KR20060017791A - Pyridinyl carbamates as hormone-sensitive lipase inhibitors - Google Patents

Abstract

Novel substituted pyridinyl carbamates of general formula (I):, pharmaceutical compositions comprising them and use thereof in the treatment and/or prevention of diseases and disorders related to hormone sensitive lipase. More particularly, the compounds are useful for the treatment and/or prevention of diseases and disorders in which modulation of the activity of hormone sensitive lipase is beneficial.

Description

Pyridinyl CARBAMATES AS HORMONE-SENSITIVE LIPASE INHIBITORS

The present invention relates to novel substituted pyridinyl carbamates, pharmaceutical compositions comprising these compounds, the use of these compounds as pharmaceutical compositions, and methods of treatment using these compounds and compositions. The compound shows inhibition of hormone sensitive lipases. As a result, the compounds are useful for the treatment and / or prevention of diseases and disorders associated with hormone sensitive lipases.

The total energy homeostasis of mammalian systems requires a high degree of control to ensure the availability of the appropriate substrate at the right time. Plasma glucose levels increase during the postprandial state and return to preprandial levels within 2-3 hours. During these 2-3 hours, insulin activates glucose uptake by skeletal muscle and adipose tissue and reduces the release of free fatty acids (FFA) from fat cells, so that the two substrates do not compete with each other. When plasma glucose levels drop, an increase in plasma FFA is necessary to switch from glucose to fat utilization by various tissues.

In individuals with insulin resistance, FFA levels do not drop in response to insulin as in normal individuals, thus preventing normal use of glucose by skeletal muscle, fat and liver. In addition, there is a negative correlation between insulin sensitivity and plasma FFA levels.

Hormone-sensitive lipases (HSLs) are enzymes expressed in adipose tissue, macrophages, muscles, adrenal glands, testes and islets (Kraemer and Shen, J. Lipid Res. 2002, 43, 1585-1594). In fat cells, HSL catalyzes the conversion of triglycerides to glycerol and fatty acids. The regulation of circulating FFA is through the regulation of this enzyme. Insulin induces inactivation of HSL with a subsequent drop in plasma FFA levels during the postprandial state and then activates this enzyme when insulin concentration drops and catecholamines increase during the post-absorption period. Activation of HSL induces an increase in plasma FFA because they become a major energy source during fasting.

Activation-inactivation of HSLs is mediated primarily through the cAMP-protein kinase A and AMP-dependent kinase pathways. There are compounds such as nicotinic acid and derivatives thereof that reduce the activation of HSL and cause a decrease in lipolysis through these pathways leading to a decrease in FFA levels. These drugs have a beneficial effect on the availability of glucose and normalization of excess triglyceride synthesis seen in patients with elevated FFAs. However, because these pathways are used by other processes in the body, these drugs have serious side effects.

Carbamates similar to the compounds of the present invention have already been prepared. Ross Kelly et al. (Org. Lett. 24 (1), 2001,3895-3898) discloses the following compounds and their use in chemically powered molecular motors:

Several publications disclose the preparation and use of HSL inhibitors (WO 01/87843, WO 01/17981, WO 01/66531, WO 01/83497, and WO 01/26664). However, the structures of these compounds are very different from those of the present compounds. Thus, none of the HSL inhibitors disclosed in these publications contain pyridinyl and carbamate structures as in the compounds of the present invention.

We have found potent pyridinyl carbamate compounds that specifically inhibit the lipolytic activity of HSL, which may be expected to reduce plasma FFA levels. These compounds can be used to treat diseases in which reduced levels of plasma FFA are desired, such as, for example, insulin resistance, X syndrome, dyslipidemia, diseases of lipoprotein metabolism.

One object of the present invention is to provide compounds and pharmaceutical compositions that inhibit the lipolytic activity of HSL. A further object is to provide compounds having good pharmaceutical properties such as, for example, solubility, bioavailability, specificity and the like.

Justice

The following is a detailed definition of the terms used to describe the compounds of the present invention.

The term "halogen" in this context refers to an atom selected from the group consisting of F, Cl, Br and I.

The term “C _1-6 -alkyl” in this context refers to a saturated, branched or straight hydrocarbon group having 1 to 6 carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec -butyl, tert -butyl, n-pentyl, isopentyl, neopentyl, tert -pentyl, n-hexyl , Isohexyl and the like.

The term "C _2-6 -alkyl" in this context refers to a saturated, branched or straight hydrocarbon group having 2 to 6 carbon atoms. Representative examples include, but are not limited to, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec -butyl, tert -butyl, n-pentyl, isopentyl, neopentyl, tert -pentyl, n-hexyl, iso Hexyl and the like.

The term "C _1-6 alkoxy" in the context of the present invention refers to the group -OC _1-6 -alkyl wherein C _1-6 -alkyl is as defined above. Representative examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, isobutoxy, sec -butoxy, tert -butoxy, n-pentoxy, isopentoxy , neo Pentoxy , tert -pentoxy, n-hexoxy, isohexoxy and the like.

As used herein, the term “C _2-6 -alkenyl” refers to a branched or straight hydrocarbon group unsaturated with an olefin having 2 to 6 carbon atoms and at least one double bond. Examples of these groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, allyl, iso-propenyl, 1,3-butadienyl, 1-butenyl, hexenyl, pentenyl, and the like. Include.

As used herein, the term “C _3-10 -cycloalkyl” denotes a mono-, non-, tri-, or spirocarboncyclic group having 3 to 10 carbon atoms. Representative examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo [3.2.1] octyl, spiro [4.5] decyl, norpinyl, norbornyl, norcaryl , Adamantyl and the like.

As used herein, the term “C _3-8 -heterocyclyl” denotes a saturated 3-8 membered ring containing one or more heteroatoms selected from hydrogen, oxygen and sulfur. Representative examples are pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, aziridinyl, tetrahydrofuranyl and the like.

As used herein, the term "aryl" refers to mono, such as, for example, phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl, biphenylenyl, and the like. Carbocyclic aromatic ring systems that are cyclic, bicyclic, or polycyclic. Aryl is also intended to include partially hydrogenated derivatives of the carbocyclic aromatic systems listed above. Non-limiting examples of such partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl and the like.

The term “heteroaryl” as used herein refers to nitrogen, oxygen and sulfur such as furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2, 3-triazolyl, 1,2,4-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazineyl, 1,2,4-triazinyl, 1 , 3,5-triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1, 2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, thiadizinyl, indolyl, isoin Doryl, benzofuranyl, benzothiophenyl (thianaphthenyl), indazolyl, benzimidazolyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinazolinyl, quinolizinyl , Quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, putridinyl, carba Heterocyclic aromatic ring systems containing one or more heteroatoms selected from zolyl, azepinyl, diazepinyl, acridinyl and the like. Heteroaryls are also intended to include partially hydrogenated derivatives of the heterocyclic systems listed above. Non-limiting examples of such hydrogenated derivatives include 2,3-dihydrobenzofuranyl, 3,4-dihydroisoquinolinyl, pyrrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxa Zefinil and the like.

As used herein, the term "perhalomethyl" refers to a methyl moiety substituted with three halogen atoms. Non-limiting examples of perhalomethyl are CF ₃ , CCl ₃ , and CF ₂ Cl.

As used herein, the term “perhalomethoxy” refers to perhalomethyl linked through, for example, —O—CF ₃ , —O—CCl ₃ , and —O—CF ₂ Cl.

As used herein, the term “ring system” includes aromatic and non-aromatic ring moieties, which may be monocyclic, bicyclic, or polycyclic, and they are 0, 1 or selected from nitrogen, oxygen, and sulfur It includes moieties having more heteroatoms. Non-limiting examples of such ring systems are aryl, C _3-8 -heterocyclyl and heteroaryl.

As used herein, the term “heterocyclic system” includes aromatic and non-aromatic ring moieties, which may be monocyclic, bicyclic or polycyclic, having one or more selected from nitrogen, oxygen and sulfur in their ring structure. It contains a hetero atom. Non-limiting examples of such heterocyclic systems are C _3-8 -heterocyclyl and heteroaryl.

Certain defined terms may occur one or more times in the structural formula, in which each term will be defined independently of one another.

As used herein, the term “optionally substituted” means that the groups in question are unsubstituted or substituted with one or more specific substituents. If the groups in question are substituted with one or more substituents, the substituents may be the same or different.

As used herein, the terms “disease”, “state” and “disease” are used interchangeably to specify the condition of a patient that is not a normal physiological state of a human. As used herein, the term “treatment” refers to the care and protection of a patient suffering from an advanced disease, condition or disorder, and to an individual at risk of developing the disease, condition or disorder prior to clinical onset of the disease, condition or disorder. Means care and protection. The purpose of treatment is to combat a disease, condition or condition, and to fight the development of the disease, condition or condition. Treatment includes the administration of an active compound to prevent or delay the development of symptoms or complications, to eliminate or control a disease, condition or disorder, and to mitigate the symptoms or complications associated with the disease, condition or disorder.

As used herein, the term “effective amount” means a sufficient dosage for the treatment of an effective patient as compared to no treatment.

As used herein, the term “modulate” means affecting, ie adjusting a parameter, affects that parameter in a preferred manner. An example is to regulate insulin secretion from beta cells and to regulate plasma levels of free fatty acids.

As used herein, the term “pharmaceutical” means a pharmaceutical composition suitable for administration of a pharmaceutically active compound to a patient.

As used herein, the term "pharmaceutically acceptable" means suitable for normal pharmaceutical application, i.e., not causing adverse events in patients and the like.

Description of the invention

In one embodiment the present invention relates to diastereomers, enantiomers or the like comprising compounds of formula (I) and mixtures thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, or polymorphs To tautomer forms of

In the above formula

R ¹ and R ² are hydrogen, hydroxy, sulfanyl, amino, amide, urea, thiourea, benzamide, thioamide, halogen, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2- Independently selected from ₆ -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl, each of hydroxy, sulfanyl, amino, amide, urea, thiourea, benz Amide, thioamide, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl Silver hydroxy, sulfanyl, oxo, thioxo, halogen, amino, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8- And optionally substituted with one or more substituents independently selected from heterocyclyl, and C _3-10 -cycloalkyl, each of hydroxy, sulfanyl, sulfo, C _1-6 -alkyl, C _1-6- Alkoxy, C _2-6 -alkenyl, aryl, hete Roaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, sulfo, perhalomethyl, perhalomethoxy, C _1-6 -alkyl, C Optionally substituted with one or more substituents independently selected from _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl; ;

R ³ , and R ⁴ are hydrogen, hydroxy, sulfanyl, halogen, amino, sulfo, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and Independently selected from C _3-10 -cycloalkyl, each of hydroxy, sulfanyl, amino, sulfo, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8- Heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 Optionally substituted with one or more substituents independently selected from heterocyclyl and C _3-10 -cycloalkyl, each of hydroxy, sulfanyl, amino, sulfo, C _1-6 -alkyl, C _2-6 -al Kenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, C _1-6 -alkyl, perhalomethyl and perhalomethoxy One or more values independently selected from Doedoe group optionally substituted;

Provided that the compound is

2,2-dimethyl-N- [6- (methyl-phenyl-carbamoyloxy) -pyridin-3-yl] -succinic acid, 3, 3-dimethyl-4- [6- (methyl-phenyl-carba Molyoxy) -pyridin-3-ylcarbamoyl] -butyric acid, methyl-phenyl-carbamic acid pyridin-2-yl ester, methyl-phenyl-carbamic acid 5-chloro-pyridin-2-yl ester, methyl-phenyl- Carbamic acid 5-trifluoromethyl-pyridin-2-yl ester, methyl-phenyl-carbamic acid 3-chloro-5-trifluoromethyl-pyridin-2-yl ester, methyl-phenyl-carbamic acid 5-benzoylamino -Pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (cyclohexanecarbonyl-amino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 4,4-dimethyl-2,6-dioxo -3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-6'-yl ester, methyl-phenyl-carbamic acid 5- (2,2-dimethyl-propionylamino)- Pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (2-cyclohexyl-acetylamino) -pyridin-2-yl ester, Methyl-phenyl-carbamic acid 5- (3,3-dimethyl-butyrylamino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5-[(pyridine-2-carbonyl) -amino3-pyridine- 2-yl ester, methyl-phenyl-carbamic acid 5-[(6-chloro-pyridine-3-carbonyl) -amino] -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (2,2- Dimethyl-propylcarbamoyl) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl -6'-yl ester, methyl-phenyl-carbamic acid 5- (2,5-dioxo-pyrrolidin-1-yl) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4- Trifluoromethyl-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4-chloro-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4 -Methoxy-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 4,4-dimethyl-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl- 6'-days Ester, methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester, methyl-phenyl-carbamic acid 5-benzenesulfonylamino-pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (3, 3-Dimethyl-2, 5-dioxo-pyrrolidin-1-yl) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- [3, 3-dimethyl-5- (4-methyl-pipee Razin-1-yl) -5-oxo-pentanoylamino] -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- [3, 3-dimethyl-4- (pyridin-3-ylcarbamoyl) -Butyrylamino] -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (3,3-dimethyl-5-morpholin-4-yl-5-oxo-pentanoylamino) -pyridine-2- One ester, methyl-phenyl-carbamic acid 5- [4- (2-dimethylamino-ethylcarbamoyl) -3, 3-dimethyl-butyrylamino] -pyridin-2-yl ester; N-methyl-N-phenylcarbamic acid 5-nitro-3-trifluoromethylpyridin-2-yl ester,

N-methyl-N-phenylcarbamic acid 3-nitropyridin-2-yl ester, and

N-methyl-N-phenylcarbamic acid 5-nitropyridin-2-yl ester.

In one embodiment R ² is hydrogen, hydroxy, amino, halogen, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocycle Aryl, amide, urea and thiourea and C _3-10 -cycloalkyl, each of hydroxy, amino, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl , Heteroaryl, C _3-8 -heterocyclyl, amide, urea and thiourea and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C _1-6 -alkyl, C Optionally substituted with one or more substituents independently selected from _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl have.

In other embodiments, R ² is halogen or hydrogen.

In other embodiments, R ⁴ is selected from hydrogen, halogen, C _1-6 -alkyl, C _2-6 -alkenyl, and each C _1-6 -alkyl, C _2-6 -alkenyl is hydroxy, Optionally substituted with one or more substituents independently selected from halogen, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 heterocyclyl and C _3-10 -cycloalkyl.

In other embodiments, R ⁴ is selected from hydrogen, halogen and C _1-6 -alkyl.

In other embodiments, R ⁴ is hydrogen.

In other embodiments, R ⁴ is halogen.

In other embodiments, R ³ is selected from hydrogen, hydroxy, halogen, C _1-6 -alkyl, C _2-6 -alkenyl, and each hydroxy, C _1-6 -alkyl, C _2-6- Alkenyl is one independently selected from hydroxy, halogen, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl It is optionally substituted with the above substituents.

In other embodiments, R ³ is selected from halogen, C _1-6 -alkyl, methoxy, perhalomethyl and perhalomethoxy.

In other embodiments, R ³ is selected from halogen, methyl, ethyl, isopropyl, methoxy and perhalomethyl.

In other embodiments, R ³ is selected from halogen, methyl, methoxy and perhalomethyl.

In another aspect, the invention provides diastereomers, enantiomers or the like comprising a compound of formula (I) and a mixture thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, or a polymorph It relates to its tautomeric form:

In the above formula

R ¹ and R ² are hydrogen, hydroxy, sulfanyl, amino, amide, urea, thiourea, halogen, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl , Heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl, each independently selected from hydroxy, sulfanyl, amino, amide, urea, thiourea, sulfo, C _1-6- Alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino Independently from sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl Optionally substituted with one or more substituents selected, and each of hydroxy, sulfanyl, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _{3-8-heterocyclyl,} and C _3-10 - cycloalkyl, hydroxy, Isoquinoline, oxo, halogen, amino, sulfonyl, perhaloalkyl, methyl, perhaloalkyl Romero-ethoxy, C _1-6 - alkyl, C _1-6 - alkoxy, C _2-6 - alkenyl, aryl, heteroaryl, C _3-8 - Optionally substituted with one or more substituents independently selected from heterocyclyl, and C _3-10 -cycloalkyl;

R ³ and R ⁴ are hydrogen, hydroxy, sulfanyl, halogen, amino, sulfo, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and C Independently selected from _3-10 -cycloalkyl, each of hydroxy, sulfanyl, amino, sulfo, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -hetero Cycyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8- Optionally substituted with one or more substituents independently selected from heterocyclyl and C _3-10 -cycloalkyl, each of hydroxy, sulfanyl, amino, sulfo, C _1-6 -alkyl, C _2-6 -al Kenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, C _1-6 -alkyl, perhalomethyl and perhalomethoxy One independently selected from Doedoe optionally substituted with a substituent;

Provided that the compound is

2,2-Dimethyl-N- [6- (methyl-phenyl-carbamoyloxy) -pyridin-3-yl] -succinic acid, 3,3-dimethyl-4- [6- (methyl-phenyl-carba Moyloxy) -pyridin-3-ylcarbamoyl] -butyric acid, methyl-phenyl-carbamic acid pyridin-2-yl ester, methyl-phenyl-carbamic acid 5-chloro-pyridin-2-yl ester, methyl-phenyl- Carbamic acid 5-trifluoromethyl-pyridin-2-yl ester, methyl-phenyl-carbamic acid 3-chloro-5-trifluoromethyl-pyridin-2-yl ester, methyl-phenyl-carbamic acid 5-benzoylamino -Pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (cyclohexanecarbonyl-amino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 4,4-dimethyl-2,6-dioxo -3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-6'-yl ester, methyl-phenyl-carbamic acid 5- (2,2-dimethyl-propionylamino)- Pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (2-cyclohexyl-acetylamino) -pyridin-2-yl ester, Methyl-phenyl-carbamic acid 5- (3,3-dimethyl-butylamino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5-[(pyridine-2-carbonyl) -amino] -pyridine-2 -Yl ester, methyl-phenyl-carbamic acid 5-[(6-chloro-pyridine-3-carbonyl) -amino] -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (2,2-dimethyl -Propylcarbamoyl) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl- 6'-yl ester, methyl-phenyl-carbamic acid 5- (2,5-dioxo-pyrrolidin-1-yl) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4-tri Fluoromethyl-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4-chloro-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 4,4-dimethyl -3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-6'-yl ester, methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester, methyl-phenyl - Carbamic acid 5-benzenesulfonylamino-pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (3,3-dimethyl-2,5-dioxo-pyrrolidin-1-yl) -pyridine-2 -Yl ester, methyl-phenyl-carbamic acid 5- [3,3-dimethyl-5- (4-methyl-piperazin-1-yl) 5-oxo-pentanoylamino] -pyridin-2-yl ester, methyl -Phenyl-carbamic acid 5- [3,3-dimethyl-4- (pyridin-3-ylcarbamoyl) -butyrylamino] -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (3, 3-dimethyl-5-morpholin-4-yl-5-oxo-pentanoylamino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- [4- (2-dimethylamino-ethylcarbamoyl ) -3,3-dimethyl-butyrylamino] -pyridin-2-yl ester.

In one embodiment, R ² is hydrogen, hydroxy, amino, halogen, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -hetero Cyclyl, amide, urea and thiourea and C _3-10 -cycloalkyl, each of hydroxy, amino, C _1-6 -alkyl, C _1-6 alkoxy, C _2-6 -alkenyl, aryl , Heteroaryl, C _3-8 -heterocyclyl, amide, urea and thiourea and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amide, sulfo, C _1-6 -alkyl, C _May be optionally substituted with one or more substituents independently selected from _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl .

In other embodiments, R ² is halogen or hydrogen.

In other embodiments, R ⁴ is selected from hydrogen, halogen, C _1-6 -alkyl, C _2-6 -alkenyl, and each C _1-6 -alkyl, C _2-6 -alkenyl is hydroxy, Optionally substituted with one or more substituents independently selected from halogen, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl do.

In other embodiments, R ⁴ is hydrogen, halogen and C _1-6 -alkyl.

In other embodiments, R ⁴ is hydrogen.

In other embodiments, R ⁴ is halogen.

In other embodiments, R ³ is selected from hydrogen, halogen, C _1-6 -alkyl, C _2-6 -alkenyl, and each C _1-6 -alkyl, C _2-6 -alkenyl is hydroxy, Optionally substituted with one or more substituents independently selected from halogen, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl do.

In other embodiments, R ³ is selected from halogen, C _1-6 -alkyl, perhalomethyl and perhalomethoxy.

In another embodiment, R ³ is selected from halogen, methyl, ethyl, isopropyl and perhalomethyl.

In another embodiment, R ³ is selected from halogen, methyl or perhalomethyl.

In another aspect, the invention provides diastereomers, enantiomers or the like comprising a compound of formula (I) and a mixture thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, or a polymorph It relates to its tautomeric form:

In the above formula,

R ¹ and R ² are hydrogen, hydroxy, sulfanyl, amino, halogen, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3- Independently selected from ₈ -heterocyclyl and C _3-10 -cycloalkyl, each of hydroxy, sulfanyl, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl , Aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy Optionally substituted with one or more substituents independently selected from C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl, each hydroxy, Sulfanyl, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl are hydrates hydroxy, sulfanyl, oxo, halogen, amino, sulfonyl, perhaloalkyl, methyl, perhaloalkyl Romero-ethoxy, C _1-6 - Optionally substituted with one or more substituents independently selected from cycloalkyl-Kiel, C _1-6 - alkoxy, C _2-6 - alkenyl, aryl, heteroaryl, C _3-8 - heterocyclyl, and C _3-10 May be;

R ³ , and R ⁴ are hydrogen, hydroxy, sulfanyl, halogen, amino, sulfo, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and Independently selected from C _3-10 -cycloalkyl, each of hydroxy, sulfanyl, amino, sulfo, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8- Heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 Is optionally selected from one or more substituents independently selected from heterocyclyl and C _3-10 -cycloalkyl, each of hydroxy, sulfanyl, amino, sulfo, C _1-6 -alkyl, C _2-6- Alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, C _1-6 -alkyl, perhalomethyl and perhalome One selected independently from oxy Doedoe optionally substituted with a substituent;

Provided that the compound is

2,2-Dimethyl-N- [6- (methyl-phenyl-carbamoyloxy) -pyridin-3-yl] -succinic acid, 3,3-dimethyl-4- [6- (methyl-phenyl-carba Moyloxy) -pyridin-3-ylcarbamoyl] -butyric acid, methyl-phenyl-carbamic acid pyridin-2-yl ester, methyl-phenyl-carbamic acid 5-chloro-pyridin-2-yl ester, methyl-phenyl- Carbamic acid 5-trifluoromethyl-pyridin-2-yl ester, methyl-phenyl-carbamic acid 3-chloro-5-trifluoromethyl-pyridin-2-yl ester, methyl-phenyl-carbamic acid 5-benzoylamino -Pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (cyclohexanecarbonyl-amino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 4,4-dimethyl-2,6-dioxo -3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-6'-yl ester, methyl-phenyl-carbamic acid 5- (2,2-dimethyl-propionylamino)- Pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (2-cyclohexyl-acetylamino) -pyridin-2-yl ester, Methyl-phenyl-carbamic acid 5- (3,3-dimethyl-butyrylamino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5-[(pyridine-2-carbonyl) -amino] -pyridine- 2-yl ester, methyl-phenyl-carbamic acid 5-[(6-chloro-pyridine-3-carbonyl) -amino] -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (2,2- Dimethyl-propylcarbamoyl) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl -6'-yl ester, methyl-phenyl-carbamic acid 5- (2,5-dioxo-pyrrolidin-1-yl) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4- Trifluoromethyl-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4-chloro-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4 -Methoxy-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 4,4-dimethyl-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl- 6'- Ester, methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester, methyl-phenyl-carbamic acid 5-benzenesulfonylamino-pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (3, 3-Dimethyl-2,5-dioxo-pyrrolidin-1-yl) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- [3,3-dimethyl-5- (4-methyl-pipe) Razin-1-yl) -5-oxo-pentanoylamino] -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- [3,3-dimethyl-4- (pyridin-3-ylcarbamoyl) -Butylamino] -pyridin-2-yl ester, methyl-phenyl-carzamic acid 5- (3,3-dimethyl-5-morpholin-4-yl-5-oxo-pentanoylamino) -pyridin-2-yl Ester, methyl-phenyl-carbamic acid 5- [4- (2-dimethylamino-ethylcarbamoyl) -3,3-dimethyl-butyrylamino] -pyridin-2-yl ester.

In another aspect, the invention provides diastereomers, enantiomers or the like comprising a compound of formula (I) and a mixture thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, or a polymorph It relates to its tautomeric form:

In the above formula

R ² is H and R ¹

Each R ⁵ is hydrogen, hydroxy, sulfanyl, amino, halogen, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -Heterocyclyl and C _3-10 -cycloalkyl, each independently selected from hydroxy, sulfanyl, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, Aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, Optionally substituted with one or more substituents independently selected from C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl, each of hydroxy, sulfanyl , Sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl are hydroxy, Sulfanyl, oxo, halogen, amino, sulfo, perhalomethyl, perhalomethoxy, C _1-6 -alkyl Optionally substituted with one or more substituents independently selected from C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl ;

R ³ , and R ⁴ are hydrogen, hydroxy, sulfanyl, halogen, amino, sulfo, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and Independently selected from C _3-10 -cycloalkyl, each of hydroxy, sulfanyl, amino, sulfo, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8- Heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 Optionally substituted with one or more substituents independently selected from heterocyclyl and C _3-10 -cycloalkyl, each of hydroxy, sulfanyl, amino, sulfo, C _1-6 -alkyl, C _2-6 -alkenyl , Aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl are derived from hydroxy, sulfanyl, oxo, halogen, amino, C _1-6 -alkyl, perhalomethyl and perhalomethoxy One or more independently selected values Doedoe group optionally substituted;

Provided that the compound is

Methyl-phenyl-carbamic acid 5-benzoylamino-pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4-trifluoromethyl-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbox It is not a chest acid 5- (4-chloro-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4-methoxy-benzoylamino) -pyridin-2-yl ester.

In another aspect, the invention provides diastereomers, enantiomers or the like comprising a compound of formula (I) and a mixture thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, or a polymorph It relates to its tautomeric form:

In the above formula

R ² is H and R ¹

Each R ⁵ is hydrogen, hydroxy, sulfanyl, amino, halogen, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 Independently selected from heterocyclyl and C _3-10 -cycloalkyl, each of hydroxy, sulfanyl, amino, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -al Kenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C _1-6 -alkyl, C _1-6- May be optionally substituted with one or more substituents independently selected from alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl, each of Hydroxy, sulfanyl, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cyclo Alkyl is hydroxy, sulfanyl, oxo, halogen, amino, sulfo, perhalomethyl, per Romero-ethoxy, C _1-6 - alkyl, C _1-6 - alkoxy, C _2-6 - alkenyl, aryl, heteroaryl, C _3-8 - independently from cycloalkyl-heterocyclyl, and C _3-10 May be optionally substituted with one or more substituents selected;

R ³ , and R ⁴ are hydrogen, hydroxy, sulfanyl, halogen, amino, sulfo, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and Independently selected from C _3-10 -cycloalkyl, each of hydroxy, sulfanyl, amino, sulfo, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8- Heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 Optionally substituted with one or more substituents independently selected from heterocyclyl and C _3-10 -cycloalkyl, each of hydroxy, sulfanyl, amino, sulfo, C _1-6 -alkyl, C _2-6- Alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, C _1-6 -alkyl, perhalomethyl and perhalome One selected independently from oxy Doedoe optionally substituted with a substituent;

Provided that the compound is

Methyl-phenyl-carbamic acid 5-benzoylamino-pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4-trifluoromethyl-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbox It is not a chest acid 5- (4-chloro-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4-methoxy-benzoylamino) -pyridin-2-yl ester.

In another aspect, the invention provides diastereomers, enantiomers or the like comprising a compound of formula (I) and a mixture thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, or a polymorph It relates to its tautomeric form:

In the above formula

R ² is H and R ¹

Each R ⁵ is hydrogen, hydroxy, sulfanyl, amino, halogen, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -Heterocyclyl and C _3-10 -cycloalkyl, each independently selected from hydroxy, sulfanyl, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, Aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, Optionally substituted with one or more substituents independently selected from C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl, each of hydroxy, sulfanyl , Sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl are hydroxy, methyl-sulfanyl, oxo, halogen, amino, sulfonyl, perhaloalkyl, perhaloalkyl Romero-ethoxy, C _1-6 - Al Optionally substituted with one or more substituents independently selected from cycloalkyl -, C _1-6 - alkoxy, C _2-6 - alkenyl, aryl, heteroaryl, C _3-8 - heterocyclyl, and C _3-10 May be;

R ₃ , and R ₄ are hydrogen

Provided that the compound is

Methyl-phenyl-carbamic acid 5-benzoylamino-pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4-trifluoromethyl-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbox It is not a chest acid 5- (4-chloro-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4-methoxy-benzoylamino) -pyridin-2-yl ester.

In another aspect, the invention provides diastereomers, enantiomers or the like comprising a compound of formula (I) and a mixture thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, or a polymorph It relates to its tautomeric form:

In the above formula

R ² is H and R ¹

Each R ⁵ is hydrogen, hydroxy, sulfanyl, amino, halogen, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 Independently selected from heterocyclyl and C _3-10 -cycloalkyl, each of hydroxy, sulfanyl, amino, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -al Kenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C _1-6 -alkyl, C _1-6- Optionally substituted with one or more substituents independently selected from alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl, each hydroxy , Sulfanyl, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl Hydroxy, sulfanyl, oxo, halogen, amino, sulfo, perhalomethyl, perhalomethok , C _1-6 - alkyl, C _1-6 - alkoxy, C _2-6 - alkenyl, aryl, heteroaryl, C _3-8 - heterocyclyl, and C _3-10 - independently selected from cycloalkyl Optionally substituted with one or more substituents;

R ³ , and R ⁴ are hydrogen

Provided that the compound is

Methyl-phenyl-carbamic acid 5-benzoylamino-pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4-trifluoromethyl-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbox It is not a chest acid 5- (4-chloro-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4-methoxy- benzoylamino) -pyridin-2-yl ester.

 In another aspect, the invention provides diastereomers, enantiomers or the like comprising a compound of formula (I) and a mixture thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, or a polymorph It relates to its tautomeric form:

In the above formula

R ² is H and R ¹

Each R ⁵ is hydrogen, hydroxy, amino, halogen, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and Independently selected from C _3-10 -cycloalkyl, each hydroxy, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8- Heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, Optionally substituted with one or more substituents independently selected from heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl,

R ³ and R ⁴ are hydrogen,

Provided that the compound is

Methyl-phenyl-carbamic acid 5-benzoylamino-pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4-trifluoromethyl-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbox It is not a chest acid 5- (4-chloro-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4-methoxy-benzoylamino) -pyridin-2-yl ester.

In another aspect, the invention provides diastereomers, enantiomers or the like comprising a compound of formula (I) and a mixture thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, or a polymorph It relates to its tautomeric form:

In the above formula

R ² is H and R ¹

Each R ⁵ is hydrogen, hydroxy, amino, halogen, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and Independently selected from C _3-10 -cycloalkyl, each hydroxy, amino, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _{3- 8} -heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, Optionally substituted with one or more substituents independently selected from aryl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl,

R ³ and R ⁴ are hydrogen,

Provided that the compound is

Methyl-phenyl-carbamic acid 5-benzoylamino-pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4-trifluoromethyl-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbox It is not a chest acid 5- (4-chloro-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4-methoxy- benzoylamino) -pyridin-2-yl ester.

In one embodiment, the invention provides that R ² is hydrogen, hydroxy, amino, halogen, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _{3- 8} -heterocyclyl and C _3-10 -cycloalkyl, each of hydroxy, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -al A compound that may be optionally substituted with one or more substituents independently selected from kenyl, aryl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl.

In one embodiment, the invention relates to compounds wherein R ³ is selected from fluorine, chlor, methyl, perhalomethyl or perhalomethoxy.

In one embodiment, the invention relates to compounds wherein R ² is hydrogen.

In another embodiment, the invention relates to compounds wherein R ² is selected from the group consisting of:

In other embodiments, R ² is selected from the group consisting of

Wherein each Rx is hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -Heterocyclyl, and C _3-10 -cycloalkyl, each independently selected from hydroxy, sulfanyl, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl , Aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, sulfo, perhalomethyl, perhalomethoxy, C _1-6- Optionally with one or more substituents independently selected from alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl May be substituted;

In another embodiment, R ² is selected from the group consisting of

Each Rx is hydroxy, sulfanyl, oxo, halogen, amino, sulfo, perhalomethyl, perhalomethoxy, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, Independently selected from heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl;

In other embodiments, R ² is selected from the group consisting of

Each Rx is hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8- Heterocyclyl, and C _3-10 -cycloalkyl, independently selected from hydroxy, sulfanyl, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, Aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, sulfo, perhalomethyl, perhalomethoxy, C _1-6 -alkyl Optionally substituted with one or more substituents independently selected from C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl do;

In other embodiments, R ² is selected from the group consisting of

Each Rx is hydroxy, sulfanyl, oxo, halogen, amino, sulfo, perhalomethyl, perhalomethoxy, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, Independently selected from heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl;

In another embodiment, R ² is selected from the group consisting of

In one embodiment, the invention relates to compounds wherein R ² is selected from the group consisting of

In one embodiment, the invention relates to compounds wherein R ² is selected from the group consisting of

In one embodiment, the invention relates to compounds wherein R ¹ is selected from the group consisting of

In one embodiment, the invention relates to compounds wherein R ¹ is selected from the group consisting of

In one embodiment, the invention relates to compounds wherein R ¹ is selected from the group consisting of

In another embodiment, the invention relates to compounds wherein R ¹ is selected from the group consisting of

In another embodiment of the invention R ¹ relates to a compound selected from the group consisting of

Wherein each Rx is hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -Heterocyclyl, and C _3-10 -cycloalkyl, each independently selected from hydroxy, sulfanyl, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl , Aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, sulfo, perhalomethyl, perhalomethoxy, C _1-6- Optionally with one or more substituents independently selected from alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl May be substituted;

In another embodiment of the invention, R ¹ relates to a compound selected from the group consisting of

Wherein each Rx is hydroxy, sulfanyl, oxo, halogen, amino, sulfo, perhalomethyl, perhalomethoxy, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl , Heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl;

In another embodiment of the invention R ¹ relates to a compound selected from the group consisting of

Wherein each R x is independently selected from halogen, perhalomethyl, perhalomethoxy, C _1-6 -alkyl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl;

In another embodiment of the invention, R ³ relates to a compound which is hydrogen.

In another embodiment of the invention, R ⁴ relates to a compound which is hydrogen.

In another embodiment of the invention, R ⁴ relates to a compound selected from fluorine, chlor, methyl, perhalomethyl or pohalmethoxy.

In another embodiment the invention relates to compounds having one free-COOH group.

In another embodiment, the present invention relates to compounds having one free amino group, or one single substituted amino group or one disubstituted amino group.

In another embodiment, the invention relates to compounds having one substituted or unsubstituted pyridine ring.

In another embodiment, the invention relates to compounds having one substituted or unsubstituted imidazole ring.

In another embodiment, the invention relates to compounds wherein the molar weight of the compound is no greater than 650 g / mole.

Properties of Compounds Having No Ionizable Groups cLog P is calculated using Sybyl 6.6, version 4.0 (provided by Biobyte Corp., Claremont CA, USA) from Triforce Corporation.

In another embodiment, the invention relates to compounds, wherein the compound has no ionizable groups and cLog P is in the range of 1.0 to 6.0.

In another embodiment, the invention relates to compounds, wherein the compound has no ionizable groups and cLog P ranges from 1.0 to 5.0.

In another embodiment, the invention relates to compounds, wherein the compound has no ionizable groups and cLog P is in the range of 1.0 to 4.0.

In another embodiment, the present invention relates to compounds, wherein the compound has no ionizable groups and cLog P ranges from 2.0 to 4.0.

Many other properties of the compounds are calculated using Sybyl 6.6 from Triforce Corporation, ie the number of H-binding donors, the number of H-binding receptors, the number of rotatable bonds. The polar surface area (PSA) is calculated using the SAVol program based on SAVol 3.7 using the Allinger vdw dadii. The polar atom is H ⁺ attached to oxygen, nitrogen, O and N, which is RS Pearlman, JM Skell and F. Deanda, Laboratory for Molecular Graphics and Theoretical Modeling, College of Pharmacy, University of Texas, Austin, TX 78712 , Developed by USA.

In another embodiment, the invention relates to compounds wherein the ACD LogD is in the range of 0.8 to 3.0.

In another embodiment, the invention relates to compounds wherein the number of H-bonds is 0, 1, 2 or 3.

In another embodiment, the invention relates to compounds, wherein the number of H-bonds is 0, 1, or 2.

In another embodiment, the invention relates to compounds, wherein the number of H-binding receptors is in the range of 4-9.

In another embodiment, the invention relates to compounds, wherein the number of H-binding receptors ranges from 6 to 8.

In another embodiment, the invention relates to a compound, wherein the number of rotatable bonds of the compound is in the range of 4 to 14.

In another embodiment, the invention relates to a compound wherein the number of rotatable bonds of the compound ranges from 8 to 12.

In another embodiment, the invention relates to compounds, wherein the polar surface portion (PSA) is in the range of 50 × ² to 120 × ² .

In another embodiment, the invention relates to compounds wherein the polar surface portion (PSA) is in the range of 60 × ² to 100 × ² .

In another embodiment, the invention relates to a compound selected from the group consisting of

[Methyl-phenyl-carbamic acid 5- [2- (4,4-dimethyl-2,6-dioxo-piperidin-1-yl) -ethyl] -pyridin-2-yl ester], [[6- (Methyl-phenyl-carbamoyloxy) -pyridin-3-ylamino] -acetic acid tert -butyl ester],

[[6- (Methyl-phenyl-carbamoyloxy) -pyridin-3-ylamino] -acetic acid],

[Methyl-phenyl-carbamic acid 5-isothiocyanato-pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- (5-oxo-2-thioxo-imidazolidin-1-yl) -pyridin-2-yl ester],

[[6- (Methyl-phenyl-carbamoyloxy) -pyridin-3-ylamino] -acetic acid methyl ester],

[Methyl-phenyl-carbamic acid 5- (4,4-dimethyl-5-oxo-2-thioxo-imidazolidin-1-yl) -pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- (4-ethyl-5-oxo-2-thioxo-imidazolidin-1-yl) -pyridin-2-yl ester],

[(S) -Methyl-phenyl-carbamic acid 5- (4-isopropyl-5-oxo-2-thioxo-imidazolidin-1-yl) -pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- (4- tert -butoxymethyl-5-oxo-2-thioxo-imidazolidin-1-yl) -pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- (3- tert -butyl- thioureido ) -pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- [3- (2,2-dimethyl-propyl) -thioureido] -pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- (3-isopropyl-thioureido) -pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- (3,3-diethyl-thioureido) -pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- (3-cyclohexyl-thioureido) -pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- (3-butyl-thioureido) -pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- (3-isobutyl-thioureido) -pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- (4-cyano-benzoylamino) -pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- (2-methyl-benzoylamino) -pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- (4-fluoro-benzoylamino) -pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- (3-methoxy-benzoylamino) -pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- (2-methoxy-benzoylamino) -pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- (3,4-dichloro-benzoylamino) -pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- (4-methyl-benzoylamino) -pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- (3-bromo-benzoylamino) -pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- (3-cyano-benzoylamino) -pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- (2-trifluoromethoxy-benzoylamino) -pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- (2-fluoro-3-trifluoromethyl-benzoylamino) -pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- (3-trifluoromethyl-benzoylamino) -pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- (3,4-difluoro-benzoylamino) -pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- (3-dimethylamino-benzoylamino) -pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- (3-dimethylamino-benzoylamino) -pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- (4-nitro-benzoylamino) -pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- (4-amino-benzoylamino) -pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- (3- tert -butyl-ureido) -pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- (4-formyl-benzoylamino) -pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- (4-morpholin-4-ylmethyl-benzoylamino) -pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- (4-hydroxymethyl-benzoylamino) -pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- (4-chloromethyl-benzoylamino) -pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- (4-piperidin-1-ylmethyl-benzoylamino) -pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- [4- (4-methyl-piperidin-1-ylmethyl) benzoylamino] -pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- [4- (2-ethyl-piperidin-1-ylmethyl) -benzoylamino] -pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- [4- (2-methyl-piperidin-1-ylmethyl) -benzoylamino] -pyridin-2-yl ester],

[Methyl-phenyl-carbamic acid 5- [4- (3-methyl-piperidin-1-ylmethyl) -benzoylamino] -pyridin-2-yl ester],

Methyl-phenyl-carbamic acid 5- (4-piperidin-1-yl-benzoylamino) -pyridin-2-yl ester

Methyl-phenyl-carbamic acid 5- [4- (2-methyl-piperidin-1-yl) -benzoylamino] -pyridin-2-yl ester,

Methyl-phenyl-carbamic acid 5- [4- (3-methyl-piperidin-1-yl) -benzoylamino] -pyridin-2-yl ester

Methyl-phenyl-carbamic acid 5- [4- (4-methyl-piperidin-1-yl) -benzoylamino] -pyridin-2-yl ester

Methyl-phenyl-carbamic acid 4- [4- (2-ethyl-piperidin-1-yl) benzoylamino] -pyridin-2-yl ester

Methyl-phenyl-carbamic acid 4- [4- (4,4-dimethyl-piperidin-1-yl) -benzoylamino] -pyridin-2-yl ester

Methyl-phenyl-carbamic acid 4- [4- (2,6-dimethyl-piperidin-1-yl) benzoylamino] -pyridin-2-yl ester

Methyl-phenyl-carbamic acid 4- [4- (2,4,6-trimethyl-piperidin-1-yl) -benzoylamino] -pyridin-2-yl ester

Methyl-phenyl-carbamic acid 4- [4- (2,6-dimethyl-piperidin-1-ylmethyl) -benzoylamino] -pyridin-2-yl ester

Methyl-phenyl-carbamic acid 4- [4- (4,4-dimethyl-piperidin-1-ylmethyl) -benzoylamino] -pyridin-2-yl ester

Methyl-phenyl-carbamic acid 4- [4- (2,4,6-trimethyl-piperidin-1-ylmethyl) benzoylamino] -pyridin-2-yl ester

Methyl-phenyl-carbamic acid 5- [4- (2-piperidin-1-yl-ethyl) -benzoylamino] -pyridin-2-yl ester

Methyl-phenyl-carbamic acid 5- {4- [2- (2-methyl-piperidin-1-yl) -ethyl] -benzoylamino} -pyridin-2-yl ester

Methyl-phenyl-carbamic acid 5-4- [2- (3-methyl-piperidin-1-yl) -ethyl] -benzoylamino} -pyridin-2-yl ester

Methyl-phenyl-carbamic acid 5- {4- [2- (4-methyl-piperidin-1-yl) -ethyl] -benzoylamino} -pyridin-2-yl ester

Methyl-phenyl-carbamic acid 5- {4- [2- (2-ethyl-piperidin-1-yl) -ethyl] -benzoylamino} -pyridin-2-yl ester

Methyl-phenyl-carbamic acid 5- {4- [2- (4,4-dimethyl-piperidin-1-yl) ethyl] -benzoylamino} -pyridin-2-yl ester

Methyl-phenyl-carbamic acid 5- {4- [2- (2,6-dimethyl-piperidin-1-yl) -ethyl] -benzoylamino} -pyridin-2-yl ester

Methyl-phenyl-carbamic acid 5- {4- [2- (2,4,6-trimethyl-piperidin-1-yl) -ethyl] -benzoylamino} -pyridin-2-yl ester.

In another embodiment, the invention relates to a compound selected from the group consisting of

Methyl-phenyl-carbamic acid 5- (4-dimethylaminomethyl-bezoylamino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4-diethylaminomethyl-benzoylamino) -pyridine-2 -Yl esters,

Methyl-phenyl-carbamic acid 5- (4-pyrrolidin-1-ylmethyl-benzoylamino) -pyridin-2-yl ester,

Methyl-phenyl-carbamic acid 5- (4-dipropylaminomethyl-benzoylamino) -pyridin-2-yl ester,

Methyl-phenyl-carbamic acid 5- (4-pyrrolidin-1-ylmethyl-benzoylamino) -pyridin-2-yl ester,

cis -methyl-phenyl-carbamic acid 5- [4- (2,6-dimethyl-piperidin-1-ylmethyl) -benzoylamino] -pyridin-2-yl ester,

Methyl-phenyl-carbamic acid 5- [4- (4-oxo-piperidin-1-ylmethyl) -benzoylamino] -pyridin-2-yl ester,

cis -methyl-phenyl-carbamic acid 5- [4- (2,6-dimethyl-morpholin-4-ylmethyl) -benzoylamino] -pyridin-2-yl ester,

Methyl-phenyl-carbamic acid 5- (4-thiomorpholin-4-ylmethyl-benzoylamino) -pyridin-2-yl ester,

Methyl-phenyl-carbamic acid 5- [3- (2-hydroxy-1,1-dimethyl-ethyl) -thioureido] -pyridin-2-yl ester,

Methyl-phenyl-carbamic acid 5- [3- (1-methyl-cyclopropyl) -thioureido] -pyridin-2-yl ester,

Methyl-phenyl-carbamic acid 5- [3- (1-methyl-cyclobutyl) -thioureido] -pyridin-2-yl ester,

Methyl-phenyl-carbamic acid 5- (4-imidazol-1-yl-benzoylamino) -pyridin-2-yl ester,

Methyl-phenyl-carbamic acid 5- (4-diethylamino-benzoylamino) -pyridin-2-yl ester,

Methyl-phenyl-carbamic acid 5- (4- [1,2,4] triazol-1-yl-benzoylamino) -pyridin-2-yl ester,

Methyl-phenyl-carbamic acid 5- (3,3-dipropyl-thioureido) -pyridin-2-yl ester,

Methyl-phenyl-carbamic acid 5- (3,3-dibutyl-thioureido) -pyridin-2-yl ester,

Methyl-phenyl-carbamic acid 5-[(piperidin-1-carbothioyl) -amino] -pyridin-2-yl ester,

Methyl-phenyl-carbamic acid 5-[(4-methyl-piperidin-1-carbothioyl) -amino] -pyridin-2-yl ester,

Methyl-phenyl-carbamic acid 5-[(4,4-dimethyl-piperidin-1-carbothioyl) -amino] -pyridin-2-yl ester,

(4-Bromo-phenyl) -methyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-6 '-Yl ester,

(4-Chloro-phenyl) -methyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-6' -Yl esters,

(3,4-Dichloro-phenyl) -methyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl- 6'-yl ester,

(3-chloro-phenyl) -methyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-6' -Yl esters,

Methyl-p-tolyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-6'-yl ester,

(3-Fluoro-phenyl) -methyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-6 '-Yl ester,

Methyl-m-tolyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-6'-yl ester,

(4-methoxy-phenyl) -methyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-6 '-Yl ester,

(3-methoxy-phenyl) -methyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-6 '-Yl ester,

Methyl- (3-trifluoromethyl-phenyl) -carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl -6'-yl ester,

(3-Bromo-phenyl) -methyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-6 '-Yl ester,

(4-Fluoro-phenyl) -methyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-6 '-Yl ester,

[4- (2-hydroxy-ethyl) -phenyl] -methyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H [1,3 '] Bipyridinyl-6'-yl ester,

In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier or diluent.

In one embodiment, the invention is in unit dosage form, from about 0.05 to about 2000 mg, preferably from about 0.1 to about 500 mg and even more preferably of the compound according to the invention or a pharmaceutically acceptable salt thereof It relates to a pharmaceutical composition comprising about 1.0 to about 100 mg.

In another embodiment, the present invention relates to a pharmaceutical composition for use as a medicament for inhibiting the lipolytic activity of triacylglycerol, diacylglycerol, cholesterol acyl ester or steroid acyl ester, the composition according to the present invention. Compounds or their pharmaceutically acceptable salts, including pharmaceutically acceptable carriers or diluents.

In another embodiment, the present invention relates to a pharmaceutical composition for oral administration.

In another embodiment, the present invention relates to pharmaceutical compositions for nasal, transdermal, pulmonary, or parenteral administration.

In another aspect, the invention relates to the use of a compound according to the invention for the preparation of a pharmaceutical composition.

In one embodiment, the invention relates to the use of a compound according to the invention for the inhibition of hormone sensitive lipase.

In another embodiment, the invention relates to a compound according to the invention for the preparation of a pharmaceutical composition for the inhibition of the lipolytic activity of hormone-sensitive lipases against triacylglycerols, diacylglycerols, cholesterol acyl esters or steroid acyl esters. It is concerned with use.

In another embodiment, the present invention relates to the use of a compound according to the invention for the preparation of a pharmaceutical composition for the treatment or prevention of a disease, wherein the disease is

Regulating plasma levels of free fatty acids, glycerol, LDL-cholesterol, HDL-cholesterol, insulin and / or glucose; And / or

Regulate intracellular triacylglycerol and cholesterol ester storage, fatty acids, fatty acid esters such as diacylglycerol, phosphatidic acid, long chain acyl-CoA's and citrate or malonyl-CoA; And / or

Increases insulin sensitivity in adipose tissue, skeletal muscle, liver or pancreatic β cells; And / or

It is desirable to regulate insulin secretion from Iza β cells.

In another embodiment, the invention is a group consisting of insulin resistance, type 1 diabetes, type 2 diabetes, X metabolic syndrome, impaired glucose tolerance, hyperglycemia, dyslipidemia, obesity, atherosclerosis, hypertension, abnormalities in lipoprotein metabolism and any combination thereof Relate to said use of said disease selected from.

In another embodiment, the present invention relates to the use of other compounds in the present invention for the preparation of pharmaceutical compositions for the treatment and / or prevention of dyslipidemia.

In another embodiment, the present invention relates to the use of a compound according to the invention for the preparation of a pharmaceutical composition for the treatment and / or prevention of hyperlipidemia.

In another embodiment, the invention relates to the use of a compound according to the invention for the preparation of a pharmaceutical composition for the treatment and / or prevention of hyperglycemia.

In another embodiment, the present invention relates to the use of a compound according to the invention for lowering HbA _1C .

In another embodiment, the present invention relates to the preparation of a pharmaceutical composition for the treatment and / or prevention of type 2 diabetes.

In another embodiment, the present invention relates to the use of a compound according to the invention for the preparation of a pharmaceutical composition for the treatment and / or prevention of impaired glucose tolerance.

In another embodiment, the present invention relates to the use of a compound according to the invention for the preparation of a pharmaceutical composition for the treatment and / or prophylaxis of X metabolic syndrome.

In another embodiment, the invention relates to the use of a compound according to the invention for the preparation of a pharmaceutical composition for the treatment and / or prevention of atherosclerosis.

In another embodiment, the invention relates to the use of a compound according to the invention for the preparation of a pharmaceutical composition for the delay or prevention of progression from impaired glucose tolerance to type 2 diabetes.

In another embodiment, the present invention relates to the use of a compound according to the invention for the preparation of a pharmaceutical composition for the delay or prevention of progression from non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes.

In another embodiment, the invention relates to the use according to the above description, wherein additional antidiabetic, antiobesity, antihypertensive or appetite suppressing drugs are used.

In another embodiment, the present invention relates to the use according to the above description, wherein metformin is also used.

In another aspect, the invention relates to a method of treating a disease in a patient in which modulation of the activity of a hormone-sensitive lipase is desired, said method comprising a therapeutically effective amount of a compound according to the invention or a pharmaceutically acceptable salt thereof. Administering to a patient in need thereof.

In one embodiment, the present invention relates to a method of treating a disease in a patient in which it is desirable to lower the activity of a hormone-sensitive lipase, said method being therapeutically effective for a compound according to the invention or a pharmaceutically acceptable salt thereof. Administering the amount to a patient in need thereof.

In another embodiment, the invention relates to the above method, wherein said administration is performed by oral, nasal, transdermal, pulmonary, or parenteral route.

In another embodiment, the present invention relates to the above method, wherein the disease is insulin resistance, type 1 diabetes, type 2 diabetes, X metabolic syndrome, impaired glucose tolerance, hyperglycemia, dyslipidemia, obesity, atherosclerosis, hypertension, lipoprotein metabolism Abnormalities and any combination thereof.

In another embodiment, the present invention relates to the above method, wherein a therapeutically effective amount of said compound is about 0.05 to about 2000 mg, preferably about 0.1 to about 500 mg and even more preferably of said compound per day. About 1.0 to about 100 mg.

In another embodiment, the invention relates to the above method, wherein an additional antidiabetic, antiobesity, antihypertensive or appetite control drug is administered to the patient.

In another embodiment, the invention relates to the above method, wherein metformin is also administered to the patient.

In another embodiment, the present invention relates to process P ₁ for the preparation of a compound of the invention or a pharmaceutically acceptable salt thereof, which reacts an appropriate alcohol with a suitable carbamoylating reagent in a solvent according to reactivity P ₁ . step

And separating the disubstituted carbamate product.

In one embodiment of the invention, the carbamoylation reagent

Is selected from the group consisting of

.

.

In another embodiment of the invention, the solvent is selected from the group consisting of tetrahydrofuran, dimethylformamide and N-methylpyrrolidone.

In another embodiment of the invention, the base is selected from the group consisting of triethylamine, N, N-diisopropyl-N-ethylamine and DABCO.

In another aspect the present invention relates to a process P ₂ for the preparation of a compound of the invention, said process comprising treatment of a suitable amine, including suitable acylation reagents in the presence of a solvent and a base according to reactivity P ₂

And separating the disubstituted carbamate.

In one embodiment of the invention, Lv is Cl.

In another embodiment of the invention, the solvent is selected from the group consisting of diethyl ether, tetrahydrofuran and dichloromethane.

In another embodiment of the invention, the base is selected from the group consisting of trimethylamine, triethylamine, ethyl-diisopropyl-amine and 1,4-diazabicyclo [2.2.2] octane.

In another embodiment of the invention, said base is present as one functional at one or two substituents R ³ and R ⁴ , thus forming a salt with acid H-Lv.

The invention also includes pharmaceutically acceptable salts of the compounds. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts include salts of inorganic and organic acids. Representatives of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitric acid and the like. Representative examples of suitable organic acids include formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, oxalic acid, picric acid, Pyruvic acid, salicylic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, tartaric acid, ascorbic acid, pamoic acid, bismethylene salicylic acid, ethanedisulfonic acid, gluconic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, p-toluenesulfonic acid, sulfates, nitrates, phosphates, perchlorates, borates, acetates, benzoates, hydroxynaphthoates, glycerophosphates, ketoglutarate, and the like. . Further examples of pharmaceutically acceptable inorganic or organic acid addition salts are described in J. References, incorporated herein by reference. Pharm. Sci. 1977, 66, 2, pharmaceutically acceptable salts. Examples of metal salts include lithium, sodium, potassium, magnesium, zinc, calcium salts, and the like. Examples of amines and organic amines are ammonium, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, propylamine, butylamine, tetramethylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylene Diamine, choline, N, N-dibenzylethylenediamine, N-benzylphenylethylamine, N-methyl-D-glucamine, guanidine and the like. Examples of cationic amino acids include lysine, arginine, histidine and the like.

Pharmaceutically acceptable salts include compounds of formula (I), for example, in solvents such as ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol and the like, for example, hydroxides, sodium methoxide, sodium hydride, potassium t -Reacted with 1 to 4 equivalents of base such as butoxide, calcium hydroxide, magnesium hydroxide and the like. Mixtures of solvents may be used. Organic bases such as lysine, arginine, diethanolamine, choline, guandin and derivatives thereof may also be used. Alternatively, whenever applicable, the acid addition salts may be selected from solvents such as ethyl acetate, ether, alcohol, acetone, THF, dioxane and the like, for example hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methane It is prepared by treatment with acids such as sulfonic acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like.

Stereoisomers of the compounds which form part of this invention are whenever possible in the process by using reactants in their single enantiomeric form or by carrying out the reaction in the presence of reactants or catalysts in their single enantiomeric form or in conventional methods. By dissolving a mixture of stereoisomers. Some preferred methods include microbial degradation, enzymatic degradation, for example chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, or the like, for example, leucine, (R)-or (S) -phenylethylamine, It includes the use of solubilizing diastereomeric salts formed with chiral bases such as cinchona alkaloids and derivatives thereof. Commonly used methods are according to Jaques et al in "Enantiomers, Racemates and Resolution" (Wiley Interscience, 1981). More specifically, compounds of formula (I) may be converted to 1: 1 mixtures of diastereomeric amides by treatment with chiral amines, amino acids, aminoalcohols derived from amino acids; Traditional reaction conditions may be used to convert acids to amides; Diastereoisomers may be separated by fractional crystallization or chromatography and the stereoisomers of the compounds of formula (I) may be prepared by hydrolyzing pure diastereomeric amides.

Various polymorphs of the compounds of formula (I) which form part of this invention may be prepared by the determination of compounds of formula (I) under different conditions. For example, using different solvents commonly used or mixtures thereof for recrystallization; Crystallization at different temperatures; Cooling in various ways, from very high speed to very slow cooling during crystallization. Polymorphs can also be obtained by heating or melting the compound followed by gradual or high speed cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.

The invention also encompasses prodrugs of the compounds, which undergo chemical conversion by metabolic processes prior to becoming active pharmacological material upon administration. In general, such prodrugs will be functional derivatives of the present compounds, which are readily convertible in vivo to the desired compounds of formula (I). Traditional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

The invention also includes active metabolites of the compounds.

The invention also relates to an active ingredient together with one or more pharmaceutically acceptable carriers or diluents, their tautomeric forms or their pharmaceutically acceptable forms comprising at least one compound of formula (I) or any optical or geometric isomer or mixture thereof It relates to pharmaceutical compositions comprising possible salts.

Moreover, the present invention relates to compounds of formula I or their tautomeric forms, for the preparation of pharmaceutical compositions for the treatment and / or prevention of diseases such as the conditions mentioned above, wherein reduced levels of plasma FFA are preferred, It relates to the use of stereoisomers, their polymorphs, their pharmaceutically acceptable salts or their pharmaceutically acceptable solvates.

In another aspect, the invention relates to a method for treating and / or preventing abnormalities in type 2 diabetes, insulin resistance, X metabolic syndrome, impaired glucose tolerance, dyslipidemia and lipoprotein metabolism.

In a still further aspect, the present invention relates to the preparation of a pharmaceutical composition for treating and / or preventing abnormalities in type 2 diabetes, insulin resistance, X metabolic syndrome, impaired glucose tolerance, dyslipidemia and lipoprotein metabolism. It relates to the use of the above compounds, or pharmaceutically acceptable salts thereof.

In still further embodiments, the compounds are useful for delaying or preventing progression from impaired glucose tolerance to type 2 diabetes.

In a still further embodiment, the compounds are useful for delaying or preventing progression from non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes.

In other embodiments, the compounds reduce triglyceride levels and are therefore useful for the treatment and / or prevention of diseases and conditions such as diabetes and / or obesity.

In another embodiment, the compounds of formula (I) are hyperglycaemia, elevated HbA1c levels, hyperinsulinemia, type 1.5 diabetes, latent autoimmune diabetes in adults, adult diabetes, beta cell apoptosis, hemochromatosis induced diabetes, impaired glucose tolerance, impaired fasting It is useful for the treatment of glucose, X metabolic syndrome, insulin resistance, impaired lipid resistance, cystic fibrosis related diabetes, polycystic ovary syndrome, and gestational diabetes.

In yet another embodiment, the compound of formula (I) is obese, dyslipidemia, diabetic dyslipidemia, hyperlipidemia, hypertriglyceridemia, hyperlipoproteinemia, hypercholesterolemia, hypertension, intrinsic hypertension, acute hypertensive emergencies, atherosclerosis, atherosclerosis Sclerosis, restenosis, intermittent claudication (atherosclerosis oblitterens), cardiovascular disease, cardiomyopathy, cardiac hypertrophy, left ventricular hypertrophy, coronary artery disease, early coronary artery disease, heart failure, exercise tolerance , Chronic heart failure, mild chronic heart failure, arrhythmia, heart rhythm irregularity, syncopy, heart attack, myocardial infarction, Q-wave myocardial infarction, stroke, acute heart syndrome, angina pectoris, unstable angina pectoris, cardiac bypass reclosure, heart It is useful for the treatment of dilatation, contractile dysfunction, non-Q-wave heart necrosis, catabolism change after surgery, acute pancreatitis, and irritable bowel syndrome.

In yet another embodiment, the compound of formula (I) may be used for diabetic retinopathy, background retinopathy, preproliferative retinopathy, proliferative retinopathy, plaque edema, cataracts, nephropathy, kidney syndrome, diabetic nephropathy, microproteinuria, macroproteinuria May be useful in the treatment of neurosis, neuropathy, diabetic neuropathy, peripheral sympathetic polyneuropathy, and diabetic autonomic neuropathy.

In yet another embodiment, the compounds of formula (I) increase the number of beta cells in a patient, increase the size of the patient's beta cells or stimulate beta cell proliferation, and inhibit beta cell action and insulin secretion in patients in need thereof. Useful for control, the method comprises the administration of an effective amount of a compound of formula (I) to a patient in need thereof.

The compounds of the present invention are also believed to be useful for weight loss in patients in need thereof.

 The compounds of the present invention are also believed to be useful for weight neutral treatment of the abovementioned diseases.

The compounds of the present invention are also believed to be useful for redistributing fat to patients in need thereof.

The compounds of the present invention are also believed to be useful for re-boning central fat in patients in need thereof.

The compounds of the present invention are also believed to be useful for reducing or preventing central obesity.

Compounds of the invention are also believed to be useful for reducing postprandial serum lipid motility.

The compounds of the present invention are also believed to be useful in the treatment of fatty acid oxidative diseases such as MCAD.

In another embodiment, the compounds of formula (I) are believed to be useful for the treatment of diseases, conditions or disorders in which cholesterol is a precursor. Such diseases, conditions or disorders may be related to testosterone such as male contraception, excess testosterone levels, PCOS and prostate cancer. They may also be related to cortisol or corticosteroids such as Cushing's disease.

The compounds of the present invention are also believed to be useful for the treatment of cancer.

Thus, the compounds of formula (I) may be useful for the treatment of insulin species, eg malignant and complex insulin species, adipocyte carcinoma, eg lipocarconoma.

The compounds of the present invention are also believed to be useful for the treatment of phaechromocytoma and other diseases associated with increased catecholamine endocrine.

The compounds of the present invention are also believed to be useful for the treatment of prostate cancer, such as adenocarcinoma.

In still other embodiments, the compounds of formula (I) may be useful for the treatment of hepatic steatosis.

In still other embodiments, the compounds of formula (I) may be useful for the treatment of sclerosis.

In still other embodiments, the compounds of formula (I) may be useful for the treatment of AIDS or AIDS related diseases, conditions or disorders.

In still other embodiments, the compounds of formula (I) may be useful for the treatment of lipodystrophy.

In still other embodiments, the compounds of formula (I) may be useful for the treatment of lactic acidosis.

In another embodiment, the compounds of the present invention are expected to be useful for the treatment of CNS diseases, conditions or conditions.

Thus, the compounds of the present invention are for the treatment of Parkinson's disease, Alzheimer's disease, ADHD (Attention Defective Multiple Disease), bulimia and anorexia, dietary disorders, depression, anxiety, cognitive memory disorders, age-related cognitive decline, mild cognitive impairment and schizophrenia May be useful for

In another embodiment, the compounds of the present invention may be useful for the treatment of inflammatory diseases such as rheumatoid arthritis, psoriasis, systemic inflammatory response syndrome, sepsis and the like.

The present compounds also include, for example, anti-obesity agents, anti-diabetic agents, antihypertensive agents, agents for the treatment and / or prevention of complications arising from or associated with diabetes and treatment of complications and diseases arising from or associated with obesity and / or Or in combination with one or more additional pharmacologically active substances selected from medicaments for prevention.

Thus, in a further aspect of the invention, the compounds may be administered in conjunction with one or more anti-obesity agents or appetite suppressants.

Such agents include CART (cocaine amphetamine-regulated transcription) agonists, NPY (neupeptide Y) antagonists, MC4 (melanocortin 4) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin-releasing factor Agonist, CRF BP (adrenal cortical stimulating hormone releasing protein binding protein) antagonist, eurocortin agonist, β3 agonist, MSH (melanosite-stimulating hormone) agonist, MCH (melanosite-concentrating hormone) antagonist, CCK (Cholecystokinin) agonists, serotonin reuptake inhibitors, serotonin and noradrenaline reuptake inhibitors, mixed serotonin and noradrenaline compounds, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hormones, growth hormone release compounds, TRH (thyreotropin-releasing hormone) agonist, UCP 2 or 3 (uncoupled protein 2 or 3) modulator, leptin agonist , DA agonists (bromocriptine, doplexin), lipase / amylase inhibitors, RXR (retinoid X receptor) modulators or TR β agonists.

In one embodiment of the invention, the anti-obesity agent is leptin.

In another embodiment, the anti-obesity agent is dexamphetamine or amphetamine.

In another embodiment, the anti-obesity agent is fenfluramine or dexfenfluramine.

In yet another embodiment, the antiobesity agent is sibutramine.

In a further embodiment, the anti-obesity agent is orlistat.

In another embodiment, the anti-obesity agent is manddol or phentermine.

Suitable antidiabetic agents include insulin, exendin-4, GLP-1 (glucacon like peptide-1) and its analogs and oral activity as disclosed in WO 98/08871 to Novo Nordisk A / S, which is incorporated herein by reference. Contains hypoglycemic agents.

Orally active hypoglycemic agents are preferably glucagon as disclosed in WO 99/01423 of sulfonylureas, biguanides, meglitinides, glucosidase inhibitors, Novo Nordisk A / S and Agouron Pharmaceuticals Inc. Antagonist, GLP-1 agonist, potassium channel opener as disclosed in WO 97/26265 and WO 99/03861 to Novo Nordisk A / S, herein incorporated by reference, DPP-IV (dipeptidyl peptidase-IV) Compounds that modify lipid metabolism, such as inhibitors, inhibitors of liver enzymes associated with stimulation of glucose neosynthesis and / or glycogen degradation, glucose uptake modulators, antihyperlipidemic agents and antilipids as HMG CoA inhibitors (statins), food intake Degrading compounds, RXR agonists and agents acting on ATP-dependent potassium channels of β-cells.

In one embodiment of the invention, the compound is administered with insulin.

In a further embodiment, the compound is administered with a sulfonylurea such as tolbutamide, glybenclamide, glyphide or glycazide.

In another embodiment, the compound is administered with a biguanide, for example metformin.

In another embodiment, the compound is administered in combination with a meglitinide, for example repaglinide or senaglinide.

In a further embodiment, the compound is administered with an α-glucosidase inhibitor such as miglitol or acarbose.

In another embodiment, the compound is administered in combination with an agent that acts on the ATP-dependent potassium channel of β-cells, for example tolbutamide, glybenclamide, glipizide, glycazide, or repaglinide .

In addition, the compounds may be administered in combination with nateglinide.

In another embodiment, the compound is an anti-hyperlipidemic or anti-lipidemia agent, for example, cholestyramine, cholestipol, clofibrate, gemfibrozil, lovastatin, paravastatin, simvastatin, probucol or dex It is administered with trothyroxine.

In a further embodiment the compound is combined with one or more of the aforementioned compounds, for example, sulfonylureas and metformin, sulfonylureas and acarbose, repaglinide and metformin, insulin and sulfonylurea, insulin and metformin , Insulin, insulin, lovastatin and the like.

Moreover, the compounds may be administered in conjunction with one or more antihypertensive agents. Examples of antihypertensive agents include, for example, β-blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, for example benazepril, captopril, alatriopril, enalapril, posino ACE (engiotensin converting enzyme) inhibitors such as prills, ricinopril, quinapril and ramipril, for example calcium channels such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil Blocking agents and α-blockers such as, for example, doxazosin, urapidyl, prazosin and terrazosin. See also Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA 1995.

It is understood that any suitable combination of compounds according to the invention with one or more of the aforementioned compounds and optionally one or more additional pharmacologically active substances is contemplated within the scope of the invention.

The present invention also relates to the reaction schemes for the preparation of the novel compounds mentioned above, their derivatives, their analogues, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts or pharmaceutically acceptable solvent compounds. It relates to the process according to P ₁ and P ₂ .

The compounds of the present invention may be administered alone or in combination, alone or in combination with pharmaceutically acceptable carriers or excipients. Pharmaceutical compositions according to the invention are disclosed in pharmaceutically acceptable carriers or diluents and in Remington: The Science and Practice of Pharmacy, 19 ^th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995. It may be prepared with any other adjuvant and excipient according to traditional techniques as described. The compositions may also appear in traditional forms, such as capsules, tablets, aerosols, solutions, suspensions or topical ointments.

The pharmaceutical compositions can be, for example, oral, rectal, nasal, lung, topical (including oral and sublingual), transdermal, intravenous, intraperitoneal, vaginal and parenteral (subcutaneous, intramuscular, intradural, venous and It may be specifically prepared for administration by any suitable route, such as intradermal route), and a percutaneous route is preferred. It is understood that the preferred route depends on the general condition and age of the patient being treated, the nature of the condition being treated and the active ingredient selected.

Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they may be prepared with a coating such as, for example, an enteric coating or they may be prepared to provide a controlled release of the active ingredient such as, for example, sustained or prolonged release according to methods well known in the art. Can be.

Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.

Pharmaceutical compositions for oral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions and sterile powders which are reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable preparations are also contemplated as being within the scope of this invention.

Other suitable dosage forms include suppositories, sprays, ointments, creams, gels, aspirators, skin patches, implants, and the like.

The therapeutic dosage of a compound depends on the frequency and manner of administration, the sex, age, weight and general condition of the patient being treated, the nature and severity of the condition being treated and any concomitant diseases to be treated and other factors apparent to those skilled in the art. Will be dependent. The formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art. In one embodiment, the composition in unit dosage form comprises about 0.05 to about 2000 mg, preferably about 0.1 to about 500 mg of a compound of Formula I pharmaceutically acceptable salt thereof.

In still further embodiments, the pharmaceutical composition is oral, nasal, transdermal, pulmonary, or parenteral administration.

For parenteral routes such as intravenous, intradural, intramuscular, and similar administration, the dosage is typically a prescription of about one half of the dosage used for oral administration.

Compounds of this invention are generally useful as free substances or as pharmaceutically acceptable salts thereof. One example is an acid addition salt of a compound having the utility of the free base. Such salts are prepared in a traditional manner when the compounds of the present invention contain free base, for example, by treating a solution or suspension of a compound of the free base comprising a chemical equivalent of a pharmaceutically acceptable acid, such as an inorganic acid and an organic acid. do. Compounds of physiologically acceptable salts comprising hydroxy groups include the anions of the compounds together with suitable cations such as sodium or ammonium ions.

For parenteral administration, sterile aqueous solution, aqueous propylene glycol or sesame oil or peanut oil may be used. This aqueous solution should be properly buffered if necessary and the liquid diluent first allowed to appear with sufficient saline or glucose. Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media used are all readily available by standard techniques known to those skilled in the art.

Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. Examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, cyclodextrin, amylose, stear Magnesium acid, talc, gelatin, agar, pectin, acacia, cellulose stearic acid or lower alkyl ethers, silicic acids, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose And polyvinylpyrrolidone. Similarly, the carrier or diluent may comprise any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or in combination with wax. The formulations may also include humectants, emulsifiers and suspending agents, preservatives, sweetening or flavoring agents.

Subsequently, the pharmaceutical composition formed by combining the compound of the present invention and a pharmaceutically acceptable carrier is easily administered in various dosage forms suitable for administration of the disclosed route. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.

Formulations of the present invention suitable for oral administration may be present as individual units, such as capsules or tablets, each containing a predetermined amount of active ingredient. These formulations may be in the form of powder or granules as solutions or suspensions in aqueous or non-aqueous pharmaceuticals, or as oil-in-water or water-in-oil liquid emulsions.

If a solid carrier is used for oral administration, the preparation may be placed and tableted in a hard gelatin capsule in powder or pellet form or it may be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will generally be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be a sterile injectable liquid such as a syrup, emulsion, soft gelatin capsule or an aqueous or non-aqueous liquid suspension or solution.

Typical tablets, which may be prepared by conventional tableting techniques, may contain the following:

center:

5 mg active compound (as a free compound or salt thereof)

Colloidal Silicon Dioxide (Aerosil) 1.5 mg

Cellulose, microcryst. (Avicel) 70 mg

7.5 mg of modified cellulose rubber (Ac-Di-Sol)

Magnesium Stearate

coating:

HPMC approximately 9 mg

* Mywacett 9-40 T approximately 0.9 mg

* Saiodi is an acylated monoglyceride as a plasticizer for film coating.

The compounds of the present invention can also be administered to a mammal, in particular a patient in need thereof. Such mammals also include both animals, such as domestic animals such as domestic pets, and non-household animals such as wild animals.

In a further aspect of the invention, the compounds comprise additional pharmacologically active substances, such as antidiabetic substances or other compounds for the treatment and / or prophylaxis of insulin resistance and diseases wherein the insulin resistance is a pathophysiological mechanism. It may also be administered with a pharmacologically active substance.

Furthermore, the compounds according to the invention can also be administered in combination with anti-obesity agents or appetite control agents.

Starting material

Methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester, N- (6-hydroxy-pyridin-3-yl) -benzamide and 6'-hydroxy-4,4-dimethyl-4, 5 See PCT / DK02 / 00852 for the synthesis of dihydro-3H- [1,3 '] bipyridinyl-2,6-dione. For the synthesis of (6-methoxy-pyridin-3-yl) -methanol, see, eg, Alan P. Kozikowski, Yan Xia, E. Rajarathnam Reddy, Werner Tuckmantel, Israel Hanin, and X. C. Tang J. Org. Chem. 1991,56, 4636-4645.

Example 1

[Methyl-phenyl-carbamic acid 5- [2- (4,4-dimethyl-2,6-dioxo-piperidin-1-yl) -ethyl] -pyridin-2-yl ester]

Step A :

Thionyl chloride (100 mL) was added to a stirred solution of (6-methoxy-pyridin-3-yl) -methanol (31.0 g, 223 mmol) in chloroform (300 mL). After refluxing for 2 hours, the solvent and excess thionyl chloride were removed by evaporation in vacuo. The residue was stripped off with toluene, dissolved in dichloromethane (400 mL) and extracted with saturated aqueous sodium bicarbonate solution (200 mL). The organic layer was dried over sodium sulfate, filtered and evaporated in vacuo to give a yellow oil. Got it. The oil was dissolved in dimethylformamide (750 mL) and then potassium cyanide (14.5 g, 223 mmol) was added. After stirring at room temperature overnight, the reaction mixture was poured into water (1.5 L). Ethyl acetate (500 mL) was added and the two layers were separated. The water layer was extracted with ethyl acetate (4 x 200 mL) and the combined organic layers were dried over sodium sulfate, filtered and evaporated in vacuo. The product was triturated by high column chromatography (SiO ₂ , ethyl acetate / heptane 1/2) to give (6-methoxy-pyridin-3-yl) -acetonitrile (13.7 g, 42% yield).

¹ H NMR (200 MHz, CDCl ₃ ): δ = 3.75 (s, 2H), 4.00 (s, 3H), 6.85 (d, 1H), 7.60 (dd, 1H), 8.15 (br.s, 1H) ;

Step B :

Stirring of boronate tetrahydrofuran complex (1M solution in tetrahydrofuran, 350 mL) to (6-methoxy-pyridin-3-yl) -acetonitrile (13.7 g, 92.5 mmol) in tetrahydrofuran (130 mL) To the prepared solution. After stirring overnight at 60 ° C., 1N aqueous hydrochloric acid (80 mL) was added. The resulting mixture was heated at reflux for 2 hours and then cooled at room temperature. The solution was washed with tert-butyl methyl ether. 9N aqueous sodium hydroxide (60 mL) was added to the water layer and extracted with dichloromethane (4 × 200 mL). The combined organic layers were dried over sodium sulfate / potassium carbonate 1/1, filtered and evaporated in vacuo to give an oil which was dissolved in dichloromethane (100 mL). 4M solution of hydrochloric acid in dioxane was added. The white precipitate was separated by filtration and dried to give 2- (6-methoxy-pyridin-3-yl) -ethylamine dihydrochloride (10.2 g, 49% yield).

¹ H NMR (200 MHz, CDCl ₃ ): δ = 2.80-2.96 (m, 2H), 2.98-3.14 (m, 2H), 6.86 (d, 1H), 7.27 (dd, 1H), 8.12 (d, 1H), 8.20 (br.s, 2H).

Step C :

2- (6-methoxy-pyridin-3-yl) -ethylamine dihydrochloride (0.94 g, 4.18 mmol), 3,3-dimethylglutar anhydride (0.71 g, 4.99 mmol) and triethylamine in dichloromethane A solution of (1.16 mL, 8.35 mmol) was stirred at rt for 30 min. 1,1′-Carbonyl-diimidazole (0.68 g, 4.18 mmol) was added and the solution was refluxed for 2 hours and then stirred at room temperature overnight. An additional small amount of 1,1'-carbonyldiimidazole was added and reflux was continued for 3 hours. The solution was extracted twice with water, dried over sodium sulfate, filtered and evaporated in vacuo to stop and solidify as a colorless oil, 1- [2- (6-methoxy-pyridin-3-yl) -ethyl] -4 , 4-Dimethyl-piperidine-2,6-dione (1.22 g, 106% yield) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 1.04 (s, 6H), 2.48 (s, 4H), 2.74 (m, 2H), 3.91 (s, 3H), 3.96 (m, 2H), 6.68 ( d, 1 H), 7. 50 (dd, 1 H), 7.98 (d, 1 H); HPLC-MS (Method A): m / z = 277 (M + H) ⁺ ; Rt = 2.72.

Step D :

HCl-gas was stirred for 5 min in 1- [2- (6-methoxy-pyridin-3- yl) -ethyl] -4,4-dimethyl-piperidine-2,6- in tetrahydrofuran (25 mL). Bubble with a solution of dione (1.15 g, 4.18 mmol). Ether (200 mL) was added and the solvent was evaporated in vacuo. The residue was heated at 180 ° C. for 5 minutes. After cooling at room temperature the solid was dissolved in dichloromethane (10 mL). 1,4-diazabicyclo [2.2.2] octane (0.47 g, 4.18 mmol) and N-methyl-N-phenylcarbamoyl chloride (0.71 g, 4.18 mmol) were added. After stirring for 30 minutes at room temperature, the product was purified by high column chromatography (Si0 ₂ , ethyl acetate / heptane 60/40) to give the title compound (0.42 g, 25% yield) as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 1.04 (s, 6H), 2.48 (s, 4H), 2.82 (m, 2H), 3.43 (br.s, 3H), 3.99 (m, 2H), 7.00 (br.s, 1 H), 7.26 (m, 1 H), 7.39 (d, 4H), 7.68 (dd, 1 H), 8. 20 (d, 1 H); HPLC-MS (Method A): m / z = 396 (M + H) ⁺ ; Rt = 3.60 min.

Example 2

[[6- (Methyl-phenyl-carbamoyloxy) -pyridin-3-ylamino] -acetic acid tert -butyl ester]

Methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (2.43 g, 10.0 mmol), bromoacetic acid tert-butylester (3.90 g, 20.0 mmol), potassium carbonate (5.52 g, 40.0 mmol) and toluene A catalytic amount of 18-crown-6 in (50 mL) was stirred at room temperature for 4 days. The solvent was evaporated in vacuo and the residue was purified by high column chromatography (SiO ₂ , ethyl acetate / heptane 50/50) to afford the title compound (0.67 g, 19% yield) as an oil.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 1.50 (s, 9H), 3.42 (br.s, 3H), 3.79 (s, 2H), 4.30 (br.s, 1H), 6.83-7 . 00 (m, 2H), 7.39 (m, 4H), 7.70 (d, 1H); HPLC-MS (Method A): m / z = 358 (M + H) ⁺ ; Rt = 3.74 min.

Example 3

[[6- (Methyl-phenyl-carbamoyloxy) -pyridin-3-ylamino] -acetic acid]

Solution of [6- (methyl-phenyl-carba molooxy) -pyridin-3-ylamino] -acetic acid tert -butyl ester (0.60 g, 1.68 mmol) in 20% trifluoroacetic acid in dichloromethane (25 mL) Was stirred for 3 hours at room temperature. The solvent was evaporated in vacuo to give a solid which was heated for a while with a small amount of ethyl acetate. After cooling at room temperature, the solid was separated by suction to afford the title compound (0.42 g, 82% yield) as a white solid.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ = 3.33 (s, 3H), 3.89 (s, 2H), 6.96 (d, 1H), 7.14 (dd, 1H), 7.27 (m, 1 H) , 7.43 (m, 4H), 7.66 (d, 1H), 11.60 (br.s, 1H); HPLC-MS (Method A): m / z = 302 (M + H) ⁺ ; Rt = 2.50 min.

Example 4

[Methyl-phenyl-carbamic acid 5-isothiocyanato-pyridin-2-yl ester]

Solution of methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (2.43 g, 10.0 mmol) and di-2-pyridyl thionocarbonate (2.32 g, 10.0 mmol) in dichloropropane (25 mL) Was stirred for 2 hours at room temperature. The solution was used as such without separating the product.

HPLC-MS (Method A): m / z = 308 (M + Na) ⁺ ; Rt = 4.08 min.

Example 5

[Methyl-phenyl-carbamic acid 5- (5-oxo-2-thioxo-imidazolidin-1-yl) -pyridin-2-yl ester]

Solution of glycine hydrochloride (2.00 mmol, 251 mg) in methyl-phenyl-carbamic acid 5-isothiocyanato-pyridin-2-yl ester (0.57 g, 2.00 mmol) in 1,2-dichloropropane (5 mL) Was added. Several milliliters of methanol were added to obtain a clear solution. Triethylamine (0.28 mL, 2.00 mmol) was added and the solution stirred at rt overnight. Dichloromethane was added and the reaction mixture was extracted twice with water, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by high speed chromatography (Si0 ₂ , ethyl acetate / heptane 70/30) to afford the title compound (0.27 g, 40% yield) as a solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 3.46 (br.s, 3H), 4.14 (s, 2H), 7.17 (m, 1H), 7.27 (m, 1H), 7.39 (m, 4H), 7.75 (m, 2 H), 8.39 (s, 1 H); HPLC-MS (Method A): m / z = 375 (M + H) ⁺ ; Rt = 2.64 min.

Example 6

[[6- (Methyl-phenyl-carbamoyloxy) -pyridin-3-ylamino] -acetic acid methyl ester]

Methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (2.43 g, 10.0 mmol), bromoacetic acid methyl ester (3.06 g, 20.0 mmol), potassium carbonate (5.52 g, 40.0 mmol) and toluene (50 A mixture of catalyst amount 18-crown-6 in mL) was stirred and stirred for 3 days. The solution was extracted twice with water, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was recrystallized from ethyl acetate / heptane to give the title compound (0.62 g, 20% yield) as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 3.42 (br.s, 3H), 3.77 (s, 3H), 3.89 (s, 2H), 4.38 (br.s, 1H), 6.89 (m, 1H ), 6.96 (dd, 1H), 7.24 (m, 1H), 7.37 (m, 4H), 7.70 (d, 1H); HPLC-MS (Method A): m / z = 316 (M + H) ⁺ ; Rt = 2.87 min.

Example 7

[Methyl-phenyl-carbamic acid 5- (4,4-dimethyl-5-oxo-2-thioxo-imidazolidin-1-yl) -pyridin-2-yl ester]

Methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (1.22 g, 5.00 mmol) was converted to di-2-pyridyl thionocarbonate (1.16 g, 5.00) in 1,2-dichloropropane (15 mL). mmol) in part to the stirred solution. After stirring for 1 hour at room temperature, alpha-aminoisobutyric acid methyl ester hydrochloride (0.77 g, 5.00 mmol) and triethylamine (0.7 mL) were added with some dimethylformamide to obtain a clear solution. After standing overnight, the solvent was evaporated in vacuo and the residue was purified by high column chromatography (Si0 ₂ , ethyl acetate / heptane 50/50) to afford the title compound (1.30 g, 70% yield) as a white solid. .

¹ H NMR (300 MHz, CDCl ₃ ): δ = 1.48 (s, 6H), 3.45 (br.s, 3H), 7.19 (br.s, 1H), 7.28 (m, 1H), 7.39 (m, 4H ), 7.79 (br.d, 1 H), 8.35 (s, 1 H, NH), 8.39 (s, 1 H); HPLC-MS (Method A): m / z = 371 (M + H) ⁺ ; Rt = 3.37 min.

Example 8

[Methyl-phenyl-carbamic acid 5- (4-ethyl-5-oxo-2-thioxo-imidazolidin-1-yl) -pyridin-2-yl ester]

DL-alpha-amino-n-butyric acid methyl ester hydrochloride (2.00 mmol, 307 mg) in methyl-phenyl-carbamic acid 5-isothiocyanato-pyridin-2-yl ester in 1,2-dichloropropane (5 mL) (0.57 g, 2.00 mmol was added to the solution. A small amount of methanol was added to obtain a clear solution. Triethylamine (0.28 mL, 2.00 mmol) was added and the solution was stirred overnight at room temperature. The reaction mixture was extracted twice with water, dried over sodium sulfate, filtered and dried in vacuo The residue was purified by high column chromatography (SiO ₂ , ethyl acetate / heptane 50/50) to give the title compound as a white solid. (0.25 g, 33% yield) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 1.00 (t, 3H), 1.90 (m, 2H); 3.43 (br.s, 3H), 4.17 (t, 1H), 7.17 (br.s, 1H), 7.28 (m, 1H), 7.39 (m, 4H), 7.74 (br.d, 1H), 8.30 ( s, 1 H), 8.36 (s, 1 H); HPLC-MS (Method A): m / z = 371 (M + H) ⁺ ; Rt = 3.39 min.

Example 9

[(S) -Methyl-phenyl-carbamic acid 5- (4-isopropyl-5-oxo-2-thioxo-imidazolidin-1-yl) -pyridin-2-yl ester]

L-valine methyl ester hydrochloride (2.00 mmol, 307 mg) to methyl-phenyl-carbamic acid 5-isothiocyanato-pyridin-2-yl ester (0.57 g, 2.00 mmol in 1,2-dichloropropane (5 mL) ) Solution. A small amount of methanol was added to get a clear solution. Triethylamine (0.28 mL, 2.00 mmol) was added and the solution was stirred at rt overnight. Dichloromethane was added and the reaction mixture was extracted twice with water, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by high column chromatography (SiO ₂ , ethyl acetate / heptane 50/50) to afford the title compound (139 mg, 18% yield) as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 0.98 (d, 3H), 1.07 (d, 3H), 2.30 (m, 1H), 3.43 (br.s, 3H), 4.10 (d, 1 H) , 7.18 (br.s, 1H), 7.27 (m, 1H), 7.39 (m, 4H), 7.72 (br.d, 1H), 8.32 (s, 1H), 8.50 (s, 1H); HPLC-MS (Method A): m / z = 385 (M + H) ⁺ ; Rt = 3.62 min.

Example 10

[Methyl-phenyl-carbamic acid 5- (4- tert -butoxymethyl-5-oxo-2-thioxo-imidazolidin-1-yl) -pyridin-2-yl ester]

0-t-butyl-D-serine acid methyl ester hydrochloride (2.00 mmol, 307 mg) was added methyl-phenyl-carbamic acid 5-isothiocyanato-pyridin-2-yl ester (0.57 g) in dichloromethane (10 mL). , 2.00 mmol). Triethylamine (0.28 mL, 2.00 mmol) was added and the solution stirred for 7 days at room temperature. Some of the solvent was removed by evaporation in vacuo. The residue was purified by high column chromatography (SiO ₂ , ethyl acetate / heptane 50/50) to give the title compound (430 mg, 50% yield) as a white foam.

¹ NMR (300 MHz, CDCl ₃ ): δ = 1.18 (s, 9H), 3.45 (br.s, 3H), 3.70 (dd, 1H), 3.80 (dd, 1H), 4.36 (dd, 1H), 7.18 (br.s, 1H), 7.29 (m, 1H), 7.39 (m, 4H), 7.73 (br. d, 1H), 7.90 (br.s, 1H), 8.34 (br.s, 1H); HPLC-MS (Method A): m / z = 429 (M + H) ⁺ ; Rt = 3.88 min.

Example 11

[Methyl-phenyl-carbamic acid 5- (3- tert -butyl- thioureido ) -pyridin-2-yl ester]

Tert -butylamine (146 mg, 2.0 mmol) in dichloromethane (5 mL) to methyl-phenyl-carbamic acid 5-isothiocyanato-pyridin-2-yl ester (0.57 g, 2.0 in dichloromethane (5 mL) mmol) solution. The solution was stirred at rt for 1 h. Without further work, the reaction mixture was purified by high column chromatography (SiO ₂ , ethyl acetate / heptane 50/50) to afford the title compound (542 mg, 76% yield) as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 1.43 (s, 9H), 3.43 + 3.50 (2 x br.s, 3H), 6.27 + 6.41 (2 x br.s, 1 H), 6.96 + 7.06 (2 x br.s, 1 H), 7.25-7. 44 (m, 5H), 7.68 + 7.78 (2 x br.s, 2H), 8.00 (br.s, 1H); HPLC-MS (Method A): m / z = 359 (M + H) ⁺ ; Rt = 3.74 min.

Example 12

[Methyl-phenyl-carbamic acid 5- [3- (2,2-dimethyl-propyl) -thioureido] -pyridin-2-yl ester]

A solution of 2,2-dimethylpropylamine (174 mg, 2.0 mmol) in dichloromethane (5 mL) was converted to methyl-phenyl-carbamic acid 5-isothiocyanato-pyridin-2-yl ester in dichloromethane (5 mL). (0.57 g, 2.0 mmol) was added to the solution. The solution was stirred at rt for 1 h. Without further work, the reaction mixture was purified by high column chromatography (SiO ₂ , ethyl acetate / heptane 50/50) to give the title compound (674 mg, 90% yield) as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 0.89 (s, 9H), 3.33-3. 60 (br.m, 5H), 6.59 + 6.70 (2 x br.s, 1 H), 6.88 + 7.01 (2 x br.s, 1 H), 7.26-7. 45 (m, 5 H), 7.75-8. 26 (5 x br.s, 3 H); HPLC-MS (Method A): m / z = 373 (M + H) ⁺ ; Rt = 4.10 min.

Example 13

[Methyl-phenyl-carbamic acid 5- (3-isopropyl-thioureido) -pyridin-2-yl ester]

A solution of isopropylamine (118 mg, 2.0 mmol) in dichloromethane (5 mL) was dissolved in methyl-phenyl-carbamic acid 5-isothiocyanato-pyridin-2-yl ester (0.57 g, in dichloromethane (5 mL). 2.0 mmol) in solution. The solution was stirred at rt for 1 h. Without further work, the product was purified by high column chromatography (Si0 ₂ , ethyl acetate / heptane (50/50) to give the title compound (560 mg, 81% yield) as a white solid).

¹ H NMR (300 MHz, CDCl ₃ ): δ = 1.08 (d, 6H), 3.45 + 3.52 (2 x br.s, 3H), 4.47 (octet, 1H), 6.38 + 6.60 (2 x br.s, 1 H), 6.90 + 7.03 (2 x br.s, 1 H), 7.26- 7.50 (m, 5H), 7.68-8. 02 (3 x br.s, 3 H); HPLC-MS (Method A): m / z = 345 (M + H) ⁺ ; Rt = 3.35 min.

Example 14

[Methyl-phenyl-carbamic acid 5- (3,3-diethyl-thioureido) -pyridin-2-yl ester]

Diethylamine (146 mg, 2.0 mmol) in dichloromethane (5 mL) to methyl-phenyl-carbamic acid 5-isothiocyanato-pyridin-2-yl ester (0.57 g, 2.0 mmol) in dichloromethane (5 mL) ) Solution. The solution was stirred at rt for 1 h. Without further work, the product was purified by high column chromatography (Si0 ₂ , ethyl acetate / heptane (50/50) to afford the title compound (196 mg, 27% yield) as a white solid).

¹ H NMR (300 MHz, CDCl ₃ ): δ = 1.27 (t, 6H), 3.42 (br.s, 3H), 3.75 (q, 4H), 6.91 (br.s, 1H), 7.26 (m, 1H ), 7.37 (m, 5H), 7.78 (br. D, 1H), 8.12 (br.s, 1H); HPLC-MS (Method A): m / z = 359 (M + H) ⁺ ; Rt = 3.44 min.

Example 15

[Methyl-phenyl-carbamic acid 5- (3-cyclohexyl-thioureido) -pyridin-2-yl ester]

Cyclohexylamine (198 mg, 2.0 mmol) in dichloromethane (5 mL) to methyl-phenyl-carbamic acid 5-isothiocyanato-pyridin-2-yl ester (0.57 g, 2.0 mmol) in dichloromethane (5 mL) ) Solution. The solution was stirred at rt for 1 h. Without further work, the product was purified by high speed column chromatography (Si0 ₂ , ethyl acetate / heptane (60/40) to give the title compound (554 mg, 72% yield) as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 0.88 (m, 2H), 1.07 (m, 1H), 1.30 (m, 2H), 1.62 (m, 3H), 1.94 (d, 2H), 3.44 + 3.54 (2 x br.s, 3H), 4.11 (m, 1H), 6.39 + 6.62 (2 x br.s, 1H), 6.90 + 7.01 (2 x br.s, 1H), 7.23-7 . 50 (m, 5H), 7.63-8. 04 (br. M, 3H); HPLC-MS (Method A): m / z = 385 (M + H) ⁺ ; Rt = 3.97 min.

Example 16

[Methyl-phenyl-carbamic acid 5- (3-butyl-thioureido) -pyridin-2-yl ester]

A solution of n-butylamine (146 mg, 2.0 mmol) in dichloromethane (5 mL) was added to methyl-phenyl-carbamic acid 5-isothiocyanato-pyridin-2-yl ester (0.57 g) in dichloromethane (5 mL). , 2.0 mmol). The solution was stirred at rt for 1 h. Without further work, the product was purified by high column chromatography (Si0 ₂ , ethyl acetate / heptane (70/30) to afford the title compound (627 mg, 87% yield) as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 0.90 (t, 3H), 1.20-1.47 (m, 4H), 3.42 + 3.53 (2 x br.s, 5H), 6.51 + 6.80 (2 x br. s, 1 H), 6.91 + 7.04 (2 x br.s, 1 H), 7.38-7. 50 (m, 5H), 7. 65-8. 17 (3 x br.s, 3 H); HPLC-MS (Method A): m / z = 359 (M + H) ⁺ ; Rt = 3.70 min.

Example 17

[Methyl-phenyl-carbamic acid 5- (3-isobutyl-thioureido) -pyridin-2-yl ester]

Isobutylamine (146 mg, 2.0 mmol) in dichloromethane (5 mL) to methyl-phenyl-carbamic acid 5-isothiocyanato-pyridin-2-yl ester (0.57 g, 2.0 mmol) in dichloromethane (5 mL) ) Solution. The solution was stirred at rt for 1 h. Without further work, the product was purified by high column chromatography (Si0 ₂ , ethyl acetate / heptane (70/30) to afford the title compound (621 mg, 87% yield) as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 0.84 (d, 6H), 1.74 (br.s, 1H), 3.29 (br.s, 2H), 3.42 + 3.53 (2 x br.s, 3H ), 6.53 + 6.82 (2 x br.s, 1 H), 6.94 + 7.06 (2 x br.s, 1 H), 7.27-7. 50 (m, 5H), 7.70-8. 14 (br. M, 3H); HPLC-MS (Method A): m / z = 359 (M + H) ⁺ ; Rt = 3.67 min.

Example 18

[Methyl-phenyl-carbamic acid 5- (4-cyano-benzoylamino) -pyridin-2-yl ester]

Methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (122 mg, 0.5 mmol), 4-cyanobenzoyl chloride (91 mg, 0.55 mmol) and triethylamine (56 in acetonitrile (2 mL) mg, 0.55 mmol) was stirred for 1 hour at room temperature. Dichloromethane (3 mL) was added to get a clear solution. The product was purified by high column chromatography (Si0 ₂ ) to give the title compound (125 mg, 67% yield) as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 3.39 + 3.53 (2 x br.s, 3H), 6. 88 (br.s, 1H), 7.27-7. 48 (m, 5H), 7.63 (d, 2H), 7.98 (d, 3H), 8.34 (d, 1H), 8. 81 + 9.08 (2 x br.s, 1H); HPLC-MS (Method A): m / z = 373 (M + H) ⁺ ; Rt = 3.50 min.

Example 19

[Methyl-phenyl-carbamic acid 5- (2-methyl-benzoylamino) -pyridin-2-yl ester]

Methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (122 mg, 0.5 mmol), 2-methylbenzoyl chloride (85 mg, 0.55 mmol) and triethylamine (56 mg in acetonitrile (2 mL) , 0.55 mmol) was stirred at room temperature for 1 hour. Dichloromethane (3 mL) was added to get a clear solution. The product was purified by high column chromatography (Si0 ₂ ) to afford the title compound (361 mg, 66% yield) as an oil.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 2.45 (s, 3H), 3.21 + 3.42 (2 x br.s, 3H), 6.90 (br.s, 1H), 7.12- 7.39 (m, 8H) , 7.45 (d, 1 H), 8.08 (dd, 1 H), 8.32 (s, 1 H), 8.54 (s, 1 H); HPLC-MS (Method A): m / z = 362 (M + H) ⁺ ; Rt = 3.62 min.

Example 20

[Methyl-phenyl-carbamic acid 5- (4-fluoro-benzoylamino) -pyridin-2-yl ester]

Methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (122 mg, 0.5 mmol), 4-fluorobenzoyl chloride (87 mg, 0.55 mmol) and triethylamine (56 in acetonitrile (2 mL) mg, 0.55 mmol) was stirred for 1 hour at room temperature. Dichloromethane (3 mL) was added to get a clear solution. The product was purified by high column chromatography (Si0 ₂ ) to afford the title compound (74 mg, 41% yield) as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ): delta = 3.41 (br.s, 3H), 6.91 (br.s, 1H), 7.07 (m, 2H), 7.27 (m, 1H), 7.32-7. 44 (m, 4H), 7.90 (m, 2H), 8.05 (dd, 1H), 8.33 (d, 1H), 8.50 + 8.65 (2 x br.s, 1H); HPLC-MS (Method A ): m / z = 366 (M + H) ⁺ ; Rt = 3.61 min.

Example 21

[Methyl-phenyl-carbamic acid 5- (3-methoxy-benzoylamino) -pyridin-2-yl ester]

Methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (122 mg, 0.5 mmol), 3-methoxybenzoyl chloride (94 mg, 0.55 mmol) and triethylamine (56 in acetonitrile (2 mL) mg, 0.55 mmol) was stirred at rt for 1 h. Dichloromethane (3 mL) was added to get a clear solution. The product was purified by high speed column chromatography (Si0 ₂ ) to afford the title compound (210 mg, 111% yield) as an oil, which solidified on standing.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 3.40 (br.s, 3H), 3.82 (s, 3H), 6.89 (br.s, 1H), 7.05 (dd, 1H), 7.21-7. 49 (m, 8 H), 8.06 (br. D, 1 H), 8.39 (d, 1 H), 8. 87 (br.s, 1 H); HPLC-MS (Method A): m / z = 378 (M + H) ⁺ ; Rt = 3.62 min.

Example 22

[Methyl-phenyl-carbamic acid 5- (2-methoxy-benzoylamino) -pyridin-2-yl ester]

Methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (122 mg, 0.5 mmol), 2-methoxybenzoyl chloride (94 mg, 0.55 mmol) and triethylamine (56 in acetonitrile (2 mL) mg, 0.55 mmol) was stirred for 1 hour at room temperature. Dichloromethane (3 mL) was added to get a clear solution. The product was purified by high column chromatography (Si0 ₂ ) to afford the title compound (109 mg, 57% yield) as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 3.44 (br.s, 3H), 4.06 (s, 3H), 7.02 (d, 1H), 7.06 (br.s, 1H), 7.12 (t, 1H ), 7.26 (m, 1H), 7.39 (d, 4H), 7.51 (m, 1H), 8.36 (dd, 1H), 8.37 (m, 1H), 8.43 (s, 1H), 9.87 (s, 1 H); HPLC-MS (Method A): m / z = 378 (M + H) ⁺ ; Rt = 3.72 min.

Example 23

[Methyl-phenyl-carbamic acid 5- (3,4-dichloro-benzoylamino) -pyridin-2-yl ester]

Methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (122 mg, 0.5 mmol), 3,4-dichlorobenzoyl chloride (91 mg, 0.55 mmol) and triethylamine in acetonitrile (2 mL) 56 mg, 0.55 mmol) was stirred for 1 hour at room temperature. Dichloromethane (3 mL) was added to get a clear solution. The product was purified by high column chromatography (Si0 ₂ ) to afford the title compound (130 mg, 63% yield) as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 3.41 (br.s, 3H), 6. 81 + 6.92 (2 x br.s, 1H), 7.27 (m, 1H), 7.38 (m, 4H) , 7.44 (d, 1 H), 7.72 (dd, 1 H), 7.92 (br.s, 1 H), 8.03 (d, 1 H), 8.30 (s, 1 H), 8.90 (br.s, 1 H); HPLC-MS (Method A): m / z = 416 (M + H) ⁺ ; Rt = 4.30 min.

Example 24

[Methyl-phenyl-carbamic acid 5- (4-methyl-benzoylamino) -pyridin-2-yl ester]

Methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (122 mg, 0.5 mmol), 4-methylbenzoyl chloride (85 mg, 0.55 mmol) and triethylamine (56 mg in acetonitrile (2 mL) , 0.55 mmol) was stirred at room temperature for 1 hour. Dichloromethane (3 mL) was added to get a clear solution. The product was purified by high speed column chromatography to give the title compound (157 mg, 83% yield) as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 2.40 (s, 3H), 3.41 (br.s, 3H), 6.90 (br.s, 1H), 7.18 (d, 2H), 7.25 (m, 1H ), 7.36 (m, 4H), 7.78 (d, 2H), 8.10 (dd, 1H), 8.35 (d, 1H), 8.63 (br.s, 1H); HPLC-MS (Method A): m / z = 362 (M + H) ⁺ ; Rt = 3.75 min.

Example 25

[Methyl-phenyl-carbamic acid 5- (3-bromo-benzoylamino) -pyridin-2-yl ester]

Methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (122 mg, 0.5 mmol), 3-bromobenzoyl chloride (121 mg, 0.55 mmol) and triethylamine (56 in acetonitrile (2 mL) mg, 0.55 mmol) was stirred at rt for 1 h. Dichloromethane (3 mL) was added to get a clear solution. The product was purified by high column chromatography (Si0 ₂ ) to afford the title compound (105 mg, 49% yield) as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 3.43 (br.s, 3H), 6.84 (br.s, 1H), 7.27 (m, 2H), 7.37 (m, 4H), 7.63 (d, 1 H), 7.83 (d, 1 H), 7.97 (br. S, 1 H), 8.05 (s, 1 H), 8.32 (s, 1 H), 8.90 (s, 1 H); HPLC-MS (Method A): m / z = 428 (M + H) ⁺ ; Rt = 4.03 min.

Example 26

[Methyl-phenyl-carbamic acid 5- (3-cyano-benzoylamino) -pyridin-2-yl ester]

Methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (122 mg, 0.5 mmol), 3-cyanobenzoyl chloride (91 mg, 0.55 mmol) and triethylamine (56 in acetonitrile (2 mL) mg, 0.55 mmol) was stirred at room temperature for an hour. Dichloromethane (3 mL) was added to get a clear solution. The product was purified by high column chromatography (Si0 ₂ ) to afford the title compound (151 mg, 81% yield) as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 3.45 (br.s, 3H), 6.80 + 6.95 (2 x br.s, 1 H), 7.28 (m, 1 H), 7.39 (m, 4H) , 7.52 (t, 1H), 7. 80 (d, 1H), 7.90 (br.s, 1H), 8.18 (d, 1H), 8. 28 (s, 1H), 8.32 (s, 1H), 9.13 (s, 1H); HPLC-MS (Method A): m / z = 373 (M + H) ⁺ ; Rt = 3.52 min.

Example 27

[Methyl-phenyl-carbamic acid 5- (2-trifluoromethoxy-benzoylamino) -pyridin-2-yl ester]

Methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (122 mg, 0.5 mmol), 2-trifluoromethoxybenzoyl chloride (124 mg, 0.55 mmol) and triethylamine in acetonitrile (2 mL) A solution of (56 mg, 0.55 mmol) was stirred for 1 hour at room temperature. The product was purified by high speed column chromatography (Si0 ₂ ) to afford the title compound (200 mg, 93% yield) as an oil, which solidified on standing.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 3.37 (br.s, 3H), 7.01 (br.s, 1H), 7.26 (m, 1H), 7.28-7. 44 (m, 6H), 7.54 (m, 1H), 7.98 (dd, 1H), 8.20 (dd, 1H), 8. 40 (s, 1H), 8.60 (s, 1H); HPLC-MS (Method A): m / z = 432 (M + H) ⁺ ; Rt = 3.94 min.

Example 28

[Methyl-phenyl-carbamic acid 5- (2-fluoro-3-trifluoromethyl-benzoylamino) -pyridin-2-yl ester]

Methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (122 mg, 0.5 mmol), 2-fluoro-3 (trifluoromethyl) benzoyl chloride (125 mg, 0.55 in acetonitrile (2 mL) mmol) and triethylamine (56 mg, 0.55 mmol) were stirred at rt for 1 h. Dichloromethane (3 mL) was added to get a clear solution. The product was purified by high column chromatography (SiO ₂ ) to afford the title compound (150 mg, 69% yield) as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 3.37 (br.s, 3H), 7.00 (br.s, 1H), 7.23 (m, 1H), 7.33 (m, 5H), 7.79 (t, 1H ), 8.18 (m, 2 H), 8.40 (s, 1 H), 8.67 (d, 1 H); HPLC-MS (Method A): m / z = 434 (M + H) ⁺ ; Rt = 4. 12 min.

Example 29

[Methyl-phenyl-carbamic acid 5- (3-trifluoromethyl-benzoylamino) -pyridin-2-yl ester]

Methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (122 mg, 0.5 mmol), 3- (trifluoromethyl) benzoyl chloride (115 mg, 0.55 mmol) and tri in acetonitrile (2 mL) A solution of ethylamine (56 mg, 0.55 mmol) was stirred for 1 hour at room temperature. Dichloromethane (3 mL) was added to get a clear solution. The product was purified by high column chromatography (Si0 ₂ ) to give the title compound (171 mg, 82% yield) as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 3.37 + 3.51 (2 x br.s, 3H), 6.80 + 6.95 (2 x br.s, 1H), 7.18-7.46 (m, 5H), 7.53 ( t, 1H), 7.78 (d, 1H), 8.00 (d, 1H), 8.11 (d, 1H), 8.21 (s, 1H), 8.30 (br.s, 1H), 9.08 (s, 1H) ; HPLC-MS (Method A): m / z = 416 (M + H) ⁺ ; Rt = 4.15 min.

Example 30

[Methyl-phenyl-carbamic acid 5- (3,4-difluoro-benzoylamino) -pyridin-2-yl ester]

Methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (122 mg, 0.5 mmol), 3,4-difluorobenzoyl chloride (91 mg, 0.55 mmol) and triethyl in acetonitrile (2 mL) Amine (56 mg, 0.55 mmol) was stirred for 1 hour at room temperature. Dichloromethane (3 mL) was added to the clear solution. The product was purified by high column chromatography (SiO ₂ ) to afford the title compound (169 mg, 88% yield) as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 3.43 (br.s, 3H), 6.81 (br.s, 1H), 7.15 (dd, 1H), 7.30 (m, 1H), 7.39 (m, 4H ), 7.68 (m, 1H), 7.82 (m, 2H), 8.30 (d, 1H), 8.90 (br.s, 1H); HPLC-MS (Method A): m / z = 384 (M + H) ⁺ ; Rt = 3.47 min.

Example 31

[Methyl-phenyl-carbamic acid 5- (3-dimethylamino-benzoylamino) -pyridin-2-yl ester]

Methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (242 mg, 1.0 mmol), 3-dimethylaminobenzoyl chloride hydrochloride (242 mg, 1.1 mmol) and triethylamine in dichloromethane (10 mL) ( 0.31 mL, 2.2 mmol) was stirred for 1 hour at room temperature. The product was purified by high column chromatography (SiO ₂ , gradient of 0-15% ethyl acetate in dichloromethane) to give the title compound (5.5 mg, 1% yield).

¹ H NMR (300 MHz, CDCl ₃ ): δ = 3.01 (s, 6H), 3.42 (br.s, 3H), 6.89 (dd, 1H), 7.02 (br.s, 1H), 7.10 (d, 1H ), 7.22-7. 3 (m, 3H), 7.40 (m, 4H), 8.13 (br.s, 1H), 8.25 (dd, 1H), 8.41 (br.s, 1H); HPLC-MS (Method A): m / z = 391 (M + H) ⁺ ; Rt = 2.94 min.

Example 32

[Methyl-phenyl-carbamic acid 5- (3-dimethylamino-benzoylamino) -pyridin-2-yl ester]

Phosgene (5 mL, 20% in toluene) was added to 6'-hydroxy-4,4-dimethyl-4,5-dihydro-3H- [1,3 '] bipyridinyl-2 in dichloromethane (10 mL). To a stirred solution of, 6-dione (0.47 g, 2.00 mmol) and triethylamine (0.29 mL, 2.00 mmol) was added. After stirring at room temperature for 0.75 hours, the solvent and excess phosgene were evaporated under reduced pressure to give a white solid. The residue was dissolved in dichloromethane (10 mL) and then 1,4-diazabicyclo [2.2.2] octane (224 mg, 2.00 mmol) and 2-methoxy-N-methylaniline (0.27 g, 2.00 mmol) Was added and stirring continued at room temperature for 0.75 hours. The solution was extracted with water and evaporated in vacuo. The residue was purified by high column chromatography (SiO ₂ , gradient of 0-15% ethyl acetate in dichloromethane) to afford the title compound (260 mg, 33% yield) as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 1.19 (s, 6H), 2.66 (s, 4H), 3.29 + 3.40 (2 xs, 3H), 3.86 (s, 3H), 6.94 (m, 2H) , 7.04-7. 54 (m, 4 H), 8.03 + 8.12 (d + s, 1H); HPLC-MS (Method A): m / z = 398 (M + H) ⁺ ; Rt = 3.62 min.

Example 33

[Methyl-phenyl-carbamic acid 5- (4-nitro-benzoylamino) -pyridin-2-yl ester]

Methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (0.97 g, 4.00 mmol), 4-nitrobenzoyl chloride (0.78 g, 4.20 mmol) and triethylamine (0.59 mL) in dichloromethane (10 mL) , 4.20 mmol) was stirred for 3 days at room temperature. The solution was extracted with water and evaporated in vacuo. The residue was purified by high column chromatography (SiO ₂ , gradient of 40-80% ethyl acetate in heptanes) to give the title compound (1.51 g, 96% yield) as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 3.42 + 3.53 (2 x br.s, 3H), 6.93 (br.s, 1H), 7.27-7. 48 (m, 5H), 8.00 (d, 1H), 8.03 (dd, 1H + d, 2H), 8.20 (d, 2H), 8.38 (s, 1H), 8.68 + 9.03 (2 x br. s, 1 H); HPLC-MS (Method A): m / z = 393 (M + H) ⁺ ; Rt = 3.67 min.

Example 34

[Methyl-phenyl-carbamic acid 5- (4-amino-benzoylamino) -pyridin-2-yl ester]

A suspension of methyl-phenyl-carbamic acid 5- (4-nitro-benzoylamino) -pyridin-2-yl ester (1.50 g, 3.82 mmol) in ethyl acetate was hydrogenated overnight in a Parr apparatus at 40 psi hydrogen pressure. The solution was filtered over a short pad of Celite and washed thoroughly with dichloromethane. The filtrate was evaporated in vacuo to afford the title compound (495 mg, 36% yield) as a pale yellow solid.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ = 3.33 (s, 3H), 5.80 (s, 2H), 6.60 (d, 2H), 7.17 (d, 1H), 7.29 (m, 1 H) , 7.44 (m, 4H), 7.72 (d, 2H), 8.22 (dd, 1H), 8.62 (d, 1H), 10.00 (s, 1H); HPLC-MS (Method A): m / z = 363 (M + H) ⁺ ; Rt = 2. 83 min.

Example 35

[Methyl-phenyl-carbamic acid 5- (3- tert -butyl-ureido) -pyridin-2-yl ester]

Methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (243 mg, 1.00 mmol) and tert -butyl isocyanate (0.114 mL, 1.00 mmol) in dichloromethane (5 mL) were stirred at room temperature. The solvent was replaced with tetrahydrofuran and the solution was heated at 40 ° C. for 3 days. Purification of the residue by evaporation of the solvent and high speed chromatography (Si0 ₂ , gradient of 50-70% ethyl acetate in heptane) gave the title compound (119 mg, 35% yield) as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.24 (s, 9H), 3.43 (br.s, 3H), 5.42 (br.s, 1H), 6.85 (br.s, 1H), 7.26 (m , 1H), 7.37 (m, 5H), 7.82 (br.s, 1H), 7.89 (dd, 1H); HPLC-MS (method A): m / z = 343 (M + H) ⁺ ; Rt = 3.31 min.

Example 36

[Methyl-phenyl-carbamic acid 5- (4-formyl-benzoylamino) -pyridin-2-yl ester]

4-formylbenzoyl chloride (1.56 g, 9.28 mmol) was stirred with methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (2.15 g, 8.84 mmol) and triethylamine (1.3 mL, 9.28 mmol) To the prepared solution. After stirring for 0.5 h, the solvent was evaporated and the residue was purified by high column chromatography (SiO ₂ , ethyl acetate / heptane 70/30) to afford the title compound (2.71 g, 82% yield).

¹ H NMR (300 MHz, CDCl ₃ ): δ 3.39 + 3.52 (2 × br.s, 3H), 6.87 (br.s, 1H), 7.23-7. 44 (m, 5H), 7.89 (d, 2H), 8.01 (m, 3H), 8.94 + 9.10 (2 x br.s, 1 H), 10.10 (s, 1H); HPLC-MS (Method A): m / z = 476 (M + H) ⁺ ; Rt = 3.36 min.

Example 37

[Methyl-phenyl-carbamic acid 5- (4-morpholin-4-ylmethyl-benzoylamino) -pyridin-2-yl ester]

Morpholine (0.144 mL, 1.65 mmol) was stirred of methyl-phenyl-carbamic acid 5- (4-formyl-benzoylamino) -pyridin-2-yl ester (0.56 g, 1.5 mmol) in methanol (15 mL). To the solution. The solution was carefully heated to bring the starting material into solution. After stirring for 0.5 h at room temperature, sodium cyanoborohydride (104 mg, 1.65 mmol) was added and stirring was continued overnight at room temperature. The solvent was evaporated and the residue was purified by high column chromatography (Si0 ₂ ) to afford the title compound (38 mg, 6% yield).

¹ H NMR (300 MHz, CDCl ₃ ): δ 2.45 (m, 4H), 3.41 (br.s, 3H), 3.53 (s, 2H), 3.71 (m, 4H), 6.91 (br.s, 1 H), 7.27 (m, 1H), 7.38 (m, 6H), 7.84 (d, 2H), 8.09 (dd, 1H), 8.38 (d, 1H), 8.75 (br.s, 1H) ; HPLC-MS (Method A): m / z = 447 (M + H) ⁺ ; Rt = 2.43 min.

Example 38

[Methyl-phenyl-carbamic acid 5- (4-hydroxymethyl-benzoylamino) -pyridin-2-yl ester]

The title compound (16.4 mg, 2% yield) was separated from the reaction mixture by high column chromatography (SiO ₂ ) as described in Example 37.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ = 3.37 (br.s, 3H), 4.61 (d, 2H), 5.35 (t, 1H), 7.22 (d, 1H), 7.30 (m, 1 H), 7.40-7. 51 (m, 6H), 7.97 (d, 2H), 8.27 (dd, 1H), 8.68 (d, 1H), 10.43 (s, 1H); HPLC-MS (Method A): m / z = 378 (M + H) ⁺ ; Rt = 2.94 min.

Example 39

[Methyl-phenyl-carbamic acid 5- (4-chloromethyl-benzoylamino) -pyridin-2-yl ester]

A solution of 4- (chloromethyl) benzoyl chloride (8.39 g, 44.36 mmol) in dichloromethane (50 mL) with some dimethylformamide was methyl-phenyl-carbamic acid 5-amino-pyridine in dichloromethane (50 mL). To the stirred solution of 2-yl ester (10.79 g, 44.36 mmol) and triethylamine (6.2 mL, 44.36 mmol) was added dropwise. After stirring for 1 h at rt, the solution was extracted with water, dried over sodium sulfate and evaporated in vacuo to give the title compound (14.8 g, 84% yield) as an off-white solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 3.37 (br.s, 3H), 4.85 (s, 2H), 7.24 (d, 1H), 7.30 (m, 1H), 7.46 (m, 4H), 7.62 (d, 2H), 8.00 (d, 2H), 8.28 (dd, 1H), 8.69 (d, 1H). ; HPLC-MS (Method A): m / z = 396 (M + H) ⁺ ; Rt = 3.83 min.

Example 40

[Methyl-phenyl-carbamic acid 5- (4-piperidin-1-ylmethyl-benzoylamino) -pyridin-2-yl ester]

Piperidine (0.17 g, 1.00 mmol) to methyl-phenyl-rbamic acid 5- (4-chloromethyl-benzoylamino) -pyridin-2-yl ester (0.40 g, 1.00 mmol) in dimethylformamide (5 mL) After addition to the stirred solution of, a catalytic amount of sodium iodide was added. After stirring for 18 hours at room temperature, water was slowly added to the reaction mixture. The solid material was separated by suction and dried in a vacuum oven to give the title compound (397 mg, 89% yield) as an off-white solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 1.46 (m, 2H), 1.58 (m, 4H), 2.38 (m, 4H), 3.41 (br.s, 3H), 3.51 (s, 2H), 6.96 (br.s, 1H), 7.27 (m, 1H), 7.40 (m, 6H), 7.84 (d, 2H), 8.18 (dd, 1H), 8.39 (d, 1 H + br.s, 1 H ); HPLC-MS (Method A): mlz = 445 (M + H) ⁺ ; Rt = 2.57 min.

Example 41

[Methyl-phenyl-carbamic acid 5- [4- (4-methyl-piperidin-1-ylmethyl) -benzoylamino] -pyridin-2-yl ester]

4-Methylpiperidine (0.20 g, 1.00 mmol) was added methyl-phenyl-carbamic acid 5- (4-chloromethyl-benzoylamino) -pyridin-2-yl ester (0.40 g, in dimethylformamide (5 mL). 1.00 mmol) was added to the stirred solution, followed by the catalytic amount of sodium iodide. After stirring for 18 hours at room temperature, water was slowly added to the reaction mixture. The solid material was separated by suction and dried in a vacuum oven to give the title compound (393 mg, 86% yield) as an off-white solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 0. 91 (d, 3H), 1.28 (m, 3H), 1.60 (m, 2H), 2.00 (m, 2H), 2.84 (m, 2H), 3.40 (br.s, 3H), 3.53 (s, 3H) , 6.97 (br.s, 1 H), 7.27 (m, 1 H), 7.39 (m, 6H), 7.85 (d, 2H), 8. 20 (dd, 1 H), 8.40 (d, 1 H) , 8.47 (br.s, 1 H); HPLC-MS (Method A): m / z = 459 (M + H) ⁺ ; Rt = 2.74 min.

Example 42

[Methyl-phenyl-carbamic acid 5- [4- (2-ethyl-piperidin-1-ylmethyl) -benzoylamino] -pyridin-2-yl ester]

2-ethylpiperidine (0.23 g, 1.00 mmol) was added methyl-phenyl-carbamic acid 5- (4-chloromethyl-benzoylamino) -pyridin-2-yl ester (0.40 g, in dimethylformamide (5 mL), 1.00 mmol) was added to the stirred solution, followed by the catalytic amount of sodium iodide. After stirring for 18 hours at room temperature, water was slowly added to the reaction mixture. The solvent was decanted and the residue was dried in a vacuum oven to give the title compound (430 mg, 91% yield) as an off white solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 0.92 (t, 3H), 1.32 (m, 1H), 1.38-1.75 (m, 7H), 2.03 (m, 1H), 2.27 (m, 1H) , 2.70 (m, 1H), 3.26 (d, 1H), 3.41 (br.s, 3H), 4.02 (d, 1H), 6.95 (br.s, 1H), 7.26 (m, 1H) , 7.38 (m, 4H), 7.43 (d, 2H), 8. 19 (dd, 1H), 8.42 (d, 1H), 8.62 (br.s, 1H); HPLC-MS (Method A): m / z = 473 (M + H) ⁺ ; Rt = 2.77 min.

Example 43

[Methyl-phenyl-carbamic acid 5- [4- (2-methyl-piperidin-1-ylmethyl) -benzoylamino] -pyridin-2-yl ester]

2-methylpiperidine (0.20 g, 1.00 mmol) was added methyl-phenyl-carbamic acid 5- (4-chloromethyl-benzoylamino) -pyridin-2-yl ester (0.40 g, in dimethylformamide (5 mL). 1.00 mmol) was added to the stirred solution followed by the addition of a catalytic amount of sodium iodide. After stirring for 18 hours at room temperature, water was slowly added to the reaction mixture. The solid material was separated by suction and dried in a vacuum oven to give the title compound (293 mg, 64% yield) as an off-white solid.

¹ H NMR (300 MHz; CDCl ₃ ): δ = 1.16 (d, 3H), 1.21-1. 72 (m, 6H), 1.98 (m, 1H), 2.34 (m, 1H), 2.69 (m, 1H), 3.24 (d, 1H), 3.45 (br.s, 3H), 4.04 (d, 1 H), 7.00 (br.s, 1 H), 7.27 (m, 1 H), 7.40 (m, 6H), 7.82 (d, 2H), 8.21 (dd, 1 H + br.s, 1 H) , 8.38 (d, 1 H); HPLC-MS (Method A): m / z = 459 (M + H) ⁺ ; Rt = 2.64 min.

Example 44

[Methyl-phenyl-carbamic acid 5- [4- (3-methyl-piperidin-1-ylmethyl) -benzoylamino] -pyridin-2-yl ester]

3-methylpiperidine (0.20 g, 1.00 mmol) was added methyl-phenyl-carbamic acid 5- (4-chloromethyl-benzoylamino) -pyridin-2-yl ester (0.40 g, in dimethylformamide (5 mL), 1.00 mmol) was added to the stirred solution followed by the addition of a catalytic amount of sodium iodide. After stirring for 18 hours at room temperature, water was slowly added to the reaction mixture. The solvent was decanted and the residue was dried in a vacuum oven to give the title compound (292 mg, 64% yield) as an off white solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 0.83 (d, 3H + m, 1H), 1.48-1. 77 (m, 5H), 1.89 (dt, 1H), 2.78 (m, 2H), 3.40 (br.s, 3H), 3.51 (s, 2H), 6.90 (br.s, 1H), 7.27 (m , 1 H), 7.38 (m, 6H), 7.85 (d, 2H), 8.10 (dd, 1H), 8.38 (d, 1H), 8.69 (br.s, 1H). ; HPLC-MS (Method A): m / z = 459 (M + H) ⁺ ; Rt = 2.71 min.

Example 45

[Methyl-phenyl-carbamic acid 5- (4-dimethylaminomethyl-benzoylamino) -pyridin-2-yl ester]

Dimethylamine hydrochloride (82 mg, 1.00 mmol) and triethylamine (0.28 mL, 2.00 mmol) were methyl-phenyl-carbamic acid 5- (4-chloromethyl- benzoylamino in N, N-dimethylformamide (5 mL). To a stirred solution of) -pyridin-2-yl ester (0.40 g, 1.00 mmol) was added followed by a catalytic amount of sodium iodide. The reaction mixture was stirred at rt for 18 h. Water was added slowly and decanted. The residue was purified by preparative HPLC to give the title compound (165 mg, 32% yield) as TFA-salt.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 2.60 (s, 6H), 3.40 (br.s, 3H), 4.06 (s, 2H), 6.99 (br.s, 1H), 7.18-7. 42 (m, 7H), 7.82 (d, 2H), 8.19 (d, 1H), 8.54 (s, 1H), 9.81 (br.s, 1H), 11.74 (br.s, 1H); HPLC-MS (Method A): m / z = 461 (M + H) ⁺ ; Rt = 2.82 min.

Example 46

[Methyl-phenyl-carbamic acid 5- (4-diethylaminomethyl-benzoylamino) -pyridin-2-yl ester]

Diethylamine (0.15 g, 2.00 mmol) was added methyl-phenylcarbamic acid 5- (4-chloromethyl-benzoylamino) -pyridin-2-yl ester (0.40 g, in N, N-dimethylformamide (5 mL). 1.00 mmol) was added to the stirred solution followed by the addition of a catalytic amount of sodium iodide. The reaction mixture was stirred at rt for 18 h. Water was added slowly and the solid material was separated by suction and dried in a vacuum oven to give the title compound (404 mg, 93% yield) as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 1.06 (t, 6H), 2.53 (q, 4H), 3.42 (br.s, 3H), 3.61 (s, 2H), 6.97 (br.s, 1H ), 7.27 (m, 1H), 7.39 (m, 4H), 7.45 (d, 2H), 7.83 (d, 2H), 8. 18 (dd, 1H), 8.38 (d, 1 H), 8.42 (br .s, 1 H); HPLC-MS (Method A): m / z = 433 (M + H) ⁺ ; Rt = 2.58 min.

Example 47

[Methyl-phenyl-carbamic acid 5- (4-pyrrolidin-1-ylmethyl-benzoylamino) -pyridin-2-yl ester]

Using the process as described in Example 46 and pyrrolidine (0.14 g, 2.00 mmol) and methyl-phenyl-carbamic acid 5- (4-chloromethyl-benzoylamino) -pyridin-2-yl ester (0.40 g, 1.00 mmol) gave the title compound (357 mg, 83% yield) as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 1.80 (m, 4H), 2.51 (m, 4H), 3.42 (br.s, 3H), 3.67 (s, 2H), 6.94 (br.s , 1H), 7.27 (m, 1H), 7.40 (m, 6H), 6.84 (d, 2H), 8.15 (dd, 1H), 8.37 (d, 1H), 8.52 (br.s, 1H); HPLC-MS (Method A): m / z = 431 (M + H) ⁺ ; Rt = 2.56 min.

Example 48

[Methyl-phenyl-carbamic acid 5- (4-dipropylaminomethyl-benzoylamino) -pyridin-2-yl ester]

Using the process as described in Example 46 and di-n-propylamine (0.20 g, 2.00 mmol) and methyl-phenyl-carbamic acid 5- (4-chloromethyl-benzoylamino) -pyridin-2-yl The step starting from ester (0.40 g, 1.00 mmol) gave the title compound (402 mg, 87% yield) as a white solid.

¹ H NMR (300 MHz, CDCl3): δ = 0.88 (t, 6H), 1.48 (Sextet, 4H), 2.37 (t, 4H), 3.42 (br.s, 3H), 3.60 (s, 2H), 6.94 (br.s, 1 H), 7.27 (m, 1 H), 7.38 (m, 4H), 7.42 (d, 2H), 7.83 (d, 2H), 8.15 (dd, 1 H), 8.38 (d, 1 H), 8. 47 (br. S, 1 H); HPLC-MS (Method A): m / z = 461 (M + H) ⁺ ; Rt = 2.82 min.

Example 49

[Methyl-phenyl-carbamic acid 5- (4-pyrrolidin-1-ylmethyl-benzoylamino) -pyridin-2-yl ester]

Using the process as described in Example 46 and 4,4-dimethylpiperidine hydrochloride (0.22 g, 1.50 mmol), N-ethyldiisopropylamine (0.52 mL, 3.00 mmol) and methyl-phenyl-carr Starting from chest acid 5- (4-chloromethyl-benzoylamino) -pyridin-2-yl ester (0.40 g, 1.00 mmol) and stirring for 3 days were the title compound (341 mg, 72% yield as white solid). )

¹ H NMR (300 MHz, CDCl ₃ ): δ = 0.92 (s, 6H), 1.40 (t, 4H), 2.40 (m, 4H), 3.40 (br.s, 3H), 3.54 (s, 2H), 6.94 (br.s, 1H), 7.27 (m, 1H), 7.38 (m, 6H), 7.83 (d, 2H), 8.14 (dd, 1H), 8. 37 (d, 1 H), 8.54 (br .s, 1 H); HPLC-MS (Method A): m / z = 473 (M + H) ⁺ ; Rt = 2.91 min.

Example 50

[cis-methyl-phenyl-carbamic acid 5- [4- (2,6-dimethyl-piperidin-1-ylmethyl) -benzoylamino] -pyridin-2-yl ester]

Using the process as described in Example 46 and cis -2,6-dimethyl-piperidine (226 mg, 2.00 mmol) and methyl-phenyl-carbamic acid 5- (4-chloromethyl- benzoylamino)- Starting from pyridin-2-yl ester (0.40 g, 1.00 mmol) and stirring for 3 days gave the title compound (410 mg, 87% yield).

¹ H NMR (300 MHz, CDCl ₃ ): δ = 1.00 (d, 6H), 1.32 (m, 3H), 1.51-1. 70 (m, 3H), 2.48 (m, 2H), 3.40 (br.s, 3H), 3.80 (s, 2H), 6.92 (br.s, 1H), 7.27 (m, 1H), 7.36 (m, 4H), 7.46 (d, 2H), 7.83 (d, 2H), 8.11 (dd, 1H), 8.40 (d, 1H), 8. 78 (br.s, 1H); HPLC-MS (Method A): m / z = 473 (M + H) ⁺ ; Rt = 2.77 min.

Example 51

[Methyl-phenyl-carbamic acid 5- [4- (4-oxo-piperidin-1-ylmethyl) -benzoylamino] -pyridin-2-yl ester]

Using the process as described in Example 46 and 4-ketopiperidine hydrate hydrochloride (154 mg, 1.00 mmol), N-ethyldiisopropylamine (259 mg, 2.00 mmol) and methyl-phenyl-carbamic acid Starting from 5- (4-chloromethyl-benzoylamino) -pyridin-2-yl ester (0.40 g, 1.00 mmol) and stirring for 2 days gave the title compound (358 mg, 78% yield). .

¹ H NMR (300 MHz, CDCl ₃ ): δ = 2.47 (m, 4H), 2.74 (m, 4H), 3.42 (br.s, 3H), 3.67 (s, 2H), 6.93 (br.s, 1H ), 7.26 (m, 1H), 7.38 (m, 4H), 7.42 (d, 2H), 7.87 (d, 2H), 8.12 (dd, 1H), 8.39 (d, 1H), 8.66 (br.s , 1 H); HPLC-MS (Method A): m / z = 459 (M + H) ⁺ ; Rt = 2.31 min.

Example 52

[ cis -methyl-phenyl-carbamic acid 5- [4- (2,6-dimethyl-morpholin-4-ylmethyl) -benzoylamino] -pyridin-2-yl ester]

Using the process as described in Example 46 and cis -2,6-dimethylmorpholine (230 mg, 2.00 mmol) and methyl-phenyl-carbamic acid 5- (4-chloromethylbenzoylamino) -pyridine-2 Step starting from -yl ester (0.40 g, 1.00 mmol) gave the title compound (300 mg, 63% yield) as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 1.12 (d, 6H), 1.77 (t, 2H), 2.66 (d, 2H), 3.38 (br.s, 3H), 3.50 (s, 2H), 3.70 (m, 2H), 6.89 (br.s, 1 H), 7.25 (m, 1H), 7.36 (m, 6H), 7.86 (d, 2H), 8.06 (dd, 1 H), 8.40 (d, 1 H), 9.03 (s, 1 H); HPLC-MS (Method A): m / z = 475 (M + H) ⁺ ; Rt = 2.63 min.

Example 53

[Methyl-phenyl-carbamic acid 5- (4-thiomorpholin-4-ylmethyl-benzoylamino) -pyridin-2-yl ester]

Thiomorpholine (206 mg, 2.00 mmol) in a stirred solution of methyl-phenyl-carbamic acid 4- (4-chloromethyl-benzoylamino) -phenyl ester (396 mg, 1.00 mmol) and dimethylformamide (5 mL ) To a catalytic amount of sodium iodide. After stirring for 3 hours at room temperature, water is added to the reaction mixture and the precipitate is separated by suction, washed thoroughly with water and dried in a vacuum oven at 40 ° C. to give the title compound (424 mg, 92% yield) as an off-white solid. Got.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 2.69 (m, 8H), 3.42 (br.s, 3H), 3.56 (s, 2H), 6.94 (br.s, 1H), 7.27 (m, 1H ), 7.38 (m, 6H), 7.85 (d, 2H), 8.12 (dd, 1H), 8.37 (d, 1H), 8.50 (s, 1H); HPLC-MS (Method A): m / z = 463 (M + H) ⁺ ; Rt = 2.61 min.

Example 54

[Methyl-phenyl-carbamic acid 5- [3- (2-hydroxy-1, 1-dimethyl-ethyl) -thioureido] -pyridin-2-yl ester]

A solution of methyl-2-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (0.73 g, 3.00 mmol) in di-2-pyridyl thionocarbonate (0.70 g, 3.00 mmol) in dichloromethane (15 mL) Was added. After stirring for 2 hours, 2-amino-2-methyl-1-propanol (0.27 g, 3.00 mmol) dissolved in a small amount of dichloromethane was added in part. Stirring was continued at rt overnight. The product was purified by high column chromatography (SiO 2, gradient of 80-100% ethyl acetate in heptanes). Crystallization from ethyl acetate / heptane gave the title compound (907 mg, 81% yield) as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 1.30 (s, 6H), 3.42 (br.s, 3H), 3.55 (s, 2H), 5.20 (br.s, 1H), 6.41 (s, 1H ), 7.00 (br.s, 1H), 7.27 (m, 1H), 7.38 (m, 4H), 8.13 (s, 1H), 8.23 (br.s, 1H), 10.70 (br.s, 1 H) ; HPLC-MS (Method A): m / z = 375 (M + H) ⁺ ; Rt = 3.04 min.

Example 55

[Methyl-phenyl-carbamic acid 5- [3- (1-methyl-cyclopropyl) -thioureido] -pyridin-2-yl ester]

Methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl (243 mg, 1.00 mmol) was added to a solution of di-2-pyridyl thionocarbonate (232 mg, 1.00 mmol) in dichloromethane (5 mL). Added. The reaction mixture was stirred for 2 hours at room temperature. 1-methylcyclopropylamine hydrochloride (113 mg, 1.05 mmol) was added in part, followed by triethylamine (146 μL, 1.05 mmol). Stirring was continued at rt overnight. Purification by high column chromatography (SiO ₂ , ethyl acetate / heptane 60/40) gave the title compound (318 mg, 89% yield) as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 0.55-1.09 (3 x br.s, 4H), 1.43 (s, 3H), 3.44 (br.s, 3H), 7.04 (br.s, 2H) , 7.28 (m, 1H), 7.39 (m, 4H), 7.73-8. 38 (3 x br.s, 3H); HPLC-MS (Method A): m / z = 357 (M + H) ⁺ ; Rt = 3.11 min.

Example 56

[Methyl-phenyl-carbamic acid 5- [3- (1-methyl-cyclobutyl) -thioureido] -pyridin-2-yl ester]

Using the process as described in Example 55 and methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl (243 mg, 1.00 mmol) and 1-methylcyclobutylamine hydrochloride (128 mg, 1.05 mmol) The step starting from gave the title compound (261 mg, 71% yield) as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 1.59 (s, 3H), 1.81 (m, 2H), 2.02 (m, 2H), 2.16 (m, 2H), 3.32-3. 60 (2 x br.s, 3H), 6.63-7. 07 (4 x br.s, 2H), 7.28 (m, 1H), 7.38 (m, 4H), 7.69-8. 00 (2 x br.s, 3 H); HPLC-MS (Method A): m / z = 371 (M + H) ⁺ ; Rt = 3.68 min.

Example 57

[Methyl-phenyl-carbamic acid 5- (4-imidazol-1-yl-benzoylamino) -pyridin-2-yl ester]

1-hydroxybenzotriazole hydrate (0.75 g, 5.55 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.06 g, 5.55 mmol) were added N, N-dimethylform at 40 ° C. To a stirred solution of 4-imidazol-1-yl-benzoic acid (0.94 g, 5.00 mmol) in amide (10 mL). After 30 minutes methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (1.35 g, 5.55 mmol) and N-ethyldiisopropylamine (0.97 mL, 5.55 mmol) were added and stirring was stirred at 40 ° C. overnight. Continued. The solvent was evaporated in vacuo and the crude product was dissolved in 1 M aqueous HCl (100 mL) and extracted with ethyl acetate (2 × 100 mL). Sodium carbonate was slowly added to the water layer. The solid was separated by suction and dried in vacuo overnight to afford the title compound (1.00 g, 50% yield) as an off-white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 7.17 (s, 1H), 7.25 (d, 1H), 7.30 (m, 1H), 7.46 (m, 4H), 7. 89 (d, 2H ), 7.91 (s, 1H), 8. 13 (d, 2H), 8.27 (dd, 1H), 8.44 (s, 1H), 8.69 (d, 1H), 10.58 (br.s, 1H); HPLC-MS (Method A): m / z = 414 (M + H) ⁺ ; Rt = 2.40 min.

Example 58

[Methyl-phenyl-carbamic acid 5- (4-diethylamino-benzoylamino) -pyridin-2-yl ester]

1-hydroxybenzotriazole hydrate (0.75 g, 5.55 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.06 g, 5.55 mmol) were added N, N-dimethylform at 40 ° C. To a stirred solution of 4-diethylamine-benzoic acid (0.97 g, 5.00 mmol) in amide (10 mL). After 30 minutes methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (1.35 g, 5.55 mmol) and N-ethyldiisopropylamine (0.97 mL, 5.55 mmol) were added and stirring was stirred at 40 ° C. overnight. Continued. The solvent was evaporated in vacuo. A small portion of the crude product (about 100 mg) was purified by preparative HPLC to give the title compound (5 mg, 1% yield) as off white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 1.12 (t, 6H), 3.42 (q, 4H), 6.73 (d, 2H), 7.18 (d, 1H), 7.29 (m, 1H), 7.45 (m, 4H), 7.87 (d, 2H), 8.24 (dd, 1H), 8.65 (d, 1H), 10.08 (s, 1H); HPLC-MS (Method A): m / z = 419 (M + H) ⁺ ; Rt = 3.20 min.

Example 59

[Methyl-phenyl-carbamic acid 5- (4- [1,2,4] triazol-1-yl-benzoylamino) -pyridin-2-yl ester]

1-hydroxybenzotriazole hydrate (0.13 g, 0.99 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.19 g, 0.99 mmol) at 40 ° C. were treated with N, N-dimethylform. To a stirred solution of 4- (1H-1,2,4triazol-1yl) benzoic acid (0.16 g, 0.82 mmol) in amide (5 mL). After 30 minutes, methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (0.20 g, 0.82 mmol) and N-ethyldiisopropylamine (0.17 mL, 0.99 mmol) were added and stirring was continued at 40 ° C. overnight. Continued. The solvent was evaporated in vacuo. A small portion of the crude product (about 100 mg) was purified by preparative HPLC to give the title compound (10 mg, 1% yield) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 7.25 (d, 1H), 7.30 (m, 1H), 7.45 (m, 4H), 8. 07 (d, 2H), 8.18 (d, 2H ), 8.28 (dd, 1H), 8.32 (s, 1H), 8.69 (d, 1H), 9.45 (s, 1H), 10.62 (s, 1H); HPLC-MS (Method A): m / z = 415 (M + H) ⁺ ; Rt = 3.13 min.

Example 60

[Methyl-phenyl-carbamic acid 5- (3,3-dipropyl-thioureido) -pyridin-2-yl ester]

Methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (2.92, 12.0 mmol) dissolved in N, N-dibutylformamide (20 mL) in N, N-dimethylformamide (15 mL) To the stirred solution of di-2-pyridylthiocarbonate (2.79 g, 12.0 mmol) was added dropwise. After stirring for 3 hours at room temperature, a 1/4 solution (3.00 mmol) was added to di-n-propylamine (334 mg, 3.30 mmol) followed by triethylamine (0.46 mL). The reaction mixture was stirred overnight at room temperature. Purification by high column chromatography (SiO ₂ , ethyl acetate / heptane 50/50) gave the title compound (252 mg, 22% yield) as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 0.94 (t, 6H), 1.72 (sextet, 4H), 3.42 (br.s, 3H), 3.60 (t, 4H), 6.86 (br.s, 1H ), 7.26 (m, 1H), 7.38 (m, 4H), 7.49 (br.s, 1H), 7.72 (d, 1H), 8.10 (d, 1H); HPLC-MS (method A): m / z = 387 (M + H) ⁺ ; Rt = 4.07 min.

Example 61

[Methyl-phenyl-carbamic acid 5- (3,3-dibutyl-thioureido) -pyridin-2-yl ester]

Using the procedure as described in Example 60 and methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (0.73 g, 3.00 mmol) and di-n-butylamine (427 mg, 3.30 mmol) The step starting from gave the title compound (283 mg, 23% yield) as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 0.97 (t, 6H), 1.38 (sextet, 4H), 1.68 (m, 4H), 3.43 (br.s, 3H), 3.66 (t, 4H), 6.93 (br.s, 1 H), 7.25 (m, 1 H), 7.38 (m, 4 H), 7.82 (d, 1 H), 8.10 (d, 1 H); HPLC-MS (Method A): m / z = 415 (M + H) ⁺ ; Rt = 4.64 min.

Example 62

[Methyl-phenyl-carbamic acid 5-[(piperidin-1-carbothioyl) -amino] -pyridin-2-yl ester]

Using the process as described in Example 60 and starting from methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (0.73 g 3.00 mmol) and piperidine (281 mg, 3.30 mmol) High column chromatography (SiO ₂ , ethyl acetate / heptane 70/30) then gave the title compound (867 mg, 78% yield) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.63 (m, 6H), 3.41 (br.s, 1H), 3.82 (br.s, 4H), 6. 83 + 6.91 (2 x br.s, 1 H), 7.27 (m, 1 H), 7.37 (m, 4H), 7.60 (br.s, 1 H), 7.68 (br.s, 1 H), 8.08 (br.s, 1 H); HPLC-MS (Method A): m / z = 371 (M + H) ⁺ ; Rt = 3.51 min.

Example 63

[Methyl-phenyl-carbamic acid 5-[(4-methyl-piperidine-1-carbothioyl) -amino] -pyridin-2-yl ester]

Using a process as described in Example 60 and from methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (0.73 g 3.00 mmol) and 4-methylpiperidine (281 mg, 3.30 mmol) After the starting step, high column chromatography (SiO ₂ , ethyl acetate / heptane 60/40) gave the title compound (0.94 g, 81% yield) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 0.95 (d, 3H), 1.22 (m, 2H), 1.68 (m, 3H), 2.99 (t, 2H), 3.41 (br.s, 3H), 4.67 (d, 2H), 6.84 (br.s, 1H), 7.28 (m, 1H), 7.37 (m, 4H), 7.52-7. 87 (3 x br.s, 2 H), 8.19 (s, 1 H); HPLC-MS (Method A): m / z = 385 (M + H) ⁺ ; Rt = 3.85 min.

Example 64

[Methyl-phenyl-carbamic acid 5-[(4,4-dimethyl-piperidin-1-carbothioyl) -amino] -pyridin-2-yl ester]

Using the process as described in Example 60 and methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (0.73 g 3.00 mmol), 4,4-dimethylpiperidine hydrochloride (494 mg, 3.30) mmol) and triethylamine (0.46 mL, 3.30 mmol) gave the title compound (678 mg, 57% yield) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.00 (s, 6H), 1.43 (m, 4H), 3.42 (br.s, 3H), 3.83 (m, 4H), 6. 87 (br.s , 1H), 7.27 (m, 1H), 7.38 (m, 4H), 7.53 (br. S, 1H), 7.62 (d, 1H), 8.10 (s, 1H); HPLC-MS (Method A): m / z = 399 (M + H) ⁺ ; Rt = 4.06 min.

Example 65

[(4-Bromo-phenyl) -methyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl- 6'-yl ester]

A solution of N- (4-bromophenyl) -N-methylcarbamoyl chloride (0.50 g, 2.00 mmol) in dichloromethane (5 mL) was added to a 6'-hydride in N, N-dimethylformamide (10 mL). Oxy-4,4-dimethyl-4, 5-dihydro-3H- [1,3 '] bipyridinyl-2,6-dione (0.47 g, 2.00 mmol) and 1,4-diazabicyclo [2.2. 2] to a stirred solution of octane (0.22 g, 2.00 mmol). After stirring for 4 hours at room temperature, the solvent was evaporated in vacuo and the residue was purified by high column chromatography (Si0 ₂ , ethyl acetate / heptane 60/40) to give the title compound (176 mg, 20% yield as white solid) )

¹ H NMR (300 MHz, CDCl ₃ ): δ = 1.20 (s, 6H), 2.68 (s, 4H), 3.43 (br.s, 3H), 7.16 (br.s, 1H), 7.27 (d, 2H), 7.50 (m, 3H), 8.09 (d, 1H); HPLC-MS (Method A): m / z = 446 +448 (M + H) ⁺ ; Rt = 3.88 min.

Example 66

[(4-Chloro-phenyl) -methyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-6 '-Yl ester]

Phosgene (20% in toluene, 45 mL) was converted to 6'-hydroxy-4,4-dimethyl-4,5-dihydro-3H- [1,3 '] bipyridinyl-2 in dichloromethane (90 mL). To a stirred solution of, 6-dione (2.11 g, 9.00 mmol) and N-ethyldiisopropylamine (1.62 mL, 9.30 mmol) was added slowly by syringe. After stirring for 1.5 hours at room temperature the solvent was removed by evaporation in vacuo and the residue was redissolved in dichloromethane (45 mL). 1/9 of this solution was diluted with (4-chlorophenyl) methylamine (156 mg, 1.10 mmol) and 1,4-diazabicyclo [2.2.2] octane (112 mg, 1.00 mmol) in dichloromethane (2 mL). Was added to the mixture. After standing overnight the solution was extracted twice with water. The dichloromethane layer was evaporated and the residue was purified by preparative HPLC to give the title compound (103 mg, 26% yield) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.20 (s, 6H), 2.69 (s, 4H), 3.41 (br.s, 3H), 7.14 (br.s, 1H), 7.33 (m, 4H), 7.50 (br. D, 1H), 8.09 (br.s, 1H); HPLC-MS (Method A): m / z = 402 (M + H) ⁺ ; Rt = 3.82 min.

Example 67

[(3,4-Dichloro-phenyl) -methyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetra hydro-2H- [1,3 '] bipyridinyl -6'-yl ester]

Using the process as described in Example 66 and starting from (3,4-dichlorophenyl) methylamine (194 mg, 1.10 mmol) gave the title compound (53 mg, 12% yield) as a white solid. It was.

¹ H NMR (400 MHz, CDCl ₃ ): = 1. 20 (s, 6H), 2.69 (s, 4H), 3.43 (br.s, 3H), 7.19 (br.s, 1 H), 7.27 (m, 1 H), 7.45 (d, 1 H), 7.51 (m, 1H), 8.10 (br.s, 1H); HPLC-MS (Method A): m / z = 436 (M + H) ⁺ ; Rt = 4. 16 min.

Example 68

[(3-Chloro-phenyl) -methyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-6 '-Yl ester]

Using the procedure as described in Example 66 and starting from (3-chlorophenyl) methylamine (156 mg, 1.10 mmol) gave the title compound (107 mg, 27% yield) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.20 (s, 6H), 2.69 (s, 4H), 3.44 (br.s, 3H), 7.19 (br.s, 1H), 7.29 (m, 3H ), 7.40 (s, 1 H), 7.50 (d, 1 H), 8.10 (s, 1 H); HPLC-MS (Method A): m / z = 402 (M + H) ⁺ ; Rt = 3.82 min.

Example 69

[Methyl-p-tolyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-6'-yl ester ]

Using the procedure as described in Example 66 and starting from (4-methylphenyl) methylamine (133 mg, 1.10 mmol) gave the title compound (118 mg, 31% yield) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.20 (s, 6H), 2.34 (s, 3H), 2.68 (s, 4H), 3.39 (br.s, 3H), 7.11 (br.s, 1H ), 7.18 (d, 2H), 7.25 (d, 2H), 7.46 (br. D, 1H), 8.08 (br.s, 1H); HPLC-MS (Method A): m / z = 382 (M + H) ⁺ ; Rt = 3.71 min.

Example 70

[(3-Fluoro-phenyl) -methyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl- 6'-yl ester]

Using the process as described in Example 66 and starting from (3-fluorophenyl) -methylamine (138 mg, 1.10 mmol) gave the title compound (60 mg, 16% yield) as a white solid. It was.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.20 (s, 6H), 2.69 (s, 4H), 3.45 (br.s, 3H), 6.98 (dt, 1H), 7.12 (br. D, 1H ), 7.19 (d, 1 H), 7.34 (m, 1 H), 7.50 (d, 1 H), 8.10 (s, 1 H); HPLC-MS (Method A): m / z = 386 (M + H) ⁺ ; Rt = 3.56 min.

Example 71

[Methyl-m-tolyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-6'-yl ester ]

Using the procedure as described in Example 66 and starting from (3-methylphenyl) methylamine (133 mg, 1.10 mmol) gave the title compound (100 mg, 26% yield) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.20 (s, 6H), 2.37 (s, 3H), 2.68 (s, 4H), 3.40 (br.s, 3H), 7.07 (d, 1 H) , 7.15 (m, 3H), 7.27 (t, 1H), 7.48 (br. D, 1H), 8.09 (br.s, 1H); HPLC-MS (Method A): m / z = 382 (M + H) ⁺ ; Rt = 3.72 min.

Example 72

[(4-methoxy-phenyl) -methyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl- 6'-yl ester]

Using a syringe, phosgene (20% in toluene, 5 mL) was added to the 6'-hydroxy-4,4-dimethyl-4,5-dihydro-3H- [1,3 '] ratio in dichloromethane (15 mL). To the solution of pyridinyl-2,6-dione (333 mg, 1.42 mmol) and N-ethyldiisopropylamine (0.14 g, 1.10 mmol) was added slowly. After stirring for 0.5 h at room temperature the solvent and excess phosgene were removed by evaporation in vacuo. The residue was redissolved in dichloromethane. The solution was poured into a cold solution of (4-methoxyphenyl) methylamine (151 mg, 1.10 mmol) and 1,4-diazabicyclo [2.2.2] octane (0.11 mmol, 1.00 mmol) in dichloromethane (4 mL). Added slowly. After stirring overnight the solution was extracted twice with water and evaporated in vacuo. The residue was purified by preparative HPLC. Crystallization from ethyl acetate gave the title compound (10 mg, 3% yield) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.21 (s, 6H), 2.68 (s, 4H), 3.37 + 3.49 (2 x br.s, 3H), 3.81 (s, 3H), 6.90 (d , 2H), 7.10 (br. D, 1H), 7.26 (m, 3H), 7.45 (br. D, 1H), 8. 06 (br.s, 1H); HPLC-MS (Method A): m / z = 398 (M + H) ⁺ ; Rt = 3.20 min.

Example 73

[(3-methoxy-phenyl) -methyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl- 6'-yl ester]

Using the process as described in Example 72 and 6'-hydroxy-4,4-dimethyl-4,5-dihydro-3H- [1,3 '] bipyridinyl-2,6-dione ( 333 mg, 1.42 mmol) and (3-methoxyphenyl) methylamine (151 mg, 1.10 mmol) starting to yield the title compound as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.21 (s, 6H), 2.69 (s, 4H), 3.43 (br.s, 3H), 3. 81 (s, 3H), 6.82 (d, 1H), 6.95 (m, 2H), 7.14 (br.s, 1H), 7.30 (d, 1H), 7.48 (br. D, 1H), 8.09 (br. s, 1H); HPLC-MS (Method A): m / z = 398 (M + H) ⁺ ; Rt = 3.14 min.

Example 74

[Methyl- (3-trifluoromethyl-phenyl) -carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridine Mono-6'-yl ester]

Using the process as described in Example 72 and 6'-hydroxy-4,4-dimethyl-4,5-dihydro-3H- [1,3 '] bipyridinyl-2,6-dione ( 333 mg, 1.42 mmol) and (3-trifluoromethylphenyl) methylamine (193 mg, 1.10 mmol) starting to yield the title compound as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.19 (s, 6H), 2.67 (s, 4H), 3.48 (br.s, 3H), 7. 19 (br.s, 1H), 7.52 (m, 3H), 7.60 (s, 1H), 7.65 (s, 1H), 8.10 (s, 1H); HPLC-MS (method A): m / z = 436 (M + H) ⁺ ; Rt = 3.71 min.

Example 75

[(3-Bromo-phenyl) -methyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl- 6'-yl ester]

Using the process as described in Example 72 and 6'-hydroxy-4,4-dimethyl-4,5-dihydro-3H- [1,3 '] bipyridinyl-2,6-dione ( 333 mg, 1.42 mmol) and (3-bromophenyl) methylamine (205 mg, 1.10 mmol) starting to yield the title compound as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ): F = 1.21 (s, 6H), 2.68 (s, 4H), 3.44 (br.s, 3H), 7.05-7. 60 (m, 6 H), 8.10 (s, 1 H); HPLC-MS (Method A): m / z = 446 + 448 (M + H) ⁺ ; Rt = 3.61 min.

Example 76

[(4-Fluoro-phenyl) -methyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl- 6'-yl ester]

Using the process as described in Example 72 and 6'-hydroxy-4,4-dimethyl-4,5-dihydro-3H- [1,3 '] bipyridinyl-2,6-dione ( 333 mg, 1.42 mmol) and (4-fluorophenyl) -methylamine (138 mg, 1.10 mmol) gave the title compound as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.20 (s, 6H), 2.68 (s, 4H), 3.38 + 3.50 (2 x br.s, 3H), 7.07 (m, 3H), 7.33 (m , 2H), 7.48 (br.s, 1H), 8.08 (s, 1H); HPLC-MS (Method A): m / z = 386 (M + H) ⁺ ; Rt = 3.48 min.

Example 77

[[4- (2-hydroxy-ethyl) -phenyl] -methyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] Bipyridinyl-6'-yl ester]

Step A :

4-aminophenethyl alcohol (2.03 g, 14.8 mmol) in ethyl formate (15 mL) was heated at reflux overnight. After cooling at room temperature, heptane was added to the reaction mixture. The solvent was decanted from the oil and the last traces of solvent were removed in vacuo. Dichloromethane was added to the residue and the precipitate was separated by aspiration to give N- [4- (2-hydroxyethyl) -phenyl] -formamide (1.95 g, 80% yield), which was the next step Used without further purification of

¹ H NMR (400 MHz, CDCl ₃ ): δ = 2.04 (br.s, 1H), 2.83 (m, 1H), 3.84 (m, 2H), 7.02 + 7.46 (2 xd, 2H), 7.18 + 7.22 ( 2 xd, 2H), 7.62 + 8.22 (br.s + br.d, 1H), 8.27 + 8.60 (s + d, 1H); HPLC-MS (Method A): m / z = 148 (M-OH) ⁺ ; Rt = 1.00 min.

Step B :

Under nitrogen atmosphere, a solution of N- [4- (2-hydroxyethyl) -phenyl] -formamide (1.50 g, 9.10 mmol) in dry tetrahydrofuran (50 mL) was dissolved in dry tetrahydrofuran (50 mL). To the stirred suspension of lithium aluminum hydride (0.76 g, 20.0 mmol) was added dropwise. After refluxing for 1 hour, the solution was cooled at room temperature and 1M aqueous potassium hydroxide (1.9 mL) was added slowly. Celite is added and the solid is removed by filtration. Evaporation of the solvent in vacuo gave 2- (4-methylamino-phenyl) -ethanol (1.00 g, yield: 73%), which was used in the next step without further purification.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 2.76 (t, 2H), 2.82 (s, 3H), 3.79 (t, 2H), 6.58 (d, 2H), 7.05 (d, 2H); HPLC-MS (Method A): m / z = 152 (M + H) ⁺ ; Rt = 0.88 min.

Step C :

N-ethyldiisopropylamine (0.7 mL, 4.00 mmol) and chlorotrimethylsilane (0.13 mL, 1.00 mmol) were added 2- (4-methylamino-phenyl) -ethanol (151 mg, 1.00) in dichloromethane (10 mL). mmol) was added to the stirred solution. In a secondary reaction flask, N-ethyldiisopropylamine (0.21 mL, 1.20 mmol) and phosgene (20% in toluene, 5 mL) were added to 6'-hydroxy-4,4-dimethyl- in dichloromethane (5 mL). To a stirred solution of 4,5-dihydro-3H- [1,3 '] bipyridinyl-2,6-dione (234 mg, 1.00 mmol) was added. After 1.5 hours the solution was evaporated in vacuo. The residue was redissolved in dichloromethane (5 mL) and added slowly to the first solution. After stirring for 1 h the solvent was evaporated in vacuo and the residue was purified by preparative HPLC to afford the title compound as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.20 (s, 6H), 1.92 (br.s, 1H), 2.68 (s, 4H), 2.86 (t, 2H), 3.40 (br.s, 3H ), 3.85 (t, 2 H), 7.12 (br. S, 1 H), 7.20-7. 34 (m, 4 H), 7.48 (br. S, 1 H), 8. 07 (s, 1 H); HPLC-MS (Method A): m / z = 412 (M + H) ⁺ ; Rt = 2.56 min.

Additional embodiments include:

Methyl-phenyl-carbamic acid 5- (4-piperidin-1-yl-benzoylamino) -pyridin-2-yl ester

Methyl-phenyl-carbamic acid 5- [4- (2-methyl-piperidin-1-yl) -benzoylamino] -pyridin-2-yl ester

Methyl-phenyl-carbamic acid 5- [4- (3-methyl-piperidin-1-yl) -benzoylamino] -pyridin-2-yl ester

Methyl-phenyl-carbamic acid 5- [4- (4-methyl-piperidin-1-yl) -benzoylamino] -pyridin-2-yl ester

Methyl-phenyl-carbamic acid 4- [4- (2-ethyl-piperidin-1-yl) -benzoylamino] -pyridin-2-yl ester

Methyl-phenyl-carbamic acid 4- [4- (4,4-dimethyl-piperidin-1-yl) -benzoylamino] -pyridin-2-yl ester

Methyl-phenyl-carbamic acid 4- [4- (2,6-dimethyl-piperidin-1-yl) -benzoylamino] -pyridin-2-yl ester

Methyl-phenyl-carbamic acid 4- [4- (2,4,6-trimethyl-piperidin-1-yl) benzoylamino] -pyridin-2-yl ester

Methyl-phenyl-carbamic acid 4- [4- (2,6-dimethyl-piperidin-1-ylmethyl) -benzoylamino] -pyridin-2-yl ester

Methyl-phenyl-carbamic acid 4- [4- (4,4-dimethyl-piperidin-1-ylmethyl) -benzoylamino] -pyridin-2-yl ester

Methyl-phenyl-carbamic acid 4- [4- (2,4,6-trimethyl-piperidin-1-ylmethyl) -benzoylamino] -pyridin-2-yl ester

Methyl-phenyl-carbamic acid 5- [4- (2-piperidin-1-yl-ethyl) -benzoylamino] -pyridin-2-yl ester

Methyl-phenyl-carbamic acid 5- {4- [2- (2-methyl-piperidin-1-yl) -ethyl] -benzoylamino} -pyridin-2-yl ester

Methyl-phenyl-carbamic acid 5- {4- [2- (3-methyl-piperidin-1-yl) -ethyl] -benzoylamino} -pyridin-2-yl ester

Methyl-phenyl-carbamic acid 5- {4- [2- (4-methyl-piperidin-1-yl) -ethyl] -benzoylamino} -pyridin-2-yl ester

Methyl-phenyl-carbamic acid 5- {4- [2- (2-ethyl-piperidin-1-yl) -ethyl] -benzoylamino} -pyridin-2-yl ester

Methyl-phenyl-carbamic acid 5- {4- [2- (4,4-dimethyl-piperidin-1-yl) -ethyl] -benzoylamino} -pyridin-2-yl ester

Methyl-phenyl-carbamic acid 5- {4- [2- (2,6-dimethyl-piperidin-1-yl) -ethyl] -benzoylamino} -pyridin-2-yl ester

Methyl-phenyl-carbamic acid 5- {4- [2- (2,4,6-trimethyl-piperidin-1-yl) -ethyl] -benzoylamino} -pyridin-2-yl ester

Pharmacological method

Compounds of formula (I) may be evaluated in vitro for their efficacy and efficacy in inhibiting HSL, and such evaluation may be performed as described below.

analysis

Hormone-sensitive Lipase (HSL)

Material . Hormone-sensitive lipase from Dr. Lund University, Sweden Provided by Cecilia Holm or Produced or purified by Novo Nordisk (NN) using the reagents and protocols used by Holm. Substrates used were ³ H-labeled triolein (TO) from Catering, Buckinghamshire, UK, cat no. TRA191; Dissolved in toluene 5-20 Ci / mmol, the triolein (Sigma, Cat No. T-1740.) , In a fluoro prepared by Novo Nordisk (NN) by conventional methods chromium-labeled tree acyl glyceride (cis Octadec-9-enoic acid 2- [12- (7-nitrobenzo [1,2,5] oxadiazol-4-ylamino) dodecanoyloxy] -1- cis -octadec-9-eno Oxymethyl-ethyl ester), and 1,3- (di [ ³ H] -stearin), 2- (PEG-biotin), prepared in collaboration with Amersham Pharmacia Biotech, UK, and described in WO 01/073442. Glycerol. All other reagents are commercial grade and are available from various commercial sources.

Method .

3190.1: Assay for determination of% inhibition of hormone sensitive lipase by compound at 10 μM sample concentration.

Lipid emulsions of fluorochrome-labeled triacylglycerides and phospholipids are used as substrates with standard concentrations of highly purified HSL (12 μg / mL initial concentration corresponding to 600 ng / mL final concentration). BSA is added as product receptor. The transfer of fluorochromes from the lipid phase to the water (BSA) changes the fluorescent properties of the fluorochromes. The change can be monitored on a fluorometer with an excitation wavelength of 450 nM and an emission wavelength of 545 nM.

Compounds and HSL (20 μL compound, 10 μL enzyme and 70 μL PED-BSA buffer) are preincubated for 30 minutes at 25 ° C. prior to addition of substrate (100 μL). The amount of product formed is measured after incubation at 37 ° C. for 120 minutes.

Results are given as% activity with respect to the uninhibited sample (no compound).

3190.2 : Assay for determination of IC ₅₀ values for inhibition of hormone sensitive lipase by compounds. Standard concentrations of compounds are 100 μΜ and 5-fold dilutions (initial concentrations corresponding to 10 μΜ final concentration and 5-fold).

Lipid emulsions comprising fluorochrome-labeled triacylglycerides and phospholipids are used as substrates with standard concentrations of highly purified HSL (12 μg / mL initial concentration corresponding to 60 ng / mL final concentration). BSA is added as product receptor. The transfer of fluorochromes from the lipid phase to the water (BSA) changes the fluorescent properties of the fluorochromes. The change can be monitored on a fluorometer with an excitation wavelength of 450 nm and an emission wavelength of 545 nm.

Compounds and HSL (20 μL compound, 10 μL enzyme and 70 μL PED-BSA buffer) are preincubated at 25 ° C. for 30 minutes prior to addition of substrate (100 μL). The amount of product formed is measured after incubation at 37 ° C. for 120 minutes.

The results are given as IC ₅₀ values after 4PL fit of the obtained activity data.

result

With these methods the compounds of the examples are found to be inhibitors of HSL:

Claims (95)

Diastereomers, enantiomers or tautomeric forms thereof, including compounds of formula (I) and mixtures thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, or polymorphs.

[In the above formula R ¹ and R ² are hydrogen, hydroxy, sulfanyl, amino, amide, urea, thiourea, benzamide, thioamide, halogen, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2- Independently selected from ₆ -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl, each of hydroxy, sulfanyl, amino, amide, urea, thiourea, benz Amide, thioamide, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl Silver hydroxy, sulfanyl, oxo, thioxo, halogen, amino, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8- And optionally substituted with one or more substituents independently selected from heterocyclyl, and C _3-10 -cycloalkyl, each of hydroxy, sulfanyl, sulfo, C _1-6 -alkyl, C _1-6- alkoxy, C _2-6 - alkenyl, ah reel, H. Loa reel, C _3-8 - heterocyclyl, and C _3-10 - cycloalkyl, hydroxy, sulfanyl, oxo, halogen, amino, sulfo, methyl perhaloalkyl, perhaloalkyl Romero-ethoxy, C _1-6 - alkyl, C Optionally substituted with one or more substituents independently selected from _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl; ; R ³ , and R ⁴ are hydrogen, hydroxy, sulfanyl, halogen, amino, sulfo, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and Independently selected from C _3-10 -cycloalkyl, each of hydroxy, sulfanyl, amino, sulfo, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8- Heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 Optionally substituted with one or more substituents independently selected from heterocyclyl and C _3-10 -cycloalkyl, each of hydroxy, sulfanyl, amino, sulfo, C _1-6 -alkyl, C _2-6 -al Kenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, C _1-6 -alkyl, perhalomethyl and perhalomethoxy One or more values independently selected from Doedoe group optionally substituted; Provided that the compound is 2,2-dimethyl-N- [6- (methyl-phenyl-carbamoyloxy) -pyridin-3-yl] -succinic acid, 3, 3- dimethyl-4- [6- (methyl-phenyl-carba Molyoxy) -pyridin-3-ylcarbamoyl] -butyric acid, methyl-phenyl-carbamic acid pyridin-2-yl ester, methyl-phenyl-carbamic acid 5-chloro-pyridin-2-yl ester, methyl-phenyl- Carbamic acid 5-trifluoromethyl-pyridin-2-yl ester, methyl-phenyl-carbamic acid 3-chloro-5-trifluoromethyl-pyridin-2-yl ester, methyl-phenyl-carbamic acid 5-benzoylamino -Pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (cyclohexanecarbonyl-amino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 4,4-dimethyl-2,6-dioxo -3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-6'-yl ester, methyl-phenyl-carbamic acid 5- (2,2-dimethyl-propionylamino)- Pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (2-cyclohexyl-acetylamino) -pyridin-2-yl ester, Methyl-phenyl-carbamic acid 5- (3,3-dimethyl-butyrylamino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5-[(pyridine-2-carbonyl) -amino3-pyridine- 2-yl ester, methyl-phenyl-carbamic acid 5-[(6-chloro-pyridine-3-carbonyl) -amino] -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (2,2- Dimethyl-propylcarbamoyl) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl -6'-yl ester, methyl-phenyl-carbamic acid 5- (2,5-dioxo-pyrrolidin-1-yl) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4- Trifluoromethyl-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4-chloro-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4 -Methoxy-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 4,4-dimethyl-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl- 6'- Ester, methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester, methyl-phenyl-carbamic acid 5-benzenesulfonylamino-pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (3, 3-Dimethyl-2, 5-dioxo-pyrrolidin-1-yl) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- [3, 3-dimethyl-5- (4-methyl-pipee Razin-1-yl) -5-oxo-pentanoylamino] -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- [3, 3-dimethyl-4- (pyridin-3-ylcarbamoyl) -Butyrylamino] -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (3,3-dimethyl-5-morpholin-4-yl-5-oxo-pentanoylamino) -pyridine-2- One ester, methyl-phenyl-carbamic acid 5- [4- (2-dimethylamino-ethylcarbamoyl) -3, 3-dimethyl-butyrylamino] -pyridin-2-yl ester; N-methyl-N-phenylcarbamic acid 5-nitro-3-trifluoromethylpyridin-2-yl ester, N-methyl-N-phenylcarbamic acid 3-nitropyridin-2-yl ester, and Not N-methyl-N-phenylcarbamic acid 5-nitropyridin-2-yl ester. The compound of claim 1, wherein R ² is hydrogen, hydroxy, amino, halogen, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8- Heterocyclyl, amide, urea and thiourea and C _3-10 -cycloalkyl, each of hydroxy, amino, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl , Aryl, heteroaryl, C _3-8 -heterocyclyl, amide, urea and thiourea and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C _1-6 -alkyl Optionally substituted with one or more substituents independently selected from C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl Compounds which may be. The compound of claim 2, wherein R ² is halogen or hydrogen. 4. The compound of claim 1, wherein R ⁴ is selected from hydrogen, halogen, C _1-6 -alkyl, C _2-6 -alkenyl, and each C _1-6 -alkyl, C _{2 -6} -alkenyl is independently selected from hydroxy, halogen, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 heterocyclyl and C _3-10 -cycloalkyl And optionally substituted with one or more substituents. The compound of claim 4, wherein in another embodiment, R ⁴ is selected from hydrogen, halogen, and C _1-6 -alkyl. The compound of claim 5, wherein R ⁴ is hydrogen. 6. A compound according to claim 5, wherein R ⁴ is halogen. 8. The compound of claim 1, wherein R ³ is selected from hydrogen, hydroxy, halogen, C _1-6 -alkyl, C _2-6 -alkenyl, and each hydroxy, C _{1- 6} -alkyl, C _2-6 -alkenyl is hydroxy, halogen, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -Optionally substituted with one or more substituents independently selected from cycloalkyls. 9. A compound according to claim 8, wherein R ³ is selected from halogen, C _1-6 -alkyl, methoxy, perhalomethyl and perhalomethoxy. 10. The compound of claim 9, wherein R ³ is selected from halogen, methyl, ethyl, isopropyl, methoxy and perhalomethyl. The compound of claim 10, wherein R ³ is selected from halogen, methyl, methoxy and perhalomethyl. Diastereomers, enantiomers or tautomeric forms thereof, including compounds of formula (I) and mixtures thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, or polymorphs.

[In the above formula, [R ¹ and R ² are hydrogen, hydroxy, sulfanyl, amino, halogen, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C ₃ Independently selected from _-8 -heterocyclyl and C _3-10 -cycloalkyl, each of hydroxy, sulfanyl, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -al Kenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C _1-6 -alkyl, C _1-6- Optionally substituted with one or more substituents independently selected from alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl, each hydroxy , Sulfanyl, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl Hydroxy, sulfanyl, oxo, halogen, amino, sulfo, perhalomethyl, perhalomethoxy, C _1-6- Optionally substituted with one or more substituents independently selected from alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl May be; R ³ , and R ⁴ are hydrogen, hydroxy, sulfanyl, halogen, amino, sulfo, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and Independently selected from C _3-10 -cycloalkyl, each of hydroxy, sulfanyl, amino, sulfo, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8- Heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 Is optionally selected from one or more substituents independently selected from heterocyclyl and C _3-10 -cycloalkyl, each of hydroxy, sulfanyl, amino, sulfo, C _1-6 -alkyl, C _2-6- Alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, C _1-6 -alkyl, perhalomethyl and perhalome One selected independently from oxy Doedoe optionally substituted with a substituent; Provided that the compound is 2,2-Dimethyl-N- [6- (methyl-phenyl-carbamoyloxy) -pyridin-3-yl] -succinic acid, 3,3-dimethyl-4- [6- (methyl-phenyl-carba Moyloxy) -pyridin-3-ylcarbamoyl] -butyric acid, methyl-phenyl-carbamic acid pyridin-2-yl ester, methyl-phenyl-carbamic acid 5-chloro-pyridin-2-yl ester, methyl-phenyl- Carbamic acid 5-trifluoromethyl-pyridin-2-yl ester, methyl-phenyl-carbamic acid 3-chloro-5-trifluoromethyl-pyridin-2-yl ester, methyl-phenyl-carbamic acid 5-benzoylamino -Pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (cyclohexanecarbonyl-amino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 4,4-dimethyl-2,6-di Oxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-6'-yl ester, methyl-phenyl-carbamic acid 5- (2,2-dimethyl-propionylamino) -Pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (2-cyclohexyl-acetylamino) -pyridin-2-yl ester, Methyl-phenyl-carbamic acid 5- (3,3-dimethyl-butyrylamino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5-[(pyridine-2-carbonyl) -amino] -pyridine- 2-yl ester, methyl-phenyl-carbamic acid 5-[(6-chloro-pyridine-3-carbonyl) -amino] -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (2,2- Dimethyl-propylcarbamoyl) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl -6'-yl ester, methyl-phenyl-carbamic acid 5- (2,5-dioxo-pyrrolidin-1-yl) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4- Trifluoromethyl-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4-chloro-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4 -Methoxy-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 4,4-dimethyl-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl- 6'- Ester, methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester, methyl-phenyl-carbamic acid 5-benzenesulfonylamino-pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (3, 3-Dimethyl-2,5-dioxo-pyrrolidin-1-yl) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- [3,3-dimethyl-5- (4-methyl-pipe) Razin-1-yl) -5-oxo-pentanoylamino] -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- [3,3-dimethyl-4- (pyridin-3-ylcarbamoyl) -Butylamino] -pyridin-2-yl ester, methyl-phenyl-carzamic acid 5- (3,3-dimethyl-5-morpholin-4-yl-5-oxo-pentanoylamino) -pyridin-2-yl Ester, not methyl-phenyl-carbamic acid 5- [4- (2-dimethylamino-ethylcarbamoyl) -3,3-dimethyl-butyrylamino] -pyridin-2-yl ester]. Diastereomers, enantiomers or tautomeric forms thereof, including compounds of formula (I) and mixtures thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, or polymorphs.

[In the above formula R ² is H and R ¹

Each R ⁵ is hydrogen, hydroxy, sulfanyl, amino, halogen, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -Heterocyclyl and C _3-10 -cycloalkyl, each independently selected from hydroxy, sulfanyl, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, Aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, Optionally substituted with one or more substituents independently selected from C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl, each of hydroxy, sulfa Neyl, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl are hydroxy , sulfanyl, oxo, halogen, amino, sulfo, methyl perhaloalkyl, perhaloalkyl Romero-ethoxy, C _1-6 - Al , C _1-6 - alkoxy, C _2-6 - alkenyl, aryl, heteroaryl, C _3-8 - heterocyclyl, and C _3-10 - optionally is substituted with one or more substituents independently selected from cycloalkyl ; R ³ , and R ⁴ are hydrogen, hydroxy, sulfanyl, halogen, amino, sulfo, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and Independently selected from C _3-10 -cycloalkyl, each of hydroxy, sulfanyl, amino, sulfo, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8- Heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 Optionally substituted with one or more substituents independently selected from heterocyclyl and C _3-10 -cycloalkyl, each of hydroxy, sulfanyl, amino, sulfo, C _1-6 -alkyl, C _2-6 -alkenyl , Aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl are derived from hydroxy, sulfanyl, oxo, halogen, amino, C _1-6 -alkyl, perhalomethyl and perhalomethoxy One or more independently selected Doedoe optionally substituted with a group; Provided that the compound is Methyl-phenyl-carbamic acid 5-benzoylamino-pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4-trifluoromethyl-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbox Not acetic acid 5- (4-chloro-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4-methoxy-benzoylamino) -pyridin-2-yl ester]. Diastereomers, enantiomers or tautomeric forms thereof, including compounds of formula (I) and mixtures thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, or polymorphs.

[In the above formula [R ² is H and R ¹

Each R ⁵ is hydrogen, hydroxy, sulfanyl, amino, halogen, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 - heterocyclyl, and C _3-10 - are independently selected from cycloalkyl, each of hydroxy, sulfanyl, amino, sulfo, C _1-6 - alkyl, C _{1- 6} - alkoxy, C _2-6-al Kenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C _1-6 -alkyl, C _1-6- May be optionally substituted with one or more substituents independently selected from alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl, each of Hydroxy, sulfanyl, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cyclo Alkyl is hydroxy, sulfanyl, oxo, halogen, amino, sulfo, perhalomethyl, Halo methoxy, C _1-6 - independent of the cycloalkyl-alkyl, C _1-6 - alkoxy, C _2-6 - alkenyl, aryl, heteroaryl, C _3-8 - heterocyclyl, and C _3-10 May be optionally substituted with one or more substituents selected from; R ³ , and R ⁴ are hydrogen, hydroxy, sulfanyl, halogen, amino, sulfo, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and Independently selected from C _3-10 -cycloalkyl, each of hydroxy, sulfanyl, amino, sulfo, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8- Heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 Optionally substituted with one or more substituents independently selected from heterocyclyl and C _3-10 -cycloalkyl, each of hydroxy, sulfanyl, amino, sulfo, C _1-6 -alkyl, C _2-6- Alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, C _1-6 -alkyl, perhalomethyl and perhal One independently selected from methoxy Optionally substituted with a substituent on the phase; Provided that the compound is Methyl-phenyl-carbamic acid 5-benzoylamino-pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4-trifluoromethyl-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbox Not acetic acid 5- (4-chloro-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4-methoxy-benzoylamino) -pyridin-2-yl ester]. Diastereomers, enantiomers or tautomeric forms thereof, including compounds of formula (I) and mixtures thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, or polymorphs.

[In the above formula R ² is H and R ¹

Each R ⁵ is hydrogen, hydroxy, sulfanyl, amino, halogen, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -Heterocyclyl and C _3-10 -cycloalkyl, each independently selected from hydroxy, sulfanyl, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, Aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, Optionally substituted with one or more substituents independently selected from C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl, each of hydroxy, sulfanyl , Sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl are hydroxy, methyl-sulfanyl, oxo, halogen, amino, sulfonyl, perhaloalkyl, perhaloalkyl Romero-ethoxy, C _1-6 - Al Optionally substituted with one or more substituents independently selected from cycloalkyl -, C _1-6 - alkoxy, C _2-6 - alkenyl, aryl, heteroaryl, C _3-8 - heterocyclyl, and C _3-10 May be; R ₃ , and R ₄ are hydrogen Provided that the compound is Methyl-phenyl-carbamic acid 5-benzoylamino-pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4-trifluoromethyl-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbox Not acetic acid 5- (4-chloro-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4-methoxy-benzoylamino) -pyridin-2-yl ester]. Diastereomers, enantiomers or tautomeric forms thereof, including compounds of formula (I) and mixtures thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, or polymorphs.

[In the above formula R ² is H and R ¹

Each R ⁵ is hydrogen, hydroxy, sulfanyl, amino, halogen, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 Independently selected from heterocyclyl and C _3-10 -cycloalkyl, each of hydroxy, sulfanyl, amino, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -al Kenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C _1-6 -alkyl, C _1-6- Each hydroxy, optionally substituted with one or more substituents independently selected from alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl Sulfanyl, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl are hydrates Hydroxy, sulfanyl, oxo, halogen, amino, sulfo, perhalomethyl, perhalomethoxy, C _1-6 - alkyl, C _1-6 - alkoxy, C _2-6 - alkenyl, aryl, heteroaryl, C _3-8 - heterocyclyl, and C _3-10 - one independently selected from cycloalkyl Optionally substituted with any of the above substituents; R ₃ , and R ₄ are hydrogen Provided that the compound is Methyl-phenyl-carbamic acid 5-benzoylamino-pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4-trifluoromethyl-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbox Not acetic acid 5- (4-chloro-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4-methoxy-benzoylamino) -pyridin-2-yl ester]. Diastereomers, enantiomers or tautomeric forms thereof, including compounds of formula (I) and mixtures thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, or polymorphs.

[In the above formula R ² is H and R ¹

Each R ⁵ is hydrogen, hydroxy, amino, halogen, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and Independently selected from C _3-10 -cycloalkyl, each hydroxy, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8- Heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, Optionally substituted with one or more substituents independently selected from heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl, R ³ and R ⁴ are hydrogen, Provided that the compound is Methyl-phenyl-carbamic acid 5-benzoylamino-pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4-trifluoromethyl-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbox Not acetic acid 5- (4-chloro-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4-methoxy-benzoylamino) -pyridin-2-yl ester]. Diastereomers, enantiomers or tautomeric forms thereof, including compounds of formula (I) and mixtures thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, or polymorphs.

[In the above formula R ² is H and R ¹

Each R ⁵ is hydrogen, hydroxy, amino, halogen, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and Independently selected from C _3-10 -cycloalkyl, each hydroxy, amino, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _{3- 8} -heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, Optionally substituted with one or more substituents independently selected from aryl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl, R ³ and R ⁴ are hydrogen, Provided that the compound is Methyl-phenyl-carbamic acid 5-benzoylamino-pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4-trifluoromethyl-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbox Not acetic acid 5- (4-chloro-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4-methoxy-benzoylamino) -pyridin-2-yl ester]. 19. The compound of any one of claims 1-18, wherein R ² is hydrogen, hydroxy, amino, halogen, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, Heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl, each of hydroxy, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, Aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, Compounds which may optionally be substituted with one or more substituents independently selected from C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl . 20. The compound of claim 1, wherein R ³ is selected from fluorine, chlor, methyl, perhalomethyl or perhalomethoxy. 13. The compound of claim 12, wherein R ² is hydrogen. 13. The compound of claim 12, wherein R ² is selected from the group consisting of

13. A compound according to any one of claims 1 and 12, wherein R ² is selected from the group consisting of:

Wherein each Rx is hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _{3 -8} -heterocyclyl, and C _3-10 -cycloalkyl, each independently selected from hydroxy, sulfanyl, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6- Alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, sulfo, perhalomethyl, perhalomethoxy, C _1- One or more substituents independently selected from ₆ -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl May be optionally substituted; 13. A compound according to any one of claims 1 and 12, wherein R ² is selected from the group consisting of:

Wherein each R x is hydroxy, sulfanyl, oxo, halogen, amino, sulfo, perhalomethyl, perhalomethoxy, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl , Aryl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl; 13. The compound of claim 12, wherein R ² is selected from the group consisting of

13. The compound of claim 12, wherein R ² is selected from the group consisting of

13. The compound of claim 12, wherein R ² is selected from the group consisting of groups.

21. The compound of any of claims 1 and 12-20, wherein R ¹ is selected from the group consisting of:

29. A compound according to any one of claims 1, 12 and 28, wherein R ¹ is selected from the group consisting of:

29. The compound of any one of claims 1, 12 and 28, wherein R ¹ is selected from the group consisting of:

29. A compound according to any one of claims 1, 12 and 28, wherein R ¹ is selected from the group consisting of:

13. A compound according to any one of claims 1 and 12, wherein R ¹ is selected from the group consisting of:

Wherein each Rx is hydroxy, sulfanyl, oxo, halogen, amino, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _{3 -8} -heterocyclyl, and C _3-10 -cycloalkyl, each independently selected from hydroxy, sulfanyl, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6- Alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl and C _3-10 -cycloalkyl are hydroxy, sulfanyl, oxo, halogen, amino, sulfo, perhalomethyl, perhalomethoxy, C _1- One or more substituents independently selected from ₆ -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl May be optionally substituted; 13. A compound according to any one of claims 1 and 12, wherein R ¹ is selected from the group consisting of:

Wherein each R x is hydroxy, sulfanyl, oxo, halogen, amino, sulfo, perhalomethyl, perhalomethoxy, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl , Aryl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl; 13. A compound according to any one of claims 1 and 12, wherein R ¹ is selected from the group consisting of:

Wherein each R x is independently selected from halogen, perhalomethyl, perhalomethoxy, C _1-6 -alkyl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl; 35. The compound of any one of claims 1 to 34, wherein R ³ is hydrogen. 36. The compound of any of claims 1-35, wherein R ⁴ is hydrogen. 36. The compound of any one of claims 1 to 35, wherein R ⁴ is selected from fluorine, chlor, methyl, perhalomethyl or pohalomethoxy. 38. A compound according to any one of claims 1 to 37, having one free -COOH group. 39. A compound according to any one of claims 1 to 38, having one free amino group, or one single substituted amino group or one disubstituted amino group. 40. The compound of any one of claims 1 to 39, having one substituted or unsubstituted pyridine ring. 41. The compound of any of claims 1-40, having one substituted or unsubstituted imidazole ring. 42. The compound of any one of claims 1 to 41, wherein the molar weight of the compound is 650 g / mole or less. 43. The compound of any of claims 1-42, wherein the compound has no ionizable groups and cLog P is in the range of 1.0 to 6.0. The compound of any one of claims 1-42, wherein the compound has no ionizable groups and cLog P is in the range of 1.0 to 5.0. 43. The compound of any of claims 1-42, wherein the compound has no ionizable groups and cLog P is in the range of 1.0 to 4.0. 46. The compound of any of claims 1-45, wherein the compound has no ionizable groups and cLog P is in the range of 2.0 to 4.0. 47. The compound of any of claims 1-46, wherein the ACD LogD is in the range of 0.8 to 3.0. 48. The compound of any one of claims 1 to 47, wherein the number of H-bonds is 0, 1, 2 or 3. 49. The compound of any one of claims 1 to 48, wherein the number of H-bonds is 0, 1, or 2. 50. The compound of any one of claims 1-49, wherein the number of H-binding receptors is in the range of 4-9. 51. The compound of any one of claims 1-50, wherein the number of H-binding receptors is in the range of 6-8. 52. The compound of any one of claims 1-51, wherein the number of rotatable bonds of the compound is in the range of 4-14. 53. The compound of any of claims 1-52, wherein the number of rotatable bonds of the compound is in the range of 8-12. Any one of claims 1 to 53. A method according to any one of claims, wherein the polar surface area (PSA) is a compound characterized in that the range of ² to 50 Å 120 Å ^2. 55. The compound of any one of claims 1-54, wherein the polar surface portion (PSA) is in the range of 60 x ² to 100 x ² . The compound of any one of the preceding claims, wherein the compound is selected from the group consisting of: [Methyl-phenyl-carbamic acid 5- [2- (4,4-dimethyl-2,6-dioxo-piperidin-1-yl) -ethyl] -pyridin-2-yl ester], [[6- (Methyl-phenyl-carbamoyloxy) -pyridin-3-ylamino] -acetic acid tert -butyl ester], [[6- (Methyl-phenyl-carbamoyloxy) -pyridin-3-ylamino] -acetic acid], [Methyl-phenyl-carbamic acid 5-isothiocyanato-pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- (5-oxo-2-thioxo-imidazolidin-1-yl) -pyridin-2-yl ester], [[6- (Methyl-phenyl-carbamoyloxy) -pyridin-3-ylamino] -acetic acid methyl ester], [Methyl-phenyl-carbamic acid 5- (4,4-dimethyl-5-oxo-2-thioxo-imidazolidin-1-yl) -pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- (4-ethyl-5-oxo-2-thioxo-imidazolidin-1-yl) -pyridin-2-yl ester], [(S) -Methyl-phenyl-carbamic acid 5- (4-isopropyl-5-oxo-2-thioxo-imidazolidin-1-yl) -pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- (4- tert -butoxymethyl-5-oxo-2-thioxo-imidazolidin-1-yl) -pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- (3- tert -butyl- thioureido ) -pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- [3- (2,2-dimethyl-propyl) -thioureido] -pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- (3-isopropyl-thioureido) -pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- (3,3-diethyl-thioureido) -pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- (3-cyclohexyl-thioureido) -pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- (3-butyl-thioureido) -pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- (3-isobutyl-thioureido) -pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- (4-cyano-benzoylamino) -pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- (2-methyl-benzoylamino) -pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- (4-fluoro-benzoylamino) -pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- (3-methoxy-benzoylamino) -pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- (2-methoxy-benzoylamino) -pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- (3,4-dichloro-benzoylamino) -pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- (4-methyl-benzoylamino) -pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- (3-bromo-benzoylamino) -pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- (3-cyano-benzoylamino) -pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- (2-trifluoromethoxy-benzoylamino) -pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- (2-fluoro-3-trifluoromethyl-benzoylamino) -pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- (3-trifluoromethyl-benzoylamino) -pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- (3,4-difluoro-benzoylamino) -pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- (3-dimethylamino-benzoylamino) -pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- (3-dimethylamino-benzoylamino) -pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- (4-nitro-benzoylamino) -pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- (4-amino-benzoylamino) -pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- (3- tert -butyl-ureido) -pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- (4-formyl-benzoylamino) -pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- (4-morpholin-4-ylmethyl-benzoylamino) -pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- (4-hydroxymethyl-benzoylamino) -pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- (4-chloromethyl-benzoylamino) -pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- (4-piperidin-1-ylmethyl-benzoylamino) -pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- [4- (4-methyl-piperidin-1-ylmethyl) benzoylamino] -pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- [4- (2-ethyl-piperidin-1-ylmethyl) -benzoylamino] -pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- [4- (2-methyl-piperidin-1-ylmethyl) -benzoylamino] -pyridin-2-yl ester], [Methyl-phenyl-carbamic acid 5- [4- (3-methyl-piperidin-1-ylmethyl) -benzoylamino] -pyridin-2-yl ester], Methyl-phenyl-carbamic acid 5- (4-piperidin-1-yl-benzoylamino) -pyridin-2-yl ester Methyl-phenyl-carbamic acid 5- [4- (2-methyl-piperidin-1-yl) -benzoylamino] -pyridin-2-yl ester, Methyl-phenyl-carbamic acid 5- [4- (3-methyl-piperidin-1-yl) -benzoylamino] -pyridin-2-yl ester Methyl-phenyl-carbamic acid 5- [4- (4-methyl-piperidin-1-yl) -benzoylamino] -pyridin-2-yl ester Methyl-phenyl-carbamic acid 4- [4- (2-ethyl-piperidin-1-yl) benzoylamino] -pyridin-2-yl ester Methyl-phenyl-carbamic acid 4- [4- (4,4-dimethyl-piperidin-1-yl) -benzoylamino] -pyridin-2-yl ester Methyl-phenyl-carbamic acid 4- [4- (2,6-dimethyl-piperidin-1-yl) benzoylamino] -pyridin-2-yl ester Methyl-phenyl-carbamic acid 4- [4- (2,4,6-trimethyl-piperidin-1-yl) -benzoylamino] -pyridin-2-yl ester Methyl-phenyl-carbamic acid 4- [4- (2,6-dimethyl-piperidin-1-ylmethyl) -benzoylamino] -pyridin-2-yl ester Methyl-phenyl-carbamic acid 4- [4- (4,4-dimethyl-piperidin-1-ylmethyl) -benzoylamino] -pyridin-2-yl ester Methyl-phenyl-carbamic acid 4- [4- (2,4,6-trimethyl-piperidin-1-ylmethyl) benzoylamino] -pyridin-2-yl ester Methyl-phenyl-carbamic acid 5- [4- (2-piperidin-1-yl-ethyl) -benzoylamino] -pyridin-2-yl ester Methyl-phenyl-carbamic acid 5- {4- [2- (2-methyl-piperidin-1-yl) -ethyl] -benzoylamino} -pyridin-2-yl ester Methyl-phenyl-carbamic acid 5-4- [2- (3-methyl-piperidin-1-yl) -ethyl] -benzoylamino} -pyridin-2-yl ester Methyl-phenyl-carbamic acid 5- {4- [2- (4-methyl-piperidin-1-yl) -ethyl] -benzoylamino} -pyridin-2-yl ester Methyl-phenyl-carbamic acid 5- {4- [2- (2-ethyl-piperidin-1-yl) -ethyl] -benzoylamino} -pyridin-2-yl ester Methyl-phenyl-carbamic acid 5- {4- [2- (4,4-dimethyl-piperidin-1-yl) ethyl] -benzoylamino} -pyridin-2-yl ester Methyl-phenyl-carbamic acid 5- {4- [2- (2,6-dimethyl-piperidin-1-yl) -ethyl] -benzoylamino} -pyridin-2-yl ester Methyl-phenyl-carbamic acid 5- {4- [2- (2,4,6-trimethyl-piperidin-1-yl) -ethyl] -benzoylamino} -pyridin-2-yl ester. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 56 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent. 59. The composition of claim 57, wherein the composition comprises about 0.05 to about 2000 mg, preferably about 0.1 to about 500 mg of the compound according to any one of claims 1 to 56 or a pharmaceutically acceptable salt thereof; Even more preferably in unit dosage form comprising from about 1.0 to about 100 mg. A pharmaceutical composition for use as a medicament for inhibiting the lipolytic activity of hormone-sensitive lipases against triacylglycerols, diacylglycerols, cholesterol acyl esters or steroid acyl esters, the composition comprising any one of claims 1-56. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent. 60. A pharmaceutical composition according to any one of claims 57 to 59 for oral administration. The pharmaceutical composition according to any one of claims 57 to 59 for nasal, transdermal, pulmonary, or parenteral administration. Use of a compound according to any one of claims 1 to 56 for the preparation of a pharmaceutical composition. Use of a compound according to any one of claims 1 to 56 for the inhibition of hormone-sensitive lipases. The compound of any one of claims 1 to 56 for the preparation of a pharmaceutical composition which inhibits the lipolytic activity of hormone-sensitive lipases against triacylglycerols, diacylglycerols, cholesterol acyl esters or steroid acyl esters. use. Regulating plasma levels of free fatty acids, glycerol, LDL-cholesterol, HDL-cholesterol, insulin and / or glucose; And / or Regulate intracellular triacylglycerol and cholesterol ester storage, fatty acids, fatty acid esters such as diacylglycerol, phosphatidic acid, long chain acyl-CoA's and citrate or malonyl-CoA; And / or Increases insulin sensitivity in adipose tissue, skeletal muscle, liver or pancreatic β cells; And / or The use of a compound according to any one of claims 1 to 56 for the preparation of a pharmaceutical composition for treating or preventing any disease in which it is desirable to modulate insulin secretion from interest β cells. 66. The method of claim 65, wherein the disease consists of insulin resistance, type 1 diabetes, type 2 diabetes, X metabolic syndrome, impaired glucose tolerance, hyperglycemia, dyslipidemia, obesity, atherosclerosis, hypertension, abnormalities in lipoprotein metabolism, and any combination thereof. Use, characterized in that selected from the group. Use of a compound according to any one of claims 1 to 56 for the preparation of a pharmaceutical composition for treating and / or preventing dyslipidemia. Use of a compound according to any one of claims 1 to 56 for the preparation of a pharmaceutical composition for treating and / or preventing hyperlipidemia. Use of a compound according to any one of claims 1 to 56 for the preparation of a pharmaceutical composition for treating and / or preventing hyperglycemia. Use of a compound according to any one of claims 1 to 56 to lower HbA _1C . Use of a compound according to any one of claims 1 to 56 relating to the manufacture of a pharmaceutical composition for the treatment and / or prevention of type 2 diabetes. Use of a compound according to any one of claims 1 to 56 relating to the manufacture of a pharmaceutical composition for the treatment and / or prevention of impaired glucose tolerance. Use of a compound according to any one of claims 1 to 56 relating to the manufacture of a pharmaceutical composition for the treatment and / or prevention of X metabolic syndrome. Use of a compound according to any one of claims 1 to 56 relating to the manufacture of a pharmaceutical composition for the treatment and / or prevention of atherosclerosis. Use of a compound according to any one of claims 1 to 56 for the preparation of a pharmaceutical composition for the delay or prevention of progression from impaired glucose tolerance to type 2 diabetes. Use of a compound according to any one of claims 1 to 56 relating to the manufacture of a pharmaceutical composition for the delay or prevention of progression from non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes. 77. The use according to any one of claims 62 to 76, wherein additional antidiabetic, antiobesity, antihypertensive or appetite suppressing drugs are used. 78. Use according to any of claims 62 to 77, wherein metformin is also used. A method of treating a disease in a patient in which modulation of the activity of a hormone-sensitive lipase is desired, said method comprising a therapeutically effective amount of a compound according to any one of claims 1 to 56 or a pharmaceutically acceptable salt thereof. A method of treatment comprising administering to a patient in need thereof. A method of treating a disease in a patient in which it is desirable to lower the activity of a hormone-sensitive lipase, the method comprising a therapeutically effective amount of a compound according to any one of claims 1 to 56 or a pharmaceutically acceptable salt thereof. Administering to the patient in need thereof. 81. The method of any one of claims 79-80, wherein said administration is performed by oral, nasal, transdermal, pulmonary, or parenteral route. 82. The method of any one of claims 79-81, wherein the disease is insulin resistance, type 1 diabetes, type 2 diabetes, X metabolic syndrome, impaired glucose tolerance, hyperglycemia, dyslipidemia, obesity, atherosclerosis, hypertension, lipoprotein metabolism. And an abnormality of and any combination thereof. The therapeutically effective amount of the compound of claim 79, wherein the therapeutically effective amount of the compound is from about 0.05 to about 2000 mg, preferably from about 0.1 to about 500 mg and even more preferably of the compound per day. 1.0 to about 100 mg. 84. The method of any one of claims 79-83, wherein additional antidiabetic, anti-obesity, antihypertensive or appetite control drugs are administered to the patient. 85. The method of any one of claims 79-84, wherein metformin is also administered to the patient. Any one of claims 1 to 52 as any one of the preceding compound or accepted methods salts prepared in a pharmaceutically according to one, wherein said step of reacting the appropriate alcohol with the appropriate carbamoyl reagent in a solvent according to the reaction P ₁

And separating the disubstituted carbamate product. 87. The method of claim 86, wherein said carbamoylation reagent

Is selected from the group consisting of:

. 88. The process according to any one of claims 86 to 87, wherein said solvent is selected from the group consisting of tetrahydrofuran, dimethylformamide and N-methylpyrrolidone. 89. The process according to any one of claims 86 to 88, wherein said base is selected from the group consisting of triethylamine, N, N-diisopropyl-N-ethylamine and DABCO. 53. The process according to any one of claims 1 to 52, wherein the process is carried out with a suitable acylation reagent of the appropriate amine in the solvent and in the presence of a base according to the reactivity P ₂

And separating the disubstituted carbamate. 91. The process of claim 90, wherein Lv is Cl. 92. The process of any one of claims 90-91, wherein said solvent is selected from the group consisting of diethyl ether, tetrahydrofuran and dichloromethane. 93. The compound of any of claims 90-92, wherein the base is selected from the group consisting of trimethylamine, triethylamine, ethyl-diisopropyl-amine and 1,4-diazabicyclo [2.2.2] octane Process characterized in that. 94. The process according to any one of claims 90 to 93, wherein said base is present as functional on one or two substituents R ³ and R ⁴ , thus forming a salt with acid H-Lv. . A compound according to any one of the preceding claims, wherein said compound is selected from the group consisting of: Methyl-phenyl-carbamic acid 5- (4-dimethylaminomethyl-benzoylamino) -pyridin-2-yl ester, methyl-phenyl-carbamic acid 5- (4-diethylaminomethyl-benzoylamino) -pyridine-2- One ester, methyl-phenyl-carbamic acid 5- (4-pyrrolidin-1-ylmethyl-benzoylamino) -pyridin-2-yl ester, Methyl-phenyl-carbamic acid 5- (4-dipropylaminomethyl-benzoylamino) -pyridin-2-yl ester, Methyl-phenyl-carbamic acid 5- (4-pyrrolidin-1-ylmethyl-benzoylamino) -pyridin-2-yl ester, cis -methyl-phenyl-carbamic acid 5- [4- (2,6-dimethyl-piperidin-1-ylmethyl) -benzoylamino] -pyridin-2-yl ester, Methyl-phenyl-carbamic acid 5- [4- (4-oxo-piperidin-1-ylmethyl) -benzoylamino] -pyridin-2-yl ester, cis -methyl-phenyl-carbamic acid 5- [4- (2,6-dimethyl-morpholin-4-ylmethyl) -benzoylamino] -pyridin-2-yl ester, Methyl-phenyl-carbamic acid 5- (4-thiomorpholin-4-ylmethyl-benzoylamino) -pyridin-2-yl ester, Methyl-phenyl-carbamic acid 5- [3- (2-hydroxy-1,1-dimethyl-ethyl) -thioureido] -pyridin-2-yl ester, Methyl-phenyl-carbamic acid 5- [3- (l-methyl-cyclopropyl) -thioureido] -pyridin-2-yl ester, Methyl-phenyl-carbamic acid 5- [3- (1-methyl-cyclobutyl) -thioureido] -pyridin-2-yl ester, Methyl-phenyl-carbamic acid 5- (4-imidazol-1-yl-benzoylamino) -pyridin-2-yl ester, Methyl-phenyl-carbamic acid 5- (4-diethylamino-benzoylamino) -pyridin-2-yl ester, Methyl-phenyl-carbamic acid 5- (4- [1,2,4] triazol-1-yl-benzoylamino) -pyridin-2-yl ester, Methyl-phenyl-carbamic acid 5- (3,3-dipropyl-thioureido) -pyridin-2-yl ester, Methyl-phenyl-carbamic acid 5- (3,3-dibutyl-thioureido) -pyridin-2-yl ester, Methyl-phenyl-carbamic acid 5-[(piperidin-1-carbothioyl) -amino] -pyridin-2-yl ester, Methyl-phenyl-carbamic acid 5-[(4-methyl-piperidin-1-carbothioyl) -amino] -pyridin-2-yl ester, Methyl-phenyl-carbamic acid 5-[(4,4-dimethyl-piperidin-1-carbothioyl) -amino] -pyridin-2-yl ester, (4-Bromo-phenyl) -methyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-6 '-Yl ester, (4-Chloro-phenyl) -methyl-carbamic acid 4, 4-dimethyl-2,6-dioxo-3,4, 5, 6-tetrahydro-2H- [1,3 '] bipyridinyl-6' -Yl esters, (3,4-Dichloro-phenyl) -methyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl- 6'-yl ester, (3-chloro-phenyl) -methyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-6' -Yl esters, Methyl-p-tolyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-6'-yl ester, (3-Fluoro-phenyl) -methyl-carbamic acid 4,4-dimethyl-2, 6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-6 '-Yl ester, Methyl-m-tolyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-6'-yl ester, (4-methoxy-phenyl) -methyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-6 '-Yl ester, (3-methoxy-phenyl) -methyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-6 '-Yl ester, Methyl- (3-trifluoromethyl-phenyl) -carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl -6'-yl ester, (3-Bromo-phenyl) -methyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-6 '-Yl ester, (4-Fluoro-phenyl) -methyl-carbamic acid 4,4-dimethyl-2, 6-dioxo-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-6 '-Yl ester, [4- (2-hydroxy-ethyl) -phenyl] -methyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4, 5,6-tetrahydro-2H- [1, 3 ' ] Bipyridinyl-6'-yl ester.