HK1213561B - Urea derivatives and their use as fatty-acid binding protein (fabp) inhibitors - Google Patents

Description

Urea derivatives and their use as fatty acid binding protein (FABP) inhibitors

The present invention relates to organic compounds for use in the treatment or prevention of diseases in mammals, and in particular to fatty acid binding protein (FABP) 4 and/or 5 inhibitors, more particularly dual FABP 4/5 inhibitors for the treatment or prevention of, for example, type 2 diabetes, atherosclerosis, chronic kidney diseases, non-alcoholic steatohepatitis and cancer.

The present invention provides novel compounds of formula (I)

in

^R1 and ^R3 together with the carbon and nitrogen atoms to which they are attached form a heterocycloalkyl group;

^R2 is H, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, cycloalkylalkyl, halocycloalkylalkyl, phenyl, or substituted phenyl, wherein the substituted phenyl is substituted with one to three substituents selected from alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, alkoxy, haloalkoxy, halogen, hydroxy, and cyano;

^R4 is H, alkyl or cycloalkyl;

W is a bond, -O-, -S-, -NR ⁵ -, -C(O)-, -S(O) ₂ -, -C(O)-NR ⁵ -, or -CR ⁶ R ⁷ -;

^R5 is H, alkyl or cycloalkyl;

^R6 and ^R7 are independently selected from H, alkyl or cycloalkyl;

A is substituted phenyl, substituted thienyl, substituted benzothienyl, substituted thienopyridinyl, wherein substituted phenyl, substituted thienyl, substituted benzothienyl and substituted thienopyridinyl are substituted with R ⁸ , R ⁹ and R ¹⁰ ;

B is substituted cycloalkyl, substituted cycloalkenyl, substituted pyridyl, substituted phenyl, substituted thienyl, substituted benzothienyl, or substituted thienopyridyl, wherein the substituted cycloalkyl, substituted cycloalkenyl, substituted pyridyl, substituted phenyl, substituted thienyl, substituted benzothienyl, and substituted thienopyridyl are substituted with R ¹¹ , R ¹² , and R ¹³ ;

R ⁸ , R ⁹ , and R ¹⁰ are independently selected from H, alkyl, alkenyl, alkynyl, hydroxyalkyl, haloalkyl, hydroxyhaloalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkylalkoxy, cycloalkoxy, cycloalkyloxyalkyl, cycloalkylalkoxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, haloalkoxyalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, phenyl, substituted phenyl, pyridyl, substituted pyridyl, halogen, hydroxy, cyano, substituted aminosulfonyl, substituted aminocarbonyl, substituted amino and substituted aminoalkyl, wherein substituted aminosulfonyl, substituted aminocarbonyl, substituted amino and substituted aminoalkyl are substituted on the nitrogen atom with one to two substituents independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkylcarbonyl and cycloalkylcarbonyl, and wherein substituted phenyl and substituted pyridyl are substituted with one to three substituents selected from alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, alkoxy, haloalkoxy, halogen, hydroxy and cyano;

R ¹¹ , R ¹² and R ¹³ are independently selected from H, alkyl, alkenyl, alkynyl, hydroxyalkyl, haloalkyl, hydroxyhaloalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkylalkoxy, cycloalkoxy, cycloalkyloxyalkyl, cycloalkylalkoxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, haloalkoxyalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, phenyl, substituted phenyl, pyridyl, substituted pyridyl, halogen, hydroxy, cyano, substituted aminosulfonyl, substituted aminocarbonyl, substituted amino and substituted aminoalkyl, wherein substituted aminosulfonyl, substituted aminocarbonyl, substituted amino and substituted aminoalkyl are substituted on the nitrogen atom with one to two substituents independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkylcarbonyl and cycloalkylcarbonyl, and wherein substituted phenyl and substituted pyridyl are substituted with one to three substituents selected from alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, alkoxy, haloalkoxy, halogen, hydroxy and cyano;

or pharmaceutically acceptable salts;

Provided that CAS 1080643-64-6 is excluded.

FABP4 (aP2) and FABP5 (mall) are members of the fatty acid binding protein family. FABPs are 14-15 kDa proteins that act as protein chaperones for fatty acids in the aqueous intracellular environment and facilitate their movement between cellular compartments. To date, at least nine members of this family have been identified with tissue-specific expression patterns. FABP4 is primarily expressed in adipocytes and macrophages, but is also expressed in other cell types, while FABP5 is expressed in a wide range of tissues and organs. FABPs are responsible for the transfer of fatty acids to different cellular 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 cytoplasmic enzyme activity, regulation of inflammatory responses, and leukotriene synthesis. Plasma FABP4 is secreted by adipose tissue in mice, and secretion is dysregulated in obesity, and blocking of plasma FABP4 in vivo by antibodies improves insulin sensitivity.

Several genetic lines of evidence in humans support a role for FABP4 and FABP5 in metabolic diseases. A mutation in the FABP4 promoter (SNP T-87C), which results in a 50% decrease in gene expression, is associated with a reduced risk of cardiovascular disease (CVD) and type 2 diabetes (T2D) and is associated with reduced plasma triglycerides (TG). Two mutations in FABP5, one in the 5'UTR (rs454550) and one in the promoter (nSNP), are associated with an 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 large number of publications have reported a correlation between FABP4 and FABP5 plasma levels and the severity of metabolic diseases. Elevated FABP4 plasma levels are associated with atherogenic dyslipidemia, reduced endothelial function, increased intima-media (IM) thickness, metabolic syndrome, obesity, and insulin resistance (IR). Elevated FABP5 plasma levels are associated with metabolic syndrome.

Genetic and pharmacological studies in mice largely confirm the human evidence. Loss of function in FABP4 and FABP5 has been shown to improve insulin sensitivity, lower glucose, and protect against atherosclerosis. FABP4 knockout mice on a high-fat diet show metabolic improvements mediated by compensatory upregulation of FABP5 in fat. Mice lacking FABP5 on a high-fat (HF) diet show weight loss and improved glucose and insulin tolerance. FABP4/FABP5 double knockout mice are strongly protected from hyperglycemia, insulin resistance, and hepatic steatosis. In addition, in an ApoE-deficient setting, the absence of FABP4 and FABP5 is highly protective against the development of atherosclerosis and increases its longevity. A specific FABP4 inhibitor (BMS309403) has been shown in clamp studies of ob/ob mice to reduce hepatic glucose production, increase glucose uptake in muscle and fat, and reduce hepatic steatosis, but without changes in body weight and energy expenditure. Furthermore, it showed reduced atherosclerotic plaque formation in ApoE KO mice. Compound 3, a dual FABP4/5 inhibitor described in J. Lipid Res. 2011, 52, 646, showed reductions in plasma triglycerides and free fatty acids in mice on a HF diet, but no improvement in insulin and glucose tolerance.

The present invention relates to compounds of formula (I) and their aforementioned salts and esters and their use as therapeutically active substances, processes for the preparation of said compounds, intermediates, pharmaceutical compositions, medicaments containing said compounds, their pharmaceutically acceptable salts or esters, and the use of said compounds, salts or esters for the treatment or prevention of diseases, in particular for the treatment or prevention of type 2 diabetes, 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. 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 inflammatory and autoimmune inflammatory diseases; preeclampsia and polycystic ovary syndrome. syndrome), and the use of the compounds, salts or esters for the preparation of medicaments for the treatment or prevention of the following diseases: type 2 diabetes, 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 inflammatory and autoimmune inflammatory diseases, preeclampsia and polycystic ovary syndrome.

The compounds of the present invention are inhibitors of FABP 4 and 5. More particularly, the compounds of formula (I) of the present invention are selective inhibitors of FABP 4 compared to FABP 5 and 3 and/or 1.

The term "alkenyl" refers to a monovalent straight or branched hydrocarbon radical of 2 to 7 carbon atoms having at least one double bond. In certain embodiments, the alkenyl radical has 2 to 4 carbon atoms and at least one double bond. Examples of alkenyl radicals include vinyl, propenyl, prop-2-enyl, isopropenyl, n-butenyl, and iso-butenyl. A particular alkenyl radical is pronenyl.

The term "alkoxy" refers to a radical of the formula -O-R', where R' is an alkyl radical. Examples of alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. Particular alkoxy radicals include methoxy, ethoxy, and isopropoxy. More particular alkoxy radicals are methoxy radicals.

The term "alkoxyalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group has been replaced by another alkoxy group. Examples of alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy, methoxyethoxy, ethoxyethoxy, methoxypropoxy, and ethoxypropoxy.

The term "alkoxyalkoxyalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the alkyl group has been replaced by an alkoxyalkoxy group. Examples of alkoxyalkoxyalkyl groups include methoxymethoxymethyl, ethoxymethoxymethyl, methoxyethoxymethyl, ethoxyethoxymethyl, methoxypropoxymethyl, ethoxypropoxymethyl, methoxymethoxyethyl, ethoxymethoxyethyl, methoxyethoxyethyl, ethoxyethoxyethyl, methoxypropoxyethyl, and ethoxypropoxyethyl.

The term "alkoxyalkyl" refers to an alkyl group in which 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 "alkyl" refers to a monovalent straight or branched saturated hydrocarbon radical of 1 to 12 carbon atoms, particularly 1 to 7 carbon atoms, more particularly 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Particular alkyl groups are methyl and ethyl.

The term "alkylcarbonyl" refers to a group of the formula -C(O)-R', wherein R' is an alkyl group. Examples of alkylcarbonyl groups include groups of the formula -C(O)-R', wherein R' is a methyl group or an ethyl group. Particular alkylcarbonyl groups include groups of the formula -C(O)-R', wherein R' is a methyl group.

The term "alkynyl" refers to a monovalent straight or branched chain saturated hydrocarbon radical of 2 to 7 carbon atoms containing one, two, or three triple bonds. In certain embodiments, the alkynyl radical has 2 to 4 carbon atoms containing one or two triple bonds. Examples of alkynyl radicals include ethynyl, propynyl, prop-2-ynyl, isopropynyl, n-butynyl, and isobutynyl.

The term "amino" refers to a _-NH2 group.

The term "aminoalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the alkyl group has been replaced by an amino group. Examples of aminoalkyl groups include aminomethyl, aminoethyl, amino-1-methyl-ethyl, aminopropyl, aminomethylpropyl and aminopropyl.

The term "aminocarbonyl" denotes a group of formula -C(O) _-NH2 .

The term "aminosulfonyl" refers to the -S(O) ₂ - _NH2 group.

The term "cyano" refers to a -C≡N group.

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

The term "cycloalkenylalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by a cycloalkenyl group. Examples of cycloalkenylalkyl groups include cyclobutenylmethyl, cyclopentenylmethyl, and cyclohexenylmethyl.

The term "cycloalkoxy" refers to a group of formula -O-R', wherein R' is a cycloalkyl group. Examples of cycloalkoxy groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.

The term "cycloalkoxyalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the alkyl group has been replaced by a cycloalkoxy group. Examples of cycloalkoxyalkyl groups include cyclopropyloxymethyl, cyclopropyloxyethyl, cyclobutyloxymethyl, cyclobutyloxyethyl, cyclopentyloxymethyl, cyclopentyloxyethyl, cyclohexyloxymethyl, cyclohexyloxyethyl, cycloheptyloxymethyl, cycloheptyloxyethyl, cyclooctyloxymethyl, and cyclooctyloxyethyl.

The term "cycloalkyl" refers to a monovalent saturated monocyclic or bicyclic hydrocarbon radical of 3 to 10 ring carbon atoms, particularly a monovalent saturated monocyclic hydrocarbon radical of 3 to 8 ring carbon atoms. Bicyclic refers to a radical consisting of two saturated or partially saturated carbocyclic rings having two carbon atoms in common. Particular cycloalkyl radicals 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. More particular cycloalkyl radicals are cyclopropyl, cyclobutyl, and cyclopentyl.

The term "cycloalkylalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group is replaced by a cycloalkyl group. Examples of cycloalkylalkoxy groups include cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, cycloheptylmethoxy, and cyclooctylmethoxy.

The term "cycloalkylalkoxyalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by a cycloalkylalkoxy group. Examples of cycloalkylalkoxyalkyl groups include cyclopropylmethoxymethyl, cyclopropylmethoxyethyl, cyclobutylmethoxymethyl, cyclobutylmethoxyethyl, cyclopentylmethoxyethyl, cyclopentylmethoxyethyl, cyclohexylmethoxymethyl, cyclohexylmethoxyethyl, cycloheptylmethoxymethyl, cycloheptylmethoxyethyl, cyclooctylmethoxymethyl, and cyclooctylmethoxyethyl.

The term "cycloalkylalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by a cycloalkyl group. Examples of cycloalkylalkyl groups include cyclopropylmethyl, cyclopropylethyl, cyclobutylpropyl and cyclopentylbutyl.

The term "cycloalkylcarbonyl" is of the formula -C(O)-R', wherein R' is a cycloalkyl group. Examples of cycloalkylcarbonyl groups include groups of the formula -C(O)-R', wherein R' is a cyclopropyl group.

The term "haloalkoxy" refers to an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group has been replaced by the same or different halogen atoms. The term "perhaloalkoxy" refers to an alkoxy group in which 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. A particular haloalkoxy group is trifluoromethoxy.

The term "haloalkoxyalkyl" represents an alkyl group in which at least one hydrogen atom of the alkyl group has been replaced by a haloalkoxy group. Examples of haloalkoxyalkyl groups include fluoromethoxymethyl, difluoromethoxymethyl, trifluoromethoxymethyl, fluoroethoxymethyl, difluoroethoxymethyl, trifluoroethoxymethyl, fluoromethoxyethyl, difluoromethoxyethyl, trifluoromethoxyethyl, fluoroethoxyethyl, difluoroethoxyethyl, trifluoroethoxyethyl, fluoromethoxypropyl, difluoromethoxypropyl, trifluoromethoxypropyl, fluoroethoxypropyl, difluoroethoxypropyl and trifluoroethoxypropyl. Special haloalkoxyalkyl group is 2,2-difluoroethoxyethyl.

The term "haloalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the alkyl group has been replaced by the same or different halogen atoms. The term "perhaloalkyl" refers to an alkyl group in which all of the hydrogen atoms of the alkyl group have been replaced by the same or different halogen atoms. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylethyl, and pentafluoroethyl. A particular haloalkyl group is trifluoromethyl.

The terms "halogen" and "halo" are used interchangeably herein and refer to fluorine, chlorine, bromine or iodine. Particular halogens are chlorine and fluorine.

The term "hydroxy" refers to an -OH group.

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

The term "hydroxyhaloalkyl" refers to a haloalkyl group in which at least one of the hydrogen atoms of the haloalkyl group has been replaced by a hydroxy group. Exemplary hydroxyhaloalkyl groups include hydroxytrifluoroethyl and hydroxytrifluoropropyl. Particular hydroxyhaloalkyl groups include hydroxytrifluoroethyl.

The term "pharmaceutical salt" refers to those salts that keep the biological effectiveness and character of free alkali or free acid, and it is not biological or other aspects undesirable.With inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc., particularly hydrochloric acid, and organic acid 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 etc. form salt.In addition, these salts can be prepared by adding inorganic base or organic base in free acid.Salt derived from inorganic base includes but not limited to sodium, potassium, lithium, ammonium, calcium, magnesium salts etc. 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. Specific pharmaceutically acceptable salts of compounds of formula (I) are hydrochlorides, methanesulfonates, and citrates. Specific pharmaceutically acceptable salts of compounds of formula (I) are also sodium and potassium salts.

"Pharmaceutically acceptable esters" refer to compounds of formula (I) that can be derivatized at functional groups to provide derivatives that 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 equivalents of compounds of formula (I), similar to the metabolically labile esters, that are capable of generating the parent compound of formula (I) in vivo are within the scope of the present invention.

The term "protecting group" (PG) represents a group that selectively blocks reactive sites in a multifunctional compound so that chemical reactions, in the sense conventionally associated with it in synthetic chemistry, proceed at another unprotected reactive site. The protecting group can be removed at the appropriate time. Exemplary protecting groups are amino-protecting groups, carboxyl-protecting groups, or hydroxyl-protecting groups. Special protecting groups are tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), and benzyl (Bn). Other special protecting groups are tert-butyloxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc). A more special protecting group is tert-butyloxycarbonyl (Boc).

CAS 1080643-64-6 means 1-(biphenyl-4-ylcarbamoyl)-pyrrolidine-2-carboxylic acid.

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 diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates.

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

Also, one embodiment of the present invention are compounds according to formula (I) as described herein and pharmaceutically acceptable salts or esters thereof, in particular compounds according to formula (I) as described herein and pharmaceutically acceptable salts thereof, more in particular compounds according to formula (I) as described herein.

A further embodiment of the present invention are compounds according to formula (I) as described herein, wherein R ¹ and R ³ together with the carbon and nitrogen atoms to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl, thiazolidinyl or 3-aza-bicyclo[3.1.0]hexyl.

A more particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R ¹ and R ³ together with the carbon and nitrogen atoms to which they are attached form an azetidinyl group.

A particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein ^R2 is H, alkyl or phenyl.

A particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R ² is H.

A particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R ⁴ is H.

A further embodiment of the present invention are compounds according to formula (I) as described herein, wherein W is a bond ^, -O- or ^-CR6R7- .

Another further embodiment of the present invention are compounds according to formula (I) as described herein, wherein W is a bond.

Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein R ⁶ and R ⁷ are H.

A further embodiment of the present invention are compounds according to formula (I) as described herein, wherein A is substituted phenyl, substituted thienyl, substituted benzothienyl, substituted thienopyridinyl, wherein substituted phenyl, substituted thienyl, substituted benzothienyl and substituted thienopyridinyl are substituted with ^R8 , ^R9 and ^R10 .

Another particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein A is phenyl substituted with R ⁸ , R ⁹ and R ¹⁰ .

The present invention also relates to compounds according to formula (I) as described herein, wherein A is 4-chlorophenyl.

A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein B is substituted cycloalkenyl, substituted pyridinyl, substituted phenyl, substituted thienyl, substituted benzothienyl, substituted thienopyridinyl, wherein substituted cycloalkenyl, substituted pyridinyl, substituted phenyl, substituted thienyl, substituted benzothienyl and substituted thienopyridinyl are substituted with R ¹¹ , R ¹² and R ¹³ .

A more particular embodiment of the present invention are compounds according to formula (I) as described herein, B is 4-fluorophenyl.

A more particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R ⁸ is halogen and R ⁹ and R ¹⁰ are H.

A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R ¹¹ is H or halogen and R ¹² and R ¹³ are H.

A more particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R ¹ and R ³ together with the carbon and nitrogen atoms to which they are attached form an azetidinyl group and are a compound of formula (Ia).

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

1-(Biphenyl-2-ylcarbamoyl)-piperidine-2-carboxylic acid;

(R)-1-(5-chlorobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid;

(R)-1-(2-phenoxyphenylcarbamoyl)pyrrolidine-2-carboxylic acid;

(R)-1-(2-Benzylphenylcarbamoyl)pyrrolidine-2-carboxylic acid;

(R)-1-(5-chloro-2-phenoxyphenylcarbamoyl)pyrrolidine-2-carboxylic acid;

1-(Biphenyl-2-ylcarbamoyl)-2-phenyl-pyrrolidine-2-carboxylic acid;

3-(Biphenyl-2-ylcarbamoyl)-thiazolidine-2-carboxylic acid;

(S)-3-(Biphenyl-2-ylcarbamoyl)-thiazolidine-4-carboxylic acid;

(1SR, 2SR, 5RS)-3-(biphenyl-2-ylcarbamoyl)-3-aza-bicyclo[3.1.0]hexane-2-carboxylic acid;

(R)-1-(4-chlorobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid;

(R)-1-(3-fluorobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid;

(R)-1-(4-chlorobiphenyl-2-ylcarbamoyl)azetidine-2-carboxylic acid;

(R)-1-(4-(trifluoromethyl)biphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid;

(R)-1-(4,6-difluorobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid;

1-(Biphenyl-2-ylcarbamoyl)-2-methylpyrrolidine-2-carboxylic acid;

(R)-1-(4-fluorobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid;

(R)-1-(4-(trifluoromethoxy)biphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid;

(R)-1-(4,6-dichlorobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid;

(R)-1-(5′-chloro-[1,1′;2′,1″]terphenyl-3′-ylcarbamoyl)-pyrrolidine-2-carboxylic acid;

(R)-1-(4-cyanobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid;

(R)-1-(2-phenylbenzo[b]thiophen-3-ylcarbamoyl)pyrrolidine-2-carboxylic acid;

(R)-1-(2-phenylthieno[2,3-b]pyridin-3-ylcarbamoyl)pyrrolidine-2-carboxylic acid;

(R)-1-(6-allyl-4-chlorobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid;

(R)-1-(2-phenylthiophen-3-ylcarbamoyl)pyrrolidine-2-carboxylic acid;

(R)-1-(4-chloro-6-cyanobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid;

(R)-1-[4-chloro-6-(cyclohexan-1-yl)-biphenyl-2-ylcarbamoyl]pyrrolidine-2-carboxylic acid;

(S)-1-(4-chlorobiphenyl-2-ylcarbamoyl)azetidine-2-carboxylic acid;

(R)-1-(Biphenyl-2-ylcarbamoyl)azetidine-2-carboxylic acid;

(R)-1-(4-chloro-4′-fluorobiphenyl-2-ylcarbamoyl)azetidine-2-carboxylic acid;

(R)-1-(4-chloro-5-fluorobiphenyl-2-ylcarbamoyl)azetidine-2-carboxylic acid;

(R)-1-(4-chloro-5-methylbiphenyl-2-ylcarbamoyl)azetidine-2-carboxylic acid;

(R)-1-(4-chloro-2′,3′-difluorobiphenyl-2-ylcarbamoyl)azetidine-2-carboxylic acid;

(R)-1-(4-chloro-2′-fluorobiphenyl-2-ylcarbamoyl)azetidine-2-carboxylic acid;

(R)-1-(4-chloro-3′-fluorobiphenyl-2-ylcarbamoyl)azetidine-2-carboxylic acid;

(R)-1-(4-chloro-3′,5′-difluorobiphenyl-2-ylcarbamoyl)azetidine-2-carboxylic acid;

(R)-1-(5-chloro-2-(thiophen-3-yl)phenylcarbamoyl)pyrrolidine-2-carboxylic acid;

(R)-1-(2-(Benzo[b]thiophen-3-yl)-5-chlorophenylcarbamoyl)pyrrolidine-2-carboxylic acid;

(R)-1-(4-chloro-4′-fluorobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid;

(R)-1-(3′,4-dichlorobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid;

(R)-1-(3′-carbamoyl-4-chlorobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid;

(R)-1-[5-chloro-2-(cyclohexan-1-yl)phenylcarbamoyl]pyrrolidine-2-carboxylic acid;

(R)-1-(5-chloro-2-(pyridin-4-yl)phenylcarbamoyl)pyrrolidine-2-carboxylic acid;

(R)-1-(4,4′-dichlorobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid;

(R)-1-(4-chloro-4′-methoxybiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid;

(R)-1-(4-chloro-2′-methylbiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid;

(R)-1-(4-ethylbiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid;

(R)-1-(4-chloro-2′,4′-difluorobiphenyl-2-ylcarbamoyl)azetidine-2-carboxylic acid;

(R)-1-(4-chloro-4′-fluoro-6-methoxybiphenyl-2-ylcarbamoyl)azetidine-2-carboxylic acid;

and pharmaceutically acceptable salts thereof.

Further particular examples of compounds of formula (I) described herein are selected from

(R)-1-(4-chlorobiphenyl-2-ylcarbamoyl)azetidine-2-carboxylic acid;

(R)-1-(4-chloro-4′-fluorobiphenyl-2-ylcarbamoyl)azetidine-2-carboxylic acid;

and pharmaceutically acceptable salts thereof.

Processes for the preparation of compounds of formula (I) as described herein are an object of the present invention.

The preparation of the compound of formula (I) of the present invention can be carried out in a sequential or combined synthetic route. The synthesis of the present invention is shown in the following general scheme. The skills required for realizing the reaction and purification of the products obtained are known to those skilled in the art. In the case of generating a mixture of enantiomers or diastereomers during the reaction, these enantiomers or diastereomers can be separated by methods described herein or known to those skilled in the art, such as chiral chromatography or crystallization. In the case of one of the raw material or compound of formula (I) containing one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups can be introduced before the key step using methods well known in the art. Such protecting groups can be removed using the standard methods described in the literature in the later stage of the synthesis. The substituents and indexes used in the following description of the method have the meanings given herein.

Compounds of formula (I) wherein R ⁴ is H can be prepared as described in Scheme 1.

Amino compound (II) can be converted to isocyanate (III) by methods well known in the art, for example, by treatment with phosgene or a synthetic equivalent of phosgene, such as triphosgene, in the presence of a base, such as triethylamine, in a solvent, such as toluene, dichloromethane, or tetrahydrofuran. Isocyanate (III) can be reacted with amino acid (IV) in the presence of a base, such as triethylamine, in a solvent, such as dichloromethane, to produce urea (I), wherein R is ^H.

An alternative synthesis of compounds of formula (I) wherein R ⁴ is H is described in Scheme 2.

^Ra is H or a functional group, such as NO2 or F

Amino compound (II) can be converted into aryl carbamate (VI) such as phenyl carbamate by methods well known in the art, for example, by optionally in the presence of a base such as triethylamine or pyridine, in a solvent such as tetrahydrofuran or toluene, at a temperature from room temperature to solvent reflux, with aryl chloroformate (V) such as phenyl chloroformate treatment. Aryl carbamate (VI) can be reacted with amino acid (IV) in the presence of a base such as potassium carbonate or triethylamine, in a solvent or solvent mixture such as water, tetrahydrofuran, toluene or N, N-dimethylformamide, at a temperature from room temperature to solvent reflux, to produce urea (I), wherein R ⁴ is H.

Compounds (I) wherein R ⁴ is H and W is a bond can alternatively be prepared as described in Scheme 3:

Using the methods described in Scheme 2, amines (VII) containing leaving groups such as Br, Cl, I, _-OSO2CF3 can be converted to _aryl carbamates (VIII) and then reacted with amino acids (IV) to produce ureas (IX). Alternatively, using the methods described in Scheme 1, ureas (IX) can be prepared from amines (VII) by conversion to isocyanates (X) followed by reaction with amino acids (IV).

Urea (IX) can be converted to compound (I) wherein W is a bond and R is H by palladium-catalyzed coupling with a suitable metal derivative such as boronic acid, boronic acid derivatives or trialkyltin derivatives in the presence of a suitable catalyst such as dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) ^{dichloromethane} adduct.

Compounds (I) wherein R ⁴ is alkyl or cycloalkyl can be prepared as described in Scheme 4:

Wherein R ⁴ is the carboxylic acid of compound (I) of H can be protected with ester such as methyl ester, ethyl ester or tert-butyl ester by using methods well known in the art. The ester (XII) obtained can be with alkylating agent such as alkyl or cycloalkyl halide or trifluoromethanesulfonate, in the presence of base such as potassium carbonate or triethylamine, in solvent such as tetrahydrofuran or N, N-dimethylformamide, react. The product (XIII) of alkylation can be purified by using chromatography method known to those skilled in the art. Wherein R ⁴ is compound (I) of alkyl or cycloalkyl can be obtained by cleaving ester by using method described in the literature or known to those skilled in the art by compound (XIII).

Furthermore, one embodiment of the present invention is a method for preparing a compound of formula (I) as described above, which comprises reacting a compound of formula (III) in the presence of a compound of formula (IV);

wherein R ¹ , R ² , R ³ , A, B and W are as defined above and wherein R ⁴ is H.

Furthermore, an object of the present invention are the compounds according to formula (I) as described herein for use as therapeutically active substances.

Likewise, 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.

According to the present invention, the compounds of formula (I) or their pharmaceutically acceptable salts and esters can be used to treat or prevent type 2 diabetes, 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 liver diseases involving inflammation, steatosis and/or fibrosis, such as non-alcoholic fatty liver disease, more particularly non-alcoholic steatohepatitis.

Special lipodystrophies are those that are hereditary or induced by treatment.

Particular ocular diseases are those that are supported by endothelial cell proliferation and angiogenesis, particularly 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 present invention also relates to the use of a compound of formula (I) as described herein for the treatment or prevention of type 2 diabetes, metabolic syndrome, atherosclerosis, dyslipidemia, liver disease, obesity, lipodystrophy, cancer, eye disease, lung disease, sarcoidosis, chronic kidney disease, chronic inflammatory and autoimmune inflammatory diseases, pre-eclampsia and polycystic ovary syndrome.

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

The present 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 present invention are compounds according to formula (I) as described herein for use in the treatment or prevention of type 2 diabetes, metabolic syndrome, atherosclerosis, dyslipidemia, liver disease, obesity, lipodystrophy, cancer, eye diseases, lung diseases, sarcoidosis, chronic kidney disease, chronic inflammatory and autoimmune inflammatory diseases, pre-eclampsia and polycystic ovary syndrome.

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

Also a particular embodiment of the present invention are compounds according to formula (I) as described herein for use in the treatment or prevention of non-alcoholic steatohepatitis.

The present 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 prevention of type 2 diabetes, metabolic syndrome, atherosclerosis, dyslipidemia, liver disease, obesity, lipodystrophy, cancer, eye disease, lung disease, sarcoidosis, chronic kidney disease, chronic inflammatory and autoimmune inflammatory diseases, pre-eclampsia and polycystic ovary syndrome.

The present invention particularly relates 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 2 diabetes, atherosclerosis, cancer, chronic kidney disease and non-alcoholic steatohepatitis.

Furthermore, one 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 2 diabetes, metabolic syndrome, atherosclerosis, dyslipidemia, liver disease, obesity, lipodystrophy, cancer, eye diseases, lung diseases, sarcoidosis, chronic kidney disease, chronic inflammatory and autoimmune inflammatory diseases, pre-eclampsia and polycystic ovary syndrome, comprising administering an effective amount of a compound according to formula (I) as described herein.

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

Furthermore, a particular embodiment of the present invention are compounds according to formula (I) as described herein, when prepared according to any of the described processes.

Determination procedure

Compound activity against human FABP4 (huFABP4) and/or human FABP5 (huFABP5) is profiled in a terbium (Tb) time-resolved fluorescence energy transfer (TR-FRET) assay (bound to a terbium-labeled anti-His6 tag antibody) that monitors direct binding of Bodipy-labeled fatty acids to His6-tagged FABP proteins (huFABP4 was expressed in-house in E. coli and purified; huFABP5 was purchased from Cayman Chemical Co., cat. no. 10010364). Following ligand binding to the FABP protein, the assay readout reflects energy transfer from the terbium donor molecule to the acceptor Bodipy moiety. The final ligand concentration (125 nM) approximates the Kd of each protein.

Compound DMSO stock solutions (1.8 mM) were diluted 3-fold into 100% DMSO over a series of ten concentrations (50 μM to 0.003 μM final compound concentration). 1 μl of these compound dilutions and 1 μl of 4.5 μM Bodipy-labeled fatty acids (Bodipy FL C11, cat. no. D3862, Invitrogen) in 100% DMSO were pipetted sequentially into the wells of a 384-well black polypropylene plate (Thermo Matrix cat. no. 4344). FABP4 or FABP5 protein was then added (28 μl of 64 nM protein in 25 mM Tris, pH 7.5, 0.4 mg/ml γ-globulin, 1 mM DTT, 0.012% NP40, final protein concentration: 50 nM). The assay blank contained ligand but no protein. The neutral control contained ligand but no compound. After adding the detection reagent (Tb anti-His6 antibody, Columbia Biosciences, TB-110, 6 μl of 24 nM Ab solution in 25 mM Tris pH 7.5, 0.4 mg/ml γ-globulin, final Tb anti-His6 Ab concentration: 4 nM), the plate was rotated at 1000 rpm for one minute. After incubation at room temperature with shaking for 30 minutes, the plate was read using an Envision reader (Perkin Elmer, extinction wavelength: 340 nm, emission: 490 nm and 520 nm, delay: 100 μs; time window: 200 μs, 50 flashes).

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

The relative fluorescence unit (RFU) ratio (520 nm * 10,000 / 488 nm) was used to calculate percent inhibition: 100 - (RFU to compound - blank) / neutral control - blank) * 100. These percent inhibition values were then fitted to the dose-response curve using a 4-parameter logistic model (Hill sigmoidal dose-response model). _{The IC50} reflects the compound concentration associated with 50% inhibition of protein activity compared to the neutral control.

The compounds of formula (I) and their pharmaceutically acceptable salts or esters as described herein have _IC50 (FABP4 inhibition) values of 0.000001 μM to 1000 μM, particular compounds have _IC50 values of 0.000005 μM to 500 μM, and further particular compounds have _IC50 values of 0.00005 μM to 5 μM.

The compounds of formula (I) and their pharmaceutically acceptable salts or esters as described herein have _IC50 (FABP5 inhibition) values of 0.000001 μM to 1000 μM, particular compounds have _IC50 values of 0.000005 μM to 500 μM, and further particular compounds have _IC50 values of 0.00005 μM to 50 μM.

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 (e.g. in the form of tablets, coated tablets, sugar-coated, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories). However, administration can also be achieved parenterally, such as intramuscularly or intravenously (e.g. in the form of injections).

The compounds of formula (I) and their pharmaceutically acceptable salts can be processed together with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, sugar coatings and hard gelatin capsules. For example, lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof etc. can be used as such adjuvants for tablets, sugar coatings and hard gelatin capsules.

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

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 may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also still contain other therapeutically valuable substances.

Dosage can vary over a wide range and will certainly be adapted to individual needs in each particular situation. Generally, in the case of oral administration, the following daily dose should be appropriate: about 0.1 mg to 20 mg/kg body weight, preferably about 0.5 mg to 4 mg/kg body weight (e.g., about 300 mg/ people), divided into preferably 1-3 single doses, which can, for example, be made up of the same amount. However, it should be understood that the upper limits given herein may be exceeded when this display is to be noted.

According to the present invention, the compounds of formula (I) or their pharmaceutically acceptable salts and esters can be used to treat or prevent microvascular complications associated with type 2 diabetes (such as but not limited to diabetic retinopathy, diabetic neuropathy and diabetic nephropathy), coronary artery disease, obesity and underlying inflammatory diseases, chronic inflammatory diseases and autoimmune/inflammatory diseases.

The invention is illustrated hereinafter by means of non-limiting examples.

In case the preparation examples are obtained as mixtures of enantiomers, the pure enantiomers can be separated by methods described herein or by methods known to those skilled in the art such as, for example, chiral chromatography or crystallization.

Example

If not stated otherwise, all examples and intermediates were prepared under argon atmosphere.

General Method A: Synthesis of Isocyanates from Aniline

To a solution of aniline (5.21 mmol, 1.00 eq) in toluene (19.0 ml) was slowly added triphosgene (0.35 eq) and the reaction mixture was heated to reflux for 1 h. The reaction mixture was concentrated to dryness and the product was purified by bulb-to-bulb distillation or used in the next step without further purification.

General Method B: Synthesis of Urea from Isocyanates

To a suspension of amino acid (1.48mmol, 1 equivalent) in DCM (4ml), triethylamine (1 equivalent) and isocyanate (1 equivalent) were added. The reaction mixture was stirred at room temperature for 5 to 36h. A semi-concentrated aqueous sodium carbonate solution was added. Layering was performed and the water layer was washed with DCM. The organic layer was extracted with a diluted sodium carbonate solution. The combined water layer was acidified with concentrated hydrochloric acid. If the product precipitated, it can be collected by filtration and drying. In the case where the product did not precipitate, it can be obtained by extraction with DCM. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to dryness. If necessary, the product can be further purified by chromatography.

General Method C: Synthesis of urea from aniline via carbamate-intermediate

A solution of aniline (2.09mmol, 1.00 equivalent) in THF (4.0ml) was cooled in an ice bath. A solution of phenyl chloroformate (1.04 equivalent) in THF (3.01ml) was added. The reaction mixture was heated to reflux for 1 to 4h. After cooling to room temperature, amino acid (1.1 equivalents), potassium carbonate (3 equivalents) and water (5.26ml) were added. The reaction mixture was stirred at room temperature for 18 to 36h. The mixture was diluted with water and washed with n-heptane. The aqueous layer was partially evaporated to remove the organic solvent. At room temperature, the aqueous layer was slowly acidified using 25% HCl. The precipitated product can be collected by filtration, washed with a small amount of water and dried. In the case where the product does not precipitate, it can be obtained by extracting with DCM. The organic layer is dried over Na ₂ SO ₄ , filtered and concentrated to dryness. If necessary, the product can be further purified by chromatography.

General Method D: Suzuki Coupling

Under argon, aromatic bromide, iodide, triflate or mesylate (0.29mmol, 1 equivalent), boric acid or boric acid ester (1.5 equivalents) and 2M sodium carbonate aqueous solution (3 equivalents) are combined with dioxane (3.5ml) and water (1.4ml). [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), dichloromethane adduct (0.05 equivalent) is added and the reaction mixture is stirred at 80°C for 3 to 10h. After cooling to room temperature, the mixture is filtered. Dilute HCl aqueous solution is added and the mixture is extracted with EtOAc. The combined organic layers are dried over _MgSO4 , filtered and concentrated in vacuo. The product can be purified by chromatography.

Synthesis of intermediates

Intermediate I14

4,6-Difluorobiphenyl-2-amine

Step 1: A solution of 2,4-difluoro-6-nitroaniline (CAS# 364-30-7; 2.00 g) in DCM (97 ml) was cooled to 0°C. At this temperature, boron trifluoride etherate (1.61 g) was added, followed by tert-butyl nitrite (1.63 g). The resulting reaction mixture was warmed to room temperature and stirred for 1 hour. The liquid was poured out of the flask and the oily residue was washed with DCM. The residue was then dried under high vacuum and used in the next step without further purification.

Step 2: the product (2.18g) of step 1 and phenylboronic acid (1.0g) are merged with 1,4-dioxane (20ml), and then palladium acetate (II) (55.2mg) is added to obtain a foamy dark brown solution. The reaction mixture is stirred at room temperature overnight and then concentrated in a vacuum. The product is purified by flash chromatography (silica gel, 0% to 50% EtOAc in heptane) to obtain 2,4-difluoro-6-nitrobiphenyl (688mg), which is a brown oil.

Step 3: 2,4-difluoro-6-nitrobiphenyl (684 mg) and sodium sulfite nonahydrate (2.08 g) were combined with ethanol (3.56 ml) and (3.56 ml) to give a brown solution. The reaction mixture was stirred at 100° C. for 4.5 h and stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc. The organic layer was washed with water and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo. The product was purified by flash chromatography (silica gel, 0% to 50% EtOAc in heptane) to give the title compound (469 mg) as a light yellow liquid.

Intermediate I17

4-(Trifluoromethoxy)biphenyl-2-amine

Under argon, 2-bromo-5-(trifluoromethoxy)aniline (CAS#887267-47-2; 200 mg), phenylboronic acid (143 mg) and 2M aqueous sodium carbonate solution (1.17 ml) were combined with dioxane (9.4 ml) and water (3.75 ml) at room temperature. [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane adduct (31.9 mg) was added to give a yellow suspension. The reaction mixture was heated to 80° C. and stirred at 80° C. overnight. The reaction mixture was cooled and filtered through glass fiber paper, washed with 30 mL of water and 30 mL of EtOAc, the layers were separated, and the aqueous layer was back-extracted with EtOAc. The organic layers were combined, dried over MgSO ₄ and concentrated in vacuo. The product was purified by flash chromatography (silica gel, 0% to 70% EtOAc in n-heptane) to give the title compound (198 mg) as a yellow oil.

Intermediate I19

5′-Chloro-[1,1′;2′,1″]terphenyl-3′-ylamine

Step 1: To a solution of 2,4-dichloro-6-nitrophenol (CAS# 609-89-2; 2.4 g) in DCM (150 ml) was added triethylamine (2.69 g). The reaction mixture was cooled to -20°C, trifluoromethanesulfonic anhydride (3.91 g) was slowly added at this temperature and stirred for 20 min. The cooling bath was removed and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was washed with saturated aqueous _NH4Cl solution and brine, and the aqueous layer was extracted with DCM. The combined organic layers were dried over _MgSO4 , filtered and concentrated in vacuo. The product was purified by flash chromatography (silica gel, 50 g, 0% to 40% EtOAc in heptane) to give 2,4-dichloro-6-nitrophenyl trifluoromethanesulfonate (3.9 g) as a light yellow solid.

Step 2: Combine 2,4-dichloro-6-nitrophenyl trifluoromethanesulfonate (3.94 g), phenylboronic acid (2.12 g), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride, dichloromethane complex (474 mg) with dioxane (34.1 ml), 2M aqueous sodium carbonate solution (17.4 ml), and water (24.7 ml) to give an orange suspension. The reaction mixture was stirred at 80° C. for 3.5 h. The reaction mixture was cooled, then filtered through glass fiber paper and washed with EtOAc and KHSO ₄ solution. The filtrate was extracted with EtOAc, and the organic layer was washed with brine, dried over MgSO ₄ , and concentrated in vacuo. The product was purified by flash chromatography (silica gel, 70 g, 0% to 50% EtOAc in hexanes) followed by preparative HPLC to afford 5'-chloro-3'-nitro-[1,1';2',1"]terphenyl (455 mg) as an off-white solid.

Step 3: 5′-Chloro-3′-nitro-[1,1′;2′,1″]terphenyl (437 mg), iron powder (473 mg) and ammonium chloride (75.5 mg) were combined with ethanol (7.15 ml) and water (0.64 ml) to give a white suspension. The reaction mixture was heated to 85°C (reflux) and stirred for 6.5 h, then stirred at room temperature overnight. Iron powder (145 mg) and ammonium chloride (25 mg) were added and the reaction was again heated to 85°C for 2.5 h, then again at room temperature overnight. The reaction mixture was filtered through glass fiber paper and concentrated in vacuo. The crude product was extracted with EtOAc and the organic phase was washed with _NaHCO₃ solution and brine. The organic layer was dried over _MgSO₄ , filtered and concentrated in vacuo. The product was purified by flash chromatography (silica gel, 0% to 20% EtOAc in heptane) to give the title compound (356 mg) as an off-white solid.

Intermediate I23

6-Allyl-4-chlorobiphenyl-2-amine

Step 1: Similar to the synthesis of intermediate I19, step 1, 2-allyl-4-chloro-6-nitrophenol (CAS# 569688-58-0) was converted to 2-allyl-4-chloro-6-nitrophenyl trifluoromethanesulfonate.

Step 2: Similar to the synthesis of intermediate I19, in step 2, 2-allyl-4-chloro-6-nitrophenyl trifluoromethanesulfonate reacts with phenylboronic acid to give 2-allyl-4-chloro-6-nitrobiphenyl.

Step 3: Analogously to the synthesis of intermediate I19, in step 3, 2-allyl-4-chloro-6-nitrobiphenyl was reduced with iron to give the title compound as a light yellow liquid.

Intermediate I25

6-Amino-4-chlorobiphenyl-2-carbonitrile

Step 1: Similar to the synthesis of intermediate I19, in step 1, 5-chloro-2-hydroxy-3-nitrobenzonitrile (CAS#88310-62-7) was converted to 4-chloro-2-cyano-6-nitrophenyl trifluoromethanesulfonate.

Step 2: Similar to the synthesis of intermediate I19, in step 2, 4-chloro-2-cyano-6-nitrophenyl trifluoromethanesulfonate reacts with phenylboronic acid to give 4-chloro-6-nitrobiphenyl-2-carbonitrile.

Step 3: Analogously to the synthesis of intermediate 119, in step 3, 4-chloro-6-nitrobiphenyl-2-carbonitrile was reduced with iron to give the title compound as a light yellow solid.

Intermediate I26

4-Chloro-6-(cyclohexyl-1-yl)-biphenyl-2-amine

Step 1: Similar to the synthesis of intermediate I19, step 2, 2-bromo-4-chloro-6-nitrophenol (CAS#15969-10-5) reacts with cyclohexenylboronic acid to give 4-chloro-2-cyclohexenyl-6-nitrophenol.

Step 2: Analogously to the synthesis of intermediate I19, step 1, 4-chloro-2-cyclohexenyl-6-nitrophenol was converted to 4-chloro-2-cyclohexenyl-6-nitrophenyl trifluoromethanesulfonate.

Step 3: Similar to the synthesis of intermediate I19, step 2, 4-chloro-2-cyclohexenyl-6-nitrophenyl trifluoromethanesulfonate was reacted with phenylboronic acid to give 4-chloro-2-cyclohexenyl-6-nitrobiphenyl.

Step 4: Analogously to the synthesis of intermediate 119, step 3, 4-chloro-2-cyclohexenyl-6-nitrobiphenyl was reduced with iron to give the title compound as a brown oil.

Intermediate I29

4-Chloro-4′-fluorobiphenyl-2-amine

2-Bromo-5-chloroaniline (CAS#823-57-4; 5g), 4-fluorophenylboronic acid (3.56g) and cesium carbonate (31.6g) were combined in THF (70ml) and water (35ml). The mixture was degassed by bubbling argon through the solution. After adding [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (886mg), the reaction mixture was stirred at 80°C for 1h in a sealed tube. The reaction mixture was diluted with EtOAc, washed with water, dried _{over Na2SO4} , evaporated and purified by chromatography (silica gel, 0% to 30% EtOAc in heptane). The product was finally distilled bulb-to-bulb at 0.3 mbar and at a 120-130°C oven temperature to give the title compound (5.07g) as a light yellow liquid.

Analogously to the synthesis of intermediate 129, the following intermediates were prepared:

Intermediate I52

(R)-1-(2-Bromo-5-chlorophenylcarbamoyl)pyrrolidine-2-carboxylic acid

Following General Procedure B, R-proline (CAS# 344-25-2) was reacted with 1-bromo-4-chloro-2-phenylisocyanate (CAS# 1261815-71-7) to afford the title compound as an off-white solid.

Intermediate I62

(R)-1-(2-Bromo-5-ethylphenylcarbamoyl)pyrrolidine-2-carboxylic acid

Following General Procedures A and B, R-proline (CAS# 344-25-2) was reacted with 2-bromo-5-ethylaniline (CAS# 80948-73-8) to afford the title compound as an off-white solid.

Intermediate I64

4-Chloro-4′-fluoro-6-methoxybiphenyl-2-amine

Step 1: Under argon, triethylamine (4.32 g) was added to a solution of 4-chloro-2-methoxy-6-nitrophenol (CAS#118724-89-3; 3.78 g) in DCM (200 ml). The reaction mixture was cooled to -20°C, followed by the dropwise addition of trifluoromethanesulfonic anhydride (6.41 g). The mixture was stirred for 20 min, after which the cooling bath was removed and the reaction mixture was stirred at room temperature for 2.5 h. The crude reaction mixture was washed with saturated aqueous _NH4Cl solution and brine. The aqueous layer was extracted with DCM. The combined organic layers were dried over _MgSO4 , filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 100% EtOAc in n-heptane) to give 4-chloro-2-methoxy-6-nitrophenyl trifluoromethanesulfonate (6.23 g) as a yellow solid.

Step 2: Analogous to the synthesis of intermediate I19, in step 2, 4-chloro-2-methoxy-6-nitrophenyl trifluoromethanesulfonate was reacted with 4-fluorophenylboronic acid to give 4-chloro-4′-fluoro-2-methoxy-6-nitrobiphenyl as a yellow solid.

Step 3: Analogously to the synthesis of intermediate 119, step 3, 4-chloro-4'-fluoro-2-methoxy-6-nitrobiphenyl was reduced with iron to give the title compound as a yellow oil, which was used crude in the next step.

Example A

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

Example B

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

Claims (13)

1. Compounds of formula (I) in ^R1 and ^R3, together with the carbon and nitrogen atoms they are attached to, form aza-butyl, pyrrolidinyl, piperidinyl, thiazolyl, or 3-aza-bicyclo[3.1.0]hexyl; ^R2 is H, _C1-7 alkyl, or phenyl; ^R4 is H; W is a key, -O- or -CR ⁶ R ⁷ -; R ⁵ is H, _C1-7 alkyl, or _C3-8 cycloalkyl; ^R6 and ^R7 are H; A is a substituted phenyl, a substituted thiophene, a substituted benzothiophene, or a substituted thiophene-pyridyl, wherein the substituted phenyl, the substituted thiophene, the substituted benzothiophene, and the substituted thiophene-pyridyl are substituted by ^R8 , ^R9 , and ^R10 . B is a substituted _C3-8 cycloalkenyl, substituted pyridyl, substituted phenyl, substituted thiophene, substituted benzothiophene, substituted thiophenepyridyl, wherein the substituted _C3-8 cycloalkenyl, substituted pyridyl, substituted phenyl, substituted thiophene, substituted benzothiophene and substituted thiophenepyridyl are substituted by ^R11 , ^R12 and ^R13 ; ^R8 , ^R9 and ^R10 are independently selected from H, _C1-7 alkyl, _C2-7 alkenyl, halo- _C1-7 alkyl, halo- _C1-7 alkoxy, halogen, phenyl and cyano; ^R11 is H or a halogen and ^R12 and ^R13 are H; Or medicinal salt; The condition is that CAS 1080643-64-6 is an exception. 2. The compound according to claim 1, wherein ^R1 and ^R3 together with the carbon and nitrogen atoms to which they are attached form a nitrogen-containing heterocyclic butyl group. 3. The compound according to claim 1 or 2, wherein ^R2 is H. 4. The compound according to claim 1 or 2, wherein W is a bond. 5. The compound according to claim 1 or 2, wherein A is a phenyl group substituted with ^R8 , ^R9 and ^R10 . 6. The compound according to claim 1 or 2, wherein A is 4-chlorophenyl. 7. The compound according to claim 1 or 2, wherein B is 4-fluorophenyl. 8. The compound according to claim 1 or 2, wherein R ⁸ is a halogen and R ⁹ and R ¹⁰ are H. 9. A compound, said compound being selected from... 1-(biphenyl-2-ylcarbamoyl)-piperidine-2-carboxylic acid; (R)-1-(5-chlorobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(2-phenoxyphenylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(2-benzylphenylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(5-chloro-2-phenoxyphenylcarbamoyl)pyrrolidine-2-carboxylic acid; 1-(biphenyl-2-ylcarbamoyl)-2-phenyl-pyrrolidine-2-carboxylic acid; 3-(biphenyl-2-ylcarbamoyl)-thiazolidin-2-carboxylic acid; (S)-3-(biphenyl-2-ylcarbamoyl)-thiazolidin-4-carboxylic acid; (1SR, 2SR, 5RS)-3-(biphenyl-2-ylcarbamoyl)-3-aza-bicyclo[3.1.0]hexane-2-carboxylic acid; (R)-1-(4-chlorobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(3-fluorobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(4-chlorobiphenyl-2-ylcarbamoyl)azacyclobutane-2-carboxylic acid; (R)-1-(4-(trifluoromethyl)biphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(4,6-difluorobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid; 1-(biphenyl-2-ylcarbamoyl)-2-methylpyrrolidine-2-carboxylic acid; (R)-1-(4-fluorobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(4-(trifluoromethoxy)biphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(4,6-dichlorobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(5′-chloro-[1,1′;2′,1″]terphenyl-3′-ylcarbamoyl)-pyrrolidine-2-carboxylic acid; (R)-1-(4-cyanobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(2-phenylbenzo[b]thiophene-3-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(2-phenylthiopheno[2,3-b]pyridin-3-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(6-allyl-4-chlorobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(2-phenylthiophene-3-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(4-chloro-6-cyanobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-[4-chloro-6-(cyclohex-1-yl)-biphenyl-2-ylcarbamoyl]pyrrolidine-2-carboxylic acid; (S)-1-(4-chlorobiphenyl-2-ylcarbamoyl)azacyclobutane-2-carboxylic acid; (R)-1-(biphenyl-2-ylcarbamoyl)azacyclobutane-2-carboxylic acid; (R)-1-(4-chloro-4′-fluorobiphenyl-2-ylcarbamoyl)azacyclobutane-2-carboxylic acid; (R)-1-(4-chloro-5-fluorobiphenyl-2-ylcarbamoyl)azacyclobutane-2-carboxylic acid; (R)-1-(4-chloro-5-methylbiphenyl-2-ylcarbamoyl)azacyclobutane-2-carboxylic acid; (R)-1-(4-chloro-2′,3′-difluorobiphenyl-2-ylcarbamoyl)azacyclobutane-2-carboxylic acid; (R)-1-(4-chloro-2′-fluorobiphenyl-2-ylcarbamoyl)azacyclobutane-2-carboxylic acid; (R)-1-(4-chloro-3′-fluorobiphenyl-2-ylcarbamoyl)azacyclobutane-2-carboxylic acid; (R)-1-(4-chloro-3′,5′-difluorobiphenyl-2-ylcarbamoyl)azacyclobutane-2-carboxylic acid; (R)-1-(5-chloro-2-(thiophen-3-yl)phenylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(2-(benzo[b]thiophen-3-yl)-5-chlorophenylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(4-chloro-4′-fluorobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(3′,4-dichlorobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(3′-carbamoyl-4-chlorobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-[5-chloro-2-(cyclohex-1-yl)phenylcarbamoyl]pyrrolidine-2-carboxylic acid; (R)-1-(5-chloro-2-(pyridin-4-yl)phenylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(4,4′-dichlorobiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(4-chloro-4′-methoxybiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(4-chloro-2′-methylbiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(4-ethylbiphenyl-2-ylcarbamoyl)pyrrolidine-2-carboxylic acid; (R)-1-(4-chloro-2′,4′-difluorobiphenyl-2-ylcarbamoyl)azacyclobutane-2-carboxylic acid; (R)-1-(4-chloro-4′-fluoro-6-methoxybiphenyl-2-ylcarbamoyl)azacyclobutane-2-carboxylic acid; And its medicinal salts. 10. The compound according to claim 1, wherein the compound is selected from... (R)-1-(4-chlorobiphenyl-2-ylcarbamoyl)azacyclobutane-2-carboxylic acid; (R)-1-(4-chloro-4′-fluorobiphenyl-2-ylcarbamoyl)azacyclobutane-2-carboxylic acid; And its medicinal salts. 11. A method for preparing the compound according to claim 1, the method comprising reacting a compound of formula (III) in the presence of a compound of formula (IV), Wherein ^R1 , ^R2 , ^R3 , A, B and W are as defined in claim 1 and wherein ^R4 is H. 12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 and a therapeutically inert carrier. 13. Use of the compound according to any one of claims 1 to 10 for the preparation of a medicament for the treatment or prevention of type 2 diabetes, atherosclerosis, cancer, chronic kidney disease, and non-alcoholic steatohepatitis.