HK1206771B - Non-annulated thiophenylamides as inhibitors of fatty acid binding proteini(fabp) 4 and/or 5 - Google Patents

Description

acyclic thienylamides as inhibitors of Fatty Acid Binding Proteins (FABP)4 and/or 5

The present invention relates to organic compounds useful for therapy or prophylaxis in a mammal, and in particular to Fatty Acid Binding Protein (FABP)4 and/or 5 inhibitors, more particularly to dual FABP4/5 inhibitors useful for therapy or prophylaxis of, for example, type 2diabetes, atherosclerosis, chronic kidney disease, non-alcoholic steatohepatitis and cancer.

The present invention provides novel compounds of formula (I):

wherein

R¹And R²Independently selected from the group consisting of H, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, halocycloalkyl, halocycloalkylalkyl, substituted aryl, substituted arylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted aminocarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, and carboxyl, wherein the substitution isSubstituted arylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted heteroaryl and substituted heteroarylalkyl of (A) with R¹⁴、R¹⁵And R¹⁶And wherein the substituted aminocarbonyl group is substituted on the nitrogen atom with one or two substituents independently selected from: H. alkyl, cycloalkyl, haloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, hydroxyalkyl and alkoxyalkyl;

R³is substituted aryl, substituted arylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted heteroaryl or substituted heteroarylalkyl, wherein substituted aryl, substituted arylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted heteroaryl and substituted heteroarylalkyl are substituted with R¹⁷、R¹⁸And R¹⁹Substitution;

R⁴is H or alkyl;

R⁵and R⁶Independently selected from H, alkyl and cycloalkyl;

R⁷is H, alkyl or cycloalkyl;

a is NR⁸Or CR⁹R¹⁰；

E is NR¹¹Or CR¹²R¹³；

R⁸And R¹¹Independently selected from H, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, cycloalkylalkyl or halocycloalkylalkyl;

R⁹、R¹⁰、R¹²and R¹³Independently selected from H, halogen, alkyl, haloalkyl or cycloalkyl;

or R⁵And R¹²Together with the carbon atom to which they are attached form a substituted cycloalkyl, substituted cycloalkenyl, substituted aryl, substituted heterocycloalkyl, or substituted heteroaryl, wherein substituted cycloalkyl, substituted ringAlkenyl, substituted aryl, substituted heterocycloalkyl and substituted heteroaryl with R²⁰Is substituted and may be further substituted by R²¹And/or R²²Substituted in which R is⁵And R¹²When taken together with the carbon atom to which they are attached to form a substituted aryl or substituted heteroaryl, then R⁶And R¹³Is absent;

or R⁸And R¹²Together with the nitrogen and carbon atoms to which they are attached form a substituted heterocycloalkyl or substituted heteroaryl, wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with R²⁰Is substituted and may be further substituted by R²¹And/or R²²Substituted in which R is⁸And R¹²In the case where they together with the carbon atom to which they are attached form a substituted heteroaryl, then R¹³Is absent;

or R⁹And R¹¹Together with the nitrogen and carbon atoms to which they are attached form a substituted heterocycloalkyl or substituted heteroaryl, wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with R²⁰Is substituted and may be further substituted by R²¹And/or R²²Substituted in which R is⁹And R¹¹In the case where they together with the carbon atom to which they are attached form a substituted heteroaryl, then R¹⁰Is absent;

or R⁹And R¹²Together with the carbon atom to which they are attached form a substituted cycloalkyl, substituted cycloalkenyl, substituted aryl, substituted heterocycloalkyl, or substituted heteroaryl, wherein substituted cycloalkyl, substituted cycloalkenyl, substituted aryl, substituted heterocycloalkyl, and substituted heteroaryl are substituted with R²⁰Is substituted and may be further substituted by R²¹And/or R²²Substituted in which R is⁹And R¹²In the case where they together with the carbon atom to which they are attached form a substituted aryl or substituted heteroaryl, then R¹⁰And R¹³Is absent;

or R¹⁰And R¹³Together with the carbon atom to which they are attached form substitutedCycloalkyl, substituted cycloalkenyl, substituted aryl, substituted heterocycloalkyl, or substituted heteroaryl, wherein substituted cycloalkyl, substituted cycloalkenyl, substituted aryl, substituted heterocycloalkyl, and substituted heteroaryl are substituted with R²³Is substituted and may be further substituted by R²⁴And/or R²⁵Substituted in which R is¹⁰And R¹³In the case where they together with the carbon atom to which they are attached form a substituted aryl or substituted heteroaryl, then R⁹And R¹²Is absent;

or R¹⁰And R¹³Together with the carbon atom to which they are attached form a double bond;

R¹⁴、R¹⁵、R¹⁶、R¹⁷、R¹⁸、R¹⁹、R²⁰、R²¹、R²³、R²⁴and R²⁵Independently selected from H, hydroxy, oxo, halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, alkoxycarbonyl, carboxy and amino substituted on the nitrogen atom with one or two substituents independently selected from: H. alkyl, cycloalkyl, haloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, hydroxyalkyl and alkoxyalkyl;

n is zero or 1;

or a pharmaceutically acceptable salt thereof.

FABPs 4(aP2) and FABPs 5(mal1) are members of the fatty acid binding protein family. FABPs are 14-15KDa proteins that function as chaperones for fatty acids in aqueous intracellular environments and facilitate their movement between cell compartments. At least nine members of this family have been identified to date as having tissue-specific expression patterns. FABP4 is expressed primarily in fat and macrophages, but also in other cell types, whereas FABP5 is expressed in a wide range of tissues and organs. FABPs are responsible for the transfer of fatty acids to different cell compartments and are therefore involved in key cellular functions such as lipid storage in adipocytes, fatty acid oxidation in mitochondria, ER signaling, fatty acid-dependent gene expression, regulation of cytosolic enzyme activity, regulation of inflammatory responses and leukotriene synthesis. Plasma FABP4 was secreted by adipose tissue in mice and secretion was deregulated in obesity and blocking of plasma FABP4 in vivo by antibodies improved insulin sensitivity.

Several genetic evidences in humans support the role of FABP4 and FABP5 in metabolic diseases. Mutations in the FABP4 promoter (SNP T-87C) that resulted in a 50% reduction in gene expression were associated with reduced risk of cardiovascular disease (CVD) and type 2diabetes (T2D) and with reduced plasma Triglycerides (TG). Two mutations in FABP5 (one in the 5' UTR (rs454550) and one in the promoter (nSNP)) were associated with increased (OR 4.24) and decreased (OR 0.48) risk of T2D, respectively. In addition, FABP4 protein and mRNA levels in atherosclerotic plaque macrophages have been shown to be associated with plaque instability and CV death. Finally, a number of publications report correlations between FABP4 and FABP5 plasma levels and metabolic disease severity. Elevated FABP4 plasma levels are associated with atherogenic dyslipidemias (atherogenic), reduced endothelial function, increased intima-media (IM) thickness, metabolic syndrome, obesity, and insulin resistance IR. Elevated plasma levels of FABP5 are associated with metabolic syndrome.

Genetic and pharmacological studies in mice largely confirm human evidence. Loss of function in FABP4 and FABP5 has been shown to increase insulin sensitivity, reduce glucose and prevent atherosclerosis. FABP4 knockout mice on high fat diet showed metabolic improvement regulated by compensatory upregulation of FABP5 in fat. Mice deficient in FABP5 on a High Fat (HF) diet show weight loss and increased glucose and insulin tolerance. FABP4/FABP5 double knockout mice were strongly protected from hyperglycemia (hyperglycaemia), insulin resistance (insulin resistance) and hepatic steatosis (hepatic steatosis). In addition, in the context of ApoE deficiency, FABP4 and FABP5 deletions are highly protective against the development of atherosclerosis and increased longevity. A specific FABP4 inhibitor (BMS309403) showed reduced hepatic glucose production, increased glucose uptake in muscle and fat and reduced hepatic steatosis in clamp studies in ob/ob mice, but no change in body weight and energy expenditure. Furthermore, it showed a reduction in atherosclerotic plaque formation in ApoE KO mice. One dual FABP4/5 inhibitor compound 3 described in j.lipid res.2011, 52, 646 showed a reduction in plasma triglycerides and free fatty acids in mice under HF diet, but no improvement in insulin and glucose tolerance.

Objects of the present invention are compounds of formula (I) and the aforementioned salts and esters thereof and their use as therapeutically active substances, processes, intermediates, pharmaceutical compositions for the preparation of said compounds, medicaments containing said compounds, pharmaceutically acceptable salts or esters thereof, the following uses of said compounds, salts or esters: for the treatment or prophylaxis of diseases, in particular for the treatment or prophylaxis of type 2diabetes mellitus, metabolic syndrome, atherosclerosis, dyslipidemia, liver disease involving inflammation (liver disorders in inflammatory bowel syndrome), steatosis (steatosis) and/or fibrosis (fibrosis), such as non-alcoholic fatty liver disease (non-alcoholic liver disease), in particular non-alcoholic steatohepatitis, obesity, lipodystrophy (lipodystrophy), such as genetic and iatrogenic lipodystrophy (lipodystrophy), cancer, ocular diseases supported by endothelial cell proliferation and angiogenesis, such as macular degeneration and retinopathy, lung diseases, such as asthma (athma), bronchopulmonary dysplasia (bronchopulmonary fibrosis), chronic obstructive pulmonary disease (glomerulosclerosis), renal glomerulosclerosis (glomerulosclerosis), chronic obstructive pulmonary disease (glomerulosclerosis), diabetic nephropathy (diabetic nephropathy), lupus nephritis (lupus nephritis), polycystic kidney disease (polycystic kidney disease) and drug-or toxin-induced chronic tubulointerstitial nephritis (chronic tubulointerstitial nephritis), chronic inflammation (chronic inflammation) and autoimmune inflammatory disease (autoimmune inflammation diseases), preeclampsia (preeclampsia) and polycystic ovary syndrome (polycystic ovary syndrome), and the use of such compounds, salts or esters for the preparation of a medicament for the treatment or prevention of: type 2diabetes, metabolic syndrome, atherosclerosis, dyslipidemia, liver diseases involving inflammation, steatosis and/or fibrosis, such as non alcoholic fatty liver disease, in particular non alcoholic steatohepatitis, obesity, lipodystrophy, such as hereditary and iatrogenic lipodystrophy, cancer, eye diseases supported by endothelial cell proliferation and angiogenesis, such as macular degeneration and retinopathy, lung diseases, such as asthma, bronchopulmonary dysplasia and chronic obstructive pulmonary disease, sarcoidosis, chronic kidney diseases, such as vasculitis, focal segmental glomerulosclerosis, diabetic nephropathy, lupus nephritis, polycystic kidney disease and drug-or toxin-induced chronic tubulointerstitial nephritis, chronic inflammation and autoimmune inflammatory diseases, preeclampsia and polycystic ovary syndrome.

The compounds of the invention are FABP4 and/or 5 inhibitors, more particularly dual FABP4 and 5 inhibitors. Some particular compounds of formula (I) of the present invention are also selective FABP4 and/or 5 inhibitors over FABP3 and/or 1.

The term "alkoxy" denotes a group of formula-O-R ', wherein R' is an alkyl group. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and t-butoxy. Particular alkoxy groups include methoxy, ethoxy and isopropoxy. More particular alkoxy group is methoxy.

The term "alkoxyalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by an alkoxy group. Exemplary alkoxyalkyl groups include methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl, and ethoxypropyl. Particular alkoxyalkyl groups include methoxymethyl and methoxyethyl. A more particular alkoxyalkyl group is methoxyethyl.

The term "alkoxycarbonyl" denotes a group of formula-C (O) -R ', wherein R' is an alkoxy group. Examples of alkoxycarbonyl groups include groups wherein R' is methoxy, ethoxycarbonyl, n-propoxycarbonyl, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. Particular alkoxycarbonyl groups include those wherein R' is methoxy, ethoxy, isopropoxy, and tert-butoxy. In more particular alkoxycarbonyl groups, R' is methoxy or ethoxy.

The term "alkyl" denotes a monovalent straight or branched chain saturated hydrocarbon group of 1 to 12 carbon atoms, particularly 1 to 7 carbon atoms, more particularly 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. A particular alkyl group is methyl.

The term "alkylcycloalkyl" denotes a cycloalkyl group wherein at least one of the hydrogen atoms of the cycloalkyl group has been replaced by an alkyl group. Examples of alkylcycloalkyl groups include methyl-cyclopropyl, dimethyl-cyclopropyl, methyl-cyclobutyl, dimethyl-cyclobutyl, methyl-cyclopentyl, dimethyl-cyclopentyl, methyl-cyclohexyl and dimethyl-cyclohexyl. Particular alkylcycloalkyl groups include methyl-cyclopropyl and dimethyl-cyclopropyl.

The term "alkylcycloalkylalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group is replaced by an alkylcycloalkyl group. Examples of alkylcycloalkylalkyl groups include methyl-cyclopropylmethyl, dimethyl-cyclopropylmethyl, methyl-cyclopropylethyl, dimethyl-cyclopropylethyl, methyl-cyclobutylmethyl, dimethyl-cyclobutylmethyl, methyl-cyclobutylethyl, dimethyl-cyclobutylethyl, methyl-cyclopentylmethyl, dimethyl-cyclopentylmethyl, methyl-cyclopentylethyl, dimethyl-cyclopentylethyl, methyl-cyclohexylmethyl, dimethyl-cyclohexylmethyl, methyl-cyclohexylethyl, dimethyl-cyclohexylethyl, methyl-cycloheptylmethyl, dimethyl-cycloheptylmethyl, methyl-cycloheptylethyl, dimethyl-cycloheptylethyl, methyl-cyclooctylmethyl, dimethyl-cyclooctylmethyl, methyl-cyclobutylmethyl, methyl-cyclopropylethyl, methyl-cyclopentylethyl, methyl-cyclohexylmethyl, methyl-cycloheptylmethyl, methyl-cycloheptylethyl, methyl, methyl-cyclooctylethyl and dimethyl-cyclooctylethyl.

The term "amino" denotes-NH₂A group.

The term "aminocarbonyl" denotes a compound of formula-C (O) -NH₂A group of (1).

The term "aryl" denotes a monovalent aromatic carbocyclic mono-or bicyclic ring system comprising 6 to 10 carbon ring atoms. Examples of aryl moieties include phenyl and naphthyl. A particular aryl group is phenyl.

The term "arylalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by an aryl group. Examples of arylalkyl groups include phenylmethyl and phenylethyl.

The term "carbonyl" denotes a-C (O) -group.

The term "carboxy" denotes a-C (O) OH group.

The term "cycloalkenyl" denotes a monovalent unsaturated non-aromatic monocyclic or bicyclic hydrocarbon group of 3 to 8 ring carbon atoms. Particular cycloalkenyl groups are monocyclic. Examples of cycloalkenyl groups include cyclobutenyl, cyclopentenyl, and cyclohexenyl.

The term "cycloalkyl" denotes a monovalent saturated monocyclic or bicyclic hydrocarbon radical of 3 to 10 ring carbon atoms, in particular of 3 to 8 ring carbon atoms. Bicyclic means consisting of two saturated or partially saturated carbocyclic rings having two common carbon atoms. Particular cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [2.2.2] heptyl, bicyclo [2.2.2] octyl, substituted bicyclo [2.2.2] heptyl and substituted bicyclo [2.2.2] octyl.

At R¹、R²、R¹⁷、R¹⁸And R¹⁹In the case of (b), a specific example of the cycloalkyl group is cyclopropyl.

In the reaction of R⁹And R¹²In the case of cycloalkyl groups formed together with the carbon atom to which they are attached, the cycloalkyl groupParticular examples of (B) are cyclopentyl, cyclohexyl and bicyclo [2.2.2]And (4) octyl.

The term "cycloalkylalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group is replaced by a cycloalkyl group. Examples of cycloalkylalkyl groups include cyclopropylmethyl, cyclopropylethyl, cyclobutylpropyl and cyclopentylbutyl.

The term "haloalkoxy" denotes an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by the same or a different halogen atom. The term "perhaloalkoxy" denotes an alkoxy group wherein all of the hydrogen atoms of the alkoxy group have been replaced by the same or different halogen atoms. Examples of haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoromethylethoxy, trifluorodimethylethoxy and pentafluoroethoxy. Particular haloalkoxy groups are trifluoromethoxy, trifluoroethoxy and trifluoromethylethoxy.

The term "haloalkoxyalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a haloalkoxy group. Examples of haloalkoxyalkyl groups include fluoromethoxymethyl, difluoromethoxymethyl, trifluoromethoxy-methyl, fluoroethoxymethyl, difluoroethoxymethyl, trifluoroethoxymethyl, fluoromethoxyethyl, difluoromethoxyethyl, trifluoromethoxyethyl, fluoroethoxyethyl, difluoroethoxyethyl, trifluoroethoxyethyl, fluoromethoxypropyl, difluoromethoxypropyl, trifluoromethoxypropyl, fluoroethoxypropyl, difluoroethoxypropyl and trifluoroethoxypropyl groups. A particular haloalkoxyalkyl group is 2, 2-difluoroethoxyethyl.

The term "haloalkoxycarbonyl" denotes a group of formula-C (O) -R ', wherein R' is a haloalkoxy group. Examples of haloalkoxycarbonyl groups include groups of the formula-C (O) -R ', wherein R' is fluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoromethylethoxy, trifluorodimethylethoxy or pentafluoroethoxy.

The term "haloalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by the same or different halogen atom. The term "perhaloalkyl" denotes an alkyl group wherein all of the hydrogen atoms of the alkyl group have been replaced by the same or different halogen atoms. Examples of the haloalkyl group include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a trifluoroethyl group, a trifluoromethylethyl group and a pentafluoroethyl group. Particular haloalkyl groups are trifluoromethyl and trifluoroethyl.

The term "halocycloalkyl" denotes a cycloalkyl group wherein at least one of the hydrogen atoms of the cycloalkyl group has been replaced by the same or different halogen atom, in particular a fluorine atom. Examples of halocycloalkyl groups include fluorocyclopropyl, difluorocyclopropyl, fluorocyclobutyl and difluorocyclobutyl.

The term "halocycloalkylalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a halocycloalkyl. Examples of halocycloalkylalkyl groups include fluorocyclopropylmethyl, fluorocyclopropylethyl, difluorocyclopropylmethyl, difluorocyclopropylethyl, fluorocyclobutylmethyl, fluorocyclobutylethyl, difluorocyclobutylethyl, and difluorocyclobutylethyl.

The terms "halogen" and "halo" are used interchangeably herein and denote fluorine, chlorine, bromine or iodine. Particular halogens are chlorine and fluorine. More particularly halogen is fluorine.

The term "heteroaryl" denotes a mono-or bicyclic ring system of a monovalent aromatic heterocyclic ring comprising 1,2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being 5 to 12 ring atoms of carbon. Examples of heteroaryl moieties include pyrrolyl, furyl, thienyl, imidazolyl, and the like,Oxazolyl, thiazolyl, triazolyl,Oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azaRadical diazaBasic group, heteroAzolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolylAzolyl, benzisoylAzolyl, benzothiazolyl, benzisothiazolyl, benzoOxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl. A particular heteroaryl group isA diazolyl group,Oxazolyl, thiazolyl, thiadiazolyl, pyridyl, or pyrimidinyl. Other particular heteroaryl groups are [1,2,4]]-Oxadiazolyl, thiazolyl, and thiadiazolyl.

At R¹And R²In the case of (a), a particular heteroaryl group is thiadiazolyl.

At R³In the case of (A), particular heteroaryl groups are thiazolyl, [1,2,4]]Thiadiazolyl and [1,2,4]]-A diazolyl group.

The term "heteroarylalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a heteroaryl group.

The term "heterocycloalkyl" denotes a monovalent saturated or partially saturated mono-or bicyclic ring system comprising 1,2 or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being 4 to 9 ring atoms of carbon. Bicyclic means consisting of two rings having two ring atoms in common, i.e. the bridge separating the two rings is a single bond or a chain of one or two ring atoms. An example of a monocyclic saturated heterocycloalkyl is 4, 5-dihydro-Azolyl, oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, and the like,Oxazolidinyl, isoOxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-dioxo-thiomorpholin-4-yl, azanylRadical (azepanyl), diazaA diazepanyl group, a homopiperazinyl group, or an oxazanyl groupAnd (oxazepanyl). An example of a bicyclic saturated heterocycloalkyl is 8-aza-bicyclo [3.2.1]Octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo [3.2.1]Octyl, 9-aza-bicyclo [3.3.1]Nonyl, 3-oxa-9-aza-bicyclo [3.3.1]Nonyl, or 3-thia-9-aza-bicyclo [3.3.1]Nonyl radical. Examples of partially saturated heterocycloalkyl groups are dihydrofuranyl, imidazolinyl, dihydro-Oxazolyl, tetrahydro-pyridyl, or dihydropyranyl. Other particular examples of heterocycloalkyl groups are oxetanyl.

The term "heterocycloalkylalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a heterocycloalkyl group.

The term "hydroxy" denotes an-OH group.

The term "hydroxyalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a hydroxyl group. Examples of hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxymethylpropyl, and dihydroxypropyl. Particular examples are hydroxymethyl and hydroxyethyl.

The term "oxo" denotes an ═ O group.

The term "pharmaceutically acceptable salts" refers to those salts that retain the biological effectiveness and properties of the free base or free acid, which are not biologically or otherwise undesirable. Salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, particularly hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine and the like. In addition, these salts can be prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimide resins, and the like. Particular pharmaceutically acceptable salts of the compounds of formula (I) are the hydrochloride, mesylate and citrate salts. Particular pharmaceutically acceptable salts of the compounds of formula (I) are also the sodium and potassium salts.

By "pharmaceutically acceptable ester" is meant that the compound of formula (I) may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives such as methoxymethyl ester, methylthiomethyl ester, and pivaloyloxymethyl ester. In addition, any physiologically acceptable equivalent of the compound of formula (I), similar to the metabolically labile ester, which is capable of producing the parent compound of formula (I) in vivo is within the scope of the invention.

The term "protecting group" (PG) denotes a group that selectively blocks a reactive site in a polyfunctional compound such that a chemical reaction proceeds at another unprotected reactive site in the sense conventionally associated therewith in synthetic chemistry. The protecting group may be removed at the appropriate time. Exemplary protecting groups are amino-protecting groups, carboxy-protecting groups or hydroxy-protecting groups. Particular protecting groups are tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn). Other particular protecting groups are tert-butoxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc). A more specific protecting group is tert-butoxycarbonyl (Boc).

The compounds of formula (I) may contain multiple asymmetric centers and may exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.

According to the Cahn-Ingold-Prelog convention, asymmetric carbon atoms may be in either the "R" or "S" configuration.

Furthermore, an embodiment of the present invention is a compound according to formula (I) as described herein and pharmaceutically acceptable salts or esters thereof, in particular a compound according to formula (I) as described herein and pharmaceutically acceptable salts thereof, more in particular a compound according to formula (I) as described herein.

Another embodiment of the invention are compounds according to formula (I) as described herein, wherein R is¹And R²Independently selected from the group consisting of H, alkyl, haloalkyl, cycloalkyl, substituted heterocycloalkyl, substituted heteroaryl, substituted aminocarbonyl, and alkoxycarbonyl, wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with R¹⁴、R¹⁵And R¹⁶And wherein the substituted aminocarbonyl group is substituted on the nitrogen atom with one or two substituents independently selected from: H. alkyl, cycloalkyl, haloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, hydroxyalkyl and alkoxyalkyl.

A particular embodiment of the invention are compounds according to formula (I), as described herein, wherein R is¹And R²Independently selected from the group consisting of H, alkyl, haloalkyl, cycloalkyl, substituted heterocycloalkyl, substituted heteroaryl, substituted aminocarbonyl, and alkoxycarbonyl, wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with R¹⁴、R¹⁵And R¹⁶And wherein the substituted aminocarbonyl group is substituted on the nitrogen atom with two substituents independently selected from: an alkyl group.

A particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is¹Is H, alkyl, haloalkyl, cycloalkyl, substituted heterocycloalkyl, substituted heteroaryl, substituted aminocarbonyl and alkoxycarbonyl wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with R¹⁴、R¹⁵And R¹⁶And wherein the substituted aminocarbonyl group is substituted on the nitrogen atom with two substituents independently selected from: H. alkyl, cycloalkyl, haloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, hydroxyalkyl and alkoxyalkyl.

Another embodiment of the invention are compounds according to formula (I) as described herein, wherein R is¹Is an alkyl or cycloalkyl group.

Another embodiment of the invention are compounds according to formula (I) as described herein, wherein R is²Is H, alkyl, haloalkyl or cycloalkyl.

Another embodiment of the invention are compounds according to formula (I) as described herein, wherein R is²Is an alkyl or haloalkyl group.

Another particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is¹And R²Independently selected from H, alkyl or cycloalkyl.

The invention also relates to compounds according to formula (I) as described herein, wherein R is¹And R²Is an alkyl group.

Another particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is³Is substituted aryl or substituted heteroaryl, wherein substituted aryl and substituted heteroaryl are substituted by R¹⁷、R¹⁸And R¹⁹And (4) substitution.

A more particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is³Is by R¹⁷、R¹⁸And R¹⁹A substituted heteroaryl group.

Also an embodiment of the invention are compounds according to formula (I) as described herein, wherein R is³Is pyrrolidinyl, substituted [1,2,4]]-A diazolyl group,Azolyl, substituted thiazolyl, substituted [1,2,4]]Thiadiazol-5-yl, or pyrimidinyl, substituted therein [1,2,4]-Oxadiazolyl, substituted [1,2,4] carboxylic acids]Thiadiazol-5-yl and substituted thiazolyl substituted by R¹⁷And (4) substitution.

Also an embodiment of the invention are compounds according to formula (I) as described herein, wherein R is³Is pyrrolidinyl, substituted [1,2,4]]-A diazolyl group,Azolyl, substituted thiazolyl or pyrimidinyl, wherein substituted [1,2,4]-Oxadiazolyl and substituted thiazolyl substituted by R¹⁷And (4) substitution.

The invention also relates to compounds according to formula (I) as described herein, wherein R is³Is substituted [1,2,4]]-Oxadiazolyl or substituted [1,2,4]]Thiadiazol-5-yl, wherein substituted [1,2,4]-Oxadiazolyl and substituted [1,2,4] s]Thiadiazol-5-yl radical substituted by R¹⁷And (4) substitution.

Another embodiment of the invention are compounds according to formula (I) as described herein, wherein R is³Is by R¹⁷Substituted [1,2,4]]-A diazolyl group.

Another embodiment of the invention are compounds according to formula (I) as described herein, wherein R is⁴Is H.

A particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is⁷Is H.

Also an embodiment of the invention are compounds according to formula (I) as described herein, wherein A is CR⁹R¹⁰。

Another particular embodiment of the invention are compounds according to formula (I) as described herein, wherein E is CR¹²R¹³。

Another particular embodiment of the invention are compounds according to formula (I) as described herein, wherein at A is NR⁸In the case of (3), then E is CR¹²R¹³。

Another particular embodiment of the invention are compounds according to formula (I) as described herein, wherein in E is NR¹¹In the case of (1), then A is CR⁹R¹⁰。

The invention also relates to compounds according to formula (I) as described herein, wherein R is⁹And R¹²Together with the carbon atom to which they are attached form a substituted cycloalkyl, substituted cycloalkenyl, substituted aryl, substituted heterocycloalkyl, or substituted heteroaryl, wherein substituted cycloalkyl, substituted cycloalkenyl, substituted aryl, substituted heterocycloalkyl, and substituted heteroaryl are substituted with R²⁰Is substituted and may be further substituted by R²¹And/or R²²Substituted in which R is⁹And R¹²In the case where they together with the carbon atom to which they are attached form a substituted aryl or substituted heteroaryl, then R¹⁰And R¹³Is absent.

Another embodiment of the invention are compounds according to formula (I) as described herein, wherein R is⁹And R¹²Together with the carbon atom to which they are attached form R²⁰A substituted cycloalkyl group.

Another embodiment of the invention are compounds according to formula (I) as described herein, wherein R is⁹And R¹²Together with the carbon atom to which they are attached form cyclopentyl, cyclohexyl or bicyclo [2.2.2]And (4) octyl.

The invention also relates to compounds according to formula (I) as described herein, wherein R is⁹And R¹²Together with the carbon atom to which they are attached form a cyclopentyl or cyclohexyl group.

Also an embodiment of the invention are compounds according to formula (I) as described herein, wherein R is¹⁰And R¹³Together with the carbon atoms to which they are attached form a double bond.

Also an embodiment of the invention are compounds according to formula (I) as described herein, wherein R is¹⁴、R¹⁵、R¹⁶、R¹⁷、R¹⁸、R¹⁹、R²⁰、R²¹、R²³、R²⁴And R²⁵Independently selected from the group consisting of H, alkyl, haloalkyl, and cycloalkyl.

One embodiment of the present invention is a compound according to formula (I) as described herein, wherein R is¹⁴Is a cycloalkyl group.

A particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is¹⁷Is H, alkyl, haloalkyl or cycloalkyl.

Another particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is¹⁷Is an alkyl or cycloalkyl group.

Another particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is¹⁷Is a cycloalkyl group.

A more particular embodiment of the invention is as described hereinA compound according to formula (I) as described herein, wherein R¹⁸、R¹⁹、R²⁰、R²¹And R²³Is H.

Also a particular embodiment of the invention are compounds according to formula (I) as described herein, wherein n is zero or 1.

Another particular embodiment of the invention are compounds according to formula (I) as described herein, wherein

R¹And R²Independently selected from the group consisting of H, alkyl, haloalkyl, and cycloalkyl;

R³is by R¹⁷Substituted heteroaryl;

R⁴is H;

R⁷is H;

a is CR⁹R¹⁰；

E is CR¹²R¹³；

R⁹And R¹²Together with the carbon atom to which they are attached form R²⁰A substituted cycloalkyl group;

R¹⁰and R¹³Together with the carbon atom to which they are attached form a double bond;

R¹⁷is H, alkyl, haloalkyl or cycloalkyl;

R²⁰is H;

n is zero;

or a pharmaceutically acceptable salt thereof.

Particular examples of compounds of formula (I) as described herein are selected from:

2- (3-phenyl-thiophen-2-ylcarbamoyl) -cyclopent-1-enecarboxylic acid;

5- [ (3-carboxy-bicyclo [2.2.2] oct-2-ene-2-carbonyl) -amino ] -3-methyl-4- (4-methyl-thiazol-2-yl) -thiophene-2-carboxylic acid methyl ester;

2- [ 4-cyclopropyl-5-methyl-3- (3-methyl- [1,2,4]]Oxadiazol-5-yl) -thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

3- [ 4-cyclopropyl-5-methyl-3- (3-trifluoromethyl- [1,2,4]]Oxadiazol-5-yl) -thiophen-2-ylcarbamoyl]-bicyclo [2.2.2]Oct-2-ene-2-carboxylic acid;

2- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -4, 5-dimethyl-thiophen-2-ylcarbamoyl]-cyclohex-1-enecarboxylic acid;

2- [ 5-cyclopropyl-3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -4-methyl-thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

3- [ 5-cyclopropyl-3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -4-methyl-thiophen-2-ylcarbamoyl]-bicyclo [2.2.2]Oct-2-ene-2-carboxylic acid;

2- [ 4-cyclopropyl-5-methyl-3- (3-methyl- [1,2,4]]Oxadiazol-5-yl) -thiophen-2-ylcarbamoyl]-cyclohex-1-enecarboxylic acid;

3- [ 4-cyclopropyl-5-methyl-3- (3-methyl- [1,2,4]]Oxadiazol-5-yl) -thiophen-2-ylcarbamoyl]-bicyclo [2.2.2]Oct-2-ene-2-carboxylic acid;

2- [ 4-cyclopropyl-3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -5-methyl-thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

3- [ 4-cyclopropyl-3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -5-methyl-thiophen-2-ylcarbamoyl]-bicyclo [2.2.2]Oct-2-ene-2-carboxylic acid;

3- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -4, 5-dimethyl-thiophen-2-ylcarbamoyl]-bicyclo [2.2.2]Oct-2-ene-2-carboxylic acid;

2- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -4, 5-dimethyl-thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

2- [ 4-cyclopropyl-5-methyl-3- (3-trifluoromethyl- [1,2,4]]Oxadiazol-5-yl) -thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

2- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -5-methyl-thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

2- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

2- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -4-methyl-5-oxetan-3-yl-thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

2- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -4-methyl-5-oxetan-3-yl-thiophen-2-ylcarbamoyl]-cyclohex-1-enecarboxylic acid;

2- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -5-methyl-4-trifluoromethyl-thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

5- [ (2-carboxy-cyclopent-1-enecarbonyl) -amino]-4- (3-cyclopropyl- [1,2, 4)]Oxadiazol-5-yl) -3-methyl-thiophene-2-carboxylic acid ethyl ester;

2- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -5-dimethylcarbamoyl-4-methyl-thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

2- [ 5-cyclopropyl-3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

2- [ 4-cyclopropyl-3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

2- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -4-methyl-thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

2- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -5- (2,2, 2-trifluoro-ethyl) -thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

2- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -4-trifluoromethyl-thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

2- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -5- (5-dimethylamino- [1,2,4]Thiadiazol-3-yl) -4-methyl-thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

and pharmaceutically acceptable salts thereof.

And particular examples of compounds of formula (I) as described herein are selected from:

3- [4, 5-dimethyl-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -thiophen-2-ylcarbamoyl ] -bicyclo [2.2.2] oct-2-ene-2-carboxylic acid;

2- [3- (3-cyclopropyl- [1,2,4] thiadiazol-5-yl) -4, 5-dimethyl-thiophen-2-ylcarbamoyl ] -cyclopent-1-enecarboxylic acid;

2- [3- (3-cyclopropyl- [1,2,4] thiadiazol-5-yl) -4, 5-dimethyl-thiophen-2-ylcarbamoyl ] -cyclohex-1-enecarboxylic acid;

3- [3- (3-cyclopropyl- [1,2,4] thiadiazol-5-yl) -4, 5-dimethyl-thiophen-2-ylcarbamoyl ] -bicyclo [2.2.2] oct-2-ene-2-carboxylic acid;

2- [ 5-cyclopropyl-4-methyl-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -thiophen-2-ylcarbamoyl ] -cyclopent-1-enecarboxylic acid;

2- [ 5-cyclopropyl-4-methyl-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -thiophen-2-ylcarbamoyl ] -cyclohex-1-enecarboxylic acid;

3- [ 5-cyclopropyl-4-methyl-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -thiophen-2-ylcarbamoyl ] -bicyclo [2.2.2] oct-2-ene-2-carboxylic acid;

2- [ 5-cyclopropyl-3- (3-cyclopropyl- [1,2,4] thiadiazol-5-yl) -4-methyl-thiophen-2-ylcarbamoyl ] -cyclopent-1-enecarboxylic acid;

2- [4, 5-dimethyl-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -thiophen-2-ylcarbamoyl ] -cyclopent-1-enecarboxylic acid;

3- [ 5-cyclopropyl-3- (3-cyclopropyl- [1,2,4] thiadiazol-5-yl) -4-methyl-thiophen-2-ylcarbamoyl ] -bicyclo [2.2.2] oct-2-ene-2-carboxylic acid;

(1SR,2SR) -2- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -4, 5-dimethyl-thiophen-2-ylcarbamoyl]-cyclohexanecarboxylic acid;

(1RS,2SR) -2- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -4, 5-dimethyl-thiophen-2-ylcarbamoyl]-cyclohexanecarboxylic acid;

2- [4, 5-dimethyl-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -thiophen-2-ylcarbamoyl ] -cyclohex-1-enecarboxylic acid;

2- [ 5-cyclopropyl-3- (3-cyclopropyl- [1,2,4] thiadiazol-5-yl) -4-methyl-thiophen-2-ylcarbamoyl ] -cyclohex-1-enecarboxylic acid;

5- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -4, 5-dimethyl-thiophen-2-ylcarbamoyl]-3, 6-dihydro-2H-pyran-4-carboxylic acid;

4- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -4, 5-dimethyl-thiophen-2-ylcarbamoyl]-5, 6-dihydro-2H-pyran-3-carboxylic acid;

(R) -1- [4, 5-dimethyl-3- (3-trifluoromethyl- [1,2, 4)]Oxadiazol-5-yl) -thiophen-2-ylcarbamoyl]-pyrrolidine-2-carboxylic acid;

and pharmaceutically acceptable salts thereof.

Other particular examples of compounds of formula (I) as described herein are selected from:

2- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -4, 5-dimethyl-thiophen-2-ylcarbamoyl]-cyclohex-1-enecarboxylic acid;

2- [ 5-cyclopropyl-3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -4-methyl-thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

2- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -5-methyl-4-trifluoromethyl-thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

2- [4, 5-dimethyl-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -thiophen-2-ylcarbamoyl ] -cyclohex-1-enecarboxylic acid;

and pharmaceutically acceptable salts thereof.

And further particular examples of compounds of formula (I) as described herein are selected from:

2- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -4, 5-dimethyl-thiophen-2-ylcarbamoyl]-cyclohex-1-enecarboxylic acid;

2- [ 5-cyclopropyl-3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -4-methyl-thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

2- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -5-methyl-4-trifluoromethyl-thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

and pharmaceutically acceptable salts thereof.

A process for the preparation of a compound of formula (I) as described herein is an object of the present invention.

The preparation of the compounds of formula (I) according to the invention can be carried out in a sequential or convergent synthetic route. The synthesis of the present invention is shown in the following general scheme. The skills required to effect the reaction and purification of the resulting product are known to those skilled in the art. Where a mixture of enantiomers or diastereomers is produced during the reaction, these enantiomers or diastereomers may be separated by methods described herein or known to those skilled in the art, such as, for example, chiral chromatography or crystallization. In the case where the starting material or one of the compounds of formula (I) contains one or more functional groups which are unstable or reactive under the reaction conditions of one or more reaction steps, suitable protecting groups may be introduced prior to the critical step using methods well known in the art. Such protecting groups can be removed at the later stages of the synthesis using standard methods described in the literature. The substituents and indices used in the following description of the process have the meanings given herein.

The following abbreviations are used herein:

AcCl-acetyl chloride, tert-BuOH-tert-butanol, CDI-N, N' -carbonyldiimidazole, CHCl₃Chloroform, CH₂Cl₂Methylene chloride, CH₃CN is acetonitrile, Cs₂CO₃Cesium carbonate and DBU 1, 8-diazabicyclo [5.4.0]Undec-7-ene, DCC ═ N, N '-dicyclohexylcarbodiimide, DIPEA ═ diisopropylethylamine (Huenig's base), DMAP ═ 4-dimethylaminopyridine, DMA ═ N, N-dimethylacetamide, DME ═ 1, 2-dimethoxyethane, DMF ═ N, N-dimethylformamide, DMSO ═ dimethyl sulfoxide, EDCI ═ 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, ESI ═ electrospray ionization, EtOAc ═ ethyl acetate, EtOH ═ ethanol, Et ═ Et₂Diethyl ether, h, HATU, O- (7-azabenzotriazol-1-yl) -N, N' -tetramethylureaHexafluorophosphate, HCl ═ hydrochloric acid, H₂Water, HOBt 1-hydroxy-1, 2, 3-benzotriazole, HPLC, and K₂CO₃Potassium carbonate, KF potassium fluoride, KHCO₃Potassium bicarbonate, LiHMDS lithium bis (trimethylsilyl) amide, LiOH lithium hydroxide, MeOH methanol, MgSO₄Magnesium sulfate, min. ═ min, MPLC ═ medium pressure liquid chromatography, MS ═ mass spectrometry, Mukaiyama reagent ═ 2-chloro-or 2-bromo-1-methylpyridineIodide, Na₂SO₄Sodium sulfate, NaClO₂Sodium chlorite; NaCN sodium cyanide, NaH sodium hydride, NaHCO₃Sodium bicarbonate, NaH₂PO₄Sodium dihydrogen phosphate, NaOEt sodium ethoxide, NaOH sodium hydroxide, NaOMe sodium methoxide, NEt₃Triethylamine, NH₄Cl ═ ammonium chloride, NH₄OAc ═ ammonium acetate, Pd (Ph)₃P)₄Tetrakis (triphenylphosphine) palladium (0), RT ═ room temperature, TBAF ═ tetrabutylammonium fluoride, TBTU ═ O-benzotriazol-1-yl-N, N' -tetramethylureaTetrafluoroborate, THF ═ tetrahydrofuran, TBME ═ tert-butyl methyl ether, TFA ═ trifluoroacetic acid, TLC ═ thin layer chromatography.

Compounds of the general formula below can be prepared, for example, as outlined in scheme 1: IA, wherein R⁴Is H, R⁷Is alkyl or cycloalkyl, A is CR⁹R¹⁰E is CR¹²R¹³And n is zero; IB, wherein R⁴Is alkyl, R⁷Is alkyl or cycloalkyl, A is CR⁹R¹⁰E is CR¹²R¹³And n is zero; IC, wherein R⁴And R⁷Is H, A is CR⁹R¹⁰E is CR¹²R¹³And n is zero; and ID, wherein R⁴Is alkyl, R⁷Is H, A is CR⁹R¹⁰E is CR¹²R¹³And n is zero.

Acylation of 2-aminothiophene II (either commercially available or prepared according to literature procedures or as described in schemes 4-6) with dicarboxylic acid monoester 1 (either commercially available or prepared according to literature procedures) affords compounds IA and IB, respectively (step a). Amide couplings of this type are widely described in the literature and can be prepared by using the coupling agent in suitable solvents such as DMF, DMA, CH₂Cl₂Or twoCoupling reagents in alkanes, such as, for example, CDI, DCC, HATU, HOBT, TBTU or Mukaiyama reagents, optionally in the presence of a base (e.g., NEt)₃DIPEA (Huenig's base) or DMAP). Alternatively, carboxylic acid 1 may be prepared by reaction with, for example, thionyl chloride (neat or optionally in a solvent such as CH₂Cl₂In (b) to convert to their acid chlorides. In a suitable solvent such as CH₂Cl₂Or DMF and a base such as NEt₃Huenig's base, pyridine, DMAP or lithium bis (trimethylsilyl) amide, at a temperature of from 0 ℃ to the reflux temperature of the solvent or solvent mixture, the acid chloride is reacted with 2-aminothiophene II to form compounds IA and IB, respectively (step a).

Compound IB can alternatively be prepared by treating with R, using a suitable base in a suitable solvent (e.g. sodium hydride in DMF) at a temperature of from 0 ℃ to the boiling temperature of the solvent⁴Compounds of type X alkylation Compound IA preparation wherein X is a suitable leaving group such as chloro, bromo, iodo, -OSO₂Alkyl (e.g. methanesulfonate (methylsulfonate), -OSO₂Fluoroalkyl groups (e.g. triflate (triflate) or-OSO)₂Aryl (e.g., tosylate (p-tosylate)) (step b).

In a suitable solvent (e.g. Et)₂O, THF 2Alkane, DMF or CH₃CN) is acylated with carboxylic anhydride 2 (commercially available or obtained by methods known in the art) to provide compounds IC and ID. The reaction may be carried out in a suitable base such as NEt₃In the presence of Huenig's base, DMAP, DBU or lithium bis (trimethylsilyl) amide (step c).

For the substituent R in the compounds of the formula IA⁷In those cases where the alkyl group is cleavable, compound IC may also be prepared from compound IA (step d). The ester functionality in IA is in basic conditions (e.g. methyl or ethyl ester with lithium or sodium hydroxide in polar solvents such as methanol, H₂O or THF or mixtures of said solvents) orCleavage under acidic conditions (e.g., tert-butyl ester, using concentrated hydrochloric acid, in tetrahydrofuran or formic acid, in a suitable solvent such as an alcohol, e.g., isopropanol) provides compound IC (step d). Other esters include, but are not limited to, allyl or benzyl esters, for example, which can be cleaved by methods known to those skilled in the art.

Compound IB can also be prepared by reacting compound R with a suitable base in a suitable solvent (e.g. sodium hydride in DMF) at a temperature of from 0 ℃ to the boiling temperature of the solvent⁷X alkylates acylation of Compound ID prepared from ID, where X is a suitable leaving group such as chloro, bromo, iodo, -OSO₂Alkyl (e.g. methanesulfonate (methylsulfonate), -OSO₂Fluoroalkyl groups (e.g. triflate (triflate) or-OSO)₂Aryl (e.g., tosylate (p-tosylate)) (step e).

The imide is cleaved by employing methods described in the literature (e.g., l.aurelio et al, j.med.chem.2010, 53(18), 6550-6559), e.g., by using suitable bases and solvents such as in THF or H₂NaOH and EtOH in O, compound IC can also be prepared from intermediate 3 (step g).

For the substituents R in the compounds of the formula IB⁷Those cases where the alkyl group is cleavable, compound ID can also be prepared from compound IB (step h) using the methods described previously.

By acylation with carboxylic anhydride 2 under the conditions described above, intermediate 3 can in turn be passed through where R⁴Is an acylation of the hydrogen of 2-aminothiophene II (step f).

An alternative synthesis of compounds IA-ID is shown in scheme 2. Those skilled in the art will recognize that the conversion is applicable only to groups and substituents, particularly by R⁷Those compounds of substituted ester functionality which are stable and not reactive under the reaction conditions employedA compound (I) is provided.

in the presence of a base such as morpholine in a suitable solvent such as EtOH, using α -cyanoester 4 (wherein R is^aIs a dissociable group such as, for example, a methyl, ethyl or tert-butyl group), an aldehyde (R)¹Or R²H) or Gewald reaction of ketone 5 with elemental sulphur affords thiophene intermediate 6 (step a).

The amine functionality is protected with a suitable protecting group such as acetyl and subsequent ester cleavage using methods known in the art and as described in the literature (e.g. y. huang et al, Chem biol. drug des.2010, 76, 116-129) to give the acid intermediate 7 (steps b, c).

Intermediate 7 may be decarboxylated to give intermediate 8 (step d) according to literature procedures (e.g. K.Gewald et al, Z.Chem.1967, 7(5), 186-187; H.Luetjens et al, J.Med.Chem.2003, 46(10), 1870-1877; S.Takada, J.Med.Chem.1988, 31(9), 1738-1745; WO2005/044008), for example using copper and quinoline at elevated temperatures.

The protecting group in 8 is removed to give 2-aminothiophene 9 (step e) using methods known to those skilled in the art and as described in the literature.

Acylation of intermediate 9 with dicarboxylic acid monoester 1 (commercially available or prepared according to literature procedures) using the conditions outlined in scheme 1 gives intermediate 10 (step f).

Iodination of intermediate 10 using literature procedures (e.g. WO2005/044008), for example using iodine in THF or iodine monochloride in acetic acid, yields intermediate 11 (step g).

11 with, for example, organoboron, -tin or-zinc reagents R³The cross-coupling reaction of M affords compound IA (step h). Reactions of this type are widely described in the literature (e.g.N.Miyaura (ed.), "Cross-coupling reactions: aprective guides", curr. Topics chem.219). For example, using a suitable catalyst (e.g., dichloro [1, 1-bis (diphenylphosphino) -ferrocene)]Palladium (II) CH₂Cl₂Adduct, tetrakis (triphenylphosphine) palladium (0) or palladium (II) acetate with triphenylphosphine)In a suitable solvent (e.g. diAlkane, DME, H₂O, toluene, DMF or mixtures thereof) and a suitable base (e.g., Na)₂CO₃、NaHCO₃KF, potassium carbonate or NEt₃) With (substituted) aryl-or heteroaryl-boronic acids R at temperatures from room temperature to the boiling temperature of the solvent or solvent mixture³-B(OH)₂Or boronic acid esters R³-B(OR’)₂(e.g., pinacol or propylene glycol esters, commercially available or available as described in, for example, "boric Acids-Preparation and Applications in Organic Synthesis and Medicine" edited by Dennis G.Hall, 1 st edition, 2005, John Wiley&Sons, prepared by the New York reference procedure) to produce compound IA (step h). Suzuki reactions of this type are widely described in the literature (e.g.A.Suzuki, N.Miyaura, chem.Rev.1979, 95, 2457-2483; A.Suzuki, J.Organomet.chem.1999, 576, 147-168; V.Polshettiwar et al, chem.Sus.chem.2010, 3, 502-522) and are well known to the person skilled in the art. Alternatively, a palladium catalyst such as tetrakis- (triphenylphosphine) palladium (0), palladium (II) acetate or dichloro [1, 1' -bis (diphenyl-phosphino) ferrocene is employed]Palladium (II) CH₂Cl₂Adducts in the presence of a suitable base such as cesium carbonate or potassium phosphate in a solvent such as toluene, THF, bisAlkane, H₂O or mixtures thereof, at a temperature from room temperature to the boiling temperature of the solvent or solvent mixture, an aryl-or heteroaryl-trifluoroborate R³BF₃K can be used for cross-coupling reactions.

Compound IA can also be synthesized by: in the presence of a suitable catalyst (for example tetrakis (triphenylphosphine) -palladium (0), benzylbis (triphenyl-phosphine) palladium (II) chloride, bis (triphenylphosphine) -palladium (II) dichloride or dichloro [1, 1' -bis (diphenylphosphino) ferrocene]Palladium (II) CH₂Cl₂Adducts) in a suitable solvent (e.g. THF, bis)Alkane, DMF or HMPA or mixtures thereof) with a (substituted) aryl-or heteroaryltin reagent R, optionally in the presence of lithium chloride, at a temperature from room temperature to the boiling temperature of the solvent or solvent mixture³-SnR₃(R-e.g., Me or n-Bu; commercially available or prepared according to literature procedures). This type of Stille coupling is widely described in the literature (e.g. j.k.stille, angle.chem.int.ed.engl.1986, 25, 508-524) and is well known to the person skilled in the art (step h).

Alternatively, compound IA can be synthesized from 11 with a (substituted) aryl-or heteroaryl zinc halide R using a nickel (e.g. tetrakis (triphenylphosphine) nickel (0)) or palladium catalyst (e.g. tetrakis (triphenylphosphine) palladium (0)) in a suitable solvent such as THF or DMA at a temperature ranging from room temperature to the boiling point of the solvent³-reaction of ZnX (X ═ Cl, Br or I) (commercially available or synthesized by methods described in the literature). Negishi couplings of this type are widely described in the literature (e.g., "Name reactions for Homologations-Part I: Negishi cross-linking reactions", Li, J.J., Corey, E.J., eds.; Wiley et al, Neugen et al, Neuglin et al, Negishi cross-linking reactions, Negishi cross-linking&Sons, Hoboken, NJ, 2009.70-99; organ, eur.j.org.chem.2010, 4343-4354) and are well known to those skilled in the art (step h).

Compound IA can then be further converted to compound IB-ID as described in scheme 1 (steps i, j, k).

Using the coupling conditions described above, the compounds IB can also be reacted via intermediates 12 with organoboron, -tin or-zinc reagents R³Crosslinking reaction preparation of M (step M).

Intermediate 12 can be prepared, for example, by using an alkylating agent R with a suitable base, such as sodium hydride, in a suitable solvent such as THF or DMF⁴X is prepared by alkylation of intermediate 11, wherein X represents a suitable leaving group such as chlorine, bromine, iodine, -OSO₂Alkyl (e.g. methanesulfonate (methylsulfonate), -OSO₂Fluoroalkyl radicals (e.g. trifluromethyl)Sulfonate (triflate) or-OSO₂Aryl (e.g., tosylate (p-tosylate)) (step 1).

An alternative synthesis from intermediate 9 to compound IC is shown in scheme 3.

In a suitable solvent (e.g. Et)₂O, THF 2Alkane, DMF or CH₃CN), acylation of 2-aminothiophene intermediate 9 (prepared as described in scheme 2) with carboxylic anhydride 2 (commercially available or a method described in the literature or obtainable by methods known in the art) provides intermediate 13. The reaction may be carried out in a suitable base such as NEt₃In the presence of Huenig's base, DMAP, DBU or lithium bis (trimethylsilyl) amide (step a).

Iodination of intermediate 13 to give intermediate 14 (step b) is carried out according to literature procedures (e.g. WO2005/044008), for example using iodine in THF or iodine monochloride in acetic acid.

Intermediate 14 is reacted with an organoboron, -tin, or-zinc reagent R using the coupling conditions described in scheme 2³The crosslinking reaction of M gives intermediate 3 (step c), which can be further converted to compound IC (step d) using the reaction conditions described in scheme 1.

For the construction of 2-aminothiophene IIa (where R is⁴) Is H, IIb (wherein R is⁴Is methyl) and IIc (wherein R is⁴Is alkyl or cycloalkyl) are shown in scheme 4.

The synthesis of substituted 2-aminothiophenes IIa is widely described in the literature. In particularis an alpha-methylenecarbonyl compound (cyclic or acyclic ketone or aldehyde), elemental sulfur, a base (e.g. NEt)₃morpholine) and α -activated nitriles (e.g. α -cyanoesters (resulting in compounds wherein R is³A compound which is an ester group), malononitrile (to give a compound in which R is³A compound which is cyano) or aryl-or heteroarylacetonitrile (resulting in a compound in which R is³Compounds that are aryl or heteroaryl)) are often used in the synthesis of poly-substituted 2-amino-thiophenes (e.g., k.gewald et al, angelw.chem.1961, 73(3), 114-114; k.gewald et al, chem.be.1965, 98, 3571-3577; gewald et al, Monatsh. chem.1988, 119, 985-992; R.W.Sabnis et al, J.het.chem.1999, 36, 333-345; zhang et al, Synthesis 2004, 18, 3055-3059; sridhar et al Tetrahedron lett, 2007, 48(18), 3171-3172; puerelov et al, Arkivoc2010(i), 209-246; wang et al, Synlett2010, 1351-1354; DE 2627935; WO 2005/044008; WO 2009/033581).

The Gewald reaction as described above uses commercially available and appropriately substituted acetonitrile 16, an aldehyde (R)¹Or R²H) or ketones (where for the present invention R is¹And R²Together form no ring and R¹Or R²One representing an optionally mono-substituted methyl group) 5 and elemental sulphur, in the presence of a base such as morpholine, the above-mentioned Gewald reaction produces 2-aminothiophene IIa (step a).

In the case where the acetonitrile derivative 16 is not commercially available, they may be prepared from compound 15, where X is a suitable leaving group such as chloro, bromo, -OSO, by nucleophilic substitution with sodium or potassium cyanide in a suitable solvent such as DMSO or DMF at a temperature of from 0 ℃ to the boiling temperature of the solvent₂Alkyl (e.g. methanesulfonate (methylsulfonate), -OSO₂Fluoroalkyl groups (e.g. triflate (triflate) or-OSO)₂Aryl (e.g., tosylate (p-tosylate) (step f) reactions of this type are known to those skilled in the art and are described in the literature (e.g., m. katkevics, Synlett 2011, 17, 2525-2528; r. gomez et al, bioorg. med. chem. lett.2011, 21(24), 7344-7350; f. factory et alEur.j.org.chem.2011, 30, 6039-6055; US 2012/0015999). At R³Is in the 3-position (R)^b)1, 2, 4-substituted with substituents such as alkyl, cycloalkyl, chloroalkyl or optionally substituted arylIn the case of the diazole ring, the acetonitrile derivative 16 may be prepared from amidoxime (amidoxime)17 (either commercially available or prepared, for example, by reacting an alkyl, cycloalkyl, chloroalkyl or aryl nitrile with a hydroxylamine analogously to literature procedures such as WO 2005/082859; WO 2005/0076347; WO 2008/093960) and commercially available 1-cyanoacetyl-3, 5-dimethylpyrazole 18 (step g) according to literature procedures (e.g. i.o.zhuravel et al, Synthetic Commun.2008, 38(21), 3778-3784; a.v.borinov et al, j.comb.chem.2009, 11(6), 1023-1029).

Using a suitable base and a solvent such as potassium carbonate (optionally in the presence of potassium iodide) in CH₃In CN or CsCO₃Alkylation of 2-aminothiophene IIa with methyl iodide or dimethyl sulfate in DMF affords compound IIb, where R is⁴Is a methyl group (step b). Microwave irradiation may be used to accelerate the reaction. Alternatively, the ethoxymethyleneamino-thiophene intermediate obtained by reaction of IIa with triethyl orthoformate and subsequent reaction with a suitable reducing agent such as NaBH₄Compound IIa can be converted to compound IIb by reduction in a suitable solvent such as EtOH. Both types of reactions are described in the literature (e.g. WO 2008/154221; WO 2011/100838; i.c. gonzalez et al, bioorg.med.chem.lett.2004, 14(15), 4037-4043) and are known to the person skilled in the art (step b).

2-aminothiophenes IIb and IIc can be prepared from IIa, for example by methods known in the art and described in the literature, by first protecting the amine function in IIa with a suitable protecting group such as acetyl or tert-butoxycarbonyl (Boc) group to give intermediate 19 (step c).

Intermediate 19 is alkylated with alkylating agent R using a suitable base such as sodium hydride in a suitable solvent such as THF or DMF⁴Alkylation of X provides the intermediate 20,wherein X represents a suitable leaving group such as chloro, bromo, iodo, -OSO₂Alkyl (e.g. methanesulfonate (methylsulfonate), -OSO₂Fluoroalkyl groups (e.g. triflate (triflate) or-OSO)₂Aryl (e.g., tosylate (p-tosylate)) (step d).

Removal of the protecting group in intermediate 20 using methods known to those skilled in the art and as described in the literature affords 2-aminothiophene IIb and IIc, respectively. Reactions of this type have also been disclosed in the literature (e.g.WO 2005/044008; P.J.Scammels et al, org.Biomol.chem.2011, 9(13), 4886-4902) (step e).

According to scheme 5, 2-aminothiophenes IIa-IIc can also be alternatively prepared from intermediate 8.

Iodination of intermediate 8, for example using iodine in THF or iodine monochloride in acetic acid, as described in scheme 2, for example, according to literature procedures (e.g. WO2005/044008) yields intermediate 21 (step a).

Intermediate 21 is reacted with an organic carbon, -tin or-zinc reagent R using the coupling conditions described in scheme 2³The crosslinking reaction of M provides intermediate 19 (step b).

Removal of the protecting group in 19 using methods known to those skilled in the art yields 2-aminothiophene IIa (step c), which can be further converted to compound IIb (step d) according to the procedure described in scheme 4.

By reaction with an alkylating agent R using a suitable base such as sodium hydride in a suitable solvent such as THF or DMF⁴Intermediate 19 may be converted to intermediate 20 by reaction with X, wherein X represents a suitable leaving group such as chloro, bromo, iodo, -OSO₂Alkyl (e.g. methanesulfonate (methylsulfonate), -OSO₂Fluoroalkyl groups (e.g. triflate (triflate) or-OSO)₂Aryl (e.g. tosylate (p-tosylate)) (step e).

Removal of the protecting group in intermediate 20 using methods known to those skilled in the art and as described in the literature gives 2-aminothiophene IIb and IIc, respectively.

Wherein R is³2-aminothiophenes that are heterocycloalkyl or heteroaryl (which can be constructed from aryl carboxylic acid precursors) can also be prepared from thiophene carboxylic acid intermediates such as 7, which in turn can be synthesized, for example, by the methods described under scheme 2. The synthesis of heterocyclic ring systems from carboxylic acids is widely described in the literature and is well known to the person skilled in the art. Wherein R is³Is 3-substituted 1,2, 4-An example of a diazole ring is shown in scheme 6.

7 with substituted N' -hydroxycarboximidamide 22 (commercially available or e.g. in analogy to literature procedures such as WO 2005/082859; WO 2005/0076347; WO2008/093960 via R using standard coupling conditions using e.g. EDCI together with HOBT or HATU in a suitable solvent such as DMF²³CN type nitrile with hydroxylamine) (step a) and cyclizing the resulting intermediate 23 in THF using, for example, TBAF to yield intermediate 24 (step b).

The protecting group in intermediate 24 is cleaved using literature methods known to those skilled in the art to yield intermediate 25 (step c).

By reaction with an alkylating agent R in a suitable solvent such as THF or DMF using a suitable base such as sodium hydride⁴Alkylation of intermediate 24 by reaction with X to give intermediate 26 (step d), wherein X represents a suitable leaving group such as chloro, bromo, iodo, -OSO₂Alkyl (e.g. methanesulfonate (methylsulfonate), -OSO₂Fluoroalkyl groups (e.g. triflate (triflate) or-OSO)₂Aryl radicals (e.g. toluene sulfonic acid)Ester (p-toluenesulfonate)).

Intermediate 27 can be prepared from intermediate 26 by removing the protecting group using literature procedures (step f). Alternatively, intermediate 25 is alkylated using, for example, the method described under scheme 4 to give intermediate 27 (step e).

Compounds of formula I, wherein A is NR, can be prepared, for example, according to scheme 7⁸E is CR¹²R¹³And n is zero or 1. In particular, compounds of the following formulae: IE, wherein R⁴Is H and R⁷Is alkyl or cycloalkyl; IF, wherein R⁴And R⁷Is H; IG, wherein R⁴Is H, R⁷Is alkyl or cycloalkyl and R⁸Is H; IH. Wherein R is⁴Is alkyl, R⁷Is alkyl or cycloalkyl and R⁸Is H; IJ. Wherein R is⁴、R⁷And R⁸Is H; IK. Wherein R is⁴Is alkyl and R⁷And R⁸Is H; IL, wherein R⁴Is H or alkyl, R⁷Is alkyl or cycloalkyl and R⁸Is an alkyl group; and IM, wherein R⁴And R⁷Is H and R⁸Is an alkyl group.

2-aminothiophene IIa (where R is⁴Is H) can be converted to isocyanate functionality, for example, in a suitable solvent such as THF or CH₂Cl₂Optionally in a base such as pyridine or NEt₃Intermediate 28 is formed by reacting IIa with phosgene or a substitute therefor, for example trichloromethyl chloroformate ("diphosphofine") or bis (trichloromethyl) carbonate ("triphosgene"), in the presence of (step a). This type of transformation is well known in the art and is widely described in the literature (e.g., G.N.Anilkumar et al, bioorg.Med.chem.Lett.2011, 21(18), 5336-5341; DE 3529247; WO 2011/140527; WO 2011/123937).

In a suitable solvent such as toluene, DMF or CH₂Cl₂Optionally in a suitable base such as NEt₃or of isocyanates 28 with appropriately substituted α -or β -amino acids (R) in the presence of Huenig's bases⁷Is H) or an ester (R)⁷Is alkyl or cycloalkyl) 29(n is zero and 1, commercially available or synthesized by methods known in the art) to yield compounds IE and IF, respectively (step b). The addition of primary or secondary amines to isocyanates is described in the literature (e.g. w.j.mcclellan et al, bioorg.med.chem.lett.2011, 21(18), 5620-5624; j.regan et al, j.med.chem.2002, 45(14), 2994-3008; US 4314842; WO2006/067385) and is well known to the person skilled in the art.

Using the method described under scheme 1 for substituents R in compounds of formula IE⁷In those cases where the alkyl group is cleavable, compound IF may alternatively be synthesized from compound IE (step c).

In a suitable solvent such as toluene, DMF or CH₂Cl₂Optionally in a suitable base such as NEt₃Or Huenig's base, 2-aminothiophene II can be reacted with isocyanate 30 (either commercially available or synthesized by methods known in the art) to give compounds IG and IH, respectively (step d).

R in Compounds IG and IH⁷In the case of cleavable ester groups, it can be cleaved using procedures known in the art and as disclosed to yield compounds IJ and IK, respectively (step e).

Using a suitable base, in a suitable solvent (e.g. sodium hydride in DMF), at a temperature of from 0 ℃ to the boiling temperature of the solvent, by reaction with R⁸Compounds of type X, where X is a suitable leaving group such as chloro, bromo, iodo, -OSO, alkylate compound IH and compound IL may be synthesized (step f)₂Alkyl (e.g. methanesulfonate (methylsulfonate), -OSO₂Fluoroalkyl groups (e.g. triflate (triflate) or-OSO)₂Aryl (e.g., tosylate (p-tosylate)).

R in Compound IL⁷Is a cleavable ester groupIn the case of a bolus, it can be dissociated to yield compound IM (step g) using procedures known in the art and as described in the literature.

Compound IN, wherein A is CR⁸R⁹E is NR¹¹N is 1 and R⁷Is alkyl or cycloalkyl, and IO, wherein A is CR⁸R⁹E is NR¹¹N is 1 and R⁷Is H can be prepared, for example, as shown in scheme 8.

Compound IN can be synthesized using literature procedures and methods described under scheme 1, for example by acylation of 2-aminothiophene II with appropriately substituted (alkoxycarbonylmethyl-amino) -acetic acid or (cycloalkoxycarbonylmethyl-amino) -acetic acid derivatives 31 (commercially available or synthesized by methods known IN the art).

If R IN the compound IN is⁷Is a cleavable ester group, it can be cleaved to yield compound IO (step b) using procedures known to those skilled in the art and as described in the literature.

Furthermore, an embodiment of the present invention is a process for the preparation of a compound of formula (I) as defined above, said process comprising:

a) reaction of a compound of formula (II) in the presence of a compound of formula (V);

b) reaction of a compound of formula (II) in the presence of a compound of formula (VI);

c) reaction of a compound of formula (VII) in the presence of a compound of formula (VIII);

or

d) Reaction of a compound of formula (II) in the presence of a compound of formula (IX);

wherein R is¹、R²、R³、R⁴、R⁵、R⁶As defined above and wherein R⁷Is alkyl or cycloalkyl, and in step a) A is CR⁹R¹⁰In step b) A is CR⁹R¹⁰E is CR¹²R¹³And n is zero, in step c) R⁴Is H and A is NR⁸And in step d) R⁴Is H, A is NR⁸E is CR¹²R¹³And n is 1.

Furthermore, another preferred embodiment of the present invention is a process for the preparation of a compound of formula (I) as defined above, comprising the reaction of a compound of formula (II) in the presence of a compound of formula (VI).

Wherein R is¹、R²、R³、R⁴、R⁵、R⁶、R⁷And n is as defined above and wherein A is CR⁹R¹⁰And E is CR¹²R¹³. In particular, it is possible to use, for example,in a solvent, in particular CH₃CN, THF or Et₂In the presence of O, in the presence or absence of a base, in particular DMAP, DIPEA or DBU, at a temperature ranging from 0 ℃ to reflux, in particular from room temperature to the temperature comprised by reflux.

Furthermore, an object of the present invention is a compound according to formula (I) as described herein for use as therapeutically active substance.

Also an object of the present invention is a pharmaceutical composition comprising a compound according to formula (I) as described herein and a therapeutically inert carrier.

In accordance with the present invention, the compounds of formula (I) or their pharmaceutically acceptable salts and esters may be used in the treatment or prevention of type 2diabetes, metabolic syndrome, atherosclerosis, dyslipidemia, liver disease, obesity, lipodystrophy, cancer, eye disease, lung disease, sarcoidosis, chronic kidney disease, chronic inflammatory and autoimmune inflammatory diseases, preeclampsia and polycystic ovary syndrome.

Particular liver diseases are those involving inflammation, steatosis and/or fibrosis, such as non-alcoholic fatty liver disease, more particularly non-alcoholic steatohepatitis.

A particular lipodystrophy is genetic or treatment-induced lipodystrophy.

Particular eye diseases are those supported by endothelial cell proliferation and angiogenesis, in particular macular degeneration and retinopathy.

Particular lung diseases are asthma, bronchopulmonary dysplasia and chronic obstructive pulmonary disease.

Particular chronic kidney diseases are vasculitis, focal segmental glomerulosclerosis, diabetic nephropathy, lupus nephritis, polycystic kidney disease and drug-or toxin-induced chronic tubulointerstitial nephritis.

The invention also relates to the use of a compound of formula (I) as described herein for the treatment or prophylaxis of type 2diabetes, metabolic syndrome, atherosclerosis, dyslipidemia, liver disease, obesity, lipodystrophy, cancer, eye disease, lung disease, sarcoidosis, chronic kidney disease, chronic inflammatory and autoimmune inflammatory diseases, preeclampsia and polycystic ovary syndrome.

The present invention relates in particular to the use of compounds according to formula (I) as described herein for the treatment or prevention of type 2diabetes, atherosclerosis, cancer, chronic kidney disease and non-alcoholic steatohepatitis.

The invention also relates to the use of a compound according to formula (I) as described herein for the treatment or prevention of non-alcoholic steatohepatitis.

A particular embodiment of the invention is a compound according to formula (I) as described herein for use in the treatment or prevention of type 2diabetes, metabolic syndrome, atherosclerosis, dyslipidemia, liver disease, obesity, lipodystrophy, cancer, eye disease, lung disease, sarcoidosis, chronic kidney disease, chronic inflammation and autoimmune inflammatory disease, preeclampsia and polycystic ovary syndrome.

Another particular embodiment of the invention is a compound according to formula (I) as described herein for use in the treatment or prevention of type 2diabetes, atherosclerosis, cancer, chronic kidney disease and non-alcoholic steatohepatitis.

Furthermore, a particular embodiment of the present invention is a compound according to formula (I) as described herein for use in the treatment or prevention of non-alcoholic steatohepatitis.

The invention also relates to the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prophylaxis of type 2diabetes, metabolic syndrome, atherosclerosis, dyslipidemia, liver disease, obesity, lipodystrophy, cancer, eye disease, lung disease, sarcoidosis, chronic kidney disease, chronic inflammation and autoimmune inflammatory disease, preeclampsia and polycystic ovary syndrome.

The invention relates in particular to the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prevention of type 2diabetes, atherosclerosis, cancer, chronic kidney disease and non-alcoholic steatohepatitis.

Furthermore, an embodiment of the present invention is the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prevention of non-alcoholic steatohepatitis.

Furthermore, an object of the present invention is a method for the treatment or prevention of: type 2diabetes, metabolic syndrome, atherosclerosis, dyslipidemia, liver disease, obesity, lipodystrophy, cancer, eye disease, lung disease, sarcoidosis, chronic kidney disease, chronic inflammatory and autoimmune inflammatory diseases, preeclampsia and polycystic ovary syndrome, comprising administering an effective amount of a compound according to formula (I) as described herein.

Another object of the invention is a method for the treatment or prevention of: type 2diabetes, atherosclerosis, cancer, chronic kidney disease and non-alcoholic steatohepatitis, said method comprising administering an effective amount of a compound according to formula (I) as described herein.

Furthermore, one embodiment of the present invention is a method for the treatment or prevention of nonalcoholic steatohepatitis, said method comprising administering an effective amount of a compound according to formula (I) as described herein.

Furthermore, one embodiment of the present invention is a method for the treatment or prevention of lipodystrophy, said method comprising administering an effective amount of a compound according to formula (I) as described herein.

Moreover, a particular embodiment of the invention is a compound according to formula (I) as described herein, which is prepared according to any one of the methods.

Measurement procedure

In monitoring direct binding of Bodipy-labeled fatty acids to His 6-tagged FABP protein (huFABP4 was expressed internally in e.coli (e. coli) and purified, huFABP5 was purchased from Cayman Chemical co., cat.no.10010364) terbium (Tb) time-resolved fluorescence energy transfer (TR-FRET) assay (bound to terbium-labeled anti-His 6-tagged antibody), the activity of the compounds was plotted against human FABP4(huFABP4) and/or human FABP5(huFABP 5). After ligand binding to FABP protein, the assay reading reflects the energy transfer from the terbium donor molecule to the acceptor Bodipy moiety. The final ligand concentration (125nM) was close to the Kd of each protein.

Compound DMSO stock solution (1.8mM) with 100% DMSO to ten concentrations series dilution 3-fold (50 u M to 0.003M final compound concentration). Mu.l of these compound dilutions and 1. mu.l of Bodipy-labeled fatty acid 4.5. mu.M (Bodipy FL C11, cat. No. D3862, Invitrogen) in 100% DMSO were pipetted sequentially into the wells of 384-well black polypropylene plates (Thermo Matrix cat. No. 4344). Then FABP4 or FABP5 protein (28. mu.l of 64nM protein in 25mM Tris pH7.5, 0.4mg/ml γ -globulin, 1mM DTT, 0.012% NP40, final protein concentration: 50nM) was added. The assay blank contained ligand but no protein. The neutral control contained the ligand, but no compound. After addition of detection reagents (Tb anti-His 6 antibody, Columbia Biosciences, TB-110, 6. mu.l of 24nM Ab solution in 25mM Tris pH7.5, 0.4mg/ml γ -globulin, final Tb anti-His 6 Ab concentration: 4nM), the plates were spun at 1000rpm for one minute. After incubation at room temperature for 30 minutes with shaking, an Envision reader (Perkin Elmer, extinction wavelength: 340nm, emission: 490nm and 520nm, time delay: 100. mu.s; time window: 200. mu.s, 50 flashes) was used for reading.

The final assay conditions were: 50nM FABP protein, 125nM Bodipy-labeled fatty acid, 0.009% (v/v) NP40, 5.5% (v/v) DMSO, and a total final assay volume of 36. mu.l. Assays were performed in triplicate.

Relative Fluorescence Unit (RFU) ratio (520nm 10000/488nm) was used to calculate percent inhibition: 100- (RFU ratio compound-blank)/neutral control-blank) 100. Then theThese percent inhibition values were fitted to the dose response curve using a4 parameter logistic model (HillS dose response model). IC (integrated circuit)₅₀Reflecting the concentration of compound associated with 50% inhibition of protein activity compared to a neutral control.

Compounds of formula (I) and their pharmaceutically acceptable salts or esters as described herein have an IC of from 0.000001 μ M to 1000 μ M₅₀(FABP4 inhibition) values, particular compounds having an IC of 0.000005. mu.M to 500. mu.M₅₀Values, further particular compounds have an IC of 0.00005. mu.M to 5. mu.M₅₀The value is obtained.

Compounds of formula (I) and their pharmaceutically acceptable salts or esters as described herein have an IC of from 0.000001 μ M to 1000 μ M₅₀(FABP5 inhibition) values, particular compounds having an IC of 0.000005. mu.M to 500. mu.M₅₀Values, further particular compounds have an IC of from 0.00005. mu.M to 50. mu.M₅₀The value is obtained.

The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments (e.g. in the form of pharmaceutical preparations). Pharmaceutical preparations can be administered internally, such as orally (for example in the form of tablets, coated tablets, sugar-coatings, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (for example in the form of nasal sprays) or rectally (for example in the form of suppositories). However, administration can also be effected parenterally, for example intramuscularly or intravenously (for example in the form of injection solutions).

The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, sugar-coated and hard gelatin capsules. As such adjuvants for tablets, dragees and hard gelatine capsules, lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof and the like may be used, for example.

Suitable adjuvants for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid substances, liquid polyols and the like.

Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like.

Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols and the like.

In addition, the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may still contain other therapeutically valuable substances.

The dosage can vary within wide limits and will of course be adapted to the individual requirements in each particular case. In general, in the case of oral administration, the following daily doses will be appropriate: about 0.1mg to 20mg/kg body weight, preferably about 0.5mg to 4mg/kg body weight (e.g. about 300 mg/person), is divided into preferably 1-3 individual doses, which may for example consist of the same amount. However, it should be clear that the upper limit given herein may be exceeded when this display is to be pointed out.

In accordance with the present invention, the compounds of formula (I) or their pharmaceutically acceptable salts and esters may be used for the treatment or prevention of type 2diabetes related microvascular complications such as, but not limited to, diabetic retinopathy (diabetic retinopathy), diabetic neuropathy (diabetic neuropathy) and diabetic nephropathy (diabetic neuropathy), coronary artery disease (coronary artery disease), obesity and potentially inflammatory diseases (inflammatory diseases), chronic inflammatory and autoimmune/inflammatory diseases.

The invention is illustrated below by means of examples, which are not limitative.

In case the preparative examples are obtained as a mixture of enantiomers, the pure enantiomers can be separated by methods described herein or known to the person skilled in the art, such as e.g. chiral chromatography or crystallization.

Examples

All examples and intermediates were prepared under argon atmosphere if not otherwise stated.

Example 1

2- (3-phenyl-thiophen-2-ylcarbamoyl) -cyclopent-1-enecarboxylic acid

3-phenyl-thiophen-2-ylamine (73mg, 417. mu. mol, Int1.1), NEt₃(84.3mg, 116. mu.L, 833. mu. mol) and 1-cyclopentene-1, 2-dicarboxylic anhydride (144mg, 1.04mmol) were dissolved in dry THF (3 mL). The green-yellow suspension was stirred at room temperature over the weekend and filtered. The filtrate was concentrated in vacuo and the residue was purified by preparative HPLC (MeOH/H)₂O, with 0.1% formic acid) to give the title compound as a yellow oil (47mg, 32%, estimated 90% purity). MS (ESI): 312.2[ M-H ] M/z]^-。

Example 2

5- [ (3-carboxy-bicyclo [2.2.2]]Oct-2-ene-2-carbonyl) -amino]-3-methyl-4- (4-methyl-thiazole-2- Yl) -thiophene-2-carboxylic acid methyl ester

To methyl 5-amino-3-methyl-4- (4-methylthiazol-2-yl) thiophene-2-carboxylate (61mg, 227. mu. mol, Int1.2) in CH₃CN (7mL) was added DMAP (55.5mg, 455. mu. mol) and bicyclo [2.2.2]Oct-2-ene-2, 3-dicarboxylic anhydride (40.5mg, 227. mu. mol, CAS RN 151813-29-5). After stirring at room temperature for 3h, the reaction mixture was stirred at 65 ℃ overnight. The reaction mixture was extracted with EtOAc and 1M aqueous HCl, and the organic layer was Na₂SO₄Dried, filtered and evaporated. The compound was purified by silica gel chromatography and CH was used₂Cl₂MeOH (20: 1v/v) as eluent. A brown solid. MS (ESI): 447.1[ M + H ] M/z]⁺。

Example 3

2- [ 4-cyclopropyl-5-methyl-3- (3-methyl- [1,2,4]] Oxadiazol-5-yl) -thiophen-2-ylcarbamoyl Base of]-cyclopent-1-enecarboxylic acid

To 4-cyclopropyl-5-methyl-3- (3-methyl- [1,2, 4)]Oxadiazol-5-yl) -thiophen-2-ylamine (100mg, 425. mu. mol, Int1.3) in CH₃To a solution in CN (8mL) was added DBU (129mg, 127. mu.L, 850. mu. mol) and 1-cyclopentene-1, 2-dicarboxylic anhydride (64.6mg, 467. mu. mol, CAS RN3205-94-5), and the dark solution was stirred at 65 ℃ for 18 h. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC (Gemini NX column) with a gradient of MeOH: H₂O (containing 0.1% formic acid) (80: 20 to 98: 2). Yellow solid (69mg, 44%). MS (ESI): 374.117[ M/z ═ M+H]⁺。

The examples in Table 1 were prepared according to the method used in example 3, using the 2-aminothiophene and carboxylic anhydride reagents listed in Table 1.

TABLE 1

Example 4

2- [ 4-cyclopropyl-5-methyl-3- (3-methyl- [1,2,4]] Oxadiazol-5-yl) -thiophen-2-ylcarbamoyl Base of]-cyclohex-1-enecarboxylic acid

To 4-cyclopropyl-5-methyl-3- (3-methyl- [1,2, 4)]Oxadiazol-5-yl) -thiophen-2-ylamine (85mg, 361. mu. mol, Int1.3) in Et₂To a solution in O (3mL) was added 1-cyclohexene-1, 2-dicarboxylic anhydride (55.0mg, 361. mu. mol, CASRN 2426-02-0) and DMAP (2.21mg, 18.1. mu. mol). The reaction mixture was stirred at room temperature for 18h and then concentrated in vacuo. The residue was purified by preparative HPLC (Gemini NX column) with a gradient of MeOH: H₂O (containing 0.1% formic acid) (80: 20 to 98: 2). Pale yellow solid (17mg, 12.1%). MS (ESI): 388.133[ M + H ] M/z]⁺。

The examples in Table 2 were prepared according to the method used in example 4, using the 2-aminothiophene and carboxylic anhydride reagents listed in Table 2.

TABLE 2

Example 5

2- [ 4-cyclopropyl-5-methyl-3- (3-trifluoromethyl- [1,2,4]] Oxadiazol-5-yl) -thiophen-2-ylaminomethyl Acyl radical]-cyclopent-1-enecarboxylic acid

To 2- [ 4-cyclopropyl-5-methyl-3- (3-trifluoromethyl- [1,2, 4)]Oxadiazol-5-yl) -thiophen-2-ylcarbamoyl]Methyl-cyclopent-1-enecarboxylate (80mg, 181. mu. mol, intermediate 7) in bisTo a solution in alkane (3mL) was added H₂O (3mL) and LiOH monohydrate (9.51mg, 227. mu. mol) and the resulting clear solution was stirred at room temperature for 8 h. The reaction mixture was poured onto 100mL of 1M aqueous HCl and 100mL EtOAc and the layers were separated. The aqueous layer was extracted twice with 100mL EtOAc. The organic layer was washed with 100mL brine, MgSO₄Dried, filtered and concentrated under vacuum. The compound was chromatographed on a 20g column on silica gelPurification using MPLC (Flashmaster) system with a gradient of CH₂Cl₂MeOH (100: 0 to 80: 20). Yellow solid (57mg, 74%). MS (ESI): 428.088[ M + H ] M/z]⁺。

Example 6

2- [3- (3-cyclopropyl- [1,2,4]] Oxadiazol-5-yl) -5-methyl-thiophen-2-ylcarbamoyl]-cyclopentyl- 1-Enecarboxylic acid

To 3- (3-cyclopropyl- [1,2,4] at-78 DEG C]Oxadiazol-5-yl) -5-methyl-thiophen-2-ylamine (75mg, 339. mu. mol, Int1.8) to a solution in THF (2.5mL) was added LiHMDS ((678. mu.L, 678. mu. mol, 1M solution in THF) and the resulting reaction mixture was stirred at-78 ℃ for 30min. 1-cyclopentene-1, 2-dicarboxylic anhydride (46.8mg, 339. mu. mol, CAS RN3205-94-5) was then added at-78 ℃. The reaction mixture was allowed to warm to 20 ℃ and stirred at this temperature for 2 h. The reaction mixture was poured onto 30mL of 1M aqueous HCl and 30mL of EtOAc and the layers were separated. The aqueous layer was extracted twice with 30mL EtOAc. The organic layer was washed with 30mL brine, MgSO₄Dried, filtered and concentrated under vacuum. The product was purified by preparative HPLC (Gemini NX column) with a gradient of MeOH: H₂O (containing 0.1% formic acid) (80: 20 to 98: 2). Yellow solid (52mg, 42.7%). MS (ESI): 360.101[ M + H ] M/z]⁺。

The examples in Table 3 were prepared according to the procedure used in example 6, using the 2-aminothiophene and carboxylic anhydride reagents listed in Table 3, using one of the following purification methods: method P1: preparative HPLC, eluent MeOH: H₂O (containing 0.1% formic acid) (gradient 80: 20 to 98: 2); method P2: MPLC, eluent CH₂Cl₂MeOH (gradient 100: 0 to 95: 5); method P3: preparative HPLC, eluent CH₃CN∶H₂O (gradient 50: 50 to 95: 5); method P4: preparative HPLC, eluent CH₃CN∶H₂O (gradient 20: 80 to 98: 2); method P5: precipitated after evaporation of the organic layer.

TABLE 3

Intermediates

General procedure a: preparation of 2-aminothiophenes

Method A1: cleavage of Boc-protected 2-aminothiophenes

Boc-protected 2-aminothiophene (0.5mmol) was dissolved in bisIn an alkane (5% solution) and added to the reaction mixture4M HCl in alkane (10 mmol). The solution was stirred at room temperature until TLC indicated completion of the reaction. The crude reaction mixture was concentrated in vacuo to afford the desired product, which was used in the next step without further purification.

Method A2: gewald reaction by one-pot method

To a solution of aldehyde or ketone (5mmol) in MeOH (5% solution) was added the heterocyclic acetonitrile derivative (5mmol), morpholine (12.5mmol) and elemental sulphur (5.5mmol) and the reaction mixture was stirred at 65 ℃ overnight. After cooling to room temperature, the reaction mixture was washed with EtOAc and half-saturated NH₄And (4) extracting with a Cl solution. Na for organic layer₂SO₄And activated carbon, evaporated and the compound purified by silica gel chromatography on a 50g column using a gradient of n-heptane: EtOAc as eluent.

Method A3: ring closure of Knoevenagel adducts

To a solution of Knoevenagel adduct (1.5mmol) in EtOH (20mL) was added DBU (3.75mmol) and sulfur (1.5 mmol). The reaction mixture was stirred at 65 ℃ for 2h and then poured into 10% NaHCO₃Aqueous (30mL) and EtOAc (30 mL). The layers were separated and the aqueous layer was extracted twice with EtOAc (30 mL). The organic layer was washed with 30mL brine, MgSO₄Dried, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography on a 20g column using an MPLC system (Combiflash company, Isco Inc.) eluting with a gradient of n-heptane: EtOAc.

Method A4: esters on 2-aminothiophenes toOxadiazole conversion

To a solution of 3- (methyl or ethyl) ester-substituted 2-aminothiophene (3.0mmol) in EtOH (5mL) was added N' -hydroxy-alkyl-or-cycloalkylcarboximidamide (3.0mmol) and NaOEt solution (21 wt% solution in EtOH, 3.0mmol) and the reaction mixture was stirred at 70 ℃ until the reaction was complete as indicated by TLC or LC-MS. Dependent on the inverseAs a matter of course, another batch of N' -hydroxycyclopropanecarboximidamide and sodium ethoxide solution may be added. The reaction mixture was poured into 30mL 10% NaHCO₃Aqueous and 30mL EtOAc and the layers were separated. The aqueous layer was extracted twice with 30mL EtOAc and the organic layer was washed with 30mL brine, MgSO₄Dried, filtered and concentrated under vacuum. The product was purified by preparative HPLC (Gemini NX column) with a gradient of MeOH: H₂O (containing 0.1% formic acid).

Method A5: by means of microwaves on 2-aminothiophenes toOxadiazole conversion

To a solution of 3- (methyl or ethyl) ester-substituted 2-aminothiophene (2mmol) in EtOH (4mL) was added N' -hydroxy-alkyl-or-cycloalkyl-carboximidamide (2mmol) and NaOEt (21 wt% solution in EtOH (2mmol), microwave heating (120 ℃) was applied to the reaction mixture until LC-MS indicated conversion was complete (typically 30 min.). the reaction mixture was poured into 30mL 10% NaHCO₃Aqueous and 30mL EtOAc and the layers were separated. The aqueous layer was extracted twice with 30mLEtOAc and the organic layer was washed with 30mL brine, MgSO₄Dried, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography on a 20g column using the MPLC (Flashmaster) system, eluting with a gradient of n-heptane: EtOAc (100: 0 to 60: 40).

Method A6: one-pot Gewald reaction using microwave conditions

To a solution of aldehyde or ketone (1mmol) in EtOH (1.5mL) was added the heterocyclic acetonitrile derivative (1mmol), sulfur (1mmol) and N-methylmorpholine (1mmol), and the reaction mixture was heated in a microwave oven at 120-150 ℃ for 30min and then poured into 30mL of 10% NaHCO₃Aqueous and 30mL EtOAc and the layers were separated. The aqueous layer was extracted twice with 30mL EtOAc. The organic layer was washed with 30mL brine, MgSO₄Dried, filtered and evaporated. The compounds were purified by silica gel chromatography on a 20g column using the MPLC system (Combiflash company, Isco)Inc.), using a gradient of n-heptane to EtOAc.

Method A7: improved one-pot Gewald reaction

To a solution of aldehyde or ketone (3mmol) in EtOH (7mL) were added the heterocyclic acetonitrile derivative (3mmol) and elemental sulphur (3mmol) and the reaction mixture was stirred at 50 ℃ for 30min. Morpholine (180mmol) was then added dropwise over 10 min. The reaction mixture was stirred at 50 ℃ for 1.5h and then poured onto 30mL of 10% NaHCO₃Aqueous and 30mL EtOAc and the layers were separated. The aqueous layer was extracted twice with 30mL EtOAc and the organic layer was washed with 30mL brine, MgSO₄Dried, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography on a 20g column using an MPLC system (CombiFlash company, Isco Inc.) eluting with a gradient of n-heptane: EtOAc.

The intermediates in table 4 were prepared according to the above method and using the starting materials listed in table 4:

TABLE 4

General procedure B: preparation of Knoevenagel adducts

Method B1: to a solution of ketone or aldehyde (3mmol) in toluene (9mL) was added heterocyclyl-acetonitrile and NH₄OAc (6 mmol). The reaction mixture was stirred at 100 ℃ for 18h and then poured onto 10% NaHCO₃Aqueous (30mL) and EtOAc (30mL) and the layers were separated. The aqueous layer was extracted twice with EtOAc (30mL) and the organic layer was washed with brine (30mL), MgSO₄Dried, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography on a 20g column using the MPLC (Flashmaster) system, eluting with a gradient of n-heptane: EtOAc.

The intermediates in table 5 were prepared according to the above method and using the starting materials listed in table 5:

TABLE 5

General procedure C: preparation of cyanomethyl-Diazoles

Method C1: to a solution of N' -hydroxy-alkyl-or-cycloalkyl-carboximidamide (50mmol) in bisTo a solution in an alkane (150mL) was added 3- (3, 5-dimethyl-1H-pyrazole-1-yl) -3-oxopropanenitrile (55 mmol). The reaction mixture was stirred at reflux temperature for 3h, then concentrated in vacuo. The compound was purified by silica gel chromatography on a 330g column using an MPLC system (CombiFlash company XL, Isco Inc.) eluting with a gradient of n-heptane: EtOAc.

Method C2: to the solution of NaCN (30mmol) in CH₃To a suspension in CN (10mL) was added 15-crown-5 (10mmol, CASRN 33100-27-5) and the suspension was stirred at room temperature for 45 min. To this mixture was added 5- (chloromethyl) -3-substituted 1,2, 4-Oxadiazole (5mmol) in CH₃CN (5 mL). The pale yellow suspension was stirred at room temperature for 3H and then poured into 100mL of H₂O and 100mL EtOAc and separate the layers. The aqueous layer was extracted twice with 100mL EtOAc and the organic layer was washed with 100mL brine, MgSO₄Dried, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography on a 50g column using an MPLC system (Combiflash company, Isco Inc.) eluting with a gradient of n-heptane: EtOAc.

The intermediates in table 6 were prepared according to the methods described above and using the starting materials listed in table 6:

TABLE 6

Intermediate 4

(3-phenyl-thiophen-2-yl) -carbamic acid tert-butyl ester

3-phenyl-thiophene-2-carboxylic acid (200mg, 979. mu. mol), NEt₃(99.1mg, 136. mu.L, 979. mu. mol) and diphenylphosphoryl azide (diphenylphosphate)L azide) (275mg, 215. mu.L, 999. mu. mol) was dissolved in t-BuOH. The solution was stirred at 85 ℃ for 5h, then at room temperature overnight. The resulting suspension was filtered and the filter cake was washed with a small amount of tert-BuOH. The filtrate was diluted with EtOAc and washed with H₂O and brine wash. Na for organic layer₂SO₄Dried and concentrated under vacuum. The crude material was purified by flash chromatography (0% to 18% EtOAc in n-heptane) to give the title compound as a yellow solid (0.122g, 45%). MS (ESI): 276.2[ M + H ] M/z]⁺。

Intermediate 5

3-phenyl-thiophene-2-carboxylic acid

3-phenyl-thiophene-2-carbaldehyde (0.527g, 2.8mmol) was diluted in CH₃CN (12.4mL) and the solution was cooled to 10 ℃. Addition of NaH₂PO₄(47mg, 0.392mmol) in H₂Solution in O (0.54mL) and hydrogen peroxide (1.36g, 1.2mL, 14.0mmol, 35 wt% solution in water), followed by addition of NaClO over 5min₂(0.166g, 1.83mmol) in H₂Solution in O (1.89 mL). The resulting biphasic system was stirred vigorously at 10 ℃ for 2 h. Stirring was continued at room temperature overnight. The reaction was cooled to 10 ℃ by addition of Na₂SO₃And (6) quenching. The reaction mixture was then poured over Na₂SO₃To an aqueous solution of (a). By adding some H₂O produces a clear two-phase system. After acidification to pH1 with 5M aqueous HCl, the resulting suspension was filtered. H for solid₂O wash and dry under high vacuum to give the title compound as a white solid (0.532g, 92%). MS (ESI): m/z 203.1[ M-H ]]^-。

Intermediate 6

3-phenyl-thiophene-2-carbaldehyde

3-bromothiophene-2-carbaldehyde (3g, 1.67mL, 14.8mmol, CAS RN 930-96-1) was dissolved in DME (180mL) and the resulting solution was evacuated and purged three times with argon. Addition of Pd (Ph)₃P)₄(512mg, 443. mu. mol), the reaction flask was again purged with argon and stirring was continued at room temperature for 15 min. Then, 2M Na was added₂CO₃Aqueous solution (14.8mL, 29.5mmol) followed by the addition of phenylboronic acid (1.98g, 16.2 mmol). The reaction flask was again flushed with argon and the reaction mixture was heated to 80 ℃ and stirred for 6.5 h. After evaporation of the solvent, the residue was taken up in Et₂O and H₂O and separating the layers. Na for organic layer₂SO₄Dried, filtered and evaporated. Suspending the crude residue in CH₂Cl₂And n-heptane and the solids were filtered off. The filtrate was evaporated and the crude product was purified by flash chromatography on silica gel (gradient EtOAc/n-heptane, 0% to 10%). Fractions containing the product were combined and further purified by preparative HPLC to give the title compound as a yellow oil (0.939g, 34%). MS (ESI): 189.2[ M + H ] M/z]⁺。

Intermediate 7

2- [ 4-cyclopropyl-5-methyl-3- (3-trifluoromethyl- [1,2,4]] Oxadiazol-5-yl) -thiophen-2-ylaminomethyl Acyl radical]-Cyclopent-1-enecarboxylic acid methyl ester

To monomethyl cyclopent-1-ene-1, 2-dicarboxylate (prepared similarly to T.yoshimutsu, T.tanaka et al, Heterocycles 2009, 77(1), 179-186) was added DMF (2.15mg, 2.28. mu.L, 29.4. mu. mol) and thionyl chloride (699mg, 429. mu.L, 5.88mmol) and the solution was heated to refluxAnd (3) 30min. The reaction mixture was concentrated in vacuo and the residue was diluted three times with toluene and subsequently evaporated to remove thionyl chloride completely. Dissolving the residue in CH₂Cl₂(2mL) and adding the solution to 4-cyclopropyl-5-methyl-3- (3-trifluoromethyl- [1,2, 4)]Oxadiazol-5-yl) -thiophen-2-ylamine (85mg, 294. mu. mol, Int1.4) and DIPEA (76.0mg, 103. mu.L, 588. mu. mol) in CH₂Cl₂(3mL) and the light brown solution was stirred at room temperature for 18 h. The reaction mixture was poured into 30mL 10% NaHCO₃Aqueous and 30mL EtOAc and the layers were separated. The aqueous layer was extracted twice with 30mL EtOAc. The organic layer was washed with 30mL brine, MgSO₄Dried, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography on 20g using MPLC (Flashmaster) system eluting with a gradient of n-heptane: EtOAc (100: 0 to 75: 25). Pale yellow solid (88mg, 67.8%). MS (ESI): 442.104[ M + H ] M/z]⁺。

The intermediates in table 7 were prepared according to the procedure described under intermediate 7 and using the starting materials listed in table 7.

TABLE 7

Example 7

Trans-2- [3- (3-cyclopropyl- [1,2, 4)] Oxadiazol-5-yl) -4, 5-dimethyl-thiophen-2-ylcarbamoyl Base of]-cyclohexanecarboxylic acid

To 3- (3-cyclopropyl-1, 2, 4-To a solution of oxadiazol-5-yl) -4, 5-dimethylthiophen-2-amine (0.08g, 340. mu. mol, Int1.5) in tert-butyl methyl ether (2mL) was added trans 1, 2-cyclohexanedicarboxylic anhydride (62.9mg, 408. mu. mol, CAS RN 14166-21-3) and the clear solution was heated to reflux for 19 h. The reaction mixture was evaporated and the product was purified by preparative HPLC (Gemini NX column) using MeOH: H₂Gradient of O (containing 0.1% formic acid) (20: 80 to 98: 2). A colorless solid (0.1 g; 75.5%). MS (ESI): 390.15[ M + H ] M/z]⁺。

The examples in table 8 were prepared according to the method used in example 7, using the 2-aminothiophene and carboxylic acid derivative reagents listed in table 8.

TABLE 8

Examples 8 and 9

5- [3- (3-cyclopropyl- [1,2,4]] Oxadiazol-5-yl) -4, 5-dimethyl-thiophen-2-ylcarbamoyl]-3， 6-dihydro-2H-pyran-4-carboxylic acid and

4- [3- (3-cyclopropyl- [1,2,4]] Oxadiazol-5-yl) -4, 5-dimethyl-thiophen-2-ylcarbamoyl]-5， 6-dihydro-2H-pyran-3-carboxylic acid

To 5- (3- (3-cyclopropyl-1, 2, 4-Oxadiazol-5-yl) -4, 5-dimethylthiophen-2-ylcarbamoyl) -3, 6-dihydro-2H-pyran-4-carboxylic acid ethyl ester (272mg, 652. mu. mol, Int7.1) in bisAlkane (3mL) and H₂To the suspension in O (3mL) was added LiOH monohydrate (15.6mg, 652. mu. mol) and the reaction mixture was stirred at room temperature for 6 h. Then another batch of LiOH monohydrate (7.8mg, 326 μmol) was added. The dark yellow suspension was evaporated. Suspending the residue in H₂O (approximately 3.5mL) and treated with 1M aqueous HCl (3 mL). This mixture was extracted twice with EtOAc. The organic layer was washed once with brine, over MgSO₄Dried, filtered and evaporated. The residue was purified by two silica gel chromatography on a 50g column using MPLC system (CombiFlash company XL, Isco Inc.) using CH₂Cl₂MeOH (100: 0 to 90: 10). Preparative HPLC (Chiralpak-AD chiral column) using an isocratic mixture of (EtOH + 0.5% formic acid) and n-heptane (40: 60) gave the desired isomer.

First eluting isomer (example 8): pale yellow solid (44mg, 17.3%). MS (ESI): 390.11[ M + H ] M/z]⁺。

Second eluting isomer (example 9): a waxy yellow solid (80mg, 31.5% yield). MS (ESI): 390.11[ M + H ] M/z]⁺。

Intermediate 8

4- (ethoxycarbonyl) -5, 6-dihydro-2H-pyran-3-carboxylic acid

A mixture of acetic anhydride (5.19g, 4.8mL, 50.9mmol), DIPEA (6.58g, 8.89mL, 50.9mmol) and sodium formate (5.19g, 76.3mmol) was stirred at room temperature for 1 h.A solution of ethyl 5- (trifluoromethylsulfonyloxy) -3, 6-dihydro-2H-pyran-4-carboxylate (8.6g, 25.4 mmol; prepared according to WO 2010038167) in DMF (50mL) was added dropwise followed by palladium (II) acetate (286mg, 1.27mmol) and LiCl (3.24g, 76.3 mmol). After stirring at room temperature for 1.5h, the black suspension was poured onto 2M aqueous HCl (100mL) and EtOAc (100mL) and the layers were separated. The aqueous layer was extracted twice with EtOAc (100 mL). H for organic layer₂O twice and once with brine, MgSO₄Dried, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 120g column using MPLC system using CH₂Cl₂MeOH (100: 0 to 80: 20). Light brown oil (4.14 g; 81.3%). MS (ESI): 199.06[ M-H ] M/z]^-。

Example 10

(R) -1- [4, 5-dimethyl-3- (3-trifluoromethyl- [1,2, 4)] Oxadiazol-5-yl) -thiophen-2-ylcarbamoyl Base of]-pyrrolidine-2-carboxylic acid

To 5- (2-isocyanato-4, 5-dimethyl-thiophen-3-yl) -3-trifluoromethyl- [1,2,4] at 25 deg.C]-Diazole (178mg, 0.615mmol) in CH₂Cl₂To a solution in (10mL) was added D-proline (142mg, 1.23mmol) and triethylamine (0.128mL, 0.923mmol), and the reaction mixture was stirred at 25 ℃ for 12 h. Reacting the mixture with CH₂Cl₂Diluted (20mL) and washed with 2N aqueous HCl (15mL), followed by H₂O (20mL) wash. Na for organic layer₂SO₄Drying, filtering and steamingAnd (4) sending. The residue was purified by silica gel column chromatography and using CH₂Cl₂MeOH (100: 0 to 95: 5) to provide the desired compound as an off-white solid (120mg, 48%). MS (ESI): m/z 403.4(M-H)^-。

Intermediate 9

5- (2-isocyanato-4, 5-dimethyl-thiophen-3-yl) -3-trifluoromethyl- [1,2,4]- Diazoles

To 4, 5-dimethyl-3- (3-trifluoromethyl- [1,2, 4)]Oxadiazol-5-yl) -thiophen-2-ylamine (165mg, 0.627mmol, Int1.22) to a solution in THF (4mL) triphosgene (149mg, 0.501mmol) was added and the reaction mixture was stirred at 25 ℃ for 2 h. The solvent was evaporated to give the desired compound as a colorless solid (178mg, 98%), which was used in the next step without purification.

The examples in table 9 were prepared according to the method used in example 4, using the 2-aminothiophene and carboxylic anhydride reagents listed in table 9.

TABLE 9

The intermediates in table 10 were prepared according to methods a7 and A3, respectively, as previously described and using the starting materials listed in table 10:

watch 10

The intermediates in table 11 were prepared according to method B1 previously described and using the starting materials listed in table 11:

TABLE 11

General procedure D: preparation of cyanomethyl-thiadiazoles

To 5-chloro-3-alkyl- [1.2.4]Thiadiazole (6mmol) in anhydrous THF (15mL) anhydrous CH was added₃CN (12mmol) and the solution was cooled to 0 ℃. LiHMDS (12mmol, 1M solution in THF) was then added dropwise at this temperature and the reaction mixture was stirred at 25 ℃ for 5 h. With saturated NH for the reaction₄Aqueous Cl (20mL) was quenched and extracted three times with EtOAc (30mL each). The combined organic layers were washed with brine, washed with Na₂SO₄Dried, filtered and evaporated. The residue was purified by silica gel column chromatography eluting with a gradient of EtOAC: n-heptane to give the desired product, which was used in the next step without further purification.

The intermediates in table 12 were prepared according to the methods described above and using the starting materials listed in table 12.

TABLE 12

Example A

The compounds of formula (I) can be used in a manner known per se as active ingredients for the preparation of tablets of the following composition:

example B

The compounds of formula (I) can be used in a manner known per se as active ingredients for the preparation of capsules of the following composition:

Claims (16)

1. A compound of the formula (I),

wherein

R¹Selected from the group consisting of H, C1-C7-alkyl, C1-C7-haloalkyl, C3-C8-cycloalkyl, substituted heterocycloalkyl, substituted heteroaryl, substituted aminocarbonyl and C1-C7-alkoxycarbonyl, wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with R¹⁴、R¹⁵And R¹⁶And wherein the substituted aminocarbonyl group is substituted on the nitrogen atom with two substituents independently selected from: H. C1-C7-alkyl, C3-C8-cycloalkyl, C1-C7-haloalkyl, C1-C7-alkyl-C3-C8-cycloalkyl, C3-C8-cycloalkyl-C1-C7-alkyl, C1-C7-alkyl-C3-C8-cycloalkyl-C1-C7-alkyl, C1-C7-hydroxyalkyl and C1-C7-alkoxy-C1-C7-alkyl, and wherein "heterocycloalkyl" denotes a monovalent saturated or partially unsaturated mono-or bicyclic ring system comprising 1,2 or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being 4 to 9 ring atoms of carbon, and wherein "heteroaryl" denotes a mono-or bicyclic ring system comprising 1,2, 3 or 4 ring atoms selected from N, a mono-or bicyclic ring system of a monovalent aromatic heterocyclic ring of 5 to 12 ring atoms with heteroatoms of O and S, the remaining ring atoms being carbon;

R²selected from H, C1-C7-alkyl, C1-C7-haloalkyl or C3-C8-cycloalkyl;

R³is pyrrolidinyl, substituted [1,2,4]]-A diazolyl group,Azolyl, substituted thiazolyl, substituted [1,2,4]]Thiadiazol-5-yl, or pyrimidinyl, substituted therein [1,2,4]-Oxadiazolyl, substituted [1,2,4] carboxylic acids]Thiadiazol-5-yl and substituted thiazolyl substituted by R¹⁷Substitution;

R⁴is H or C1-C7-alkyl;

R⁵and R⁶Independently selected from H, C1-C7-alkyl and C3-C8-cycloalkyl;

R⁷is H, C1-C7-alkyl or C3-C8-cycloalkyl;

a is NR⁸Or CR⁹R¹⁰；

E is CR¹²R¹³；

R⁸And R¹²Together with the nitrogen and carbon atoms to which they are attachedTogether form a substituted heterocycloalkyl or substituted heteroaryl, wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with R²⁰Is substituted and may be further substituted by R²¹Substituted in which R is⁸And R¹²In the case where they together with the carbon atom to which they are attached form a substituted heteroaryl, then R¹³Absent and wherein "heterocycloalkyl" represents a monovalent saturated or partially unsaturated mono-or bicyclic ring system comprising 1,2 or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being 4 to 9 ring atoms of carbon, and wherein "heteroaryl" represents a monovalent aromatic heterocyclic mono-or bicyclic ring system comprising 1,2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being 5 to 12 ring atoms of carbon;

or R⁹And R¹²Together with the carbon atom to which they are attached form a substituted C3-C8-cycloalkyl, substituted C3-C8-cycloalkenyl, substituted C6-C10-aryl, substituted heterocycloalkyl or substituted heteroaryl group, wherein substituted C3-C8-cycloalkyl, substituted C3-C8-cycloalkenyl, substituted C6-C10-aryl, substituted heterocycloalkyl and substituted heteroaryl are substituted by R²⁰Is substituted and may be further substituted by R²¹Substituted in which R is⁹And R¹²Together with the carbon atom to which they are attached form a substituted C6-C10-aryl or substituted heteroaryl group, then R¹⁰And R¹³Absent and wherein "heterocycloalkyl" represents a monovalent saturated or partially unsaturated mono-or bicyclic ring system comprising 1,2 or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being 4 to 9 ring atoms of carbon, and wherein "heteroaryl" represents a monovalent aromatic heterocyclic mono-or bicyclic ring system comprising 1,2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being 5 to 12 ring atoms of carbon;

R¹⁰and R¹³Together with the carbon atom to which they are attached form a double bond;

R¹⁴、R¹⁵、R¹⁶、R¹⁷、R²⁰and R²¹Independently selected from H, hydroxy, oxo, halogen, C1-C7-alkyl, C1-C7-haloalkyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C7-Alkoxy, C1-C7-haloalkoxy, C1-C7-alkoxy-C1-C7-alkyl, C1-C7-haloalkoxy-C1-C7-alkyl, C1-C7-alkoxycarbonyl, carboxyl and substituted amino substituted on the nitrogen atom with one to two substituents independently selected from: H. C1-C7-alkyl, C3-C8-cycloalkyl, C1-C7-haloalkyl, C1-C7-alkyl-C3-C8-cycloalkyl, C3-C8-cycloalkyl-C1-C7-alkyl, C1-C7-alkyl-C3-C8-cycloalkyl-C1-C7-alkyl, C1-C7-hydroxyalkyl and C1-C7-alkoxy-C1-C7-alkyl;

n is zero;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein R¹Is C1-C7-alkyl or C3-C8-cycloalkyl.

3. A compound according to claim 1 or 2, wherein R²Is C1-C7-alkyl or C1-C7-haloalkyl.

4. A compound according to claim 1 or 2, wherein R³Is by R¹⁷Substituted [1,2,4]]-A diazolyl group.

5. A compound according to claim 1 or 2, wherein R⁴Is H.

6. A compound according to claim 1 or 2, wherein R⁷Is H.

7. A compound according to claim 1 or 2, wherein a is CR⁹R¹⁰。

8. A compound according to claim 1 or 2, wherein R⁹And R¹²Together with the carbon atom to which they are attached form cyclopentyl, cyclohexyl or bicyclo [2.2.2]And (4) octyl.

9. A compound according to claim 1 or 2, wherein R¹⁴、R¹⁵、R¹⁶、R¹⁷、R²⁰And R²¹Independently selected from H, C1-C7-alkyl, C1-C7-haloalkyl and C3-C8-cycloalkyl.

10. A compound selected from:

2- (3-phenyl-thiophen-2-ylcarbamoyl) -cyclopent-1-enecarboxylic acid;

5- [ (3-carboxy-bicyclo [2.2.2] oct-2-ene-2-carbonyl) -amino ] -3-methyl-4- (4-methyl-thiazol-2-yl) -thiophene-2-carboxylic acid methyl ester;

2- [ 4-cyclopropyl-5-methyl-3- (3-methyl- [1,2,4]]Oxadiazol-5-yl) -thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

3- [ 4-cyclopropyl-5-methyl-3- (3-trifluoromethyl- [1,2,4]]Oxadiazol-5-yl) -thiophen-2-ylcarbamoyl]-bicyclo [2.2.2]Oct-2-ene-2-carboxylic acid;

2- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -4, 5-dimethyl-thiophen-2-ylcarbamoyl]-cyclohex-1-enecarboxylic acid;

2- [ 5-cyclopropyl-3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -4-methyl-thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

3- [ 5-cyclopropyl-3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -4-methyl-thiophen-2-ylcarbamoyl]-bicyclo [2.2.2]Oct-2-ene-2-carboxylic acid;

2- [ 4-cyclopropyl-5-methyl-3- (3-methyl- [1,2,4]]Oxadiazol-5-yl) -thiophen-2-ylcarbamoyl]-cyclohex-1-enecarboxylic acid;

3- [ 4-cyclopropyl-5-methyl-3- (3-methyl- [1,2,4]]Oxadiazol-5-yl) -thiophen-2-ylcarbamoyl]-bicyclo [2.2.2]Oct-2-ene-2-carboxylic acid;

2- [ 4-cyclopropyl-3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -5-methyl-thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

3- [ 4-cyclopropyl-3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -5-methyl-thiophen-2-ylcarbamoyl]-bicyclo [2.2.2]Oct-2-ene-2-carboxylic acid;

3- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -4, 5-dimethyl-thiophen-2-ylcarbamoyl]-bicyclo [2.2.2]Oct-2-ene-2-carboxylic acid;

2- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -4, 5-dimethyl-thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

2- [ 4-cyclopropyl-5-methyl-3- (3-trifluoromethyl- [1,2,4]]Oxadiazol-5-yl) -thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

2- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -5-methyl-thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

2- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

2- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -4-methyl-5-oxetan-3-yl-thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

2- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -4-methyl-5-oxetan-3-yl-thiophen-2-ylcarbamoyl]-cyclohex-1-enecarboxylic acid;

2- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -5-methyl-4-trifluoromethyl-thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

5- [ (2-carboxy-cyclopent-1-enecarbonyl) -amino]-4- (3-cyclopropyl- [1,2, 4)]Oxadiazol-5-yl) -3-methyl-thiophene-2-carboxylic acid ethyl ester;

2- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -5-dimethylcarbamoyl-4-methyl-thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

2- [ 5-cyclopropyl-3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

2- [ 4-cyclopropyl-3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

2- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -4-methyl-thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

2- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -5- (2,2, 2-trifluoro-ethyl) -thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

2- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -4-trifluoromethyl-thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

2- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -5- (5-dimethylamino- [1,2,4]Thiadiazol-3-yl) -4-methyl-thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

and pharmaceutically acceptable salts thereof.

11. A compound selected from:

3- [4, 5-dimethyl-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -thiophen-2-ylcarbamoyl ] -bicyclo [2.2.2] oct-2-ene-2-carboxylic acid;

2- [3- (3-cyclopropyl- [1,2,4] thiadiazol-5-yl) -4, 5-dimethyl-thiophen-2-ylcarbamoyl ] -cyclopent-1-enecarboxylic acid;

2- [3- (3-cyclopropyl- [1,2,4] thiadiazol-5-yl) -4, 5-dimethyl-thiophen-2-ylcarbamoyl ] -cyclohex-1-enecarboxylic acid;

3- [3- (3-cyclopropyl- [1,2,4] thiadiazol-5-yl) -4, 5-dimethyl-thiophen-2-ylcarbamoyl ] -bicyclo [2.2.2] oct-2-ene-2-carboxylic acid;

2- [ 5-cyclopropyl-4-methyl-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -thiophen-2-ylcarbamoyl ] -cyclopent-1-enecarboxylic acid;

2- [ 5-cyclopropyl-4-methyl-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -thiophen-2-ylcarbamoyl ] -cyclohex-1-enecarboxylic acid;

3- [ 5-cyclopropyl-4-methyl-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -thiophen-2-ylcarbamoyl ] -bicyclo [2.2.2] oct-2-ene-2-carboxylic acid;

2- [ 5-cyclopropyl-3- (3-cyclopropyl- [1,2,4] thiadiazol-5-yl) -4-methyl-thiophen-2-ylcarbamoyl ] -cyclopent-1-enecarboxylic acid;

2- [4, 5-dimethyl-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -thiophen-2-ylcarbamoyl ] -cyclopent-1-enecarboxylic acid;

3- [ 5-cyclopropyl-3- (3-cyclopropyl- [1,2,4] thiadiazol-5-yl) -4-methyl-thiophen-2-ylcarbamoyl ] -bicyclo [2.2.2] oct-2-ene-2-carboxylic acid;

(1SR,2SR) -2- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -4, 5-dimethyl-thiophen-2-ylcarbamoyl]-cyclohexanecarboxylic acid;

(1RS,2SR) -2- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -4, 5-dimethyl-thiophen-2-ylcarbamoyl]-cyclohexanecarboxylic acid;

2- [4, 5-dimethyl-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -thiophen-2-ylcarbamoyl ] -cyclohex-1-enecarboxylic acid;

2- [ 5-cyclopropyl-3- (3-cyclopropyl- [1,2,4] thiadiazol-5-yl) -4-methyl-thiophen-2-ylcarbamoyl ] -cyclohex-1-enecarboxylic acid;

5- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -4, 5-dimethyl-thiophen-2-ylcarbamoyl]-3, 6-dihydro-2H-pyran-4-carboxylic acid;

4- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -4, 5-dimethyl-thiophen-2-ylcarbamoyl]-5, 6-dihydro-2H-pyran-3-carboxylic acid;

(R) -1- [4, 5-dimethyl-3- (3-trifluoromethyl- [1,2, 4)]Oxadiazol-5-yl) -thiophen-2-ylcarbamoyl]-pyrrolidine-2-carboxylic acid;

and pharmaceutically acceptable salts thereof.

12. A compound according to claim 1 or 2 selected from:

2- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -4, 5-dimethyl-thiophen-2-ylcarbamoyl]-cyclohex-1-enecarboxylic acid;

2- [ 5-cyclopropyl-3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -4-methyl-thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

2- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -5-methyl-4-trisFluoromethyl-thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

2- [4, 5-dimethyl-3- (3-methyl- [1,2,4] thiadiazol-5-yl) -thiophen-2-ylcarbamoyl ] -cyclohex-1-enecarboxylic acid;

and pharmaceutically acceptable salts thereof.

13. A compound according to claim 1 or 2 selected from:

2- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -4, 5-dimethyl-thiophen-2-ylcarbamoyl]-cyclohex-1-enecarboxylic acid;

2- [ 5-cyclopropyl-3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -4-methyl-thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

2- [3- (3-cyclopropyl- [1,2,4]]Oxadiazol-5-yl) -5-methyl-4-trifluoromethyl-thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid;

and pharmaceutically acceptable salts thereof.

14. A process for the preparation of compounds wherein A is CR⁹R¹⁰A process for preparing a compound according to claim 1, which comprises reacting a compound of formula (II) in the presence of a compound of formula (VI),

wherein R is¹、R²、R³、R⁴、R⁵、R⁶、R⁷As defined in claim 1, and wherein n is zero, A is CR⁹R¹⁰And E is CR¹²R¹³。

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 and a therapeutically inert carrier.

16. The use of a compound according to any one of claims 1 to 13 for the preparation of medicaments for the treatment or prophylaxis of type 2diabetes, atherosclerosis, cancer, chronic kidney disease and non-alcoholic steatohepatitis.