 7.03 (dd, J=7.8, 1.8 Hz, 1 H), 7.1 1-7.16 (m, 2H), 8.63 (s, 1 H).

INTERMEDIATE 20

Ethyl 3-fluoro-4-(2-isopropyl-4-nonylphenyl)-1 H-pyrrole-2-carboxylate

a) 4-lodo-2-isopropylaniline Obtained as an oil (68%) from 2-isopropylaniline following the experimental procedure described in Intermediate 18a followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 262 [M+1]⁺.

¹ H NMR d (400 MHz, CDCIs): 1.23 (d, J=6.8 Hz, 6H), 2.81 (hept, J=6.8 Hz, 1 H), 3.66 (s, 2H), 6.45 (d, J=8.3 Hz, 1 H), 7.28 (dd, J=8.3, 2.1 Hz, 1 H), 7.37 (d, J=2.0 Hz, 1 H). b) 1-Bromo-4-iodo-2-isopropylbenzene

Obtained as a red oil (75%) from 4-iodo-2-isopropylaniline (Intermediate 20a) following the experimental procedure described in Intermediate 18b followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCIs): 1.22 (d, J=6.9 Hz, 6H), 3.28 (hept, J=6.8 Hz, 1 H), 7.24 (d, J=8.4 Hz, 2H), 7.34 (dd, J=8.3, 2.2 Hz, 1 H), 7.55 (d, J=2.2 Hz, 1 H). c) 1 -Bromo-2-isopropyl-4-(non-1 -yn-1 -yl)benzene

Obtained as an oil (66%) from 1-bromo-4-iodo-2-isopropylbenzene (Intermediate 20b) and non- 1-yne following the experimental procedure described in Intermediate 15a followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCIs): 0.87-0.91 (m, 3H), 1.21-1.24 (d, J=6.9 Hz, 6H), 1.25-1.37 (m, 6H), 1.40-1.49 (m, 2H), 1.56-1.65 (m, 2H), 2.39 (t, J=7.1 Hz, 2H), 3.31 (hept, J=6.9 Hz, 1 H), 7.05 (dd, J=8.2, 2.1 Hz, 1 H), 7.29 (d, J=2.1 Hz, 1 H), 7.43 (d, J=8.2 Hz, 1 H). d) 1-Bromo-2-isopropyl-4-nonylbenzene

Obtained as an oil (58%) from 1-bromo-2-isopropyl-4-(non-1-yn-1-yl)benzene (Intermediate 20c) following the experimental procedure described in Intermediate 15b followed by purification of the crude product by reverse phase chromatography (water/methanol).

¹ H NMR d (400 MHz, CDCIs): 0.85-0.90 (m, 3H), 1.23 (d, J=6.9 Hz, 6H), 1.25-1.34 (m, 12H), 1.55-1.62 (m, 2H), 2.50-2.59 (m, 2H), 3.33 (hept, J=6.9 Hz, 1 H), 6.85 (dd, J=8.1 , 2.2 Hz, 1 H), 7.07 (d, J=2.2 Hz, 1 H), 7.41 (d, J=8.1 Hz, 1 H). e) 2-(2-lsopropyl-4-nonylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Obtained as an oil (57%) from 1-bromo-2-isopropyl-4-nonylbenzene (Intermediate 20d) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) following the experimental procedure described in Intermediate 15c followed by purification by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCIs): 0.85-0.90 (m, 3H), 1.22 (d, J=6.9 Hz, 6H), 1.25-1.32 (m, 12H), 1.33 (s, 12H), 1.56-1.62 (m, 2H), 2.54-2.62 (m, 2H), 3.61-3.75 (m, 1 H), 6.98 (dd, J=7.6, 1.6 Hz, 1 H), 7.11 (d, J=1.6 Hz, 1 H), 7.66 (d, J=7.6 Hz, 1 H). f) Ethyl 3-fluoro-4-(2-isopropyl-4-nonylphenyl)-1 H-pyrrole-2-carboxylate

Obtained as an oil (10%) from ethyl 4-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and 2-(2-isopropyl-4-nonylphenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (Intermediate 20e) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 400 [M-1]\

INTERMEDIATE 21

Ethyl 3-fluoro-4-(2-methyl-5-nonylphenyl)-1H-pyrrole-2-carboxylate a) 2-Bromo-1 -methyl -4-(non-1 -yn-1 -yl)benzene

Obtained as an oil (100%) from 2-bromo-4-iodo-1-methylbenzene and non-1-yne following the experimental procedure described in Intermediate 15a followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCIs): 0.84-0.89 (m, 3H), 1.22-1.34 (m, 8H), 1.35-1.43 (m, 2H), 1.53 (p, J=7.0 Hz, 2H), 2.33 (s, 3H), 2.40 (t, J=7.0 Hz, 2H), 7.28 (dd, J=7.8, 1.6 Hz, 1 H), 7.32 (d, J=7.9 Hz, 1 H), 7.55 (d, J=1.5 Hz, 1 H). b) 2-Bromo-1-methyl-4-nonylbenzene

Obtained as a colourless oil (88%) from 2-bromo-1-methyl-4-(non-1-yn-1-yl)benzene (Intermediate 21 a) following the experimental procedure described in Intermediate 15b followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCIs): 7.35 (d, J=1.7 Hz, 1 H), 7.12 (d, J=7.7 Hz, 1 H), 7.00 (dd, J=7.7, 1.6 Hz, 1 H), 2.56-2.49 (m, 2H), 2.35 (s, 3H), 1.61-1.53 (m, 2H), 1.28 (d, J=16.3 Hz, 12H), 0.90-0.85 (m, 3H). c) 4,4,5,5-Tetramethyl-2-(2-methyl-5-nonylphenyl)-1,3,2-dioxaborolane Obtained as a colourless oil (51 %) from 2-bromo-1-methyl-4-nonylbenzene (Intermediate 21 b) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) following the experimental procedure described in Intermediate 15c followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCh): 0.85-0.91 (m, 3H), 1.28 (d, J=15.2 Hz, 12H), 1.34 (s, 12H), 1.55-1.65 (m, 2H), 2.49 (s, 3H), 2.52-2.58 (m, 2H), 7.07 (d, J=7.8 Hz, 1 H), 7.13 (dd, J=7.8, 2.0 Hz, 1 H), 7.56 (d, J=1.9 Hz, 1 H). d) Ethyl 3-fluoro-4-(2-methyl-5-nonylphenyl)-1 H-pyrrole-2-carboxylate

Obtained as a colourless oil (66%) from ethyl 4-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and 4,4,5,5-tetramethyl-2-(2-methyl-5-nonylphenyl)-1 ,3,2-dioxaborolane (Intermediate 21c) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 374 [M+1]⁺.

¹ H NMR d (400 MHz, CDCh): 0.85-0.90 (m, 3H), 1.23-1.35 (m, 12H), 1.39 (t, J=7.1 Hz, 3H), 1.57-1.65 (m, 2H), 2.30 (s, 3H), 2.54-2.61 (m, 2H), 4.38 (q, J=7.1 Hz, 2H), 6.78 (dd, J=4.4, 3.7 Hz, 1 H), 7.06 (dd, J=7.7, 1.8 Hz, 1 H), 7.09 (s, 1 H), 7.17 (d, J=7.7 Hz, 1 H), 8.67 (s, 1 H).

INTERMEDIATE 22

Ethyl 3-fluoro-4-(2-methyl-3-nonylphenyl)-1H-pyrrole-2-carboxylate a) 1 -Bromo-2-methyl-3-(non-1 -yn-1 -yl)benzene

Obtained as an oil (87%) from 1-bromo-3-iodo-2-methylbenzene and non-1-yne following the experimental procedure described in Intermediate 15a followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCh): 0.87-0.92 (m, 3H), 1.26-1.38 (m, 6H), 1.42-1.51 (m, 2H), 1.57-1.66 (m, 2H), 2.45 (t, J=7.0 Hz, 2H), 2.53 (s, 3H), 6.92-6.97 (m, 1 H), 7.31 (dd, J=7.7, 0.9 Hz, 1 H), 7.44 (dd, J=8.0, 1.0 Hz, 1 H). b) 1-Bromo-2-methyl-3-nonylbenzene

Obtained as an oil (80%) from 1-bromo-2-methyl-3-(non-1-yn-1-yl)benzene (Intermediate 22a) following the experimental procedure described in Intermediate 15b followed by purification of the crude product by flash chromatography (hexanes/diethyl ether). ¹ H NMR d (400 MHz, CDCb): 0.88 (t, J=6.9 Hz, 3H), 1.23-1.38 (m, 12H), 1.48-1.58 (m, 2H), 2.38 (s, 3H), 2.60-2.66 (m, 2H), 6.95 (t, J=7.7 Hz, 1 H), 7.06 (d, J=7.5 Hz, 1 H), 7.39 (dd, J=7.9, 1.0 Hz, 1 H). c) 4,4,5,5-Tetramethyl-2-(2-methyl-3-nonylphenyl)-1 ,3,2-dioxaborolane

Obtained as an oil (68%) from 1-bromo-2-methyl-3-nonylbenzene (Intermediate 22b) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) following the experimental procedure described in Intermediate 15c followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCb): 0.86-0.91 (m, 3H), 1.24-1.33 (m, 12H), 1.34 (s, 12H), 1.49- 1.59 (m, 2H), 2.50 (s, 3H), 2.56-2.62 (m, 2H), 7.10 (t, J=7.4 Hz, 1 H), 7.19 (dd, J=7.4, 1.4 Hz, 1 H), 7.59 (dd, J=7.4, 1.4 Hz, 1 H). d) Ethyl 3-fluoro-4-(2-methyl-3-nonylphenyl)-1 H-pyrrole-2-carboxylate

Obtained as an oil (23%) from ethyl 4-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and 4,4,5,5-tetramethyl-2-(2-methyl-3-nonylphenyl)-1 ,3,2-dioxaborolane (Intermediate 22c) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 372 [M-1]\

¹ H NMR d (400 MHz, CDCb): 0.85-0.91 (m, 3H), 1.25-1.36 (m, 12H), 1.39 (t, J=7.1 Hz, 3H), 1.55-1.65 (m, 2H), 2.26 (s, 3H), 2.61-2.67 (m, 2H), 4.38 (q, J=7.1 Hz, 2H), 6.76 (dd, J=4.4, 3.7 Hz, 1 H), 7.07-7.1 1 (m, 1 H), 7.12-7.16 (m, 2H), 8.76 (s, 1 H).

INTERMEDIATE 23

Ethyl 4-(3-decyl-2-methylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylate

a) 1 -Bromo-3-(dec-1 -yn-1 -yl)-2-methylbenzene

Obtained as an orange oil (95%) from 1-bromo-3-iodo-2-methylbenzene and dec-1-yne following the experimental procedure described in Intermediate 15a followed by purification of the crude product by flash chromatography (hexanes).

¹ H NMR d (400 MHz, CDCb): 0.83-0.93 (m, 3H), 1.25-1.37 (m, 10H), 1.41-1.50 (m, 2H), 1.57-1.66 (m, 2H), 2.45 (t, J=7.0 Hz, 2H), 2.53 (s, 3H), 6.95 (t, J=7.0 Hz, 1 H), 7.32 (d, J=8.0 Hz, 1 H), 7.44 (d, J=8.0 Hz, 1 H). b) 1 -Bromo-3-decyl-2-methylbenzene

A solution of 1-bromo-3-(dec-1-yn-1-yl)-2-methylbenzene (Intermediate 23a, 4.90 g, 16.00 mmol) and chloridotris(triphenylphosphane)rhodium(l) (Wilkinson catalyst, 738 mg, 0.80 mmol) in toluene (10 ml_) was hydrogenated overnight at 50 bar. The reaction mixture was filtered through a Celite^® pad, washing with methyl tert- butyl ether several times. The filtrate and washings were combined and the solvents were evaporated to dryness. Purification of the residue by flash chromatography (hexanes) yielded the title compound (4.1 g, 83%) as a yellow oil.

¹ H NMR d (400 MHz, CDCh): 0.87 (t, J=6.4 Hz, 3H), 1.19-1.40 (m, 14H), 1.47-1.61 (m, 2H), 2.39 (s, 3H), 2.59-2.67 (m, 2H), 6.96 (t, J=7.7 Hz, 1 H), 7.06 (d, J=7.3 Hz, 1 H), 7.39 (d, J=7.3, 1.0 Hz, 1 H). c) 2-(3-Decyl-2-methylphenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane

Obtained as a yellow oil (0.82 g, 74%) from 1-bromo-3-decyl-2-methylbenzene (Intermediate 23b) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) following the experimental procedure described in Intermediate 15c followed by purification of the crude product by flash chromatography (hexanes/methyl tert- butyl ether).

¹ H NMR d (400 MHz, CDCh): 0.85 (t, J=6.7 Hz, 3H), 1.24-1.33 (m, 14H), 1.24 (s, 12H), 1.49-1.59 (m, 2H), 2.41 (s, 3H), 2.55 (t, J=7.8 Hz, 2H), 7.07 (t, J=7.4 Hz, 1 H), 7.20 (d, J=6.3 Hz, 1 H), 7.43 (d, J=7.4 Hz, 1 H). d) Ethyl 4-(3-decyl-2-methylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylate

Obtained as a white solid (36%) from ethyl 3-fluoro-4-iodo-1 H-pyrrole-2-carboxylate (Intermediate 2) and 2-(3-decyl-2-methylphenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (Intermediate 23c) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography ((hexanes/methyl tert- butyl ether).

MS (m/z): 386 [M-1]\

INTERMEDIATE 24

Ethyl 4-(3-decyl-2-methylphenyl)-3-fluoro-1 -methyl-1 H-pyrrole-2-carboxylate

To a cooled (0 °C) solution of ethyl 4-(3-decyl-2-methylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 23d, 60 g, 0.15 mmol) in DMF (1 ml_) was added sodium hydride (60% dispersion in mineral oil, 7.5 mg, 0.19 mmol) and the mixture was stirred at 0 °C for 30 min. lodomethane (12 mI_, 0.19 mmol) was then added and the solution was stirred at room temperature for 1 h. The reaction mixture was then poured into water and extracted with EtOAc (x3). The combined organic layers were washed with water (x2) and brine, dried over magnesium sulfate, filtered and the solvents concentrated in vacuo to give the title compound (50 mg, 80%) which was used in the next synthetic step without further purification.

MS (m/z): 402 [M+1]⁺.

¹ H NMR d (400 MHz, CDCh): 0.88 (t, J=6.8 Hz, 3H), 1.23-1.34 (m, 14H), 1.38 (t, J=7.1 Hz, 3H), 1.56-1.63 (m, 2H), 2.26 (d, J=1.5 Hz, 3H), 2.60-2.67 (m, 2H), 3.90 (s, 3H), 4.35 (q, J=7.1 Hz, 2H), 6.59 (d, J=5.2 Hz, 1 H), 7.06 (dd, J=5.4, 3.7 Hz, 1 H), 7.1 1-7.14 (m, 2H).

INTERMEDIATE 25

Ethyl 4-(2-ethyl-3-nonylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylate a) 1-Bromo-2-ethyl-3-iodobenzene

To a cooled (-78 °C) solution of diisopropylamine (3.2 ml_, 22.95 mmol) in THF (20 ml_) under argon atmosphere was slowly added n-butyl lithium (2.5M solution in hexanes, 9.2 ml_, 23 mmol) and the resulting solution was stirred at -78 °C for 20 min. This solution was slowly added to a cooled (-78 °C) solution of 1-bromo-3-iodobenzene (5.00 g, 17.67 mmol) and iodoethane (1.7 ml_, 21.15 mmol) in THF (20 ml_) and the mixture was stirred at -78 °C for 3 h. The reaction mixture was then poured into saturated aqueous ammonium chloride solution, stirred for 15 min and extracted with DCM (x3). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and the solvents were evaporated to dryness. Purification of the residue by flash chromatography (hexanes/diethyl ether) gave the title compound (5.38 g, 98%) as a colourless oil.

¹ H NMR d (400 MHz, CDCh): 1.16 (t, J=7.5 Hz, 3H), 3.05 (q, J=7.5 Hz, 2H), 6.69 (t, J=7.9 Hz, 1 H), 7.52 (dd, J=8.0, 1.2 Hz, 1 H), 7.77 (dd, J=7.9, 1.2 Hz, 1 H). b) 1 -Bromo-2-ethyl-3-(non-1 -yn-1 -yl)benzene

Obtained as an oil (78%) from 1-bromo-2-ethyl-3-iodobenzene (Intermediate 25a) and non-1-yne following the experimental procedure described in Intermediate 15a followed by purification of the crude product by flash chromatography (hexanes/diethyl ether). ¹ H NMR d (400 MHz, CDCIs): 0.87-0.92 (m, 3H), 1.19 (t, J=7.5 Hz, 3H), 1.25-1.38 (m, 6H), 1.42-1.51 (m, 2H), 1.57-1.66 (m, 2H), 2.44 (t, J=7.0 Hz, 2H), 2.99 (q, J=7.5 Hz, 2H), 6.94 (t, J=7.8 Hz, 1 H), 7.31 (dd, J=7.8, 1.2 Hz, 1 H), 7.43 (dd, J=7.8, 1.2 Hz, 1 H). c) 1-Bromo-2-ethyl-3-nonylbenzene

Obtained as an oil (76%) from 1-bromo-2-ethyl-3-(non-1-yn-1-yl)benzene (Intermediate 25b) following the experimental procedure described in Intermediate 15b followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCIs): 0.88 (t, J=6.8 Hz, 5H), 1.16 (t, J=7.5 Hz, 3H), 1.22-1.41 (m, 12H), 1.55-1.62 (m, 2H), 2.58-2.68 (m, 2H), 2.82 (q, J=7.5 Hz, 2H), 6.95 (t, J=7.8 Hz, 1 H), 7.06-7.09 (m, 1 H), 7.37 (dd, J=7.9, 1.0 Hz, 1 H). d) 2-(2-Ethyl-3-nonylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Obtained as a colourless oil (98%) from 1-bromo-2-ethyl-3-nonylbenzene (Intermediate 25c) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) following the experimental procedure described in Intermediate 15c followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCIs): 0.88 (t, J=6.8 Hz, 3H), 1.14 (t, J=7.5 Hz, 3H), 1.24-1.31 (m, 12H), 1.34 (s, 12H), 1.51-1.62 (m, 2H), 2.57-2.64 (m, 2H), 2.94 (q, J=7.5 Hz, 2H), 7.10 (t, J=7.4 Hz, 1 H), 7.21 (dd, J=7.6, 1.4 Hz, 1 H), 7.60 (dd, J=7.3, 1.5 Hz, 1 H). e) Ethyl 4-(2-ethyl-3-nonylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylate

Obtained as a colourless oil (27%) from ethyl 3-fluoro-4-iodo-1 H-pyrrole-2-carboxylate (Intermediate 2) and 2-(2-ethyl-3-nonylphenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (Intermediate 25d) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 388 [M+1]⁺.

¹ H NMR d (400 MHz, CDCIs): 0.86-0.91 (m, 3H), 1.02 (t, J=7.5 Hz, 3H), 1.23-1.32 (m, 12H), 1.39 (t, J=7.1 Hz, 3H), 1.57-1.67 (m, 2H), 2.62-2.70 (m, 4H), 4.38 (q, J=7.1 Hz, 2H), 6.75 (dd, J=4.4, 3.6 Hz, 1 H), 7.05 (dd, J=7.3, 1.6 Hz, 1 H), 7.13 (t, J=7.4 Hz, 1 H), 7.18 (dd, J=7.6, 1.7 Hz, 1 H), 8.65 (s, 1 H).

INTERMEDIATE 26 Ethyl 3-fluoro-4-(2-fluoro-3-nonylphenyl)-1 H-pyrrole-2-carboxylate a) 1-Bromo-2-fluoro-3-(non-1-yn-1-yl)benzene

Obtained as a light yellow oil (86%) from 1-bromo-2-fluoro-3-iodobenzene and non-1-yne following the experimental procedure described in Intermediate 15a followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCIs): 0.92 (m, 3H), 1.26-1.37 (m, 6H), 1.41-1.50 (m, 2H), 1.58- 1.66 (m, 2H), 2.45 (t, J=7.1 Hz, 2H), 6.93 (td, J=7.9, 0.9 Hz, 1 H), 7.32 (ddd, J=7.9, 6.4, 1.6 Hz, 1 H), 7.44 (ddd, J=8.1 , 6.4, 1.6 Hz, 1 H). b) 1-Bromo-2-fluoro-3-nonylbenzene

Obtained as a colourless oil (100%) from 1-bromo-2-fluoro-3-(non-1-yn-1-yl)benzene (Intermediate 26a) following the experimental procedure described in Intermediate 15b followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCIs): 0.84-0.91 (m, 3H), 1.28 (d, J=18.2 Hz, 12H), 1.59 (p, J=7.4 Hz, 2H), 2.59-2.68 (m, 2H), 6.89-6.95 (m, 1 H), 7.08-7.14 (m, 1 H), 7.33-7.39 (m, 1 H). c) 2-(2-Fluoro-3-nonylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Obtained as a colourless oil (34%) from 1-bromo-2-fluoro-3-nonylbenzene (Intermediate 26b) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) following the experimental procedure described in Intermediate 15c followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCIs): 0.85-0.90 (m, 3H), 1.23-1.33 (m, 12H), 1.36 (s, 12H), 1.53- 1.65 (m, 2H), 2.57-2.65 (m, 2H), 7.05 (t, J=7.4 Hz, 1 H), 7.24-7.30 (m, 2H), 7.55 (ddd, J=7.4, 5.6, 1.8 Hz, 1 H). d) Ethyl 3-fluoro-4-(2-fluoro-3-nonylphenyl)-1 H-pyrrole-2-carboxylate

Obtained as a white solid (75%) from ethyl 4-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and 2-(2-fluoro-3-nonylphenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (Intermediate 26c) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 376 [M-1]\ ¹ H NMR d (400 MHz, CDCb): 0.85-0.90 (m, 3H), 1.30 (d, J=25.8 Hz, 12H), 1.39 (t, J=7.1 Hz, 3H), 1.62 (p, J=7.6 Hz, 2H), 2.62-2.70 (m, 2H), 4.38 (q, J=7.1 Hz, 2H), 7.06-7.12 (m, 2H), 7.16-7.20 (m, 1 H), 7.47-7.54 (m, 1 H), 8.71 (s, 1 H).

INTERMEDIATE 27

Ethyl 4-(2-chloro-3-nonylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylate

a) 1 -Bromo-2-chloro-3-(non-1 -yn-1 -yl)benzene

Obtained as a yellow oil (47%) from 1-bromo-2-chloro-3-iodobenzene and non-1-yne following the experimental procedure described in Intermediate 15a followed by purification of the crude product by flash chromatography (hexanes/diethyl ether) and reverse phase chromatography (water/methanol).

¹ H NMR d (400 MHz, CDCb): 0.85-0.92 (m, 3H), 1.26-1.39 (m, 6H), 1.44-1.52 (m, 2H), 1.58-1.67 (m, 2H), 2.47 (t, J=7.0 Hz, 2H), 7.03 (t, J=7.9 Hz, 1 H), 7.38 (dd, J=7.9, 1.5 Hz, 1 H), 7.52 (dd, J=7.9, 1.5 Hz, 1 H). b) 1-Bromo-2-chloro-3-nonylbenzene

Obtained as a colourless oil (85%) from 1-bromo-2-chloro-3-(non-1-yn-1-yl)benzene (Intermediate 27a) following the experimental procedure described in Intermediate 15b followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCb): 0.84-0.92 (m, 3H), 1.21-1.38 (m, 12H), 1.55-1.66 (m, 2H), 2.73-2.79 (m, 2H), 7.03 (t, J=7.8 Hz, 1 H), 7.15 (dd, J=7.7, 1.6 Hz, 1 H), 7.46 (dd, J=7.9, 1.6 Hz, 1 H). c) 2-(2-Chloro-3-nonylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Obtained as a colurless oil (34%) from 1-bromo-2-chloro-3-nonylbenzene (Intermediate 27b) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) following the experimental procedure described in Intermediate 15c followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCb): 0.85-0.91 (m, 3H), 1.24-1.35 (m, 12H), 1.38 (s, 12H), 1.55- 1.63 (m, 2H), 2.68-2.74 (m, 2H), 7.15 (t, J=7.3 Hz, 1 H), 7.23-7.27 (m, 1 H), 7.46 (dd, J=7.3, 1.8 Hz, 1 H). d) Ethyl 4-(2-chloro-3-nonylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylate Obtained as a white solid (65%) from ethyl 4-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and 2-(2-chloro-3-nonylphenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (Intermediate 27c) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 392 [M-1]\

¹ H NMR d (400 MHz, CDCh): 0.85-0.91 (m, 3H), 1.24-1.36 (m, 12H), 1.39 (t, J=7.1 Hz, 3H), 1.64 (p, J=7.6 Hz, 2H), 2.73-2.82 (m, 2H), 4.38 (q, J=7.1 Hz, 2H), 6.99-7.02 (m, 1 H), 7.19-7.21 (m, 2H), 7.22-7.25 (m, 1 H), 8.72 (s, 1 H).

INTERMEDIATE 28

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

a) 1-Bromo-2-fluoro-4-(non-1-yn-1-yl)benzene

Obtained as a deep yellow oil (74%) from 1-bromo-2-fluoro-4-iodobenzene and non-1-yne following the experimental procedure described in Intermediate 15a followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCh): 0.86-0.93 (m, 3H), 1.21-1.38 (m, 6H), 1.39-1.47 (m, 2H), 1.56-1.64 (m, 2H), 2.38 (t, J=7.1 Hz, 2H), 7.02-7.06 (m, 1 H), 7.10-7.15 (m, 1 H), 7.44 (dd, J=8.2, 7.3 Hz, 1 H). b) 1-Bromo-2-fluoro-4-nonylbenzene

Obtained as a yellow oil (94%) from 1-bromo-2-fluoro-4-(non-1-yn-1-yl)benzene (Intermediate 28a) following the experimental procedure described in Intermediate 15b followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCh): 0.84-0.90 (m, 3H), 1.23-1.33 (m, 12H), 1.52-1.63 (m, 2H), 2.52-2.62 (m, 2H), 6.82-6.86 (m, 1 H), 6.92-6.96 (m, 1 H), 7.41 (dd, J=8.1 , 7.3 Hz, 1 H). c) 2-(2-Fluoro-4-nonylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Obtained as an oil (20%) from 1-bromo-2-fluoro-4-nonylbenzene (Intermediate 28b) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) following the experimental procedure described in Intermediate 15c followed by purification of the crude product by flash chromatography (hexanes/diethyl ether). ¹ H NMR d (400 MHz, CDCh): 0.84-0.91 (m, 3H), 1.24-1.32 (m, 12H), 1.35 (s, 12H), 1.56- 1.62 (m, 2H), 2.57-2.62 (m, 2H), 6.82-6.87 (m, 1 H), 6.93-6.97 (m, 1 H), 7.63 (dd, J=7.4, 6.6 Hz, 1 H). d) Ethyl 3-fluoro-4-(2-fluoro-4-nonylphenyl)-1 H-pyrrole-2-carboxylate

Obtained as an oil (31 %) from ethyl 4-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and 2-(2-fluoro-4-nonylphenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (Intermediate 28c) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 378 [M+1]⁺.

¹ H NMR d (400 MHz, CDCh): 0.88 (t, J=6.8 Hz, 3H), 1.23-1.36 (m, 12H), 1.39 (t, J=7.1 Hz, 2H), 1.57-1.66 (m, 2H), 2.56-2.64 (m, 2H), 4.38 (q, J=7.1 Hz, 2H), 6.92-7.03 (m, 2H), 7.13- 7.18 (m, 1 H), 7.58 (t, J=8.1 Hz, 1 H), 8.65 (s, 1 H).

INTERMEDIATE 29

Ethyl 3-fluoro-4-(2-fluoro-5-nonylphenyl)-1 H-pyrrole-2-carboxylate a) 2-Bromo-1 -fluoro-4-(non-1 -yn-1 -yl)benzene

Obtained as an oil (97%) from 2-bromo-1-fluoro-4-iodobenzene and non-1-yne following the experimental procedure described in Intermediate 15a followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCh): 0.86-0.92 (m, 3H), 1.25-1.38 (m, 6H), 1.39-1.47 (m, 2H), 1.54-1.64 (m, 2H), 2.38 (t, J=7.1 Hz, 2H), 7.02 (t, J=8.5 Hz, 1 H), 7.29 (ddd, J=8.5, 4.7, 2.1 Hz, 1 H), 7.59 (dd, J=6.6, 2.1 Hz, 1 H). b) 2-Bromo-1 -fluoro-4-nonylbenzene

Obtained as an oil (90%) from 2-bromo-1-fluoro-4-(non-1-yn-1-yl)benzene (Intermediate 29a) following the experimental procedure described in Intermediate 15b followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCh): 0.86-0.90 (m, 3H), 1.23-1.32 (m, 12H), 1.53-1.59 (m, 2H), 2.51-2.58 (m, 2H), 7.02 (d, J=8.4 Hz, 1 H), 7.04-7.09 (m, 1 H), 7.35 (dd, J=6.7, 2.1 Hz, 1 H). c) 2-(2-Fluoro-5-nonylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Obtained as an oil (50%) from 2-bromo-1-fluoro-4-nonylbenzene (Intermediate 29b) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) following the experimental procedure described in Intermediate 15c followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCh): 0.85-0.90 (m, 3H), 1.23-1.32 (m, 12H), 1.36 (s, 12H), 1.55- 1.62 (m, 2H), 2.51-2.60 (m, 2H), 6.89-6.96 (m, 1 H), 7.22 (ddd, J=8.0, 5.5, 2.5 Hz, 1 H), 7.51 (dd, J=5.5, 2.5 Hz, 1 H). d) Ethyl 3-fluoro-4-(2-fluoro-5-nonylphenyl)-1 H-pyrrole-2-carboxylate

Obtained as a white solid (74%) from ethyl 4-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and 2-(2-fluoro-5-nonylphenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (Intermediate 29c) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 378 [M+1]⁺.

¹ H NMR d (400 MHz, CDCh): 0.84-0.91 (m, 3H), 1.23-1.35 (m, 12H), 1.40 (t, J=7.1 Hz, 3H), 1.56-1.65 (m, 2H), 2.55-2.63 (m, 2H), 4.39 (q, J=7.1 Hz, 2H), 7.00-7.04 (m, 2H), 7.16- 7.19 (m, 1 H), 7.49 (d, J=7.6 Hz, 1 H), 8.68 (s, 1 H).

INTERMEDIATE 30

Ethyl 4-(2-chloro-4-heptylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylate a) 1 -Bromo-2-chloro-4-(hept-1 -yn-1 -yl)benzene

Obtained as an oil (43%) from 1-bromo-2-chloro-4-iodobenzene and hept-1-yne following the experimental procedure described in Intermediate 15a followed by purification of the crude product by flash chromatography (hexanes/diethyl ether). b) 1-Bromo-2-chloro-4-heptylbenzene

Obtained as an oil (87%) from 1-bromo-2-chloro-4-(hept-1-yn-1-yl)benzene (Intermediate 30a) following the experimental procedure described in Intermediate 15b followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCh): 0.84-0.91 (m, 3H), 1.24-1.33 (m, 8H), 1.55-1.61 (m, 2H), 2.49-2.57 (m, 2H), 6.92 (dd, J=8.2, 2.1 Hz, 1 H), 7.26 (d, J=2.0 Hz, 1 H), 7.48 (d, J=8.2 Hz, 1 H). c) 2-(2-Chloro-4-heptylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Obtained as a colourless oil (34%) from 1-bromo-2-chloro-4-heptylbenzene (Intermediate 30b) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) following the experimental procedure described in Intermediate 15c followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCh): 0.84-0.90 (m, 3H), 1.24-1.32 (m, 8H), 1.36 (s, 12H), 1.56- 1.62 (m, 2H), 2.52-2.60 (m, 2H), 7.04 (dd, J=7.6, 1.5 Hz, 1 H), 7.17 (d, J=1.2 Hz, 1 H), 7.60 (d, J=7.6 Hz, 1 H). d) Ethyl 4-(2-chloro-4-heptylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylate

Obtained as a solid (41 %) from ethyl 3-fluoro-4-iodo-1 H-pyrrole-2-carboxylate (Intermediate 2) and 2-(2-chloro-4-heptylphenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (Intermediate 30c) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 364 [M-1]\

¹ H NMR d (400 MHz, CDCh): 0.85-0.91 (m, 3H), 1.25-1.35 (m, 8H), 1.39 (t, J=7.1 Hz, 3H), 1.59-1.67 (m, 2H), 2.55-2.63 (m, 2H), 4.38 (q, J=7.1 Hz, 2H), 7.04-7.07 (m, 1 H), 7.10 (dd, J=7.9, 1.8 Hz, 1 H), 7.28 (d, J=1.7 Hz, 1 H), 7.35 (dd, J=7.9, 1.2 Hz, 1 H), 8.75 (s, 1 H).

INTERMEDIATE 31

Ethyl 4-(2-chloro-4-nonylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylate

a) 1 -Bromo-2-chloro-4-(non-1 -yn-1 -yl)benzene

Obtained as a colourless oil (76%) from 1-bromo-2-chloro-4-iodobenzene and non-1-yne following the experimental procedure described in Intermediate 15a followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCh): 0.87-0.92 (m, 3H), 1.26-1.37 (m, 6H), 1.38-1.47 (m, 2H), 1.55-1.63 (m, 2H), 2.38 (t, J=7.1 Hz, 2H), 7.11 (dd, J=8.3, 1.9 Hz, 1 H), 7.47 (d, J=1.9 Hz, 1 H), 7.51 (d, J=8.3 Hz, 1 H). b) 1-Bromo-2-chloro-4-nonylbenzene

Obtained as a colourless oil (100%) from 1-bromo-2-chloro-4-(non-1-yn-1-yl)benzene (Intermediate 31a) following the experimental procedure described in Intermediate 15b. ¹ H NMR d (400 MHz, CDCb): 0.88 (t, J=6.9 Hz, 3H), 1.23-1.31 (m, 12H), 1.53-1.63 (m, 2H), 2.49-2.57 (m, 2H), 6.92 (dd, J=8.2, 2.1 Hz, 1 H), 7.25-7.28 (m, 2H), 7.49 (d, J=8.2 Hz, 1 H). c) 2-(2-Chloro-4-nonylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Obtained as a colourless oil (25%) from 1-bromo-2-chloro-4-nonylbenzene (Intermediate 31 b) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) following the experimental procedure described in Intermediate 15c followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCb): 0.88 (t, J=6.9 Hz, 3H), 1.23-1.31 (m, 12H), 1.36 (s, 12H), 1.56-1.62 (m, 2H), 2.52-2.60 (m, 2H), 7.04 (dd, J=7.6, 1.5 Hz, 1 H), 7.17 (d, J=1.3 Hz, 1 H), 7.60 (d, J=7.6 Hz, 1 H). d) Ethyl 4-(2-chloro-4-nonylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylate

Obtained as a white solid (63%) from ethyl 4-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and 2-(2-chloro-4-nonylphenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (Intermediate 31c) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 392 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.82-0.89 (m, 3H), 1.26 (d, J=9.6 Hz, 12H), 1.30 (d, J=7.1 Hz, 3H), 1.51-1.62 (m, 2H), 2.55-2.62 (m, 2H), 4.27 (q, J=7.1 Hz, 2H), 7.10 (d, J=4.7 Hz, 1 H), 7.19 (dd, J=7.9, 1.7 Hz, 1 H), 7.31-7.37 (m, 2H), 12.01 (s, 1 H).

INTERMEDIATE 32

Ethyl 3-fluoro-4-(2-chloro-5-nonylphenyl)-1 H-pyrrole-2-carboxylate

a) 2-Bromo-1 -chloro-4-(non-1 -yn-1 -yl)benzene

Obtained as a yellow oil (71 %) from 2-bromo-1-chloro-4-iodobenzene and non-1-yne following the experimental procedure described in Intermediate 15a followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCb): 0.86-0.93 (m, 3H), 1.24-1.38 (m, 6H), 1.38-1.47 (m, 2H), 1.55-1.63 (m, 2H), 2.38 (t, J=7.1 Hz, 2H), 7.24 (dd, J=8.3, 1.9 Hz, 1 H), 7.34 (d, J=8.3 Hz, 1 H), 7.64 (d, J=1.9 Hz, 1 H). b) 2-Bromo-1 -chloro-4-nonylbenzene

Obtained as a colourless oil (55%) from 2-bromo-1-chloro-4-(non-1-yn-1-yl)benzene (Intermediate 32a) following the experimental procedure described in Intermediate 15b followed by purification of the crude product by reverse phase chromatography (water/methanol).

¹H NMR d (400 MHz, CDCh): 0.85-0.90 (m, 3H), 1.22-1.33 (m, 12H), 1.55-1.62 (m, 2H), 2.51-2.57 (m, 2H), 7.04 (dd, J=8.2, 2.0 Hz, 1 H), 7.33 (d, J=8.2 Hz, 1 H), 7.43 (d, J=2.0 Hz, 1 H). c) 2-(2-Chloro-5-nonylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Obtained as an oil (38%) from 2-bromo-1-chloro-4-nonylbenzene (Intermediate 32b) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) following the experimental procedure described in Intermediate 15c followed by purification of the crude product by flash chromatography (hexanes/diethyl ether). d) Ethyl 3-fluoro-4-(2-chloro-5-nonylphenyl)-1 H-pyrrole-2-carboxylate

Obtained as a solid (64%) from ethyl 4-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and 2-(2-chloro-5-nonylphenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (Intermediate 32c) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 392 [M-1]\

¹ H NMR 6 (400 MHz, CDCh): 0.85-0.91 (m, 3H), 1 .22-1 .35 (m, 12H), 1 .39 (t, J=7.1 Hz, 3H), 1 .58-1 .65 (m, 2H), 2.54-2.62 (m, 2H), 4.38 (q, J=7.1 Hz, 2H), 7.04-7.09 (m, 2H), 7.26-7.27 (m, 1 H), 7.35 (d, J=8.2 Hz, 1 H), 8.75 (s, 1 H).

INTERMEDIATE 33

Ethyl 3-fluoro-4-(2-methoxy-4-nonylphenyl)-1 H-pyrrole-2-carboxylate

a) 1 -Bromo-2-methoxy-4-(non-1 -yn-1 -yl)benzene

Obtained as an oil (88%) from 1-bromo-4-iodo-2-methoxybenzene and non-1-yne following the experimental procedure described in Intermediate 15a followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹H NMR d (400 MHz, CDCh): 0.86-0.92 (m, 3H), 1.24-1.38 (m, 6H), 1.39-1.49 (m, 2H), 1.60 (p, J=7.1 Hz, 2H), 2.39 (t, J=7.1 Hz, 2H), 3.88 (s, 3H), 6.87 (dd, J=8.1 , 1.7 Hz, 1 H), 6.91 (d, J=1.7 Hz, 1 H), 7.43 (d, J=8.1 Hz, 1 H). b) 1-Bromo-2-methoxy-4-nonylbenzene

Obtained as an oil (97%) from 1-bromo-2-methoxy-4-(non-1-yn-1-yl)benzene (Intermediate 33a) following the experimental procedure described in Intermediate 15b.

¹ H NMR d (400 MHz, CDCh): 0.82-0.92 (m, 3H), 1.22-1.34 (m, 12H), 1.54-1.63 (m, 2H), 2.51-2.61 (m, 2H), 3.89 (s, 3H), 6.66 (dd, J=8.0, 1.9 Hz, 1 H), 6.71-6.74 (m, 1 H), 7.41 (d, J=8.0 Hz, 1 H). c) 2-(2-Methoxy-4-nonylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Obtained as an oil (24%) from 1-bromo-2-methoxy-4-nonylbenzene (Intermediate 33b) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) following the experimental procedure described in Intermediate 15c followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCh): 0.85-0.90 (m, 3H), 1.24-1.32 (m, 12H), 1.34 (s, 12H), 1.55- 1.64 (m, 2H), 2.55-2.62 (m, 2H), 3.83 (s, 3H), 6.66-6.68 (m, 1 H), 6.77 (dd, J=7.5, 1.3 Hz, 1 H), 7.59 (d, J=7.4 Hz, 1 H). d) Ethyl 3-fluoro-4-(2-methoxy-4-nonylphenyl)-1 H-pyrrole-2-carboxylate

Obtained as a solid (69%) from ethyl 4-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and 2-(2-methoxy-4-nonylphenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (Intermediate 33c) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 388 [M-1]\

¹ H NMR d (400 MHz, CDCh): 0.84-0.91 (m, 3H), 1.24-1.35 (m, 12H), 1.38 (t, J=7.1 Hz, 3H), 1.59-1.68 (m, 2H), 2.58-2.64 (m, 2H), 3.70 (s, 3H), 4.37 (q, J=7.1 Hz, 2H), 6.78 (d, J= 1.3 Hz, 1 H), 6.83 (dd, J=7.8, 1.4 Hz, 1 H), 7.18-7.23 (m, 1 H), 7.49 (d, J=7.1 Hz, 1 H), 8.59 (s, 1 H).

INTERMEDIATE 34

Ethyl 3-fluoro-4-(4-nonyl-2-(trifluoromethyl)phenyl)-1H-pyrrole-2-carboxylate

a) 1 -Bromo-4-(non-1 -yn-1 -yl)-2-(trifluoromethyl)benzene Obtained as an oil (83%) from 1-bromo-4-iodo-2-(trifluoromethyl)benzene and non-1-yne following the experimental procedure described in Intermediate 15a followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCh): 0.85-0.92 (m, 3H), 1.21-1.38 (m, 6H), 1.38-1.49 (m, 2H), 1.60 (p, J=7.1 Hz, 2H), 2.39 (t, J=7.1 Hz, 2H), 7.36 (dd, J=8.3, 1.9 Hz, 1 H), 7.61 (d, J=8.3 Hz, 1 H), 7.69 (d, J=1.9 Hz, 1 H). b) 1-Bromo-4-nonyl-2-(trifluoromethyl)benzene

Obtained as an oil (96%) from 1-bromo-4-(non-1-yn-1-yl)-2-(trifluoromethyl)benzene (Intermediate 34a) following the experimental procedure described in Intermediate 15b.

¹ H NMR d (400 MHz, CDCh): 0.88 (t, J=6.9 Hz, 3H), 1.21-1.33 (m, 10H), 1.53-1.64 (m, 4H), 2.55-2.64 (m, 2H), 7.19 (dd, J=8.1 , 1.9 Hz, 1 H), 7.48 (d, J=1.9 Hz, 1 H), 7.59 (d, J=8.1 Hz, 1 H). c) 4,4,5,5-Tetramethyl-2-(4-nonyl-2-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane

Obtained as an oil (22%) from 1-bromo-4-nonyl-2-(trifluoromethyl)benzene (Intermediate 34b) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) following the experimental procedure described in Intermediate 15c followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCh): 0.88 (t, J=6.9 Hz, 3H), 1.23-1.31 (m, 12H), 1.36 (s, 12H), 1.55-1.64 (m, 2H), 2.61-2.68 (m, 2H), 7.31 (d, J=7.6 Hz, 1 H), 7.46 (s, 1 H), 7.64 (d, J=7.6 Hz, 1 H). d) Ethyl 3-fluoro-4-(4-nonyl-2-(trifluoromethyl)phenyl)-1 H-pyrrole-2-carboxylate

Obtained as an oil (21 %) from ethyl 4-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and 4,4,5,5-tetramethyl-2-(4-nonyl-2-(trifluoromethyl)phenyl)-1 ,3,2-dioxaborolane (Intermediate 34c) following the experimental procedure described in Intermediate 12 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): 0.83-0.91 (m, 3H), 1.24-1.35 (m, 14H), 1.38 (t, J=7.1 Hz, 3H), 2.64-2.71 (m, 2H), 4.37 (q, J=7.1 Hz, 2H), 6.83 (t, J=3.7 Hz, 1 H), 7.31-7.40 (m, 2H), 7.54 (s, 1 H), 8.70 (s, 1 H). INTERMEDIATE 35

Ethyl 3-fluoro-4-(6-nonylpyridin-3-yl)-1H-pyrrole-2-carboxylate

a) 5-Bromo-2-(non-1 -yn-1 -yl)pyridine

Obtained from 5-bromo-2-iodopyridine and non-1-yne following the experimental procedure described in Intermediate 15a followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCh): 0.84-0.92 (m, 3H), 1.26-1.36 (m, 6H), 1.40-1.48 (m, 2H), 1.57-1.67 (m, 2H), 2.42 (t, J=7.2 Hz, 2H), 7.25 (dd, J=8.4, 0.6 Hz, 1 H), 7.73 (dd, J=8.3, 2.4 Hz, 1 H), 8.59 (dd, J=2.4, 0.6 Hz, 1 H).

b) 5-Bromo-2-nonylpyridine

Obtained as a yellow oil (75%) from 5-bromo-2-(non-1-yn-1-yl)pyridine (Intermediate 35a) following the experimental procedure described in Intermediate 15b followed by purification of the crude product by flash chromatography (hexanes/diethyl ether). c) 2-Nonyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

Obtained as an oil (9%) from 5-bromo-2-nonylpyridine (Intermediate 35b) and 4, 4, 4', 4', 5, 5, 5', 5'- octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) following the experimental procedure described in Intermediate 15c followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCh): 0.83-0.91 (m, 3H), 1.22-1.28 (m, 10H), 1.35 (s, 12H), 1.65- 1.76 (m, 4H), 2.75-2.82 (m, 2H), 7.14 (dd, J=7.7, 0.8 Hz, 1 H), 7.96 (dd, J=7.7, 1.8 Hz, 1 H), 8.85 (dd, J=1.7, 0.9 Hz, 1 H). d) Ethyl 3-fluoro-4-(6-nonylpyridin-3-yl)-1 H-pyrrole-2-carboxylate

Obtained as an oil (77%) from ethyl 3-fluoro-4-iodo-1 H-pyrrole-2-carboxylate (Intermediate 2) and 2-nonyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (Intermediate 35c) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 361 [M+1]⁺.

¹ H NMR d (400 MHz, CDCh): 0.84-0.89 (m, 3H), 1.23-1.37 (m, 12H), 1.41 (t, J=7.1 Hz, 2H), 1.68-1.78 (m, 2H), 2.74-2.84 (m, 2H), 4.39 (q, J=7.1 Hz, 2H), 7.01-7.06 (m, 1 H), 7.17 (d, J=8.0 Hz, 1 H), 7.77 (dd, J=7.9, 2.2 Hz, 1 H), 8.71 (d, J=2.3 Hz, 1 H), 8.75 (s, 1 H). INTERMEDIATE 36

Ethyl 3-fluoro-4-(5-nonylpyridin-2-yl)-1H-pyrrole-2-carboxylate

a) 2-Bromo-5-(non-1 -yn-1 -yl)pyridine

Obtained as an oil (87%) from 2-bromo-5-iodopyridine and non-1-yne following the experimental procedure described in Intermediate 15a followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, DMSO-de): 0.83-0.90 (m, 3H), 1.22-1.35 (m, 6H), 1.36-1.45 (m, 2H), 1.55 (p, J=7.1 Hz, 2H), 2.45 (t, J=7.1 Hz, 2H), 7.64 (dd, J=8.3, 0.7 Hz, 1 H), 7.75 (dd, J=8.3, 2.4 Hz, 1 H), 8.38-8.41 (m, 1 H). b) 2-Bromo-5-nonylpyridine

Obtained as a brown oil (95%) from 2-bromo-5-(non-1-yn-1-yl)pyridine (Intermediate 36a) following the experimental procedure described in Intermediate 15b.

¹ H NMR d (400 MHz, CDCh): 0.84-0.92 (m, 3H), 1.21-1.33 (m, 12H), 1.59 (p, J=7.4 Hz, 2H), 2.50-2.60 (m, 2H), 7.35 (m, 1 H), 7.39 (m, 1 H), 8.19 (d, J=1.7 Hz, 1 H). c) 5-Nonyl-2-(tributylstannyl)pyridine

To a cooled (-78 °C) solution of 2-bromo-5-nonylpyridine (Intermediate 36b, 100 mg, 0.35 mmol) in THF (1 ml_) was added under argon atmosphere n-butyl lithium (1.6 M solution in hexanes, 0.26 ml_, 0.42 mmol) and the reaction mixture was stirred at -78 °C for 1 h. Tributyltin chloride (0.11 ml_, 0.42 mmol) was then added and the reaction mixture was stirred at -78 °C for 1 h and at 0 °C for 30 min. Saturated aqueous ammonium chloride solution (1.3 ml_) was added and the reaction mixture was extracted with diethyl ether (x 2). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and the solvents were evaporated to dryness. Purification of the residue by flash chromatography (hexanes/diethyl ether) gave the title compound (88 mg, 50%) as a colourless oil.

¹ H NMR d (400 MHz, CDCh): 0.85-0.91 (m, 12H), 1.08-1.13 (m, 4H), 1.23-1.37 (m, 18H), 1.51-1.63 (m, 10H), 2.51-2.57 (m, 2H), 7.29-7.33 (m, 2H), 8.58 (s, 1 H). d) Ethyl 3-fluoro-4-(5-nonylpyridin-2-yl)-1 H-pyrrole-2-carboxylate

A solution of ethyl 4-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1 , 35 mg, 0.15 mmol) and 5-nonyl-2-(tributylstannyl)pyridine (Intermediate 36c, 88 mg, 0.18 mmol) in xylene (1 ml_) was subjected to three cycles of evacuation-backfilling with argon and tetrakis(triphenylphosphine)palladium(0) (8.6 mg, 0.07 mmol) was added. After three further cycles of evacuation-back filling with argon, the mixture was stirred at 150 °C overnight. After cooling to room temperature, EtOAc was added and the reaction mixture was filtered through a Celite^® pad, washing with EtOAc several times. The filtrate and washings were combined and the solvents were evaporated to dryness. Purification of the residue by flash chromatography (hexanes/diethyl ether) yielded the title compound (19 mg, 36%) as an oil.

MS (m/z): 361 [M+1]⁺.

¹ H NMR 5 (400 MHz, CDCh): 0.88 (t, J=6.9 Hz, 3H), 1.23-1.36 (m, 12H), 1.40 (t, J=7.1 Hz, 3H), 1.59-1.66 (m, 2H), 2.56-2.63 (m, 2H), 4.38 (q, J=7.1 Hz, 2H), 7.43-7.47 (m, 1 H), 7.51 (dd, J=8.1 , 2.0 Hz, 1 H), 7.59 (d, J=8.1 Hz, 1 H), 8.37 (d, J=2.0 Hz, 1 H), 8.74 (s, 1 H).

INTERMEDIATE 37

Ethyl 4-(1-decyl-1 H-pyrazol-4-yl)-3-fluoro-1 H-pyrrole-2-carboxylate

a) 1 -Decyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole

To a solution of 4-(4, 4,5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl)-1 H-pyrazole (1.00 g, 5.45 mmol) in DMF (12 ml_) were added cesium carbonate (1.67 g, 5.12 mmol) and 1-bromodecane (1.1 ml_, 5.10 mmol) and the reaction mixture was stirred at 90 °C for 3 h. The mixture was cooled to room temperature, then poured into water and extracted with EtOAc (x3). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and the solvent evaporated to dryness. Purification of the residue by flash chromatography (hexanes/diethyl ether) gave the title compound (0.98 g, 58%) as a colourless oil.

MS (m/z): 335 [M+1]⁺.

¹ H NMR d (400 MHz, CDCh): 0.87 (t, J=6.9 Hz, 3H), 1.22-1.30 (m, 14H), 1.32 (s, 12H), 1.78-1.90 (m, 2H), 4.1 1 (t, J=7.2 Hz, 2H), 7.67 (s, 1 H), 7.78 (s, 1 H). b) Ethyl 4-(1 -decyl-1 H-pyrazol-4-yl)-3-fluoro-1 H-pyrrole-2-carboxylate

Obtained as an oil (86%) from ethyl 4-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and 1-decyl-4-(4, 4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl)-1 H-pyrazole (Intermediate 37 a) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 364 [M+1]⁺. ¹ H NMR d (400 MHz, CDCIs): 0.84-0.90 (m, 3H), 1.23-1.33 (m, 12H), 1.38 (t, J=7.1 Hz, 3H), 1.82-1.93 (m, 4H), 4.12 (t, J=7.2 Hz, 2H), 4.37 (q, J=7.1 Hz, 2H), 6.88 (dd, J=4.5, 3.7 Hz, 1 H), 7.58 (s, 1 H), 7.64 (s, 1 H), 8.57 (s, 1 H).

INTERMEDIATE 38

Ethyl 3-fluoro-5-(4-nonylphenyl)-1 H-pyrrole-2-carboxylate

Obtained (52%) as an oil from ethyl 5-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and (4-nonylphenyl)boronic acid following the experimental procedure described in Intermediate 13 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 360 [M+1]⁺

¹ H NMR d (400 MHz, CDCIs): 0.85-0.90 (m, 3H), 1.23-1.34 (m, 12H), 1.39 (t, J=7.1 Hz, 3H), 1.59-1.67 (m, 2H), 2.55-2.64 (m, 2H), 4.38 (q, J=7.2 Hz, 2H), 6.99 (dd, J=4.5, 3.8 Hz, 1 H), 7.20 (d, J=8.3 Hz, 2H), 7.47 (d, J=8.0 Hz, 2H), 8.69 (s, 1 H).

INTERMEDIATE 39

Ethyl 3-fluoro-5-(4-(octyloxy)phenyl)-1 H-pyrrole-2-carboxylate

Obtained as an off-white solid (39%) from ethyl 5-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and (4-(octyloxy)phenyl)boronic acid following the experimental procedure described in Intermediate 13 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether) and reverse phase chromatography (water/methanol).

MS (m/z): 362 [M+1]⁺

¹ H NMR d (400 MHz, CDCIs): 0.86-0.92 (m, 3H), 1.26-1.36 (m, 8H), 1.38 (t, J=7.1 Hz, 3H), 1.43-1.51 (m, 2H), 1.75-1.84 (m, 2H), 3.98 (t, J=6.6 Hz, 2H), 4.37 (q, J=7.1 Hz, 2H), 6.17 (d, J=3.2 Hz, 1 H), 6.93 (d, J=8.9 Hz, 2H), 7.42 (d, J=8.9 Hz, 2H), 8.67 (s, 1 H).

INTERMEDIATE 40

Ethyl 3-fluoro-5-(3-nonylphenyl)-1 H-pyrrole-2-carboxylate

Obtained as a white solid (12%) from ethyl 5-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and 4,4,5,5-tetramethyl-2-(3-nonylphenyl)-1 ,3,2-dioxaborolane (Intermediate 15c) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether) and reverse phase chromatography (water/methanol). MS (m/z): 358 [M-1]

INTERMEDIATE 41

Ethyl 3-fluoro-5-(2-methyl-5-nonylphenyl)-1H-pyrrole-2-carboxylate

Obtained as colourless oil (75%) from ethyl 5-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and 4,4,5,5-tetramethyl-2-(2-methyl-5-nonylphenyl)-1 ,3,2-dioxaborolane (Intermediate 21c) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 372 [M-1]\

¹ H NMR d (400 MHz, CDCh): 0.85-0.90 (m, 3H), 1.23-1.34 (m, 12H), 1.39 (t, J=7.1 Hz, 3H), 1.58-1.65 (m, 2H), 2.39 (s, 3H), 2.55-2.63 (m, 2H), 4.37 (q, J=7.1 Hz, 2H), 7.10 (dd, J=7.7, 1.8 Hz, 1 H), 7.15 (d, J=1.7 Hz, 1 H), 7.17 (d, J=7.8 Hz, 1 H), 8.52 (s, 1 H).

INTERMEDIATE 42

Ethyl 5-(2-ethyl-4-nonylphenyl)-3-fluoro-1H-pyrrole-2-carboxylate

Obtained as a white solid (88%) from ethyl 5-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and 2-(2-ethyl-4-nonylphenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (Intermediate 19c) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 386 [M-1]\

¹ H NMR d (400 MHz, CDCh): 0.85-0.90 (m, 3H), 1.18 (t, J=7.6 Hz, 3H), 1.24-1.35 (m, 12H), 1.38 (t, J=7.1 Hz, 3H), 1.58-1.66 (m, 2H), 2.54-2.65 (m, 2H), 2.71 (q, J=7.6 Hz, 2H), 4.36 (q, J=7.1 Hz, 2H), 6.06 (d, J=3.2 Hz, 1 H), 7.07 (dd, J=7.8, 1.7 Hz, 1 H), 7.1 1 (s, 1 H), 7.22 (d, J=7.8 Hz, 1 H), 8.46 (s, 1 H).

INTERMEDIATE 43

Ethyl 3-fluoro-5-(2-methyl-3-nonylphenyl)-1H-pyrrole-2-carboxylate

Obtained as a solid (53%) from ethyl 5-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and 4,4,5,5-tetramethyl-2-(2-methyl-3-nonylphenyl)-1 ,3,2-dioxaborolane (Intermediate 22c) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 372 [M-1]\ ¹ H NMR d (400 MHz, CDCIs): 0.86-0.91 (m, 3H), 1.24-1.33 (m, 12H), 1.37 (t, J=7.1 Hz, 3H), 1.53-1.62 (m, 2H), 2.60-2.68 (m, 2H), 4.35 (q, J=7.1 Hz, 2H), 6.05 (d, J=3.2 Hz, 1 H), 7.14-7.21 (m, 3H), 8.50 (s, 1 H).

INTERMEDIATE 44

Ethyl 3-fluoro-5-(2-isopropyl-4-nonylphenyl)-1 H-pyrrole-2-carboxylate

Obtained as a solid (80%) from ethyl 5-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and 2-(2-isopropyl-4-nonylphenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (Intermediate 20e) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 400 [M-1]\

¹ H NMR d (400 MHz, CDCIs): 0.88 (t, J=7.0 Hz, 3H), 1.21 (d, J=6.9 Hz, 6H), 1.24-1.34 (m, 12H), 1.37 (t, J=7.1 Hz, 3H), 1.58-1.67 (m, 2H), 2.57-2.66 (m, 2H), 3.21 (hept, J=6.9 Hz, 1 H), 4.34 (q, J = 7.1 Hz, 2H), 7.05 (dd, J=7.9, 1.7 Hz, 1 H), 7.17-7.20 (m, 2H), 8.49 (s, 1 H).

INTERMEDIATE 45

Ethyl 3-fluoro-5-(2-fluoro-3-nonylphenyl)-1 H-pyrrole-2-carboxylate

Obtained as a white solid (77%) from ethyl 5-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and 2-(2-fluoro-3-nonylphenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (Intermediate 26c) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 376 [M-1]\

¹ H NMR d (400 MHz, CDCIs): 0.84-0.90 (m, 3H), 1.23-1.36 (m, 12H), 1.39 (t, J=7.1 Hz, 3H), 1.62 (p, J=7.6 Hz, 2H), 2.68 (t, J=7.7 Hz, 2H), 4.38 (q, J=7.1 Hz, 2H), 6.37 (d, J=3.0 Hz, 1 H), 7.06-7.18 (m, 2H), 7.37 (td, J=7.4, 2.1 Hz, 1 H), 9.15 (s, 1 H).

INTERMEDIATE 46

Ethyl 3-fluoro-5-(2-fluoro-4-nonylphenyl)-1 H-pyrrole-2-carboxylate

Obtained as a beige solid (79%) from ethyl 5-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and 2-(2-fluoro-4-nonylphenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (Intermediate 28c) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 376 [M-1]\ ¹ H NMR d (400 MHz, CDCb): 0.85-0.91 (m, 3H), 1.22-1.35 (m, 12H), 1.39 (t, J=7.1 Hz, 3H), 1.59-1.66 (m, 2H), 2.58-2.64 (m, 2H), 4.37 (q, J=7.1 Hz, 2H), 6.34 (d, J=3.1 Hz, 1 H), 6.95-7.03 (m, 2H), 7.43 (t, J=8.1 Hz, 1 H), 9.09 (s, 1 H).

INTERMEDIATE 47

Ethyl 3-fluoro-5-(2-fluoro-5-nonylphenyl)-1 H-pyrrole-2-carboxylate

Obtained as an oil (93%) from ethyl 5-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and 2-(2-fluoro-5-nonylphenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (Intermediate 29c) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 376 [M-1]\

¹ H NMR d (400 MHz, CDCb): 0.83-0.91 (m, 3H), 1.23-1.34 (m, 12H), 1.39 (t, J=7.1 Hz, 3H), 1.56-1.65 (m, 2H), 2.56-2.62 (m, 2H), 4.38 (q, J=7.1 Hz, 2H), 6.38 (d, J=2.9 Hz, 1 H), 7.01-7.11 (m, 2H), 7.31 (dd, J=7.5, 1.8 Hz, 1 H), 9.10 (s, 1 H).

INTERMEDIATE 48

Ethyl 5-(2-chloro-4-nonylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylate

Obtained as a colourless oil (73%) from ethyl 5-bromo-3-fluoro-1 H-pyrrole-2-carboxylate

(Intermediate 1) and 2-(2-chloro-4-nonylphenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane

(Intermediate 31c) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 394 [M+1]⁺.

¹ H NMR d (400 MHz, CDCb): 0.86-0.90 (m, 3H), 1.24-1.33 (m, 12H), 1.39 (t, J=7.1 Hz, 3H), 1.57-1.65 (m, 2H), 2.56-2.64 (m, 2H), 4.37 (q, J=7.1 Hz, 2H), 6.32 (d, J=3.3 Hz, 1 H), 7.12 (dd, J=8.0, 1.7 Hz, 1 H), 7.25-7.27 (m, 1 H), 7.39 (d, J=8.0 Hz, 1 H), 9.12 (s, 1 H).

INTERMEDIATE 49

Ethyl 5-(2-chloro-5-nonylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylate

Obtained as a colourless oil (39%) from ethyl 5-bromo-3-fluoro-1 H-pyrrole-2-carboxylate

(Intermediate 1) and 2-(2-chloro-5-nonylphenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (Intermediate 32c) following the experimental procedure described in Intermediate 12 followed by purification by flash chromatography (hexanes/diethyl ether).

MS (m/z): 394 [M+1]⁺. ¹ H NMR d (400 MHz, CDCh): 0.85-0.90 (m, 3H), 1.23-1.34 (m, 12H), 1.39 (t, J=7.1 Hz, 3H), 1.57-1.65 (m, 2H), 2.53-2.65 (m, 2H), 4.38 (q, J=7.1 Hz, 2H), 6.35 (d, J=3.3 Hz, 1 H), 7.09 (dd, J=8.2, 2.2 Hz, 1 H), 7.28 (d, J=2.1 Hz, 1 H), 7.34 (d, J= 8.2Hz, 1 H), 9.14 (s, 1 H).

INTERMEDIATE 50

Ethyl 3-fluoro-5-(2-methoxy-4-nonylphenyl)-1 H-pyrrole-2-carboxylate

Obtained as a white solid (50%) from ethyl 5-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and and 2-(2-methoxy-4-nonylphenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (Intermediate 33c) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 390 [M+1]⁺.

¹ H NMR d (400 MHz, CDCh): 0.85-0.90 (m, 3H), 1.25-1.35 (m, 12H), 1.39 (t, J=7.1 Hz, 3H), 1.58-1.66 (m, 2H), 2.57-2.65 (m, 2H), 4.36 (q, J=7.1 Hz, 2H), 6.29 (d, J=3.2 Hz, 1 H), 6.80 (d, J= 1.2 Hz, 1 H), 6.84 (dd, J=7.9, 1.5 Hz, 1 H), 7.45 (d, J= 7.9Hz, 1 H), 9.91 (s, 1 H).

INTERMEDIATE 51

Ethyl 5-(1-decyl-1H-pyrazol-4-yl)-3-fluoro-1 H-pyrrole-2-carboxylate

Obtained as a white solid (82%) from ethyl 5-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and 1-decyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (Intermediate 37a) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 364 [M+1]⁺.

¹ H NMR d (400 MHz, CDCh): 0.87 (t, J=6.9 Hz, 3H), 1.21-1.34 (m, 14H), 1.38 (t, J=7.1 Hz, 3H), 1.82-1.92 (m, 2H), 4.12 (t, J=7.2 Hz, 2H), 4.36 (q, J=7.1 Hz, 2H), 6.02 (d, J=3.2 Hz, 1 H), 7.54-7.57 (m, 1 H), 7.66 (d, J=0.7 Hz, 1 H), 8.55 (s, 1 H).

INTERMEDIATE 52

Ethyl 5-(1-decyl-3,5-dimethyl-1H-pyrazol-4-yl)-3-fluoro-1 H-pyrrole-2-carboxylate

a) 1-Decyl-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-pyrazole

Obtained as an oil (81 %) from 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- pyrazole and 1-bromodecane following the experimental procedure described in Intermediate 37a heating at 90 °C overnight and followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 363 [M+1]⁺.

¹ H NMR d (400 MHz, CDCh): 0.85-0.90 (m, 3H), 1.23-1.27 (m, 14H), 1.29 (s, 12H), 1.70- 1.80 (m, 2H), 2.33 (s, 3H), 2.37 (s, 3H), 3.90-3.95 (m, 2H). b) Ethyl 5-(1-decyl-3,5-dimethyl-1 H-pyrazol-4-yl)-3-fluoro-1 H-pyrrole-2-carboxylate

Obtained as an oil (65%) from ethyl 5-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and 1-decyl-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole

(Intermediate 52a) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 392 [M+1]⁺.

¹ H NMR d (400 MHz, CDCh): 0.84-0.90 (m, 3H), 1.22-1.34 (m, 14H), 1.38 (t, J=7.1 Hz, 3H), 1.75-1.85 (m, 2H), 2.16-2.24 (m, 6H), 3.94-4.02 (m, 2H), 4.37 (q, J=7.1 Hz, 2H), 6.68 (dd, J=4.4, 3.7 Hz, 1 H), 8.66 (s, 1 H).

INTERMEDIATE 53

Ethyl 3-fluoro-4-(4-pentylcyclohex-1 -en-1 -yl)-1 H-pyrrole-2-carboxylate

Obtained as a solid (62%) from ethyl 3-fluoro-4-iodo-1 H-pyrrole-2-carboxylate (Intermediate 2) and (4-pentylcyclohex-1-en-1-yl)boronic acid following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 306 [M-1]\

¹ H NMR d (400 MHz, CDCh): 0.89 (t, J=7.0 Hz, 3H), 1.27-1.34 (m, 8H), 1.36 (t, J=7.1 Hz, 3H), 1.72-1.90 (m, 3H), 2.23-2.35 (m, 4H), 4.34 (q, J=7.1 Hz, 2H), 6.12-6.15 (m, 1 H), 6.67- 6.70 (m, 1 H), 8.45 (s, 1 H).

INTERMEDIATE 54

Ethyl 3-fluoro-4-((1r,4s)-4-pentylcyclohexyl)-1 H-pyrrole-2-carboxylate and ethyl 3-fluoro-4- ((1s,4r)-4-pentylcyclohexyl)-1 H-pyrrole-2-carboxylate

To a solution of ethyl 3-fluoro-4-(4-pentylcyclohex-1-en-1-yl)-1 H-pyrrole-2-carboxylate (Intermediate 53, 103 mg, 0.33 mmol) in methanol (4 ml_) was added 10% palladium on carbon (18 mg, 0.017 mmol) and the resulting suspension was stirred under a hydrogen atmosphere at room temperature overnight. Additional 10% palladium on carbon (18 mg, 0.017 mmol) was added and the suspension was stirred under hydrogen atmosphere for additional 18 h. The catalyst was then filtered through a Celite® pad, washing with methanol several times. The filtrate and washings were combined and the solvent was evaporated to dryness to give the title compounds (86 mg, 83%) as a white solid.

INTERMEDIATE 55

Ethyl 3-fluoro-4-((1r,4s)-4-octylcyclohexyl)-1H-pyrrole-2-carboxylate and ethyl 3-fluoro-4- ((1s,4r)-4-octylcyclohexyl)-1H-pyrrole-2-carboxylate a) 4-Octylcyclohex-1-en-1-yl trifluoromethanesulfonate

To a cooled (-78 °C) solution of 4-octylcyclohexan-1-one (1.00 g, 4.75 mmol) in THF (12 ml_) was added lithium bis(trimethylsilyl)amide (1 M solution in THF, 5.3 ml_, 5.30 mmol) under argon atmosphere and the resulting solution was stirred at -78 °C for 1 h. A solution of 1 ,1 ,1 -trifluoro-A/- phenyl-/\/-((trifluoromethyl)sulfonyl)methanesulfonamide (1.87 g, 5.23 mmol) in THF (8 ml_) was then slowly added. The cooling bath was removed and the reaction mixture was stirred for further 3 h. Water and diethyl ether were added, the organic layer was separated and the aqueous layer was extracted with diethyl ether (x2). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried over magnesium sulfate, filtered and the solvents were evaporated to yield the title compound as an orange oil (1.63 g, 98%).

¹ H NMR d (400 MHz, CDCh): 0.88 (t, J=6.8 Hz, 3H), 1.20-1.33 (m, 12H), 1.38-1.46 (m, 1 H), 1.50-1.60 (m, 2H), 1.75-1.91 (m, 2H), 2.20-2.42 (m, 4H), 5.71 (dd, J=4.9, 2.3 Hz, 1 H). b) 4,4,5,5-Tetramethyl-2-(4-octylcyclohex-1 -en-1 -yl)-1 ,3,2-dioxaborolane

Obtained as a colourless oil (40%) from 4-octylcyclohex-1-en-1-yl trifluoromethanesulfonate (Intermediate 55a) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) following the experimental procedure described in Intermediate 15c followed by purification of the crude product by flash chromatography (hexanes/diethyl ether). c) Ethyl 3-fluoro-4-(4-octylcyclohex-1 -en-1 -yl)-1 H-pyrrole-2-carboxylate

Obtained as a light yellow solid (56%) from ethyl 3-fluoro-4-iodo-1 H-pyrrole-2-carboxylate (Intermediate 2) and 4,4,5,5-tetramethyl-2-(4-octylcyclohex-1-en-1-yl)-1 ,3,2-dioxaborolane (Intermediate 55b) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 348 [M-1]\

¹ H NMR d (400 MHz, CDCh): 0.86-0.91 (m, 3H), 1.25-1.33 (m, 16H), 1.36 (t, J=7.1 Hz, 3H), 1.73-1.89 (m, 3H), 2.20-2.33 (m, 3H), 4.34 (q, J=7.1 Hz, 2H), 6.12-6.15 (m, 1 H), 6.66- 6.70 (m, 1 H), 8.45 (s, 1 H). d) Ethyl 3-fluoro-4-((1r,4s)-4-octylcyclohexyl)-1 H-pyrrole-2-carboxylate and ethyl 3-fluoro- 4-((1s,4r)-4-octylcyclohexyl)-1H-pyrrole-2-carboxylate

To a solution of ethyl 3-fluoro-4-(4-octylcyclohex-1-en-1-yl)-1 H-pyrrole-2-carboxylate (Intermediate 55c, 230 mg, 0.66 mmol) in a mixture of methanol (6 ml_) and ethanol (2 ml_) was added 10% palladium on carbon (23 mg, 0.21 mmol) and the resulting suspension was stirred under a hydrogen atmosphere overnight. The catalyst was filtered through a Celite^® pad, washing with methanol several times. The filtrate and washings were combined and the solvents were evaporated to give the title compounds (231 mg, 100%) as a white solid.

MS (m/z): 352 [M+1]⁺.

INTERMEDIATE 56

Ethyl 3-fluoro-5-(4-pentylcyclohex-1 -en-1 -yl)-1 H-pyrrole-2-carboxylate

Obtained as a white solid (54%) from ethyl 5-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and (4-pentylcyclohex-1-en-1-yl)boronic acid following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 308 [M+1]⁺.

¹ H NMR d (400 MHz, CDCh): 0.89 (t, J=7.0 Hz, 3H), 1.22-1.33 (m, 8H), 1.36 (t, J=7.1 Hz, 3H), 1.74-1.93 (m, 2H), 2.21-2.39 (m, 3H), 4.34 (q, J=7.1 Hz, 2H), 5.94 (d, J=3.2 Hz, 1 H), 6.09-6.12 (m, 1 H), 8.41 (s, 1 H).

INTERMEDIATE 57

Ethyl 3-fluoro-5-((1r,4s)-4-pentylcyclohexyl)-1H-pyrrole-2-carboxylate and ethyl 3-fluoro-5- ((1s,4r)-4-pentylcyclohexyl)-1H-pyrrole-2-carboxylate Obtained as a colourless oil (87%) from ethyl 3-fluoro-5-(4-pentylcyclohex-1-en-1-yl)-1 H-pyrrole- 2-carboxylate (Intermediate 56) following the experimental procedure described in Intermediate 55d.

MS (m/z): 310 [M+1]⁺.

INTERMEDIATE 58

Ethyl 5-((1 ,4s)-4-decylcyclohexyl)-3-fluoro-1 H-pyrrole-2-carboxylate and ethyl 5-((1s,4r)-4- decylcyclohexyl)-3-fluoro-1 H-pyrrole-2-carboxylate

a) 4-Decylcyclohex-1-en-1-yl trifluoromethanesulfonate

Obtained as an orange oil (99%) from 4-decylcyclohexan-1-one and 1 ,1 ,1 -trifluoro-/\/-phenyl-/\/- ((trifluoromethyl)sulfonyl)methanesulfonamide following the experimental procedure described in Intermediate 55a.

¹H NMR d (400 MHz, CDCb): 0.88 (t, J=6.8 Hz, 3H), 1.20-1.33 (m, 16H), 1.38-1.46 (m, 1 H), 1.50-1.60 (m, 2H), 1.75-1.91 (m, 2H), 2.20-2.42 (m, 4H), 5.71 (dd, J=4.9, 2.3 Hz, 1 H). b) 2-(4-Decylcyclohex-1 -en-1 -yl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane

Obtained as a colourless oil (59%) from 4-decylcyclohex-1-en-1-yl trifluoromethanesulfonate (Intermediate 58a) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) following the experimental procedure described in Intermediate 15c followed by purification of the crude product by flash chromatography (hexanes/diethyl ether). c) Ethyl 5-(4-decylcyclohex-1 -en-1 -yl)-3-fluoro-1 H-pyrrole-2-carboxylate

Obtained as an oil (69%) from ethyl 5-bromo-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 1) and 2-(4-decylcyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (Intermediate 58b) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 378 [M+1]⁺.

¹H NMR d (400 MHz, CDCb): 0.86-0.91 (m, 3H), 1.24-1.33 (m, 18H), 1.36 (t, J=7.1 Hz, 3H), 1.75-1.93 (m, 3H), 2.19-2.39 (m, 4H), 4.34 (q, J=7.1 Hz, 2H), 5.94 (d, J=3.2 Hz, 1 H), 6.09-6.12 (m, 1 H), 8.37 (s, 1 H). d) Ethyl 5-((1 ,4s)-4-decylcyclohexyl)-3-fluoro-1H-pyrrole-2-carboxylate and ethyl 5- ((1s,4r)-4-decylcyclohexyl)-3-fluoro-1H-pyrrole-2-carboxylate Obtained as a white solid (85%) from ethyl 5-(4-decylcyclohex-1-en-1-yl)-3-fluoro-1 H-pyrrole-2- carboxylate (Intermediate 58c) following the experimental procedure described in Intermediate 55d.

MS (m/z): 380 [M+1]⁺.

INTERMEDIATE 59

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

a) 1-Bromo-2,3-difluoro-4-(hept-1-yn-1-yl)benzene

Obtained as a colourless oil (44%) from 1-bromo-2,3-difluoro-4-iodobenzene and hept-1-yne following the experimental procedure described in Intermediate 15a followed by purification of the crude product by flash chromatography (hexanes/diethyl ether) and reverse phase chromatography (water/methanol). b) 1-Bromo-2,3-difluoro-4-heptylbenzene

Obtained as a colourless oil (100%) from 1-bromo-2,3-difluoro-4-(hept-1-yn-1-yl)benzene (Intermediate 59a) following the experimental procedure described in Intermediate 15b.

¹ H NMR d (400 MHz, CDCh): 0.88 (t, J=6.9 Hz, 3H), 1.23-1.35 (m, 10H), 2.59-2.65 (m, 2H), 6.81-6.87 (m, 1 H), 7.17-7.23 (m, 1 H). c) 2-(2,3-Difluoro-4-heptylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Obtained as an oil (71 %) from 1-bromo-2,3-difluoro-4-heptylbenzene (Intermediate 59b) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) following the experimental procedure described in Intermediate 15c followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCh): 0.85-0.91 (m, 3H), 1.24-1.28 (m, 4H), 1.28-1.33 (m, 4H), 1.35 (s, 12H), 1.56-1.65 (m, 2H), 2.62-2.69 (m, 2H), 6.90-6.95 (m, 1 H), 7.36 (ddd, J=1.6, 5.2, 7.0 Hz, 1 H). d) Ethyl 4-(2,3-difluoro-4-heptylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylate

Obtained as an oil (23%) from ethyl 3-fluoro-4-iodo-1 H-pyrrole-2-carboxylate (Intermediate 2) and 2-(2,3-difluoro-4-heptylphenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (Intermediate 59c) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/ethyl acetate).

MS (m/z): 366 [M-1]\ ¹ H NMR 5 (400 MHz, CDCIs): 0.86-0.91 (m, 3H), 1.25-1.36 (m, 8H), 1.40 (t, J=7.1 Hz, 3H), 1.58-1.66 (m, 2H), 2.66 (t, J=7.4 Hz, 2H), 4.39 (q, J=7.1 Hz, 2H), 6.93-6.99 (m, 1 H), 7.18 (td, J=2.6, 4.0 Hz, 1 H), 7.35 (t, J=8.0 Hz, 1 H), 8.74 (s, 1 H).

INTERMEDIATE 60

Ethyl 4-(2,5-difluoro-4-heptylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylate a) 1-Bromo-2,5-difluoro-4-(hept-1-yn-1-yl)benzene

Obtained as a colourless oil (48%) from 1-bromo-2,5-difluoro-4-iodobenzene and hept-1-yne following the experimental procedure described in Intermediate 15a followed by purification of the crude product by flash chromatography (hexanes/diethyl ether) and reverse phase chromatography (water/methanol).

¹ H NMR 5 (400 MHz, CDCIs): 0.92 (t, J=7.2 Hz, 3H), 1.32-1.48 (m, 4H), 1.58-1.67 (m, 2H), 2.42 (t, J=7.1 Hz, 2H), 7.13 (dd, J=8.4, 6.1 Hz, 1 H), 7.26 (dd, J=8.4, 6.1 Hz, 1 H). b) 1-Bromo-2,5-difluoro-4-heptylbenzene

Obtained as a colourless oil (85%) from 1-bromo-2,5-difluoro-4-(hept-1-yn-1-yl)benzene

(Intermediate 60a) following the experimental procedure described in Intermediate 15b followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR 5 (400 MHz, CDCIs): 0.88 (t, J=6.9 Hz, 3H), 1.24-1.35 (m, 8H), 1.55-1.62 (m, 2H), 2.54-2.60 (m, 2H), 6.95 (dd, J=8.8, 6.1 Hz, 1 H), 7.20 (dd, J=8.8, 6.1 Hz, 1 H). c) 2-(2,5-Difluoro-4-heptylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Obtained as an oil (38%) from 1-bromo-2,5-difluoro-4-heptylbenzene (Intermediate 60b) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) following the experimental procedure described in Intermediate 15c followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCIs): 0.85-0.90 (m, 3H), 1.24-1.33 (m, 8H), 1.35 (s, 12H), 1.58 (p, J=7.4 Hz, 2H), 2.61 (t, J=7.7 Hz, 2H), 6.85 (dd, J=9.3, 5.0 Hz, 1 H), 7.32 (dd, J=9.3, 5.0 Hz, 1 H). d) Ethyl 4-(2,5-difluoro-4-heptylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylate

Obtained as a white solid (67%) from ethyl 3-fluoro-4-iodo-1 H-pyrrole-2-carboxylate (Intermediate 2) and 2-(2,5-difluoro-4-heptylphenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxa borolane (Intermediate 60c) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 366 [M-1]\

¹ H NMR 5 (400 MHz, CDCIs): 0.84-0.92 (m, 3H), 1.24-1.37 (m, 8H), 1.39 (t, J=7.1 Hz, 3H), 1.57-1.65 (m, 2H), 2.57-2.65 (m, 2H), 4.38 (q, J=7.1 Hz, 2H), 6.93 (dd, J=11.0, 6.3 Hz, 1 H), 7.19 (td, J=2.8, 4.0 Hz, 1 H), 7.36 (dd, J=11.0, 6.3 Hz, 1 H), 8.73 (s, 1 H).

INTERMEDIATE 61

Ethyl 4-(2,3-difluoro-4-(hexyloxy)phenyl)-3-fluoro-1 H-pyrrole-2-carboxylate

a) 1-Bromo-2,3-difluoro-4-(hexyloxy)benzene

To a solution of 4-bromo-2,3-difluorophenol (500 mg, 2.39 mmol) and 1-bromohexane (0.40 ml_, 2.87 mmol) in DMF (5 ml_) was added potassium carbonate (991 mg, 7.17 mmol) and the resulting mixture was stirred at 100 °C for 50 min. After cooling to room temperature, the reaction mixture was poured into water and extracted with EtOAc (x3). The combined organic layers were washed with water (x2), brine, dried over sodium sulfate, filtered and the solvent was evaporated to dryness. Purification of the residue by flash chromatography (hexanes/ethyl acetate) gave the title compound (690 mg, 98%) as a colourless oil.

MS (m/z): 292, 294 [M, M+2]⁺.

¹ H NMR 5 (300 MHz, CDCIs): 0.84 (t, J=6.6 Hz, 3H), 1.22-1.33 (m, 4H), 1.34-1.45 (m, 2H), 1.67-1.81 (m, 2H), 3.95 (t, J=6.5 Hz, 2H), 6.58 (ddd, J=9.5, 7.5, 2.3 Hz, 1 H), 7.12 (ddd, J=9.5, 7.4, 2.3 Hz, 1 H). b) 2-(2,3-Difluoro-4-(hexyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Obtained as a colourless oil (32%) from 1-bromo-2,3-difluoro-4-(hexyloxy)benzene (Intermediate 61 a) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) following the experimental procedure described in Intermediate 15c followed by purification of the crude product by flash chromatography (hexanes/ethyl acetate).

MS (m/z): 294 [M+1]⁺.

¹ H NMR d (400 MHz, CDCIs): 0.87-0.94 (m, 3H), 1.31-1.40 (m, 16H), 1.42-1.50 (m, 2H), 1.76-1.87 (m, 2H), 4.05 (t, J=6.3 Hz, 2H), 6.67-6.75 (m, 1 H), 7.34-7.42 (m, 1 H). c) Ethyl 4-(2,3-difluoro-4-(hexyloxy)phenyl)-3-fluoro-1 H-pyrrole-2-carboxylate

Obtained as an oil (26%) from ethyl 3-fluoro-4-iodo-1 H-pyrrole-2-carboxylate (Intermediate 2) and 2-(2,3-difluoro-4-(hexyloxy)phenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (Intermediate 61 b) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 368 [M-1]\

¹ H NMR d (300 MHz, CDCh): 0.88-0.95 (m, 3H), 1.30-1.42 (m, 6H), 1.44-1.52 (m, 2H), 1.76-1.88 (m, 2H), 4.06 (t, J=6.6 Hz, 2H), 4.38 (q, J=7.1 Hz, 3H), 6.72-6.81 (m, 1 H), 7.09- 7.15 (m, 1 H), 7.29-7.37 (m, 1 H), 8.80 (s, 1 H).

INTERMEDIATE 62

Ethyl 4-(2,5-difluoro-4-(hexyloxy)phenyl)-3-fluoro-1 H-pyrrole-2-carboxylate a) 1-Bromo-2,5-difluoro-4-(hexyloxy)benzene

Obtained as a colourless oil (94%) from 4-bromo-2,5-difluorophenol and 1-bromohexane following the experimental procedure described in Intermediate 61a followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, DMSO-de): 0.84-0.90 (m, 3H), 1.26-1.34 (m, 4H), 1.35-1.44 (m, 2H), 1.72 (p, J=6.6 Hz, 2H), 4.05 (t, J=6.5 Hz, 2H), 7.34 (dd, J=10.5, 7.5 Hz, 1 H), 7.67 (dd, J = 10.5, 6.7 Hz, 1 H).

b) 2-(2,5-Difluoro-4-(hexyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Obtained as an oil (55%) from 1-bromo-2,5-difluoro-4-(hexyloxy)benzene (Intermediate 62a) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) following the experimental procedure described in Intermediate 15c followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCh): 0.88-0.93 (m, 3H), 1.29-1.38 (m, 16H), 1.42-1.51 (m, 2H), 1.78-1.86 (m, 2H), 4.01 (t, J=6.6 Hz, 2H), 6.62 (dd, J=10.3, 6.5 Hz, 1 H), 7.38 (dd, J = 1 1.3, 5.5 Hz, 1 H). c) Ethyl 4-(2,5-difluoro-4-(hexyloxy)phenyl)-3-fluoro-1 H-pyrrole-2-carboxylate

Obtained as an oil (46%) from ethyl 3-fluoro-4-iodo-1 H-pyrrole-2-carboxylate (Intermediate 2) and 2-(2,5-difluoro-4-(hexyloxy)phenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (Intermediate 62b) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether) and reverse phase chromatography (water/methanol).

MS (m/z): 368 [M-1]\ ¹ H NMR d (400 MHz, CDCh): 0.94 (m, 3H), 1.32-1.37 (m, 4H), 1.39 (t, J=7.1 Hz, 3H), 1.44- 1.52 (m, 2H), 1.78-1.87 (m, 2H), 4.01 (t, J=6.6 Hz, 2H), 4.38 (q, J=7.1 Hz, 2H), 6.75 (dd, J= 12.1 , 7.2 Hz, 1 H), 7.1 1-7.15 (m, 1 H), 7.42 (dd, J=12.1 , 7.2 Hz, 1 H), 8.72 (s, 1 H).

INTERMEDIATE 63

Ethyl 3-fluoro-4-(4-((6-hydroxyhexyl)oxy)phenyl)-1 H-pyrrole-2-carboxylate a) 6-(4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)hexan-1 -ol

Obtained as a colourless oil (36%) from 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol and 6-bromohexan-1-ol following the experimental procedure described in Intermediate 61 a followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR d (400 MHz, CDCh): 1.26 (s, 12H), 1.33-1.46 (m, 4H), 1.50-1.58 (m, 2H), 1.69- 1.77 (m, 2H), 3.59 (t, J=6.5 Hz, 2H), 3.92 (t, J=6.5 Hz, 2H), 6.78-6.84 (m, 2H), 7.64-7.69 (m, 2H). b) Ethyl 3-fluoro-4-(4-((6-hydroxyhexyl)oxy)phenyl)-1 H-pyrrole-2-carboxylate

Obtained as a white solid (23%) from ethyl 3-fluoro-4-iodo-1 H-pyrrole-2-carboxylate (Intermediate 2) and 6-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)hexan-1-ol (Intermediate 63a) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 348 [M-1]\

¹ H NMR d (400 MHz, CDCh): 1.39 (t, J=7.1 Hz, 3H), 1.42-1.55 (m, 4H), 1.59-1.67 (m, 2H), 1.76-1.85 (m, 2H), 3.64-3.70 (m, 2H), 3.98 (t, J=6.5 Hz, 2H), 4.38 (q, J=7.1 Hz, 2H), 6.89- 6.96 (m, 3H), 7.46 (d, J=8.5 Hz, 2H), 8.68 (s, 1 H).

INTERMEDIATE 64

Ethyl 4-(4-((6-ethoxyhexyl)oxy)phenyl)-3-fluoro-1 H-pyrrole-2-carboxylate a) Ethyl 3-fluoro-4-(4-((6-((methylsulfonyl)oxy)hexyl)oxy)phenyl)-1H-pyrrole-2-carboxylate

To a cooled (0 °C) solution of ethyl 3-fluoro-4-(4-((6-hydroxyhexyl)oxy)phenyl)-1 H-pyrrole-2- carboxylate (Intermediate 63b, 164 mg, 0.47 mmol) in DCM (3 ml_) were added triethylamine (0.09 ml_, 0.64 mmol) and methanesulfonyl chloride (0.040 ml_, 0.52 mmol) and the resulting mixture was stirred at 0 °C for 4 hours. The reaction mixture was diluted with DCM and washed with saturated aqueous solution of ammonium chloride, sodium hydrogen carbonate solution (4 g/100 mL) and brine. The organic layer was dried over magnesium sulfate, filtered and the solvent was evaporated to dryness to yield the title compound (173 mg, 86%) as an orange solid.

MS (m/z): 428 [M+1]⁺.

¹ H NMR d (400 MHz, CDCIs): 1.39 (t, J=7.1 Hz, 3H), 1.48-1.54 (m, 4H), 1.76-1.85 (m, 4H), 3.00 (s, 3H), 3.49 (d, J=5.1 Hz, 1 H), 3.98 (t, J=6.4 Hz, 2H), 4.25 (t, J=6.5 Hz, 2H), 4.38 (q, J=7.1 Hz, 2H), 6.89-6.96 (m, 3H), 7.47 (d, J=8.5 Hz, 2H), 8.59 (s, 1 H). b) Ethyl 4-(4-((6-ethoxyhexyl)oxy)phenyl)-3-fluoro-1 H-pyrrole-2-carboxylate

A round bottom flask was charged with ethanol (3 mL). Sodium (47 mg, 2.04 mmol) was added and the resulting mixture was stirred at room temperature until sodium was consumed. A solution of ethyl 3-fluoro-4-(4-((6-((methylsulfonyl)oxy)hexyl)oxy)phenyl)-1 H-pyrrole-2-carboxylate (Intermediate 64a, 167 mg, 0.39 mmol) in DCM (4 mL) was added and the reaction mixture was stirred at 70 °C for 4 h. Ethanol was evaporated to dryness and the residue was partitioned between EtOAc and water. The organic layer was separated and washed with brine, dried over magnesium sulfate, filtered and the solvent was evaporated to dryness. The residue was purified by reverse phase chromatography (water/methanol) to yield the title compound (15 mg, 10%) as an oil.

MS (m/z): 376 [M-1]\

INTERMEDIATE 65

Ethyl 4-(4-(3-ethoxypropoxy)phenyl)-3-fluoro-1H-pyrrole-2-carboxylate

a) 3-(4-Bromophenoxy)propan-1-ol

Obtained as a colourless oil (78%) from 4-bromophenol and 3-bromopropan-1-ol following the experimental procedure described in Intermediate 61 a followed by purification of the crude product by reverse phase chromatography (water/methanol).

¹ H NMR d (400 MHz, CDCIs): 2.02 (p, J=6.0 Hz, 3H), 3.83 (t, J=5.9 Hz, 2H), 4.06 (t, J=6.0 Hz, 2H), 6.77 (d, J=9.0 Hz, 2H), 7.36 (d, J=9.1 Hz, 2H). b) 3-(4-Bromophenoxy)propyl methanesulfonate

Obtained as a yellow oil (98%) from 3-(4-bromophenoxy)propan-1-ol (Intermediate 65a) following the experimental procedure described in Intermediate 64a.

¹ H NMR d (400 MHz, CDCIs): 2.23 (p, J=6.0 Hz, 2H), 3.00 (s, 3H), 4.06 (t, J=5.9 Hz, 2H), 4.44 (t, J=6.1 Hz, 2H), 6.78 (d, J=9.0 Hz, 2H), 7.38 (d, J=9.0 Hz, 2H). c) 1 -Bromo-4-(3-ethoxypropoxy)benzene

Obtained as a colourless oil (85%) from 3-(4-bromophenoxy)propyl methanesulfonate (Intermediate 65b) and sodium ethoxide following the experimental procedure described in Intermediate 64b followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR 5 (400 MHz, CDCh): 1.12 (t, J=7.0 Hz, 3H), 1.96 (p, J=6.2 Hz, 2H), 3.41 (q, J=7.0 Hz, 2H), 3.50 (t, J=6.2 Hz, 2H), 3.95 (t, J=6.3 Hz, 2H), 6.71 (d, J=9.0 Hz, 2H), 7.28 (d, J=9.1 Hz, 2H). d) 2-(4-(3-Ethoxypropoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Obtained as a colourless oil (80%) from 1-bromo-4-(3-ethoxypropoxy)benzene (Intermediate 65c) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) following the experimental procedure described in Intermediate 15c followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

¹ H NMR 5 (400 MHz, CDCh): 1.20 (t, J=7.0 Hz, 3H), 1.33 (s, 12H), 2.05 (p, J=6.2 Hz, 2H), 3.49 (q, J=7.0 Hz, 2H), 3.59 (t, J=6.2 Hz, 2H), 4.09 (t, J=6.3 Hz, 2H), 6.89 (d, J=8.7 Hz, 2H), 7.74 (d, J=8.7 Hz, 2H). e) Ethyl 4-(4-(3-ethoxypropoxy)phenyl)-3-fluoro-1H-pyrrole-2-carboxylate

Obtained as a white solid (48%) from ethyl 3-fluoro-4-iodo-1 H-pyrrole-2-carboxylate (Intermediate 2) and 2-(4-(3-ethoxypropoxy)phenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (Intermediate 65d) following the experimental procedure described in Intermediate 12 followed by purification of the crude product by flash chromatography (hexanes/diethyl ether).

MS (m/z): 334 [M-1]\

¹ H NMR 5 (400 MHz, CDCh): 1.21 (t, J=7.0 Hz, 3H), 1.39 (t, J=7.1 Hz, 3H), 2.06 (p, J=6.2 Hz, 2H), 3.50 (q, J=7.0 Hz, 2H), 3.61 (t, J=6.2 Hz, 2H), 4.09 (t, J=6.2 Hz, 2H), 4.38 (q, J=7.1 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 7.47 (d, J=8.6 Hz, 2H), 8.60 (s, 1 H).

INTERMEDIATE 66

Ethyl 3-fluoro-4-(4-hydroxy-4-octylcyclohex-1-en-1-yl)-1 H-pyrrole-2-carboxylate

a) Ethyl 3-fluoro-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1H-pyrrole-2-carboxylate

Obtained as an oil (81 %) from ethyl 3-fluoro-4-iodo-1 H-pyrrole-2-carboxylate (Intermediate 2) and 2-(1 ,4-dioxaspiro[4.5]dec-7-en-8-yl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane following the experimental procedure described in Intermediate 12 followed by prufication of the crude product by flash chromatography (hexanes/ethyl acetate).

MS (m/z): 296 [M+1]⁺.

¹ H NMR d (300 MHz, CDCh): 1.38 (t, J=7.1 Hz, 3H), 1.91 (t, J=6.5 Hz, 2H), 2.43-2.48 (m, 2H), 2.50-2.60 (m, 2H), 4.03 (s, 4H), 4.36 (q, J=7.2 Hz, 2H), 6.06-6.10 (m, 1 H), 6.72 (t, J=4.0 Hz, 1 H), 8.53 (s, 1 H). b) Ethyl 3-fluoro-4-(4-oxocyclohex-1 -en-1 -yl)-1 H-pyrrole-2-carboxylate

To a solution of ethyl 3-fluoro-4-(1 ,4-dioxaspiro[4.5]dec-7-en-8-yl)-1 H-pyrrole-2-carboxylate (Intermediate 66a, 300 mg, 1.01 mmol) in dioxane (2 ml_) was added 6N hydrochloric acid solution (2.7 ml_, 16 mmol) and the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was poured into a saturated aqueous sodium carbonate solution (80 ml_) and extracted with EtOAc (x 2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the solvent was evaporated to dryness. The residue was purified by flash chromatography (hexanes/ethyl acetate) to yield the title compound (175 mg, 69%) as a white solid.

MS (m/z): 250 [M-1]\

¹ H NMR d (300 MHz, CDCh): 1.39 (t, J=7.1 Hz, 3H), 2.63 (t, J=6.9 Hz, 2H), 2.77 (q, J=6.2 Hz, 2H), 3.07 (s, 2H), 4.38 (q, J=6.9 Hz, 2H), 6.18 (s, 1 H), 6.77 (t, J=3.9 Hz, 1 H), 8.76 (s, 1 H). c) Ethyl 3-fluoro-4-(4-hydroxy-4-octylcyclohex-1-en-1-yl)-1H-pyrrole-2-carboxylate

To a solution of ethyl 3-fluoro-4-(4-oxocyclohex-1-en-1-yl)-1 H-pyrrole-2-carboxylate (Intermediate 66b, 76 mg, 0.30 mmol) in THF (4 ml_) was added dropwise octylmagnesium bromide (1 M solution in THF, 0.66 ml_, 0.66 mmol) and the resulting mixture was stirred at room temperature until consumption of the starting ketone. The reaction mixture was cooled to 0 °C and saturated aqueous solution of ammonium chloride (5 ml_) was added. The mixture was extracted with EtOAc (3 x 25 ml_) and the combined organic layers were washed with brine. The organic phase was dried over sodium sulfate, filtered and the solvent was evaporated to dryness. The residue was purified by flash chromatography (hexanes/EtOAc) to yield the title compound (12 mg, 11 %) as a colourless oil.

MS (m/z): 364 [M-1]\

INTERMEDIATE 67 Ethyl 3-fluoro-4-(4-hydroxy-4-octylcyclohexyl)-1H-pyrrole-2-carboxylate

a) Ethyl 3-fluoro-4-(1,4-dioxaspiro[4.5]decan-8-yl)-1 H-pyrrole-2-carboxylate

A solution of ethyl 4-(1 ,4-dioxaspiro[4.5]dec-7-en-8-yl)-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 66a, 350 g, 1.18 mmol) in EtOAc (10 ml_) was deoxygenated with nitrogen for 10 min. Palladium on carbon (10%, 35 mg, 0.03 mmol) was then added and the resulting suspension was stirred under hydrogen atmosphere for 4 h. The catalyst was filtered through a Celite^® pad and washed with EtOAc. The filtrate and washings were combined and the solvent was evaporated to dryness to give the title compound (330 mg, 94%) as a white solid.

MS (m/z): 298 [M+1]⁺.

¹ H NMR 5 (300 MHz, CDCIs): 1.37 (t, J=7.1 Hz, 3H), 1.64-1.72 (m, 4H), 1.80-1.88 (m, 2H), 1.92-2.01 (m, 2H), 2.54-2.67 (m, 1 H), 3.98 (s, 4H), 4.35 (q, J=7.0 Hz, 2H), 6.58 (t, J=3.9 Hz, 1 H), 8.46 (s, 1 H). b) Ethyl 3-fluoro-4-(4-oxocyclohexyl)-1 H-pyrrole-2-carboxylate

To a solution of ethyl 3-fluoro-4-(1 ,4-dioxaspiro[4.5]decan-8-yl)-1 H-pyrrole-2-carboxylate (Intermediate 67a, 330 mg, 1.11 mmol) in acetone (15 ml_) was added dropwise a solution of hydrochloric acid (37%, 0.18 ml_, 2.21 mmol) and the resulting mixture was stirred at room temperature overnight. The solvent was evaporated to dryness and EtOAc was added. The resulting solution was washed with saturated aqueous solution of sodium hydrogen carbonate, dried over sodium sulfate, filtered and the solvent was evaporated to dryness. The residue was purified by flash chromatography (hexanes/EtOAc) to yield the title compound (206 mg, 73%) as a white solid.

MS (m/z): 254 [M+1]⁺.

¹ H NMR 5 (300 MHz, CDCIs): 1.38 (t, J=7.1 Hz, 3H), 1.80-1.96 (m, 2H), 2.25-2.35 (m, 2H), 2.43-2.55 (m, 4H), 3.00-3.13 (m, 1 H), 4.36 (q, J=7.1 Hz, 2H), 6.60 (t, J=4.1 Hz, 1 H), 8.58 (s, 1 H). c) Ethyl 3-fluoro-4-(4-hydroxy-4-octylcyclohexyl)-1 H-pyrrole-2-carboxylate

To a cooled (0 °C) solution of ethyl 3-fluoro-4-(4-oxocyclohexyl)-1 H-pyrrole-2-carboxylate (Intermediate 67b, 90 mg, 0.35 mmol) in THF (3 ml_) was added dropwise octylmagnesium bromide (1 M solution in THF, 0.71 ml_, 0.71 mmol) and the resulting mixture was stirred at room temperature overnight. The solution was cooled again to 0 °C, octylmagnesium bromide (1 M solution in THF, 0.35 ml_, 0.35 mmol) was added and the reaction mixture was stirred at room temperature for 2 additional hours. Methanol (10 ml_) was then added, the solvents were evaporated to dryness and the resulting residue was dissolved in a 8:2 mixture of DCM/methanol (10 mL). The organic solution was washed with saturated aqueous solution of ammonium chloride, dried over sodium sulfate and the solvent was concentrated to dryness. The residue was purified by reverse phase chromatography (water/ACN-methanol 70:30) to yield the title compound as a white solid (65 mg, 50%).

MS (m/z): 366 [M-1]\

¹ H NMR 5 (300 MHz, CDCh): 0.89 (t, J=7.0 Hz, 3H), 1.26-1.33 (m, 9H), 1.38 (t, J=7.3 Hz, 5H), 1.42-1.50 (m, 4H), 1.66-1.85 (m, 6H), 2.43-2.57 (m, 1 H), 4.35 (q, J=6.7 Hz, 2H), 6.59 (s, 1 H), 8.44 (s, 1 H).

EXAMPLE 1

4-(Dodec-1-yn-1-yl)-1 H-pyrrole-2-carboxylic acid

A mixture of ethyl 4-(dodec-1-yn-1-yl)-1-tosyl-1 H-pyrrole-2-carboxylate (Intermediate 3b, 140 mg, 0.30 mmol), THF (0.4 mL), water (0.2 mL) and lithium hydroxide hydrate (51 mg, 1.21 mmol) was heated in a microwave reactor at 100 °C for 90 min. After cooling to room temperature, the organic solvent was removed in vacuo, water was added and the pH of the solution was adjusted to 2-3 by addition of 2N hydrochloric acid solution. The precipitate was filtered, rinsed with water, dried and purified by reverse phase chromatography (water/methanol) to yield the title compound (26 mg, 31 %) as a white solid.

MS (m/z): 274 [M-1]⁺.

¹ H NMR 5 (400 MHz, CDCh): 0.85-0.91 (m, 3H), 1.20-1.36 (m, 14H), 1.37-1.47 (m, 3H), 1.55-1.61 (m, 3H), 2.36 (t, J=7.1 Hz, 2H), 7.03 (dd, J=2.5, 1.5 Hz, 1 H), 7.09 (dd, J=3.0, 1.5 Hz, 1 H), 9.07 (s, 1 H).

EXAMPLE 2

3-Chloro-4-(dodec-1-yn-1-yl)-1H-pyrrole-2-carboxylic acid

Obtained as a solid (6%) from methyl 3-chloro-4-(dodec-1-yn-1-yl)-1-tosyl-1 H-pyrrole-2- carboxylate (Intermediate 4c) following the experimental procedure described in Example 1.

MS (m/z): 310, 308 [M, M-2]\

¹ H NMR 5 (400 MHz, DMSO-de): 0.82-0.88 (m, 3H), 1.19-1.33 (m, 12H), 1.40 (dd, J=13.9, 6.8 Hz, 2H), 1.50 (dt, J=13.7, 6.7 Hz, 2H), 2.38 (t, J=6.8 Hz, 2H), 7.15 (s, 1 H), 12.1 1 (s, 1 H), 12.89 (s, 1 H). EXAMPLE 3

4-(Dodec-1-yn-1 -yl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

Obtained as a solid (34%) from ethyl 4-(dodec-1-yn-1-yl)-3-fluoro-1-tosyl-1 H-pyrrole-2- carboxylate (Intermediate 5b) following the experimental procedure described in Example 1.

MS (m/z): 292 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.82-0.88 (m, 3H), 1.20-1.31 (m, 14H), 1.33-1.42 (m, 2H), 1.49 (p, J=6.7 Hz, 2H), 2.36 (t, J=7.0 Hz, 2H), 7.00 (d, J=3.9 Hz, 1 H), 11.75 (s, 1 H), 12.76 (s, 1 H).

EXAMPLE 4

5-(Dodec-1-yn-1 -yl)-1 H-pyrrole-2-carboxylic acid

To a suspension of methyl 5-(dodec-1-yn-1-yl)-1 H-pyrrole-2-carboxylate (Intermediate 6, 120 mg, 0.14 mmol) in ethanol (1 mL) and water (0.3 mL) was added lithium hydroxide monohydrate (90 mg, 2.14 mmol) and the mixture was stirred at 80 °C for 4 h. After cooling to room temperature, the organic solvent was removed in vacuo, water was added and the pH of the solution was adjusted to 2-3 by addition of 2N hydrochloric acid solution. The resulting suspension was extracted with EtOAc (x3) and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and the solvent was evaporated to dryness. Purification of the residue by reverse phase chromatography (water/methanol) gave the title compound (28 mg, 24%) as a solid.

MS (m/z): 274 [M-1]\

¹ H NMR d (400 MHz, CDCh): 0.85-0.92 (m, 3H), 1.21-1.35 (m, 12H), 1.38-1.48 (m, 2H), 1.59 (dt, J= 14.8, 7.1 Hz, 2H), 2.40 (t, J=7.1 Hz, 2H), 6.35 (dd, J=3.8, 2.5 Hz, 1 H), 6.93 (dd, J=3.8, 2.6 Hz, 1 H), 9.04 (s, 1 H).

EXAMPLE 5

5-(Dodec-1-yn-1 -yl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

To a suspension of ethyl 5-(dodec-1-yn-1-yl)-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 7, 50 mg, 0.15 mmol) in ethanol (0.75 mL) and water (0.25 mL) was added lithium hydroxide monohydrate (90 mg, 2.14 mmol) and the mixture was stirred at 50 °C for 8 h. The reaction mixture was cooled to room temperature, the organic solvent was removed in vacuo, water was added and the pH of the solution was adjusted to 2-3 by addition of 2N hydrochloric acid solution. The precipitate was filtered, rinsed with water and dried to yield the title compound (14 mg, 31 %) as a white solid.

MS (m/z): 292 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.83-0.88 (m, 3H), 1.21-1.31 (m, 12H), 1.34-1.43 (m, 2H), 1.45-1.55 (m, 2H), 2.37-2.42 (m, 2H), 6.17 (s, 1 H), 12.00 (s, 1 H), 12.61 (s, 1 H).

EXAMPLE 6

3-Fluoro-5-(tridec-1 -yn-1 -yl)-1 H-pyrrole-2-carboxylic acid

Obtained as a beige solid (43%) from ethyl 3-fluoro-5-(tridec-1-yn-1-yl)-1 H-pyrrole-2-carboxylate (Intermediate 8) following the experimental procedure described in Example 4.

MS (m/z): 306 [M-1]\

¹ H NMR d (400 MHz, CDCh): 0.82-0.88 (m, 3H), 1.20-1.31 (m, 14H), 1.35-1.43 (m, 2H), 1.50 (m, 2H), 2.39 (t, J=6.9 Hz, 2H), 1 1.96 (s, 1 H).

EXAMPLE 7

3-Fluoro-5-(tetradec-1 -yn-1 -yl)-1 H-pyrrole-2-carboxylic acid

Obtained as a white solid (74%) from ethyl 3-fluoro-5-(tetradec-1-yn-1-yl)-1 H-pyrrole-2- carboxylate (Intermediate 9) following the experimental procedure described in Example 4.

MS (m/z): 320 [M-1]\

¹ H NMR d (400 MHz, CDCh): 0.81-0.89 (m, 2H), 1.25 (d, J=7.0 Hz, 16H), 1.34-1.44 (m, 2H), 1.50 (dt, J=14.3, 6.8 Hz, 2H), 2.39 (t, J=6.9 Hz, 2H), 6.16 (s, 1 H), 1 1.97 (s, 1 H), 12.62 (br s, 1 H).

EXAMPLE 8

3-Fluoro-5-(pentadec-1-yn-1-yl)-1 H-pyrrole-2-carboxylic acid

Obtained as a solid (53%) from ethyl 3-fluoro-5-(pentadec-1-yn-1-yl)-1 H-pyrrole-2-carboxylate (Intermediate 10) following the experimental procedure described in Example 4.

MS (m/z): 334 [M-1]⁺.

¹ H NMR d (400 MHz, CDCh): 0.82-0.88 (m, 3H), 1.20-1.31 (m, 18H), 1.34-1.43 (m, 2H), 1.50 (p, J=6.8 Hz, 2H), 2.39 (t, J=6.9 Hz, 2H), 6.16 (s, 1 H), 12.00 (s, 1 H), 12.63 (s, 1 H).

EXAMPLE 9

3-Fluoro-5-(hexadec-1-yn-1-yl)-1 H-pyrrole-2-carboxylic acid Obtained as a white solid (46%) from ethyl 3-fluoro-5-(hexadec-1-yn-1-yl)-1 H-pyrrole-2- carboxylate (Intermediate 11) following the experimental procedure described in Example 4.

MS (m/z): 348 [M-1]⁺.

1 H NMR d (400 MHz, DMSO-de): 0.81-0.88 (m, 3H), 1.20-1.31 (m, 20H), 1.35-1.44 (m, 2H), 1.45-1.54 (m, 2H), 2.39 (t, J=6.9 Hz, 2H), 6.15 (s, 1 H), 11.97 (s, 1 H), 12.64 (br. s, 1 H).

EXAMPLE 10

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

To a suspension of ethyl 3-fluoro-4-(4-nonylphenyl)-1 H-pyrrole-2-carboxylate (Intermediate 12, 0.77 g, 2.14 mmol) in ethanol (10 mL) and water (3.5 mL) was added lithium hydroxide monohydrate (358 mg, 8.53 mmol) and the mixture was stirred at 70 °C for 4 h. The reaction mixture was cooled to room temperature, the organic solvent was removed in vacuo, water was added and the pH of the solution was adjusted to 2-3 by addition of 2N hydrochloric acid solution. The precipitate was filtered, rinsed with water and dried to yield the title compound (708 mg, 100%) as a white solid.

MS (m/z): 330 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.82-0.88 (m, 3H), 1.21-1.31 (m, 12H), 1.50-1.60 (m, 2H), 2.52-2.55 (m, 2H), 6.74 (d, J=4.7 Hz, 1 H), 7.12 (d, J=8.1 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H), 11.69 (s, 1 H), 12.55 (s, 1 H).

EXAMPLE 11

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

Obtained as an off-white solid (40%) from ethyl 3-fluoro-4-(4-(octyloxy)phenyl)-1 H-pyrrole-2- carboxylate (Intermediate 13) following the experimental procedure described in Example 10.

MS (m/z): 332 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.84-0.89 (m, 3H), 1.23-1.35 (m, 8H), 1.36-1.46 (m, 2H), 1.70 (dt, J= 14.4, 6.6 Hz, 2H), 3.95 (t, J=6.6 Hz, 2H), 6.88-6.92 (m, 3H), 7.43 (d, J=8.6 Hz, 2H), 11.65 (s, 1 H), 12.51 (s, 1 H).

EXAMPLE 12

3-Fluoro-4-(4-(nonyloxy)phenyl)-1 H-pyrrole-2-carboxylic acid Obtained as a beige solid (99%) from ethyl 3-fluoro-4-(4-(nonyloxy)phenyl)-1 H-pyrrole-2- carboxylate (Intermediate 14) following the experimental procedure described in Example 10.

MS (m/z): 346 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.83-0.87 (m, 3H), 1.25-1.37 (m, 10H), 1.35-1.46 (m, 2H), 1.74 (dt, J= 14.4, 6.6 Hz, 2H), 3.90 (t, J=6.6 Hz, 2H), 6.87-6.90 (m, 3H), 7.43 (d, J=8.6 Hz, 2H), 1 1.60 (s, 1 H), 12.55 (s, 1 H).

EXAMPLE 13

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

To a solution of ethyl 3-fluoro-4-(3-nonylphenyl)-1 H-pyrrole-2-carboxylate (Intermediate 15d, 144 g, 0.40 mmol) in ethanol (2.5 mL) and water (2 mL) was added lithium hydroxide monohydrate (38 mg, 1.58 mmol) and the 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 2N hydrochloric acid solution. The precipitate was filtered, rinsed with water, dried and purified by reverse phase chromatography (water/methanol) to yield the title compound (59 mg, 44%) as a white solid.

MS (m/z): 330 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.82-0.87 (m, 3H), 1.18-1.31 (m, 12H), 1.54-1.62 (m, 2H), 2.54-2.61 (m, 2H), 7.04 (d, J=7.6 Hz, 1 H), 7.24-7.30 (m, 2H), 7.35-7.41 (m, 2H), 1 1.75 (s, 1 H), 12.61 (s, 1 H).

EXAMPLE 14

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

Obtained as a white solid (83%) from ethyl 3-fluoro-4-(4-heptyl-2-methylphenyl)-1 H-pyrrole-2- carboxylate (Intermediate 16d) following the experimental procedure described in Example 10.

MS (m/z): 316 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.83-0.88 (m, 3H), 1.22-1.32 (m, 8H), 1.50-1.61 (m, 2H), 2.23 (s, 3H), 2.50-2.56 (m, 2H), 6.90-6.94 (m, 1 H), 7.02 (d, J=7.8 Hz, 1 H), 7.07-7.14 (m, 2H), 11.73 (s, 1 H), 12.55 (s, 1 H).

EXAMPLE 15

3-Fluoro-4-(2-methyl-4-nonylphenyl)-1 H-pyrrole-2-carboxylic acid Obtained as a beige solid (99%) from ethyl 3-fluoro-4-(2-methyl-4-nonylphenyl)-1 H-pyrrole-2- carboxylate (Intermediate 17d) following the experimental procedure described in Example 10.

MS (m/z): 344 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.82-0.89 (m, 3H), 1.27 (d, J=17.7 Hz, 12H), 1.52-1.61 (m, 2H), 2.23 (s, 3H), 2.51-2.56 (m, 2H), 6.89 (s, 1 H), 7.01 (d, J=7.8 Hz, 1 H), 7.08 (s, 1 H), 7.12 (d, J=7.7 Hz, 1 H), 11.68 (s, 1 H), 12.54 (s, 1 H).

EXAMPLE 16

4-(2-Ethyl-4-heptylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

Obtained as a white solid (41 %) from ethyl 4-(2-ethyl-4-heptylphenyl)-3-fluoro-1 H-pyrrole-2- carboxylate (Intermediate 18f) following the experimental procedure described in Example 10 followed by purification of the crude product by reverse phase chromatography (water/methanol).

MS (m/z): 330 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.83-0.89 (m, 3H), 1.06 (t, J=7.5 Hz, 3H), 1.22-1.34 (m, 9H), 1.52-1.62 (m, 2H), 2.52-2.59 (m, 4H), 6.86-6.89 (m, 1 H), 7.01 (dd, J=7.8, 1.5 Hz, 1 H), 7.06-7.12 (m, 2H), 11.71 (s, 1 H), 12.55 (s, 1 H).

EXAMPLE 17

4-(2-Ethyl-4-nonylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

Obtained as an off-white solid (61 %) from ethyl 4-(2-ethyl-4-nonylphenyl)-3-fluoro-1 H-pyrrole-2- carboxylate (Intermediate 19d) following the experimental procedure described in Example 10.

MS (m/z): 358 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.83-0.88 (m, 3H), 1.06 (t, J=7.5 Hz, 3H), 1.21-1.33 (m, 10H), 1.52-1.62 (m, 2H), 2.52-2.59 (m, 4H), 6.85-6.88 (m, 1 H), 7.01 (d, J=7.7 Hz, 1 H), 7.06-7.12 (m, 2H), 11.70 (s, 1 H), 12.56 (s, 1 H).

EXAMPLE 18

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

Obtained as a white solid (69%) from ethyl 3-fluoro-4-(2-isopropyl-4-nonylphenyl)-1 H-pyrrole-2- carboxylate (Intermediate 20f) following the experimental procedure described in Example 10.

MS (m/z): 372 [M-1]\ ¹ H NMR d (400 MHz, DMSO-de): 0.83-0.88 (m, 3H), 1.12 (d, J=6.8 Hz, 6H), 1.22-1.33 (m, 10H), 1.53-1.61 (m, 2H), 2.54-2.60 (m, 3H), 3.02 (dt, J=13.6, 6.7 Hz, 2H), 6.80 (s, 1 H), 6.99 (dd, J=7.8, 1.6 Hz, 1 H), 7.04 (d, J=7.7 Hz, 1 H), 7.17 (d, J=1.4 Hz, 1 H), 1 1.64 (s, 1 H), 12.56 (s, 1 H).

EXAMPLE 19

3-Fluoro-4-(2-methyl-5-nonylphenyl)-1 H-pyrrole-2-carboxylic acid

Obtained as a white solid (76%) from ethyl 3-fluoro-4-(2-methyl-5-nonylphenyl)-1 H-pyrrole-2- carboxylate (Intermediate 21 d) following the experimental procedure described in Example 10.

MS (m/z): 344 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.80-0.88 (m, 3H), 1.26 (d, J=16.7 Hz, 12H), 1.49-1.61 (m, 2H), 2.23 (s, 3H), 2.48-2.55 (m, 2H), 6.57 (d, J=4.6 Hz, 1 H), 6.97 (dd, J=7.7, 1.8 Hz, 1 H), 7.02 (s, 1 H), 7.12 (d, J=7.8 Hz, 1 H), 1 1.12 (s, 1 H).

EXAMPLE 20

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

Obtained as a solid (63%) from ethyl 3-fluoro-4-(2-methyl-3-nonylphenyl)-1 H-pyrrole-2- carboxylate (Intermediate 22d) following the experimental procedure described in Example 10.

MS (m/z): 344 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.82-0.89 (m, 3H), 1.21-1.39 (m, 12H), 1.52 (p, J=7.3 Hz, 2H), 2.57-2.64 (m, 2H), 6.89-6.91 (m, 1 H), 7.02-7.06 (m, 1 H), 7.09-7.12 (m, 2H), 11.74 (s, 1 H), 12.54 (s, 1 H).

EXAMPLE 21

4-(3-Decyl-2-methylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

Obtained as an off-white solid (56%) from ethyl 4-(3-decyl-2-methylphenyl)-3-fluoro-1 H-pyrrole- 2-carboxylate (Intermediate 23d) following the experimental procedure described in Example 10.

1 H NMR d (400 MHz, CD₃OD): 0.90 (t, J=6.9 Hz, 3H), 1.21-1.47 (m, 14H), 1.52-1.64 (m, 2H), 2.24 (s, 3H), 2.60-2.73 (m, 2H), 6.77 (d, J=4.7 Hz, 1 H), 7.02-7.1 1 (m, 3H).

EXAMPLE 22

4-(3-Decyl-2-methylphenyl)-3-fluoro-1 -methyl-1 H-pyrrole-2-carboxylic acid Obtained as a white solid (62%) from ethyl 4-(3-decyl-2-methylphenyl)-3-fluoro-1 -methyl-1 H- pyrrole-2-carboxylate (Intermediate 24) following the experimental procedure described in Example 10.

MS (m/z): 372 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.81-0.89 (m, 3H), 1.21-1.37 (m, 14H), 1.46-1.58 (m, 2H), 2.18 (s, 3H), 2.58-2.64 (m, 2H), 3.82 (s, 3H), 7.01-7.04 (m, 1 H), 7.04-7.07 (m, 1 H), 7.10-7.13 (m, 2H), 12.56 (s, 1 H).

EXAMPLE 23

4-(2-Ethyl-3-nonylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

Obtained as a white solid (72%) from ethyl 4-(2-ethyl-3-nonylphenyl)-3-fluoro-1 H-pyrrole-2- carboxylate (Intermediate 25e) following the experimental procedure described in Example 10.

MS (m/z): 358 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.83-0.88 (m, 3H), 0.94 (t, J=7.4 Hz, 3H), 1.22-1.41 (m, 12H), 1.50-1.59 (m, 2H), 2.62-2.70 (m, 4H), 6.82-6.87 (m, 1 H), 6.98 (dd, J=6.9, 1.9 Hz, 1 H), 7.08-7.16 (m, 2H), 11.68 (s, 1 H), 12.56 (s, 1 H).

EXAMPLE 24

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

Obtained as a white solid (77%) from ethyl 3-fluoro-4-(2-fluoro-3-nonylphenyl)-1 H-pyrrole-2- carboxylate (Intermediate 26d) following the experimental procedure described in Example 10 followed by purification of the crude product by reverse phase chromatography (water/methanol).

MS (m/z): 348 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.81-0.88 (m, 3H), 1.27 (d, J=23.8 Hz, 12H), 1.52-1.61 (m, 2H), 2.63 (t, J=7.5 Hz, 2H), 7.10-7.13 (m, 1 H), 7.15 (d, J=7.5 Hz, 1 H), 7.16-7.21 (m, 1 H), 7.35-7.41 (m, 1 H), 11.89 (s, 1 H), 12.67 (s, 1 H).

EXAMPLE 25

4-(2-Chloro-3-nonylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

Obtained as a white solid (55%) from ethyl 4-(2-chloro-3-nonylphenyl)-3-fluoro-1 H-pyrrole-2- carboxylate (Intermediate 27d) following the experimental procedure described in Example 10 followed by purification of the crude product by reverse phase chromatography (water/methanol). MS (m/z): 364 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.81-0.89 (m, 3H), 1.21-1.39 (m, 12H), 1.51-1.62 (m, 2H), 2.70-2.77 (m, 2H), 6.99-7.03 (m, 1 H), 7.22-7.25 (m, 1 H), 7.26-7.31 (m, 2H), 1 1.79 (s, 1 H), 12.62 (s, 1 H).

EXAMPLE 26

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

Obtained as a brown solid (76%) from ethyl 3-fluoro-4-(2-fluoro-4-nonylphenyl)-1 H-pyrrole-2- carboxylate (Intermediate 28d) following the experimental procedure described in Example 10.

MS (m/z): 348 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.85 (t, J=6.8 Hz, 3H), 1.20-1.32 (m, 12H), 1.52-1.63 (m, 2H), 2.58 (t, J=7.6 Hz, 2H), 7.04-7.12 (m, 3H), 7.46 (t, J=8.0 Hz, 1 H), 11.86 (s, 1 H), 12.62 (s, 1 H).

EXAMPLE 27

3-Fluoro-4-(2-fluoro-5-nonylphenyl)-1H-pyrrole-2-carboxylic acid

Obtained as a white solid (96%) from ethyl 3-fluoro-4-(2-fluoro-5-nonylphenyl)-1 H-pyrrole-2- carboxylate (Intermediate 29d) following the experimental procedure described in Example 10.

MS (m/z): 348 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.82-0.88 (m, 3H), 1.17-1.32 (m, 12H), 1.51-1.61 (m, 2H), 2.54-2.60 (m, 2H), 7.08-7.18 (m, 3H), 7.36 (dd, J=7.4, 1.8 Hz, 1 H), 11.89 (s, 1 H), 12.68 (s, 1 H).

EXAMPLE 28

4-(2-Chloro-4-heptylphenyl)-3-fluoro-1H-pyrrole-2-carboxylic acid

Obtained as an off-white solid (71 %) from ethyl 4-(2-chloro-4-heptylphenyl)-3-fluoro-1 H-pyrrole- 2-carboxylate (Intermediate 30d) following the experimental procedure described in Example 10.

MS (m/z): 336 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.82-0.88 (m, 3H), 1.22-1.33 (m, 8H), 1.51-1.63 (m, 2H), 2.55-2.62 (m, 2H), 7.02-7.06 (m, 1 H), 7.19 (dd, J=7.9, 1.6 Hz, 1 H), 7.31-7.37 (m, 2H), 11.84 (s, 1 H), 12.63 (s, 1 H). EXAMPLE 29

4-(2-Chloro-4-nonylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

Obtained as a beige solid (53%) from ethyl 4-(2-chloro-4-nonylphenyl)-3-fluoro-1 H-pyrrole-2- carboxylate (Intermediate 31 d) following the experimental procedure described in Example 10.

MS (m/z): 364 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.82-0.88 (m, 3H), 1.21-1.31 (m, 12H), 1.53-1.62 (m, 2H), 2.55-2.62 (m, 2H), 7.02 (d, J=3.9 Hz, 1 H), 7.19 (dd, J=7.9, 1.7 Hz, 1 H), 7.30-7.36 (m, 2H), 1 1.79 (s, 1 H), 12.60 (s, 1 H).

EXAMPLE 30

4-(2-Chloro-5-nonylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

Obtained as a white solid (40%) from ethyl 3-fluoro-4-(2-chloro-5-nonylphenyl)-1 H-pyrrole-2- carboxylate (Intermediate 32d) following the experimental procedure described in Example 10 followed by purification of the crude product by reverse phase chromatography (water/methanol).

MS (m/z): 364 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.80-0.88 (m, 3H), 1.20-1.30 (m, 12H), 1.51-1.61 (m, 2H), 2.54-2.60 (m, 2H), 7.15 (dd, J=8.2, 2.2 Hz, 1 H), 7.24 (d, J=1.9 Hz, 1 H), 7.41 (d, J=8.2 Hz, 1 H), 1 1.83 (s, 1 H), 12.65 (s, 1 H).

EXAMPLE 31

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

Obtained as a beige solid (15%) from ethyl 3-fluoro-4-(2-methoxy-4-nonylphenyl)-1 H-pyrrole-2- carboxylate (Intermediate 33d) following the experimental procedure described in Example 10.

MS (m/z): 360 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.85 (t, J=6.8 Hz, 3H), 1.21-1.33 (m, 12H), 1.53-1.62 (m, 2H), 2.54-2.60 (m, 2H), 3.79 (s, 3H), 6.79 (d, J=7.8 Hz, 1 H), 6.87-6.90 (m, 1 H), 7.08 (t, J=4.2 Hz, 1 H), 7.32 (d, J=7.6 Hz, 1 H), 1 1.65 (s, 1 H), 12.51 (s, 1 H).

EXAMPLE 32

3-Fluoro-4-(4-nonyl-2-(trifluoromethyl)phenyl)-1H-pyrrole-2-carboxylic acid

Obtained as a brown solid (76%) from ethyl 3-fluoro-4-(4-nonyl-2-(trifluoromethyl)phenyl)-1 H- pyrrole-2-carboxylate (Intermediate 34d) following the experimental procedure described in Example 10. MS (m/z): 398 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.82-0.89 (m, 3H), 1.22-1.32 (m, 12H), 1.57-1.64 (m, 2H), 2.65-2.72 (m, 2H), 6.87 (t, J=4.2 Hz, 1 H), 7.36 (d, J=7.8 Hz, 1 H), 7.51 (d, J=7.9 Hz, 1 H), 7.61 (d, J=1.4 Hz, 1 H), 11.84 (s, 1 H), 12.64 (s, 1 H).

EXAMPLE 33

3-Fluoro-4-(6-nonylpyridin-3-yl)-1 H-pyrrole-2-carboxylic acid

Obtained as a white solid (93%) from ethyl 3-fluoro-4-(6-nonylpyridin-3-yl)-1 H-pyrrole-2- carboxylate (Intermediate 35d) following the experimental procedure described in Example 10 followed by purification of the crude product by reverse phase chromatography (water/methanol).

MS (m/z): 333 [M+1]⁺.

¹ H NMR d (400 MHz, DMSO-de): 0.82-0.88 (m, 3H), 1.21-1.32 (m, 12H), 1.61-1.70 (m, 2H), 2.67-2.73 (m, 2H), 7.25 (d, J=8.1 Hz, 1 H), 7.38-7.41 (m, 1 H), 7.84 (dd, J=8.0, 2.4 Hz, 1 H), 8.69 (d, J=2.2 Hz, 1 H), 11.90 (s, 1 H), 12.69 (s, 1 H).

EXAMPLE 34

3-Fluoro-4-(5-nonylpyridin-2-yl)-1 H-pyrrole-2-carboxylic acid

Obtained as a beige solid (100%) from ethyl 3-fluoro-4-(5-nonylpyridin-2-yl)-1 H-pyrrole-2- carboxylate (Intermediate 36d) following the experimental procedure described in Example 10.

MS (m/z): 333 [M+1]⁺.

¹ H NMR d (400 MHz, DMSO-de): 0.82-0.87 (m, 3H), 1.19-1.32 (m, 12H), 1.53-1.61 (m, 2H), 2.54-2.59 (m, 2H), 7.36 (t, J=4.2 Hz, 1 H), 7.51 (d, J=8.0 Hz, 1 H), 7.62 (dd, J=8.1 , 2.2 Hz, 1 H), 8.37 (d, J=1.8 Hz, 1 H), 11.89 (s, 1 H), 12.65 (s, 1 H).

EXAMPLE 35

4-(1 -Decyl-1 H-pyrazol-4-yl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

Obtained as a white solid (73%) from ethyl 4-(1-decyl-1 H-pyrazol-4-yl)-3-fluoro-1 H-pyrrole-2- carboxylate (Intermediate 37b) following the experimental procedure described in Example 10 followed by purification of the crude product by reverse phase chromatography (water/methanol).

MS (m/z): 336 [M+1]⁺.

¹ H NMR d (400 MHz, DMSO-de): 0.80-0.88 (m, 3H), 1.17-1.30 (m, 12H), 1.75 (p, J=7.1 Hz, 2H), 4.08 (t, J=7.0 Hz, 2H), 7.08 (d, J=3.9 Hz, 1 H), 7.62 (s, 1 H), 7.85 (s, 1 H), 1 1.55 (s, 1 H), 12.50 (s, 1 H). EXAMPLE 36

3-Fluoro-5-(4-nonylphenyl)-1 H-pyrrole-2-carboxylic acid

Obtained as a solid (28%) from ethyl 3-fluoro-5-(4-nonylphenyl)-1 H-pyrrole-2-carboxylate (Intermediate 38) following the experimental procedure described in Example 10 followed by purification of the crude product by flash chromatography (DCM to DCM/MeOH 95:5).

MS (m/z): 330 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.85 (t, J=6.8 Hz, 3H), 1.21-1.31 (m, 12H), 1.50-1.59 (m, 2H), 2.37-2.57 (m, 2H), 7.13 (d, J=8.1 Hz, 1 H), 7.65 (d, J=8.1 Hz, 1 H), 1 1.55 (s, 1 H), 12.50 (s, 1 H).

EXAMPLE 37

3-Fluoro-5-(4-(octyloxy)phenyl)-1 H-pyrrole-2-carboxylic acid

Obtained as a light grey solid (20%) from ethyl 3-fluoro-5-(4-(octyloxy)phenyl)-1 H-pyrrole-2- carboxylate (Intermediate 39) following the experimental procedure described in Example 10 followed by purification of the crude product by reverse phase chromatography (water/metanol).

MS (m/z): 332 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.83-0.90 (m, 3H), 1.22-1.34 (m, 8H), 1.36-1.45 (m, 2H), 1.70 (p, J=6.6 Hz, 2H), 3.98 (t, J=6.5 Hz, 2H), 6.42 (s, 1 H), 6.93 (d, J=8.9 Hz, 2H), 7.74 (d, J=8.9 Hz, 1 H), 11.59 (s, 1 H), 12.42 (s, 1 H).

EXAMPLE 38

3-Fluoro-5-(3-nonylphenyl)-1 H-pyrrole-2-carboxylic acid

Obtained as a beige solid (67%) from ethyl 3-fluoro-5-(3-nonylphenyl)-1 H-pyrrole-2-carboxylate (Intermediate 40) following the experimental procedure described in Example 10.

MS (m/z): 330 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.81-0.88 (m, 3H), 1.27 (d, J=21.0 Hz, 12H), 1.55-1.63 (m, 2H), 2.54-2.61 (m, 2H), 6.81 (s, 1 H), 7.10 (d, J=7.6 Hz, 1 H), 7.27 (t, J=7.7 Hz, 1 H), 7.59 (d, J=7.9 Hz, 1 H), 7.71 (s, 1 H), 11.69 (s, 1 H), 12.51 (s, 1 H).

EXAMPLE 39

3-Fluoro-5-(2-methyl-5-nonylphenyl)-1 H-pyrrole-2-carboxylic acid Obtained as a solid (55%) from ethyl 3-fluoro-5-(2-methyl-5-nonylphenyl)-1 H-pyrrole-2- carboxylate (Intermediate 41) following the experimental procedure described in Example 10.

MS (m/z): 344 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.81-0.88 (m, 3H), 1.19-1.31 (m, 12H), 1.50-1.60 (m, 2H), 2.32 (s, 3H), 2.49-2.56 (m, 2H), 6.10 (s, 1 H), 7.03 (dd, J=7.7, 1.5 Hz, 1 H), 7.13 (d, J=7.8 Hz, 1 H), 7.24 (d, J=1.4 Hz, 1 H), 1 1.21 (s, 1 H).

EXAMPLE 40

5-(2-Ethyl-4-nonylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

Obtained as a light pink solid (91 %) from ethyl 5-(2-ethyl-4-nonylphenyl)-3-fluoro-1 H-pyrrole-2- carboxylate (Intermediate 42) following the experimental procedure described in Example 10 followed by purification of the crude product by reverse phase chromatography (water/methanol).

MS (m/z): 358 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.82-0.89 (m, 3H), 1.05 (t, J=7.5 Hz, 3H), 1.20-1.34 (m, 12H), 1.50-1.61 (m, 2H), 2.54-2.61 (m, 2H), 2.66 (q, J=7.5 Hz, 2H), 6.08 (d, J=1.6 Hz, 1 H), 7.04 (dd, J=7.9, 1.6 Hz, 1 H), 7.11 (d, J=1.4 Hz, 1 H), 7.21 (d, J=7.8 Hz, 1 H), 11.52 (s, 1 H), 12.40 (s, 1 H).

EXAMPLE 41

3-Fluoro-5-(2-methyl-3-nonylphenyl)-1 H-pyrrole-2-carboxylic acid

Obtained as a solid (39%) from ethyl 3-fluoro-5-(2-methyl-3-nonylphenyl)-1 H-pyrrole-2- carboxylate (Intermediate 43) following the experimental procedure described in Example 10 followed by purification of the crude product by reverse phase chromatography (water/metanol).

MS (m/z): 344 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.83-0.88 (m, 3H), 1.21-1.37 (m, 12H), 1.51 (p, J=7.3 Hz, 2H), 2.23 (s, 3H), 2.57-2.64 (m, 2H), 6.08 (s, 1 H), 7.10-7.18 (m, 3H), 1 1.54 (s, 1 H), 12.42 (s, 1 H).

EXAMPLE 42

3-Fluoro-5-(2-isopropyl-4-nonylphenyl)-1 H-pyrrole-2-carboxylic acid

Obtained as a solid (26%) from ethyl 3-fluoro-5-(2-isopropyl-4-nonylphenyl)-1 H-pyrrole-2- carboxylate (Intermediate 44) following the experimental procedure described in Example 10 followed by purification of the crude product by reverse phase chromatography (water/methanol). MS (m/z): 372 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.83-0.89 (m, 3H), 1.13 (d, J=6.9 Hz, 6H), 1.21-1.34 (m, 12H), 1.52-1.63 (m, 2H), 2.55-2.64 (m, 2H), 3.08-3.19 (m, 1 H), 6.00 (s, 1 H), 7.03 (dd, J=7.9, 1.5 Hz, 1 H), 7.15 (d, J=7.9 Hz, 1 H), 7.19 (d, J=1.5 Hz, 1 H), 11.52 (s, 1 H), 12.38 (s, 1 H).

EXAMPLE 43

3-Fluoro-5-(2-fluoro-3-nonylphenyl)-1H-pyrrole-2-carboxylic acid

Obtained as a light pink solid (71 %) from ethyl 3-fluoro-5-(2-fluoro-3-nonylphenyl)-1 H-pyrrole-2- carboxylate (Intermediate 45) following the experimental procedure described in Example 10 followed by purification of the crude product by reverse phase chromatography (water/methanol).

MS (m/z): 348 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.81-0.89 (m, 3H), 1.21-1.34 (m, 12H), 1.51-1.62 (m, 2H), 2.63 (t, J=7.6 Hz, 2H), 6.39 (d, J=2.9 Hz, 1 H), 7.15 (t, J=7.6 Hz, 1 H), 7.21-7.27 (m, 1 H), 7.70 (td, J=7.6, 1.7 Hz, 1 H), 11.69 (s, 1 H), 12.65 (s, 1 H).

EXAMPLE 44

3-Fluoro-5-(2-fluoro-4-nonylphenyl)-1H-pyrrole-2-carboxylic acid

Obtained as white solid (56%) from ethyl 3-fluoro-5-(2-fluoro-4-nonylphenyl)-1 H-pyrrole-2- carboxylate (Intermediate 46) following the experimental procedure described in Example 10 followed by purification of the crude product by reverse phase chromatography (water/methanol).

MS (m/z): 348 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.82-0.89 (m, 3H), 1.20-1.31 (m, 12H), 1.52-1.62 (m, 2H), 2.55-2.62 (m, 2H), 6.35 (d, J=2.9 Hz, 1 H), 7.04-7.14 (m, 2H), 7.80 (t, J=8.2 Hz, 1 H), 11.56 (s, 1 H).

EXAMPLE 45

3-Fluoro-5-(2-fluoro-5-nonylphenyl)-1H-pyrrole-2-carboxylic acid

Obtained as an off-white solid (97%) from ethyl 3-fluoro-5-(2-fluoro-5-nonylphenyl)-1 H-pyrrole-2- carboxylate (Intermediate 47) following the experimental procedure described in Example 10.

MS (m/z): 348 [M-1]\ ¹ H NMR d (400 MHz, DMSO-de): 0.81-0.88 (m, 3H), 1.20-1.32 (m, 12H), 1.56-1.64 (m, 2H), 2.54-2.60 (m, 2H), 6.40 (d, J=3.1 Hz, 1 H), 7.12-7.19 (m, 2H), 7.80 (d, J=8.3 Hz, 1 H), 11.75 (s, 1 H), 12.68 (s, 1 H).

EXAMPLE 46

5-(2-Chloro-4-nonylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

Obtained as a white solid (50%) from ethyl 5-(2-chloro-4-nonylphenyl)-3-fluoro-1 H-pyrrole-2- carboxylate (Intermediate 48) following the experimental procedure described in Example 10 followed by purification of the crude product by reverse phase chromatography (water/methanol).

MS (m/z): 364 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.82-0.89 (m, 3H), 1.20-1.33 (m, 12H), 1.50-1.62 (m, 2H), 2.55-2.63 (m, 2H), 6.34 (s, 1 H), 7.21 (dd, J=8.0, 1.6 Hz, 1 H), 7.36 (d, J=1.6 Hz, 1 H), 7.50 (d, J=7.9 Hz, 1 H), 11.63 (s, 1 H).

EXAMPLE 47

5-(2-Chloro-5-nonylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

Obtained as an off-white solid (21 %) from ethyl 5-(2-chloro-5-nonylphenyl)-3-fluoro-1 H-pyrrole-2- carboxylate (Intermediate 49) following the experimental procedure described in Example 10 followed by purification of the crude product by reverse phase chromatography (water/methanol).

MS (m/z): 364 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.82-0.88 (m, 3H), 1.19-1.31 (m, 12H), 1.52-1.64 (m, 2H), 2.54-2.60 (m, 2H), 6.40 (s, 1 H), 7.18 (dd, J=8.2, 2.1 Hz, 1 H), 7.41 (d, J=8.2 Hz, 1 H), 7.47 (d, J=2.1 Hz, 1 H), 11.75 (s, 1 H), 12.64 (s, 1 H).

EXAMPLE 48

3-Fluoro-5-(2-methoxy-4-nonylphenyl)-1H-pyrrole-2-carboxylic acid

Obtained as a beige solid (55%) from ethyl 3-fluoro-5-(2-methoxy-4-nonylphenyl)-1 H-pyrrole-2- carboxylate (Intermediate 50) following the experimental procedure described in Example 10.

MS (m/z): 360 [M-1 ]-.

¹ H NMR 6 (400 MHz, DMSO-de): 0.81 -0.88 (m, 3H), 1 .21 -1 .32 (m, 12H), 1 .54-1 .63 (m, 2H), 2.55-2.62 (m, 2H), 3.87 (s, 3H), 6.46 (d, J=2.8 Hz, 1 H), 6.82 (dd, J=8.0, 1 .2 Hz, 1 H), 6.92-6.95 (m, 1 H), 7.62 (d, J=8.0 Hz, 1 H), 10.94 (s, 1 H), 12.51 (s, 1 H). EXAMPLE 49

5-(1 -Decyl-1 H-pyrazol-4-yl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

Obtained as an off-white solid (49%) from ethyl 5-(1-decyl-1 H-pyrazol-4-yl)-3-fluoro-1 H-pyrrole- 2-carboxylate (Intermediate 51) following the experimental procedure described in Example 10 followed by purification of the crude product by reverse phase chromatography (water/methanol).

MS (m/z): 336 [M+1]⁺.

¹ H NMR d (400 MHz, DMSO-de): 0.80-0.88 (m, 3H), 1.17-1.30 (m, 12H), 1.69-1.81 (m, 2H), 4.07 (t, J=6.9 Hz, 2H), 6.19 (s, 1 H), 7.85-7.90 (m, 1 H), 8.16 (s, 1 H), 11.55 (s, 1 H), 12.32 (s, 1 H).

EXAMPLE 50

5-(1 -Decyl-3,5-dimethyl-1 H-pyrazol-4-yl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

Obtained as a beige solid (98%) from ethyl 5-(1-decyl-3,5-dimethyl-1 H-pyrazol-4-yl)-3-fluoro-1 H- pyrrole-2-carboxylate (Intermediate 52b) following the experimental procedure described in Example 10.

MS (m/z): 362 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.81-0.87 (m, 3H), 1.22-1.30 (m, 14H), 1.63-1.72 (m, 2H), 2.04 (s, 3H), 2.13 (s, 3H), 3.93 (t, J=7.2 Hz, 2H), 6.78 (s, 1 H), 11.59 (s, 1 H).

EXAMPLE 51

3-fluoro-4-(4-pentylcyclohex-1-en-1-yl)-1 H-pyrrole-2-carboxylic acid

Obtained as a yellowish solid (94%) from ethyl 3-fluoro-4-(4-pentylcyclohex-1-en-1-yl)-1 H- pyrrole-2-carboxylate (Intermediate 53) following the experimental procedure described in Example 10.

MS (m/z): 278 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.87 (t, J=6.9 Hz, 3H), 1.18-1.35 (m, 8H), 1.44-1.54 (m, 2H), 1.68-1.83 (m, 3H), 2.14-2.35 (m, 4H), 5.95 (s, 1 H), 6.65 (s, 1 H), 11.09 (s, 1 H).

EXAMPLES 52 and 53

3-Fluoro-4-((1r,4s)-4-pentylcyclohexyl)-1H-pyrrole-2-carboxylic acid and 3-fluoro-4- ((1s,4r)-4-pentylcyclohexyl)-1H-pyrrole-2-carboxylic acid Obtained as a white solid (56%) from a mixture of ethyl 3-fluoro-4-((1 r,4s)-4-pentylcyclohexyl)- 1 H-pyrrole-2-carboxylate and ethyl 3-fluoro-4-((1 s,4r)-4-pentylcyclohexyl)-1 H-pyrrole-2- carboxylate (Intermediate 54) following the experimental procedure described in Example 10. Purification of the crude product by reverse phase chromatography (water/methanol) provided a sample of pure first eluting isomer (Example 52):

MS (m/z): 280 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.86 (t, J=6.9 Hz, 3H), 1.20-1.33 (m, 8H), 1.34-1.44 (m, 2H), 1.46-1.70 (m, 7H), 2.55-2.62 (m, 1 H), 6.63 (s, 1 H), 11.21 (s, 1 H), 12.31 (s, 1 H).

Along with a 6:4 mixture of first eluting/second eluting isomers (Example 53).

EXAMPLES 54 and 55

3-Fluoro-4-((1r,4s)-4-octylcyclohexyl)-1H-pyrrole-2-carboxylic acid and 3-fluoro-4-((1s,4r)-

4-octylcyclohexyl)-1 H-pyrrole-2-carboxylic acid

Obtained as a white solid (42%) from a mixture of ethyl 3-fluoro-4-((1r,4s)-4-octylcyclohexyl)-1 H- pyrrole-2-carboxylate and ethyl 3-fluoro-4-((1 s,4r)-4-octylcyclohexyl) -1 H-pyrrole-2-carboxylate (Intermediate 55d) following the experimental procedure described in Example 10. Purification of the crude product by reverse phase chromatography (water/methanol) provided pure samples of both isomers:

First eluting isomer (Example 54)

MS (m/z): 322 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.82-0.88 (m, 3H), 1.21-1.31 (m, 14H), 1.35-1.44 (m, 2H), 1.46-1.68 (m, 7H), 2.55-2.64 (m, 1 H), 6.62-6.67 (m, 1 H), 11.25 (s, 1 H), 12.32 (s, 2H).

Second eluting isomer (Example 55)

MS (m/z): 322 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.83-0.88 (m, 3H), 0.90-1.04 (m, 2H), 1.14-1.34 (m, 17H), 1.72-1.87 (m, 4H), 2.31-2.37 (m, 1 H), 6.59-6.62 (m, 1 H), 11.23 (s, 1 H), 12.31 (s, 1 H). EXAMPLE 56

3-Fluoro-5-(4-pentylcyclohex-1-en-1-yl)-1H-pyrrole-2-carboxylic acid

Obtained as an off-white solid (84%) from ethyl 3-fluoro-5-(4-pentylcyclohex-1-en-1-yl)-1 H- pyrrole-2-carboxylate (Intermediate 56) following the experimental procedure described in Example 10.

MS (m/z): 278 [M-1]\

¹H NMR d (400 MHz, DMSO-de): 0.87 (t, J=7.0 Hz, 3H), 1.18-1.34 (m, 8H), 1.39-1.51 (m, 2H), 1.67-1.83 (m, 2H), 2.15-2.26 (m, 2H), 2.29-2.37 (m, 1 H), 5.93 (s, 1 H), 6.30 (s, 1 H), 10.71 (s, 3H).

EXAMPLES 57 and 58

3-Fluoro-5-((1r,4s)-4-pentylcyclohexyl)-1H-pyrrole-2-carboxylic acid and 3-fluoro-5- ((1s,4r)-4-pentylcyclohexyl)-1H-pyrrole-2-carboxylic acid

Obtained as a solid (22%) from a mixture of ethyl 3-fluoro-5-((1r,4s)-4-pentylcyclohexyl)-1 H- pyrrole-2-carboxylate and ethyl 3-fluoro-5-((1s,4r)-4-pentylcyclohexyl)-1 H-pyrrole-2-carboxylate (Intermediate 57) following the experimental procedure described in Example 10. Purification of the crude product by reverse phase chromatography (water/methanol)provided a sample of pure first eluting isomer (Example 57) along with a 6:4 mixture of first eluting/second eluting isomers (Example 58).

MS (m/z): 280 [M-1]\

EXAMPLES 59 and 60

5-((1r,4s)-4-Decylcyclohexyl)-3-fluoro-1H-pyrrole-2-carboxylic acid and 5-((1s,4r)-4- decylcyclohexyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

Obtained as a white solid (24%) from a mixture of ethyl 5-((1r,4s)-4-decylcyclohexyl)-3-fluoro-1 H- pyrrole-2-carboxylate and ethyl 5-((1s,4r)-4-decylcyclohexyl)-3-fluoro-1 H-pyrrole-2-carboxylate (Intermediate 58d) following the experimental procedure described in Example 10. Purification of the crude product by reverse phase chromatography (water/methanol) provided pure samples of both isomers (Examples 59 and 60).

First eluting isomer (Example 59)

MS (m/z): 350 [M-1]\ ¹ H NMR d (400 MHz, DMSO-de): 0.84-0.92 (m, 3H), 1.21-1.29 (m, 20H), 1.46-1.53 (m, 1 H), 1.54-1.64 (m, 2H), 1.68-1.82 (m, 4H), 2.70-2.78 (m, 1 H), 5.83 (d, J=3.1 Hz, 1 H), 8.32 (s, 1 H).

Second eluting isomer (Example 60)

MS (m/z): 350 [M-1]\

EXAMPLE 61

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

Obtained as an off-white solid (64%) from ethyl 4-(2,3-difluoro-4-heptylphenyl)-3-fluoro-1 H- pyrrole-2-carboxylate (Intermediate 59d) following the experimental procedure described in Example 10.

MS (m/z): 338 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.82-0.89 (m, 3H), 1.20-1.34 (m, 8H), 1.52-1.62 (m, 2H), 2.64 (t, J=7.3 Hz, 2H), 7.09-7.21 (m, 2H), 7.28 (t, J=7.1 Hz, 1 H), 12.02 (s, 1 H), 12.76 (s, 1 H).

EXAMPLE 62

4-(2,5-Difluoro-4-heptylphenyl)-3-fluoro-1H-pyrrole-2-carboxylic acid

Obtained as a white solid (76%) from ethyl 4-(2,5-difluoro-4-heptylphenyl)-3-fluoro-1 H-pyrrole-2- carboxylate (Intermediate 60d) following the experimental procedure described in Example 10.

MS (m/z): 338 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 0.82-0.89 (m, 3H), 1.22-1.32 (m, 8H), 1.50-1.61 (m, 2H), 2.59 (t, J=7.6 Hz, 2H), 7.16 (s, 1 H), 7.23 (dd, J=6.5, 11.0 Hz, 1 H), 7.31 (dd, J=6.4, 10.8 Hz, 1 H), 1 1.98 (s, 1 H), 12.74 (s, 1 H).

EXAMPLE 63

4-(2,3-Difluoro-4-(hexyloxy)phenyl)-3-fluoro-1H-pyrrole-2-carboxylic acid Obtained as a white solid (63%) from ethyl 4-(2,3-difluoro-4-(hexyloxy)phenyl)-3-fluoro-1 H- pyrrole-2-carboxylate (Intermediate 61 c) following the experimental procedure described in Example 10.

MS (m/z): 340 [M-1]\

¹ H NMR 5 (300 MHz, DMSO-de): 0.83-0.90 (m, 3H), 1.25-1.34 (m, 4H), 1.35-1.45 (m, 2H), 1.65-1.79 (m, 2H), 4.06 (t, J=6.5 Hz, 2H), 6.78 (s, 1 H), 6.97-7.06 (m, 1 H), 7.20-7.30 (m, 1 H).

EXAMPLE 64

4-(2,5-Difluoro-4-(hexyloxy)phenyl)-3-fluoro-1H-pyrrole-2-carboxylic acid

Obtained as a white solid (80%) from ethyl 4-(2,5-difluoro-4-(hexyloxy)phenyl)-3-fluoro-1 H- pyrrole-2-carboxylate (Intermediate 62c) followed the experimental procedure described in Example 10.

MS (m/z): 340 [M-1]\

¹ H NMR 5 (400 MHz, DMSO-de): 0.85-0.91 (m, 3H), 1.27-1.36 (m, 4H), 1.37-1.45 (m, 2H), 1.73 (p, J=6.6 Hz, 2H), 4.07 (t, J=6.6 Hz, 2H), 7.10 (s, 1 H), 7.20 (dd, J=12.1 , 7.3 Hz, 1 H), 7.36 (dd, J= 12.1 , 7.3 Hz, 1 H), 1 1.92 (s, 1 H), 12.70 (s, 1 H).

EXAMPLE 65

3-Fluoro-4-(4-((6-hydroxyhexyl)oxy)phenyl)-1H-pyrrole-2-carboxylic acid

Obtained as a solid (34%) from ethyl 3-fluoro-4-(4-((6-hydroxyhexyl)oxy)phenyl)-1 H-pyrrole-2- carboxylate (Intermediate 63b) following the experimental procedure described in Example 4.

MS (m/z): 320 [M-1]\

¹ H NMR 5 (400 MHz, DMSO-de): 1.29-1.49 (m, 6H), 1.65-1.75 (m, 2H), 3.36-3.44 (m, 2H), 3.96 (t, J=6.5 Hz, 2H), 4.34 (s, 1 H), 6.93 (d, J=8.7 Hz, 2H), 7.20 (s, 1 H), 7.48 (d, J=8.6 Hz, 2H), 1 1.68 (s, 1 H), 12.60 (s, 2H).

EXAMPLE 66

4-(4-((6-Ethoxyhexyl)oxy)phenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

Obtained as a white solid (52%) from ethyl 4-(4-((6-ethoxyhexyl)oxy)phenyl)-3-fluoro-1 H-pyrrole- 2-carboxylate (Intermediate 64b) following the experimental procedure described in Example 10. MS (m/z): 348 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 1.09 (t, J=7.0 Hz, 3H), 1.32-1.46 (m, 4H), 1.47-1.55 (m, 2H), 1.66-1.76 (m, 2H), 3.35-3.42 (m, 4H), 3.96 (t, J=6.5 Hz, 2H), 6.91-6.96 (m, 2H), 7.21 (d, J=4.3 Hz, 1 H), 7.47 (d, J=8.7 Hz, 2H), 11.69 (s, 1 H), 12.56 (s, 1 H).

EXAMPLE 67

4-(4-(3-Ethoxypropoxy)phenyl)-3-fluoro-1H-pyrrole-2-carboxylic acid

Obtained as a white solid (85%) from ethyl 4-(4-(3-ethoxypropoxy)phenyl)-3-fluoro-1 H-pyrrole-2- carboxylate (Intermediate 65e) following the experimental procedure described in Example 10.

MS (m/z): 306 [M-1]\

¹ H NMR d (400 MHz, DMSO-de): 1.1 1 (t, J=7.0 Hz, 3H), 1.94 (p, J=6.3 Hz, 2H), 3.43 (q, J=7.0 Hz, 2H), 3.51 (t, J=6.3 Hz, 2H), 4.02 (t, J=6.4 Hz, 2H), 6.94 (d, J=8.8 Hz, 2H), 7.20- 7.24 (m, 1 H), 7.48 (d, J=8.7 Hz, 2H), 11.71 (s, 1 H), 12.55 (s, 1 H).

EXAMPLE 68

3-Fluoro-4-(4-hydroxy-4-octylcyclohex-1-en-1-yl)-1H-pyrrole-2-carboxylic acid

Obtained as a light brown solid (46%) from ethyl 3-fluoro-4-(4-hydroxy-4-octylcyclohex-1-en-1- yl)-1 H-pyrrole-2-carboxylate (Intermediate 66c) following the experimental procedure described in Example 10.

MS (m/z): 336 [M-1]\

EXAMPLE 69

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

Obtained as a solid (75%) from ethyl 3-fluoro-4-(4-hydroxy-4-octylcyclohexyl)-1 H-pyrrole-2- carboxylate (Intermediate 67c) following the experimental procedure described in Example 10.

MS (m/z): 338 [M-1]\

¹ H NMR d (300 MHz, DMSO-de): 0.86 (t, J=6.3 Hz, 3H), 1.22-1.33 (m, 15H), 1.50-1.61 (m, 4H), 1.62-1.78 (m, 2H), 2.24-2.40 (m, 2H), 3.80 (s, 1 H), 6.58 (s, 1 H), 11.21 (s, 1 H). EXAMPLE 70

2,2,2-Trifluoroethyl 3-fluoro-5-(tetradec-1-yn-1-yl)-1H-pyrrole-2-carboxylate

EXAMPLE 71

2-(2-Ethoxyethoxy)ethyl 3-fluoro-5-(tetradec-1-yn-1-yl)-1H-pyrrole-2-carboxylate

EXAMPLE 72

1-((lsopropoxycarbonyl)oxy)ethyl 3-fluoro-5-(tetradec-1-yn-1-yl)-1 H-pyrrole-2-carboxylate

EXAMPLE 73

1-(((2-Methoxyethoxy)carbonyl)oxy)ethyl 3-fluoro-5-(tetradec-1-yn-1-yl)-1 H-pyrrole-2- carboxylate

EXAMPLE 74

4-Oxo-3,5,8,11-tetraoxatridecan-2-yl 3-fluoro-5-(tetradec-1-yn-1-yl)-1H-pyrrole-2- carboxylate

EXAMPLE 75

2,2,2-Trifluoroethyl 3-fluoro-4-(4-nonylphenyl)-1H-pyrrole-2-carboxylate

EXAMPLE 76

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

EXAMPLE 77

1-((lsopropoxycarbonyl)oxy)ethyl 3-fluoro-4-(4-nonylphenyl)-1 H-pyrrole-2-carboxylate

EXAMPLE 78

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

EXAMPLE 79

4-Oxo-3,5,8,11-tetraoxatridecan-2-yl 3-fluoro-4-(4-nonylphenyl)-1H-pyrrole-2-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

PHARMACOLOGICAL ACTIVITY

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 mM (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 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/lntravaqinal 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:

• R² represents a hydrogen atom or a halogen atom,

• R³ represents a hydrogen atom or a linear or branched C_1-4 alkyl group,

• R⁵ is selected from the group consisting of a linear or branched C1-4 alkyl group and a - [(CH₂)i-2-0]i-₂-R^d group;

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

• R^e represents a hydrogen atom or a linear or branched C_1-4 alkyl group.

2. A pyrrole derivative according to claim 1 , wherein in the compound of Formula (I):

• R¹ is selected from the group consisting of a linear or branched C5-14 alkyl group and a linear or branched C_S-M alkoxy group, • R² represents a hydrogen atom or a halogen atom,

• L represents a -º- group, a phenyl ring, a monocyclic C3-7 cycloalkyl group, a monocyclic C5-7 cycloalkenyl group or a monocyclic 5- to 6-membered heteroaryl group containing one or more heteroatoms selected from the group consisting of O and N, wherein the phenyl, cycloalkyl, cycloalkenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a linear or branched C1-6 alkyl group, a linear or branched Ci-₆ alkoxy group, a linear or branched Ci-3 haloalkyl group and a halogen atom,

• R³ represents a hydrogen atom or a linear or branched C_1-4 alkyl group,

• R^a, R^b, R^c and R^d are independently selected from the group consisting of a hydrogen atom and a linear or branched C_1-4 alkyl group.

3. A pyrrole derivative according to claim 1 wherein the compound of Formula (I) is represented by Formula (la):

Formula (la)

4. A pyrrole derivative according to claim 1 wherein the compound of Formula (I) is represented by Formula (lb):

Formula (lb)

5. A pyrrole derivative according to claims 1 to 4, wherein R¹ represents a linear or branched Cg. 14 alkyl group or a linear or branched Cs-9 alkoxy group.

6. A pyrrole derivative according to claims 1 to 5, wherein R² represents a hydrogen atom or fluorine atom, preferably a fluorine atom.

7. A pyrrole derivative according to claims 1 to 6, wherein L represents a -º- group, a phenyl ring, a monocyclic C5-6 cycloalkyl group, a monocyclic C5-6 cycloalkenyl group or a monocyclic 5- to 6- membered heteroaryl group containing at least one heteroatom selected from the group consisting of O and N, wherein the phenyl, cycloalkyl, cycloalkenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a linear or branched C1-3 alkyl group, a Ci-2 alkoxy group, a Ci-2 haloalkyl group and a halogen atom.

8. A pyrrole derivative according to claims 1 to 7, wherein R³ represents a hydrogen atom.

9. A pyrrole derivative according to claims 1 to 8, wherein R⁴ represents a hydrogen atom, a C2 fluoroalkyl group, a -[(Chh^Ok-ChhCF group or a -(CH(CH₃))-0C(0)0-R⁵ group; preferably R⁴ represents a hydrogen atom.

10. A pyrrole derivative according to claims 1 to 9, wherein R^a, R^b and R^d each independently represent a methyl group or an ethyl group.

11. A pyrrole derivative according to claims 1 to 10, wherein R^c represents a hydrogen atom.

12. A pyrrole derivative according to claims 1 to 3 wherein the compound of Formula (I) is represented by Formula (la):

Formula (la)

Wherein:

• R¹ is selected from the group consisting of a linear or branched C9-14 alkyl group or a linear or branched Cs-9 alkoxy group,

• R² represents a hydrogen atom or a fluorine atom, preferably a fluorine atom, • L represents a -º- group, a phenyl ring, a monocyclic C_5-6 cycloalkyl group, a monocyclic C_5-6 cycloalkenyl group or a monocyclic 5- to 6-membered heteroaryl group containing at least one heteroatom selected from the group consisting of O and N, wherein the phenyl, cycloalkyl, cycloalkenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a linear or branched C_1-3 alkyl group, a Ci-₂ alkoxy group, a Ci-₂ haloalkyl group and a halogen atom,

• R³ represents a hydrogen atom,

• R^c represents a hydrogen atom.

13. A pyrrole derivative according to claim 1 to 4 wherein the compound of Formula (I) is represented by Formula (lb):

Formula (lb)

Wherein:

• R³ represents a hydrogen atom,

• R⁴ represents a hydrogen atom, a C₂ fluoroalkyl group, a -[(CFb^Ok-CFbCF group or a -(CH(CH₃))-0C(0)0-R⁵ group; preferably R⁴ represents a hydrogen atom, • R^a, R^b and R^d each independently represent a methyl group or an ethyl group, and

• R^c represents a hydrogen atom.

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

• R¹ is selected from the group consisting of a pentyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, an undecyl group, a dodecyl group, a tridecyl group, a tetradecyl group, a hexyloxy group, an octyloxy group, a nonyloxy group, a -0-(CH₂)₆- OH group, a -0-(CH₂)6-0CH₂CH3 group and a -0-(CH₂)3-0CH₂CH3 group,

• R² represents a hydrogen atom, a fluorine atom or a chlorine atom,

• R³ represents a hydrogen atom,

• R⁴ is selected from the group consisting of a hydrogen atom, a CH₂CF3 group, a - [(CH₂)₂0]₂-CH₂CH₃ group, a -CH(CH₃)0C(0)0CH(CH₃)2 group, a CH(CH₃)0C(0)0CH₂CH₂0CH₃ group and a -CH(CH₃)0C(0)0[(CH₂)₂0]₂CH₂CH₃ group, and

15. A pyrrole derivative according to claims 1 to 14, wherein the compound of Formula (I) is one of:

4-(Dodec-1-yn-1-yl)-1 H-pyrrole-2-carboxylic acid

3-Chloro-4-(dodec-1-yn-1-yl)-1 H-pyrrole-2-carboxylic acid

4-(Dodec-1-yn-1-yl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

5-(Dodec-1-yn-1-yl)-1 H-pyrrole-2-carboxylic acid

5-(Dodec-1-yn-1-yl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

3-Fluoro-5-(tridec-1-yn-1-yl)-1 H-pyrrole-2-carboxylic acid

3-Fluoro-5-(tetradec-1-yn-1-yl)-1 H-pyrrole-2-carboxylic acid

3-Fluoro-5-(pentadec-1-yn-1-yl)-1 H-pyrrole-2-carboxylic acid -Fluoro-5-(hexadec-1-yn-1-yl)-1 H-pyrrole-2-carboxylic acid-Fluoro-4-(4-nonylphenyl)-1 H-pyrrole-2-carboxylic acid

-Fluoro-4-(4-(octyloxy)phenyl)-1 H-pyrrole-2-carboxylic acid

-Fluoro-4-(4-(nonyloxy)phenyl)-1 H-pyrrole-2-carboxylic acid

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

-Fluoro-4-(2-methyl-4-nonylphenyl)-1 H-pyrrole-2-carboxylic acid

-(2-Ethyl-4-heptylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

-(2-Ethyl-4-nonylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

-Fluoro-4-(2-isopropyl-4-nonylphenyl)-1 H-pyrrole-2-carboxylic acid-Fluoro-4-(2-methyl-5-nonylphenyl)-1 H-pyrrole-2-carboxylic acid

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

-(3-Decyl-2-methylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

-(2-Ethyl-3-nonylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

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

-(2-Chloro-3-nonylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

-Fluoro-4-(2-fluoro-4-nonylphenyl)-1 H-pyrrole-2-carboxylic acid

-Fluoro-4-(2-fluoro-5-nonylphenyl)-1 H-pyrrole-2-carboxylic acid

-(2-Chloro-4-heptylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

-(2-Chloro-4-nonylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

-(2-Chloro-5-nonylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

-Fluoro-4-(2-methoxy-4-nonylphenyl)-1 H-pyrrole-2-carboxylic acid-Fluoro-4-(4-nonyl-2-(trifluoromethyl)phenyl)-1 H-pyrrole-2-carboxylic acid-fluoro-4-(6-nonylpyridin-3-yl)-1 H-pyrrole-2-carboxylic acid

-Fluoro-4-(5-nonylpyridin-2-yl)-1 H-pyrrole-2-carboxylic acid

-(1-Decyl-1 H-pyrazol-4-yl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

-Fluoro-5-(4-nonylphenyl)-1 H-pyrrole-2-carboxylic acid "3-Fluoro-5-(4-(octyloxy)phenyl)-1 H-pyrrole-2-carboxylic acid

3-Fluoro-5-(3-nonylphenyl)-1 H-pyrrole-2-carboxylic acid

3-Fluoro-5-(2-methyl-5-nonylphenyl)-1 H-pyrrole-2-carboxylic acid

5-(2-Ethyl-4-nonylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

3-Fluoro-5-(2-methyl-3-nonylphenyl)-1 H-pyrrole-2-carboxylic acid

3-Fluoro-5-(2-isopropyl-3-nonylphenyl)-1 H-pyrrole-2-carboxylic acid

3-Fluoro-5-(2-fluoro-3-nonylphenyl)-1 H-pyrrole-2-carboxylic acid

3-Fluoro-5-(2-fluoro-4-nonylphenyl)-1 H-pyrrole-2-carboxylic acid

3-Fluoro-5-(2-fluoro-5-nonylphenyl)-1 H-pyrrole-2-carboxylic acid

5-(2-Chloro-4-nonylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

5-(2-Chloro-5-nonylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

3-Fluoro-5-(2-methoxy-4-nonylphenyl)-1 H-pyrrole-2-carboxylic acid

5-(1-Decyl-1 H-pyrazol-4-yl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

5-(1-Decyl-3,5-dimethyl-1 H-pyrazol-4-yl)-3-fluoro-1 H-pyrrole-2-carboxylic acid 3-fluoro-4-(4-pentylcyclohex-1-en-1-yl)-1 H-pyrrole-2-carboxylic acid

3-Fluoro-4-(4-pentylcyclohexyl)-1 H-pyrrole-2-carboxylic acid (mixture of regioisomers) 3-Fluoro-4-(4-pentylcyclohexyl)-1 H-pyrrole-2-carboxylic acid (1 isomer)

3-Fluoro-4-((1 r,4s)-4-octylcyclohexyl)-1 H-pyrrole-2-carboxylic acid

3-Fluoro-4-((1 s,4r)-4-octylcyclohexyl)-1 H-pyrrole-2-carboxylic acid

3-Fluoro-5-(4-pentylcyclohex-1-en-1-yl)-1 H-pyrrole-2-carboxylic acid

3-Fluoro-5-(4-pentylcyclohexyl)-1 H-pyrrole-2-carboxylic acid (mixture of regioisomers)

3-Fluoro-5-(4-pentylcyclohexyl)-1 H-pyrrole-2-carboxylic acid (one regioisomer) 5-((1s,4r)-4-Decylcyclohexyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

5-((1r,4s)-4-Decylcyclohexyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

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

2,2,2-Trifluoroethyl 3-fluoro-5-(tetradec-1-yn-1-yl)-1 H-pyrrole-2-carboxylate 2-(2-Ethoxyethoxy)ethyl 3-fluoro-5-(tetradec-1-yn-1-yl)-1 H-pyrrole-2-carboxylate

4-Oxo-3,5,8,11-tetraoxatridecan-2-yl 3-fluoro-5-(tetradec-1-yn-1-yl)-1 H-pyrrole-2-carboxylate 2,2,2-T rifluoroethyl 3-fluoro-4-(4-nonylphenyl)-1 H-pyrrole-2-carboxylate

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

1-(((2-Methoxyethoxy)carbonyl)oxy)ethyl 3-fluoro-4-(4-nonylphenyl)-1 H-pyrrole-2-carboxylate 4-Oxo-3,5,8,11-tetraoxatridecan-2-yl 3-fluoro-4-(4-nonylphenyl)-1 H-pyrrole-2-carboxylate 4-(2,3-Difluoro-4-heptylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

4-(2,5-Difluoro-4-heptylphenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid 4-(2,3-Difluoro-4-(hexyloxy)phenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid 4-(2,5-Difluoro-4-(hexyloxy)phenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

3-fluoro-4-(4-((6-hydroxyhexyl)oxy)phenyl)-1 H-pyrrole-2-carboxylic acid

4-(4-((6-Ethoxyhexyl)oxy)phenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid 4-(4-(3-Ethoxypropoxy)phenyl)-3-fluoro-1 H-pyrrole-2-carboxylic acid

3-Fluoro-4-(4-hydroxy-4-octylcyclohex-1-en-1-yl)-1 H-pyrrole-2-carboxylic acid 3-Fluoro-4-(4-hydroxy-4-octylcyclohexyl)-1 H-pyrrole-2-carboxylic acid

16. A pyrrole derivative as defined in any one of claims 1 to 15, for use in the treatment of the human or animal body by therapy.

17. A pyrrole derivative as defined in any one of claims 1 to 15, for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibition of Acetyl-CoA carboxylase.

18. A pyrrole derivative according to any one of claims 1 to 15, for use according to claim 17 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.

19. A pyrrole derivative according to any one of claims 1 to 15, for use according to claims 17 and 18 wherein the pathological condition or disease is selected from acne vulgaris, acne conglobate, inflammatory acne, chroacne, plaque psoriasis, guttate psoriasis, inverse psoriasis, erythodermic psoriasis, scalp psoriasis, nail psoriasis and postular psoriasis.

20. A pharmaceutical composition comprising a pyrrole derivative as defined in any one of claims 1 to 15 in association with a pharmaceutically acceptable diluent or carrier.

21. Use of a pyrrole derivative as defined in any one of claims 1 to 15, for the manufacture of a medicament for the treatment of a pathological condition or disease as defined in claims 17 to 19.

22. A method for treating a subject afflicted with a pathological condition or disease as defined in claims 17 to 19, which comprises administering to said subject a therapeutically effective amount of a pyrrole derivative as defined in any one of claims 1 to 15, or a pharmaceutical composition as defined in claim 20.

23. A combination product comprising (i) at least one pyrrole derivative as defined in any one of claims 1 to 15, 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; 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;

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;

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;

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.