WO2020245297A1 - Dérivés de pyrrole utilisés en tant qu'inhibiteurs d'acc - Google Patents

Dérivés de pyrrole utilisés en tant qu'inhibiteurs d'acc Download PDF

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WO2020245297A1
WO2020245297A1 PCT/EP2020/065526 EP2020065526W WO2020245297A1 WO 2020245297 A1 WO2020245297 A1 WO 2020245297A1 EP 2020065526 W EP2020065526 W EP 2020065526W WO 2020245297 A1 WO2020245297 A1 WO 2020245297A1
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pyrrole
fluoro
group
carboxylic acid
nonylphenyl
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PCT/EP2020/065526
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English (en)
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Jordi Bach Taña
Cristina Esteve Trias
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Almirall, S.A.
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Publication of WO2020245297A1 publication Critical patent/WO2020245297A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • 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.
  • Acetyl-CoA carboxylase 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.
  • ACC activity is produced by two isoenzymes, namely ACC1 (also known as ACCa) and ACC2 (also known as A ⁇ b) 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).
  • CPT-I carnitine palmitolyltransferase I
  • 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).
  • AMPK AMP-activated protein kinase
  • PKA cAMP-dependent protein kinase
  • 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).
  • 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).
  • 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).
  • 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.
  • Sebum is formed mainly from lipids such as triglycerides (TAG), free fatty acids, wax esters, squalene, cholesterol and cholesterol esters.
  • TAG triglycerides
  • Human sebum is formed mainly from lipids derived from fatty acids such as TAGs and wax esters (Pappas A.
  • 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.
  • ACC inhibitors are useful to reduce sebum production and block IL-17 expression.
  • 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.
  • 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.
  • 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:
  • R 1 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-(CH 2 ) 3-6 -0R e group,
  • R 2 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,
  • R 3 represents a hydrogen atom or a linear or branched C 1-4 alkyl group
  • R 4 is selected from the group consisting of a hydrogen atom, a linear or branched C1-2 haloalkyl group, a -[(CH 2 ) 2 0)]i- 2 -R a and a -(CR b R c )-0C(0)0-R 5 group,
  • R 5 is selected from the group consisting of a linear or branched C1-4 alkyl group and a - [(CH 2 )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
  • 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
  • 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.
  • ACC Acetyl-CoA carboxylase
  • 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
  • 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.
  • ACC Acetyl-CoA carboxylase
  • 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
  • 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.
  • ACC Acetyl-CoA carboxylase
  • 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 ps thereof; preferably
  • 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.
  • 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.
  • C1-6 alkyl embraces linear or branched radicals having 1 to 6 carbon atoms.
  • C1-4 alkyl embraces unsubstituted linear or branched radicals having 1 to 4 carbon atoms.
  • C1 -6 alkyl examples 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.
  • Ce-14 alcoxy (or alkyloxy) embraces linear or branched oxy-containing radicals each having alkyl portions of 6 to 14 carbon atoms.
  • C6-i4 alkoxy radicals include hexyloxy, heptyloxyl, octyloxyl, nonyloxyl, decyloxyl, undecyloxyl, dodecyloxyl, tridecyloxyl, 4-methyldodecyloxyl, 5,6-dimethylundecyloxyl and tetradecyloxyl.
  • 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.
  • 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.
  • C 3-7 cycloalkyl embraces saturated monocyclic carbocyclic radicals having from 3 to 7 carbon atoms.
  • monocyclic cycloalkyl groups include cyclopropyl, cycobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • 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.
  • substituents on a cycloalkenyl group are themselves unsubtituted. Examples include, cyclopentenyl, cyclohexenyl or cycloheptenyl.
  • 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.
  • 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 CCI 3 , CF 3 , CHF 2 , CH 2 CF 3 and CH 2 CHF 2 .
  • halogen atom embraces fluorine, chlorine, bromine and iodine.
  • a halogen atom is typically a fluorine, chlorine or bromine atom.
  • halo when used as a prefix has the same meaning.
  • some of the atoms, radicals, moieties, chains and cycles present in the general structures of the invention are “unsubstituted or substituted”.
  • 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.
  • enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate using, for example, chiral high pressure liquid chromatography (HPLC).
  • HPLC high pressure liquid chromatography
  • 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.
  • 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 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).
  • terapéuticaally effective amount refers to an amount sufficient to effect treatment when administered to a patient in need of treatment.
  • treatment refers to the treatment of a disease or medical condition in a human patient which includes:
  • 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.
  • disease states include, but are not limited to, dermatological diseases, inflammatory or autoimmune-mediated diseases and a metabolism/endocrine function disorders.
  • 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.
  • a N-oxide is formed from the tertiary basic amines or imines present in the molecule, using a convenient oxidising agent.
  • 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.
  • hydrate is employed when said solvent is water.
  • 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.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI , fluorine, such as 18 F, iodine, such as 123 l and 125 l, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 0 and 18 0, phosphorus, such as 32 P, and sulfur, such as 35 S.
  • Preferred isotopically-labelled compounds include deuterated derivatives of the compounds of the invention.
  • deuterated derivative embraces compounds of the invention where in a particular position at least one hydrogen atom is replaced by deuterium.
  • Deuterium (D or 2 H) 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.
  • 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.
  • tautomerism 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.
  • 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).
  • 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).
  • 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.
  • the compound of Formula (I) is a compound of Formula (la) or a compound of Formula (lb):
  • the compound of Formula (I) is a compound of Formula (la).
  • the compound of Formula (I) is a compound of Formula (lb).
  • R 1 represents a linear or branched Cg- M group and a linear or branched Cs-9 alcoxy group.
  • R 1 represents a linear or branched C9-12 alkyl group.
  • R 2 is selected from the group consisting of a hydrogen atom and a fluorine atom.
  • R 2 represents a fluorine atom.
  • R 3 is selected from the group consisting of a hydrogen atom and a C1-4 linear or branched alkyl group.
  • R 3 may be selected from the group consisting of a hydrogen atom and a methyl group
  • R 3 represents a hydrogen atom.
  • 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.
  • 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.
  • 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.
  • R 4 represents a hydrogen atom, a C2 fluoroalkyl group, a -[(Chb ⁇ Ok-ChhCF group and a -(CH(CH 3 ))-0C(0)0-R 5 group.
  • R 4 is a hydrogen atom.
  • R a , R b , R c and R d each independently represent a hydrogen atom, a methyl group or an ethyl group.
  • R a , R b and R d each independently represent a methyl group or an ethyl group.
  • R c represents a hydrogen atom.
  • R 1 is selected from the group consisting of a pentyl group, a heptyl group, an octyl
  • R 2 represents a hydrogen atom, a fluorine atom or a chlorine atom
  • R 3 represents a hydrogen atom or a methyl group
  • R 4 is selected from the group consisting of a hydrogen atom, a CH2CF3 group, a - [(CH 2 )20]2-CH 2 CH3 group, a -CH(CH 3 )0C(0)0CH(CH 3 )2 group, a - CH(CH3)0C(0)0CH 2 CH 2 0CH3 group and a -CH(CH 3 )0C(0)0[(CH2)20]2CH 2 CH3 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.
  • R 1 is selected from the group consisting of a pentyl group, a heptyl group, an octyl
  • a nonyl 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-(CH 2 ) 6 -0H group, a -0-(CH 2 ) 6 -0CH 2 CH 3 group and a -0-(CH 2 ) 3 -0CH 2 CH 3 group,
  • R 2 represents a hydrogen atom, a fluorine atom or a chlorine atom
  • R 3 represents a hydrogen atom
  • R 4 is selected from the group consisting of a hydrogen atom, a CH2CF3 group, a - [(CH 2 )20]2-CH 2 CH3 group, a -CH(CH 3 )0C(0)0CH(CH 3 )2 group, a - CH(CH3)0C(0)0CH 2 CH 2 0CH3 group and a -CH(CH 3 )0C(0)0[(CH2)20]2CH 2 CH3 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.
  • R 1 represents a linear or branched Cg alkyl group
  • R 2 represents a fluorine atom
  • R 3 and R 4 represent a hydrogen atom.
  • the compound of Formula (I) is represented by Formula (la)
  • R 1 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,
  • R 2 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,
  • R 3 represents a hydrogen atom
  • R 4 represents a hydrogen atom, a C 2 fluoroalkyl group, a -[(CFb ⁇ Ok-CFbCF group or a -(CH(CH 3 ))-0C(0)0-R 5 group; preferably R 4 represents a hydrogen atom,
  • R a , R b and R d each independently represent a methyl group or an ethyl group
  • R c represents a hydrogen atom
  • R 1 represents a linear or branched C 9-12 alkyl group
  • R 2 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
  • R 3 and R 4 represent a hydrogen atom.
  • the compound of Formula (I) is represented by Formula (lb),
  • R 1 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,
  • R 2 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,
  • R 3 represents a hydrogen atom
  • R 4 represents a hydrogen atom, a C 2 fluoroalkyl group, a -[(Chh ⁇ Ok-ChhCF group or a -(CH(CH 3 ))-0C(0)0-R 5 group; preferably R 4 represents a hydrogen atom,
  • R a , R b and R d each independently represent a methyl group or an ethyl group
  • R c represents a hydrogen atom
  • R 1 represents a linear or branched Cg alkyl group
  • R 2 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
  • R 3 and R 4 represents a hydrogen atom.
  • R 1 represents a linear or branched Cg alkyl group
  • R 2 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
  • R 3 and R 4 represents a hydrogen atom.
  • the R 1 group attached to the L group can be present at the ortho, meta or para positions.
  • the L group is a phenyl group or a 6-membered heteroaryl, it is preferred that the R 1 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;
  • 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.
  • 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.
  • Compounds of formula (I”), a subset of general formula (I), wherein R 4 is other than a hydrogen atom may be obtained from compounds of formula (G), a subset of general formula (I), wherein R 4 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.
  • a base such as 4-dimethylaminopyridine or triethylamine
  • a coupling reagent such as 3- ((ethylimino)methyleneamino)-/ ⁇ /,/ ⁇ /-dimethylpropan-1-aminium chloride
  • 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”).
  • 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
  • intermediate acid chlorides which may be treated with alcohols of formula (VI) without the presence
  • 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 R 5 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 R 3 is a hydrogen atom.
  • a suitable base such as lithium hydroxide, sodium hydroxide or potassium hydroxide
  • a solvent such as methanol, ethanol or tetrahydrofuran
  • Pyrroles of formula (IV), wherein R 3 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.
  • a suitable base such as sodium hydride in a solvent such as N,N- dimethylformamide
  • 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.
  • a base such as trimethylamine or 4-dimethylaminopyridine
  • Halogenated pyrroles of formula (IX) may be reacted with boronic acids (wherein R 8 is a hydrogen atom) or boronate esters (wherein R 8 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.
  • 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-diox
  • 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.
  • a suitable catalyst such as bis(triphenylphosphine) palladium(ll) dichloride
  • a base such as potassium acetate
  • 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.
  • a suitable base such as potassium carbonate
  • a solvent such as A/,/ ⁇ /-dimethylformamide
  • 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.
  • a suitable catalyst such as bis(triphenylphosphine) palladium(ll) dichloride
  • a base such as potassium acetate
  • compounds of formula (lie) and (lid), subsets of general formula (II), wherein L is a phenyl ring and R 1 is a -0-(CH 2 ) n -OH group and a -0-(CH 2 ) n -0-R 11 group respectively, may be prepared by the following synthetic route as illustrated in Scheme 6:
  • 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.
  • a suitable palladium catalyst such as [1 , T-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride dichloromethane complex
  • a solvent such as 1 ,4-dioxane
  • a base such as cesium carbonate
  • 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.
  • sodium alkoxides of formula (XXVII) such as sodium ethoxide
  • a solvent such as a mixture of ethanol and dichloromethane
  • 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).
  • a suitable catalyst such as platinum (IV) oxide or chloridotris(triphenylphosphane)rhodium(l)
  • a solvent such as ethanol or toluene
  • 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.
  • a suitable catalyst such as tetrakis(triphenylphosphine) palladium(O)
  • a solvent such as xylene at 150 °C under an argon atmosphere.
  • 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.
  • a suitable catalyst such as bis(triphenylphosphine)palladium(ll) dichloride
  • a base such as potassium acetate
  • 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.
  • 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.
  • a suitable base such as lithium bis(trimethylsilyl)amide
  • a solvent such as tetrahydrofuran at -78 °C
  • 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.
  • a suitable palladium catalyst such as bis(triphenylphosphine)palladium(ll) dichloride
  • a base such as potassium acetate
  • 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:
  • Ketones of formula (XLI) and (XLIV) 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.
  • 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.
  • 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.
  • 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%).
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.

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Abstract

L'invention concerne de nouveaux dérivés de pyrrole de formule (I), ainsi que des procédés pour leur préparation, des compositions pharmaceutiques les comprenant et leur utilisation thérapeutique en tant qu'inhibiteurs de l'acétyl-CoA carboxylase (ACC).
PCT/EP2020/065526 2019-06-06 2020-06-04 Dérivés de pyrrole utilisés en tant qu'inhibiteurs d'acc WO2020245297A1 (fr)

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