# Patent

## Title
Compounds and uses thereof for decreasing activity of hormone-sensitive lipase

## Abstract

Use of compounds to inhibit hormone-sensitive lipase, pharmaceutical compositions comprising the compounds, methods of treatment employing these compounds and compositions, and novel compounds. The present compounds are inhibitors of hormone-sensitive lipase and may be useful in the treatment and/or prevention of medical disorders where a decreased activity of hormone-sensitive lipase is desirable.

## Background
Priority of Danish Application No. PA 2001 01879 filed on Dec. 14, 2001; Danish Application No. PA 2002 00645 filed on Apr. 30, 2002; Danish Application No. PA 2002 01000 filed on Jun. 27, 2002; and Danish Application No. PA 2002 01562 filed on Oct. 11, 2002 is claimed under 35 U.S.C. 119; the contents of which are herein incorporated by reference.
Priority of U.S. Provisional Application No. 60/346,909 filed on Jan. 3, 2002; U.S. Provisional Application No. 60/384,253 filed on May 10, 2002; U.S. Provisional Application No. 60/393,068 filed on Jun. 28, 2002 and U.S. Provisional Application No. 60/418,481 filed on Oct. 15, 2002 is claimed under 35 U.S.C. 119; the contents of which are herein incorporated by reference.


FIELD OF THE INVENTION
The present invention relates to compounds, compositions containing them, and their use for treating medical disorders where it is desirable to modulate the activity of hormone-sensitive lipase.
BACKGROUND OF THE INVENTION
The overall energy homeostasis of a mammalian system requires a high degree of regulation to ensure the availability of the appropriate substrate at the appropriate time. Plasma glucose levels rise during the post-prandial state, to return to pre-prandial levels within 2-3 hours. During these 2-3 hours, insulin promotes glucose uptake by skeletal muscle and adipose tissue and decreases the release of free fatty acids (FFA) from adipocytes, to ensure that the two substrates do not compete with each other. When plasma glucose levels fall, an elevation in plasma FFA is necessary to switch from glucose to fat utilization by the various tissues.
In individuals with insulin resistance, FFA levels do not fall in response to insulin, as they do in normal individuals, preventing the normal utilization of glucose by skeletal muscle, adipose and liver. Furthermore, there is a negative correlation between insulin sensitivity and plasma FFA levels.
Hormone-sensitive lipase (HSL) is an enzyme, expressed primarily in adipocytes, that catalyses the conversion of triglycerides to glycerol and fatty acids. It is through the regulation of this enzyme that the levels of circulating FFA are modulated. Insulin leads to the inactivation of HSL with a subsequent fall in plasma FFA levels during the post-prandial state, followed by the activation of the enzyme when the insulin concentration falls and catecholamines rise during the post-absorptive period. The activation of HSL leads to an increase in plasma FFA, as they become the main source of energy during fasting.
The activation-inactivation of HSL is primarily mediated through the cAMP-protein kinase A and AMP-dependent kinase pathways. There are compounds like nicotinic acid and its derivatives, that decrease the activation of HSL via these pathways and cause a decrease in lipolysis that leads to a reduction in the FFA levels. These drugs have a beneficial effect in the utilization of glucose and in the normalization of the excess triglyceride synthesis seen in patients with elevated FFA. However, since these pathways are used by other processes in the body, these drugs have severe side effects.
We have found compounds that specifically inhibit the lipolytic activity of HSL and lead to a decrease in plasma FFA levels. These compounds can be used to treat disorders where a decreased level of plasma FFA is desired, such as insulin resistance, syndrome X, dyslipidemia, abnormalities 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 which have good pharmaceutical properties such as solubility, bioavailability etc.
Definitions
The following is a detailed definition of the terms used to describe the compounds of the invention.
“Halogen” designates an atom selected from the group consisting of F, Cl, Br and I.
The term “C1-6-alkyl” in the present context designates a saturated, branched or straight hydrocarbon group having from 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 “C2-6-alkyl” in the present context designates a saturated, branched or straight hydrocarbon group having from 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, isohexyl and the like.
The term “C1-6alkoxy” in the present context designates a group —O—C1-6-alkyl wherein C1-6-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, neopentdxy, tert-pentoxy, n-hexoxy, isohexoxy and the like.
The term “C3-8-alkoxy” in the present context designates a group —O—C1-6alkyl wherein C3-8-alkyl is a saturated, branched or straight hydrocarbon group having from 3-6 carbon atoms. Representative examples of C3-6-alkoxy include, but are not limited to, n-propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, tert-pentoxy, n-hexoxy, isohexoxy and the like.
The term “C2-6-alkenyl” as used herein, represent an olefinically unsaturated branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one double bond. Examples of such 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.
The term “C3-10-cycloalkyl” as used herein represents a saturated mono-, bi-, tri- or spirocarbocyclic group having from 3 to 10 carbon atoms. Representative examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo[3.2.1]octyl, spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl and the like.
The term “C3-8-heterocyclyl” as used herein represents a saturated 3 to 8 membered ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur. Representative examples are pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, aziridinyl, tetrahydrofuranyl and the like.
The term “aryl” as used herein represents a carbocyclic aromatic ring system being either monocyclic, bicyclic, or polycyclic, such as phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl, biphenylenyl and the like. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic aromatic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl and the like.
The term “aryloxy” as used herein represents an aryl which is linked via an oxygen atom, e.g. phenoxy, 1-naphthyloxy, 2-naphthyloxy and the like.
The term “heteroaryl” as used herein represents a heterocyclic aromatic ring system containing one or more heteroatoms selected from 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-triazinyl, 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, thiadiazinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl (thianaphthenyl), indazolyl, benzimidazolyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinazolinyl, quinolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl and the like. Heteroaryl is also intended to include the partially hydrogenated derivatives of the heterocyclic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 2,3-dihydrobenzofuranyl, 3,4-dihydroisoquinolinyl, pyrrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl and the like.
The term “perhalomethyl” as used herein designates a methyl moiety substituted with three halogen atoms. Non-limiting examples of perhalomethyl are CF3, CCl3, and CF2Cl.
The term “perhalomethoxy” as used herein designates a perhalomethyl linked via an oxygen atom, e.g. —O—CF3, —O—CCl3, and —O—CF2Cl
The term “ring system” as used herein includes aromatic as well as non-aromatic ring moieties, which may be monocyclic, bicyclic or polycyclic, and they encompass moieties with zero, one or more hetereatoms selected from nitrogen, oxygen and sulphur. Non-limiting examples of such ring systems are aryl, C3-8-heterocyclyl and heteroaryl.
The term “heterocyclic system” as used herein includes aromatic as well as non-aromatic ring moieties, which may be monocyclic, bicyclic or polycyclic, and containing in their ring structure one or more heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of such heterocyclic systems are C3-8-heterocyclyl and heteroaryl.
Certain of the above defined terms may occur more than once in the structural formulae, and upon such occurrence each term shall be defined independently of the other.
The term “optionally substituted” as used herein means that the groups in question are either unsubstituted or substituted with one or more of the substituents specified. When the groups in question are substituted with more than one substituent the substituents may be the same or different.
The term “optionally covalently bound” as used herein means that the substituents in question are either not covalently bound to each other or the substituents are directly connected to each other by a covalent bond. A non-limiting example of such optionally covalently bound substituents is —NR1R2 wherein R1 is ethyl and R2 is propyl which provided that the substituents, ethyl and propyl, are optionally covalently bound may be ethyl-propyl-amino, 1-piperidyl, 3-methyl-1-pyrrolidyl or 2,3-dimethyl-1-azetidyl.
The term “hydrolysable group” as used herein means a group which can be hydrolysed at certain chemical conditions, i.e. an internal covalent bond in the group can be cleaved to give two compounds. A hydrolysable group does not have to be hydrolysed during carrying out the present invention. For instance, the hydrolysable group —C(═X)-L can be hydrolysed to give the products —C(═X)OH and HL, which means that the covalent bond between —C(X) and L is cleaved. Examples of hydrolysable groups are carbamates, esters and amides.
The terms “disease”, “condition” and “disorder” as used herein are used interchangeably to specifiy a state of a patient which is not the normal physiological state of man.
The term “treatment” as used herein means the management and care of a patient having developed a disease, condition or disorder, as well as the management and care of an individual at risk of developing the disease, condition or disorder prior to the clinical onset of said disease, condition or disorder. The purpose of treatment is to combat the disease, condition or disorder, as well as to to combat the development of the disease, condition or disorder. Treatment includes the administration of the active compounds to prevent or delay the onset of the symptoms or complications and to eliminate or control the disease, condition or disorder as well as to alleviate the symptoms or complications associated with the disease, condition or disorder.
The term “effective amount” as used herein means a dosage which is sufficient in order for the treatment of the patient to be effective compared with no treatment.
The term “modulate” as used herein means to influence, i.e. to modulate a parameter means to influence that parameter in a desired way. Examples are to modulate insulin secretion from beta cells and to modulate the plasma level of free fatty acids.
The term “medicament” as used herein means a pharmaceutical composition suitable for administration of the pharmaceutically active compound to a patient.
The term “pharmaceutically acceptable” as used herein means suited for normal pharmaceutical applications, i.e. giving rise to no adverse events in patients etc.


DESCRIPTION OF THE INVENTION
The present invention relates to compounds of the general formula II




    wherein R1 is selected from C1-6-alkyl, C2-6-alkenyl and C3-10-cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano and nitro; and
    R2 is selected from C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, perhalomethyl and perhalomethoxy; and
    wherein R2 is optionally covalently bound to R1 by an ether, thioether, C—C or C—N bond, to form a ring system with the N-atom to which R1 and R2 are bound; and
    R3 is selected from hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C3-10-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, perhalomethyl and perhalomethoxy; and
    X is O or S; or

a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or any tautomeric forms, stereoisomers, mixture of stereoisomers including a racemic mixture, or polymorphs.



In an aspect of the invention, compounds are of the general formula III




    wherein R1a and R2a are independently selected from C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano and nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, perhalomethyl and perhalomethoxy; and
    wherein R1a is optionally covalently bound to R2a by an ether, thioether, C—C or C—N bond, to form a ring system with the N-atom to which R1a and R2a are bound; and
    R4a, R5a, R6a and R7a are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, each of which is optionally substituted by one or more substituents selected from hydroxy, sulfanyl, sulfo, oxo, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, perhalomethyl and perhalomethoxy; and
    A1a is N or C—R8a; A2a is N or C—R9a; A3a, is N or C—R10a; A4a is N or C—R11a; and A5a is N or C—R12a; and
    wherein R8a, R9a, R10a, R11a and R12a are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, perhalomethyl and perhalomethoxy.


In one embodiment, the invention is concerned with compounds of formula (III), wherein R2a is phenyl, optionally substituted by halogen or methyl.
In another embodiment, the invention in concerned with compounds of formula (III), wherein R1a is selected from methyl and ethyl, optionally substituted by one or more halogen.
In another embodiment, the invention in concerned with compounds of formula (III), wherein R1a and R2a are covalently bound so as to form a ring system with the N-atom to which they are bound, wherein said ring system is a piperidine, piperazine, morpholine, or thiomorpholine.
In another embodiment, the invention in concerned with compounds of formula (III), wherein R4a, R5a, R6a and R7a are independently selected from hydrogen, F, Cl, C1-6alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another embodiment, the invention in concerned with compounds of formula (III), wherein A1a, A2a, A3a, A4a and A5a are independently selected from N, CH, CF, C—Cl and C—CF3.
In an aspect of the invention, compounds are of the general formula IV




    wherein R1b and R2b are independently selected from C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, each of which may optionally be substituted with one or more substituents selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6alkyl, C1-6alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy;
    wherein R1b is optionally covalently bound to R2b by an ether, thioether, C—C or C—N bond, to form a ring system with the N-atom to which R1b and R2b are bound;
    R5b and R6b are independently selected from hydrogen, hydroxy, sulfanyl, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, perhalomethyl and perhalomethoxy;
    R4b and R7b are independently selected from hydrogen, hydroxy, sulfanyl, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, perhalomethyl and perhalomethoxy; and
    A1b is N or C—R8b; A2b is N or C—R9b; A3b is N or C—R10b; A4b is N or C—R11b; and A5b is N or C—R12b; and
    wherein R8b, R9b, R10b, R11b and R12b are selected from hydrogen, hydroxy, sulfanyl, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, perhalomethyl and perhalomethoxy;
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group consisting of R4b, R5b, R6b, R7b, R8b, R9b, R10b, R11b and R12b.


In one embodiment, the invention is concerned with compounds of formula IV, wherein R2b is phenyl, optionally substituted by halogen. In another embodiment, the invention is concerned with compounds of the general formula IV, wherein R1b is selected from methyl and ethyl, optionally substituted by one or more halogen.
In another embodiment, the invention is concerned with compounds of the general formula IV, wherein R1b and R2b are covalently bound so as to form a ring system with the N-atom to which they are bound, wherein the ring system is a piperidine, piperazine, morpholine, or thiomorpholine.
In another embodiment, the invention is concerned with compounds of the general formula IV, wherein R4b, R5b, R6b and R7b are independently selected from hydrogen, F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another embodiment, the invention is concerned with compounds of the general formula IV, wherein A1b, A2b, A3b, A4b and A5b are independently selected from N, CH and CF.
In an aspect of the invention, compounds are of the general formula V




wherein R4c, R5c, R6c, R7c and R8c are independently selected from hydrogen, hydroxy, sulfanyl, amino, halogen, cyano, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and

    R9c, R10c, R11c, R12c and R13c are independently selected from hydrogen, sulfanyl, amino, halogen, cyano, nitro, sulfo, C1-6alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of sulfanyl, amino, sulfo, C1-6-alkyl, C1-6 alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group consisting of R4c, R5c, R6c, R7c and R8c; and
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group consisting of R9c, R10c, R11c, R12c and R13c; and
    at least one of R4c, R5c, R6c, R7c, R8c, R9c, R10c, R11c, R12c and R13c are different from hydrogen.


In one embodiment, the invention is concerned with compounds of formula V, wherein R9c, R10c, R11c, R12c and R13c are selected from H and F.
In another embodiment, the invention is concerned with compounds of the general formula V, wherein R4c, R5c, R6c, R7c and R8c are independently selected from hydrogen, F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another embodiment, the invention is concerned with compounds of the general formula V, where there are no covalent bonds between any of the substituents R9c, R10c, R11c, R12c and R13c.
In another embodiment, the invention is concerned with compounds of the general formula V, where there are no covalent bonds between any of the substituents R4c, R5c, R6c, R7c and R8c.
In an aspect of the invention, compounds are of the general formula VI




    wherein R4d and R5d are independently selected from hydrogen, hydroxy, sulfanyl, amino, C2-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, amino, C2-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy: and
    R6d, R7d, R8d, R9d, R10d, R11d, R12d, R13d and R14d are independently select hydroxy, sulfanyl, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6alkyl, C1-6alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6 alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy:
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group-consisting of R4d, R5d, R6d, R7d, R8d and R9d; and
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group consisting of R10d, R11d, R12d, R13d and R14d.


In one embodiment, the invention is concerned with compounds of the general formula VI, wherein R4d and R5d are H.
In another embodiment, the invention is concerned with compounds of the general formula VI, wherein R6d, R7d, R8d and R9d are selected from the group consisting of hydrogen, F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another embodiment, the invention is concerned with compounds of the general formula VI, wherein R10d, R11d, R12d, R13d and R14d are selected from the group consisting of hydrogen, F, Cl, C1-6-alkyl, C1-6alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another embodiment, the invention is concerned with compounds of the general formula VI, wherein there are no covalent bonds between any of the substituents R4d, R5d, R6d, R7d, R8d and R9d.
In another embodiment, the invention is concerned with compounds of the general formula VI, wherein there are no covalent bonds between any of the substituents R10d, R11d, R12d, R13d and R14d.
In an aspect of the invention, compounds are of the general formula VII




wherein R4e is selected from hydrogen, hydroxy, sulfanyl, halogen, amino, cyano, nitro, C2-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of C2-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy: and

    R5e is selected from hydrogen, F, cyano, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy;
    wherein R4e and R5e may be covalently bound to each other by a C—O bond.


In one embodiment, the invention is concerned with compounds of the general formula VII, wherein R4e or R5e is selected from the group consisting of




wherein R6e, R7e, R8e, R9e and R10e are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl.

In another embodiment, the invention is concerned with compounds of the general formula VII, wherein R4e or R5e is selected from the group consisting of




    wherein R6e, R7e, R8e, R9e and R10e are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy and C2-6-alkenyl.


In another embodiment, the invention is concerned with compounds of the general formula VII, wherein at least one of the substituents R6e, R7e, R8e, R9e and R10e are selected from the group consisting of F and perhalomethyl.
In another embodiment, the invention is concerned with compounds of the general formula VII, wherein R4e and R5e are connected by a C—O bond to form the compound




    wherein R11e is selected from hydrogen, hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
    R12e is selected from hydrogen, F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.


In an aspect of the invention, compounds are of the general formula VIII




    wherein R4f, R5f, R6f, R7f, R9f and R10f are independently selected from hydrogen, hydroxy, sulfanyl, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy: with the proviso that R4f and R5f are not both methoxy; and
    R8f is selected from hydrogen, sulfo, C1-6-alkyl, C1-1-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, perhalomethyl and perhalomethoxy;
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group consisting of R4f, R5f, R6f, R7f and R8f; and
    wherein there may optionally be a covalent bond between R9f and R10f.


In one embodiment, the invention is concerned with compounds of the general formula VIII, wherein R9f and R10f are covalently bound so as to form a ring system with the C-atom to which they are bound.
In another embodiment, the invention is concerned with compounds of the general formula VIII, wherein said ring system is a cycloalkyl, phenyl, heteroaryl, piperidine, piperazine, morpholine, or thiomorpholine.
In another embodiment, the invention is concerned with compounds of the general formula VIII, wherein R4f and R8f are connected by a C—O bond to form the compound




    wherein R11f is selected from hydrogen, hydroxy, sulfanyl, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
    R17f is selected from hydrogen, F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl; and
    wherein there may optionally be a covalent bond between R9f and R10f.


In an aspect of the invention, compounds are of the general formula IX




    wherein R4g, R5g, R6g, R7g, R8g, R9g, R10g and R11g are independently selected from hydroxy, sulfanyl, halogen, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy: and
    R12g is selected from the group consisting of —C(═O)—, —C(═O)NH—, —CH2—, —CH2CH2—, —CHR15g—, —CH2CHR15g—, —CHR15g—CH2—, —NH—, —NR15g—, —NHC(═O)—, —NR15g—C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—;
    wherein R15g is selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, perhalomethyl and perhalomethoxy; and
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group consisting of R4g, R5g, R6g, R7g and R15g; and
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group consisting of R8g, R9g, R10g, R11g and R15g; and
    R13g is selected from hydrogen, hydroxy, sulfanyl, halogen, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy: and
    R14g is selected from hydrogen, hydroxy, sulfanyl, halogen, amino, cyano, nitro, C2-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of C2-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy: and
    wherein R13g and R14g may optionally be covalently bound to each other.


In one embodiment, the invention is concerned with compounds of the general formula IX, wherein R13g and R14g are covalently bound so as to form a ring system with the N-atom to which they are bound.
In another embodiment, the invention is concerned with compounds of the general formula IX, wherein said ring system is a piperidine, piperazine, morpholine, or thiomorpholine.
In another embodiment, the invention is concerned with compounds of the general formula IX, wherein there are no covalent bonds between any of the substituents R4g, R5g, R6g, R7g and R15g.
In another embodiment, the invention is concerned with compounds of the general formula IX, wherein there are no covalent bonds between any of the substituents R8g, R9g, R10g, R11g and R15g.
In another embodiment, the invention is concerned with compounds of the general formula IX, wherein R4g, R5g, R6g, R7g, R8g, R9g, R10g, R11g are selected from the group consisting of hydrogen, F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In an aspect of the invention, compounds are of the general formula X




    wherein R4h and R5h are independently selected from cyano, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy: and
    R6h, R7h, R8h, R9h, R10h, R12h, R14h and R15h are independently selected from hydrogen, hydroxy, sulfanyl, halogen, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, perhalomethyl and perhalomethoxy: and
    R11h and R13h are independently selected from hydrogen, hydroxy, sulfanyl, halogen, amino, cyano, nitro, perhalomethyl, perhalomethoxy, C2-6-alkyl, methoxy, C3-8-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of sulfanyl, amino, C2-6-alkyl, C3-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, perhalomethyl and perhalomethoxy: and
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group consisting of R4h, R5h, R6h, R7h, R8h, R9h; and
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group consisting of R10h, R11h, R12h, R13h, R14h and R15h.


In one embodiment, the invention is concerned with compounds of the general formula X, wherein R6h, R7h, R8h, R9h, R10h, R12h and R14h are selected from the group consisting of hydrogen, F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another embodiment, the invention is concerned with compounds of the general formula X, wherein there are no covalent bonds between R4h, R5h, R6h, R7h, R8h and R9h.
In another embodiment, the invention is concerned with compounds of the general formula X, wherein there are no covalent bonds between R10h, R11h, R12h, R13h, R14h and R15h.
In another embodiment, the invention is concerned with compounds of the general formula X, wherein R15h is hydrogen.
In another embodiment, the invention is concerned with compounds of the general formula X, wherein R11h and R13h are selected from the group consisting of hydrogen, F, Cl, C2-6-alkyl, methoxy, C3-6-alkoxy, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In an aspect of the invention, compounds are of the general formula XI




    R5i is selected from hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy: and
    R6i, R7i, R8i, R9i, R10i, R14i and R15i are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, perhalomethyl and perhalomethoxy: and
    R11i and R13i are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, methoxy, C3-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of sulfanyl, sulfo, C1-6-alkyl, C3-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, perhalomethyl and perhalomethoxy: and
    R12i is selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, F, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, perhalomethyl and perhalomethoxy.


In one embodiment, the invention is concerned with compounds of the general formula XI, wherein R6i, R7i, R8i and R9i are selected from the group consisting of hydrogen, F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another embodiment, the invention is concerned with compounds of the general formula XI, wherein R10i, R11i, R12i, R13i and R14i are selected from the group consisting of hydrogen, F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another embodiment, the invention is concerned with compounds of the general formula XI, wherein R15i is hydrogen.
In another embodiment, the invention is concerned with compounds of the general formula XI, wherein R10i, R11i, R12i, R13i, R14i and R15i are selected from the group consisting of H, F and methyl.
In an aspect of the invention, compounds are of the general formula XII




    wherein R4j, R5j, R6j, R7j, R8j, R9j and R10j are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy: and
    wherein there may optionally be a covalent bond between the substituents R6j and R7j; and
    wherein there may optionally be a covalent bond between R5j and R8j; and
    R11j and R12j are independently selected from cyano, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one-or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
    with the proviso that R9j and R10j are both hydrogen, there may optionally be a covalent bond connecting R11j and R12j.


In one embodiment, the invention is concerned with compounds of the general formula XII, wherein R4j, R5j, R6j and R7j are selected from the group consisting of hydrogen, F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another embodiment, the invention is concerned with compounds of the general formula XII, wherein at least one of the substituents R4j, R5j, R6j and R7j are different from hydrogen. In another embodiment, the invention is concerned with compounds of the general formula XII, wherein R8j is covalently bound to R5j.
In an aspect of the invention, compounds are of the general formula XIII




    wherein R4k is selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, perhalomethyl and perhalomethoxy: and
    R5k is selected from hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, perhalomethyl and perhalomethoxy: with the proviso that when R4k is hydrogen, then R5k is not C(═O)N(Me)2; and
    R6k, R7k, R8k, R9k, R10k, R11k, R12k, R13k and R14k are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, perhalomethyl and perhalomethoxy: and
    R12k is selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, perhalomethyl and perhalomethoxy: and
    wherein there may optionally be a covalent bond between any of the substituents selected from the group consisting of R4k, R5k, R7k and R8k; and
    wherein there may optionally be a covalent bond between R5k and any one of the substituents R7k and R8k; and
    wherein there may optionally be one or more covalent bonds between R10k, R11k, R12k, R13k and R14k.


In one embodiment, the invention is concerned with compounds of the general formula XIII, wherein the substituents R4k and R5k are connected by a covalent bond.
In another embodiment, the invention is concerned with compounds of the general formula XIII, wherein the substituents R5k and R8k are connected by a covalent bond.
In another embodiment, the invention is concerned with compounds of the general formula XIII, wherein the substituents R10k and R11k are connected by a covalent bond.
In another embodiment, the invention is concerned with compounds of the general formula XIII, wherein the substituents R12k and R13k are connected by a covalent bond.
In another embodiment, the invention is concerned with compounds of the general formula XIII, wherein R6k, R7k, R8k and R9k are selected from the group consisting of hydrogen, F, Cl, hydroxy, amino, methyl, methoxy, ethoxy and perhalomethyl.
In another embodiment, the invention is concerned with compounds of the general formula XIII, wherein R10k, R11k, R12k, R13k and R14k are selected from the group consisting of hydrogen, F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In an aspect of the invention, compounds are of the general formula XIV




    wherein R1 is C1-6-alkyl, C2-6-alkenyl or C3-10-cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano and nitro; and
    R2 is C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, or C3-10-cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, perhalomethyl and perhalomethoxy; with the proviso that when R1 and R2 are identical they are not methyl or benzyl; and
    R2 is optionally covalently bound to R1 by an ether, thioether or C—C bond, to form a ring system with the N-atom to which R1 and R2 are bound; and
    R5l, R6l, R8l, R9l, R10l and R11l are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl; sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, perhalomethyl and perhalomethoxy: and
    R4l and R7l are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, methoxy, C3-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of sulfanyl, sulfo, amino, C1-6-alkyl, C3-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, perhalomethyl and perhalomethoxy: and
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group consisting of R4l, R5l, R6l, R7l, R8l, R9l, R10l and R11l.


In one embodiment, the invention is concerned with compounds of the general formula XIV, wherein R1 and R2 are covalently bound so as to form a ring system with the N-atom to which they are bound.
In another embodiment, the invention is concerned with compounds of the general formula XIV, wherein said ring system is a piperidine, piperazine, morpholine, or thiomorpholine.
In another embodiment, the invention is concerned with compounds of the general formula XIV, wherein there are no covalent bonds between R1 and R2.
In another embodiment, the invention is concerned with compounds of the general formula XIV, wherein there are no covalent bonds between R8l and any of the substituents selected from the group consisiting of R9l, R10l, R11l.
In another embodiment, the invention is concerned with compounds of the general formula XIV, wherein there are no covalent bonds between R8l and any of the substituents selected from the group consisting of R4l, R5l, R6l and R7l.
In another embodiment, the invention is concerned with compounds of the general formula XIV, wherein there are no covalent bonds between any of the substituents R4l, R5l, R6l, R7l, R8l, R9l, R10l and R11l.
In another embodiment, the invention is concerned with compounds of the general formula XIV, wherein R4l, R5l, R6l and R7l are selected from the group consisting of hydrogen, F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In an aspect of the invention, compounds are of the general formula XV




    wherein R4m is selected from hydrogen, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy: and
    R5m, R6m, R7m, R8m, R9m, R10m, R11m, R12m, R13m, R14m, R15m an from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, perhalomethyl and perhalomethoxy: and
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group consisting of R4m, R5m, R6m, R7m and R8m; and
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group consisting of R9m, R10m, R11m, R12m, R13m, R14m, R15m and R16m.


In one embodiment, the invention is concerned with-compounds of the general formula XV, wherein there are no covalent bonds between any of the substituents selected from the group consisting of R5m, R6m, R7m and R8m.
In another embodiment, the invention is concerned with compounds of the general formula XV, wherein there are no covalent bonds between any of the substituents R9m, R10m, R11m, R12m and R13m.
In another embodiment, the invention is concerned with compounds of the general formula XV, wherein there are no covalent bonds between any of the substituents R14m, R15m and R16m.
In another embodiment, the invention is concerned with compounds of the general formula XV, wherein R4m is covalently bound to R6m.
In another embodiment, the invention is concerned with compounds of the general formula XV, wherein R5m, R6m, R7m, R8m, R9m, R10m, R11m, R12m, R13m and R14m are selected from the group consisting of hydrogen, F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another embodiment, the invention is concerned with compounds of the general formula XV, wherein R14m, R15m and R16m are selected from the group consisting of hydrogen, F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In an aspect of the invention, compounds are of the general formula XVI




    wherein R4n is selected from hydrogen, sulfo, C2-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of sulfo, C2-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
    Z is selected from S, S(═O) and S(═O)2; and
    R5n, R6n, R7n, R8n, R9n, R10n, R11n, R12n, R13n and R14n are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, perhalomethyl and perhalomethoxy: and
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group consisting of R4n, R5n, R6n, R7n and R8n; and
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group consisting of R10n, R11n, R12n and R14n; and
    at least one of the substituents R5n, R6n, R7n, R8n, R9n, R10n, R11n, R12n, R13n and R14n are different from hydrogen.


In one embodiment, the invention is concerned with compounds of the general formula XVI, wherein there are no covalent bonds between any of the substituents R5n, R6n, R7n and R8n.
In another embodiment, the invention is concerned with compounds of the general formula XVI, wherein there are no covalent bonds between any of the substituents R10n, R11n, R12n.
In another embodiment, the invention is concerned with compounds of the general formula XVI, wherein R14n is not covalently bound to any other substituent selected from the group consisting of R4n, R5n, R6n, R7n, R8n, R10n, R11n, R12n.
In another embodiment, the invention is concerned with compounds of the general formula XVI, wherein R4n is covalently bound to R6n.
In another embodiment, the invention is concerned with compounds of the general formula XVI, wherein R5n, R6n, R7n and R8n are independently selected from the group consisting of hydrogen, F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another embodiment, the invention is concerned with compounds of the general formula XVI, wherein R14n is selected from the group consisting of hydrogen, F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In an aspect of the invention, compounds are of the general formula XVII




    wherein R2o, is selected from sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, each of which may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; with the proviso that R2o, is not methyl; and
    R4o, R5o, R6o and R7o are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, perhalomethyl and perhalomethoxy: and
    A1o is N or C—R8o; A2o is N or C—R9o; A3o is N or C—R10o; A4o is N or C—R11o; and A5o is N or C—R12o; and
    wherein R8o, R9o, R10o, R11o and R12o are independently selected from hydrogen, hydroxy, sulfanyl, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano,-nitro-, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, amino, sulfo, C1-6alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, amino, sulfo, C1-6alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, perhalomethyl and perhalomethoxy; with the proviso that
    when A1o, A2o, A3o, A4o and A5o are all CH, and R4o, R5o, R6o and R7o are all hydrogen, then R2o is not phenyl; and
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group consisting of R4o, R5o, R6o, R7o, R8o, R9o, R10o, R11o and R12o 


In one embodiment, the invention is concerned with compounds of the general formula XVII, wherein there are no covalent bonds between any of the substituents R4o, R5o, R6o and R7o. In another embodiment, the invention is concerned with compounds of the general formula XVII, wherein there are no covalent bonds between any of the substituents A1o, A2o, A3o, A4o and A5o.
In another embodiment, the invention is concerned with compounds of the general formula XVII, wherein R2o is selected from the group consisting of cycloalkyl, phenyl, piperidine, piperazine, morpholine, thiomorpholine and heteroaryl.
In another embodiment, the invention is concerned with compounds of the general formula XVII, wherein R4o, R5o, R6o and R7o are independently selected from the group consisting of hydrogen, F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In an aspect of the invention, compounds are of the general formula XVIII




    wherein R4p is selected from hydrogen, sulfo, C2-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of sulfo, C2-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, F, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6alkyl, C1-6alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy: and
    R5p, R6p, R7p and R8p are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, F, amino, cyano, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6alkyl, C1-6alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
    R9p, R10p, R11p, R12p, R13p, R14p, R15p and R16p are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6alkyl, C1-6alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy: and
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group consisting of R5p, R6p and R7p; and
    wherein there may optionally be a covalent bond between R4p and R5p so as to form a chromen ring system; and
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group consisting of R9p, R10p, R11p, R12p, R13p, R14p, R15p and R16p; and
    E is selected from the group consisting of —O—, —S—, —S(═O)—, —S(═O)2—, —NR17p— and —CR17pR18p—; and
    wherein R17p and R18p are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy.


In one embodiment, the invention is concerned with compounds of the general formula XVIII, wherein E is selected from the group consisting of —O— and —CR17pR18p—.
In another embodiment, the invention is concerned with compounds of the general formula XVIII, wherein R4p and R5p are connected by a covalent bond so as to form said chromen ring system.
In another embodiment, the invention is concerned with compounds of the general formula XVIII, wherein R4p and R5p are connected by a covalent bond so as to form the chromen ring system




    wherein R19p is selected from the group consisting of hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy.


In another embodiment, the invention is concerned with compounds of the general formula XVIII, wherein R4p is selected from the group consisting of




    wherein R20p, R21p, R22p, R23p and R24p are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, perhalomethyl and perhalomethoxy.


In another embodiment, the invention is concerned with compounds of the general formula XVIII, wherein there are no covalent bonds between any of the substituents R4p, R5p, R6p, R7p and R8p.
In another embodiment, the invention is concerned with compounds of the general formula XVIII, wherein there are no covalent bonds between any of the substituents R9p, R10p, R11p, R12p, R13p, R14p, R15p and R16p.
In another embodiment, the invention is concerned with compounds of the general formula XVIII, wherein R10p and R11p are connected by a covalent bond.
In another embodiment, the invention is concerned with compounds of the general formula XVIII, wherein R9p, R10p, R11p, R12p, R13p, R14p, R15p and R16p are independently selected from hydrogen, F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another embodiment, the invention is concerned with compounds of the general formula XVIII, wherein R5p, R6p, R7p and R8p are independently selected from hydrogen, F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In an aspect of the invention, compounds are of the general formula XIX




    wherein R4q, R6q, R7q, R9q, R10q, R11q, R12q, R13q, R14q, R15q, R16q, R17q,and R18q are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alky;, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy,-sulfanyl, amino, sulfo, C1-4-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alky;, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy: and
    R5q and R8q are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, F, Br, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents-independently-selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy: and
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group consisting of R4q, R5q, R6q, R7q and R8q; and
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group consisting of R9q, R10q, R11q, R12q, R13q, R14q, R15q, R16q, R17q and R18q.


In one embodiment, the invention is concerned with compounds of the general formula XIX, wherein R4q and R6q are connected by a covalent bond.
In another embodiment, the invention is concerned with compounds of the general formula XIX, wherein R4q is selected from the group consisting of substituted heteroaryl and substituted C3-8-heterocyclyl.
In another embodiment, the invention is concerned with compounds of the general formula XIX, wherein R4q is selected from the group consisting of




    wherein R19q, R20q, R21q, R22q and R23q are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alky;, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alky;, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alky;, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy.


In another embodiment, the invention is concerned with compounds of the general formula XIX, wherein there are no covalent bonds between any of the substituents R4q, R5q, R6q, R7q and R8q.
In another embodiment, the invention is concerned with compounds of the general formula XIX, wherein there are no covalent bonds between any of the substituents R9q, R10q, R11q, R12q, R13q, R14q, R15q, R16q, R17q and R18q.
In another embodiment, the invention is concerned with compounds of the general formula XIX, wherein R10p and R11p are connected by a covalent bond.
In another embodiment, the invention is concerned with compounds of the general formula XIX, wherein R10p and R13p are connected by a covalent bond.
In another embodiment, the invention is concerned with compounds of the general formula XIX, wherein R9q, R10q, R11q, R12q, R13q, R14q, R15q, R16q, R17q and R18q are independantly selected from hydrogen, F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another embodiment, the invention is concerned with compounds of the general formula XIX, wherein R9q, R10q, R11q, R12q, R14q, R15q, R16q, R17q and R18q are all hydrogen or F.
In another embodiment, the invention is concerned with compounds of the general formula XIX, wherein R5q, R6q, R7q and R8q are independently selected from hydrogen, F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In an aspect of the invention, compounds are of the general formula XX




    wherein R4r is selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy: provided that R4r is not methyl or phenyl; and
    R5r, R6r, R7r, R8r, R9r, R10r, R11r, R12r, R13r, R14r, R15r, R16r, R17r and R18r are independantly selected from hydrogen, hydroxy, sulfanyl, sulfo, F, amino, cyano, nitro, C1-6-alky;, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alky;, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy: and
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group consisting of R5r, R6r, R7r and R8r; and
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group consisting of R9r, R10r, R11r, R12r, R13r, R14r, R15r, R16r, R17r and R18r.


In one embodiment, the invention is concerned with compounds of the general formula XX, wherein R4r and R5r are connected by a covalent bond.
In another embodiment, the invention is concerned with compounds of the general formula XX, wherein R4r is selected from the group consisting of substituted heteroaryl and substituted C3-8-heterocyclyl.
In another embodiment, the invention is concerned with compounds of the general formula XX, wherein R4r is selected from the group consisting of




    wherein R19r, R20r, R21r, R22r and R23r are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alky;, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy.


In another embodiment, the invention is concerned with compounds of the general formula XX, wherein there are no covalent bonds between any of the substituents R5r, R6r, R7r and R8r.
In another embodiment, the invention is concerned with compounds of the general formula XX, wherein there are no covalent bonds between any of the substituents R9r, R10r, R11r, R12r, R13r, R14r, R15r and R16r.
In another embodiment, the invention is concerned with compounds of the general formula XX, wherein R10r and R11r are connected by a covalent bond.
In another embodiment, the invention is concerned with compounds of the general formula XX, wherein R11r and R13r are connected by a covalent bond.
In another embodiment, the invention is concerned with compounds of the general formula XX, wherein R9r, R10r, R11r, R12r, R13r, R14r, R15r, R16r, R17r and R18r are independently selected from hydrogen, F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another embodiment, the invention is concerned with compounds of the general formula XX, wherein R9r, R10r, R11r, R12r, R14r, R15r, R16r, R17r and R18r are all hydrogen or F.
In another embodiment, the invention is concerned with compounds of the general formula XX, wherein R5r, R6r, R7r and R8r are independently selected from hydrogen, F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In an aspect of the invention, compounds are of the general formula XXI




    wherein A1s is N or C—R17s; A2s is N or C—R18s; A3s is N or C—R19s; A4s is N or C —R20s; and A5s is N or C—R21s; and
    wherein R17, R18s, R19s, R20s and R21s are independently selected from hydrogen, hydroxy, sulfanyl, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
    R5s, R6s, R7s and R8s are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, F, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy: and
    R9s, R10s, R11s, R12s, R13s, R14s, R15s and R16s are independently selected from hydroxy, sulfanyl, sulfo, F, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl,-wherein-each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy: and
    E is selected from the group consisting of —O—, —S—, —S(═O)—, —S(═O)2—, —NR22s— and —CR22sR23s—; and
    wherein R22s and R23s are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alky;, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group consisting of R5s, R6s, R7s and R8s; and
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group consisting of R9s, R10s, R11s, R12s, R13s, R14s, R15s, R16s, R18s, R19s, R20s, R21s, R22s and R23s.


In one embodiment, the invention is concerned with compounds of the general formula XXI, wherein E is selected from the group consisting of —O— and —CR22 R23s—.
In another embodiment, the invention is concerned with compounds of the general formula XXI, wherein there are no covalent bonds between any of the substituents R5s, R6s, R7s and R8s.
In another embodiment, the invention is concerned with compounds of the general formula XXI, wherein R5s, R6s, R7s and R8s are independently selected from the group consisting of hydrogen, F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another embodiment, the invention is concerned with compounds of the general formula XXI, wherein there is a covalent bond between R10s and R11s.
In another embodiment, the invention is concerned with compounds of the general formula XXI, wherein there is a covalent bond between R3s and R22s.
In another embodiment, the invention is concerned with compounds of the general formula XXI, wherein R9s, R10s, R11s, R12s, R13s, R14s, R15s and R16s are all hydrogen or F.
In an aspect of the invention, compounds are of the general formula XXII




    wherein E is selected from the group consisting of —O—, —S—, —S(═O)—, —S(═O)2—, —NR18t— and —CR18tR19t—; and
    R4t, R5t, R6t, R7t, R8t, R9t, R10t, R11t, R12t, R13t, R14t, R15t, R16t, R17t, R18t and R19t and independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, nitro, C1-6-alky;, C1-4-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy,-sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alky;, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; with the proviso that R4t and R5t are not both methyl; and
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group consisting of R9t, R10t, R11t, R12t, R13t, R14t, R15t, R16t, R17t, R18t and R19t.


In one embodiment, the invention is concerned with compounds of the general formula XXII, wherein E is selected from the group consisting of —O—, —S—, —S(═O)—, —S(═O)2— and —CR18tR19t—.
In another embodiment, the invention is concerned with compounds of the general formula XXII, wherein R18t is hydrogen or F.
In another embodiment, the invention is concerned with compounds of the general formula XXII, wherein R10t, R12t, R14t and R16t are all hydrogen
In another embodiment, the invention is concerned with compounds of the general formula XXII, wherein R6t, R7t, R8t and R9t are independently selected from the group consisting of hydrogen, F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another embodiment, the invention is concerned with compounds of the general formula XXII, wherein there is a covalent bond between R11t and R13t.
In another embodiment, the invention is concerned with compounds of the general formula XXII, wherein there is a covalent bond between R13t and R19t.
In another embodiment, the invention is concerned with compounds of the general formula XXII, wherein R10t, R11t, R12t, R13t, R14t, R15t, R16t and R17t are all hydrogen or F.
In an aspect of the invention, compounds are of the general formula XXIII




    wherein R4u, R5u, R6u, R7u, R8u, R9u, R10u, R11u, R12u, R13u, R14u and R15u and independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alky;, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy: with the proviso that R4u, R5u and R6u are not all hydrogen; and
    E is selected from the group consisting of —O—, —S—, —S(═O)—, —S(═O)2—, —NR16u— and —CR16uR17u—;
    wherein R16u and R17u are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8--heterocyclyl and C3-10-cycloalkyl; wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alky;, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alky;, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group consisting of R4u, R5u and R6u; and
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group consisting of R8u, R9u, R10u and R11u; and
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group consisting of R2u; R13u, R14u, R15u, R16u and R17u.


In one embodiment, the invention is concerned with compounds of the general formula XXIII, wherein E is selected from the group consisting of —O—, —S—, —S(═O)—, —S(═O)2— and —CR16uR17u—.
In another embodiment, the invention is concerned with compounds of the general formula XXIII, wherein R17u is hydrogen or F.
In another embodiment, the invention is concerned with compounds of the general formula XXIII, wherein there are no covalent bonds between any of the substituents R8u, R9u, R10u and R11u.
In another embodiment, the invention is concerned with compounds of the general formula XXIII, wherein R8u, R9u, R10u and R11u are independently selected from the group consisting of hydrogen, F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another embodiment, the invention is concerned with compounds of the general formula XXIII, wherein there is a covalent bond between R12u and R13u.
In another embodiment, the invention is concerned with compounds of the general formula XXIII, wherein R12u, R13u, R14u and R15u are all selected from the group consisting of hydrogen, F, methyl and C1-6-alkyl.
In an aspect of the invention, compounds are of the general formula XXIVa-b




wherein R4v, R5v, R6v, R7v, R8v, R9v, R10v, R11v, R12v, R13v, R14v, R15v, R16v, R17v and R18v are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alky;, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; with the proviso that none of the substituents R4v, R5v and R6v are benzothiazolyl or benzooxazolyl; and

    E is selected from the group consisting of —O—, —S—, —S(═O)—, —S(═O)2—, —NR19v— and —CR19vR20v—; and
    wherein R19v and R20v are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
    wherein there may optionally be a covalent bond between the substituents R7v and R8v or between the substituents R9v and R10v; and
    wherein there may optionally be a covalent bond between R6v and a substituent selected from R8v and R9v; and
    wherein there may be a covalent bond between any of the substituents selected from the group consisting of R4v, R5v and R6v; and
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group consisting of R11v, R12v, R13v, R14v, R15v, R16v, R17v R18v, R19v and R20v.


In one embodiment, the invention is concerned with compounds of the general formula XXIV, wherein E is selected from the group consisting of —O—, —S—, —S(═O)—, —S(═O)2— and —CR19vR20v—.
In another embodiment, the invention is concerned with compounds of the general formula XXIV, wherein R20v is hydrogen or F.
In another embodiment, the invention is concerned with compounds of the general formula XXIV, wherein there are no covalent bonds between any of the substituents R4v, R5v and R6v.
In another embodiment, the invention is concerned with compounds of the general formula XXIV, wherein there are no covalent bonds between any of the substituents R7v, R8v, R9v and R10v.
In another embodiment, the invention is concerned with compounds of the general formula XXIV, wherein there are no covalent bonds between a substituent selected from the group consisting of R4v, R5v and R6v and a substituent selected from the group consisting of R7v, R8v, R9v and R10v.
In another embodiment, the invention is concerned with compounds of the general formula XXIV, wherein R7v, R8v, R9v and R10v are independently selected from the group consisting of hydrogen, F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another embodiment, the invention is concerned with compounds of the general formula XXIV, wherein there is a covalent bond between R12v and R13v.
In another embodiment, the invention is concerned with compounds of the general formula XXIV, wherein R11v, R12v, R13v, R14v, R15v, R16v, R17v and R18v are all hydrogen or F.
In an aspect of the invention, compounds are of the general formula XXV




    wherein R4w is selected from hydrogen, hydroxy, amino, sulfo, C2-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, amino, sulfo, C2-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, nitro, sulfo, C1-6alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, -and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, nitro, sulfo, C1-6alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy: with the proviso that R4w is not methyl, morpholine or a 2-chromen derivative; and
    Z is selected from S, S(═O) and S(═O)2; and
    R5w, R6w, R7w, R8w, R9w, R10w, R11w, R12w, R13w, R14w, R15w and R16w are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8 heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, perhalomethyl and perhalomethoxy: and
    E is selected from the group consisting of —O—, —S—, —S(═O)—, —S(═O)2—, —NR17w— and —CR17wR18w—; and
    wherein R17w and R18w are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group consisting of R4w, R5w, R6w, R7w and R8w; and
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group consisting of R9w, R10w, R11w, R12w, R13w, R14w, R15w, R16w, R17w and R18w.


In one embodiment, the invention is concerned with compounds of the general formula XXV, wherein the only substituents which are covalently bound are R4w and R5w.
In another embodiment, the invention is concerned with compounds of the general formula XXV, wherein there are no covalent bonds between any of the substituents R5w, R6w, R7w and R8w.
In another embodiment, the invention is concerned with compounds of the general formula XXV, wherein there are no covalent bonds between any of the substituents R9w, R10w, R11w, R12w, R13w, R14w, R15w and R16w.
In another embodiment, the invention is concerned with compounds of the general formula XXV, wherein E is selected from the group consisting of —O—, —S—, —S(═O)—, —S(═O)2— and —CR17wR18w—.
In another embodiment, the invention is concerned with compounds of the general formula XXV, wherein R18w is hydrogen or F.
In another embodiment, the invention is concerned with compounds of the general formula XXV, wherein R5w, R6w, R7w and R8w are independently selected from the group consisting of hydrogen, F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another embodiment, the invention is concerned with compounds of the general formula XXV, wherein there is a covalent bond between R10w and R11w.
In another embodiment, the invention is concerned with compounds of the general formula XXV, wherein there is a covalent bond between R13w and R17w.
In another embodiment, the invention is concerned with compounds of the general formula XXV, wherein R9w, R10w, R11w, R12w, R13w, R14w, R15w and R16w are all hydrogen or F.
In an aspect of the invention, compounds are of the general formula XXVI




    wherein R4x is selected from imino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of imino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, perhalomethyl and perhalomethoxy; and
    R5x, R6x, R7x, R8x, R9x, R10x, R11x, R12x and R13x are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
    E is selected from the group consisting of —O—, —S—, —S(═O)—, —S(═O)2—, —NR14x— and —CR15xR16x—;
    wherein R14x is selected from hydrogen, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, F, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, F, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, F, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
    R15x and R16x are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
    wherein there may optionally be a covalent bond between the substituents R4x and R5x; and
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group consisting of R6x, R7x, R8x and R9x; and
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group consisting of R10x, R11x, R12x, R13x, R14x, R15x and R16x.


In one embodiment, the invention is concerned with compounds of the general formula XXVI, wherein R6x, R7x, R8x and R9x are independently selected from the group consisting of hydrogen, F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another embodiment, the invention is concerned with compounds of the general formula XXVI, wherein R10x, R11x, R12x and R13x are independently selected from the group consisting of hydrogen, F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another embodiment, the invention is concerned with compounds of the general formula XXVI, wherein there is a covalent bond between the substituents R6x and R7x.
In another embodiment, the invention is concerned with compounds of the general formula XXVI, wherein there is a covalent bond between the substituents R10x and R11x.
In another embodiment, the invention is concerned with compounds of the general formula XXVI, wherein there is a covalent bond between R10x and a substituent selected from R14x and R15x.
In an aspect of the invention, compounds are of the general formula XXVII




    wherein R4y and R11y are independently selected from imino, C1-6alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of imino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, nitro, sulfo, C1-6alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, nitro, sulfo, C1-6alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, perhalomethyl and perhalomethoxy; and
    R5y, R6y, R7y, R8y, R9y and R10y are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
    wherein there may optionally be a covalent bond between the substituents R4y and R5y; and
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group consisting of R6y, R7Y, R8y and R9y; and
    wherein there may optionally be a covalent bond between the substituents R10y and R11y.


In one embodiment, the invention is concerned with compounds of the general formula XXVII, wherein R6y, R7y, R8y and R9y are independently selected from the group consisting of hydrogen, F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another embodiment, the invention is concerned with compounds of the general formula XXVII, wherein there are no covalent bonds between any of the substituents R6y, R7y, R8y and R9y.
In another embodiment, the invention is concerned with compounds of the general formula XXVII, wherein there is a covalent bond between the substituents R4y and R5y.
In another embodiment, the invention is concerned with compounds of the general formula XXVII, wherein there is a covalent bond between the substituents R10y and R11y.
In an aspect of the invention, compounds are of the general formula XXVIII




    wherein R4z, R8z, R9z, R10z, R11z, R12z, R13z, R14z, R15z, R16z and R17z are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
    R5z is a carbon bound substituent selected from C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, each of which may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
    R6z and R7z are independently selected from hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
    E is selected from the group consisting of —O—, —S—, —S(═O)—, —S(═O)2—, —NR18z— and —CR19zR20z—;
    wherein R18z is selected from hydrogen, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, F, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, F, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6alkyl, C1-6alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, F, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
    R19z and R20z are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
    wherein there may optionally be a covalent bond between the substituents R4z and R5z; and
    wherein there may optionally be a covalent bond between any of the substituents R7z, R8z, and R9z; and
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group consisting of R10z, R11z, R12z, R13z, R14z, R15z, R16z, R17z, R18z, R19z, and R20z.


In one embodiment, the invention is concerned with compounds of the general formula XXVIII, wherein there is a covalent bond between the substituents R4z and R5z.
In another embodiment, the invention is concerned with compounds of the general formula XXVIII, wherein R6z, R7z, R8z and R9z are independently selected from the group consisting of hydrogen, F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another embodiment, the invention is concerned with compounds of the general formula XXVIII, wherein there is a covalent bond between R13z and a substituent selected from R18z and R19z.
In an aspect of the invention, compounds are of the general formula XXIX




    wherein R4aa is selected from hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, each of which may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, F, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
    R5aa, R6aa, R7aa, R8aa, R9aa, R10aa, R11aa, R12aa and R13aa are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
    wherein there may optionally be a covalent bond between the substituents R5aa and R6aa or between the substituent R7aa and R8aa; and
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group consisting of R9aa, R10aa, R11aa and R12aa; and
    E is selected from the group consisting of —O—, —S—, —S(═O)— and —S(═O)2—.


In one embodiment, the invention is concerned with compounds of the general formula XXIX, wherein there is a covalent bond between the substituents R9aa and R10aa.
In another embodiment, the invention is concerned with compounds of the general formula XXIX, wherein R5aa, R6aa, R7aa and R8aa are independently selected from the group consisting of hydrogen, F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another embodiment, the invention is concerned with compounds of the general formula XXIX, wherein at least one of the substituents R5aa, R6aa, R7aa and R8aa are different from hydrogen.
In an aspect of the invention, compounds are of the general formula XXX




    wherein R4ab is selected from sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, each of which may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, F, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
    E is selected from the group consisting of —NR13ab— and —CR14abR15ab—; and
    R5ab, R6ab, R7ab, R8ab, R9ab, R10ab, R11ab, R12ab, R13ab, R14ab and R15ab are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
    wherein there may optionally be a covalent bond between the substituents R5ab and R6ab or between the substituent R7ab and R8ab; and
    wherein there may optionally be one or more covalent bonds between any of the substituents selected from the group consisting of R9ab, R10ab, R11ab, R12ab, R13ab, R14ab and R15ab.


In one embodiment, the invention is concerned with compounds of the general formula XXX, wherein there is a covalent bond between the substituents R9ab and R10ab.
In another embodiment, the invention is concerned with compounds of the general formula XXX, wherein there is a covalent bond between R10ab and a substituent selected from R13ab and R14ab.
In another embodiment, the invention is concerned with compounds of the general formula XXX, wherein R5ab, R6ab, R7ab and R8ab are independently selected from the group consisting of hydrogen, F, Cl, C1-6alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another embodiment, the invention is concerned with compounds of the general formula XXX, wherein at least one of the substituents R5ab, R6ab, R7ab and R8ab are different from hydrogen.
In another embodiment, the invention is concerned with compounds of the general formula XXX, wherein at least one of the substituents R9ab, R10ab, R11ab, R12ab, R13ab, R14ab and R15ab are different from hydrogen.
In an aspect of the invention, compounds are of the general formula XXXI




    wherein R4ac is a carbon bound substituent selected from C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, each of which may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
    A1ac is N or C—R9ac; A3ac is N or C—R10ac; and A5ac is N or C—R11ac; and
    R5ac, R6ac, R7ac, R8ac, R9ac, R10ac and R11ac are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; with the proviso that A3ac is not C—C(OH)(CF3)2; and
    A2ac is N or C—R12ac; and A4ac is N or C—R13ac; wherein
    R12ac and R13ac are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
    wherein there may optionally be a covalent bond between R4ac and a substituent selected from the group consisting of R5ac and R6ac; with the proviso that A1ac, A2ac, A3ac, A4ac and A5ac are not all CH; and
    wherein there may optionally be a covalent bond between any of the substituents R6ac, R7ac and R8ac; and
    wherein there may optionally be one or more covalent bonds between any of the substituents in A1ac, A2ac, A3ac, A4ac and A5ac.


In one embodiment, the invention is concerned with compounds of the general formula XXXI, wherein there is a covalent bond between the substituents R4ac and R6ac.
In another embodiment, the invention is concerned with compounds of the general formula XXXI, wherein there is a covalent bond between A3ac and A4ac.
In another embodiment, the invention is concerned with compounds of the general formula XXXI, wherein there is a covalent bond between A3ac and A2ac.
In another embodiment, the invention is concerned with compounds of the general formula XXXI, wherein R5ac, R6ac, R7ac and R8ac are independently selected from the group consisting of hydrogen, F, Cl, C1-6-alkyl, C1-6alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another embodiment, the invention is concerned with compounds of the general formula XXXI, wherein at least one of the substituents A1ac, A2ac, A3ac, A4ac and A5ac are different from CH.
In an aspect of the invention, compounds are of the general formula XXXIIa-b




    wherein R4ad is selected from hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, each of which may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, F, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
    R5ad, R6ad, R7ad, R8ad and R9ad are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
    R10ad are selected from imino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, each of which may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C1-6-alkoxy, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
    wherein there may optionally be a covalent bond between R4ad and a substituent selected from R6ad and R7ad; and
    wherein there may optionally be a covalent bond between the substituents R9ad and R10ad so as to form a 5-membered ring system.


In one embodiment, the invention is concerned with compounds of the general formula XXXIIa-b, wherein the substituents R9ad and R10ad are covalently bound so as to form a 5-membered ring system.
In another embodiment, the invention is concerned with compounds of the general formula XXXIIa-b, wherein said 5-membered ring system comprises at least one nitrogen atom in the ring.
In another embodiment, the invention is concerned with compounds of the general formula XXXIIa-b, wherein said 5-membered ring system contains 5 carbons in the ring.
In another embodiment, the invention is concerned with compounds of the general formula XXXIIa-b, wherein there is a covalent bond between the substituents R4ad and R7ad.
In another embodiment, the invention is concerned with compounds of the general formula XXXIIa-b, wherein R5ad, R6ad, R7ad and R8ad are independently selected from the group consisting of hydrogen, F, Cl, C1-6-alkyl, C1-6alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another aspect of the invention, compounds are of the general formula XXXIIIa-b




    wherein E is selected from the group consisting of —O—, —S—, —S(═O)—, —S(═O)2—, —NR16ae— and —CR17aeR18ae—; and
    R4ae, R5ae, R6ae, R7ae, R8ae, R9ae, R10ae, R11ae, R12ae, R13ae, R14ae, R15ae, R16ae, R17ae, R18ae are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
    wherein there may optionally be a covalent bond between any of the substituents selected from R4ae, R5ae, R6ae and R7ae; with the proviso that when R5ae and R6ae are covalently bound they do not form a isoquinolin-3-yl or a substituted isoquinolin-3-yl together with the pyridine which they are both bound to; and
    wherein there may optionally be a covalent bond between any of the substituents selected from R8ae, R9ae, R10ae, R11ae, R12ae, R13ae, R14ae, R15ae, R16ae, R17ae and R18ae.


In one embodiment, the invention is concerned with compounds of the general formula XXXIIIa-b, wherein there is a covalent bond between R6ae and R7ae.
In another embodiment, the invention is concerned with compounds of the general formula XXXIIIa-b, wherein there is a covalent bond between R5ae and R7ae.
In another embodiment, the invention is concerned with compounds of the general formula XXXIIIa-b, wherein at least one of R8ae, R9ae, R10ae, R11ae, R12ae, R13ae, R14ae and R15ae is selected from F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino, and perhalomethyl.
In another aspect of the invention, compounds are of the general formula XXXIV




    wherein R4af, R5af, R6af, R7af, R8af, R9af, R10af, R11af, R12af, R13af, R14af, R15af are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
    wherein there may optionally be a covalent bond between R6af and any of the substituents selected from R5af and R7af; and
    wherein there may optionally be a covalent bond between the substituents R9af and R10af; and
    R16af is selected from hydrogen, hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; with the proviso that R16af is not methyl; and
    wherein there may optionally be a covalent bond between the substituents R12af and R16af.


In one embodiment, the invention is concerned with compounds of the general formula XXXIV, wherein there is a covalent bond between the substituents R5af and R6af.
In another embodiment, the invention is concerned with compounds of the general formula XXXIV, wherein there is a covalent bond between the substituents R9af and R10af.
In another embodiment, the invention is concerned with compounds of the general formula XXXIV, wherein at least one of R8af, R9af, R10af, R11af, R12af, R13af, R14af and R15af is selected from F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino, and perhalomethyl.
In another aspect of the invention, compounds are of the general formula XXXV




    wherein E is selected from the group consisting of —O—, —S—, —S(═O)—, —S(═O)2— and —CR16agR17ag—; and
    R4ag, R5ag, R6ag, R10ag, R11ag, R12ag, R13ag, R16ag and R17ag are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl-and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; with the proviso that R4ag is not —CH2—N(CH3)2; and
    wherein there may optionally be a covalent bond between the substituents R5ag and R6ag; and
    R7ag is selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy;
    R8ag, R9ag, R14ag and R15ag are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-1-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
    wherein there may optionally be a covalent bond between the substituents R9ag and R10ag; and
    wherein there may optionally be a covalent bond between the substituents R12ag and R16ag.


In one embodiment, the invention is concerned with compounds of the general formula XXXV, wherein there is a covalent bond between the substituents R5ag and R6ag.
In another embodiment, the invention is concerned with compounds of the general formula XXXV, wherein there is a covalent bond between the substituents R9ag and R10ag.
In another embodiment, the invention is concerned with compounds of the general formula XXXV, wherein at least one of R8ag, R9ag, R10ag, R11ag, R12ag, R13ag, R14ag and R15ag are selected from F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino, and perhalomethyl.
In another aspect of the invention, compounds are of the general formula XXXVIa-b




    wherein R4ah, R5ah, R6ah, R7ah, R8ah and R9ah are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; with the proviso that R5ah and R6ah are not both CF3; and
    wherein there may optionally be a covalent bond between any of the substituents selected from R4ah, R5ah, R6ah and R7ah; and
    wherein there may optionally be a covalent bond between the substituents R8ah and R9ah; with the proviso that when R8ah and R9ah together with the carbon to which they are bound forms phenyl then R5ah, R6ah, R7ah and R8ah are not all hydrogen.


In one embodiment, the invention is concerned with compounds of the general formula XXXVIa-b, wherein there is a covalent bond between R8ah and R9ah.
In another embodiment, the invention is concerned with compounds of the general formula XXXVIa-b, wherein there is a covalent bond between R6ah and R7ah.
In another embodiment, the invention is concerned with compounds of the general formula XXXVIa-b, wherein there is a covalent bond between R5ah and R6ah.
In another embodiment, the invention is concerned with compounds of the general formula XXXVIa-b, wherein at least one of R5ah, R6ah, R7ah and R8ah are selected from F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another aspect of the invention, compounds are of the general formula XXXVII




    R4ai, R5ai, R6ai, R7ai, R8ai and R9ai are independently selected from hydrogen, hydroxy, sulfanyl sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; with the proviso that R4ai is not CH2—N(Me)2; and
    wherein there may optionally be a covalent bond between any of the substituents selected from R4ai, R5ai, R6ai and R7ai; and
    wherein there may optionally be a covalent bond between the substituents R8ai and R9ai; with the proviso that R8ai and R9ai together with the carbon to which they are bound do not form 4-methoxy-phenyl, 4-chloro-phenyl or 4-nitro-phenyl.


In one embodiment, the invention is concerned with compounds of the general formula XXXVII, wherein there is a covalent bond between R8ai and R9ai.
In another embodiment, the invention is concerned with compounds of the general formula XXXVII, wherein there is a covalent bond between R6ai and R7ai.
In another embodiment, the invention is concerned with compounds of the general formula XXXVII, wherein there is a covalent bond between R5ai and R6ai.
In another embodiment, the invention is concerned with compounds of the general formula XXXVII, wherein at least one of R5ai, R6ai, R7ai and R8ai are selected from F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another aspect of the invention, compounds are of the general formula XXXVIII




    wherein R4aj, R5aj, R6aj and R7aj are independently selected from amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
    wherein there may optionally be a covalent bond between the substituents R4aj and R5aj; and
    wherein there may optionally be a covalent bond between the substituents R6aj and R7aj.


In one embodiment, the invention is concerned with compounds of the general formula XXXVIII, wherein there is a covalent bond between R6aj and R7aj.
In another embodiment, the invention is concerned with compounds of the general formula XXXVIII, wherein R6aj, R7aj and said covalent bond are selected so as to form a ring system selected from an optionally substituted piperedine, piperazine, morpholine and thiomorpholine.
In another embodiment, the invention is concerned with compounds of the general formula XXXVIII, wherein said ring system is selected from piperedine, piperazine, morpholine and thiomorpholine
In another embodiment, the invention is concerned with compounds of the general formula XXXVIII, wherein there is a covalent bond between R4aj and R5aj.
In another aspect of the invention, compounds are of the general formula XXXIX




    wherein R4ak, R5ak, R6ak and R7ak are independently selected from amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; with the proviso that none of R4ak and R5ak are —C(═O)—O— isopropyl; and
    wherein there may optionally be a covalent bond between the substituents R4ak and R5ak; with the proviso that R4ak, R5ak and the nitrogen to which they are bound do not form a substituted tetrazolyl moiety; and
    wherein there may optionally be a covalent bond between the substituents R6ak and R7ak;


In one embodiment, the invention is concerned with compounds of the general formula XXXIX, wherein there is a covalent bond between R6ak and R7ak.
In another embodiment, the invention is concerned with compounds of the general formula XXXIX, wherein R6ak, R7ak and said covalent bond are selected so as to form a ring system selected from an optionally substituted piperedine, piperazine, morpholine and thiomorpholine.
In another embodiment, the invention is concerned with compounds of the general formula XXXIX, wherein said ring system is selected from piperedine, piperazine, morpholine and thiomorpholine
In another embodiment, the invention is concerned with compounds of the general formula XXXIX, wherein there is a covalent bond between R4ak and R5ak.
In another aspect of the invention, compounds are of the general formula XXXX




    wherein R4al and R5al are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-0-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
    wherein there may optionally be a covalent bond between R4al and R5al; with the proviso that R4al and R5al together with the nitrogen to which they are bound do not form 2,5-pyrrolidinedione or an annealed ring system comprising 3 or more rings; and
    wherein E is selected from the group consisting of —O—, —S—, —S(═O)—, —S(═O)2— and —NR14al—, —CR15alR6al—; and
    R6al, R7al, R8al, R9al, R10al, R11al, R12al, R13al, R14al, R15al and from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
    wherein there may optionally be a covalent bond between the substituents R7al and R8al; and
    wherein there may optionally be a covalent bond between the substituents R10al and a substituent selected from R14al and R5al.


In one embodiment, the invention is concerned with compounds of the general formula XXXX, wherein there is a covalent bond between the substituents R4al and R5al.
In another embodiment, the invention is concerned with compounds of the general formula XXXX, wherein there is a covalent bond between the substituents R7al and R8al.
In another embodiment, the invention is concerned with compounds of the general formula XXXX, wherein there is a covalent bond between R10al and a substituent selected from R14al or R15al.
In another embodiment, the invention is concerned with compounds of the general formula XXXX, wherein E is —NR14al—.
In another embodiment, the invention is concerned with compounds of the general formula XXXX, wherein R14al is selected from F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another embodiment, the invention is concerned with compounds of the general formula XXXX, wherein E is —CR15alR16al—.
In another embodiment, the invention is concerned with compounds of the general formula XXXX, wherein R16al is selected from F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another embodiment, the invention is concerned with compounds of the general formula XXXX, wherein R15al is hydrogen.
In another embodiment, the invention is concerned with compounds of the general formula XXXX, wherein at least one of R6al, R7al, R8al, R9al, R10al, R11al, R12al and R13al are selected from F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another aspect of the invention, compounds are of the general formula XXXXI




    wherein E is selected from the group consisting of —O—, —S—, —S(═O)—, —S(═O)2— and —NR14am—, —CR15amR16am—; and
    wherein A1am is N or C—R17am; A2am is N or C—R18am; A3am is N or C—R19am; A4am is and
    R6am, R7am, R8am, R9am, R10am, R11am, R12am, R13am, R14am, R15am, R16am, R17am,R18am, R19amand R20am are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; with the proviso that R17am and R20am are not both hydroxy; and
    wherein there may optionally be a covalent bond between R18am and a substituent selected from R17am and R19am; and
    wherein there may optionally be a covalent bond between the substituents R10am and a substituent selected from R14am and R15am; and
    wherein there may optionally be a covalent bond between the substituents R7am and R8am.


In one embodiment, the invention is concerned with compounds of the general formula XXXXI, wherein there is a covalent bond between R18am and a substituents selected from R17am and R19am.
In another embodiment, the invention is concerned with compounds of the general formula XXXXI, wherein there is a covalent bond between R10am and a substituent selected from R14am or R15am.
In another embodiment, the invention is concerned with compounds of the general formula XXXXI, wherein E is —NR14am—.
In another embodiment, the invention is concerned with compounds of the general formula XXXXI, wherein R14am is selected from F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another embodiment, the invention is concerned with compounds of the general formula XXXXI, wherein E is —CR15amR16am—.
In another embodiment, the invention is concerned with compounds of the general formula XXXXI, wherein R16am is selected from F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another embodiment, the invention is concerned with compounds of the general formula XXXXI, wherein R15am is hydrogen.
In another embodiment, the invention is concerned with compounds of the general formula XXXXI, wherein there is a covalent bond between R15am and R16am.
In another embodiment, the invention is concerned with compounds of the general formula XXXXI, wherein at least one of R6am, R7am, R8am, R9am, R10am, R11am, R12am and R13am are selected from F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another aspect of the invention, compounds are of the general formula XXXXII




    wherein E is selected from the group consisting of —O—, —S—, —S(═O)—, —S(═O)2— and —NR17an—, —CR18anR19an—; and
    R4an, R5an, R6an, R7an, R8an, R9an, R10an, R11an, R12an, R13an, R14an, R15an, R16an,R17an,R18an, and R19an are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl,-heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; with the proviso that R4an is not methyl or phenyl; and
    wherein there may optionally be a covalent bond between R13an and a substituent selected from R17an and R18an; and
    wherein there may optionally be a covalent bond between the substituents R7an and R8an.


In one embodiment, the invention is concerned with compounds of the general formula XXXXII, wherein R4an is a substituted heteroaryl.
In another embodiment, the invention is concerned with compounds of the general formula XXXXII, wherein said substituted heteroaryl is a substituted pyridine.
In another embodiment, the invention is concerned with compounds of the general formula XXXXII, wherein there is a covalent bond between the substituents R7an and R8an.
In another embodiment, the invention is concerned with compounds of the general formula XXXXII, wherein there is a covalent bond between R13an and a substituents selected from R17an and R18an.
In another embodiment, the invention is concerned with compounds of the general formula XXXXII, wherein E is —NR17an—.
In another embodiment, the invention is concerned with compounds of the general formula XXXXII, wherein E is —CR18anR19an—.
In another embodiment, the invention is concerned with compounds of the general formula XXXXII, wherein R19an is selected from F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another embodiment, the invention is concerned with compounds of the general formula XXXXII, wherein R18an is hydrogen.
In another embodiment, the invention-is concerned with compounds of the general formula XXXXII, wherein at least one of R5an, R6an, R7an, R8an, R9an, R10an, R11an, R12an, R13an, R14an, R15an and R16an are selected from F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.
In another aspect of the invention, compounds are of the general formula XXXXIII




    wherein R4ao is selected from hydrogen, hydroxy, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of hydroxy, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, perhalomethyl and perhalomethoxy; and
    wherein R5ao, R6ao, R7ao, R8ao, R9ao, R10ao, R11ao and R12ao are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, perhalomethyl and perhalomethoxy;
    with the proviso that any one of R6ao and R8ao is not methyl; and with the further proviso that R4ao, R5ao, R6ao, R7ao and R8ao are not all hydrogen; and
    wherein there may optionally be a covalent bond between R4ao and R6ao; and
    wherein there may optionally be a covalent bond between R7ao and R8ao; and
    wherein there may optionally be a covalent bond between R9ao and R10ao.


In one embodiment the invention is concerned with compounds of the general formula XXXXIII, wherein R5ao, R6ao, R7ao and R8ao are independently selected from hydrogen and fluor.
In another embodiment the invention is concerned with compounds of the general formula XXXXIII, wherein R9ao, R10ao, R11ao and R12ao are independently selected from hydrogen and fluor.
In another aspect of the invention, compounds are of the general formulae XXXXIVa-b




    wherein R1ap and R2ap are independently selected from C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, perhalomethyl and perhalomethoxy; with the proviso that if R1ap and R2ap are identical then they are not methyl or ethyl; and
    wherein there may optionally be a covalent bond between the substituents R1a and R2ap; and
    wherein R5ap, R6ap and R7ap are independently selected from hydrogen and F; and
    wherein R4ap is selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6 alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8—-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, perhalomethyl and perhalomethoxy; with the proviso that R4ap is not methyl.


In one embodiment the invention is concerned with compounds of the general formulae XXXXIVa-b, wherein R1ap and R2ap are not identical.
In another aspect of the invention, compounds are of the general formulae XXXXVa-b




    wherein R1aq and R2aq are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, perhalomethyl and perhalomethoxy; with the proviso that R1aq and R2aq are not both methyl; and
    wherein there may optionally be a covalent bond between R1aq and R2aq; and
    wherein R3aq, R4aq, R5aq, R6aq, R7aq, R8aq, R9aq, R10aq and R11ao are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, perhalomethyl and perhalomethoxy; and
    wherein there may optionally be a covalent bond between R4aq and R5aq; and
    wherein R3aq is selected from the group consisting of —C(═O)—, —C(═O)NH—, —CH2—, —CH2CH2—, —CHF—, —CH2CHF—, —CHFCH2—, —NH—, —S(═O)2—NH—, —NH—S(═O)2—, —NHC(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—; and
    wherein there may optionally be a covalent bond between two substituents selected from R8aq, R9aq, R10aq and R11ao.


In one embodiment the invention is concerned with compounds of the general formulae XXXXVa-b, wherein there is one covalent bond between the substituents R1aq and R2aq.
In another embodiment the invention is concerned with compounds of the general formulae XXXXVa-b, wherein R4aq, R5aq, R6aq and R7aq are independently selected from hydrogen and fluor.
In another embodiment the invention is concerned with compounds of the general formula XXXXVa-b, wherein R3aq is selected from —O—, —S—, —CH2—, —CH2CH2—, —NH—, —NH—C(═O)—, —C(═O)—NH—, —S(═O)2—NH— and —NH—S(═O)2—.
In another aspect of the invention, compounds are of the general formula XXXXVI




    wherein A1ar is N or C—R10ar; and A2ar is N or C—R11ar; and A3ar is N or C—R12ar; and
    wherein R1ar, R2ar, R3ar, R4ar, R5ar, R6ar, R7ar, R8ar, R9ar, R10ar, R11ar and R12ar are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, perhalomethyl and perhalomethoxy; with the proviso that if R1ar and R2ar are identical then they are not methyl or ethyl; and
    wherein there may optionally be a covalent bond between R1ar and R2ar.


In one embodiment the invention is concerned with compounds of the general formula XXXXVI, wherein R9ar is S(═O)2—R13ar or C(═O)—R13ar; and wherein R13ar is selected from hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6alkyl, C2-6-alkenyl, perhalomethyl and perhalomethoxy
In another embodiment the invention is concerned with compounds of the general formula XXXXVI, wherein R1ar and R2ar are not identical.
In another embodiment the invention is concerned with compounds of the general formula XXXXVI, wherein there is a covalent bond between the substituents R1ar and R2ar.
In another aspect of the invention, compounds are of the general formula XXXXVII




    wherein R1as, R2as, R3as, R4as, R5as, R6as, R7as R8as and R9as are independently selected from hydrogen and fluor; and
    wherein R10as is selected from aryl and heteroaryl, which is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6alkyl, C2-6-alkenyl, perhalomethyl and perhalomethoxy; and
    wherein R12as is selected from hydrogen, hydroxy, sulfanyl, sulfo, amino, cyano, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, perhalomethyl and perhalomethoxy; and
    wherein R13as, R14as, R15as and R16as are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8 heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, perhalomethyl and perhalomethoxy; with the proviso that R12as, R13as, R14as, R15as and R16as are not all hydrogen; and
    wherein there may optionally be a covalent bond between the substituents R13as and R14as.


In one embodiment the invention is concerned with compounds of the general formula XXXXVII, wherein R13as, R14as, R15as and R16as are independently selected from hydrogen and fluor.
In another aspect of the invention, compounds are of the general formula XXXXVIII




    wherein R5at, R6at, R7at, R8at, R9at, R10at, R11at, R12at, R13at, R14at, R15at, R16at, R17at and R18at are independently selected from hydrogen and fluor; and
    wherein R4at is selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6alkyl, C2-6-alkenyl, perhalomethyl and perhalomethoxy; and
    wherein R19at is selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, fluor, iodine, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl; with the proviso that R19at is not methoxy.


In one embodiment the invention is concerned with compounds of the general formula XXXXVIII, wherein R5at, R6at, R7at R8at, R9at, R10at R11at, R12at, R13at R14at, R15at, R16at, R17at and R18at are all hydrogen.
In another embodiment the invention is concerned with compounds of the general formula XXXXVIII, wherein R4at is an optionally substituted aryl or heteroaryl.
In another embodiment, the invention is concerned with compounds of the general formulae I-XXXXVIII, wherein said compound comprises only one F.
In another embodiment, the invention is concerned with compounds of the general formulae I-XXXXVIII, wherein said compound comprises two F and preferably three F.
In another embodiment; the invention is concerned with compounds of the general formulae I-XXXXVIII, wherein said compound comprises a CF3 moiety.
In another embodiment, the invention is concerned with compounds of the general formulae I-XXXXVIII, wherein said compound comprises a hydrophilic substituent selected from the group consisting of hydroxy, amino, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NHS(═O)2—OH, —NHC(═O)—R1am, —NHS(═O)2—R1am, —N(R1am)C(═O)—R2am, —N(R1am)S(═O)2—R2am, wherein R1am and R2am are independently selected from C1-6-alkyl.
In another embodiment, the invention is concerned with compounds of the general formulae I-XXXXVIII, wherein said compound comprises a moiety selected from the group consisting of




Examples of specific compounds of the invention are:

    Methyl-phenyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    Methyl-phenyl-carbamic acid 3-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(3,5-dichloro-pyridin-2-yloxy)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-ylamino)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(3,5-dichloro-pyridin-4-yloxy)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(4-trifluoromethyl-phenoxy)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(2-cyano-5-trifluoromethyl-pyridine-3-yloxy)-phenyl ester,
    Methyl-phenyl-carbamic acid 2-benzenesulfonyl-4-(3-chloro-5-trifluoromethyl-pyridine-2-yloxy)-phenyl ester,Methyl-phenyl-carbamic acid 4-tert-butoxy-phenyl ester,Methyl-phenyl-carbamic acid 3-(4-fluorobenzyl)-4-methyl-2-oxo-2H-chromen-7-yl ester,
    Methyl-phenyl-carbamic acid 4-phenoxy-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(4-chlorobenzoyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(3-chloro-5-trifluoromethyl)-pyridine-2-yloxy)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[4-(4-chloro-phenyl)-thiazol-2-yl]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-pyrrol-1-yl-phenyl ester,
    Methyl-phenyl-carbamic acid 4-imidazol-1-yl-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(3-chloro-5-trifluoromethyl)-pyridine-2-ylmethyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-trifluoromethylsulfanyl-phenyl ester,
    Methyl-phenyl-carbamic acid 4-pentafluoroethyloxy-phenyl ester,
    Methyl-phenyl-carbamic acid 4-benzyloxy-phenyl ester,
    Methyl-phenyl-carbamic acid 4-benzyl-phenyl ester,
    Methyl-phenyl-carbamic acid 4′-cyano-biphenyl-4-yl-ester,
    Methyl-phenyl-carbamic acid 4′-bromo-biphenyl-4-yl-ester,
    Methyl-phenyl-carbamic acid biphenyl-4-yl-ester,
    Methyl-phenyl-carbamic acid 4-[3-(4-chlorophenyl)-ureido]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(4-nitro-phenoxy)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-heptylsulfanyl-phenyl ester,
    Methyl-phenyl-carbamic acid 4-butoxy-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(4-chloro-benzenesulfonyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(4-chloromethyl-thiazol-2-yl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(4,4-dimethyl-2,6-dioxo-piperidin-1-yl)-phenyl ester,
    cis-Methyl-phenyl-carbamic Acid 4-(1,3-dioxo-octahydro-isoindol-2-yl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(cyclohexanecarbonyl-amino)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(2-cyclohexyl-acetylamino)-phenyl ester,
    cis/trans-Methyl-phenyl-carbamic acid 4-[(4-tert-butyl-cyclohexanecarbonyl)-amino]-phenyl ester, cis-Methyl-phenyl-carbamic acid 4-[(4-tert-butyl-cyclohexanecarbonyl)-amino]-phenyl ester, trans-Methyl-phenyl-carbamic acid 4-[(4-tert-butyl-cyclohexanecarbonyl)-amino]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(3,3-dimethyl-butyrylamino)-phenyl ester,
    Methyl-phenyl-carbamic acid 3-benzyl-4-methyl-2-oxo-2H-chromen-7-yl ester,
    Methyl-phenyl-carbamic acid 3-(3,4-dichloro-benzyl)-4-methyl-2-oxo-2H-chromen-7-yl ester,
    Methyl-phenyl-carbamic acid 3-(2-chloro-6-fluoro-benzyl)-4-methyl-2-oxo-2H-chromen-7-yl ester,
    Methyl-phenyl-carbamic acid 3-(2,6-dichloro-benzyl)-4-methyl-2-oxo-2H-chromen-7-yl ester,
    Methyl-phenyl-carbamic acid 3-(2,6-dichloro-benzyl)-6-chloro-4-methyl-2-oxo-2H-chromen-7-yl ester,
    Methyl-phenyl-carbamic acid 6-chloro-3-(2-chloro-6-fluoro-benzyl)-4-n-propy-2-oxo-2H-chromen-7-yl ester,
    Methyl-phenyl-carbamic acid 3-(4-methoxy-phenyl)-4-methyl-2-oxo-2H-chromen-7-yl ester,
    Methyl-phenyl-carbamic acid 4-methyl-2-oxo-3-phenyl-2H-chromen-7-yl ester,
    Methyl-phenyl-carbamic acid 3-(2,5-dimethoxy-phenyl)-4-methyl-2-oxo-2H-chromen-7-yl ester,
    Methyl-phenyl-carbamic acid 3-(3,4-dimethoxy-phenyl)-4-methyl-2-oxo-2H-chromen-7-yl ester,
    Methyl-phenyl-carbamic acid 4-pyrrolidine-1-yl-phenyl ester,
    Methyl-phenyl-carbamic acid 4-piperidine-1-yl-phenyl ester,
    Methyl-phenyl-carbamic acid 4-morpholine-1-yl-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[(6-chloro-pyridine-3-carbonyl)-amino]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[(6-chloro-pyridine-3-carbonyl)-amino]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[(pyridine-2-carbonyl)-amino]-phenyl ester,
    4-Chlor-phenyl-methyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-Chlor-phenyl-methyl-carbamic acid 4-(3,5-dichloro-pyridin-2-yloxy)-phenyl ester,
    (4-Chloro-phenyl)-methyl-carbamic acid 4-(2-cyano-5-trifluoromethyl-pyridin-3-yloxy)-phenyl ester,
    Ethyl-phenyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    Ethyl-phenyl-carbamic acid 4-(4-trifluoromethyl-phenoxy)-phenyl ester,
    Methyl-phenyl-carbamic acid pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 4-bromo-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 3,4,5-tribromo-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 3-(4-methoxy-phenyl)-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid imidazol-1-yl ester,
    Methyl-phenyl-carbamic acid [1,2,3]triazol-1-yl ester,
    Methyl-phenyl-carbamic acid 3-bromo-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 5-bromo-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 3-chloro-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 4-chloro-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 5-chloro-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 4-iodo-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 5-iodo-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 3-methyl-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 4-methyl-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 5-methyl-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 4-(4-methoxy-phenyl)-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 5-(4-methoxy-phenyl)-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 3-(2-methoxy-phenyl)-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 3-(4-nitro-phenyl)-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 3-(2-nitro-phenyl)-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 3-pyridin-2-yl-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 4-pyridin-2-yl-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 3-(2-fluoro-phenyl)-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 4-(2-fluoro-phenyl)-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 5-(2-fluoro-phenyl)-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 3-phenylsulfanyl-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 4-phenylsulfanyl-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 5-phenylsulfanyl-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 4-thiophen-3-yl-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 3-thiophen-2-yl-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 4-thiophen-2-yl-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 5-thiophen-2-yl-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 2-chloro-imidazol-1-yl ester,
    Methyl-phenyl-carbamic acid 2-bromo-imidazol-1-yl ester,
    Methyl-phenyl-carbamic acid 2-iodo-imidazol-1-yl ester,
    Methyl-phenyl-carbamic acid 2-methyl-imidazol-1-yl ester,
    Methyl-phenyl-carbamic acid 2-phenylsulfanyl-imidazol-1-yl ester,
    Methyl-phenyl-carbamic acid 2-(4-methoxy-phenyl)-imidazol-1-yl ester,
    Methyl-phenyl-carbamic acid 2-(4-fluoro-phenyl)-imidazol-1-yl ester,
    Methyl-phenyl-carbamic acid 2-thiophen-2-yl-imidazol-1-yl ester,
    Methyl-phenyl-carbamic acid 2-pyridin-2-yl-imidazol-1-yl ester,
    Methyl-phenyl-carbamic acid 2,5-dichloro-imidazol-1-yl ester,
    Methyl-phenyl-carbamic acid 4-bromo-2,5-dichloro-imidazol-1-yl ester,
    4-(Methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester,
    Methyl-phenyl-carbamic acid 4-(1,3,5-trimethyl-1H-pyrazol-4-ylmethyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(2-cyano-ethyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-([1,2,3,4]thiatriazol-5-ylamino)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-pentyl-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(2-methoxy-ethyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-acetyl-phenyl ester,
    Methyl-phenyl-carbamic acid pyridin-4-yl ester,
    Methyl-phenyl-carbamic acid pyridin-3-yl ester,
    Methyl-phenyl-carbamic acid 6-methyl-pyridin-3-yl ester,
    Methyl-phenyl-carbamic acid isoquinolin-1-yl ester,
    Methyl-phenyl-carbamic acid 3-phenoxy-phenyl ester,
    Methyl-phenyl-carbamic acid 3-acetyl-phenyl ester,
    Methyl-phenyl-carbamic acid 4-acetyl-2-carbamoyl-phenyl ester,
    Methyl-phenyl-carbamic acid 4-acetyl-3-methyl-phenyl ester,
    Methyl-phenyl-carbamic acid 1-oxo-indan-4-yl ester,
    Methyl-phenyl-carbamic acid benzothiazol-2-yl ester,
    Methyl-phenyl-carbamic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester,
    Methyl-phenyl-carbamic acid benzo[d]isoxazol-3-yl ester,
    Methyl-phenyl-carbamic acid pyridin-2-yl ester,
    Methyl-phenyl-carbamic acid 1-(methyl-phenyl-carbamoyl)-1H-benzimidazol-2-yl ester,
    Methyl-phenyl-carbamic acid 4-[(pyridine-3-carbonyl)-amino]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(3-pyridin-3-yl-acryloyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[3-(3,4,5-trimethoxy-phenyl)-acryloyl]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-diethylcarbamoyl-2-methoxy-phenyl ester,
    Methyl-phenyl-carbamic acid 3-phenylcarbamoyl-phenyl ester,
    Methyl-phenyl-carbamic acid quinolin-7-yl ester,
    Methyl-phenyl-carbamic acid 4-(4-methyl-piperazine-1-carbonyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 3-acetylamino-phenyl ester,
    Methyl-phenyl-carbamic acid 4-benzoyl-phenyl ester,
    Methyl-phenyl-carbamic acid biphenyl-3-yl ester,
    Methyl-phenyl-carbamic acid 1H-indol-4-yl ester,
    Methyl-phenyl-carbamic acid 5,6,7,8-tetrahydro-naphthalen-1-yl ester,
    Methyl-phenyl-carbamic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl ester,
    Methyl-phenyl-carbamic acid 1,3-dioxo-1,3-dihydro-isobenzofuran-4-yl ester,
    Methyl-phenyl-carbamic acid 4-(5-chloro-pyridin-2-yloxy)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-morpholin-4-yl-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(5,6-dichloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-phenyl ester, Methyl-phenyl-carbamic acid 4-(2-phenoxy-acetylamino)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[2-(4-chloro-phenyl)-ethyl]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[(pyridine-2-carbonyl)-amino]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[methyl-(thiophene-2-carbonyl)-amino]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-butyrylamino-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(4,6-dimethyl-pyrimidin-2-ylsulfanyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-methanesulfonyl-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[2-(3-oxo-1-, 2, 3, 4-tetrahydro-quinoxalin-2-yl)-acetylamino]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-phenylacetyl-phenyl ester,
    Methyl-phenyl-carbamic acid 4-{[4-(methyl-phenyl-carbamoyloxy)-2-oxo-1,2-dihydro-quinoline-3-carbonyl]-amino}-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[(4-hydroxy-2-oxo-1,2-dihydro-quinoline-3-carbonyl)-amino]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(4-hydroxy-benzyl)-phenyl ester
    Methyl-phenyl-carbamic acid 4-(4-trifluoromethyl-benzylcarbamoyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(butyl-methyl-carbamoyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(methyl-phenethyl-carbamoyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[(pyridin-2-ylmethyl)-carbamoyl]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(2-pyridin-2-yl-ethylcarbamoyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(2-phenylamino-ethylcarbamoyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(3-methyl-butylcarbamoyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(3,3-dimethyl-butylcarbamoyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[(tetrahydro-furan-2-ylmethyl)-carbamoyl]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-cyclohexylcarbamoyl-phenyl ester,
    Methyl-phenyl-carbamic acid 4-cyclopropylcarbamoyl-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(cyclohexylmethyl-carbamoyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 5-nitro-pyridin-2-yl ester,
    Methyl-phenyl-carbamic acid pyrimidin-2-yl ester,
    Methyl-phenyl-carbamic acid 7-chloro-quinolin-4-yl ester,
    Methyl-phenyl-carbamic acid quinolin-4-yl ester,
    Methyl-phenyl-carbamic acid 5-methyl-isoxazol-3-yl ester,
    Methyl-phenyl-carbamic acid quinoxalin-2-yl ester,
    Methyl-phenyl-carbamic acid 4-methyl-quinolin-2-yl ester,
    Methyl-phenyl-carbamic acid 3-methyl-quinoxalin-2-yl ester,
    Methyl-phenyl-carbamic acid 4,6-dimethyl-pyrimidin-2-yl ester,
    Methyl-phenyl-carbamic acid isoquinolin-6-yl ester,
    Methyl-phenyl-carbamic acid quinolin-2-yl ester,
    Methyl-phenyl-carbamic acid isoquinolin-3-yl ester,
    Methyl-phenyl-carbamic acid 4-trifluoromethyl-pyrimidin-2-yl ester,
    Methyl-phenyl-carbamic acid 3-nitro-pyridin-2-yl ester,
    Methyl-phenyl-carbamic acid 5-chloro-pyridin-2-yl ester,
    Methyl-phenyl-carbamic acid 5-(2-nitro-phenyl)-pyrimidin-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-nitro-3-trifluoromethyl-pyridin-2-yl ester,
    Methyl-phenyl-carbamic acid 4,5-dichloro-pyridazin-3-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-(4-methoxy-phenoxy)-pyrimidin-2-yl ester,
    Methyl-phenyl-carbamic acid 5-(3,4-dichloro-phenoxy)-pyrimidin-2-yl ester,
    Methyl-phenyl-carbamic acid 6-pyridin-2-ylmethyl-pyridazin-3-yl ester,
    Methyl-phenyl-carbamic acid 6-(4-methoxy-benzyl)-pyridazin-3-yl ester,
    Methyl-phenyl-carbamic acid 6-(2,4-dichloro-benzyl)-pyridazin-3-yl ester,
    Methyl-phenyl-carbamic acid 4-iodo-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid benzotriazol-1-yl ester,
    Methyl-phenyl-carbamic acid [1,2,3]triazolo[4,5-b]pyridin-3-yl ester,
    Methyl-phenyl-carbamic acid 3-(2-nitro-phenyl)-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 3-(4-nitro-phenyl)-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 3-pyridin-2-yl-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 3-thiophen-2-yl-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 3-(2-fluoro-phenyl)-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 3-bromo-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 5-iodo-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 2-chloro-imidazol-1-yl ester,
    Methyl-phenyl-carbamic acid 4-(4-methoxy-phenyl)-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 5-benzoyl-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 5-(4-methoxy-phenyl)-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 5-(4-dimethylamino-phenyl)-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 4,5-diiodo-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 5-thiophen-2-yl-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 2-(4-methoxy-phenyl)-imidazol-1-yl ester,
    Methyl-phenyl-carbamic acid 2-methylsulfanyl-imidazol-1-yl ester,
    Methyl-phenyl-carbamic acid 3,5-bis-(4-methoxy-phenyl)-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 4-(4-fluoro-phenyl)-5-(4-methoxy-phenyl)-3-(4-methylphenyl)pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 4-benzyl-5-(4-methoxy-phenyl)-3-(methylphenyl)-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 4-acetyl-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 2-(4-nitro-phenyl)-imidazol-1-yl ester,
    Methyl-phenyl-carbamic acid 2-chloro-5-(4-methylphenyl)-imidazol-1-yl ester,
    Methyl-phenyl-carbamic acid 4-formyl-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 4-hydroxymethyl-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 4-phenylethynyl-pyrazol-1-yl ester,
    Methyl-phenyl-carbamic acid 2-bromo-imidazol-1-yl ester,
    Methyl-phenyl-carbamic acid 2-phenylsulfanyl-imidazol-1-yl ester,
    Methyl-o-tolyl-carbamic acid 4-(trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    Methyl-m-tolyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    (3-Chloro-phenyl)-methyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    Methyl-p-tolyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    (3-Fluoro-phenyl)-methyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    (3-Chloro-phenyl)-methyl-carbamic acid 4-trifluoromethyl-pyrimidin-2-yl ester,
    Methyl-m-tolyl-carbamic acid 4-trifluoromethyl-pyrimidin-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]-pyridin-2-yl ester,
    Methyl-phenyl-carbamic acid 2-(4,4-dimethyl-2,6-dioxo-piperidin-1-yl)-pyrimidin-5-yl ester,
    Methyl-phenyl-carbamic acid 5-bromo-pyrimidin-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 6-(3,4-dichloro-phenoxy)-pyridazin-3-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 quinolin-6-yl ester,
    Methyl-phenyl-carbamic acid 5-(4-chloro-benzoylamino)-pyridin-2-yl ester,
    4 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′-yl ester,
    Methyl-phenyl-carbamic acid 2-methyl-quinolin-6-yl ester,
    {2-[4-(Methyl-phenyl-carbamoyloxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester,
    Methyl-phenyl-carbamic acid 4-(2-amino-ethyl)phenyl ester,
    Methyl-phenyl-carbamic acid 4-[2-(toluene-4-sulfonylamino)-ethyl]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[2-(5-dimethylamino-naphthalene-1-sulfonylamino)-ethyl]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[2-(3,4-difluoro-benzenesulfonylamino)-ethyl]-phenyl ester,
    2-{2-[4-(Methyl-phenyl-carbamoyloxy)-phenyl]-ethylsulfamoyl}-benzoic acid methyl ester,
    Methyl-phenyl-carbamic acid 4-[2-(2,5-dichloro-thiophene-3-sulfonylamino)-ethyl]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[2-(5-pyridin-2-yl-thiophene-2-sulfonylamino)-ethyl]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[2-(1-methyl-1H-imidazole-4-sulfonylamino)-ethyl]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[2-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonylamino)-ethyl]-phenyl,
    Methyl-phenyl-carbamic acid 4-[2-(4-nitro-benzenesulfonylamino)-ethyl]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[2-(6-chloro-imidazo[2, 1-b]thiazole-5-sulfonylamino)-ethyl]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[2-(2-trifluoromethoxy-benzenesulfonylamino)-ethyl]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(2-dimethylaminosulfonylamino-ethyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(2-methanesulfonylamino-ethyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[2-(6-morpholin-4-yl-pyridine-3-sulfonylamino)-ethyl]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[2-(6-phenoxy-pyridine-3-sulfonylamino)-ethyl]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-{2-[4-(4-methyl-piperazin-1-yl)-benzenesulfonylamino]-ethyl}-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[2-(4-dimethylamino-benzenesulfonylamino)-ethyl]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-benzenesulfonylamino]-ethyl}-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(2-cyclohexyl-ethylsulfamoyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(3-methyl-butylsulfamoyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(1,1,3,3-tetramethyl-butylcarbamoyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[(2-dimethylamino-ethyl)-methyl-carbamoyl]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(cyclopropylmethyl-carbamoyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(methyl-pyridin-3-ylmethyl-carbamoyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[(1H-benzimidazol-2-ylmethyl)-carbamoyl]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[2-(4-chloro-phenyl)-ethylcarbamoyl]-phenyl ester,
    Methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester,
    Methyl-phenyl-carbamic acid 5-benzenesulfonylamino-pyridin-2-yl ester,
    3,3-Dimethyl-4-[6-(methyl-phenyl-carbamoyloxy)-pyridin-3-ylcarbamoyl]-butyric acid,
    2,2-Dimethyl-N-[6-(methyl-phenyl-carbamoyloxy)-pyridin-3-yl]-succinamic acid,
    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-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,
    Methyl-phenyl-carbamic acid 4-iodo-phenyl ester,
    Methyl-phenyl-carbamic acid 4′-trifluoromethyl-biphenyl-4-yl ester,
    Methyl-phenyl-carbamic acid 4′-trifluoromethoxy-biphenyl-4-yl ester,
    Methyl-phenyl-carbamic acid 4-pyridin-3-yl-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(5-chloro-thiophen-2-yl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4′-benzylsulfamoyl-biphenyl-4-yl ester,
    Methyl-phenyl-carbamic acid 4-styryl-phenyl ester,
    Methyl-phenyl-carbamic acid 4-phenylethynyl-phenyl ester,
    3-[4-(Methyl-phenyl-carbamoyloxy)-phenyl]-acrylic acid methyl ester,
    Methyl-phenyl-carbamic acid 4-(toluene-4-sulfonylamino)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(5-pyridin-2-yl-thiophene-2-sulfonylamino)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(1-methyl-1H-imidazole-4-sulfonylamino)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(2,5-dichloro-thiophene-3-sulfonylamino)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonylamino)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(5-dimethylamino-naphthalene-1-sulfonylamino)-phenyl ester,
    2-[4-(Methyl-phenyl-carbamoyloxy)-phenylsulfamoyl]-benzoic acid methyl ester,
    Methyl-phenyl-carbamic acid 4-(3,4-difluoro-benzenesulfonylamino)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-pyridin-2-ylmethyl-phenyl ester,
    Methyl-phenyl-carbamic acid 4-pyridin-3-ylmethyl-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(4-trifluoromethyl-benzyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-thiophen-3-ylmethyl-phenyl ester,
    Methyl-phenyl-carbamic acid 4-thiophen-2-ylmethyl-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[2-(4-amino-benzenesulfonylamino)-ethyl]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-{2-[(pyridine-3-carbonyl)-amino]-ethyl}-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[2-(2-dimethylamino-acetylamino)-ethyl]-phenyl ester,
    Methyl-phenyl-carbamic acid 2-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-isoquinolin-7-yl ester,
    Methyl-phenyl-carbamic acid 4-[4-(2-pyrrolidin-1-yl-ethoxy)-benzyl]-phenyl ester,
    Methyl-phenyl-carbamic acid 2-[4-(2-pyrrolidin-1-yl-ethoxy)-benzenesulfonyl]-1,2,3,4-tetrahydro-isoquinolin-7-yl ester,
    Methyl-phenyl-carbamic acid 4-{2-[(1-methyl-piperidine-4-carbonyl)-amino]-ethyl}-phenyl ester,
    Methyl-phenyl-carbamic acid 2-(3,4-difluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-7-yl ester,
    Methyl-phenyl-carbamic acid 1-methyl-2-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-isoquinolin-7-yl ester,
    Methyl-phenyl-carbamic acid 2-[4-(4-methyl-piperazin-1-yl)-benzenesulfonyl]-1,2,3,4-tetrahydro-isoquinolin,
    Methyl-phenyl-carbamic acid 1-methyl-2-[4-(4-methyl-piperazin-1-yl)-benzenesulfonyl]-1,2,3,4-tetrahydro-isoquinolin-7-yl ester,
    3,3-Dimethyl-4-{2-[4-(methyl-phenyl-carbamoyloxy)-phenyl]-ethylcarbamoyl}-butyric acid,
    Methyl-phenyl-carbamic acid 4-{2-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-ethyl}-phenyl ester,
    Methyl-phenyl-carbamic acid 4-{2-[4-(4-methyl-piperazin-1-ylmethyl)-benzoylamino]-ethyl}-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[2-(4,4-dimethyl-2,6-dioxo-piperidin-1-yl)-ethyl]-phenyl ester,
    3,3-Dimethyl-4-{2-[4-(methyl-phenyl-carbamoyloxy)-phenyl]-ethylcarbamoyl}-butyric acid ethyl ester,
    Methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(4-dimethylamino-pyridin-2-ylmethyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(4-imidazol-1-yl-phenoxymethyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[4-(2-dimethylamino-ethyl)-phenoxymethyl]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(pyrazol-1-yloxymethyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(imidazol-1-yloxymethyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(2-oxo-2H-pyridin-1-ylmethyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[2-(pyridin-2-yloxy)-ethyl]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[2-(4-imidazol-1-yl-phenoxy)-ethyl]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-{2-[4-(2-dimethylamino-ethyl)-phenoxy]-ethyl}-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[2-(pyrazol-1-yloxy)-ethyl]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[2-(imidazol-1-yloxy)-ethyl]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(5-methyl-pyridin-2-ylmethyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(4-oxo-4H-pyridin-1-ylmethyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[2-(pyridin-3-yloxy)-ethyl]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(2-oxo-2H-pyridin-1-ylmethyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(pyridin-3-yloxymethyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethyl]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[2-(1,3-dioxo-1,3-dihydro-pyrrolo[3,4-]pyridin-2-yl)-ethyl]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(1-methyl-1H-imidazol-2-ylsulfanylmethyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-tetrazol-1-ylmethyl-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(2,5-dioxo-pyrrolidin-1-ylmethyl)-phenyl ester,Methyl-phenyl-carbamic acid 4-[2-(2-thioxo-2H-pyridin-1-yl)-ethyl]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(1,3-dioxo-1,3-dihydro-pyrrolo[3,4]pyridin-2-ylmethyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[1,2,4]triazol-1-ylmethyl-phenyl ester,
    Methyl-phenyl-carbamic acid 4-(2-thioxo-2H-pyridin-1-ylmethyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[2-(1-methyl-1H-imidazol-2-ylsulfanyl)-ethyl]-phenyl ester, ethyl-phenyl-carbamic acid 4-(2-tetrazol-1-yl-ethyl)-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[2-(pyrimidin-2-yloxy)-ethyl]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[2-(pyridin-4-ylsulfanyl)-ethyl]-phenyl ester,
    Methyl-phenyl-carbamic acid 4-[2-(1-pyridin-3-yl-1H-imidazol-2-ylsulfanyl)-ethyl]-phenyl ester, and
    Methyl-phenyl-carbamic acid 4-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-phenyl ester.


Further examples of specific compounds of the invention are:

    Benzyl-methyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester, and
    Benzyl-methyl-carbamic acid 4-(3,5-dichloro pyridin-2-yloxy)-phenyl ester.


Further examples of specific compounds of the invention are:

    Isopropyl-methyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    Cyclohexyl-methyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester.
    Dimethyl-carbamic acid 4-(3,5-dichloro pyridin-2-yloxy)-phenyl ester.
    Methyl-pyridin-2-yl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    (2-Dimethylamino-ethyl)methylcarbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    (6-Methoxy-pyridin-2-yl)-methyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    (4-Methoxy-phenyl)-methyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    (2-Methoxy-phenyl)-methyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    (2-Carbamoyl-4-chloro-phenyl)-methyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester(2-Carbamoyl-phenyl)-methyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    (2-Chloro-phenyl)-methyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    (2,4-Difluoro-phenyl)-methyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester, and
    Methyl-(2-trifluoromethoxy-phenyl)-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester.


Further examples of specific compounds of the invention are:

    Pyrrolidine-1-carboxylic acid 4-(3,5-dichloro-pyridin-2-yloxy)-phenyl ester,
    2,3-Dihydro-indole-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester. and
    1,3-Dihydro-isoindole-2-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester.


Further examples of specific compounds of the invention are:

    Piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    Piperidine-1-carboxylic acid 3-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    Piperidine-1-carboxylic acid 4-(3,5-dichloro-pyridin-2-yloxy)-phenyl ester,
    Piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-ylamino)-phenyl ester,
    Piperidine-1-carboxylic acid 4-(3,5-dichloro-pyridin-4-yloxy)-phenyl ester,
    Piperidine-1-carboxylic acid 4-(4-trifluoromethyl-phenoxy)-phenyl ester,
    Piperidine-1-carboxylic acid 4-(2-cyano-5-trifluoromethyl-pyridine-3-yloxy)-phenyl ester,
    Piperidine-1-carboxylic acid 2-benzenesulfonyl-4-(3-chloro-5-trifluoromethyl-pyridine-2-yloxy)-phenyl ester,
    Piperidine-1-carboxylic acid 4-tert-butoxy-phenyl ester,
    Piperidine-1-carboxylic acid 3-(4-fluorobenzyl)-4-methyl-2-oxo-2H-chromen-7-yl ester,
    Piperidine-1-carboxylic acid 4-phenoxy-phenyl ester,
    Piperidine-1-carboxylic acid 4-(4-chlorobenzoyl)-phenyl ester,
    Piperidine-1-carboxylic acid 4-(3-chloro-5-trifluoromethyl)-pyridine-2-yloxy)-phenyl ester,
    Piperidine-1-carboxylic acid 4-[4-(4-chloro-phenyl)-thiazol-2-yl]-phenyl ester,
    Piperidine-1-carboxylic acid 4-pyrrol-1-yl-phenyl ester,
    Piperidine-1-carboxylic acid 4-imidazol-1-yl-phenyl ester,
    Piperidine-1-carboxylic acid 4-(3-chloro-5-trifluoromethyl)-pyridine-2-ylmethyl)-phenyl ester,
    Piperidine-1-carboxylic acid 4-trifluoromethylsulfanyl-phenyl ester,
    Piperidine-1-carboxylic acid 4-pentafluoromethyloxy-phenyl ester,
    Piperidine-1-carboxylic acid 4-benzyloxy-phenyl ester,
    Piperidine-1-carboxylic acid 4-benzyl-phenyl ester,
    Piperidine-1-carboxylic acid 4′-cyano-biphenyl-4-yl-ester,
    Piperidine-1-carboxylic acid 4′-bromo-biphenyl-4-yl-ester,
    Piperidine-1-carboxylic acid biphenyl-4-yl-ester,
    Piperidine-1-carboxylic acid 4-[3-(4-chlorophenyl)-ureido]-phenyl ester,
    Piperidine-1-carboxylic acid 4-(4-nitro-phenoxy)-phenyl ester,
    Piperidine-1-carboxylic acid 4-heptylsulfanyl-phenyl ester,
    Piperidine-1-carboxylic acid 4-butoxy-phenyl ester,
    Piperidine-1-carboxylic acid 4-(4-chloro-benzenesulfonyl)-phenyl ester,
    Piperidine-1-carboxylic-acid 4-(4-chloromethyl-thiazol-2-yl)-phenyl ester,
    Piperidine-1-carboxylic acid 4-(4,4-dimethyl-2,6-dioxo-piperidin-1-yl)-phenyl ester,
    cis-Piperidine-1-carboxylic acid 4-(1,3-dioxo-octahydro-isoindol-2-yl)-phenyl ester,
    Piperidine-1-carboxylic acid 4-(cyclohexanecarbonyl-amino)-phenyl ester,
    Piperidine-1-carboxylic acid 4-(2-cyclohexyl-acetylamino)-phenyl ester,
    cis/trans-Piperidine-1-carboxylic acid 4-[(4-tert-butyl-cyclohexanecarbonyl)-amino]-phenyl ester,
    cis-Piperidine-1-carboxylic acid 4-[(4-tert-butyl-cyclohexanecarbonyl)-amino]-phenyl ester,
    trans-Piperidine-1-carboxylic acid 4-[(4-tert-butyl-cyclohexanecarbonyl)-amino]-phenyl ester,
    Piperidine-1-carboxylic acid 4-(3,3-dimethyl-butyrylamino)-phenyl ester,
    Piperidine-1-carboxylic acid 3-benzyl-4-methyl-2-oxo-2H-chromen-7-yl ester,
    Piperidine-1-carboxylic acid 3-(3,4-dichloro-benzyl)-4-methyl-2-oxo-2H-chromen-7-yl ester,
    Piperidine-1-carboxylic acid 3-(2-chloro-6-fluoro-benzyl)-4-methyl-2-oxo-2H-chromen-7-yl ester,
    Piperidine-1-carboxylic acid 3-(2,6-dichloro-benzyl)-4-methyl-2-oxo-2H-chromen-7-yl ester,
    Piperidine-1-carboxylic acid 3-(2,6-dichloro-benzyl)-6-chloro-4-methyl-2-oxo-2H-chromen-7-yl ester,
    Piperidine-1-carboxylic acid 6-chloro-3-(2-chloro-6-fluoro-benzyl)-4-n-propyl-2-oxo-2H-chromen-7-yl ester,
    Piperidine-1-carboxylic acid 3-(4-methoxy-phenyl)-4-methyl-2-oxo-2H-chromen-7-yl ester,
    Piperidine-1-carboxylic acid 4-methyl-2-oxo-3-phenyl-2H-chromen-7-yl ester,
    Piperidine-1-carboxylic acid 3-(2,5-dimethoxy-phenyl)-4-methyl-2-oxo-2H-chromen-7-yl ester,
    Piperidine-1-carboxylic acid 3-(3,4-dimethoxy-phenyl)-4-methyl-2-oxo-2H-chromen-7-yl ester,
    Piperidine-1-carboxylic acid 4-pyrrolidine-1-yl-phenyl ester,
    Piperidine-1-carboxylic acid 4-piperidine-1-yl-phenyl ester,
    Piperidine-1-carboxylic acid 4-morpholine-1-yl-phenyl ester,
    Piperidine-1-carboxylic acid 4-[(6-chloro-pyridine-3-carbonyl)-amino]-phenyl ester,
    Piperidine-1-carboxylic acid 4-[(6-chloro-pyridine-3-carbonyl)-amino]-phenyl ester,
    Piperidine-1-carboxylic acid 4-[(pyridine-2-carbonyl)-amino]-phenyl ester,
    Piperidine-1-carboxylic acid pyrazol-1-yl ester,
    Piperidine-1-carboxylic acid 3-bromo-pyrazol-1-yl ester,
    Piperidine-1-carboxylic acid 4-bromo-pyrazol-1-yl ester,
    Piperidine-1-carboxylic acid 5-bromo-pyrazol-1-yl ester,
    Piperidine-1-carboxylic acid 3,4,5-tribromo-pyrazol-1-yl ester,
    Piperidine-1-carboxylic acid 4-chloro-pyrazol-1-yl ester,
    Piperidine-1-carboxylic acid 4-iodo-pyrazol-1-yl ester,
    Piperidine-1-carboxylic acid 3-(4-methoxy-phenyl)-pyrazol-1-yl ester,
    Piperidine-1-carboxylic acid 3-(2-methoxy-phenyl)-pyrazol-1-yl ester,
    Piperidine-1-carboxylic acid 3-(4-nitro-phenyl)-pyrazol-1-yl ester,
    Piperidine-1-carboxylic acid 3-(2-fluoro-phenyl)-pyrazol-1-yl ester,
    Piperidine-1-carboxylic acid 3-pyridin-2-yl-pyrazol-1-yl ester,
    Piperidine-1-carboxylic acid 4-phenylsulfanyl-pyrazol-1-yl ester,
    Piperidine-1-carboxylic acid 3-thiophen-2-yl-pyrazol-1-yl ester,
    Piperidine-1-carboxylic acid 5-thiophen-2-yl-pyrazol-1-yl ester,
    Piperidine-1-carboxylic acid imidazol-1-yl ester,
    Piperidine-1-carboxylic acid 2-chloro-imidazol-1-yl ester,
    Piperidine-1-carboxylic acid 2-bromo-imidazol-1-yl ester,
    Piperidine-1-carboxylic acid 2-iodo-imidazol-1-yl ester,
    Piperidine-1-carboxylic acid 2-methyl-imidazol-1-yl ester,
    Piperidine-1-carboxylic acid 2-phenylsulfanyl-imidazol-1-yl ester,
    Piperidine-1-carboxylic acid 2-(4-methoxy-phenyl)-imidazol-1-yl ester,
    Piperidine-1-carboxylic acid 2-(4-fluoro-phenyl)-imidazol-1-yl ester,
    Piperidine-1-carboxylic acid 2-thiophen-2-yl-imidazol-1-yl ester,
    Piperidine-1-carboxylic acid 2-pyridin-2-yl-imidazol-1-yl ester,
    Piperidine-1-carboxylic acid 2,5-dichloro,-imidazol-1-yl ester,
    Piperidine-1-carboxylic acid 4-bromo-2,5-dichloro-imidazol-1-yl ester,
    2-Methyl-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    3-Methyl-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-Methyl-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-Benzyl-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    1,4-Dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    3-Hydroxy-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    3,4-Dihydro-2H-quinoline-1-carboxylic acid 4-(3,5-dichloro-pyridin-2-yloxy)-phenyl ester,
    3,4-Dihydro-2H-quinoline-1-carboxylic acid 4-(2-cyano-5-trifluoromethyl-pyridin-3-yloxy)-phenyl ester,
    3,4-Dihydro-2H-quinoline-1-carboxylic acid 3-(3,4-dichloro-benzyl)-4-methyl-2-oxo-2H-chromen-7-yl ester,
    3,4-Dihydro-2H-quinoline-1-carboxylic acid 3-benzyl-4-methyl-2-oxo-2H-chromen-7-yl ester,
    3,4-Dihydro-2H-quinoline-1-carboxylic acid 3-(2-chloro-6-fluoro-benzyl)4-methyl-2-oxo-2H-chromen-7-yl ester,
    3,4-Dihydro-2H-quinoline-1-carboxylic acid 3-(2,6-dichloro-benzyl)-4-methyl-2-oxo-2H-chromen-7-yl ester,
    3,4-Dihydro-2H-quinoline-1-carboxylic acid 3-(2,6-dichloro-benzyl)-6-chloro-4-methyl-2-oxo-2H-chromen-7-yl ester,
    3,4-Dihydro-2H-quinoline-1-carboxylic acid 3-(4-fluoro-benzyl)-4-methyl-2-oxo-2H-chromen-7-yl ester,
    3,4-Dihydro-2H-quinoline-1-carboxylic acid 6-chloro-3-(2-chloro-6-fluoro-benzyl)-4-n-propyl -2-oxo-2H-chromen-7-yl ester,
    3,4-Dihydro-2H-quinoline-1-carboxylic acid 3-(4-methoxy-phenyl)-4-methyl-2-oxo-2H-chromen -7-yl ester,
    3,4-Dihydro-2H-quinoline-1-carboxylic acid 4-methyl-2-oxo-3-phenyl-2H-chromen-7-yl ester,
    3,4-Dihydro-2H-quinoline-1-carboxylic acid 3-(2,5-dimethoxy-phenyl)-4-methyl-2-oxo-2H -chromen-7-yl ester,
    3,4-Dihydro-2H-quinoline-1-carboxylic acid 3-(3,4-dimethoxy-phenyl)-4-methyl-2-oxo-2H-chromen-7-yl ester,
    7-Trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-Hydroxymethyl-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-Oxo-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-[5-(4-Dimethylamino-phenyl)-1H-pyrazol-3-yl]-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(5-Furan-2-yl-1H-pyrazol-3-yl)-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin -2-yloxy)-phenyl ester,
    4-Benzylamino-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)-piperidine-1-carboxylic acid 4-(5-trifluoromethyl -pyridin-2-yloxy)-phenyl ester,
    3-Hydroxymethyl-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    3-Hydroxy-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-Benzyl-4-hydroxy-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-Hydroxy-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-Pyrrolidin-1-yl-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-Hydroxymethyl-piperidine-1-carboxylic acid 4-(5-chloro-pyridin-2-yloxy)-phenyl ester,
    1,4-Dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy) -phenyl ester,
    4-Benzoyl-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    [1,4′]Bipiperidinyl-1′-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(2-Oxo-2,3-dihydro-benzimidazol-1-yl)-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin -2-yloxy)-phenyl ester,
    3-Diethylcarbamoyl-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-Carbamoyl-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    3-Carbamoyl-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(tert-Butyl-dimethyl-silanyloxy)-piperidine-1-carboxylic acid 5-benzoylamino-pyridin-2-yl ester,
    4-Hydroxy-piperidine-1-carboxylic acid 5-benzoylamino-pyridin-2-yl ester,
    4-Hydroxy-piperidine-1-carboxylic acid 5-trifluoromethyl-pyridin-2-yl ester,
    4-Hydroxy-piperidine-1-carboxylic acid 5-(4-chloro-benzoylamino)-pyridin-2-yl ester,
    4-Hydroxy-piperidine-1-carboxylic acid 5-(3-methoxy-benzoylamino)-pyridin-2-yl ester,
    4-Hydroxy-piperidine-1-carboxylic acid 5-(4-methoxy-benzoylamino)-pyridin-2-yl ester,
    4-Hydroxy-piperidine-1-carboxylic acid 5-(2,4-dichloro-benzoylamino)-pyridin-2-yl ester,
    4-Hydroxy-piperidine-1-carboxylic acid 5-(4-trifluoromethyl-benzoylamino)-pyridin-2-yl ester,
    4-Hydroxy-piperidine-1-carboxylic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-yl ester,
    4-Hydroxy-piperidine-1-carboxylic acid 5-(5-trifluoromethyl-pyridin-2-yloxy)-pyridin-2-yl ester,
    4-Hydroxy-piperidine-1-carboxylic acid 5-(3,5-dichloro-pyridin-2-yloxy)-pyridin-2-yl ester,
    4-Aminomethyl-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-Benzimidazol-1-yl-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-Hydroxymethyl-piperidine-1-carboxylic acid 4-(2-cyclohexyl-acetylamino)-phenyl ester,
    4-(4-Amino-phenyl)-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(Methyl-pyridin-3-ylmethyl-amino)-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(2-Oxo-pyrrolidin-1-yl)-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy) -phenyl ester,
    4-(Methyl-phenethyl-amino)-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-[(Benzyl-ethyl-amino)-methyl]-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-[Methyl-phenethyl-amino)-methyl]-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-[(Cyclohexyl-methyl-amino)-methyl]-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-[(Ethyl-pyridin-4-ylmethyl-amino)-methyl]-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-[(Benzyl-methyl-amino)-methyl]-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-[(Methyl-pyridin-3-ylmethyl-amino)-methyl]-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(1,3-Dihydro-isoindol-2-ylmethyl)-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-Benzotriazol-1-yl-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-[(Cyclopropylmethyl-amino)-methyl]-piperidine-1-carboxylic acid 4-(5-trifluoromthyl-pyridin-2-yloxy)-phenyl ester,
    4-[Methyl-(2-pyridin-2-yl-ethyl)-amino]-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin -2-yloxy)-phenyl ester,
    4-(Cyclohexyl-methyl-amino)-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(Isopropyl-methyl-amino)-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-Hydroxymethyl-piperidine-1-carboxylic acid 4-(3,3-dimethyl-butylcarbamoyl)-phenyl ester ester,
    Piperidine-1-carboxylic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6 ′yl,
    4-[Methyl-(2-pyridin-4-yl-ethyl)-amino]-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin -2-yloxy)-phenyl ester,
    4-(Cyclopropyl-pyridin-4-ylmethyl-amino)-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-[Cyclopropyl-(2-fluoro-benzyl)-amino]-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(Cyclopropyl-pyridin-3-ylmethyl-amino)-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2 -yloxy)-phenyl ester,
    4-(Cyclopropylmethyl-pyridin-3-ylmethyl-amino)-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(Cyclopropylmethyl-pyridin-3-ylmethyl-amino)-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(4-Hydroxy-piperidin-1-ylmethyl)-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-{3-[1-(2-Hydroxy-ethyl)-piperidin-4-yl]-propyl}-piperidine-1-carboxylic acid 4-(5 -trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(2-Pyrrolidin-1-yl-ethyl)-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy) -phenyl ester,
    4-Hydroxy-piperidine-1-carboxylic acid 4-[2-(toluene-4-sulfonylamino)-ethyl]-phenyl ester,
    4-Hydroxy-piperidine-1-carboxylic acid 4-[2-(5-pyridin-2-yl-thiophene-2-sulfonylamino)-ethyl]-phenyl,
    4-Hydroxy-piperidine-1-carboxylic acid 4-(5-pyridin-2-yl-thiophene-2-sulfonylamino)-phenyl ester,
    4-Hydroxy-piperidine-1-carboxylic acid 4-pyridin-2-ylmethyl-phenyl ester,
    4-Hydroxy-piperidine-1-carboxylic acid 4-pyridin-3-ylmethyl-phenyl ester,
    4-Hydroxy-piperidine-1-carboxylic acid 4-(4-trifluoromethyl-benzyl)-phenyl ester,
    4-Hydroxy-piperidine-1-carboxylic acid 4-(5-methyl-pyridin-2-ylmethyl)-phenyl ester,
    4-(3-Amino-phenyl)-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-Phenyl-piperidine-1-carboxylic acid 4-(5-methyl-pyridin-2-ylmethyl)-phenyl ester, and
    4-(4-Methoxy-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid 4-(5-methyl-pyridin-2-ylmethyl)-phenyl ester.


Further examples of specific compounds of the invention are:

    4-Methyl-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-Benzyl-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(2-Hydroxyethyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(Pyridin-2-yl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(Pyrrolidinocarbonylmethyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-Phenyl-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(Isopropylaminocarbonylmethyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-Ethyl-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-Propyl-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-Butyl-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(4-Chlorobenzyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(4-Chlorophenyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(Diphenylmethyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(3-Hydroxypropyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(3-Trifluoromethylphenyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(3-Chlorophenyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(2-Chlorophenyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(3,4-Dichlorophenyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(4-Fluorophenyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(4-Methoxyphenyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(3-Methoxyphenyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(2-Methoxyphenyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(2,4-Dimethoxyphenyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(3,4,5-Trimethoxyphenyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-[3-(Trifluoromethyl)pyridin-2-yl]-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2 -yloxy)-phenyl ester,
    4-(3,4-Methylenedioxy-phenyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(3,4-Methylenedioxy-benzyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(Pyridin-4-yl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-Cyclopentyl-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(2-Pyrimidinyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(4-Acetylphenyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(2-(2-Hydroxyethoxy)ethyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-Benzyl-piperazine-1-carboxylic acid pyrazol-1-yl ester,
    4-Benzyl-piperazine-1-carboxylic acid 3-bromo-pyrazol-1-yl ester,
    4-Benzyl-piperazine-1-carboxylic acid 4-bromo-pyrazol-1-yl ester,
    4-Benzyl-piperazine-1-carboxylic acid 5-bromo-pyrazol-1-yl ester,
    4-Benzyl-piperazine-1-carboxylic acid 3,4,5-tribromo-pyrazol-1-yl ester,
    4-Benzyl-piperazine-1-carboxylic acid 4-chloro-pyrazol-1-yl ester,
    4-Benzyl-piperazine-1-carboxylic acid 4-iodo-pyrazol-1-yl ester,
    4-Benzyl-piperazine-1-carboxylic acid 3-(4-methoxy-phenyl)-pyrazol-1-yl ester,
    4-Benzyl-piperazine-1-carboxylic acid 3-(2-methoxy-phenyl)-pyrazol-1-yl ester,
    4-Benzyl-piperazine-1-carboxylic acid 3-(4-nitro-phenyl)-pyrazol-1-yl ester,
    4-Benzyl-piperazine-1-carboxylic acid 3-(2-fluoro-phenyl)-pyrazol-1-yl ester,
    4-Benzyl-piperazine-1-carboxylic acid 3-pyridin-2-yl-pyrazol-1-yl ester,
    4-Benzyl-piperazine-1-carboxylic acid 4-phenylsulfanyl-pyrazol-1-yl ester,
    4-Benzyl-piperazine-1-carboxylic acid 3-thiophen-2-yl-pyrazol-1-yl ester,
    4-Benzyl-piperazine-1-carboxylic acid 5-thiophen-2-yl-pyrazol-1-yl ester,
    4-Benzyl-piperazine-1-carboxylic acid imidazol-1-yl ester,
    4-Benzyl-piperazine-1-carboxylic acid 2-chloro-imidazol-1-yl ester,
    4-Benzyl-piperazine-1-carboxylic acid 2-bromo-imidazol-1-yl ester,
    4-Benzyl-piperazine-1-carboxylic acid 2-iodo-imidazol-1-yl ester,
    4-Benzyl-piperazine-1-carboxylic acid 2-methyl-imidazol-1-yl ester,
    4-Benzyl-piperazine-1-carboxylic acid 2-phenylsulfanyl-imidazol-1-yl ester,
    4-Benzyl-piperazine-1-carboxylic acid 2-(4-methoxy-phenyl)-imidazol-1-yl ester,
    4-Benzyl-piperazine-1-carboxylic acid 2-(4-fluoro-phenyl)-imidazol-1-yl ester,
    4-Benzyl-piperazine-1-carboxylic acid 2-thiophen-2-yl-imidazol-1-yl ester,
    4-Benzyl-piperazine-1-carboxylic acid 2-pyridin-2-yl-imidazol-1-yl ester,
    4-Benzyl-piperazine-1-carboxylic acid 2,5-dichloro-imidazol-1-yl ester,
    4-Benzyl-piperazine-1-carboxylic acid 4-bromo-2,5-dichloro-imidazol-1-yl ester,
    4-Benzyl-piperazine-1-carboxylic acid 4-bromo-2-chloro-imidazol-1-yl ester,
    4-Benzyl-piperazine-1-carboxylic acid 5-(4-methoxy-phenyl)-imidazol-1-yl ester,
    4-Benzyl-piperazine-1-carboxylic acid 5-(4-fluoro-phenyl)-imidazol-1-yl ester,
    4-Benzyl-piperazine-1-carboxylic acid 5-thiophen-2-yl-imidazol-1-yl ester,
    4-Benzyl-piperazine-1-carboxylic acid 5-pyridin-2-yl-imidazol-1-yl ester,
    4-Benzyl-piperazine-1-carboxylic acid 4-(5-chloro-pyridin-2-yloxy)-phenyl ester,
    4-Pyridin-3-ylmethyl-piperazine-1-carboxylic acid 4-(5-chloro-pyridin-2-yloxy)-phenyl ester,
    4-Pyridin-2-yl-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)phenyl ester,
    4-(1,3-Benzodioxol-5-yl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-[2-(2-Hydroxyethoxy)ethyl]-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(Diphenylmethyl)piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(4-tert-Butylbenzyl)piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)phenyl ester,
    4-(4-Fluorobenzyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(2-Thienylethyl)piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)phenyl ester,
    4-(1-Phenylethyl)piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)phenyl ester,
    4-Octylpiperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)phenyl ester,
    4-(3-Dimethylamino-propyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-Pyrimidin-2-yl-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-Cyclopropylmethyl-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-Phenethyl-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-Pyridin-2-ylmethyl-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-Pyridin-3-ylmethyl-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(3-Phenylpropyl)piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(4-Phenylbutyl)piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(3,4-Dichlorophenyl)piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)phenyl ester,
    4-(4-Fluorophenyl)piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)phenyl ester,
    4-(2-Chlorophenyl)piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)phenyl ester,
    4-Methylpiperazine-1-carboxylic acid 4-chlorophenyl ester,
    4-(4-Phenylbutyl)piperazine-1-carboxylic acid 4-chlorophenyl ester,
    4-[2-(2-Hydroxyethoxy)ethyl]piperazine-1-carboxylic acid 4-(4-trifluoromethylphenoxy)phenyl ester,
    4-(1-Ethylpropyl)piperazine-1-carboxylic acid 4-(4-trifluoromethylphenoxy)phenyl ester,
    4-Cycloheptylpiperazine-1-carboxylic acid 4-(4-trifluoromethyl-phenoxy)phenyl ester,
    4-Cyclohexylpiperazine-1-carboxylic acid 4-(4-trifluoromethyl-phenoxy)phenyl ester,
    4-(4-Chlorobenzyl)piperazine-1-carboxylic acid 4-(4-trifluoromethylphenoxy)phenyl ester,
    4-(4-Methylbenzyl)piperazine-1-carboxylic acid 4-(4-trifluoromethylphenoxy)phenyl ester,
    4-(4-Methoxybenzyl)piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(2-Chloro-6-fluoro-benzyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(3-Methoxyphenyl)piperazine-1-carboxylic acid 4-(4-trifluoromethylphenoxy)phenyl ester,
    4-Benzyl-piperazine-1-carboxylic acid 4-(3-chloro-5-trifluoromethyl-pyridin-2-yloxy)phenyl ester,
    4-Methyl-piperazine-1-carboxylic acid pyrazol-1-yl ester,
    4-Cyclopentyl-piperazine-1-carboxylic acid pyrazol-1-yl ester,
    4-Phenyl-piperazine-1-carboxylic acid pyrazol-1-yl ester,
    4-Pyridin-2-yl-piperazine-1-carboxylic acid pyrazol-1-yl ester,
    4-Pyrimidin-2-yl-piperazine-1-carboxylic acid pyrazol-1-yl ester,
    4-Benzo[1,3]dioxol-5-yl-piperazine-1-carboxylic acid pyrazol-1-yl ester,
    4-Benzyl-piperazine-1-carboxylic acid 4-iodo-pyrazol-1-yl ester,
    4-Cyclopentyl-piperazine-1-carboxylic acid 4-iodo-pyrazol-1-yl ester,
    4-(4-Fluoro-benzyl)-piperazine-1-carboxylic acid 4-iodo-pyrazol-1-yl ester,
    4-Phenyl-piperazine-1-carboxylic acid 4-iodo-pyrazol-1-yl ester,
    4-Pyridin-2-yl-piperazine-1-carboxylic acid 4-iodo-pyrazol-1-yl ester,
    4-Pyrimidin-2-yl-piperazine-1-carboxylic acid 4-iodo-pyrazol-1-yl ester,
    4-Benzo[1,3]dioxol-5-yl-piperazine-1-carboxylic acid 4-iodo-pyrazol-1-yl ester,
    4-Methyl-1,4-diazepane-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)phenyl ester,
    4-Benzyl-1,4-diazepane-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(Tetrahydrofuran-2-ylmethyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-Cyclopropylmethyl-piperazine-1-carboxylic acid 4-(3-chloro-5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(Tetrahydro-furan-2-ylmethyl)-piperazine-1-carboxylic acid 4-(4-trifluoromethylphenoxy)-phenyl ester,
    4-Cyclohexylmethyl-piperazine-1-carboxylic acid 4-(4-trifluoromethyl-phenoxy)-phenyl ester,
    4-Cyclohexylmethyl-piperazine-1-carboxylic acid 4-(3-chloro-5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-Cyclopropylmethyl-piperazine-1-carboxylic acid 4-(4-trifluoromethyl-phenoxy)-phenyl ester,
    4-(Tetrahydrofuran-2-ylmethyl)-piperazine-1-carboxylic acid 4-(3-chloro-5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-Naphthalen-1-ylmethyl-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(2-Cyclohexyl-ethyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(3-Methoxy-phenyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-Cyclopropylmethyl-piperazine-1-carboxylic acid 4-[2-(4-chloro-phenyl)-ethylcarbamoyl]-phenyl ester,
    4-(Tetrahydro-furan-2-ylmethyl)-piperazine-1-carboxylic acid 4-[2-(4-chloro-phenyl)-ethylcarbamoyl]-phenyl ester,
    4-(3,4-Dichloro-benzyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-Cyclopropylmethyl-[1,4]diazepane-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(2-Pyridin-2-yl-ethyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(Pyrazin-2-yl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(Benzo-isothiazol-3-yl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(5-Chloro-thiophen-2-ylmethyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(3-Trifluoromethyl-phenyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(5-Chloro-2-methyl-phenyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(1-Methyl-piperidin-4-ylmethyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-Biphenyl-4-ylmethyl-[1,4]diazepane-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(5-Dimethylamino-naphthalene-1-sulfonyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(3-Methoxy-benzyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(3-Fluoro-benzyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(3-Trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    4-(3-Fluorobenzyl)-piperazine-1-carboxylic acid 4-(4,6-dimethyl-pyrimidin-2-ylsulfanyl)-phenyl ester,
    5-(4-Trifluoromethoxybenzyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid 4-(5-trifluoromethylpyridin-2-yloxy)-phenyl ester,
    4-(2,4-Dimethoxyphenyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    5-Benzyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid 4-(5-trifluoromethylpyridin-2-yloxy)-phenyl ester,
    4-Pyrimidin-2-yl-piperazine-1-carboxylic acid 4-(5-chloro-pyridin-2-yloxy)-phenyl ester,
    4-Cyclopropylmethyl-piperazine-1-carboxylic acid 4-(4,4-dimethyl-2,6-dioxo-piperidin-1-yl)-phenyl ester,
    4-(4-Methoxy-benzyl)-piperazine-1-carboxylic acid 4-(4,4-dimethyl-2,6-dioxo-piperidin-1-yl)-phenyl ester,
    4-Pyridin-3-ylmethyl-piperazine-1-carboxylic acid 4-(4,4-dimethyl-2,6-dioxo-piperidin-1-yl) -phenyl ester,
    4-(4-Methoxy-benzyl)-piperazine-1-carboxylic acid 4-(2-cyclohexyl-acetylamino)-phenyl ester,
    4-Cyclopropylmethyl-piperazine-1-carboxylic acid 4-(2-cyclohexyl-acetylamino)-phenyl ester,
    4-Pyridin-3-ylmethyl-piperazine-1-carboxylic acid 4-(2-cyclohexyl-acetylamino)-phenyl ester,
    4-Cyclopropylmethyl-piperazine-1-carboxylic acid 4-(3,3-dimethyl-butylcarbamoyl)-phenyl ester,
    4-Pyridin-3-ylmethyl-piperazine-1-carboxylic acid 4-(3,3-dimethyl-butylcarbamoyl)-phenyl ester, 4-(4-Methoxy-benzyl)-piperazine-1-carboxylic acid 4-(3,3-dimethyl-butylcarbamoyl)-phenyl ester,
    4-(2-Pyridin-2-yl-acetyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy) -phenyl ester,
    Piperazine-1,4-dicarboxylic acid tert-butyl ester 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    Piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester hydrochloride,
    4-(2-Pyridin-2-yl-acetyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy) -phenyl ester, and
    4-(2-Pyridin-4-yl-ethyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy) -phenyl


Further examples of specific compounds of the invention are:

    Morpholine-4-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    Morpholine-4-carboxylic acid 3-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    Morpholine-4-carboxylic acid 4-(3,5-dichloro-pyridin-2-yloxy)-phenyl ester,
    Morpholine-4-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-ylamino)-phenyl ester,
    Morpholine-4-carboxylic acid 4-(3,5-dichloro-pyridin-4-yloxy)-phenyl ester,
    Morpholine-4-carboxylic acid 4-(4-trifluoromethyl-phenoxy)-phenyl ester,
    Morpholine-4-carboxylic acid 4-(2-cyano-5-trifluoromethyl-pyridine-3-yloxy)-phenyl ester,
    Morpholine-4-carboxylic acid 2-benzenesulfonyl-4-(3-chloro-5-trifluoromethyl-pyridine-2-yloxy)-phenyl ester,
    Morpholine-4-carboxylic acid 4-tert-butoxy-phenyl ester,
    Morpholine-4-carboxylic acid 3-(4-fluorobenzyl)-4-methyl-2-oxo-2H-chromen-7-yl ester,
    Morpholine-4-carboxylic acid 4-phenoxy-phenyl ester,
    Morpholine-4-carboxylic acid 4-(4-chlorobenzoyl)-phenyl ester,
    Morpholine-4-carboxylic acid 4-(3-chloro-5-trifluoromethyl)-pyridine-2-yloxy)-phenyl ester,
    Morpholine-4-carboxylic acid 4-[4-(4-chloro-phenyl)-thiazol-2-yl]-phenyl ester,
    Morpholine-4-carboxylic acid 4-pyrrol-1-yl-phenyl ester,
    Morpholine-4-carboxylic acid 4-imidazol-1-yl-phenyl ester,
    Morpholine-4-carboxylic acid 4-(3-chloro-5-trifluoromethyl)-pyridine-2-ylmethyl)-phenyl ester,
    Morpholine-4-carboxylic acid 4-trifluoromethylsulfanyl-phenyl ester,
    Morpholine-4-carboxylic acid 4-pentafluoromethyloxy-phenyl ester,
    Morpholine-4-carboxylic acid 4-benzyloxy-phenyl ester,
    Morpholine-4-carboxylic acid 4-benzyl-phenyl ester,
    Morpholine-4-carboxylic acid 4′-cyano-biphenyl-4-yl-ester,
    Morpholine-4-carboxylic acid 4′-bromo-biphenyl-4-yl-ester,
    Morpholine-4-carboxylic acid biphenyl-4-yl-ester,
    Morpholine-4-carboxylic acid 4-[3-(4-chlorophenyl)-ureido]-phenyl ester,
    Morpholine-4-carboxylic acid 4-(4-nitro-phenoxy)-phenyl ester,
    Morpholine-4-carboxylic acid 4-heptylsulfanyl-phenyl ester,
    Morpholine-4-carboxylic acid 4-butoxy-phenyl ester,
    Morpholine-4-carboxylic acid 4-(4-chloro-benzenesulfonyl)-phenyl ester,
    Morpholine-4-carboxylic acid 4-(4-chloromethyl-thiazol-2-yl)-phenyl ester
    Morpholine-4-carboxylic acid 4-(4,4-dimethyl-2,6-dioxo-piperidin-1-yl)-phenyl ester,
    cis-Morpholine-4-carboxylic acid 4-(1,3-dioxo-octahydro-isoindol-2-yl)-phenyl ester,
    Morpholine-4-carboxylic acid 4-(cyclohexanecarbonyl-amino)-phenyl ester,
    Morpholine-4-carboxylic acid 4-(2-cyclohexyl-acetylamino)-phenyl ester,
    cis/trans-Morpholine-4-carboxylic acid 4-[(4-tert-butyl-cyclohexanecarbonyl)-amino]-phenyl ester,
    cis-Morpholine-4-carboxylic acid 4-[(4-tert-butyl-cyclohexanecarbonyl)-amino]-phenyl ester,
    trans-Morpholine-4-carboxylic acid 4-[(4-tert-butyl-cyclohexanecarbonyl)-amino]-phenyl ester,
    Morpholine-4-carboxylic acid 4-(3,3-dimethyl-butyrylamino)-phenyl ester,
    Morpholine-4-carboxylic acid 3-benzyl-4-methyl-2-oxo-2H-chromen-7-yl ester,
    Morpholine-4-carboxylic acid 3-(3,4-dichloro-benzyl)-4-methyl-2-oxo-2H-chromen-7-yl ester,
    Morpholine-4-carboxylic acid 3-(2-chloro-6-fluoro-benzyl)-4-methyl-2-oxo-2H-chromen-7-yl ester,
    Morpholine-4-carboxylic acid 3-(2,6-dichloro-benzyl)-4-methyl-2-oxo-2H-chromen-7-yl ester,
    Morpholine-4-carboxylic acid 3-(2,6-dichloro-benzyl)-6-chloro-4-methyl-2-oxo-2H-chromen-7-yl ester,
    Morpholine-4-carboxylic acid 6-chloro-3-(2-chloro-6-fluoro-benzyl)-4-n-propyl-2-oxo-2H -chromen-7-yl ester,
    Morpholine-4-carboxylic acid 3-(4-methoxy-phenyl)-4-methyl-2-oxo-2H-chromen-7-yl ester,
    Morpholine-4-carboxylic acid 4-methyl-2-oxo-3-phenyl-2H-chromen-7-yl ester,
    Morpholine-4-carboxylic acid 3-(2,5-dimethoxy-phenyl)-4-methyl-2-oxo-2H-chromen-7-yl ester,
    Morpholine-4-carboxylic acid 3-(3,4-dimethoxy-phenyl)-4-methyl-2-oxo-2H-chromen-7-yl ester,
    Morpholine-4-carboxylic acid 4-(5,7-bis-trifluoromethyl-[1,8]naphthypyridin-2-yloxy)-phenyl ester,
    Morpholine-4-carboxylic acid 4-pyrrolidine-1-yl-phenyl ester,
    Morpholine-4-carboxylic acid 4-piperidine-1-yl-phenyl ester,
    Morpholine-4-carboxylic acid 4-morpholine-1-yl-phenyl ester,
    Morpholine-4-carboxylic acid 4-[(6-chloro-pyridine-3-carbonyl)-amino]-phenyl ester,
    Morpholine-4-carboxylic acid 4-[(6-chloro-pyridine-3-carbonyl)-amino]-phenyl ester,
    Morpholine-4-carboxylic acid 4-[(pyridine-2-carbonyl)-amino]-phenyl ester,
    2.6-dimethyl-morpholine-4-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester,
    Morpholine-4-carboxylic acid pyrazol-1-yl ester,
    Morpholine-4-carboxylic acid 3-bromo-pyrazol-1-yl ester,
    Morpholine-4-carboxylic acid 4-bromo-pyrazol-1-yl ester,
    Morpholine-4-carboxylic acid 5-bromo-pyrazol-1-yl ester,
    Morpholine-4-carboxylic acid 3,4,5-tribromo-pyrazol-1-yl ester,
    Morpholine-4-carboxylic acid 4-chloro-pyrazol-1-yl ester,
    Morpholine-4-carboxylic acid 4-iodo-pyrazol-1-yl ester,
    Morpholine-4-carboxylic acid 3-(4-methoxy-phenyl)-pyrazol-1-yl ester,
    Morpholine-4-carboxylic acid 3-(2-methoxy-phenyl)-pyrazol-1-yl ester,
    Morpholine-4-carboxylic acid 3-(4-nitro-phenyl)-pyrazol-1-yl ester,
    Morpholine-4-carboxylic acid 3-(2-fluoro-phenyl)-pyrazol-1-yl ester,
    Morpholine-4-carboxylic acid 3-pyridin-2-yl-pyrazol-1-yl ester,
    Morpholine-4-carboxylic acid 4-phenylsulfanyl-pyrazol-1-yl ester,
    Morpholine-4-carboxylic acid 3-thiophen-2-yl-pyrazol-1-yl ester,
    Morpholine-4-carboxylic acid 5-thiophen-2-yl-pyrazol-1-yl ester,
    Morpholine-4-carboxylic acid imidazol-1-yl ester,
    Morpholine-4-carboxylic acid 2-chloro-imidazol-1-yl ester,
    Morpholine-4-carboxylic acid 2-bromo-imidazol-1-yl ester,
    Morpholine-4-carboxylic acid 2-iodo-imidazol-1-yl ester,
    Morpholine-4-carboxylic acid 2-methyl-imidazol-1-yl ester,
    Morpholine-4-carboxylic acid 2-phenylsulfanyl-imidazol-1-yl ester,
    Morpholine-4-carboxylic acid 2-(4-methoxy-phenyl)-imidazol-1-yl ester,
    Morpholine-4-carboxylic acid 2-(4-fluoro-phenyl)-imidazol-1-yl ester,
    Morpholine-4-carboxylic acid 2-thiophen-2-yl-imidazol-1-yl ester,
    Morpholine-4-carboxylic acid 2-pyridin-2-yl-imidazol-1-yl ester
    Morpholine-4-carboxylic acid 2,5-dichloro-imidazol-1-yl ester,
    Morpholine-4-carboxylic acid 4-bromo-2,5-dichloro-imidazol-1-yl ester,
    Morpholine-4-carboxylic acid 4-bromo-2-chloro-imidazol-1-yl ester,
    Morpholine-4-carboxylic acid 5-(4-methoxy-phenyl)-imidazol-1-yl ester,
    Morpholine-4-carboxylic acid 5-(4-fluoro-phenyl)-imidazol-1-yl ester,
    Morpholine-4-carboxylic acid 5-thiophen-2-yl-imidazol-1-yl ester,
    Morpholine-4-carboxylic acid 5-pyridin-2-yl-imidazol-1-yl ester,
    Morpholine-4-carboxylic acid 4-trifluoromethyl-pyrimidin-2-yl ester,
    Morpholine-4-carboxylic acid 4-trifluoromethyl-pyrimidin-2-yl ester,
    Morpholine-4-carboxylic acid imidazol-1-yl ester,
    Morpholine-4-carboxylic acid 2-bromo-imidazol-1-yl ester,
    Morpholine-4-carboxylic acid 2-chloro-imidazol-1-yl ester,
    Morpholine-4-carboxylic acid 2-phenylsulfanyl-imidazol-1-yl ester,
    Morpholine-4-carboxylic acid 2-(4-methoxy-phenyl)-imidazol-1-yl ester,
    Morpholine-4-carboxylic acid 4-bromo-pyrazol-1-yl ester,
    Morpholine-4-carboxylic acid 4-iodo-pyrazol-1-yl ester,
    Morpholine-4-carboxylic acid 3,4,5-tribromo-pyrazol-1-yl ester,
    Morpholine-4-carboxylic acid 3-(4-methoxy-phenyl)-pyrazol-1-yl ester,
    Morpholine-4-carboxylic acid 3-thiophen-2-yl-pyrazol-1-yl ester,
    Morpholine-4-carboxylic acid pyrazol-1-yl ester, and
    1-Oxo-1λ4-thiomorpholine-4-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester


Further examples of specific compounds of the invention are:

    Methyl-o-tolyl-carbamic acid 4-iodo-pyrazol-1-yl ester,
    Methyl-m-tolyl-carbamic acid 4-iodo-pyrazol-1-yl ester,Methyl-p-tolyl-carbamic acid 4-iodo -pyrazol-1-yl ester,
    (3-Chloro-phenyl)-methyl-carbamic acid 4-iodo-pyrazol-1-yl ester,
    (3-Fluoro-phenyl)-methyl-carbamic acid 4-iodo-pyrazol-1-yl ester,
    4-(3-Trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic acid 4-iodo-pyrazol-1-yl ester,
    2,6-Dimethyl-morpholine-4-carboxylic acid 4-iodo-pyrazol-1-yl ester,
    Thiomorpholine-4-carboxylic acid 4-iodo-pyrazol-1-yl ester,
    3,5-Dimethyl-morpholine-4-carboxylic acid 4-iodo-pyrazol-1-yl ester,
    Piperidine-1-carboxylic acid 4-iodo-pyrazol-1-yl ester,
    Methyl-o-tolyl-carbamic acid 2-chloro-imidazol-1-yl ester,
    (3-Fluoro-phenyl)-methyl-carbamic acid 2-chloro-imidazol-1-yl ester, and
    Methyl-phenyl-carbamic acid 5-phenylsulfanyl-pyrazol-1-yl ester.


Further examples of compounds of the invention are:

    N-Methyl-N-phenyl-5-hexylsulfanyl-3-p-tolyl-[1,2,4]triazole-1-carboxamide,
    N-Methyl-N-phenethyl-5-ethyl-3-(4-chlorophenyl)-[1,2,4]triazole-1-carboxamide,
    [3-(4-Chlorophenyl)-5-methylsulfanyl-[1,2,4]triazol-1-yl]-morpholin-4-yl-methanone,
    N,N-Dimethyl-5-methylsulfanyl-3-naphthalen-2-yl-[1,2,4]triazole-1-carboxamide,
    N,N-Dimethyl-3-(4-chloro-phenyl)-5-ethylsulfanyl-[1,2,4]triazole-1-carboxamide, and
    N,N-Dimethyl-3-biphenyl-4-yl-5-methylsulfanyl-[1,2,4]triazole-1-carboxamide.


The present invention also encompasses compounds of formulae I-XXXXVIII, which possess a range of pharmaceutically desirable properties.
In one embodiment, the invention is concerned with compounds of formulae I-XXXXVIII, which have a solubility in water of at least 0.5 mg/L, preferably at least 2 mg/L, more preferable at least 10 mg/L, more preferable at least 50 mg/L and most preferable at least 200 mg/L as determined at 25° C. and pH 7.0.
In another embodiment, the invention is concerned with compounds of formulae I-XXXXVIII, which have a solubility in water of at least 0.5 mg/L, preferably at least 2 mg/L, more preferable at least 10 mg/L, more preferable at least 50 mg/L and most preferable at least 200 mg/L as determined at 25° C. and pH 2.0.
In another embodiment, the invention is concerned with compounds of formulae I-XXXXVIII, which have an IC50 value of no greater than 5 μM as determined by the assay 3190.2 or 3180.1 disclosed herein.
In another embodiment, the invention is concerned with compounds of formulae I-XXXXVIII, which have an IC50 value of less than 1 μM, preferably less than 500 nM, preferably less than 100 nM, preferably less than 50 nM, more preferable less than 25 nM, more preferable less than 10 nM and even more preferable less than 5 nM as determined by the assay 3190.2 or 3180.1 disclosed herein.
In another embodiment, the invention is concerned with compounds of formulae I-XXXXVIII, which are ionized at pH 7.0.
In another embodiment, the invention is concerned with compounds of formulae I-XXXXVIII, which have a pKa in the range from 8 to 12, preferable from 9 to 12, more preferable from 10 to 12.
In another embodiment, the invention is concerned with compounds of formulae I-XXXXVIII, which have a molar weight of no greater than 1000 D.
In another embodiment, the invention is concerned with compounds of formulae I-XXXXVIII, which have a molar weight of less than 750 D, preferably less than 500 D, more preferable less than 400 D, more preferable less than 300D and even more preferably less than 250 D.
In another aspect the present invention relates to the use of a compound of the general formula I




wherein R1 is selected from hydrogen, C1-6-alkyl, C2-6-alkenyl and C3-10-cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano and nitro; and

    R2 is selected from C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, perhalomethyl and perhalomethoxy; and
    wherein R2 is optionally covalently bound to R1 by an ether, thioether, C—C or C—N bond, to form a ring system with the N-atom to which R1 and R2 are bound; and
    X is O or S; and
    L is a group such that —C(═X)-L is a hydrolysable group; or
    a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or any tautomeric forms, stereoisomers, mixture of stereoisomers including a racemic mixture, or polymorphs
    for inhibition of the lipolytic activity of hormone-sensitive lipase against triacylglycerols, diacylglycerols, cholesterol acyl esters or steroid acyl esters.


Another aspect of the invention relates to use of a compound of the general formula I




    wherein R1 is selected from hydrogen, C1-6-alkyl, C2-6-alkenyl and C3-10-cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano and nitro; and
    R2 is selected from C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, perhalomethyl and perhalomethoxy; and
    wherein R2 is optionally covalently bound to R1 by an ether, thioether, C—C or C—N bond, to form a ring system with the N-atom to which R1 and R2 are bound; and
    X is O or S; and
    L is a group such that —C(═X)-L is a hydrolysable group; or
    a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or any tautomeric forms, stereoisomers, mixture of stereoisomers including a racemic mixture, or polymorphs for the preparation of a medicament for the treatment of any disorder where it is desirable to
    modulate the plasma level of free fatty acids, glycerol, LDL-cholesterol, HDL-cholesterol, insulin and/or glucose; and/or
    modulate intracellular triacylglycerol and cholesterol ester stores, intracellular level of fatty acids, fatty acid esters such as diacylglycerols, phosphatidic acids, long chain acyl-CoA's as well as citrate or malonyl-CoA; and/or
    increase insulin sensitivity in adipose tissue, skeletal muscle, liver or pancreatic β cells; and/or
    modulate insulin secretion from pancreatic β cells.


Another aspect of the invention is the use of a compound of the general formula I for the preparation of a pharmaceutical medicament.
In one embodiment the present invention relates to the use of a compound of the general formula (I) for the preparation of a medicament for the treatment of insulin resistance, diabetes type 1, diabetes type 2, metabolic syndrome X, impaired glucose tolerance, hyperglycemia, dyslipidemia, obesity, abnormalities of lipoprotein metabolism and any combination thereof.
Another aspect of the invention is pharmaceutical compositions comprising a compound of formula I




wherein R1 is selected from hydrogen, C1-6-alkyl, C2-6-alkenyl and C3-10-cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano and nitro; and

    R2 is selected from C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, perhalomethyl and perhalomethoxy; and
    wherein R2 is optionally covalently bound to R1 by an ether, thioether, C—C or C—N bond, to form a ring system with the N-atom to which R1 and R2 are bound; and
    X is O or S; and
    L is a group such that —C(═X)-L is a hydrolysable group; or
    a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or any tautomeric forms, stereoisomers, mixture of stereoisomers including a racemic mixture, or polymorphs.


In another embodiment, the invention is concerned with pharmaceutical compositions containing a compound of formula (I) and uses of the compounds of formula (1), wherein X is O. In another embodiment, the invention is concerned with pharmaceutical compositions comprising a compound of formula (I) and uses of the compounds of formula (1), wherein X is O.
In another embodiment, the invention is concerned with pharmaceutical compositions containing a compound of formula (I) and uses of the compounds of formula (I), wherein the group L contains an O, via which L is bound to the C in formula (I).
In another embodiment, the invention is concerned with pharmaceutical compositions comprising a compound of formula (I) and uses of the compounds of formula (I), wherein the group L contains an O, via which L is bound to the C in formula (I).
In another embodiment, the invention is concerned with pharmaceutical compositions containing a compound of formula (I) and uses of the compounds of formula (I), wherein the group L contains a N, via which L is bound to the C in formula (I).
In another embodiment, the invention is concerned with pharmaceutical compositions comprising a compound of formula (I) and uses of the compounds of formula (I), wherein the group L contains a N, via which L is bound to the C in formula (I).
In another embodiment, the invention is concerned with pharmaceutical compositions containing a compound of formula (I) and uses-of the-compounds of formula (I), wherein the group L is selected from the group consisting of













wherein Y is O or S; and

Ra1, Ra2, Ra3, Ra4, Ra5 and Ra6 are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, or C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8 heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, perhalomethyl and perhalomethoxy.
In another embodiment, the invention is concerned with pharmaceutical compositions containing a compound of formula (I) and uses of the compounds of formula (I), wherein at least one of Ra1, Ra2, Ra3, Ra4, Ra5 and Ra6 is F.
In another embodiment, the invention is concerned with pharmaceutical compositions containing a compound of formula (I) and uses of the compounds of formula (I), wherein the group L is an optionally substituted —O-phenyl, via which L is bound to the C in formula (I). In another embodiment, the invention is concerned with pharmaceutical compositions containing a compound of formula (I) and uses of the compounds of formula (I), wherein R1 and R2 are covalently bound to each other so that the group R1—N—R2 forms a piperazine, said piparazine being bound to the C in formula (I).
In another embodiment, the invention is concerned with pharmaceutical compositions containing a compound of formula (I) and uses of the compounds of formula (I), wherein R1 and R2 are covalently bound to each other so that the group R1—N—R2 forms a piperedine, said piperidine being bound to the C in formula (I).
In another embodiment, the invention is concerned with pharmaceutical compositions containing a compound of formula (I) and uses of the compounds of formula (I), wherein R1 is selected from the group consisting of C1-6-alkyl, C2-6-alkenyl and C3-10-cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano and nitro.
In another embodiment, the invention is concerned with pharmaceutical compositions containing a compound of formula (I) and uses of the compounds of formula (I), wherein R1 is methyl.
In yet another embodiment, the invention is concerned with pharmaceutical compositions containing a compound of formula (I) and uses of the compounds of formula (I), wherein R1 is phenyl.
In another embodiment, the invention is concerned with pharmaceutical compositions containing a compound of formula (I) and uses of the compounds of formula (I), wherein R2 is a heteroaryl.
In another embodiment, the invention is concerned with pharmaceutical compositions containing a compound of formula (I) and uses of the compounds of formula (I), wherein R1 is methyl and R2 is phenyl.
In another embodiment, the invention is concerned with pharmaceutical compositions containing a compound of formula (I) and uses of the compounds of formula (I), wherein the group L is anoptionally substituted —O-phenyl via which L is bound to the C in formula (I), and R1 and R2 are covalently bound to each other so that the group R1—N—R2 forms a piparazine, said piparazine being bound to the C in formula (I).
In another embodiment, the invention is concerned with pharmaceutical compositions containing a compound of formula (I) and uses of the compounds of formula (I), wherein the group L is an optionally substituted —O-phenyl via which L is bound to the C in formula (I),

    and R1 and R2 are covalently bound to each other so that the group R1—N—R2 forms a piperedine, said piperedine being bound to the C in formula (I).


In another embodiment, the invention is concerned with pharmaceutical compositions containing a compound of formula (I) and uses of the compounds of formula (I), wherein the group L is an optionally substituted —O-phenyl via which L is bound to the C in formula (I), and R1 is methyl and R2 is phenyl.
In another embodiment, the invention is concerned with pharmaceutical compositions containing a compound of formula (I) and uses of the compounds of formula (I), wherein pKa of the group L is between 4 and 12, between 6 and 12, between 7 and 12, between 8 and 12, preferably between 8.5 to 11.5, and most preferable between 9.0 to 11.0.
In another embodiment, the invention is concerned with pharmaceutical compositions containing the compounds of formula (I) and uses of the compounds of formula (I), wherein administration of said compound is by oral administration
In another embodiment, the invention is concerned with pharmaceutical compositions containing the compounds of formula (I) and uses of the compounds of formula (I), the nasal, transdermal, pulmonal, or parenteral route.
Another aspect of the invention is a method of treating any disorder where it is desirable to inhibit the lipolytic activity of hormone-sensitive lipase against triacylglycerols, diacylglycerols, cholesterol acyl esters or steroid acyl esters, wherein said method comprises the use as described above.
In another embodiment, the invention is concerned with a method of treating any disorder where it is desirable to modulate the plasma level of free fatty acids or to modulate the handling, storage and oxidation of intracellular fatty acid and cholesterol, wherein said method comprises the use as described above.
In another embodiment, the invention is concerned with said method, wherein said disorder is selected from the group consisting of insulin resistance, diabetes type 1, diabetes type 2, metabolic syndrome X, impaired glucose tolerance, hyperglycemia, dyslipidemia, obesity, abnormalities of lipoprotein metabolism and any combination thereof.
In another aspect the invention is concerned with a process for the preparation of a compound of formulae I-XXXXVIII or their pharmaceutically acceptable salts, which process comprises reacting the appropriate alcohol, Rz-OH, with the appropriate carbamoylating reagent, Lv-C(═O)—NRxRy, in a solvent according to the reaction scheme P1




and isolating the disubstituted carbamate product.

In one embodiment, the invention is concerned with process P1, wherein said carbamoylating reagent




is selected from the group consisting of





In another embodiment, the invention is concerned with the process of scheme P1, wherein said solvent is selected from the group consisting of tetrahydrofurane, dimethylformamide and N-methylpyrolidone.
In another embodiment, the invention is concerned with the process of scheme P1, wherein said base is selected from the group consisting of triethylamine, N,N-diisopropyl-N-ethylamine and DABCO.
In another aspect the invention is concerned with a process for the preparation of a compound according to the general formula




wherein R1 is selected from C1-6-alkyl, C2-6-alkenyl and C3-10-cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano and nitro; and

    R2 is selected from C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8 heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, perhalomethyl and perhalomethoxy; and
    wherein R2 is optionally covalently bound to R1 by an ether, thioether, C—C or C—N bond, to form a ring system with the N-atom to which R1 and R2 are bound; and
    R3 is selected from hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, perhalomethyl and perhalomethoxy; and
    X is O or S; or
    a compound according to any one of formulae III-XXXXVIII; or
    a pharmaceutically acceptable salt thereof;
    said process comprising the treatment of the appropriate amine, R1—NH—R2, with the appropriate acylating reagent, Y—C(═X)—R3, in a solvent and in the presence of a base according to the reaction scheme P2






In one embodiment, the invention is concerned with the process of scheme P2, wherein Y is Cl.
In another embodiment, the invention is concerned with the process of scheme P2, wherein R3 is an aryloxy group.
In another embodiment, the invention is concerned with the process of scheme P2, wherein said solvent is selected from the group consisting of diethyl ether, tetrahydrofuran and dichloromethane.
In another embodiment, the invention is concerned with the process of scheme P2, wherein said base is selected from the group consisting of trimethylamine, triethylamine, ethyl-diisopropyl-amine and 1,4-diazabicyclo[2.2.2]octane.
In another embodiment, the invention is concerned with the process of scheme P2, wherein said base is present as a functionality in one or both of the substituents R1 and R2, thus forming a salt with the acid H—Y.
In another aspect the invention is concerned with a pharmaceutical composition comprising a compound of formulae I-XXXXVIII or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
In one embodiment the invention is concerned with a pharmaceutical composition, wherein said composition is in unit dosage form, comprising from about 0.05 to about 2000 mg, preferably from about 0.1 to about 500 mg and even more preferable from about 1.0 to about 100 mg of a compound of formulae I-XXXXVIII or a pharmaceutically acceptable salt thereof.
In another embodiment the invention is concerned with a pharmaceutical composition for use as a medicament for inhibiting the lipolytic activity of hormone-sensitive lipase against triacylglycerols, diacylglycerols, cholesterol acyl esters or steroid acyl esters, said composition comprising a compound of any one of formulae I-XXXXVIII or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
In another embodiment the invention is concerned with a pharmaceutical composition for oral, nasal, transdermal, pulmonal, or parenteral administration.
In another aspect the invention is concerned with use of a compound according to any one of formulae I-XXXXVIII for preparation of a medicament for inhibition of the lipolytic activity of hormone-sensitive lipase against triacylglycerols, diacylglycerols, cholesterol acyl esters or steroid acyl esters.
In one embodiment the invention is concerned with said use, wherein a further antidiabetic, antiobesity, antihypertensive or appetite regulating drug is used.
In another aspect the invention is concerned with use of a compound according to any one of formulae I-XXXXVIII for the preparation of a medicament for the treatment of any disorder where it is desirable to

    modulate the plasma level of free fatty acids, glycerol, LDL-cholesterol, HDL-cholesterol, insulin and/or glucose; and/or
    modulate intracellular triacylglycerol and cholesterol ester stores, intracellular level of fatty acids, fatty acid esters such as diacylglycerols, phosphatidic acids, long chain acyl-CoA's as well as citrate or malonyl-CoA; and/or
    increase insulin sensitivity in adipose tissue, skeletal muscle, liver or pancreatic β cells; and/or
    modulate insulin secretion from pancreatic β cells.


In one embodiment the invention is concerned with said use, wherein said disorder is selected from the group consisting of insulin resistance, diabetes type 1 and 2, metabolic syndrome X, impaired glucose tolerance, hyperglycemia, dyslipidemia, obesity, abnormalities of lipoprotein metabolism and any combination thereof.
In another aspect the invention is concerned with use of a compound according to any one of formulae I-XXXXVIII or a pharmaceutically acceptable salt thereof for the preparation of a medicament.
In another aspect the invention is concerned with a method of treating a disorder of a patient where modulation of the activity of hormone-sensitive lipase is desired, the method comprising administering to said patient an effective amount of a compound according to any one of formulae I-XXXXVIII or a pharmaceutically acceptable salt thereof.
In one embodiment the invention is concerned with said method, wherein said administration is carried out by the oral, nasal, transdermal, pulmonal, or parenteral route.
In another embodiment the invention is concerned with said method, wherein said disorder is selected from the group consisting of insulin resistance, diabetes type 1 and 2, metabolic syndrome X, impaired glucose tolerance, hyperglycemia, dyslipidemia, obesity, abnormalities of lipoprotein metabolism and any combination thereof.
In another embodiment the invention is concerned with said method, wherein a further antidiabetic, antiobesity, antihypertensive or appetite regulating drug is administered to the patient.
The present invention also encompasses pharmaceutically acceptable salts of the present 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 acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, sulphates, nitrates, phosphates, perchlorates, borates, acetates, benzoates, hydroxynaphthoates, glycerophosphates, ketoglutarates and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference. Examples of metal salts include lithium, sodium, potassium, magnesium, zinc, calcium salts and the like. Examples of amines and organic amines include ammonium, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, propylamine, butylamine, tetramethylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, 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.
The pharmaceutically acceptable salts are prepared by reacting the compound of formulae I-XXXXVIII with 1 to 4 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixture of solvents may be used. Organic bases like lysine, arginine, diethanolamine, choline, guandine and their derivatives etc. may also be used. Alternatively, acid addition salts wherever applicable are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic 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 in solvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane etc. Mixture of solvents may also be used.
The stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by resolving the mixture of stereoisomers by conventional methods. Some of the preferred methods include use of microbial resolution, enzymatic resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like wherever applicable or chiral bases such as brucine, (R)- or (S)-phenylethylamine, cinchona alkaloids and their derivatives and the like. Commonly used methods are compiled by Jaques et al in “Enantiomers, Racemates and Resolution” (Wiley Interscience, 1981). More specifically the compound of formula I may be converted to a 1:1 mixture of diastereomeric amides by treating with chiral amines, aminoacids, aminoalcohols derived from aminoacids; conventional reaction conditions may be employed to convert acid into an amide; the dia-stereomers may be separated either by fractional crystallization or chromatography and the stereoisomers of compound of formulae I-XXXXVIII may be prepared by hydrolysing the pure diastereomeric amide.
Various polymorphs of compound of general formulae I-XXXXVIII forming part of this invention may be prepared by crystallization of compound of formulae I-XXXXVIII under different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast 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 present compounds, which on administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances. In general, such prodrugs will be functional derivatives of the present compounds, which are readily convertible in vivo into the required compound of the formulae I-XXXXVIII. Conventional 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 encompasses active metabolites of the present compounds.
The invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one compound of the formula I or any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers or diluents. Furthermore, the invention relates to the use of compounds of the general formulae I-XXXXVIII or their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof for the preparation of a pharmaceutical composition for the treatment and/or prevention of disorders where a decreased level of plasma FFA is desirable, such as the conditions mentioned above. In another aspect, the present invention relates to a method of treating and/or preventing type 2 diabetes, insulin resistance, metabolic syndrome X, impaired glucose tolerance, dyslipidemia and abnormalities of lipoprotein metabolism.
In a still further aspect, the present invention relates to the use of one or more compounds of the general formulae I-XXXXVIII, or pharmaceutically acceptable salts thereof, for the preparation of a pharmaceutical composition for the treatment and/or prevention of type 2 diabetes, insulin resistance, metabolic syndrome X, impaired glucose tolerance, dyslipidemia and abnormalities of lipoprotein metabolism.
In a still further aspect, the present compounds are useful for the delaying or prevention of the progression from impaired glucose tolerance to type 2 diabetes.
In a still further aspect, the present compounds are useful for the delaying or prevention of the progression from non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes.
In another aspect, the present compounds reduce triglyceride levels and are accordingly useful for the treatment and/or prevention of ailments and disorders such as diabetes and/or obesity.
In still another aspect, the compounds of general formulae I-XXXXVIII are useful for the treatment of hyperglycemia, elevated HbA1c level, hyperinsulinemia, type 1.5 diabetes, latent autoimmune diabetes in adults, maturity onset diabetes, beta-cell apoptosis, hemochromatosis induced diabetes, impaired glucose tolerance, impaired fasting glucose, metabolic syndrome X, insulin resistance, impaired lipid tolerance, cystic fibrosis related diabetes, polycystic ovarian syndrome, and gestational diabetes.
In still another aspect, the compounds of general formulae I-XXXXVIII are useful for the treatment of obesity, dyslipidemia, diabetic dyslipidemia, hyperlipidemia, hypertriglyceridemia, hyperlipoproteinemia, hypercholesterolemia, hypertension, essential hypertension, acute hypertensive emergency, arteriosclerosis, atherosclerosis, restenosis, intermittent claudication (atherosclerosis oblitterens), cardiovascular disease, cardiomyopathy, cardiac hypertrophy, left ventricular hypertrophy, coronary artery disease, early coronary artery disease, heart insufficiency, exercise tolerance, chronic heart failure, mild chronic heart failure, arrhythmia, cardiac dysrythmia, syncopy, heart attack, myocardial infarction, Q-wave myocardial infarction, stroke, acute coronary syndrome, angina pectoris, unstable angina, cardiac bypass reocclusion, diastolic dysfunction, systolic dysfunction, non-Q-wave, cardiac necrosis, catabolic changes after surgery, acute pancreatitis, and irritable bowel syndrome
In still another aspect, the compounds of general formulae I-XXXXVIII may be useful for the treatment of diabetic retinopathy, background retinopathy, preproliferative retinopathy, proliferative retinopathy, macular edema, cataracts, nephropathy, nephrotic syndrome, diabetic nephropathy, microalbuminuria, macroalbuminuria, neuropathy, diabetic neuropathy, distal symmetrical sensorimotor polyneuropathy, and diabetic autonomic neuropathy.
In still another aspect, the compounds of general formulae I-XXXXVIII are useful for increasing the number of beta-cells in a patient, increasing the size of beta-cells in a patient or stimulating beta-cell proliferation, modulating beta-cell function and insulin secretion in a patient in need thereof, which method comprises administration of an effective amount of a compound of formulae I-XXXXVIII to a patient in need thereof.
The compounds of the invention are also believed to be useful for reducing body weight in a patient in need thereof.
The compounds of the invention are also believed to be useful Use for weight neutral treatment of above mentioned diseases.
The compounds of the invention are also believed to be useful for redistributing fat in a patient in need thereof.
The compounds of the invention are also believed to be useful for redistributing central fat in a patient in need thereof.
The compounds of the invention are also believed to be useful for reducing or preventing central obesity.
The compounds of the invention are also believed to be useful for reducing postprandial serum lipid excursions.
The compounds of the invention are also believed to be useful for the treatment of fatty acid oxidation disorders such as MCAD.
In still another aspect, the compounds of general formulae I-XXXXVIII are believed to be useful for the treatment of a disease, condition or disorder wherein cholesterol is a precursor. Such diseases, conditions or disorders may relate to testosterone, e.g. male contraception, excessive testosterone levels, PCOS and prostate cancer. They may also relate to cortisol or corticotropin, e.g. Cushing disease.
The compounds of the invention are also believed to be useful for the treatment of cancer. Thus, the compounds of the general formulae I-XXXXVIII may be useful for the treatment of insulinoma (pancreatic islet cell tumors), e.g. malignant insulinomas and multiple insulinomas, adipose cell carcinomas, e.g. lipocarconoma.
The compounds of the invention are also believed to be useful for the treatment of phaechromocytoma and other diseases with increased catecholamine incretion.
The compounds of the invention are also believed to be useful for the treatment of prostate cancer, e.g. adenocarcinoma.
In still another aspect, the compounds of general formulae I-XXXXVIII may be useful for the treatment of hepatic steatosis.
In still another aspect, the compounds of general formulae I-XXXXVIII may be useful for the treatment of cirrhosis.
In still another aspect, the compounds of general formulae I-XXXXVIII may be useful for the treatment of AIDS or an AIDS related diseases, condition or disorders
In still another aspect, the compounds of general formulae I-XXXXVIII may be useful for the treatment of lipodystrophy
In still another aspect, the compounds of general formulae I-XXXXVIII may be useful for the treatment of lactic acidosis.
In yet another aspect, the compounds of the present invention are expected to be useful for the treatment of CNS diseases, conditions or disorders.
Thus, the compound of the present invention may be used for the treatment of Parkinsons disease, Alzheimers disease, ADHD (Attention Deficit Hyperactivity Disorder), feeding disorders such as bulimia and anorexia, depression, anxiety, cognitive memory disorders, age related cognitive decline, mild cognitive impairment and schizophrenia.
In yet another aspect, the compounds of the present invention may be useful for the treatment of inflammatory disorders, e.g. rheumatoid arthritis, psoriasis, systemic inflammatory response syndrome, sepsis and the like.
The present compounds may also be administered in combination with one or more further pharmacologically active substances eg., selected from antiobesity agents, antidiabetics, antihypertensive agents, agents for the treatment and/or prevention of complications resulting from or associated with diabetes and agents for the treatment and/or prevention of complications and disorders resulting from or associated with obesity.
Thus, in a further aspect of the invention the present compounds may be administered in combination with one or more antiobesity agents or appetite regulating agents.
Such agents may be selected from the group consisting of CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melanocortin 4) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, β3 agonists, MSH (melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin re-uptake inhibitors, serotonin and noradrenaline re-uptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone releasing compounds, TRH (thyreotropin releasing hormone) agonists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DA agonists (bromocriptin, doprexin), lipase/amylase inhibitors, RXR (retinoid X receptor) modulators or TR β agonists.
In one embodiment of the invention the antiobesity agent is leptin.
In another embodiment the antiobesity agent is dexamphetamine or amphetamine.
In another embodiment the antiobesity agent is fenfluramine or dexfenfluramine.
In still another embodiment the antiobesity agent is sibutramine.
In a further embodiment the antiobesity agent is orlistat.
In another embodiment the antiobesity agent is mazindol or phentermine.
Suitable antidiabetics comprise insulin, exendin-4, GLP-1 (glucagon like peptide-1) derivatives such as those disclosed in WO 98/08871 to Novo Nordisk A/S, which is incorporated herein by reference as well as orally active hypoglycaemic agents.
The orally active hypoglycaemic agents preferably comprise sulphonylureas, biguamides, meglitinides, glucosidase inhibitors, glucagon antagonists such as those disclosed in WO 99/01423 to Novo Nordisk A/S and Agouron Pharmaceuticals, Inc., GLP-1 agonists, potassium channel openers such as those disclosed in WO 97/26265 and WO 99/03861 to Novo Nordisk A/S which are incorporated herein by reference, DPP-IV (dipeptidyl peptidase-IV) inhibitors, inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenolysis, glucose uptake modulators, compounds modifying the lipid metabolism such as antihyperlipidemic agents and antilipidemic agents as HMG CoA inhibitors (statins), compounds lowering food intake, RXR agonists and agents acting on the ATP-dependent potassium channel of the β-cells.
In one embodiment of the invention the present compounds are administered in combination with insulin.
In a further embodiment the present compounds are administered in combination with a sulphonylurea eg. tolbutamide, glibenclamide, glipizide or glicazide.
In another embodiment the present compounds are administered in combination with a biguamide eg. mefformin.
In yet another embodiment the present compounds are administered in combination with a meglitinide eg. repaglinide or senaglinide.
In a further embodiment the present compounds are administered in combination with an α-glucosidase inhibitor eg. miglitol or acarbose.
In another embodiment the present compounds are administered in combination with an agent acting on the ATP-dependent potassium channel of the β-cells eg. tolbutamide, glibenclamide, glipizide, glicazide or repaglinide.
Furthermore, the present compounds may be administered in combination with nateglinide.
In still another embodiment the present compounds are administered in combination with an antihyperlipidemic agent or antilipidemic agent eg. cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
In a further embodiment the present compounds are administered in combination with more than one of the above-mentioned compounds eg. in combination with a sulphonylurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, insulin, insulin and lovastatin, etc.
Furthermore, the present compounds may be administered in combination with one or more antihypertensive agents. Examples of antihypertensive agents are β-blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as benazepril, captopril, alatriopril, enalapril, fosinopril, lisinopril, quinapril and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and α-blockers such as doxazosin, urapidil, prazosin and terazosin. Further reference can be made to Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995. It should be understood that any suitable combination of the compounds according to the invention with one or more of the above-mentioned compounds and optionally one or more further pharmacologically active substances are considered to be within the scope of the present invention.
The present invention also relates to processes according to reaction schemes P1 and P2 for the preparation of the above said novel compounds, their derivatives, their analogs, their tautomeric forms their stereoisomers, their polymorphs, their pharmaceutically acceptable salts or pharmaceutically acceptable solvates.
Pharmaceutical Compositions.
The compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses. The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995. The compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
The pharmaceutical compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well-known in the art.
Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also contemplated as being within the scope of the present invention.
Other suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc.
The therapeutic dose of the compound will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art. 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 from about 0.05 to about 2000 mg, preferably from about 0.1 to about 500 mg of the compound of formula I pharmaceutically acceptable salt thereof.
In a still further embodiment the pharmaceutical composition is for oral, nasal, transdermal, pulmonal, or parenteral administration.
For parenteral routes, such as intravenous, intrathecal, intramuscular and similar administration, typically doses are in the order of about half the dose employed for oral administration.
The compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof. One example is an acid addition salt of a compound having the utility of a free base. When a compound of the invention contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of the compound with a chemical equivalent of a pharmaceutically acceptable acid, for example, inorganic and organic acids. Representative examples are mentioned above. Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as sodium or ammonium ion.
For parenteral administration, solutions of the present compounds in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be employed. Such aqueous solutions should be suitable buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed 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 solution and various organic solvents. Examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatine, lactose, terra alba, sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The formulations may also include welting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents.
The pharmaceutical compositions formed by combining the compounds of the invention and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. 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 presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. These formulations may be in the form of powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion.
If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
A typical tablet which may be prepared by conventional tabletting techniques may contain:

















Core:





Active compound (as free compound or salt thereof)
5
mg



Colloidal silicon dioxide (Aerosil)
1.5
mg



Cellulose, microcryst. (Avicel)
70
mg



Modified cellulose gum (Ac-Di-Sol)
7.5
mg



Magnesium stearate
q.s.



Coating:



HPMC approx.
9
mg



*Mywacett 9-40 T approx.
0.9
mg







*Acylated monoglyceride used as plasticizer for film coating.






The compounds of the invention may be administered to a patient which is a mammal, especially a human in need thereof. Such mammals-include also animals, both domestic animals, e.g. household pets, and non-domestic animals such as wildlife.
In a further aspect of the invention the present compounds may be administered in combination with further pharmacologically active substances e.g. an antidiabetic or other pharmacologically active material, including other compounds for the treatment and/or prevention of insulin resistance and diseases, wherein insulin resistance is the pathophysiological mechanism.
Furthermore, the compounds according to the invention may be administered in combination with antiobesity agents or appetite regulating agents.
EXAMPLES
General Methods
All reactions involving air-sensitive reagents were performed under nitrogen using syringe-septum cap techniques. The glassware were dried by heating with a heath-gun. MgSO4 were used to dry solutions. Solvents were removed in vacuo by rotary evaporation. Melting points were recorded on a Büchi 535, Bruker AMX 400 and Bruker DRX 300 instruments were used to record 1H NMR spectra at 400 and 300 MHz respectively with tetramethylsilane (TMS) as internal standard. Coupling constants (J) are given in Hz.
Materials
Test compounds were synthesized or when commercially available they were purchased from Specs, Maybridge, Comgenex, Peakdale or Bionet. For the synthesized compounds the procedure for synthesis and measured characteristics of the compound are stated in the example. All compounds for which no synthesis procedure is stated in the examples are commercially available and have been purchased, or were prepared by standard methods described in the literature.
N-methyl-phenethylcarbamoyl chloride was prepared from N-methyl-phenethylamine and phosgene using triethylamine as a base in dichloromethane. 1-Methyl-3-(morpholine-4-carbonyl)-3H-imidazol-1-ium iodide, 3-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-methyl-3H -imidazol-1-ium iodide and 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide was prepared as described by Batey, R. A., Tetrahedron Lett. 39, 1998, 6267.
1-Hydroxypyrazole was prepared as described in Begtrup, VedsØ, J. Chem. Soc. Perkin Trans 1, 1995, 243. 1-hydroxy-4-bromopyrazole was prepared as described in Balle et al., J. Org. Chem. 64,1999, 5366. 1-hydroxy-3-(4-methoxyphenyl)pyrazole was prepared as described in Eskildsen et al., J. Org. Chem. 2001 (in press). 1-hydroxyimidazole was prepared as described in Eriksen et al., J. Org. Chem. 63, 1998, 12. 1-hydroxy-1,2,3-triazole was prepared as described in Uhlmann et al., J. Org. Chem. 62, 1997, 9177.
2-Piperidin-4-ylmethyl-1,2,3,4-tetrahydro-isoquinoline, cyclohexyl-methyl-piperidin-4-ylmethyl-amine, methyl-phenethyl-piperidine-4-ylmethyl-amine, ethyl-piperidin-4-ylmethyl -piperidin-4-ylmethylamine, benzyl-methyl-piperidin-4-ylmethyl-amine, benzyl-ethyl-piperidin-4-ylmethyl-amine, methyl-piperidin-4-ylmethyl-piperidin-3-ylmethyl-amine, 1-piperidin-4-ylmethyl-piperidin-4-ol, 2-piperidin-4-ylmethyl-2,3-dihydro-1H-isoindole, cyclopropylmethyl -piperidin-4-ylmethyl-amine was prepared from 4-formylpiperidine-1-carboxylic acid tert. -butyl ester prepared as described by Ting, P. C. (Bioorg, Med. Chem. Lett, 11, 4, 491, 2001) and an appropriate amine by a reductive amination (general procedure 19).
Benzylpiperidine-4-yl-amine, methyl-piperidin-4-yl-(2-pyridin-2-yl-ethyl)-amine, cyclohexyl -methyl-piperidin-4-yl-amine, Isopropyl-methyl-piperidin-4-yl-amine, methyl-phenethyl -piperidin-4-yl-amine, methyl-piperidin-4-yl-pyridin-3-ylmethyl-amine, was prepared from 4-oxopiperidine-1-carboxylic acid tert-butyl ester by a standard reductive amination procedure as described by Mattson R. J. (J. Org. Chem. 55, 2552, 1990).
Cyclopropyl-piperidin-4-yl-pyridin-4-ylmethyl-amine was prepared from 4-(cyclopropyl-pyridin-4-ylmethyl-amino)-piperidine-1-carboxylic acid tert-butyl ester by a classical N-deprotection reaction (HCl (g) in diethyl ether or ethanol). 4-(Cyclopropyl-pyridin-4-ylmethyl-amino) -piperidine-1-carboxylic acid tert-butyl ester was prepared from 4-cyclopropylamino -piperidine-1-carboxylic acid tert-butyl ester and pyridine-4-yl-acetaldehyde by a classical reductive amination procedure as described by Mattson R. J. 4-Cyclopropylamino-piperidine-1-carboxylic acid tert-butyl ester was prepared from cyclopropylamine and 4-oxopiperidine-1-carboxylic acid tert-butyl ester by a standard reductive amination procedure as described by Mattson R. J. Cyclopropyl-(2-fluoro-benzyl)-piperidin-4-yl-amine, cyclopropyl-piperidin-4-yl-pyridin-3-ylmethyl-amine, cyclopropylmethyl-piperidin-4-yl-pyridin-3-ylmethyl-amine and cyclopropylmethyl-piperidin-4-yl-pyridin-4-ylmethyl-amine was prepared by a procedure similar to the one described for cyclopropyl-piperidin-4-yl-pyridin-4-ylmethyl-amine.
Chloroformates were synthesized from the appropriate phenols and phosgene or a phosgene substitute like e.g. trichloromethyl chloroformate as described in K onakahara, Ozaki, Sato, Gold, Synthesis 1993 (1) 103-106, except that the crude product was separated from the diisopropylethylamine hydrochloride by extraction with diethyl ether rather than with THF.
Non-commercial N-monosubstituted piperazines were prepared by alkylation (alkylation procedure as described in e.g. Masaguer, Ravina, Tetrahedron Lett. 1996, 37 (29) 5171-5174) of 1-Boc-piperazine, and subsequent removal of the Boc group under acidic conditions, e.g. by heating in a mixture of hydrochloric acid and ethanol. N-Monosubstituted homopiprazines and N-monosubstituted 2,5-diazabicyclo[2.2.1]heptanes were prepared in a similar manner.
Thin layer chromatography was performed on Merck DC-Alufolien, silica gel 60 F254 and components were visualized by UV254. Flash chromatography was performed using silica gel Merck 60 size 0.04-0-063 mm and a Quad 12/25 flash system.
Preparative HPLC (Method A).
The system consists of two Gilson 322 pumps equipped with 30 ml pump heads. A Gilson 215 combined autoinjector and fraction collector performs injection and fraction collection. Detection is performed with a Gilson Diode array detector.
Separation is performed on Waters Xterra columns 19.8 mm*100 mm, flow rate 25 ml/min. The most widely used gradient starts at 10% acetonitrile in water and ends after 11 min on 100% acetonitrile, the system is buffered by 0.01% TFA. In special cases the gradient is altered to fit the separation need.
Preparative HPLC (Method B)
HPLC Purification:
The following instrumentation is used:

    Gilson 306 Pump
    Gilson 806 Manometric module
    Gilson 811C Dynamic mixer
    Gilson UV/VIS-155
    Gilson 202 Fraction collector


The instrument is controlled by Gilson Unipoint software.
The HPLC pump is connected to two eluent reservoirs containing:

    A: 0.01% TFA in water
    B: 0.01% TFA in acetonitrile


The purification is performed at room temperature by injecting an appropriate volume of the sample (preferably 2 ml) onto the column, which is eluted with a gradient of acetonitrile.
The HPLC conditions and detector settings used are as follows:













Column:
Waters Xterra MS C-18 × 19 × 100 mm


Gradient:
50%-60% acetonitrile linearly during 12 min at 20 ml/min


Detection:
210 and 270 nm









Preparative HPLC (Method C)

The system consists of two Gilson 322 pumps equipped with 30 ml pump heads. Gilson manometric module 805. A Gilson 215 combined autoinjector and fraction collector performs injection and fraction collection. Detection is performed with a Gilson Diode array detector 170. A sample contain 25-100 mg of material dissolved in 0.5-2.0 ml of solvent (minimum water concentration: 10%).
Separation is performed on Waters Xterra, RP18 7 μm, columns 19 mm×150 mm, flow rate 15 ml/min (sample added with a flow rate of 5 ml/min for about 1 min). The most widely used gradient starts at 5% acetonitrile in water and ends after 14 min on 95% acetonitrile. This concentration is maintained for 6 min. The system is buffered with 0.05% TFA. In special cases the gradient is altered to fit the separation need. The pooled fractions are evaporated to dryness in vacuo.
HPLC-MS.
The following instrumentation was used:

    
    
        Hewlett Packard series 1100 G1312A Bin Pump
        Hewlett Packard series 1100 Column compartment
        Hewlett Packard series 1100 G1315A DAD diode array detector
        Hewlett Packard series 1100 MSD
    
    


The instrument was controlled by HP Chemstation software.
The HPLC pump was connected to two eluent reservoirs containing:
















A:
0.01% TFA in water



B:
0.01% TFA in acetonitrile










The analysis was performed at 40° C. by injecting an appropriate volume of the sample (preferably 1 μl) onto the column, which is eluted with a gradient of acetonitrile.
The HPLC conditions, detector settings and mass spectrometer settings which were used are as follows:













Column
Waters Xterra MS C-18 × 3 mm id


Gradient
10%-100% acetonitrile linear during 7.5 min at 1.0 ml/min


Detection
210 nm (analogue output from DAD)


MS
Ionisation mode API-ES, Scan 100-1000 amu step 0.1 amu









General Procedure 1

The phenol (1.0 mmol) was dissolved in tetrahydrofuran (15 ml) in a glass screw cap vessel, 1,4-diazabicyclo[2.2.2]octane (DABCO) (2.0 mmol) was added together with the respective carbamoyl chloride (2.0 mmol) at room temperature. The reaction mixture was shaken for 16 hours and poured into ethyl acetate (20 ml) and aqueous citric acid (5%; 20 ml). The organic phase was dried and evaporated to give the crude product.
General Procedure 2
The phenol (1.0 mmol) was dissolved in acetonitrile (15 ml) in a glass screw cap vessel. Triethylamine (1.0 mmol) was added together with the respective 1-methyl-3H-imidazol-1-ium iodide (1.0 mmol) at room temperature. The reaction mixture was shaken for 16-48 hours at 80° C., cooled to room temperature and evaporated. The evaporated reaction mixture was dissolved in dichloromethane (20 ml) and extracted with aqueous hydrogen chloride (0.1 M; 20 ml). The aqueous phase was extracted with dichloromethane (3×20 ml). The combined organic phases were dried and evaporated to give the crude product.
General Procedure 3
The respective phenol (1.0 mmol), 3H-imidazol-1-ium iodide (1.0 mmol) and triethylamine (1.0 mmol) in acetonitrile (3 ml) was heated at 50° C. overnight in a closed vial. The crude product was purified by flash column chromatography (SiO2, ethyl acetate/heptane) yielding the respective carbamate.
General Procedure 4
Carbonyidiimidazole (3.6 mmol) was suspended in THF (10 ml) and the appropriate secondary amine (3.0 mmol) was added. The reaction mixture was refluxed for 24 to 72 hours until no traces of amine could be detected. The reaction mixture was cooled to room temperature and the organic phase evaporated to give the crude product of high purity. The crude product was used without further purification.
General Procedure 5
The crude imidazole carboxamide (3.0 mmol) was dissolved in acetonitrile (10 ml) and methyl iodide (12 mmol.) was added at room temperature. The reaction mixture was stirred for 24 to 48 hours before the organic phase was evaporated to give the crude product, which was used without further purification.
General Procedure 6
The respective 1,2,4-(1H)-triazoles were prepared as described by Blaine (U.S. Pat. No. 3,308,131).
The 1,2,3-(1H)-triazoles were carbamoylated using the following method:
The respective 1,2,4-(1H)-triazole (2.0 mmol) was dissolved in dimethylformamide (10 ml) in a glass screw cap vessel, 1,4-diazabicyclo[2.2.2]octane (DABCO) (5.0 mmol) was added together with the respective carbamoyl chloride (5.0 mmol) at room temperature. The reaction mixture was stirred for 16 hours, evaporated to dryness and ethyl acetate (20 ml) and aqueous citric acid (5%; 20 ml) was added. The phases were separated and the aqueous phase extracted with ethyl acetate (20 ml). The combined organic phases were dried and evaporated to give the crude product.
General Procedure 7
The aryl chloroformate was prepared from the corresponding phenol, trichloromethyl chloroformate and ethyldiisopropylamine in dichloromethane according to the procedure described by T. Konakahara, T. Ozaki, K. Sato and B. Gold, Synthesis, 1993 (1) 103-106, except that the crude reaction mixture was used without removal of ethyldiisopropylamine hydrochloride. To a stirred, freshly prepared solution of the aryl chloroformate in dichloromethane (1 mmol in 3 ml) at −15° C. was added a solution of the substituted piperazine (1 mmol) in dichloromethane (1 mL). The mixture was stirred at 0° C. for 2-6 h. The solvent was removed in vacuo and the solid residue was triturated with diethyl ether (3×5 ml), then with a minute amount of water (1⁄2-2 ml) to remove the ethyldiisopropylamine hydrochloride, filtered and dried to give the hydrochloride of the respective piperazine-1-carboxylic acid aryl ester.
General Procedure 8
To a solution of the N-hydroxyazole (1.0 mmol) and ethyldiisopropylamine (1.5 mmol) in CH2Cl2 (3 mL) was added the respective carbamoyl chloride (1.5 mmol) at room temperature. The reaction mixture was stirred for 16 hours, added CH2Cl2 (20 mL) and washed with aqueous citric acid (5%; 3×20 mL). The organic phase was separated, dried (MgSO4) and evaporated to give the crude product.
General Procedure 9
A solution of the substituted piperazine in diethyl ether is added to a stirred solution of an equimolar amount of the aryl chloroformate (prepared from the corresponding phenol by conventional methods) in the same solvent at 0° C. After completion of the addition, the mixture is stirred at 0° C. for 1 hour, then for 1 more hour at room temperature. The mixture is filtered, the filter cake rinsed with diethyl ether and dried to give the hydrochloride of the respective piperazine-1-carboxylic acid aryl ester.
General Procedure 10
A disubstituted amine (1.0 eq) and diisopropylethylamine (1.5 eq) was added to a dried reaction flask under nitrogen. Dichloromethane or tetrahydrofuran was added to give a 0.5 mM concentration of the amine. The appropriate aryl chloroformate (1.0 eq) (prepared from the corresponding phenol by conventional methods) was dissolved in a minimum amount of dichloromethane or tetrahydrofuran and added drop by drop at room temperature. The reaction mixture was stirred overnight, citric acid (5%) was added, and the two phases separated. The aqueous phase was extracted twice with dichloromethane, the combined organic phases were dried with MgSO4, filtered and evaporated to give the crude product.
General Procedure 11
An appropriate amine (1.0 eq.) was dissolved in dichloromethane (0.5 mM concentration of the amine) in a dried reaction flask under nitrogen. The appropriate aryl chloroformate (1.0 eq.) (prepared from the corresponding phenol by conventional methods) was dissolved in a minimum amount of dichloromethane and added drop by drop at room temperature. Heptane was added to give a 20% solution in dichloromethane and the crude product was isolated by filtration. The crude product was washed with a mixture of dichloromethane/heptane (5:1) and dried in vacuum.
General Procedure 12
An appropriate amine (1.0 eq.) and diisopropylethylamine (1.0 eq.) was dissolved in tetrahydrofuran (0.5 mM concentration of the amine) in a dried reaction flask under nitrogen. The appropriate aryl chloroformate (1.0 eq.) (prepared from the corresponding phenol by conventional methods) was dissolved in a minimum amount of tetrahydrofuran and added drop by drop at room temperature. Acetic acid was added to the reaction mixture (pH 3-5) and the reaction mixture filtered. The organic phase was evaporated and the crude product subjected to preparative HPLC.
General Procedure 13
4-(Methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester (1 eq.), diisopropylethylamine (1.5 eq.) was dissolved in tetrahydrofuran (50 mM of phenol).The reaction mixture was added to a mono or disubstituted amine. The reaction mixture was stirred at 50° C. for 16 hours. Citric acid (5%) and tert-butyl-methylether was added and the two phases separated. The organic phase was evaporated to give the crude product.
General Procedure 14
The phenol (1.0 mmol) was dissolved in tetrahydrofuran (15 ml) in a glass screw cap vessel, 1,4-diazabicyclo[2.2.2]octane (DABCO) (2.0 mmol) was added together with the respective carbamoyl chloride (2.0 mmol) at room temperature. The reaction mixture was shaken for 16 hours. Acetic acid was added to the reaction mixture (pH 3-5) and the reaction mixture filtered. The organic phase was evaporated and the crude product subjected to preparative HPLC.
General Procedure 15
A solution of the substituted piperazine in diethyl ether was added to a stirred solution of an equimolar amount of the aryl chloroformate in the same solvent at 0° C. After completion of the addition, the mixture was stirred at ambient temperature for 1-2 hours. Stirring was discontinued and as much as possible of the solvent was removed by decantation. The residue was rinsed twice with ether by stirring and subsequent decantation and finally dried on a rotary evaporator to give the hydrochloride of the respective piperazine-1-carboxylic acid aryl ester.
If necessary, further purification was achieved by treating the crude product with a mixture of ethyl acetate and a slight excess of sodium bicarbonate (approx. 1.1 eqv.) in water, extracting the aqueous phase twice with ethyl acetate, drying the combined extracts, filtering and evaporating to give the piperazine-1-carboxylic acid aryl ester as a free base.
General Procedure 16
To a solution of the N-hydroxyazole (1.0 mmol) and ethyldiisopropylamine (1.0 mmol) in CHCl3 (1 mL) at −30° C. was added trichloromethyl chloroformiate (1.1 mmol). The solution was stirred at −30° C. for 10 min and at room temperature for 1 h. The solution was evaporated to dryness at room temperature and redissolved in CHCl3 (2 mL) and cooled to −30° C. before addition of the appropriate piperazine (3 mmol). The solution was allowed to warm to room temperature over 30 min and evaporated to give the crude product.
General Procedure 17
To a suspention of N-methyl-N-phenyl-carbamic acid 4-(2-amino-ethyl)phenyl ester as its TFA salt (0.5 mmol) and an aryl sulfonyl chloride(0.75 mmol) in CH2Cl2 (2 mL) was added DIPEA (1.25 mmol). The reaction mixture was stirred at rt for 2-16 h, and evaporated to dryness and redissolved in MeCN and purified by preparative HPLC (Gilson).
General Procedure 18
A solution of the substituted piperazine in diethyl ether was added to a stirred solution of an equimolar amount of the aryl chloroformate in the same solvent at 0° C. Then an equimolar amount of diisopropylethylamine (DIPEA) in diethyl ether solution was added and the mixture was stirred at ambient temperature for 1-2 hours. The solvent was removed on a rotary evaporator and the residue was partitioned between ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were dried and filtered. Removal of the solvent gave the piperazine-1-carboxylic acid aryl ester.
General Procedure 19
4-Formyl-piperidine-1-carboxylic acid tert-butyl ester (1.5 g, 7.03 mmol) prepared as described by Ting, P. C. was added to a dryed screw cap wessel under nitrogen. The appropriate amine (7.03 mmol) methanol (10 ml) and acetic acid 100 (μl) was added and the reaction mixture was stirred for 2 h. at room temperature. Sodium cyanoborohydride (1.0 M sol. In THF, 4.7 ml) was added during 1 minute and the mixture was stirred for 16 h. at room temperature. The reaction mixture was evaporated to dryness and extracted with dichloromethane (3×75 ml) from a 10% aqueous sodium hydrogene carbonate solution (100 ml). The organic phases were pooled, dryed, and evaporated to dryness to give the crude intermediate, which was subjected to flash chromatography (ethyl acetate/heptane/methanole, 1:2:0→4:0:1).
A 3M solution of hydrogen chloride (50 ml) was added to the intermediate and the reaction mixture was stirred for 16 h. The reaction mixture was evaporated to dryness to give the crude product, which was dryed in vacuum. The crude product was used without without further purification.
General Procedure 20
The arylboronic acid (1.2 mmol), KF (3.3 mmol), Pd2(dba)3 (0.03 mmol) and Pd(P(t-Bu)3)2 (0.06 mmol) were added to a Schlenk tube under nitrogen. The Schlenk tube was evacuated and refilled with nitrogen five times. Next the aryl halide (1.0 mmol) in THF (2 mL) was added. The reaction mixture was stirred at rt for 16 h.
General Procedure 21
To a suspension of methyl-phenyl-carbamic acid 4-amino-phenyl ester (0.5 mmol), (see preparation below) and an aryl sulfonyl chloride (0.75 mmol) in CH2Cl2 (2 mL) was added DIPEA (1.25 mmol). The reaction mixture was stirred at rt for 2-16 h, and evaporated to dryness and redissolved in MeCN and purified by preparative HPLC (Gilson).
General Procedure 22
A solution of 1-benzyloxy-4-iodobenzene (4.1 mmol) in dry THF (20 mL) was cooled to −78° C. n-Butyllithium (1.57 M in hexanes, 4.1 mmol) was added during 2 min. After the mixture was stirred for another 5 min, an aryl aldehyde (4.1 mmol) was added. The mixture was allowed to warm to rt during 20 min and quenched with aqueous NaHCO3. Extraction with CH2Cl2, drying (MgSO4), filtration and evaporation provided the crude diarylmethanols which were recrystallised from EtOAc-heptane. A solution of the diarylmethanol product (2 mmol), NaI (14 mmol) in dry MeCN (20 mL) was added trimethylsilyl chloride (14 mmol) and stirred at 80° C. for 19 h. The purple reaction mixture was evaporated to dryness and treated with an aqueous solution of Na2SO3. The 4-arylmethylphenols were isolated by filtration or after extraction with CH2Cl2 and subsequent purification by flash chromatography (Quad flash 12, EtOAc-heptane).
General Procedure 23
A solution of the sulfonamide (0.2 mmol), 37% aqueous formaldehyde (0.5 mL), anf TFA (2 mL) was heated in a closed vessel in a Smith Creator microwave oven for 300 s at 150° C. The crude product was evaporated to dryness and purified by preparative HPLC (Gilson).
General Procedure 24
A suspention of the phenol (1.0 mmol), 1,4-diazabicyclo[2.2.2]octane (DABCO) (1.5 mmol) and 3-[4-(tert-butyl-dimethyl-silanyloxy)-piperidine-1-carbonyl]-1-methyl-3H-imidazol-1-ium; iodide (1.5 mmol) in CH2Cl2 (1 mL) was stirred at room temperature for 16 hours. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane). The purified tert-butyldimethylsilyl ether was desilylated by stirring with a 3.2 M solution of HCl in Et2O (20 mL) for 3 h at rt.
General Procedure 25
A solution of an alcohol (0.4 mmol), a phenol (0.4 mmol), diisopropylethylamin (0.44 mmol) and tributylphosphine (0.5 mmol) in THF (2 mL) was stirred under nitrogen at rt. ADDP (0.5 mmol) dissolved in THF (2 mL) was added and the reaction mixture was stirred at rt for 16 h, filtered, evaporated to dryness and redissolved in MeCN and purified by preparative HPLC (Gilson).
General Procedure 26
A solution of an alcohol (0.4 mmol), a phenol/thiophenol/N-hydroxyazole/azole or imide (0.4 mmol), diisopropylethylamin (0.44 mmol) and solid supported triphenylphosphine (3 mmol/g, 1.2 mmol) in CH2Cl2 (2 mL) was stirred under nitrogen at rt. Di-tert-butylazodicarboxylate (DBAD, 1.2 mmol) dissolved in CH2Cl2 (1 mL) was added and the reaction mixture was stirred at rt for 16 h. TFA (0.5 mL) was added and the mixture was stirred for further 1 h at rt. Addition of EtOAc, filtration, followed by evaporation to dryness gave a crude which was either purified by flash chromatography (Quad flash 12, EtOAc-heptane) or redissolved in MeCN and purified by preparative HPLC (Gilson).
Preparation of 1-methyl-3H-imidazol-1-ium iodides
1-Methyl-3-(7-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carbonyl)-3H-imidazol-1-ium iodide
Step A: Imidazol-1-yl-(7-trifluoromethyl-3,4-dihydro-2H-quinolin-1-yl)-methanone
The title product was prepared from 7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline, as described in the general procedure 4. Light yellow oil. HPLC-MS: m/z=296.1 (M+1); Rt: 2.85 min.
δH(300 MHz; CDCl3): 2.11 (qi, 2H), 2.93 (t, 2H), 3.90 (t, 2H), 7.01 (s, 2H), 7.05 (s, 1H), 7.34 (s, 1H), 7.34 (d, 1H), 7.77 (s, 1H).
Step B: 1-Methyl-3-(7-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carbonyl)-3H-imidazol-1-ium  iodide
The title product was prepared from imidazol-1-yl-(7-trifluoromethyl-3,4-dihydro-2H-quinolin-1-yl)-methanone, as described in the general procedure 5. Light yellow crystals. HPLC-MS: m/z=310.2 (M+1), Rt: 1.84 min.
δH(300 MHz; CDCl3): 2.01 (qi, 2H), 2.94 (t, 2H), 3.83 (t, 2H), 3.92 (s, 3H), 7.52 (s, 2H), 7.76 (s, 1H), 7.80 (s, 1H), 7.85 (s, 1H), 9.62 (s, 1H).
3-(cyclohexyl-methyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide
Step A: Imidazole-1-carboxylic acid cyclohexyl-methyl-amide
The title product was prepared from cyclohexyl-methyl-amine, as described in the general procedure 4. Off-white crystals. HPLC-MS: m/z=208.1 (M+1), Rt: 1.85 min
δH(300 MHz; CDCl3): 1.05-1.22 (m, 1H), 1.25-1.45 m, 2H), 1.50-1.61 (dt, 2H), 1.63-1.75 (d, 1H), 1.76.1.95 (m, 4H), 3.80-3.95 (m, 1H), 7.09 (bs, 1H), 7.21 (bs 1H), 7.87 (bs, 1H).
Step B: 3-(cyclohexyl-methyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide
The title product was prepared from imidazole-1-carboxylic acid cyclohexyl-methyl-amide, as described in the general procedure 5. Yellow crystals; HPLC-MS: m/z=222.2 (M+1), Rt: 1.15 min.
δH(300 MHz; CDCl3): 1.03-1.25, (m, 1H), 1.30-1.60 (m, 4H), 1.62-1.1.78 (m, 1H), 1.82-2.00 (t, 4H), 3.21 (s, 3H), 3.90-4.10 (m, 1H), 4.29 (s, 3H), 7.52 (bs, 1H), 7.66 (bs, 1H), 10.37 (bs, 1H).
3-(2,6-dimethyl-morpholine-4-carbonyl)-1-methyl-3H-imidazol-1-ium iodide
Step A: (2,6-Dimethyl-morpholin-4-yl)-imidazol-1-yl-methanone
The title product was prepared from 2,6-dimethyl-morpholine, as described in the general procedure 4. Colourless oil. PPLC-MS: m/z=210.10 (M+1), Rt: 0.63 min.
δH(300 MHz; CDCl3): 1.20 (s, 3H), 1.22 (s, 3H), 2.82 (dd, 2H), 3.60-3.75 (m, 2H), 3.93 (d, 2H), 7.11 (s, 1H), 7.20 (s, 1H), 7.87 (s, 1H).
Step B: 3-(2,6-dimethyl-morpholine-4-carbonyl)-1-methyl-3 h-imidazol-1-ium iodide
The title product was prepared from, (2,6-Dimethyl-morpholin-4-yl)-imidazol-1-yl-methanone, as described in the general procedure 5. Light yellow oil; HPLC-MS: m/z=224.2 (M+1), Rt: 0.40 min.
δH(300 MHz; CDCl3): 1.23 (s, 3H), 1.25 (s, 3H), 2.90-3.10 (m, 2H), 3.7-3.9 (m, 2H), 3.95-4.15 (m, 2H), 4.26 (s, 3H), 7.67 (s, 1H), 7.73 (s, 1H) 10.05 (s, 1H).
3-(Benzyl-methyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide
Step A: Imidazole-1-carboxylic acid benzyl-methyl-amide
The title product was prepared from benzyl-methyl-amine, as described in the general procedure 4. Light yellow crystals. HPLC-MS: m/z=216.1 (M+1), Rt: 1.53 min.
δH(300 MHz; CDCl3): 3.04 (s, 3H), 4.65 (s, 3H), 7.08 (bs, 1H), 7.22-7.34 (m, 3H), 7.34-7.50 (m, 3H), 7.93 (bs, bs, 1H).
Step B: 3-(Benzyl-methyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide
The title product was prepared from imidazole-1-carboxylic acid benzyl-methyl-amide, as described in the general procedure 5. Light yellow crystals. HPLC-MS m/z=230.1 (M+1), Rt: 1.23 min.
δH(300 MHz; CDCl3): 3.25 (s, 3H), 4.2 (s, 3H), 4.76 (s, 2H), 7.27-7.50 (m, 5H), 7.56 (bs, 1H), 7.70 (bs, 1H), 10.29 (bs, 1H).
3-(Phenyl-ethyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide
Step A: Imidazole-1-carboxylic acid phenyl-ethyl-amide
The title product was prepared from phenyl-ethyl-amine, as described in the general procedure 4. Light brown oil. HPLC-MS m/z=216.1 (M+1), Rt: 1.75 min.
δH(300 MHz; CDCl3): 1.26 (t, 3H), 3.92 (q, 2H), 6.79 (s, 1H), 6.84 (s, 1H), 7.10 (d, 2H), 7.27-7.45 (m, 3H), 7.55 (s, 1H).
Step B: 3-(Phenyl-ethyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide
The title product was prepared from imidazole-1-carboxylic acid phenyl-ethyl-amide, as described in the general procedure 5. Light yellow crystals. HPLC-MS m/z=230.2 (M+1), Rt: 1.16 min.
δH(300 MHz; CDCl3): 1.28 (t, 3H), 3.96 (q, 2H), 4.10 (s, 3H), 7.03 (s, 1H), 7.27 (s, 1H), 7.35-7.60 (m, 6H), 9.70 (s, 1H).
3-(2,3-Dihydro-indole-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide
Step A: (2,3-Dihydro-indol-1-yl)-imidazol-1-yl-methanone
The title product was prepared from Indoline, as described in the general procedure 4. Pink crystals. HPLC-MS m/z=214.1 (M+1), Rt: 1.62 min.
δH(300 MHz; CDCl3): 3.21 (t, 2H), 4.21 (t, 2H), 7.21 (dt, 1H, 7.15 (s, 1H), 7.17-7.29 (m, 2H) 7.36 (t, 1H), 7.40 (d, 1H), 8.03 (bs, 1H).
Step B: 3-(2,3-Dihydro-indole-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide
The title product was prepared from (2,3-dihydro-indol-1-yl)-imidazol-1-yl-methanone, as described in the general procedure 5. Light brown crystals. HPLC-MS m/z=228.1 (M+1), Rt: 0.94 min.
δH(300 MHz; CDCl3): 3.42 (t, 2H), 4.34 (s, 3H), 4.71 (t, 2H), 7.17-7.36 (m, 4H), 7.78 (bs, 1H), 7.86 (d, 1H), 10.76 (bs, 1H).
3[(4-Chlorophenyl)-methyl-carbamoyl]-1-methyl-3H-imidazol-1-ium iodide
Step A: Imidazole-1-carboxylic acid (4-chloro-phenyl)-methyl-amide
The title product was prepared from 4-chlor-N-methylaniline, as described in the general procedure 4. Light yellow crystals. HPLC-MS m/z=236.1 g/mol (M+1), Rt: 1.91 min.
δH(300 MHz; CDCl3): 3.47 (s, 3H), 6.85 (s, 1H), 6.87 (s, 1H), 7.06 (d, 2H), 7.36 (d, 2H), 7.06 (s, 1H).
Step B: [(4-Chlorophenyl)-methyl-carbamoyl]-1-methyl-3H-imidazol-1-ium iodide
The title product was prepared from imidazole-1-carboxylic acid (4-chloro-phenyl)-methyl-amide, as described in the general procedure 5. Orange crystals. HPLC-MS m/z=250.1 (M+1), Rt: 1.06 min.
δH(300 MHz; CDCl3): 3.55 (s, 3H), 4.12 (s, 3H), 7.16 (bs, 1H), 7.35 (t, 1H), 7.41 (d,1H), 7.45 (t, 1H), 7.51 (t, 1H), 7.53-7.55 (m, 1H), 9.92 (bs, 1H).
3-(isopropyl-methyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide
Step A: Imidazole-1-carboxylic acid isopropyl-methyl-amide
The title product was prepared from isopropyl-methylamine, as described in the general procedure 4. Light yellow oil. HPLC-MS m/z=168.1 (M+1), Rt: 0.51 min.
δH(300 MHz; CDCl3): 1.25 (s, 3H), 1.27 (s, 3H), 2.93 (s, 3H), 4.36 (Qi, 1H), 7.08 (bs, 1H), 7.22 (bs, 1H), 7.88 (bs, 1H).
Step B: 3-(isopropyl-methyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide
The title product was prepared from imidazole-1-carboxylic acid isopropyl-methyl-amide, as described in the general procedure 5. Light yellow crystals. HPLC-MS m/z=182.2 (M+1), Rt: 0.41 min.
δH(300 MHz; CDCl3): 1.31 (s, 3H), 1.35 (s, 3H), 3.17 (s, 3H), 4.29 (s, 3H), 4.30-4.50 (m, 2H), 7.62 bs, 1H), 7.71 (bs, 1H), 10.29 (bs, 1H).
3-(1,3-Dihydroisoindole-2-carbonyl)-1-methyl-3H-imidazol-1-ium iodide
Step A: (1,3-Dihydroisoindole-1-yl)-imidazol-1-yl-methanone
The title product was prepared from isoindole, as described in the general procedure 4. Oil.
Step B: 3-(1,3-Dihydroisoindole-2-carbonyl)-1-methyl-3H-imidazol-1-ium iodide
The title product was prepared from (1,3-dihydroisoindole-1-yl)-imidazol-1-yl-methanone, as described in the general procedure 5. Crystals.
δH(300 MHz; CDCl3): 3.96 (s, 3H), 4.98 (s, 2H), 5.04 (s, 2H), 7.35 (bs, 3H), 7.44 (bs, 1H), 7.91 (s, 1H), 8.21 (s, 1H), 9.74 (s, 1H).
1-Methyl-3-(piperidine-1-carbonyl)-3H-imidazol-1-ium iodide
Step A: Piperidin-1-yl-imidazol-1-yl-methanone
The title product was prepared from piperidine, as described in the general procedure 4. Oil.
Step B: 1-Methyl-3-(piperidine-1-carbonyl)-3H-imidazol-1-ium iodide
The title product was prepared from piperidin-1-yl-imidazol-1-yl-methanone, as described in the general procedure 5. Oil.
δH(300 MHz; CDCl3): 1.74 (s, 6H), 3.66 (bs, 4H), 4.28 (s, 3H), 7.78 (s, 1H), 7.83 (s, 1H), 10.07 (s, 1H).
1-Methyl-3-(2-methyl-piperidine-1-carbonyl)-3H-imidazol-1-ium iodide
Step A: (2-Methyl-piperidin-1-yl)-imidazol-1-yl-methanone
The title product was prepared from 2-methyl-piperidine, as described in the general procedure 4. light yellow oil. HPLC-MS m/z=194.2 (M+1), Rt: 0.92 min.
δH(300 MHz; CDCl3): 1.33 (d, 3H) 1.45-1.67 (m, 2H), 1.68-1.85 (m, 4H), 3.17 (dt, 1H), 3.86 (dd, 1H), 4.35-4.50 (m, 1H), 7.09 (s, 1H), 7.18 (s, 1H), 7.84 (s, 1H).
Step B: 1-Methyl-3-(2-methyl-piperidine-1-carbonyl)-3H-imidazol-1-ium iodide
The title product was prepared from (2-methyl-piperidin-1-yl)-imidazol-1-yl-methanone, as described in the general procedure 5. Orange solid. HPLC-MS m/z=208.1 (M+1), Rt: 0.57 min.
δH(300 MHz; CDCl3): 1.40 (d, H), 1.60-1.98 m, 6H), 3.45 (t, 1H), 3.90 (d, 1H), 4.30 (s, 3H), 4.45-4.60 (m, 1H), 7.59 (s, 1H), 7.62 (s, 1H), 10.06 (s, 1H).
1-Methyl-3-(3-methyl-piperidine-1-carbonyl)-3H-imidazol-1-ium iodide
Step A: (3-Methyl-piperidin-1-yl)-imidazol-1-yl-methanone
The title product was prepared from 3-methyl-piperidine, as described in the general procedure 4. light yellow oil. HPLC-MS m/z=194.2 (M+1), Rt: 1.15 min.
δH(300 MHz; CDCl3): 0.94 (d, 3H), 1.05-1.35 (m, 1H), 1.50-2.00 (m, 4H), 2.67 (t, 1H), 3.01 (dt, 1H), 3.98 (t, 2H), 7.09 (s, 1H), 7.19 (s, 1H), 7.85 (s, 1H).
Step B: 1-Methyl-3-(3-methyl-piperidine-1-carbonyl)-3H-imidazol-1-ium iodide
The title product was prepared from (3-methyl-piperidin-1-yl)-imidazol-1-yl-methanone, as described in the general procedure 5. Yellow oil. HPLC-MS m/z=208.1 (M+1), Rt: 0.69 min.
δH(300 MHz; CDCl3): 0.97 (d, 3H), 1.15-1.40 (m, 1H), 1.55-2.00 (m, 4H), 2.92 (t, 1H), 3.28 (t, 1H), 3.90-4.15 (m, 2H), 4.28 (s, 3H), 7.60-7.75 (m, 2H), 10.14 (s, 1H).
1-Methyl-3-(4-methyl-piperidine-1-carbonyl)-3H-imidazol-1-ium iodide
Step A: (4-Methyl-piperidin-1-yl)-imidazol-1-yl-methanone
The title product was prepared from 4-methyl-piperidine, as described in the general procedure 4. light yellow oil. HPLC-MS m/z=194.2 (M+1), Rt: 1.32 min.
δH(300 MHz; CDCl3): 1.00 (d, 3H), 1.15-1.35 (m, 2H), 1.55-1.85 (m, 3H), 3.02 (dt, 2H), 4.08 (d, 2H), 7.08 (s, 1H), 7.19 (s, 1H), 7.85 (s, 1H).
Step B: 1-Methyl-3-(4-methyl-piperidine-1-carbonyl)-3H-imidazol-1-ium iodide
The title product was prepared from (4-methyl-piperidin-1-yl)-imidazol-1-yl-methanone, as described in the general procedure 5. Yellow oil. HPLC-MS m/z=208.1 (M+1), Rt: 0.65 min.
δH(300 MHz; CDCl3): 1.00 (d, 3H), 1.20-1.50 (m, 2H), 1.66-1.90 (m, 3H), 3.32 (t, 2H), 4.13 (d, 2H), 4.28 (s, 3H), 7.58 (s, 1H), 7.64 (s, 1H), 10.15 (s, 1H).
1-Methyl-3-(4-benzyl-piperidine-1-carbonyl)-3H-imidazol-1-ium iodide
Step A: (4-Benzyl-piperidin-1-yl)-imidazol-1-yl-methanone
The title product was prepared from 4-methyl-piperidine, as described in the general procedure 4. light yellow oil. HPLC-MS m/z=270.2 (M+1), Rt: 2.58 min.
δH(300 MHz; CDCl3): 1.10-1.50 (m, 2H), 1.65-2.00 (m, 3H), 2.59 (d, 2H), 2.97 (dt, 2H), 4.08 (d, 2H), 7.05-7.40 (m, 7H), 7.84 (s, 1H).
Step B: 1-Methyl-3-(4-benzyl-piperidine-1-carbonyl)-3H-imidazol-1-ium iodide
The title product was prepared from (4-benzyl-piperidin-1-yl)-imidazol-1-yl-methanone, as described in the general procedure 5. Yellow oil. HPLC-MS m/z=208.1 (M+1), Rt: 0.65 min.
δH(300 MHz; CDCl3): 1.30-1.50 (m, 2H), 1.75-1.95 (m, 3H), 2.59 (d, 2H), 3.15-3.40 (m, 2H), 4.05-4.20 (m, 2H), 4.25 (s, 3H), 7.10-7.35 (m, 5H), 7.45 (bs, 1H), 7.60 (bs, 1H), 10.22 (s, 1H).
1-Methyl-3-(1,2,3,4-tetrahydroisoquinoline-1-carbonyl)-3H-imidazol-1-ium iodide
Step A: (1,2,3,4-Tetrahydroisoquinoline-1-yl)-imidazol-1-yl-methanone
The title product was prepared from 1,2,3,4-tetrahydroisoquinoline, as described in the general procedure 4. Oil.
Step B: 1-Methyl-3-(1,2,3,4-tetrahydroisoquinoline-1-carbonyl)-3H-imidazol-1-ium iodide
The title product was prepared from (1,2,3,4-tetrahydroisoquinoline-1-yl)-imidazol-1-yl-methanone, as described in the general procedure 5. Oil.
δH(300 MHz; CDCl3): 2.97 (t, 2H), 3.73 (bs, 2H), 3.94 (s, 3H), 4.75 (s, 2H), 7.15-7.35 (m, 4H), 7.88 (d, 1H), 8.09 (d, 1H), 9.63 (s, 1H).
Preparation of Phenols
1-(4-Hydroxy-phenyl)-4,4-dimethyl-piperidine-2,6-dione
A mixture of 4-aminophenol (3.27 g, 30.0 mmol) and 3,3-dimethylglutaric anhydride (4.26 g, 30.0 mmol) was heated in a round bottom flask at 165° C. for 1 h, followed by heating at 180° C. for 7 h. After cooling to room temperature the solid material was dissolved in hot ethanol, activated charcoal was added and the solution was heated at reflux for 1 h. The solid material was removed by hot filtration. The solvent was evaporated and the residue was crystallised from water/ethanol yielding the title compound (3.51 g, 50% yield, pink solid).
1H NMR (300 MHz, DMSO-d6): 11.08 (s, 6H), 2.63 (s, 4H), 6.77+6.86 (AB-system, 4H), 9.56 (s, 1H).
cis-2-(4-Hydroxy-phenyl)-hexahydro-isoindole-1,3-dione
A mixture of 4-aminophenol (5.46 g, 50.0 mmol) and cis-1,2-cyclohexanedicarboxylic anhydride (7.71 g, 50.0 mmol) was heated in a round bottom flask at 170 IC for 2 h. After cooling to room temperature the solid material was dissolved in hot ethanol (200 ml), activated charcoal was added and the solution was heated at reflux for 1 h. The solid material was removed by hot filtration. The solvent was partially evaporated. The solids were collected by filtration, washed quickly with a small amount of ethanol and dried in vacuo at 40° C. yielding the title compound (8.52 g, 69% yield, pink solid).
1H NMR (300 MHz, DMSO-d6): δ1.38 (m, 4H), 1.73 (m, 4H), 3.02 (m, 2H), 6.82 (d, 2H), 7.02 (d, 2H), 9.66 (s, 1H, OH); HPLC-MS: m/z=246 (M+1); Rt=2.53 min.
Cyclohexanecarboxylic acid (4-hydroxy-phenyl)-amide
To a solution of 4-aminophenol (5.00 g, 45.8 mmol) in dichloromethane (50 ml) were added cyclohexanecarbonyl chloride (6.72 g, 45.8 mmol) and pyridine (3.70 ml, 45.8 mmol), while cooling the reaction mixture in an ice bath. After the addition was completed, the cooling bath was removed and stirring was continued overnight at room temperature. Water (100 ml) was added, the organic phase was removed and the resulting solution was extracted with ethyl acetate (3×300 ml). The combined organic phases were washed with water (2×200 ml), dried, filtered and evaporated, yielding an off-white solid. The crude product was purified by flash column chromatography (SiO2, ethyl acetate/heptane (40:60)), yielding a mixture of two compounds, which were dissolved in THF. 6N NaOH (aq, 32 ml) was added and the mixture was stirred at room temperature for 2.5 h. The solution was acidified with concentrated hydrochloric acid and the organic solvent was removed by evaporation. The solid material was collected by filtration, dried and recrystallised from ethyl acetate/heptane, yielding the title compound (4.20 g, 41%, off-white solid).
1H NMR (300 MHz, DMSO-d6): δ1.12-1.48 (m, 5H), 1.65 (m, 1H), 1.70-1.82 (m, 4H), 2.27 (m, 1H), 6.66 (d, 2H), 7.36 (d, 2H), 9.10 (s, 1H), 9.50 (s, 1H); HPLC-MS: m/z=220 (M +1); Rt=2.69 min.
2-Cyclohexyl-N-(4-hydroxy-phenyl)-acetamide
To a solution of 4-aminophenol (3.83 g, 35.1 mmol) in dichloromethane (50 ml) were added cyclohexylacetyl chloride (11.26 g, 70.1 mmol) and pyridine (5.67 ml, 70.1 mmol), while cooling the reaction mixture in an ice bath. After the addition was completed, the cooling bath was removed and stirring was continued overnight at room temperature. The solvent was removed and the residue was dissolved in THF (300 ml). 6N NaOH (aq, 41 ml) was added and the mixture was stirred at room temperature for 4 h. The solution was acidified with 1 N hydrochloric acid. The solvent was removed by evaporation. The solid material was collected by filtration, dried in vacuo at 40° C. and dissolved in methanol (100 ml). A solution of KOH (5.5 g) in methanol (50 ml) was added. After stirring for 1 h at room temperature water (200 ml) was added and the organic solvent was removed by evaporation. The aqueous phase was acidified with 1 N HCl. The solid material was isolated by filtration and dried in vacuo at 40° C. yielding the title compound (6.31 g, 77% yield, pink crystals).
1H NMR (200 MHz, DMSO-d6): δ0.82-1.32 (m, 5H), 1.54-1.76 (m, 6H), 2.12 (d, 2H), 6.66 (d, 2H), 7.32 (d, 2H), 9.12 (s, 1H), 9.57 (s, 1H); HPLC-MS: m/z=234 (M+1); Rt=3.09 min.
cis/trans-4-tert-Butyl-cyclohexanecarboxylic acid (4-hydroxy-phenyl)-amide
To a solution of 4-aminophenol (3.08 g, 28.2 mmol) in dichloromethane (50 ml) were added cis/trans-4-tert-butyl-cyclohexanecarbonyl chloride (11.43 g, 56.4 mmol) and pyridine (4.56 ml, 56.4 mmol), while cooling the reaction mixture in an ice bath. After the addition was completed, the cooling bath was removed and stirring was continued overnight at room temperature. The solvent was removed by evaporation and the residue was dissolved in THF (300 ml). 6N NaOH (aq, 33 ml) was added and the mixture was stirred at room temperature overnight. The organic phase was removed by evaporation. Water (200 ml) was added and the solid material was collected by filtration, washed with water, dried in vacuo at 40° C. and dissolved in methanol (100 ml). A solution of KOH (2.4 g) in methanol (50 ml) was added. After stirring for 2 h at room temperature water (200 ml) was added and the organic phase was removed by evaporation. The aqueous phase was acidified with 1 N HCl and extracted with ethyl acetate (3×300 ml). The combined organic phases were washed with saturated sodium bicarbonate, dried, filtered and evaporated, yielding a pink oil, which was dried in vacuo at 40° C. The solid material was crystallised from ethyl acetate/heptane yielding the title compound (2.03 g, 26%, pink crystals). From the first aqueous extract a second portion of product was isolated by extraction with ethyl acetate (3×250 ml). The combined organic phases were washed with water (400 ml), saturated sodium bicarbonate (2×400 ml), dried, filtered and evaporated, yielding a pink thick oil. Crystallisation from ethyl acetate/heptane yielded a further amount of title compound (2.75 g, 35%).
1H NMR (300 MHz, DMSO-d6): δ0.80+0.84 (2×s, 9H), 0.98 (m, 2H), 1.23-1.57 (m, 4H), 1.76-1.90 (m, 2H), 2.02-2.14 (m, 1.5H), 2.57 (m, 0.5H), 6.65 (d, 2H), 7.34 (d x d, 2H), 9.09 (s, 1H), 9.36+9.50 (2 x s, 1H); HPLC-MS: m/z=276 (M+1); Rt=4.19 and 4.27 min.
N-(4-Hydroxy-phenyl)-3,3-dimethyl-butyramide
To a solution of 4-aminophenol (3.27 g, 30.0 mmol) in dichloromethane (50 ml) were added 3,3-dimethyl-butyryl chloride (8.08 g, 60.0 mmol) and pyridine (4.85 ml, 60.0 mmol), while cooling the reaction mixture in an ice bath. After the addition was completed, the cooling bath was removed and stirring was continued overnight at room temperature. The solvent was removed by evaporation and the residue was dissolved in THF (300 ml). 6N NaOH (aq, 35 ml) was added and the mixture was stirred at room temperature overnight. The organic phase was removed by evaporation. Water (200 ml) was added and the solid material was collected by filtration, washed with water, dried in vacuo at 40° C. and dissolved in methanol (100 ml). A solution of KOH (3.37 g) in methanol (50 ml) was added. After stirring for 2 days at room temperature water (300 ml) was added and the organic solvent was removed by evaporation. The aqueous phase was acidified with 1 N HCl. The solids were collected by filtration and dried under vacuum at 40° C. yielding the title compound (1.97 g, 31%, pink solid). The mother liquor was extracted with ethyl acetate (3×250 ml). The combined organic phases were washed with saturated sodium bicarbonate (2×250 ml), dried in vacuo, filtered and evaporated yielding a second amount of the title compound (0.67 g, 10%). From the first aqueous extract another portion of product was isolated by extraction with ethyl acetate (4×250 ml). The combined organic phases were washed with water (400 ml), saturated sodium bicarbonate (2×400 ml), dried, filtered and evaporated yielding a pink thick oil. Crystallisation from ethyl acetate/heptane yielded a third amount of the title compound (2.11 g, 34%).
1H NMR (300 MHz, DMSO-d6): δ1.00 (s, 9H), 2.12 (s, 2H), 6.67 (d, 2H), 7.33 (d, 2H), 9.12 (s, 1H), 9.50 (s, 1H); HPLC-MS: m/z=208 (M+1); Rt=2.50 min.
1-(4-Hydroxy-phenyl)-4,4-dimethyl-piperidine-2,6-dione
A mixture of 4-aminophenol (3.27 g, 30.0 mmol) and 3,3-dimethylglutaric anhydride (4.26 g, 30.0 mmol) was heated in a round bottom flask at 165° C. for 1 h, followed by heating at 180° C. for 7 h. After cooling to room temperature the solid material was dissolved in hot ethanol, activated charcoal was added and the solution was heated at reflux for 1 h. The solid material was removed by hot filtration. The solvent was evaporated and the residue was crystallised (water/ethanol) yielding the title compound (3.51 g, 50%, pink solid).
1H NMR (300 MHz, DMSO-d6): δ 1.08 (s, 6H), 2.63 (s, 4H), 6.77+6.86 (AB-system, 4H), 9.56 (s, 1H).
cis-2-(4-Hydroxy-phenyl)-hexahydro-isoindole-1,3-dione
A mixture of 4-aminophenol (5.46 g, 50.0 mmol) and cis-1,2-cyclohexanedicarboxylic anhydride (7.71 g, 50.0 mmol) was heated in a round bottom flask at 170° C. for 2 h. After cooling to room temperature the solid material was dissolved in hot ethanol (200 ml), activated charcoal was added and the solution was heated at reflux for 1 h. The solid material was removed by hot filtration. The solvent was partially evaporated. The solids were collected by filtration, washed quickly with a small amount of ethanol and dried in vacuo yielding the title compound (8.52 g, 69%, pink solid).
1H NMR (300 MHz, DMSO-d6): δ 1.38 (m, 4H), 1.73 (m, 4H), 3.02 (m, 2H), 6.82 (d, 2H), 7.02 (d, 2H), 9.66 (s, 1H, OH); HPLC-MS: m/z=246 (M+1); Rt=2.53 min.
Cyclohexanecarboxylic acid (4-hydroxy-phenyl)-amide
To a solution of 4-aminophenol (5.00 g, 45.8 mmol) in dichloromethane (50 ml) were added cyclohexanecarbonyl chloride (6.72 g, 45.8 mmol) and pyridine (3.70 ml, 45.8 mmol), while cooling the reaction mixture in an ice bath. After the addition was completed, the cooling bath was removed and stirring was continued overnight at room temperature. Water (100 ml) was added, the dichloromethane was removed by evaporation and the resulting solution was extracted with ethyl acetate (3×300 ml). The combined organic phases were washed with water (2×200 ml), dried, filtered and evaporated, yielding an off-white solid. The crude product was purified by flash column chromatography (SiO2, ethyl acetate/heptane (2:3)), yielding a mixture of two compounds, which were dissolved in THF. 6N NaOH (aq, 32 ml) was added and the mixture was stirred at room temperature for 2.5 h. The solution was acidified with concentrated hydrochloric acid. The THF was removed by evaporation. The solid material was collected by filtration, dried in vacuo and recrystallised (ethyl acetate/heptane), yielding the title compound (4.20 g, 41%, off-white solid).
1H NMR (300 MHz, DMSO-d6): δ 1.12-1.48 (m, 5H), 1.65 (m, 1H), 1.70-1.82 (m, 4H), 2.27 (m, 1H), 6.66 (d, 2H), 7.36 (d, 2H), 9.10 (s, 1H), 9.50 (s, 1H); HPLC-MS: m/z=220 (M+1); Rt=2.69 min.
2-Cyclohexyl-N-(4-hydroxy-phenyl)-acetamide
To a solution of 4-aminophenol (3.83 g, 35.1 mmol) in dichloromethane (50 ml) were added cyclohexylacetyl chloride (11.26 g, 70.1 mmol) and pyridine (5.67 ml, 70.1 mmol), while cooling the reaction mixture in an ice bath. After the addition was completed, the cooling bath was removed and stirring was continued overnight at room temperature. The solvent was removed by evaporation and the residue was dissolved in THF (300 ml). 6N NaOH (aq, 41 ml) was added and the mixture was stirred at room temperature for 4 h. The solution was acidified with 1 N hydrochloric acid and the organic phase was removed by evaporation. The solid material was collected by filtration, dried and dissolved in methanol (100 ml). A solution of KOH (5.5 g) in methanol (50 ml) was added. After stirring for 1 h at room temperature water (200 ml) was added and the organic solvent was removed by evaporation. The aqueous phase was acidified with 1 N HCl. The title product was isolated by filtration and dried in vacuo (6.31 g, 77%, pink crystals).
1H NMR (200 MHz, DMSO-d6): δ0.82-1.32 (m, 5H), 1.54-1.76 (m, 6H), 2.12 (d, 2H), 6.66 (d, 2H), 7.32 (d, 2H), 9.12 (s, 1H), 9.57 (s, 1H); HPLC-MS: m/z=234 (M+1); Rt=3.09 min.
cis/trans-4-tert-Butyl-cyclohexanecarboxylic acid (4-hydroxy-phenyl)-amide
To a solution of 4-aminophenol (3.08 g, 28.2 mmol) in dichloromethane (50 ml) were added cis/trans-4-tert-butyl-cyclohexanecarbonyl chloride (11.43 g, 56.4 mmol) and pyridine (4.56 ml, 56.4 mmol), while cooling the reaction mixture in an ice bath. After the addition was completed, the cooling bath was removed and stirring was continued overnight at room temperature. The solvent was removed by evaporation and the residue was dissolved in THF (300 ml). 6N NaOH (aq, 33 ml) was added and the mixture was stirred at room temperature overnight. The organic phase was removed by evaporation. Water (200 ml) was added and the solid material collected by filtration, washed with water, dried and dissolved in methanol (100 ml). A solution of KOH (2.4 g) in methanol (50 ml) was added. After stirring for 2 h at room temperature water (200 ml) was added and the organic solvent was removed by evaporation. The aqueous phase was acidified with 1 N HCl and extracted with ethyl acetate (3×300 ml). The combined organic phases were dried and evaporated, yielding a pink oil, which was dried in vacuo. The solid material was crystallised from ethyl acetate/heptane yielding the title compound (2.03 g, 26%) as pink crystals. From the first aqueous extract a second portion of product was isolated by extraction with ethyl acetate (3×250 ml). The combined organic layers were washed with water (400 ml), saturated sodium bicarbonate (2×400 ml), dried, filtered and evaporated, yielding a pink thick oil. Crystallisation from ethyl acetate/heptane yielded a second amount of the title compound (2.75 g, 35%).
1H NMR (300 MHz, DMSO-d6): δ 0.80+0.84 (2×s, 9H), 0.98 (m, 2H), 1.23-1.57 (m, 4H), 1.76-1.90 (m, 2H), 2.02-2.14 (m, 1.5H), 2.57 (m, 0.5H), 6.65 (d, 2H), 7.34 (d×d, 2H), 9.09 (s, 1H), 9.36+9.50 (2×s, 1H); HPLC-MS: m/z=276 (M+1); Rt=4.19 and 4.27 min.
N-(4-Hydroxy-phenyl)-3,3-dimethyl-butyramide
To a solution of 4-aminophenol (3.27 g, 30.0 mmol) in dichloromethane (50 ml) were added 3,3-dimethyl-butyryl chloride (8.08 g, 60.0 mmol) and pyridine (4.85 ml, 60.0 mmol), while cooling the reaction mixture in an ice bath. After the addition was completed, the cooling bath was removed and stirring was continued overnight at room temperature. The solvent was removed by evaporation and the residue was dissolved in THF (300 ml). 6N NaOH (aq, 35 ml) was added, the mixture was stirred at room temperature overnight and the solvent was removed by evaporation. Water (200 ml) was added and the solid material is collected by filtration, washed with water, dried in vacuo at 40° C. and dissolved in methanol (100 ml). A solution of KOH (3.37 g) in methanol (50 ml) was added. After stirring for 2 days at room temperature water (300 ml) was added, the organic solvent was removed and the aqueous phase was acidified with 1 N HCl. The solids were collected and dried yielding the title compound (1.97 g, 31% yield, pink solid). The mother liquor was extracted with ethyl acetate (3×250 ml). The combined organic phases were washed with saturated sodium bicarbonate (2×250 ml), dried over sodium sulphate, filtered and evaporated yielding a second amount of the title compound (0.67 g, 10%). From the first aqueous extract another portion of product was isolated by extraction with ethyl acetate (4×250 ml). The combined organic phases were washed with water (400 ml), dried, filtered and evaporated yielding a pink thick oil. Crystallisation from ethyl acetate/heptane yielded a third amount of the title compound (2.11 g, 34%).
1H NMR (300 MHz, DMSO-d6): δ1.00 (s, 9H), 2.12 (s, 2H), 6.67 (d, 2H), 7.33 (d, 2H), 9.12 (s, 1H), 9.50 (s, 1H); HPLC-MS: m/z=208 (M+1); Rt=2.50 min.
4-(3-Trifluoromethyl-phenoxy)-phenol
Hydroquinone monobenzylether (1 g, 5.0 mmol), 3-(trifluoromethyl)-phenyl boronic acid (1.9 g, 10.0 mmol), copper (II) acetate (0.91 g, 5.0 mmol) and triethylamine (2.53 g, 25.0 mmol) were dissolved/suspended in dichloromethane (50 ml). The reaction mixture was stirred for 70 h. at room temperature and evaporated to dryness. The crude intermediate was subjected to flash chromatography (ethyl acetate/heptane (1:4)) (42%) and hydrogenated (10% Pd/C) using ethanol as a solvent. The organic phase was evaporated and aqueous sodium hydroxide (1 N, 30 ml) was added together with dichloromethane. The two phases were separated and the aqueous phase extracted with dichloromethane (30 ml×2). The aqueous phase was acidified with aqueous hydrochloric acid (2N) and extracted with dichloromethane (30 ml×5). The organic phase was dried and evaporated to give the crude product (47%). HPLC-MS m/z=254.9 (M+1), Rt: 4.39 min.
δH(300 MHz; CDCl3): 6.85 (dt, 2H), 6.94 (dt, 2H), 7.10 (dd, 1H), 7.16 (bs, 1H), 7.24-7.30 (m, 1H), 7.39 (t, 1H).
4-Hydroxy-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester
4-Hydroxybenzoic acid (30 g, 0.217 mmol) and 4-hydroxysuccinamide (25.32 g, 0.220 mmol) were dissolved in 1.4-dioxane (550 ml) at room temperature. After 20 min. the clear solution was cooled to 15° C. and dicyclohexylcarbodiimide (44.82 ml, 0.217 mmol) was added. The reaction mixture was stirred for 18 hours and filtered. The organic phase was evaporated to dryness (86 g). Ethanol (250 ml) was added to the crude product and the mixture heated to reflux. The crude product was crystallized from ethanol/water (5:1) (22 g, 43%), and the mother liquor recrystallized from ethanol/water (25 g, 49%). HPLC-MS: m/z=(M+1); Rt: min.
N-(6-Methoxy-pyridin-3-yl)-benzamide
A solution of 5-amino-2-methoxypyridine (2.48 g, 20.0 mmol) and N-ethyldiisopropylamine (2.84 g, 22.0 mmol) in dichloromethane (20 ml) was cooled in an ice-bath. Benzoyl chloride (3.09 g, 22 mmol) was slowly added by means of a syringe. The cooling bath was removed and stirring was continued at room temperature for 18 hours. Dichloromethane was added and the solution was extracted with water. The organic layer was dried over sodium sulphate, filtered and evaporated in vacuo leaving a dark solid. Crystallisation from ethyl acetate:heptane yielded the title compound (3.44 g, 75% yield).
1H NMR (300 MHz, CDCl3): δ 3.93 (s, 3H), 6.77 (d, 1H), 7.44-7.59 (m, 3H), 7.81 (br.s, 1H), 7.87 (d, 2H), 8.01 (dd, 1H), 8.16 (d, 1H); HPLC-MS (Method A): m/z=229 (M+H); Rt=2.52 min.
Cyclohexanecarboxylic acid (6-methoxy-pyridin-3-yl)-amide hydrochloride
5-Amino-2-methoxypyride (3.72 g, 30.0 mmol), dissolved in a small amount of tetrahydrofuran, was added slowly to a solution of cyclohexanecarbonyl chloride (4.40 g, 30.0 mmol) in tetrahydrofuran (25 ml). After standing for 0.5 hours diethyl ether (250 ml) was added and the solids were collected by suction yielding the title compound (8.12 g, 100% yield) as a purple solid.
1H NMR (300 MHz, CDCl3): δ 1.11-1.48 (m, 5H), 1.63 (m, 1H), 1.68-1.83 (m, 4H), 2.32 (m, 1H), 3.81 (s, 3H), 6.80 (d, 1H), 7.92 (dd, 1H), 8.00 (br.s, 1H), 8.38 (d, 1H), 9.92 (s, 1H); HPLC-MS (Method A): m/z=235 (M+H); Rt=2.89 min.
6′-Methoxy-4,4-dimethyl-4,5-dihydro-3H-[1,3′] bipyridinyl-2,6-dione
A mixture of 5-amino-2-methoxypyride (3.72 g, 30.0 mmol) and 3,3-dimethylglutaric anhydride (4.26 g, 30.0 mmol) was heated at 175° C. for 7 hours. After cooling down to room temperature the solid material was dissolved in a small amount of dichloromethane and purified by flash column chromatography (SiO2, ethyl acetate:heptane (40:60)) yielding the title compound (2.56 g, 34% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ 1.20 (s, 6H), 2.69 (s, 4H), 3.95 (s, 3H), 3.81 (d, 1H), 7.28 (dd, 1H), 7.89 (d, 1H); HPLC-MS (Method A): m/z=249 (M+H); Rt=2.43 min.
N-(6-Methoxy-pyridin-3-yl)-2,2-dimethyl-propionamide hydrochloride
5-Amino-2-methoxypyride (3.72 g, 30.0 mmol), dissolved in a small amount of tetrahydrofuran, was added slowly to a solution of 2,2-dimethylpropionyl chloride (3.62 g, 30.0 mmol) in tetrahydrofuran (25 ml). After standing for 0.5 hours diethyl ether (250 ml) was added and a thick oil precipitated. The solvent was decanted and the residue was dried under reduced pressure yielding the title compound (5.50 g, 75% yield) as a purple foam.
1H NMR (300 MHz, CDCl3): δ 1.22 (s, 9H), 3.83 (s, 3H), 6.86 (d, 1H), 8.00 (dd, 1H), 8.42 (d, 1H), 9.41 (s, 1H), 9.54 (br.s, 1H); HPLC-MS (Method A): m/z=209 (M+H); Rt=2.28 min.
2-Cyclohexyl-N-(6-methoxy-pyridin-3-yl)-acetamide hydrochloride
5-Amino-2-methoxypyride (3.72 g, 30.0 mmol), dissolved in a small amount of tetrahydrofuran, was added slowly to a solution of cyclohexylacetyl chloride (4.82 g, 30.0 mmol) in tetrahydrofuran (25 ml). After standing for 0.5 hours diethyl ether (250 ml) was added and the solids were collected by suction yielding the title compound (8.54 g, 100% yield) as a purple solid.
1H NMR (300 MHz, DMSO-d6): δ0.88-1.04 (m, H), 1.09-1.32 (m, 3H), 1.54-1.82 (m, 6H), 2.18 (d, 2H), 3.84 (s, 3H), 6.85 (d, 1H), 7.98 (dd, 1H), 8.41 (d, 1H), 9.81 (br.s, 1H), 10.10 (s, 1H); HPLC-MS (Method A): m/z=249 (M+H); Rt=3.32 min.
N-(6-Hydroxy-pyridin-3-yl)-benzamide
N-(6-Methoxy-pyridin-3-yl)-benzamide (2.38 g, 10.4 mmol) was dissolved in a mixture of tetrahydrofuran and diethyl ether. HCl-gas was bubbled into the solution for 5 minutes. More diethyl ether was added and the white precipitate was collected by suction, washed twice with diethyl ether and heated in a kugelrohr apparatus at 180° C. for 0.5 hours. The solid material was crystallised from methanol:water, washed twice with water and dried overnight in a vacuum oven, yielding the title compound (1.19 g, 53% yield) as a grey solid.
1H NMR (300 MHz, CDCl3): δ6.39 (d, 1H), 7.47-7.61 (m, 3H), 7.18 (dd, 1H), 7.91 (d, 2H), 7.96 (d, 1H); HPLC-MS (Method A): m/z=215 (M+H); Rt=1.52 min.
Cyclohexanecarboxylic acid (6-hydroxy-pyridin-3-yl)-amide
Cyclohexanecarboxylic acid (6-methoxy-pyridin-3-yl)-amide hydrochloride (8.12 g, 30.0 mmol) was heated in a kugelrohr apparatus at 190° C. for 25 minutes. After cooling to room temperature the solid material was crystallised from methanol:water, washed twice with water and dried overnight in a vacuum oven, yielding the title compound (3.09 g, 47% yield) as a purple solid.
1H NMR (300 MHz, CDCl3): δ1.09-1.46 (m, 5H), 1.63 (m, 1H), 1.68-1.80 (m, 4H), 2.23 (m, 1H), 6.33 (d, 1H), 7.44 (dd, 1H), 7.87 (d, 1H), 9.54 (s, 1H), 11.29 (br.s, 1H); HPLC-MS (Method A): m/z=221 (M+H); Rt=1.84 min.
6′-Hydroxy-4,4-dimethyl-4,5-dihydro-3H-[1,3′]bipyridinyl-2,6-dione
6′-Methoxy-4,4-dimethyl-4,5-dihydro-3H-[1,3′]bipyridinyl-2,6-dione (2.56 g, 10.3 m dissolved in a mixture of tetrahydrofuran and diethyl ether. HCl-gas was bubbled into the solution for 5 minutes. More diethyl ether was added and the white precipitate was collected by suction, washed twice with diethyl ether and heated in a kugelrohr apparatus at 190° C. for 15 minutes yielding the title compound (2.16 g, 89% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ1.08 (s, 6H), 2.52 (s, 4H), 6.34 (d, 1H), 7.19 (dd, 1H), 7.31 (d, 1H), 11.42 (br.s, 1H); HPLC-MS (Method A): m/z=235 (M+H); Rt=1.32 min.
N-(6-Hydroxy-pyridin-3-yl)-2,2-dimethyl-propionamide
Under a stream of nitrogen gas N-(6-methoxy-pyridin-3-yl)-2,2-dimethyl-propionamide hydrochloride (5.50 g, 22.5 mmol) was heated in a round bottom flask at 180° C. for 15 minutes. After cooling to room temperature the solid material was crystallised from a methanol-water mixture, yielding the title compound (1.13 g, 26% yield) as a dark grey solid.
1H NMR (300 MHz, CDCl3): δ1.18 (s, 9H), 6.32 (d, 1H), 7.53 (dd, 1H), 7.76 (d, 1H), 8.97 (br.s, 1H), 11.30 (br.s, 1H); HPLC-MS (Method A): m/z=195 (M+H); Rt=1.15 min.
2-Cyclohexyl-N-(6-hydroxy-pyridin-3-yl)-acetamide
2-Cyclohexyl-N-(6-methoxy-pyridin-3-yl)-acetamide hydrochloride (8.54 g, 30.0 mmol) was heated in a kugelrohr apparatus at 160° C. for 0.5 hours. After cooling to room temperature the solid material was crystallised from a methanol-water mixture, washed twice with water and dried overnight in a vacuum oven, yielding the title compound (4.53 g, 64% yield) as a grey solid.
1H NMR (300 MHz, CDCl3): δ 0.90-1.38 (m, 5H), 1.60-1.92 (m, 6H), 2.17 (d, 2H), 6.50 (d, 1H), 7.50 (dd, 1H), 7.97 (d, 1H), 8.80 (br.s, 1H), 11.81 (br.s, 1H); HPLC-MS (Method A): m/z=235 (M+H); Rt=2.29 min.
3-Dimethylamino-2-(4-methoxy-phenoxy)-propenal
Phosphorus oxychloride (18.4 g, 120 mmol) was added to dimethylformamide (8.8 g, 120 mmol), maintaining the temperature below 25° C. by an external ice-bath. Upon completion of the addition the reaction mixture was heated to 50° C. for 45 minutes and then cooled to room temperature. Chloroform (35 ml) was added and the resulting solution was brought to reflux. 4-Methoxyphenoxyacetaldehyde diethylacetal (9.61 g, 40.0 mmol) was added in portions. After heating for 3 hours at reflux the solution was cooled to room temperature and poured carefully onto a solution of potassium carbonate (115 g) in water (100 ml). The mixture was cooled in an ice-bath to around room temperature and extracted twice with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo yielding a brown oil. The residue was heated with ethyl acetate:heptane and decanted, leaving a brown oil. The solvent was removed in vacuo to give a brown oil, which was purified by flash column chromatography (SiO2, ethyl acetate) yielding the title compound (3.87 g, 44% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ 3.00 (s, 6H), 3.75 (s, 3H), 6.54 (s, 1H), 7.80+7.87 (AB-system, 4H), 8.80 (s, 1H); HPLC-MS (Method A): m/z=222 (M+H); Rt=1.73 min.
2-(3,4-Dichloro-phenoxy)-3-dimethylamino-propenal
Phosphorus oxychloride (18.4 g, 120 mmol) was added to dimethylfonmamide (8.8 g, 120 mmol), maintaining the temperature below 25° C. by an external ice-bath. Upon completion of the addition the reaction mixture was heated to 50° C. for 45 minutes and then cooled to room temperature. Chloroform (35 ml) was added and the resulting solution was brought to reflux. 3,4-Dichlorophenoxyacetaldehyde diethylacetal (9.61 g, 40.0 mmol) was added in portions. After heating for 3 hours at reflux the solution was cooled to room temperature and poured carefully onto a solution of potassium carbonate (115 g) in water (100 ml). The mixture was cooled in an ice-bath to around room temperature and extracted twice with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo yielding a brown oil, which was purified by flash column chromatography (SiO2, ethyl acetate) yielding the title compound (5.38 g, 52% yield) as a brown solid.
1H NMR (300 MHz, CDCl3): δ3.10 (s, 6H), 6.58 (s, 1H), 6.82 (dd, 1H), 7.03 (d, 1H), 7.03 (d, 1H), 8.80 (s, 1H); HPLC-MS (Method A): m/z=260 (M+H); Rt=3.14 min.
5-(4-Methoxy-phenoxy)-pyrimidin-2-ol
A solution of sodium ethoxide, prepared from sodium (0.80 g, 35.0 mmol), 3-dimethylamino-2-(4-methoxy-phenoxy)-propenal (3.87 g, 17.5 mmol) and urea (2.10 g, 35.0 mmol) in ethanol (25 ml) was heated at reflux for 4 hours. Water (1 ml) was added and heating was continued for an additional 2 hours. The solution was cooled to room temperature and neutralised with glacial acetic acid. Most of the solvent was removed by evaporation in vacuo. Water was added and the precipitate was isolated by suction, followed by drying in a vacuum oven, yielding the title compound (0.80 g, 21% yield) as a yellow solid.
1H NMR (300 MHz, CDCl3): δ 3.80 (s, 3H), 6.85-7.95 (AB-system, 4H), 8.12 (s, 2H); HPLC-MS (Method A): m/z=219 (M+H); Rt=1.77 min.
5-(3,4-Dichloro-phenoxy)-pyrimidin-2-ol
A solution of sodium ethoxide, prepared from sodium (0.95 g, 41.4 mmol), 2-(3,4-dichlorophenoxy)-3-dimethylamino-propenal (5.38 g, 20.7 mmol) and urea (2.48 g, 41.4 mmol) in ethanol (25 ml) was heated at 60° C. for 4 hours. Water (1 ml) was added and heating was continued for an additional 2 hours. The solution was cooled to room temperature and neutralised with glacial acetic acid. Most of the solvent was removed by evaporation in vacuo. Water was added and the precipitate was isolated by suction, followed by drying in a vacuum oven, yielding the title compound (0.92 g, 17% yield) as a brown solid.
1H NMR (300 MHz, DMSO-d6): δ7.08 (dd, 1H), 7.38 (d, 1H), 7.59 (d, 1H), 8.35 (s, 2H), 12.06 (br.s, 1H); HPLC-MS (Method A): m/z=257 (M+H); Rt=2.75 min.
5-(2-Nitro-phenyl)-pyrimidin-2-ol
A solution of 3-(dimethylamino)-2-(2-nitrophenyl)acrylaldehyde (2.00 g, 9.08 mmol), urea (0.60 g, 9.99 mmol) and concentrated hydrochloric acid (0.50 ml) in ethanol (25 ml) was heated at 60° C. for 18 hours under a nitrogen atmosphere. An additional aliquot of concentrated hydrochloric acid (0.50 ml) was added followed by heating at 70° C. for 24 hours. The solvent was removed by evaporation under reduced pressure. The residue was crystallised from methanol yielding the title compound (0.35 g, 18% yield) as a-yellow solid.
1H NMR (300 MHz, DMSO-d6): δ7.54 (dd, 1H), 7.62 (dt, 1H), 7.76 (dt, 1H), 8.06 (dd, 1H), 8.29 (s, 2H); HPLC-MS (Method A): m/z=218 (M+H); Rt=1.26 min.
N-(6-Hydroxy-pyridin-3-yl)-3,3-dimethyl-butyramide
3,3-Dimethylbutyroyl chloride (4.04 g, 30.0 mmol) was added dropwise to a stirred solution of 5-amino-2-methoxypyridine (3.72 g, 30.0 mmol) in tetrahydrofuran (25 mL). After stirring for 1 hour at room temperature, diethyl ether was added and the solid material was isolated by suction. The N-(6-methoxy-pyridin-3-yl)-3,3-dimethyl-butyramide hydrochloride (4.13 g, 15.96 mmol) was heated at 180° C. for 15 minutes. After cooling to room temperature the product was dissolved in methanol. Partial evaporation of the solvent yielded the title compound (1.15 g, 35% yield) as a solid.
1H NMR (300 MHz, DMSO-d6): δ=1.00 (s, 9H), 2.12 (s, 2H), 6.38 (d, 1H), 7.44 (dd, 1H), 7.89 (d, 1H), 9.59 (s, 1H), 11.42 (br.s, 1H); HPLC-MS (Method A): m/z =209 (M+H)+; Rt=1.71 min.
Pyridine-2-carboxylic acid (6-methoxy-pyridin-3-yl)-amide dihydrochloride
5-Amino-2-methoxypyridine (4.40 g, 35.4 mmol), dissolved in a small amount of tetrahydrofuran, was added slowly to a stirred solution of pyridine-2-carbonyl chloride hydrochloride (7.12 g, 40.0 mmol) in tetrahydrofuran (75 mL). After stirring overnight at room temperature diethyl ether was added. The solids were isolated by suction, washed with diethyl ether and dried in a vacuum oven at 45° C., yielding the title compound (7.89 g, 75%).
1H NMR (300 MHz, CDCl3): δ=3.87 (s, 3H), 6.90 (d, 1H), 7.03 (br.s, 2 HCl+H2O), 7.70 (m, 1H), 8.09 (dt, 1H), 8.17 (d, 1H), 8.22 (dd, 1H), 8.68 (d, 1H), 8.73 (m, 1H), 10.82 (s, 1H); HPLC-MS (Method A): m/z=230(M+H)+; Rt=2.45 min and 264+266; Rt=3.15 min.
Pyridine-2-carboxylic acid (6-hydroxy-pyridin-3-yl)-amide hydrochloride
Pyridine-2-carboxylic acid (6-methoxy-pyridin-3-yl)=amide dihydrochloride (0.66 g, 1.99 mmol) was heated at 180° C. for 10 minutes. After cooling to room temperature, the title compound was obtained and used without further purification.
HPLC-MS (Method A): m/z=216 (M+H)+; Rt=2.14 min.
5-Methoxy-pyrimidin-2-ylamine
Under a nitrogen atmosphere phosphorus pentachloride (21 g, 0.10 mol) was added portionwise to 1,1,3-trimethoxyethane (12.0 g, 0.10 mol) with stirring and external cooling (ice-bath). After addition was completed, stirring was continued for an additional 30 minutes at room temperature. Dimethylformamide (22.5 mL) was added by means of a dropping funnel, while the reaction mixture was cooled externally with an ice-bath. After completion of the addition, the reaction mixture was heated at 60° C. for 70 minutes. The reaction mixture was then cooled in an ice-bath and methanol (50 mL) was added dropwise. The resulting solution was added dropwise to a stirred solution of sodium hydroxide (24 g) in methanol (80 mL) while cooling in an ice-bath. Guanidine nitrate (20.0 g, 0.16 mol) and sodium hydroxide (7.0 g, 0.175 mol) were added and the solution was stirred for 18 hours at room temperature. Water (150 mL) was added and the solution was extracted three times with dichloromethane. The combined organic layers were evaporated in vacuo leaving a brown oil. According to 1H NMR analysis a mixture of the desired product and the intermediate β-dimethylamine-α-methoxyacroleine was obtained. The mixture was dissolved in methanol (100 mL). Guanidine nitrate (15.0 g, 0.12 mol) and sodium hydroxide (5.25 g, 0.13 mol) were added and the reaction mixture was heated at 60° C. for 3 hours, followed by stirring at room temperature for 3 days. Water was added and the solution was extracted three times with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo yielding the title compound (5.43 g, 43% yield) as a yellow solid.
1H NMR (300 MHz, CDCl3): δ=3.80 (s, 3H), 5.08 (br.s, 2H), 8.04 (s, 2H); HPLC-MS (Method A): m/z=126 (M+H)+; Rt=0.39 min.
1-(5-Methoxy-pyrimidin-2-yl)-4,4-dimethyl-piperidine-2,6-dione
A mixture of 5-methoxy-pyrimidin-2-ylamine (1.00 g, 7.99 mmol) and 3,3-dimethylglutaric anhydride (1.14 g, 7.99 mmol) was heated at 180° C. for 9 hours. After cooling to room temperature the reaction mixture was dissolved in a small amount of dichloromethane and purified by flash column chromatography (SiO2, ethyl acetate:heptane 70:30), yielding the title compound (0.79 g, 40% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ=1.23 (s, 6H), 2.67 (s, 4H), 3.97 (s, 3H), 8.48 (s, 2H); HPLC-MS (Method A): m/z=250 (M+H)+; Rt=1.86 min.
1-(5-Hydroxy-pyrimidin-2-yl)-4,4-dimethyl-piperidine-2,6-dione
A mixture of 1-(5-methoxy-pyrimidin-2-yl)-4,4-dimethyl-piperidine-2,6-dione (0.99 g, 3.97 mmol) and pyridine hydrochloride (1.50 g, 7.99 mmol) was heated at 190° C. for 2.5 hours. After cooling to room temperature the reaction mixture was dissolved in a small amount of dichloromethane and filtered over a short pad of silicagel and washed with ethyl acetate. Evaporation of the solvent in vacuo yielded the title compound (0.60 g, 64% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ=1.23 (s, 6H), 2.65 (s, 4H), 8.42 (s, 2H), 9.94 (br.s, 1H); HPLC-MS (Method A): m/z=236 (M+H)+; Rt=1.53 min.
6-Chloro-N-(6-hydroxy-pyridin-3-yl)-nicotinamide
A solution of 6-chloro-nicotinoyl chloride (0.40 g, 2.27 mmol) and 5-amino-2-hydroxypyridine hydrochloride (0.33 g, 2.25 mmol) in dry tetrahydrofuran (15 mL) was stirred at room temperature for 1 hour. Saturated sodium bicarbonate (aq) was added and the solution was extracted three times with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo. The residue was dissolved in a mixture of methanol (10 mL) and aqueous sodium hydroxide (1N, 2 mL). After stirring for 2 hours at room temperature water was added and the solution was extracted with dichloromethane. The organic layer was dried over sodium sulphate, filtered and evaporated in vacuo, yielding the title compound which was used without further purification.
HPLC-MS (Method A): m/z=250 (M+H)+; Rt=1.52 min.
N-(2,2-Dimethyl-propyl)-6-hydroxy-nicotinamide
A solution of 6-hydroxynicotinic acid (1.39 g, 10.0 mmol), 1-hydroxy-7-azabenztriazole (1.50 g, 11.0 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.11 g, 11.0 mmol) in dimethylformamide (25 mL) was stirred at room temperature for 20 minutes. A solution of 2,2-dimethylpropylamine (0.96 g, 11.0 mmol) and N,N-diisopropylethylamine (1.42 g, 11.0 mmol) in a small amount of dimethylformamide was added. Stirring was continued for 0.5 hour at room temperature. Ethyl acetate was added and the reaction mixture was extracted twice with water. The solvent was evaporated in vacuo yielding the title compound, which was used without further purification.
HPLC-MS (Method A): m/z=209 (M+H)+; Rt=1.86 min.
3-Chloro-6-(3,4-dichloro-phenoxy)-pyridazine
A solution of 3,6-dichloropyridazine (4.47 g, 30.0 mmol), 3,4-dichlorophenol (4.89 g, 30.0 mmol) and potassium hydroxide (1.68 g, 30.0 mmol) in dimethyl sulfoxide (20 mL) was heated at 60° C. overnight. The solvent was removed by evaporation in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 50:50). Small amounts of starting material were removed by kugelrohr distillation. Crystallisation from ethyl acetate:heptane yielded the title compound (1.74 g, 21% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ=7.10 (dd, 1H), 7.20 (d, 1H), 7.37 (d, 1H), 7.49 (d, 1H), 7.54 (d, 1H); HPLC-MS (Method A): m/z=275 and 277 (M+H)+; Rt=4.00 min.
6-(3,4-dichloro-phenoxy)-pyridazin-3-ol
A solution of 3-chloro-6-(3,4-dichloro-phenoxy)-pyridazine (1.74 g, 6.32 mmol) in formic acid (25 mL) was heated at 100° C. for 3 hours. The solvent was removed by evaporation in vacuo yielding the title compound, which was used without further purification.
HPLC-MS (Method A): m/z=257 (M+H)+; Rt=3.13 min.
(4-Hydroxy-piperidin-1-yl)-imidazol-1-yl-methanone
A solution of 4-hydroxypiperidine (20.0 g, 198 mmol) and N,NA-carbonyldiimidazole (32.06 g, 198 mmol) in tetrahydrofuran (250 mL) was heated overnight at reflux, followed by stirring at room temperature for two days. The solvent was evaporated yielding the title compound, which was used without further purification.
HPLC-MS (Method A): m/z=196 (M+H)+; Rt=0.39 min.
[4-(tert-Butyl-dimethyl-silanyloxy)-piperidin-1-yl]-imidazol-1-yl-methanone
tert-Butyidimethylsilyl chloride (30.14 g, 0.20 mol) was added to a stirred solution of (4-hydroxy-piperidin-1-yl)-imidazol-1-yl-methanone (39.05 g, 0.20 mol) in dimethylformamide (200 mL). After stirring for 3 days at room temperature, the solvent was removed by evaporation in vacuo. The residue was redissolved in dichloromethane, extracted twice with water, dried over sodium sulphate, filtered and evaporated in vacuo, yielding the title compound, which was used without further purification.
1H NMR (300 MHz, CDCl3): δ=0.07 (s, 6H), 0.90 (s, 9H), 1.64 (m, 2H), 1.81 (m, 2H), 3.53-3.74 (m, 4H), 4.06 (m, 1H), 7.07 (m, 1H), 7.18 (m, 1H), 7. 86 (m, 1H); HPLC-MS (Method A): m/z=310 (M+H)+; Rt=3.40 min.
3-[4-(tert-Butyl-dimethyl-silanyloxy)-piperidine-1-carbonyl]-1-methyl-3H-imidazol-1-ium iodide
Methyl iodide (113.5 g, 0.80 mol) was added to a stirred solution of [4-(tert-butyl-dimethyl-silanyloxy)-piperidin-1-yl]-imidazol-1-yl-methanone (61.9 g, 0.20 mol) in acetonitrile (400 mL). After stirring overnight at room temperature the solvent was evaporated in vacuo. The residue was washed with ethyl acetate:heptane and dried in a vacuum oven at 45° C., yielding the title compound (60.92 g, 68% yield over three steps) as a white solid
1H NMR (300 MHz, CDCl3): δ=0.08 (s, 6H), 0.88 (s, 9H), 1.57 (m, 2H), 1.83 (m, 2H), 3.45 (m, 2H), 3.65 (m, 2H), 3.93 (s, 3H), 4.06 (m, 1H), 7.87 (m, 1H), 8.03 (m, 1H), 9.56 (s, 1H); HPLC-MS (Method A): m/z=324 (M−I−)+; Rt=2.95 min.
4-Chloro-N-(6-hydroxy-pyridin-3-yl)-benzamide
4-Chlorobenzoyl chloride (1.75 g, 10.0 mmol) was added carefully to a stirred solution of 5-amino-2-methoxypyridine (1.24 g, 10.0 mmol) in dichloromethane (10 mL). After stirring overnight at room temperature, the solvent is evaporated in vacuo and the residue is heated in a pre-heated kugelrohr oven at 200° C. for 5-10 minutes under house-vacuum (around 20 mbar) yielding the title compound, which was used without further purification.
HPLC-MS (Method A): m/z=249 (M+H)+; Rt=2.18 min.
4-Fluoro-N-(6-hydroxy-pyridin-3-yl)-benzamide
Starting from 4-fluorobenzoyl chloride (1.59 g, 10.0 mmol) and using the procedure as described for the preparation of 4-Chloro-N-(6-hydroxy-pyridin-3-yl)-benzamide yielded the title compound, which was used without further purification.
HPLC-MS (Method A): m/z=233 (M+H)+; Rt=1.76 min.
N-(6-Hydroxy-pyridin-3-yl)-3-methoxy-benzamide
Starting from 3-methoxybenzoyl chloride (1.71 g, 10.0 mmol) and using the procedure as described for the preparation of 4-Chloro-N-(6-hydroxy-pyridin-3-yl)-benzamide yielded the title compound, which was used without further purification.
HPLC-MS (Method A): m/z=245 (M+H)+; Rt=1.81 min.
N-(6-Hydroxy-pyridin-3-yl)-4-methoxy-benzamide
Starting from 4-methoxybenzoyl chloride (1.71 g, 10.0 mmol) and using the procedure as described for the preparation of 4-Chloro-N-(6-hydroxy-pyridin-3-yl)-benzamide yielded the title compound, which was used without further purification.
HPLC-MS (Method A): m/z=245 (M+H)+; Rt=1.72 min.
N-(6-Hydroxy-pyridin-3-yl)-4-methoxy-benzamide
Starting from 2,4-dichlorobenzoyl chloride (2.10 g, 10.0 mmol) and using the procedure as described for the preparation of 4-Chloro-N-(6-hydroxy-pyridin-3-yl)-benzamide yielded the title compound, which was used without further purification.
HPLC-MS (Method A): m/z=283 (M+H)+; Rt=2.28 min.
N-(6-Hydroxy-pyridin-3-yl)-4-trifluoromethyl-benzamide
Starting from 4-trifluoromethylbenzoyl chloride (2.09 g, 10.0 mmol) and using the procedure as described for the preparation of 4-Chloro-N-(6-hydroxy-pyridin-3-yl)-benzamide yielded the title compound, which was used without further purification.
HPLC-MS (Method A): m/z=283 (M+H)+; Rt=2.28 min.
6′-Hydroxy-4,5-dihydro-3H-[1,3′]bipyridinyl-2,6-dione
Glutaric anhydride (1.14 g, 10.0 mmol) was added to a solution of 5-amino-2-methoxypyridine (1.24 g, 10.0 mmol) in dichloromethane (25 mL). After standing for 1 hour at room temperature, thionyl chloride (5.95 g, 50.0 mmol) was added, followed by heating to reflux for 0.5 hour. The solvent and excess thionyl chloride were evaporated in vacuo, yielding 4-(6-methoxy-pyridin-3-ylcarbamoyl)-butyryl chloride, which was used without further purification.
1H NMR (300 MHz, CDCl3): δ=1.81 (quintet, 2H), 2.28 (t, 2H), 2.38 (t, 2H), 3.87 (s, 3H), 6.91 (d, 1H), 8.00 (dd, 1H), 8.43 (d, 1H), 10.24 (s, 1H, NH).; HPLC-MS (Method A): m/z=253 (M+H)+; Rt=1.94 min. (analysed as methyl ester).
The crude 4-(6-methoxy-pyridin-3-ylcarbamoyl)-butyryl chloride was redissolved in dichloromethane (25 mL). Thionyl chloride (5.95 g, 50 mmol) was added and the solution was heated to reflux overnight. The solvent and excess thionyl chloride were evaporated in vacuo, yielding 6′-methoxy-4,5-dihydro-3H-[1,3′]bipyridinyl-2,6-dione hydrochloride, which was used without further purification.
1H NMR (300 MHz, CDCl3): δ=2.00 (quintet, 2H), 2.72 (t, 4H), 3.88 (s, 3H), 6.90 (d, 1H), 7.51 (dd, 1H), 6.92 (d, 1H), 9.71 (br.s, HCl+H2O); HPLC-MS (Method A): m/z=221 (M+H)+; Rt=1.38 min.
The crude 6′-methoxy-4,5-dihydro-3H-[1,3′]bipyridinyl-2,6-dione hydrochloride (2.57 g, 10.0 mmol) was heated in a pre-heated kugerohr oven at 180° C. for 5 minutes. After cooling to room temperature the product was purified by flash column chromatography (SiO2, ethyl acetate:acetone 25:75), yielding the title compound (0.48 g, 23% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ=2.10 (quintet, 2H), 2.81 (t, 4H), 3.53 (br.s, 3H), 7.12 (br.s, 1H), 7.27 (m, 1H), 7.38 (m, 4H), 7.50 (d, 1H), 8.09 (s, 1H); HPLC-MS (Method A): m/z=340 (M+H)+; Rt=2.89 min.
1-(6-Methoxy-pyridin-3-yl)-pyrrolidine-2,5-dione
A mixture of 5-amino-2-methoxypyridine (1.24 g, 10.0 mmol) and succinic anhydride (1.00 g, 10.0 mmol) was heated with a heat gun for 10 minutes. After cooling to room temperature the product was purified by flash column chromatography (SiO2, ethyl acetate:acetone 25:75). Evaporation of the solvent yielded the title compound as a white solid.
1H NMR (300 MHz, CDCl3): δ=2.92 (s, 4H), 3.96 (s, 3H), 6.82 (d, 1H), 7.50 (dd, 1H), 8.11 (d, 1H); HPLC-MS (Method A): m/z=207 (M+H)+; Rt=1.26 min.
1-(6-Hydroxy-pyridin-3-yl)-pyrrolidine-2,5-dione
1-(6-Methoxy-pyridin-3-yl)-pyrrolidine-2,5-dione was dissolved in tetrahydrofuran and HCl-gas was bubbled into the solution for 5 minutes. The solvent was evaporated in vacuo and the residue was heated for 10 minutes at 180° C. in a pre-heated kugelrohr oven. After cooling to room temperature the residue was purified by flash column chromatography (SiO2), yielding the title compound (285 mg, 15% yield over two steps).
1H NMR (400 MHz, DMSO-d6): δ=2.72 (s, 4H), 6.40 (d, 1H), 7.31 (dd, 1H), 7.39 (d, 1H), 11.76 (br.s, 1H, OH); HPLC-MS (Method A): m/z=193 (M+H)+; Rt=0.37 min.
2-Methoxy-5-(5-trifluoromethyl-pyridin-2-yloxy)-pyridine
A solution of 5-hydroxy-2-methoxypyridine (1.25 g, 10.0 mmol), 2-chloro-5-trifluoromethylpyridine (1.82 g, 10.0 mmol) and potassium hydroxide (85% pure, 1.08 g, 10.0 mmol) in dimethyl sulfoxide (25 mL) was heated at 90° C. for 2.5 hours. The solution was cooled to room temperature and poured slowly into water (200 mL). After cooling with an external ice-bath, the precipitate was collected by suction, washed thoroughly with water and dried in a vacuum oven at 45° C., yielding the title compound (2.56 g, 95% yield).
1H NMR (300 MHz, CDCl3): δ=3.95 (s, 3H), 6.80 (d, 1H), 7.04 (d, 1H), 7.41 (dd, 1H), 7.91 (dd, 1H), 8.03 (d, 1H), 8.40 (d, 1H); HPLC-MS (Method A): m/z=271 (M+H)+; Rt=3.88 min.
5-(5-Trifluoromethyl-pyridin-2-yloxy)-pyridin-2-ol
A mixture of 2-methoxy-5-(5-trifluoromethyl-pyridin-2-yloxy)-pyridine (0.28 g, 1.04 mmol) and pyridine hydrochloride (1.00 g, 8.65 mmol) was heated in a kugelrohr oven at 200° C. for 10 minutes. After cooling to room temperature, the reaction mixture is dissolved in dichloromethane and extracted with water, dried over sodium sulphate, filtered and evaporated in vacuo, yielding the title compound (180 mg, 68% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ=6.63 (m, 1H), 7.06 (d, 1H), 7.42 (m, 2H), 7.92 (dd, 1H), 8.42 (d, 1H); HPLC-MS (Method A): m/z=257 (M+H)+; Rt=2.32 min.
5-(3,5-Dichloro-pyridin-2-yloxy)-2-methoxy-pyridine
A solution of 5-hydroxy-2-methoxypyridine (1.25 g, 10.0 mmol), 2,3,5-trichloropyridine (1.82 g, 10.0 mmol) and potassium hydroxide (85% pure, 1.08 g, 10.0 mmol) in dimethyl sulfoxide (25 mL) was heated at 90° C. for 1.5 hours. The solution was poured slowly into water (200 mL). The precipitate was collected by suction, washed thoroughly with water and dried in a vacuum oven at 45° C., yielding the title compound (2.39 g, 88% yield).
1H NMR (300 MHz, CDCl3): δ=3.95 (s, 3H), 6.80 (d, 1H), 7.41 (dd, 1H), 7.77 (d, 1H), 7.93 (d, 1H), 8.03 (d, 1H); HPLC-MS (Method A): m/z=271 (M+H)+; Rt=4.18 min.
5-(3,5-Dichloro-pyridin-2-yloxy)-pyridin-2-ol
A mixture of 5-(3,5-dichloro-pyridin-2-yloxy)-2-methoxy-pyridine (2.39 g, 8.82 mmol) and pyridine hydrochloride (7.00 g, 60.6 mmol) was heated in a kugelrohr apparatus at 200° C. for 25 minutes. After cooling to room temperature dichloromethane and water were added. The solid material, which was insoluble in dichloromethane and water, was isolated by suction and dried in a vacuum oven at 45° C., yielding the title compound, which was used without further purification.
HPLC-MS (Method A): m/z=257 (M+H)+; Rt=2.53 min.
4,4-Dimethyl-3,4,5,6-tetrahydro-2H-[1,3] bi pyridinyl-6′-ol
Under a nitrogen atmosphere lithium aluminium hydride (1.90 g, 50.0 mmol) was added portionwise to a-stirred suspension of 6′-methoxy-4,4-dimethyl-4,5-dihydro-3H-[1,3′]bipyridinyl-2,6-dione (2.85 g, 10.0 mmol) in dry diethyl ether (100 mL). After stirring for 3 hours at room temperature, water (1.90 mL), 15% aqueous sodium hydroxide (1.90 mL) and water (5.70 mL) were added respectively. After stirring for 1 hour at room temperature the salts were removed by filtration and washed three times with diethyl ether. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, dichloromethane followed by ethyl acetate/heptane 25/75) yielding the title compound (1.28 g, 58% yield) as a yellow oil.
1H NMR (300 MHz, CDCl3): δ=0.98 (s, 6H), 1.53 (m, 4H), 3.03 (m, 4H), 3.89 (s, 3H), 6.67 (d, 1H), 7.30 (dd, 1H), 7.80 (d, 1H); HPLC-MS (Method A): m/z=221 (M+H)+; Rt=2.14 min.
4,4-Dimethyl-3,4,5,6-tetrahydro-2H-[1,3]bipyridinyl-6′-ol
A mixture of 6′-methoxy-4,4-dimethyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl (1.28 g, 5.81 mmol) and pyridine hydrochloride (5.00 g, 43.3 mmol) was heated in a kugelrohr oven at 200° C. for 15 minutes. After cooling to room temperature water was added and the solution was made slightly basic with aqueous 1N sodium hydroxide. The solution was extracted three times with dichloromethane and the combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo, yielding the title compound (0.86 g, 72% yield).
HPLC-MS (Method A): m/z=207 (M+H)+; Rt=1.31 min.
Methyl-phenyl-carbamic acid 4-amino-phenyl ester
To a solution of N-Boc protected 4-aminophenol (10 mmol) in CH2Cl2 (50 mL) was added N-methyl-N -phenylcarbamoyl chloride (15 mmol) and DABCO (15 mmol) at room temperature. The reaction mixture was stirred for 16 hours at rt, added CH2Cl2 (20 mL) and washed with aqueous citric acid (5%) and brine. The organic phase was separated, dried (MgSO4) and evaporated to give the crude product which was purified by FC (Quad flash 40 MeOH—CH2Cl2 5:95). The purified intermediate was dissolved in CH2Cl2 (90 mL). Addition of TFA (6 mL) and stirring for 4 h. The reaction mixture was evaporated to dryness and dried in vacuo at 50° C. overnight producing the title compound in 72% yield as colorless crystals.
HPLC-MS: m/z=243.1 (M+1); Rt=2.02 min.
Example 1
(General Procedure 9)
4-[(1,3-Benzodioxol-5-yl)methyl]-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-piperonylpiperazine, yield 67%. Recrystallisation from 96% ethanol gave white crystals, m.p. 239-240° C.; HPLC-MS m/z=502 (M+H), 524 (M+Na), Rt=3.3 min.; 1H NMR (bMSO-d6): δ 11.64 (br, H, NH), 8.62-8.52 (br, 1H, py-H6), 8.31-8.19 (m, 1H, py-H4), 7.40-7.15 (m, 6H, py-H3+C6H4+1 arom.), 7.15-6.93 (m, 2H, arom), 4.53-3.96 (br, 4H, CH2 at 4.26+2 CH), 3.80-2.89 (br, 6H, water at 3.38+4C-H); lR (KBr): ν 1724 (C═O).
Example 2
General Procedure 1
Methyl-phenyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was purified by preparative HPLC (36%, white crystals). HPLC-MS m/z=389.1 (M+1), Rt: 5.13 min.
δH(300 MHz; CDCl3): 3.43 (s, 3H), 6.98 (d, 1H, J 8.7), 7.09-7.22 (m, 4H), 7.30-7.34 (m, 1H), 7.35 (d, 2H, J 7.1), 7.40 (t, 2H, J 6.8), 7.88 (dd, 1H, J 8.7 and 2.3), 8.42 (s, 1H)
Example 3
General Procedure 1
Methyl-phenyl-carbamic acid 3-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 3-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to flash chromatography (Quad flash 25, dichlormethane) (89%, oil). HPLC-MS m/z=389.1 (M+1), Rt: 5.08 min.
δH(300 MHz; DMSO-d6): 3.34 (s, 3H), 7.00-7.15 (m, 3H), 7.27 (t, 2H), 7.35-7.55 (m, 5H), 8.24 (dd, 1H), 8.58 (s, 1H).
Example 4
General Procedure 1
Methyl-phenyl-carbamic acid 4-(3,5-dichloro-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(3,5-dichloro-pyridin-2-yloxy)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was purified by preparative HPLC (53%, crystals). HPLC-MS m/z=389.1 (M+1), Rt: 5.1 min.
δH(300 MHz; CDCl3): 3.43 (s, 3H), 7.07-7.20 (m, 4H), 7.27-7.48 (m, 5H), 7.75 (d, 1H, J 2.2), 7.93 (d, 1H, J 2.2).
Example 5
General Procedure 1
Methyl-phenyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-ylamino)-phenyl ester
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-ylamino)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was purified by preparative HPLC to give the title product (32%, white crystals). HPLC-MS m/z=388.2 (M+1), Rt: 4.72 min. δH(300 MHz; CDCl3): 3.44 (s, 3H), 6.76 (d, 1H), 6.81 (bs, 1H), 7.12 (d, 2H), 7.27-7.45 (m, 6H), 7.63 (dd, 1H), 8.42 (bs, 1H).
Example 6
General Procedure 1
Methyl-phenyl-carbamic acid 4-(3,5-dichloro-pyridin-4-yloxy)-phenyl ester
The title compound was prepared from 4-(3,5-dichloro-pyridine-4-yloxy)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was purified by preparative HPLC (41%, white crystals). HPLC-MS m/z=389.1 (M+1), Rt: 4.97 min.
δH(300 MHz; CDCl3): 3.42 (s, 3H), 6.81 (d, 2H, J 9.0), 7.07 (d, 2H, J 7. 9), 7.25-7.43 (m, 5H), 8.55 (s, 2H).
Example 7
General Procedure 1
Methyl-phenyl-carbamic acid 4-(4-trifluoromethyl-phenoxy)-phenyl ester
The title compound was prepared from 4-(4-trifluoromethyl-phenoxy)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was purified by preparative HPLC (78%, white crystals). HPLC-MS m/z=388.0 (M+1), Rt: 5.59 min.
δH(300 MHz; CDCl3): 3.43 (s, 3H), 7.02 (d, 4H, J 8.7), 7.14 (d, 2H, J 8. 7), 7.31 (1H, d, J 6.8), 7.35 (d, 2H, J 7.2), 7.41 (t, 2H, J 7.1), 7.55 (d, 2H, J 8.6).
Example 8
General Procedure 1
Methyl-phenyl-carbamic acid 4-(3-trifluoromethyl-phenoxy)-phenyl ester
The title compound was prepared from 4-(3-trifluoromethyl-phenoxy)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was purified by preparative HPLC (73%, white crystals). HPLC-MS m/z=388.2 (M+1), Rt: 5.37 min.
Example 9
General Procedure 1
Methyl-phenyl-carbamic acid 4-(2-cyano-5-trifluoromethyl-pyridine-3-yloxy)-phenyl ester
The title compound was prepared from 4-(2-cyano-5-trifluoromethyl-pyridin-3-yloxy)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was purified by preparative HPLC (74%, colourless oil). HPLC-MS m/z=414.1 (M+1), Rt: 4.8 min.
δH(300 MHz; CDCl3): 3.44 (s, 3H), 7.11 (d, 2H, J 9), 7.32-7.1 (m, 3H) 7.32-7.1 (m, 3H), 7.32-7.50 (m, 5H), 8.63 (s, 1H).
Example 10
General Procedure 1
Methyl-phenyl-carbamic acid 2-benzenesulfonyl-4-(3-chloro-5-trifluoromethyl-pyridine-2-yloxy)-phenyl ester
The title compound was prepared from 2-benzenesulfonyl-4-(3-chloro-5-trifluoromethyl-pyridine-2-yloxy)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was purified by preparative HPLC (68%, white crystals). HPLC-MS m/z=563.1 (M+1), Rt: 5.3 min.
δH(300 MHz; CDCl3): 3.44 (s, 3H), 7.20-7.50 (m, 12H), 7.91 (bs, 1H), 8.00 (d, 1H, J 2.3), 8.23 (s, 1H).
Example 11
General Procedure 1
Methyl-phenyl-carbamic acid 4-tert-butoxy-phenyl ester
The title compound was prepared from 4-tert-butoxy-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to flash chromatography (Quad12/25, flash 12, dichloromethane) followed by a recrystallization from ethanol (41%, crystals). HPLC-MS m/z=300.3 (M+1), Rt: 4.7 min.
δH(300 MHz; CDCl3): 1.31 (s, 9H), 3.41 (s, 3H), 6.90-7.07 (m, 4H), 7.32-7.43 (m, 4H).
Example 12
General Procedure 1
Methyl-phenyl-carbamic acid 3-(4-fluorobenzyl)-4-methyl-2-oxo-2H-chromen-7-yl ester
The title compound was prepared from 3-(4-fluorobenzyl)-7-hydroxy-4-methyl-2H-chromen-2-one and N-methyl-N-phenylcarbamoyl chloride.
The crude product was of high purity and tested without purification (≈100%, crystals); mp: 185-186° C. HPLC-MS m/z=418.2 (M+1), Rt: 5.2 min.
δH(300 MHz; CDCl3): 2.43 (s, 3H), 3.43 (s, 3H), 6.95 (dt, 2H, J 8.7 and 2.3), 7.17 (m, 2H), 7.21 (dt, 2H, J 7.2 and 2.3), 7.27-7.45 (m, 5H), 7.58 (d, 1H, J 8.3).
Example 13
General Procedure 1
Methyl-phenyl-carbamic acid 4-phenoxy-phenyl ester
The title compound was prepared from 4-phenoxy-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was recrystallized (ethanol/water) (86%, white crystals). HPLC-MS m/z=320.1 (M+1), Rt: 5.13 min.
δH(300 MHz; CDCl3): 3.43 (s, 3H), 6.94-7.02 (m, 4H), 7.08 (t, 2H, J 6.8), 7.04-7.12 (m, 1H), 7.32 (t, 2H, J 7.5), 7.28-7.35 (m, 1H), 7.35-7.45 (m, 4H).
Example 14
General Procedure 1
Methyl-phenyl-carbamic acid 4-(4-chlorobenzoyl)-phenyl ester
The title compound was prepared from 4-(4-chlorobenzoyl)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was recrystallized (ethanol/water) (90%, white crystals). HPLC-MS m/z=366.1 (M+1), Rt: 5.19 min.
δH(300 MHz; CDCl3): 3.45 (s, 3H), 7.19-7.37 (m, 4H), 7.40 (t, 2H, J 7.2), 7.37-7.40 (m, 1H), 7.46 (dt, 2H, J 8.7 and 2,3), 7.73 (dt, 2H, J 8.7 and 2.2), 7.79 (d, 2H, J 8.7).
Example 15
General Procedure 1
Methyl-phenyl-carbamic acid 4-(3-chloro-5-trifluoromethyl)-pyridine-2-yloxy)-phenyl ester
The title compound was prepared from 4-(3-chloro-5-trifluoromethyl)-pyridine-2-yloxy)-phenol and N-methyl-N-phenylcarbamoyl chloride. Prepared as described in general procedure 1. The crude product was recrystallized (ethanol/water (78%, white crystals). HPLC-MS m/z=423.1 (M+1), Rt: 5.31 min.
δH(300 MHz; CDCl3): 3.43 (s, 3H), 7.10-7.23 (m, 4H), 7.27 (t, 1H, J 6.8), 7.35 (d, 2H, J 7.5), 7.41 (t, 2H, J 7.4), 7.96 (d, 1H, J 1.9), 8.23 (bs, 1H).
Example 16
General Procedure 1
Methyl-phenyl-carbamic acid 4-[4-(4-chloro-phenyl)-thiazol-2-yl]-phenyl ester
The title compound was prepared from 4-[4-(4-chloro-phenyl)-thiazol-2-yl]-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was recrystallized (ethanol/water) (59%, white crystals). HPLC-MS m/z=421.1 (M+1), Rt: 5.85 min
δH(300 MHz; CDCl3): 3.45 (s, 3H), 7.18-7.25 (m, 2H), 7.27-7.33 (m, 1H), 7.34-7.41 (m, 4H), 7.43 (d, 2H, J 6.8), 7.41-7.46 (m, 1H), 7.92 (dt, 2H, J 8.6 and 2.2), 8.00 (d, 2H, J 8.7).
Example 17
General Procedure 1
Methyl-phenyl-carbamic acid 4-pyrrol-1-yl-phenyl ester
The title compound was prepared from 4-pyrrol-1-yl-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was recrystallized (ethanol/water) (27%, off-white crystals). HPLC-MS m/z=293.2 (M+1), Rt: 4.51 min.
δH(300 MHz; CDCl3): 3.44 (s, 3H), 6.33 (t, 2H, J 2.2), 7.03 (t, 2H, J 2.2), 7.17 (bd, 2H, J 8.3), 7.29 (d, 1H, J 6.8), 7.31-7.38 (m, 4H), 7.41 (t, 2H, J 6.8).
Example 17a
General Procedure 1
Methyl-phenyl-carbamic acid 4-imidazol-1-yl-phenyl ester
The title compound was prepared from 4-imidazol-1-yl-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (4%, clear oil). HPLC-MS m/z=294.1 (M+1), Rt: 2.25 min.
δH(300 MHz; CDCl3): 3.44 (s, 3H), 7.27-7.39 (m, 4H), 7.39-7.50 (m, 5H), 7.53 (bs, 1), 8.83 (bs, 1H).
Example 18
General Procedure 1
Methyl-phenyl-carbamic acid 4-(3-chloro-5-trifluoromethyl)-pyridine-2-ylmethyl)-phenyl ester
The title compound was prepared from 4-(3-chloro-5-trifluoromethyl)-pyridine-2-ylmethyl)-phenol and N-methyl-N-phenylcarbamoyl chloride.
The crude product was recrystallized (ethanol/water) (74%, white crystals). HPLC-MS m/z=421.1 (M+1), Rt: 5.23 min.
δH(300 MHz; CDCl3): 3.40 (s, 3H), 4.33 (s, 2H), 7.03 (d, 2H, J 8.3), 7.2 0-7.30 (m, 3H), 7.3 (d, 2H, J 7.2), 7.38 (t, 2H, J 7.2), 7.87 (d, 1H, J 1.5), 8.69 (bs, 1H,).
Example 19
General Procedure 1
Methyl-phenyl-carbamic acid 4-trifluoromethylsulfanyl-phenyl ester
The title compound was prepared from 4-trifluoromethylsulfanyl-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (70%, clear oil). HPLC-MS m/z=328.0 (M+1), Rt: 5.16 min.
δH(300 MHz; CDCl3): 3.42 (s, 3H), 7.19 (d, 2H, J 6.4), 7.26-7.7.37 (m, 3H), 7.41 (t, 2H, J 7.9), 7.63 (d, 2H, J 8.3).
Example 20
General Procedure 1
Methyl-phenyl-carbamic acid 4-pentafluoromethyloxy-phenyl ester
The title compound was prepared from 4-pentafluoromethyloxy-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (66%, clear oil). HPLC-MS m/z=362.0 (M+1), Rt: 5.31 min. H(300 MHz; CDCl3): 3.42 (s, 3H), 7.10-7.22 (m, 4H), 7.29 (d, 1H, J 7.2), 7.34 (d, 2H, J 7.1), 7.41 (t, 2H, J 7.1).
Example 21
General Procedure 1
Methyl-phenyl-carbamic acid 4-benzyloxy-phenyl ester
The title compound was prepared from 4-benzyloxy-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was recrystallized (ethanol/water) (83%, white crystals). HPLC-MS m/z=334.2 (M+1), Rt: 4.88 min.
δH(300 MHz; CDCl3): 3.41 (s, 3H), 5.03 (s, 2H), 6.92 (dt, 2H, J 9.0 and 2.2), 7.02 (d, 2H, J 8.7), 7.26-7.34 (m, 2H), 7.34-7.38 (m, 4H), 7.38-7.44, m, 4H).
Example 22
General Procedure 1
Methyl-phenyl-carbamic acid 4-benzyl-phenyl ester
The title compound was prepared from 4-benzyl-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was recrystallized (ethanol/water) (56%, white crystals). HPLC-MS m/z=318.1 (M+1), Rt: 5.05 min.
δH(300 MHz; CDCl3): 3.41 (s, 3H), 3.95 (s, 2H), 7.02 (d, 2H), 7.12-7.19 (m, 5H), 7.20-7.25 (m, 2H), 7.26-7.28 (m, 1H), 7.28-7.34 (m, 1H), 7.34-7.42 (m, 3H).
Example 23
General Procedure 1
Methyl-phenyl-carbamic acid 4′-cyano-biphenyl-4-yl-ester
The title compound was prepared from 4-hydroxy-4-biphenylcarbonitrile and N-methyl-N-phenylcarbamoyl chloride applying procedure 1. The crude product was recrystallized (ethanol/water) (87%, white crystals). HPLC-MS m/z=329.2 (M+1), Rt: 4.63 min. δH(300 MHz; CDCl3): 3.44 (s, 3H), 7.18-7.26 (m, 2H), 7.26-7.32 (m, 2H), 7.34-7.46 (m, 4H), 7.56 (d, 2H), 7.64 (d, 2H), 7.712 (d, 2H).
Example 24
General Procedure 1
Methyl-phenyl-carbamic acid 4′-bromo-biphenyl-4-yl-ester
The title compound was prepared from 4-bromo-4′-hydroxybiphenyl and N-methyl-N-phenylcarbamoyl chloride. The crude product was recrystallized (ethanol) (72%, white crystals). HPLC-MS m/z=382.0) (M+1), Rt: 5.41 min.
δH(300 MHz; CDCl3): 3.44 (s, 3H), 7.15-7.23 (d, 2H), 7.26-7.31 (m, 1H), 7.34-7.45 (m, 6H), 7.47.7.57 (m, 4H).
Example 25
General Procedure 1
Methyl-phenyl-carbamic acid biphenyl-4-yl-ester
The title compound was prepared from 4-hydroxybiphenyl and N-methyl-N-phenylcarbamoyl chloride applying. The crude product was recrystallized (ethanol) (75%, white crystals).
HPLC-MS m/z=304.2 (M+1), Rt: 4.95 min.
δH(300 MHz; CDCl3): 3.45 (s, 3H), 7.19 (d, 2H), 7.26-7.37 (m, 2H), 7.37-7.46 (m, 6H), 7.55 (d, 4H).
Example 26
General Procedure 1
Methyl-phenyl-carbamic acid 4-[3-(4-chlorophenyl)-ureido]-phenyl ester
The title compound was prepared from 4-[3-(4-chlorophenyl)-ureido]-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (33%, off-white crystals). HPLC-MS m/z=396.1 (M+1), Rt: 4.40 min.
δH(300 MHz; CDCl3): 3.52 (s, 3H), 6.85-7.03 (m, 7H), 7.09 (d, 2H), 7.30-7.50 (m, 6H).
Example 27
General Procedure 1
Methyl-phenyl-carbamic acid 4-(4-nitro-phenoxy)-phenyl ester
The title compound was prepared from 4-(4-nitro-phenoxy)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (71%, white crystals). HPLC-MS m/z=365.0 (M+1), Rt: 4.83 min. 4(300 MHz; CDCl3): 3.44 (s, 3H), 7.00 (d, 2H), 7.06 (d, 2H), 7.26-7.32 (m, 1H), 7.33-7.49 (m, 4H), 8.20 (dt, 2H).
Example 28
General Procedure 1
Methyl-phenyl-carbamic acid 4-heptylsulfanyl-phenyl ester
The title compound was prepared from 4-heptylsulfanyl-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (74%, colourless oil, HPLC-MS m/z=358.2 (M+1), Rt: 6.21 min. δH (200 MHz; CDCl3): 0.87 (t, 3H), 1.15-1.50 (m, 8H), 1.50-1.75 (m, 2H), 2.86 (t, 2H), 3.41 (s, 3H), 7.04 (d, 2H), 7.15-7.50 (m, 7H).
Example 29
General Procedure 1
Methyl-phenyl-carbamic acid 4-butoxy-phenyl ester
The title compound was prepared from 4-butoxy-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was recrystallized from ethanol (22%, white crystals). HPLC-MS m/z=300.1 (M+1), Rt: 5.20.
δH(300 MHz; CDCl3): 0.96 (t, 3H), 1.45 (qi, 2H), 1.74 (qi, 2H), 3.41 (s, 3H), 3.92 (t, 2H), 6.84 (d, 2H), 6.99 (d, 2H), 7.25-7.27 (m, 1H), 7.30-7.45 (m, 4H).
Example 30
General Procedure 1
Methyl-phenyl-carbamic acid 4-(4-chloro-benzenesulfonyl)-phenyl ester
The title compound was prepared from 4-(4-chloro-benzenesulfonyl)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (46%, colourless oil). HPLC-MS m/z=402.1(M+1), Rt: 4.65 min.
δH(200 MHz; CDCl3): 3.41 (s, 3H), 7.21-7.35 (m, 5H), 7.39 (d, 2H), 7.46 (dt, 2H, 7.84 (dt, 2H) 7,90 (d, 2H).
Example 31
General Procedure 1
Methyl-phenyl-carbamic acid 4-(4-chloromethyl-thiazol-2-yl)-phenyl ester
The title compound was prepared from 4-(4-chloromethyl-thiazol-2-yl)-phenol and N-methyl-N-phenylcarbamoyl chloride. The aqueous phase was adjusted to PH 7.0 (phosphate buffer), before extraction with ethyl acetate. The crude product was subjected to preparative HPLC (21%, white crystals). HPLC-MS m/z=359.0 (M+1), Rt: 4.60.
δH(200 MHz; CDCl3): 3.44 (s, 3H), 4.73 (s, 2H), 7.20 (bd, 2H), 7.26-7.48 (m, 6H), 7.92 (bd, 2H).
Example 32
(General Procedure 3)
Methyl-phenyl-carbamic acid 4-(4,4-dimethyl-2,6-dioxo-piperidin-1-yl)-phenyl ester
The title product was prepared from 1-(4-hydroxyphenyl)-4,4-dimethylpiperidine-2,6-dione (233 mg, 1.00 mmol)) and 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (343 mg, 1.00 mmol) by applying general procedure 3 (192 mg, 52%, white solid). HPLC-MS m/z=367 (M+1); Rt=3.78 min.
1H NMR (300 MHz, CDCl3): δ 1.19 (s, 6H), 2.65 (s, 4H), 3.42 (s, 3H), 7.03 (d, 2H), 7.15-7.43 (m, 7H).
Example 33
(General Procedure 3)
cis-Methyl-phenyl-carbamic acid 4-(1,3-dioxo-octahydro-isoindol-2-yl)-phenyl ester
The title compound (293 mg, 77% yield, white crystals) was prepared from cis-2-(4-hydroxy-phenyl)hexahydroisoindole-1,3-dione (245 mg, 1.00 mmol) and 1-methyl-3-(methyl-phenyl—carbamoyl)-3H-imidazol-1-ium iodide (343 mg, 1.00 mmol). HPLC-MS m/z=379 (M+1); Rt=4.08 min.
1H NMR (300 MHz, CDCl3): δ 1.50 (m, 4H), 1.90 (m, 4H), 3.00 (m, 1H), 3.42 (s, 3H), 7.13-7.44 (m, 9H).
Example 34
(General Procedure 3)
Methyl-phenyl-carbamic acid 4-(cyclohexanecarbonyl-amino)-phenyl ester
The title compound (283 mg, 80% yield, white crystals) was prepared from cyclohexanecarboxylic acid (4-hydroxyphenyl) amide (219 mg, 1.00 mmol) and 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (343 mg, 1.00 mmol). HPLC-MS m/z=353 (M+1); Rt=4.23 min.
1H NMR (300 MHz, CDCl3): δ 1.27 (m, 3H), 1.52 (m, 2H), 1.70 (m, 1H), 1.76-1.97 (m, 4H), 2.20 (m, 1H), 3.42 (s, 3H), 7.01 (d, 2H), 7.18 (d, 2H), 7.32-7.50 (m, 7H).
Example 35
(General Procedure 3)
Methyl-phenyl-carbamic acid 4-(2-cyclohexyl-acetylamino)-phenyl ester
The title compound (284 mg, 77% yield, white crystals) was prepared from 2-cyclohexyl-N-(4-hydroxy-phenyl)-acetamide (233 mg, 1.00 mmol) and 1-methyl-3-(methyl-phenyl—carbamoyl)-3H-imidazol-1-ium iodide (343 mg, 1.00 mmol). HPLC-MS m/z=367 (M+1); Rt=4.51 min
1H NMR (300 MHz, CDCl3): δ 0.87-1.03 (m, 2H), 1.07-1.38 (m, 3H), 1.60-1.92 (m, 6H), 2.14 (d, 2H), 3.41 (s, 3H), 6.97 (d, 2H), 7.26 (m, 1H), 7.30-7.44 (m, 6H), 7.55 (br.s, 1H, NH);.
Example 36
(General Procedure 3)
cis/trans-Methyl-phenyl-carbamic acid 4-[(4-tert-butyl-cyclohexanecarbonyl)-amino]-phenyl ester
The title compound (353 mg, 86% yield, white crystals) was prepared from cis/trans-4-tert-butyl-cyclohexanecarboxylic acid (4-hydroxy-phenyl)-amide (275 mg, 1.00 mmol) and 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (343 mg, 1.00 mmol). HPLC-MS m/z=409 (M+1); Rt=5.28 and 5.42 min.
1H NMR (300 MHz, CDCl3): δ 0.82+0.86 (2×s, 9H), 1.03 (m, 2H), 1.23-1.7 0 (m, 4H), 1.82-2.22+2.58 (m, 4H), 3.42 (s, 3H), 7.01 (m, 2H), 7.26 (m, 1H), 7.31-7.48 (m, 7H, arom. +NH).
Example 37
(General Procedure 3)
trans-Methyl-phenyl-carbamic acid 4-[(4-tert-butyl-cyclohexanecarbonyl)-amino]-phenyl ester
The title compound was obtained from cis/trans-4-tert-butyl-cyclohexanecarboxylic acid (4-hydroxy-phenyl)-amide by preparative HPLC (method B). Rt=5.50 min.
1H NMR (300 MHz, CDCl3): δ 0.85 (s, 9H), 1.03 (m, 3H), 1.52 (m, 2H), 1.88 (m, 2H), 2.01 (m, 2H), 2.12 (tt, J=12.1, 3.3 Hz, 1H), 3.41 (s, 3H), 7.01 (br.d, 2H), 7.26 (m, 1H), 7.31-7.48 (m, 7H, arom.+NH).
Example 38
(General Procedure 3)
cis-Methyl-phenyl-carbamic acid 4-[(4-tert-butyl-cyclohexanecarbonyl)-amino]-phenyl ester
The title compound was obtained from cis/trans-4-tert-butyl-cyclohexanecarboxylic acid (4-hydroxy-phenyl)-amide by preparative HPLC (method B). Rt=6.34 min.
Example 39
(General Procedure 3)
Methyl-phenyl-carbamic acid 4-(3,3-dimethyl-butyrylamino)-phenyl ester
The title compound (262 mg, 77% yield) was prepared from N-(4-hydroxyphenyl)-3,3-dimethyl-butyramide (275 mg, 1.00 mmol) and 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (343 mg, 1.00 mmol). HPLC-MS m/z=341 (M+1); Rt=4.15 min.
1H NMR (300 MHz, CDCl3): δ 1.07 (s, 9H), 2.16 (s, 2H), 3.43 (s, 3H), 6.98 (d, 2H), 7.26 (m, 1H), 7.32-7.43 (m, 6H), 7.51 (br.s, 1H, NH).
Example 40
(General Procedure 3)
Methyl-phenyl-carbamic acid 3-(benzyl)-4-methyl-2-oxo-2H-chromen-7-yl ester
The title compound was prepared from 3-benzyl-7-hydroxy-4-methyl-2H-chromen-2-one and 3-(methyl-phenyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide. HPLC-MS m/z=400 (M+1), Rt: 4.90 min.
Example 41
(General Procedure 3)
Methyl-phenyl-carbamic acid 3-(3,4-dichloro-benzyl)-4-methyl-2-oxo-2H-chromen-7-yl ester
The title compound was prepared from 3-(3,4-dichloro-benzyl)-7-hydroxy-4-methyl-2H-chromen-2-one and 3-(methyl-phenyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide (white solid). HPLC-MS m/z=468 (M+1), Rt: 5.47 min.
Example 42
(General Procedure 3)
Methyl-phenyl-carbamic acid 3-(2-chloro-6-fluoro-benzyl)-4-methyl-2-oxo-2H-chromen-7-yl ester
The title compound was prepared from 3-(2-chloro-6-fluoro-benzyl)-7-hydroxy-4-methyl-2H-chromen-2-one and 3-(methyl-phenyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide by applying procedure 3. HPLC-MS m/z=452 (M+1), Rt: 5.15 min.
Example 43
(General Procedure 3)
Methyl-phenyl-carbamic acid 3-(2,6-dichloro-benzyl)-4-methyl-2-oxo-2H-chromen-7-yl ester
The title compound was prepared from 3-(2,6-dichloro-benzyl)-7-hydroxy-4-methyl-2H-chromen-2-one and 3-(methyl-phenyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide. HPLC-MS m/z=468 (M+1), Rt: 5.37 min.
Example 44
(General Procedure 3)
Methyl-phenyl-carbamic acid 3-(2,6-dichloro-benzyl)-6-chloro-4-methyl-2-oxo-2H-chromen-7-yl ester
The title compound was prepared from 3-(2,6-dichloro-benzyl)-6-chloro-7-hydroxy-4-methyl-2H-chromen-2-one and 3-(methyl-phenyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide. HPLC-MS m/z=502 (M+1), Rt: 5.68 min.
Example 45
(General Procedure 3)
Methyl-phenyl-carbamic acid 6-chloro-3-(2-chloro-6-fluoro-benzyl)-4-n-propy-2-oxo-2H-chromen-7 -yl ester
The title compound was prepared from 3-(4-fluoro-benzyl)-6-chloro-7-hydroxy-4-n-propyl-2H-chromen-2-one and 3-(methyl-phenyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide. HPLC-MS m/z=480 (M+1), Rt: 5.61 min.
Example 46
(General Procedure 3)
Methyl-phenyl-carbamic acid 3-(4-methoxy-phenyl)-4-methyl-2-oxo-2H-chromen-7-yl ester
The title compound (90 mg, 43% yield, white solid) was prepared from 7-hydroxy-3-(4-methoxy-phenyl)-4-methyl-chromen-2-one (141 mg, 0.50 mmol) and 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (175 mg, 0.51 mmol).
1H NMR (300 MHz, DMSO-d6): δ 2.28 (s, 3H), 3.38 (s, 3H), 3.80 (s, 3H), 7.00 (d, 2H), 7.18-7.33 (m, 5H), 7.40-7.53 (m, 4H), 7.83 (d, 1H); HPLC-MS: m/z=416 (M+1); Rt=4.67 min.
Example 47
(General Procedure 3)
Methyl-phenyl-carbamic acid 4-methyl-2-oxo-3-phenyl-2H-chromen-7-yl ester
The title compound (120 mg, 52% yield, white solid) was prepared from 7-hydroxy-4-methyl-3-phenyl-chromen-2-one (126 mg, 0.50 mmol) and 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (175 mg, 0.51 mmol).
1H NMR (300 MHz, DMSO-d6): δ 2.26 (s, 3H), 3.37 (s, 3H), 7.16-7.54 (m, 12H), 7.86 (d, 1H);
HPLC-MS: m/z=386 (M+1); Rt=4.69 min.
Example 48
(General Procedure 3)
Methyl-phenyl-carbamic acid 3-(2,5-dimethoxy-phenyl)-4-methyl-2-oxo-2H-chromen-7-yl ester
The title compound (30 mg, 13% yield, white solid) was prepared from 3-(2,5-dimethoxy-phenyl)-7-hydroxy-4-methyl-chromen-2-one (156 mg, 0.50 mmol) and 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (175 mg, 0.51 mmol).
1H NMR (300 MHz, CDCl3): δ 2.21 (s, 3H), 3.45 (br.s, 3H), 3.72 (s, 3H), 3.79 (s, 3H), 6.74 (m, 1H), 6.92 (m, 2H), 7.12 (br.s, 2H), 7.26-7.46 (m, 5H), 7.63 (d, 1H); HPLC-MS: m/z=446 (M+1); Rt=4.60 min.
Example 49
(General Procedure 3)
Methyl-phenyl-carbamic acid 3-(3,4-dimethoxy-phenyl)-4-methyl-2-oxo-2H-chromen-7-yl ester.
The title compound (30 mg, 13% yield, oil) was prepared from 3-(3,4-dimethoxy-phenyl)-7-hydroxy-4-methyl-chromen-2-one (156 mg, 0.50 mmol) and 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (175 mg, 0.51 mmol).
1H NMR (300 MHz, CDCl3): δ(2.31 (s, 3H), 3.45 (br.s, 3H), 3.89 (s, 3H), 4.02 (s, 3H), 6.83 (m, 2H), 6.94 (d, 1H), 7.12 (br.s, 2H), 7.27-7.48 (m, 5H), 7.62 (d, 1H); HPLC-MS: m/z=446 (M+1); Rt=4.61 min.
Example 50
(General Procedure 2)
4-Chlor-phenyl-methyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 3[(4-chlorophenyl)-methyl-carbamoyl]-1-methyl-3H-imidazol-1-ium iodide. The crude product was subjected to flash chromatography (ethyl acetate/heptan, 1:5) (77%, white crystals). HPLC-MS m/z=423.1 (M+1), Rt: 5.3 min.
δH(300 MHz; CDCl3): 3.42 (s, 3H), 6.99 (d, 1H, J 8.7), 7.10-7.20 (m, 4H), 7.30 (d, 2H, J 8.3), 7.37 (d, 2H, J 8.6), 7.88 (dd, 1H, J 8.7 and 2.2), 8.42 bs, 1H).
Example 51
(General Procedure 2)
4-Chlor-phenyl-methyl-carbamic acid 4-(3,5-dichloro-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(3,5-dichloro-pyridin-2-yloxy)-phenol and 3-[(4-chlorophenyl)-methyl-carbamoyl]-1-methyl-3H-imidazol-1-ium iodide. The crude product was subjected to flash chromatography (Quad flash 12, dichlormethane (67%). HPLC-MS m/z=422.9 (M+1), Rt: 5.5 min.
δH(300 MHz; CDCl3): 3.41 (s, 3H), 7.20-7.08 (m, 4H), 7.29 (d, 2H, J 9), 7.37 (dd, 2H, J 6.4 and 2.2), 7.76 (d, 1H, J 2.3), 7.93 (d, 1H, J 2.3).
Example 52
(General Procedure 2)
(4-Chloro-phenyl)-methyl-carbamic acid 4-(2-cyano-5-trifluoromethyl-pyridin-3-yloxy)-phenyl ester
The title compound was prepared from 4-(2-cyano-5-trifluoromethyl-pyridin-3-yloxy)-phenol and 3-[(4-chlorophenyl)-methyl-carbamoyl]-1-methyl-3H-imidazol-1-ium iodide. The crude product was purified by preparative HPLC (25%). HPLC-MS m/z=448.2 (M+1), Rt: 5.1 min.
δH(300 MHz; CDCl3): 3.43 (s, 3H), 7.12 (d, 2H, J 9.0), 7.19-7.35 (m, 4H), 7.39 (dd, 2H, J 6.6 and 1.8), 7.36-7.41 (m, 1H), 8.63 (d, 1H, J 0.7).
Example 53
General Procedure 1
Ethyl-phenyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(4-trifluoromethyl-pyridin-2-yloxy)-phenol and N-ethyl-N-phenylcarbamoyl chloride. The crude product was subjected to flash chromatography (ethyl acetate/heptane, 1:5) (78%, white crystals). HPLC-MS m/z=403.2 (M+1), Rt: 5.17 min.
δH(300 MHz; CDCl3): 1.25 (t, 3H, J 6.8), 3.83 (q, 2H, J 6.8), 6.98 (d, 1H, J 8.6), 7.12 (m, 4H), 7.32 (d, 2H, J 7.1), 7.32 (m, 1H), 7.41 (t, 2H, J 7.5), 7.87 (dt, 1H, J 8.7 and 2.7), 8.42 (bs, 1H).
Example 54
General Procedure 1
Ethyl-phenyl-carbamic acid 4-(4-trifluoromethyl-phenoxy)-phenyl ester
The title compound was prepared from 4-(4-trifluoromethyl-phenoxy)-phenol and N-ethyl-N-phenylcarbamoyl chloride. The crude product was subjected to flash chromatography (ethyl acetate/heptane, 1:5) (77%, white crystals. HPLC-MS m/z=402.1 (M+1), Rt: 5.6 min.
δH(300 MHz; CDCl3): 1.25 (t, 3H, J 7.2), 3.83 (q, 2H, J 7.2), 7.01 (d, 4H, J 8.6) 7.12 (d, 2H, J 8.3), 7.30 (t, 2H, J 6.8), 7.30 (m, 1H), 7.42 (dt, 2H, J 7.5), 7.54 (d, 2H, J 8.6)
Example 55
(General Procedure 2)
Benzyl-methyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 3-(benzyl-methyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide. The crude product was subjected to flash chromatography (ethyl acetate/heptane, (1:5) (69%, colourless oil) HPLC-MS m/z=403.2 (M+1), Rt: 5.11 min
δH(300 MHz; CDCl3): 3.03 (d, 3H, J 8.0), 4.64 (d, 2H, J 24.9), 7.00 (d, 1H), 7.10-7.26 (m, 4H), 7.30-7.50 (m, 5H), 7.88 (dd, 1H), 8.43 (s, 1H).
Example 56
(General Procedure 2)
Benzyl-methyl-carbamic acid 4-(3,5-dichloro pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(3,5-dichloro pyridin-2-yloxy)-phenol and 3-(benzyl-methyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide.
The crude product was subjected to flash chromatography (Quad flash 12, dichloromethane) (92%, oil). HPLC-MS m/z=403.2 (M+1), Rt: 5.4 min. H(300 MHz; CDCl3): 3.02 (d, 3H, J 7.2), 4.60 (d, 2H, J 24.1), 7.05-7.25 (m, 4H), 7.28-7.45 (m, 5H), 7.76 (d, 1H. J 2.3) 7.95 (d, 1H, J J 2.2).
Example 57
(General Procedure 2)
tert-Butyl-methyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 3-(tert-Butyl-methyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide. The crude product was subjected to preparative HPLC (34%, white crystals). HPLC-MS m/z=369.1 (M+1), Rt: 5.17 min.
δH(300 MHz; CDCl3): 1.47 (s, 9H), 3.08 (s, 3H), 6.99 (d, 1H), 7.09-7.20 (m, 4H), 7.87 (dd, 1H), 8.43 (bs, 1H).
Example 58
(General Procedure 2)
Isopropyl-methyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 3-(isopropyl-methyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide. The crude product was subjected to flash chromatography (ethyl acetate/heptane 1:5) (77%, white crystals). HPLC-MS m/z=355.1 (M+1), Rt: 4.80 min.
δH(300 MHz; CDCl3): 1.21 (m, 6H), 2.91 (d, 3H), 4.49 (qi, 1H), 6.99 (d, 1H), 7.10-7.25 (m, 4H) 7.88 (dd, 1H), 8.44 (s, 1H).
Example 59
(General Procedure 2)
Cyclohexyl-methyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester.
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 3-(cyclohexyl-methyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide. The crude product was subjected to flash chromatography (ethyl acetate/heptane, 1:5) (80%, white crystals). HPLC-MS m/z=395.2 (M+1), Rt: 5.7 min.
δH(300 MHz; CDCl3): 1.13 (m, 1H), 1.50-1.30 (m, 4H), 1.68 (d, 1H, J 13.2), 1.75-1.95 (m, 4H), 2.93 (d, 2H, J 12.1), 2.90-3.00 (m, 1H), 4.02 (t, 1H, J 12.1), 6.99 (d, 1H, J 8.7), 7.10-7.17 (4H), 7.88 (dd, 1H, J 8.7 and 2.3), 8.44 (s, 1H).
Example 60
General Procedure 1
Dimethyl-carbamic acid 4-(3,5-dichloro pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(3,5-dichloro pyridin-2-yloxy)-phenol and dimethyl-carbamoyl chloride. The crude product was purified by preparative HPLC (38%). HPLC-MS m/z=327.0 (M+1), Rt: 4.7 min.
δH(300 MHz; CDCl3): 2.92 (s, 3H), 3.05 (s, 3H), 7.10-7.25 (m, 4H), 8.17 (d, 1H), 8.34 (d, 1H).
Example 61
General Procedure 1
Pyrrolidine 1-carboxylic acid 4-(3,5-dichloro-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(3,5-dichloro-pyridine-2-yloxy)-phenol and 1-pyrrolidinecarbamoyl chloride. The crude product was purified by preparative HPLC (64%, white crystals). HPLC-MS m/z=353.0 (M+1), Rt: 5.00 min.
δH(300 MHz; CDCl3): 1.95 (qi, 4H, J 6.4), 3.48 (t, 2H, J 6.4), 3.56 (t, 2H, 6.4), 7.10 (t, 1H, J 2.7), 7.13 (t, 1H, J 2.7), 7.17 (t, 1H, J 2.0), 7.20 (t, 1H, J 2.3), 7.76 (d, 1H, J 2.6), 7.95 (d, 1H J, 2.6).
Example 62
(General Procedure 2)
2,3-Dihydro-indole-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester.
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 3-(2,3-dihydro-indole-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. The crude product was subjected to column chromatography(ethyl acetate/heptane, 1:5) (73%, crystals. HPLC-MS m/z=401.1) (M+1), Rt: 5.5 min.
δH(300 MHz; CDCl3): 3.24 (t, 2H, J 8.4), 4.25 (t, 2H, J 8.4), 7.10 (m, 2H), 7.15-7.35 (m, 6H), 7.90 (dd, 2H, J 8.7 and 2.6), 8.44 (bs, 1H).
Example 63
(General Procedure 2)
1,3-Dihydro-isoindole-2-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester.
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 3-(1,3-dihydro-isoindole-2-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. The crude product was recrystallized (ethanol) (≈100). HPLC-MS m/z=401.1 (M+1), Rt: 5.1 min.
δH(300 MHz; CDCl3): 4.85 (s, 2H), 4.95 (s, 2H), 7.01(d, 1H, J 8.69), 7.16 (dt, 2H, J 9.4 and 2.7), 7.22-7.29 (m, 2H), 7.30-7.35 (m, 4H), 7.89 (dd, 1H, J 8.6 and 3.0), 8.45 (m, 1H).
Example 64
(General Procedure 2)
Piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 1-methyl-3-(piperidine-1-carbonyl)-3H-imidazol-1-ium iodide. The crude product was recrystallized (ethanol) (45%). HPLC-MS m/z=367.02 (M+1), Rt: 4.9 min.
δH(300 MHz; CDCl3): 1.65 (bs, 6H), 3.58 (d, 4H, J 21.4), 6.99 (d, 1H, J 8.7), 7.10-7.24 (m, 4H), 7.88 (dd, 1H, J 8.7 and 2.2), 8.44 (bs, 1H).
Example 65
(General Procedure 2)
2-Methyl-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 1-methyl-3-(2-methyl-piperidine-1-carbonyl)-3H-imidazol-1-ium iodide. The crude product was purified by flash chromatography using a Quad flash 25 (ethyl acetate/heptane (1:6), (71%, white crystals). HPLC-MS m/z=381.1 (M+1), Rt: 5.2 min.
δH(300 MHz; CDCl3): 1.26 (d, 3H), 1.40-1.85 (m, 6H), 3.03 (t, 1H), 4.11 (dd, 1H), 4.50-4.65 (m, 1H), 6.95-7.02 (d, 1H), 7.10-7.20 m, 4H), 7.88 (dd, 1H), 8.43 (bs, 1H).
Example 66
(General Procedure 2)
3-Methyl-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 1-methyl-3-(3-methyl-piperidine-1-carbonyl)-3H-imidazol-1-ium iodide. The crude product was purified by flash chromatography using a Quad flash 25 (ethyl acetate/heptane (1:6), (75%, white crystals). HPLC-MS m/z=381.1 (M+1), Rt: 5.4 min.
δH(300 MHz; CDCl3): 0.94 (d, 3H), 1.05-1.20 (m, 1H), 1.50-1.80 (m, 3H), 1.80-1.95 (m, 1H), 2.45-2.75 (dt, 1H), 2.80-3.00 (m, 1H), 4.00-4.25 (m, 2H), 6.95-7.05 (d, 1H), 7.10-7.25 (m, 4H), 7.88 (dd, 1H), 8.43 (bs, 1H).
Example 67
(General Procedure 2)
4-Methyl-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 1-methyl-3-(4-methyl-piperidine-1-carbonyl)-3H-imidazol-1-ium iodide. The crude product was purified by flash chromatography using a Quad flash 25 (ethyl acetate/heptane (1:6), (73%, white crystals). HPLC-MS m/z=381.1 (M+1), Rt: 5.4 min.
δH(300 MHz; CDCl3): 1.00 (d, 3H), 1.23 (dq, 2H), 1.52-1.65 (m, 1H), 1.70 (d, 2H), 2.75-3.05 (m, 2H), 4.15-4.35 (m, 2H), 6.99 (d, 1H), 7.05-7.20 (m, 4H), 7.88 (dd, 1H), 8.43 (s, 1H).
Example 68
(General Procedure 2)
4-Benzyl-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 1-methyl-3-(4-benzyl-piperidine-1-carbonyl)-3H-imidazol-1-ium iodide. The crude product was purified by flash chromatography using a Quad flash 25 (ethyl acetate/heptane (1:6), (72%, white crystals). HPLC-MS m/z=457.2 (M+1), Rt: 6.0 min.
δH(300 MHz; CDCl3): 1.20-1.40 (m, 2H), 1.65-1.85 (m, 3H), 2.59 (d, 2H), 2.70-3.00 (m, 2H), 4.15-4.35 (m, 2H), 6.99 (d, 1H), 7.05-7.22 (m, 6H), 7.22-7.35 (m, 3H), 7.88 (dd, 1H), 8.43 (bs, 1H).
Example 69
(General Procedure 2)
3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 3-(3,4-dihydro-1H-isoquinoline-2-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. The crude product was recrystallized (ethanol) (53%). HPLC-MS m/z=415.2 (M+1), Rt: 5.3 min.
δH(300 MHz; CDCl3): 2.96 (d, 2H, J 4.9), 3.86 (dt, 2H, J 23.3 and 6.0), 4.79 (d, 2H, J 35.4), 7.00 (d, 1H, J 8.7), 7.10-7.23 (m, 8H), 7.88 (dt, 1H, J 8.7 and 2.1), 8.44 (s, 1H).
Example 70
(General Procedure 2)
3,4-Dihydro-2H-quinoline-1-carboxylic acid 4-(3,5-dichloro-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(3,5-dichloro-pyridin-2-yloxy)-phenol and 3-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. The crude product was recrystallized (ethanol) (68%). HPLC-MS m/z=415.2 (M+1), Rt: 5.6 min.
δH(300 MHz; CDCl3): 2.05 (Qi, 2H, J 6.8), 2.85 (t, 2H, J 6.8), 3.92 (t, 2H, J 6.8), 7.06 (dt, (1H, J 7.4 and 1.1), 7,11-7.19 (m, 4H), 7.21 (t, 1H, J 2.8), 7.24 (t, 1H, J 2.7), 7.77 (d, 1H, J 2.3), 7.75-7.80 (m, 1H), 7.95 (d, 1H, J 2.39).
Example 71
(General Procedure 2)
3,4-Dihydro-2H-quinoline-1-carboxylic acid 4-(2-cyano-5-trifluoromethyl-pyridin-3-yloxy)-phenyl ester
The title compound was prepared from 4-(2-cyano-5-trifluoromethyl-pyridin-3-yloxy)-phenol and 3-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. The crude product was subjected to flash chromatography (Quad flash 12, dichlormethane) (43%, oil).
HPLC-MS m/z=440.2 (M+1), Rt: 5.2 min.
δH(300 MHz; CDCl3): 2.07 (Qi, 2H, J 6.4), 2.87 (t, 2H, J 6.4), 3.94 (t, 2H, J 6.4), 7.25-7.04 m, 5H), 7.26-7.7.36 (m, 2H), 7.44 (d, 1H, J 1.5), 7.76 (bd, 1H, J 7.2), 8.64 (s, 1H).
Example 72
(General Procedure 3)
3,4-Dihydro-2H-quinoline-1-carboxylic acid 3-(3,4-dichloro-benzyl)-4-methyl-2-oxo-2H-chromen-7-yl ester
The title compound was prepared from 3-(3,4-dichloro-benzyl)-7-hydroxy-4-methyl-2H-chromen-2-one and 3-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. HPLC-MS m/z=494 (M+1), Rt: 5.86 min.
Example 73
(General Procedure 3)
3,4-Dihydro-2H-quinoline-1-carboxylic acid 3-benzyl-4-methyl-2-oxo-2H-chromen-7-yl ester
The title compound was prepared from 3-benzyl-7-hydroxy-4-methyl-2H-chromen-2-one and 3-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. HPLC-MS m/z=426 (M+1), Rt: 5.34 min.
Example 74
(General Procedure 3)
3,4-Dihydro-2H-quinoline-1-carboxylic acid 3-(2-chloro-6-fluoro-benzyl)-4-methyl-2-oxo-2H-chromen-7-yl ester
The title compound was prepared from 3-(2-chloro-6-fluoro-benzyl)-7-hydroxy-4-methyl-2H-chromen-2-one and 3-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. HPLC-MS m/z =478 (M+1), Rt: 5.58 min.
Example 75
(General Procedure 3)
3,4-Dihydro-2H-quinoline-1-carboxylic acid 3-(2,6-dichloro-benzyl)-4-methyl-2-oxo-2H-chromen-7-yl ester
The title compound was prepared from 3-(2,6-dichloro-benzyl)-7-hydroxy-4-methyl-2H-chromen-2-one and 3-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. HPLC-MS m/z=494 (M+1), Rt: 5.79 min.
Example 76
(General Procedure 3)
3,4-Dihydro-2H-quinoline-1-carboxylic acid 3-(2,6-dichloro-benzyl)-6-chloro-4-methyl-2-oxo-2H-chromen-7-yl ester
The title compound was prepared from 3-(2,6-dichloro-benzyl)-6-chloro-7-hydroxy-4-methyl-2H-chromen-2-one and 3-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. HPLC-MS m/z=530 (M+1), Rt: 6.09 min.
Example 77
(General Procedure 3)
3,4-Dihydro-2H-quinoline-1-carboxylic acid 3-(4-fluoro-benzyl)-4-methyl-2-oxo-2H-chromen-7-yl ester
The title compound was prepared from 3-(4-fluoro-benzyl)-7-hydroxy-4-methyl-2H-chromen-2-one and 3-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. HPLC-MS m/z=444 (M+1), Rt: 5.36 min.
Example 78
(General Procedure 3)
3,4-Dihydro-2H-quinoline-1-carboxylic acid 6-chloro-3-(2-chloro-6-fluoro-benzyl)-4-n-propy-2-oxo-2H-chromen-7-yl ester
The title compound was prepared from 3-(4-fluoro-benzyl)-6-chloro-7-hydroxy-4-n-propyl-2H-chromen-2-one and 3-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. HPLC-MS m/z=506 (M+1), Rt: 6.01 min.
Example 79
(General Procedure 3)
3,4-Dihydro-2H-quinoline-1-carboxylic acid 3-(4-methoxy-phenyl)-4-methyl-2-oxo-2H-chromen-7-yl ester
The title compound (130 mg, 59% yield, white solid) was prepared from 7-hydroxy-3-(4-methoxy-phenyl)-4-methyl-chromen-2-one (141 mg, 0.50 mmol) and 3-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide (188 mg, 0.51 mmol).
1H NMR (300 MHz, DMSO-d6): δ 2.00 (quintet, 2H), 2.30 (s, 3H), 2.82 (t, 2H), 3.81 (s, 3H), 3.88 (t, 2H), 7.02 (d, 2H), 7.08 (m, 1H), 7.19 (m, 2H), 7.27 (d, 2H), 7.31 (dd, 1H), 7.41 (d, 1H), 7.72 (d, 1H), 7.88 (d, 1H); HPLC-MS: m/z=442 (M+1); Rt=5.13 min.
Example 80
(General Procedure 3)
3,4-Dihydro-2H-quinoline-1-carboxylic acid 4-methyl-2-oxo-3-phenyl-2H-chromen-7-yl ester
The title compound (150 mg, 73% yield, white solid) was prepared from 7-hydroxy-4-methyl-3-phenyl-chromen-2-one (126 mg, 0.50 mmol) and 3-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide (188 mg, 0.51 mmol).
1H NMR (300 MHz, DMSO-d6): δ51.99 (quintet, 2H), 2.28 (s, 3H), 2.82 (t, 2H), 3.88 (t, 2H), 7.08 (m, 1H), 9.19 (m, 2H), 7.33 (m, 3H), 7.46 (m, 4H), 7.74 (d, 1H), 7.90 (d, 1H); HPLC-MS: m/z=412 (M+1); Rt=5.14 min.
Example 81
(General Procedure 3)
3,4-Dihydro-2H-quinoline-1-carboxylic acid 3-(2,5-dimethoxy-phenyl)-4-methyl-2-oxo-2H-chromen-7-yl ester
The title compound (50 mg, 21% yield, white solid) was prepared from 3-(2,5-dimethoxy-phenyl)-7-hydroxy-4-methyl-chromen-2-one (156 mg, 0.50 mmol) and 3-(3,4-dihydro-2H-quinoline-1H-quinoline-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide (188 mg, 0.51 mmol).
1H NMR (300 MHz, CDCl3): δ 2.08 (quintet, 2H), 2.34 (s, 3H), 2.87 (t, 2H), 3.73 (s, 3H), 3.80 (s, 3H), 3.94 (t, 2H), 6.74 (m, 1H), 6.93 (m, 2H), 7.07-7.26 (m, 5H), 7.68 (d, 1H), 7.77 (br.d, 1H); HPLC-MS: m/z=472 (M+1); Rt=5.04 min.
Example 82
General Procedure 3
3,4-Dihydro-2H-quinoline-1-carboxylic acid 3-(3,4-dimethoxy-phenyl)-4-methyl-2-oxo-2H-chromen-7-yl ester
The title compound (50 mg, 21% yield, oil) was prepared from 3-(3,4-dimethoxy-phenyl)-7-hydroxy-4-methyl-chromen-2-one (156 mg, 0.50 mmol) and 3-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide (188 mg, 0.51 mmol).
1H NMR (300 MHz, CDCl3): δ 2.08 (quintet, 2H), 2.33 (s, 3H), 2.88 (t, 2H), 3.89 (s, 3H), 4.03 (s, 3H), 4.06 (t, 2H), 6.65 (m, 2H), 6.96 (d, 1H), 7.05-7.25 (m, 5H), 7.68 (d, 1H), 7.77 (br.d, 1H); HPLC-MS: m/z=472 (M+1); Rt=5.14 min.
Example 83
General Procedure 2
7-Trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester.
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 1-methyl-3-(7-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carbonyl)-3H-imidazol-1-ium iodide. The crude product was subjected to preparative HPLC (66%). HPLC-MS m/z: 483.1 (M+1), Rt: 5.87 min.
δH(200 MHz; CDCl3): 2.08 (Qi, 2H), 2.90 (t, 2H), 3.98 (t, 2H), 7.03 (d, 1H), 7.1-7.40 (m, 6H), 7.90 (dd, 1H), 8.18 (s, 1H), 8.44 (d, 1H).
Example 84
General Procedure 1
Morpholine-4-carboxylic Acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and morpholine-4-carbonyl chloride. The crude product was purified by preparative HPLC (37%, white crystals). HPLC-MS m/z=369.1 (M+1), Rt: 4.3 min.
δH(300 MHz; CDCl3): 3.59 (bs, 2H), 3.67 (bs, 2H), 3.76 (m, 4H), 7.01 (d, 1H, J 8.7), 7.12-7.18 (m, 2H), 7.16 (d, 2H, J 3.7), 7.90 (dd, 1H, J 8.7 and 2.6), 8.43 (s, 1H).
Example 85
General Procedure 1
Morpholine-4-carboxylic acid 4-(3,5-dichloro-pyridin-4-yloxy)-phenyl ester
The title compound was prepared from 4-(3,5-dichloro-pyridin-4-yloxy)-phenol and morpholine-4-carbonyl chloride. The crude product was purified by preparative HPLC (66%, white crystals. HPLC-MS m/z=368.9 (M+1), Rt: 4.0 min.
δH(300 MHz; CDCl3): 3.57 (bs, 2H), 3.65 (bs, 2H) 3.74 (m, 4H), 6.83 (d, 1H, J9), 6.83 (m, 1H) 7.08 (d, 1H, J 9), 7.08 (m, 1H), 8.56 (s, 2H).
Example 86
General Procedure 1
Morpholine-4-carboxylic acid 4-(4-trifluoromethyl-phenoxy)-phenyl ester
The title compound was prepared from 4-(4-trifluoromethyl-phenoxy)-phenol and morpholine-4-carbonyl chloride. The crude product was purified by preparative HPLC (74%, white crystals). HPLC-MS m/z=368.1 (M+1), Rt: 4.85 min.
δH(300 MHz; CDCl3): 3.59 (bs, 2H), 3.68 (bs, 2H), 3.75 (m, 4H), 7.04 (d, 2H, J6.4), 7.04 (m, 2H), 7.14 (d, 1H, J 9), 7.13 (m, 1H), 7.57 (d, 2H, J 8.3).
Example 87
General Procedure 1
Morpholine-4-carboxylic Acid 4-tert-butoxy-phenyl ester
The title compound was prepared from 4-(tert-butoxy)-phenol and 4-morpholine-carbamoyl chloride. The crude product was recrystallized (ethanol) (69%, crystals); mp: 128.8-129.5° C. HPLC-MS m/z=280.1 (M+1), Rt: 3.6 min.
δH(300 MHz; CDCl3): 1.33 (s, 9H,), 3.58 (bs, 2H), 3.66,(bs, 2H), 6.8-7.1 (m, 4H)
Example 88
General Procedure 1
Morpholine-4-carboxylic acid 4-(3,5-dichloro-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(3,5-dichloro-pyridin-2-yloxy)-phenol and morpholine-4-carbonyl chloride. The crude product was purified by preparative HPLC (45%, crystals. HPLC-MS m/z=369.1 (M+1), Rt: 4.3 min.
Example 89
General Procedure 1
Morpholine-4-carboxylic acid 3-(4-fluoro-benzyl)-4-methyl-2-oxo-2H-chromen-7-yl ester
The title compound was prepared from 3-(4-fluorobenzyl)-7-hydroxy-4-methyl-2H-chromen-2-one and morpholine-4-carbonyl chloride. The crude product was recrystallized (ethanol) (78%, crystals). HPLC-MS m/z=398.0 (M+1), Rt: 4.3 min.
δH(200 MHz; DMSO-d6): 2.47 (s, 3H), 3.45 (bs, 2H), 3.56-3.72 (m, 6H), 3.96 (s, 2H), 7.08 (t, 2H), 7.16-7.35 (m, 4H, 7.83 (d, 1H).
Example 90
General Procedure 1
Morpholine-4-carboxylic acid 4-(5,7-bis-trifluoromethyl-[1,8]naphthypyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(5,7-bis-trifluoromethyl-[1,8]naphthypyridin-2-yloxy)-phenol and morpholine-4-carbonyl chloride. The crude product was tested without purification (≈100%). HPLC-MS m/z=488.0 (M+1), Rt: 5.0 min.
Example 91
General Procedure 3
Morpholine-4-carboxylic acid 3-(3,4-dichloro-benzyl)-4-methyl-2-oxo-2H-chromen-7-yl ester
The title compound was prepared from 3-(3,4-dichloro-benzyl)-7-hydroxy-4-methyl-2H-chromen-2-one and 3-(morpholine-4-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. HPLC-MS m/z=448 (M+1), Rt: 4.73 min.
Example 92
General Procedure 3
Morpholine-4-carbamic acid 3-(benzyl)-4-methyl-2-oxo-2H-chromen-7-yl ester
The title compound was prepared from 3-(benzyl)-7-hydroxy-4-methyl-2H-chromen-2-one and 1-methyl-3-(morpholine-4-carbonyl)-3H-imidazol-1-ium iodide. HPLC-MS m/z=380 (M+1), Rt: 4.05 min.
Example 93
General Procedure 3
Morpholine-4-carbamic acid 3-(2-chloro-6-fluoro-benzyl)-4-methyl-2-oxo-2H-chromen-7-yl ester
The title compound was prepared from 3-(2-chloro-6-fluoro-benzyl)-7-hydroxy-4-methyl-2H-chromen-2-one and 1-methyl-3-(morpholine-4-carbonyl)-3H-imidazol-1-ium iodide. HPLC-MS m/z=432 (M+1), Rt: 4.36 min.
Example 94
General Procedure 3
Morpholine-4-carbamic acid 3-(2,6-dichloro-benzyl)-4-methyl-2-oxo-2H-chromen-7-yl ester
The title compound was prepared from 3-(2,6-dichloro-benzyl)-7-hydroxy-4-methyl-2H-chromen-2-one and 1-methyl-3-(morpholine-4-carbonyl)-3H-imidazol-1-ium iodide. HPLC-MS m/z=448 (M+1), Rt: 4.59 min.
Example 95
General Procedure 3
Morpholine-4-carbamic acid 3-(2,6-dichloro-benzyl)-4-methyl-2-oxo-2H-chromen-7-yl ester
The title compound was prepared from 3-(2,6-dichloro-benzyl)-6-chloro-7-hydroxy-4-methyl-2H-chromen-2-one and 1-methyl-3-(morpholine-4-carbonyl)-3H-imidazol-1-ium iodide. HPLC-MS m/z=484 (M+1), Rt: 4.99 min.
Example 96
General Procedure 3
Morpholine-4-carbamic acid 3-(4-fluoro-benzyl)-4-methyl-2-oxo-2H-chromen-7-yl ester
The title compound was prepared from 3-(4-fluoro-benzyl)-7-hydroxy-4-methyl-2H-chromen-2-one and 1-methyl-3-(morpholine-4-carbonyl)-3H-imidazol-1-ium iodide. HPLC-MS m/z=398 (M+1), Rt: 4.12 min.
Example 97
General Procedure 3
Morpholine-4-carbamic acid 6-chloro-3-(2,6-dichloro-benzyl)-4-n-propy-2-oxo-2H-chromen-7-yl ester
The title compound was prepared from 3-(4-fluoro-benzyl)-6-chloro-7-hydroxy-4-n-propyl-2H-chromen-2-one and 1-methyl-3-(morpholine-4-carbonyl)-3H-imidazol-1-ium iodide. HPLC-MS m/z=460 (M+1), Rt: 4.90 min.
Example 98
General Procedure 3
Morpholine-4-carboxylic acid 4-methyl-2-oxo-3-phenyl-2H-chromen-7-yl ester
The title compound (75 mg, 41% yield, crystals) was prepared from 7-hydroxy-4-methyl-3-phenyl-chromen-2-one (126 mg, 0.50 mmol) and 1-methyl-3-(morpholine-4-carbonyl)-3H-imidazol-1-ium iodide (165 mg, 0.51 mmol).
1H NMR (300 MHz, CDCl3): δ 2.27 (s, 3H), 3.45 (br.s, 2H), 3.62 (br.s, 2H), 3.68 (m, 4H), 7.83 (dd, 1H), 7.32 (m, 3H), 7.43 (m, 3H), 7.87 (d, 1H); HPLC-MS: m/z=366 (M+1); Rt=3.79 min.
Example 99
General Procedure 3
Morpholine-4-carboxylic acid 3-(4-methoxy-phenyl)-4-methyl-2-oxo-2H-chromen-7-yl ester
The title compound (120 mg, 61% yield, crystals) was prepared from 7-hydroxy-3-(4-methoxy-phenyl)-4-methyl-chromen-2-one (141 mg, 0.50 mmol) and 1-methyl-3-(morpholine-4-carbonyl)-3H-imidazol-1-ium iodide (165 mg, 0.51 mmol).
1H NMR (300 MHz, DMSO-d6): δ 2.29 (s, 3H), 3.43 (br.s, 2H), 3.61 (br.s, 2H), 3.60 (m, 4H), 3.81 (s, 3H), 7.01 (d, 2H), 7.20-7.30 (m, 4H), 7.84 (d, 1H); HPLC-MS: m/z=396 (M+1); Rt=3.80 min.
Example 100
General Procedure 3
Morpholine-4-carboxylic acid 3-(3,4-dimethoxy-phenyl)-4-methyl-2-oxo-2H-chromen-7-yl ester
The title compound (120 mg, 56% yield) was prepared from 3-(3,4-dimethoxy-phenyl)-7-hydroxy-4-methyl-chromen-2-one (156 mg, 0.50 mmol) and 1-methyl-3-(morpholine-4-carbonyl)-3H-imidazol-1-ium iodide (165 mg, 0.51 mmol).
1H NMR (300 MHz, DMSO-d6): 52.29 (s, 3H), 3.46 (br.s, 2H), 3.62 (br.s, 2H), 3.67 (m, 4H), 3.74 (s, 3H), 3.81 (s, 3H), 6.83 (dd, 1H), 6.92 (d, 1H), 7.02 (d, 1H), 7.22 (dd, 1H), 7.30 (d, 1H), 7.85 (d, 1H); HPLC-MS: m/z=426 (M+1); Rt=3.80 min.
Example 101
General Procedure 3
Morpholine-4-carboxylic acid 3-(2,5-dimethoxy-phenyl)-4-methyl-2-oxo-2H-chromen-7-yl ester
The title compound (120 mg, 56% yield) was prepared from 3-(2,5-dimethoxy-phenyl)-7-hydroxy-4-methyl-chromen-2-one (156 mg, 0.50 mmol) and 1-methyl-3-(morpholine-4-carbonyl)-3H-imidazol-1-ium iodide (165 mg, 0.51 mmol).
1H NMR (300 MHz, CDCl3): δ 2.23 (s, 3H), 3.60 (br.s, 2H), 3.74 (br.s, 2H+s, 3H), 3.80 (m, 4H+s, 3H), 6.73 (m, 1H), 6.92 (m, 2H), 7.13 (m, 2H), 7.64 (d, 1H); HPLC-MSA): m/z=426 (M+1); Rt=3.69 min.
Example 102
General Procedure 2
2.6-dimethyl-morpholine-4-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 3-(2,6-dimethyl-morpholine-4-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. The crude product was purified by preparative HPLC (39%, colorless oil). HPLC-MS m/z=397.1 (M+1), Rt: 4.64 min.
δH(200 MHz; CDCl3): 1.22 (s, 3H), 1.25 (s, 3H), 2.50-3.00 (m, 2H), 3.55-3.9 (m, 2), 4.00-3.30 bd, 2H), 6.90-7.50 (m, 5H), 7.91 (dd, 1H), 8.44 (bs, 1H).
Example 103
Dimethylcarbamic acid benzotriazol-1-yl ester
Example 104
2-Oxo-N-p-tolylacetamide O-(cyclohexylcarbamoyl)-oxime
Example 105
10,11-Dihydro-dibenzo[a,d]cyclohepten-5-one O-cyclohexylcarbamoyl-oxime
Example 106
1-(4-Chlorophenyl)-non-1-en-3-one O-cyclohexylcarbamoyl-oxime
Example 107
1,7,7-Trimethyl-bicyclo[2.2.1]heptan-2-one O-cyclohexylcarbamoyl-oxime
Example 108
1-(4-Bromophenyl)-6-methyl-hept-1-en-3-one O-isopropylcarbamoyl-oxime
Example 109
1-(4-Chloro-phenyl)-non-1-en-3-one O-isopropylcarbamoyl-oxime
Example 110
4-Bromo-2-(4-chlorobenzyl)-2H-pyrazole-3-carbaldehyde O-methylcarbamoyl-oxime
Example 111
1-(4-Bromophenyl)-6-methyl-hept-1-en-3-one O-propylcarbamoyl-oxime
Example 112
N-(4-Fluorobenzylcarbamoyloxy)-isobutyrimidoyl Chloride
Example 113
N-(2-Hydroxy-2-phenylethylcarbamoyloxy)-isobutyrimidoyl Chloride
Example 114
Dimethylcarbamic acid 6-methanesulfonyl-indol-1-yl ester
Example 115
1-Biphenyl-4-yl-3-methylamino-propenone-cyclohexyl-carbamic acid
Example 116
Dimethylcarbamic acid 4-oxo-1,2,3-benzotriazin-3-yl ester
Example 117
[1-(3-Chloro-5-trifluoromethyl-pyridin-2-yl)-1H-pyrrol-2-yl]-carbamic acid 4-chloro-phenyl ester
Example 118
General Procedure 6
N-Methyl-N-phenyl-5-hexylsulfanyl-3-p-tolyl-[1, 2,4]triazole-1-carboxamide
The title compound was prepared from p-toluoyl chloride, 1-bromo-hexane and N-methyl-pheny-lcarbamoyl chloride. The crude product was recrystallized (ethanol/water); HPLC-MS m/z=409.2 (M+1), Rt: 6.66 min.
δH(300 MHz; [2H6]DMSO): 0.87 (t, 3H), 1.20-1.35 (m, 4H), 1.35-1.48 (m, 2H), 1.72 (Qi, 2H), 2.99 (s, 3H), 3.25 (t, 2H), 3.46 (s, 3H), 7.13-7.30 (m, 5H), 7.36 (t, 2H), 7.52 (d, 2H).
Example 119
General Procedure 6
N-Methyl-N-phenethyl-5-ethyl-3-(4-chlorophenyl)-[1,2,4]triazole-1-carboxamide
The title compound was prepared from 4-chlorobenzoyl chloride, 1-bromo-ethane and N-methyl-phenethyl-carbamoyl chloride. The crude product was subjected to preparative HPLC; HPLC-MS m/z=401.1 (M+1), Rt: 6.17 min.
δH(300 MHz; [2H6]DMSO): 1.37 (t, 3H), 2.98 (t, 2H), 3.11 (bs, 3H), 3.23 (Q, 2H), 3.80 (m, 2H), 7.10-7.40 (m, 5H), 7.58 (d, 2H), 8.03 (d, 2H).
Example 120
General Procedure 6
[3-(4-Chlorophenyl)-5-methylsulfanyl-[1,2,4]triazol-1-yl]-morpholin-4-yl-methanone
The title compound was prepared from 4-chlorobenzoyl chloride, methyl iodide and morpholine-4-carbonyl chloride. The crude product was used without further purification; HPLC-MS m/z=339.1 (M+1), Rt: 4.68 min.
δH(300 MHz; [2H6]DMSO): 2.68 (s, 3H), 3.25-3.65 (m, 4H), 3.65-3.85 (m, 4H), 7.58 (d, 2H), 8.03 (d, 2H).
Example 121
General Procedure 6
N,N-Dimethyl-5-methylsulfanyl-3-naphthalen-2-yl-[1,2,4]triazole-1-carboxamide
The title compound was prepared from 2-naphthoyl chloride, methyl iodide and dimethyl carbamoyl chloride. The crude product was recrystallized from ethanol; HPLC-MS m/z=313.2 (M+1), Rt: 4.91 min.
δH(300 MHz; [2H6]DMSO): 2.74 (s, 3H), 3.18 (s, 6H), 7.53-7.65 (m, 2H), 7.92-8.00 (m, 1H), 8.00-8.17 (m, 3H), 8.62 (s, 1H).
Example 122
General Procedure 6
N,N-Dimethyl-3-(4-chloro-phenyl)-5-ethylsulfanyl-[1,2,4]triazole-1-carboxamide
The title compound was prepared from 2-naphthoyl chloride, methyl iodide and dimethyl carbamoyl chloride. The crude product was recrystallized from ethanol; HPLC-MS m/z=311.0 (M+1), Rt: 5.13 min.
δH(300 MHz; [2H6]DMSO): 1.39 (t, 3H), 3.13 (bs, 6H), 3.26 (q, 2H), 7.58 (d, 2H), 8.03 (d, 2H),
Example 123
General Procedure 6
N,N-Dimethyl-3-biphenyl-4-yl-5-methylsulfanyl-[1,2,4]triazole-1-carboxamide
The title compound was prepared from 3-biphenylcarbonyl chloride, methyl iodide and dimethyl carbamoyl chloride. The crude product was without further purification; HPLC-MS m/z=339.1 (M+1), Rt: 5.27 in.
δH(300 MHz; [2H6]DMSO): 2.70 (s, 3H), 3.16 (bs, 6H), 7.40 (t, 1H), 7.50 (t, 2H), 7.73 (d, 2H), 7.82 (d, 2H), 8.12 (d, 2H).
Example 124
N,N-Dimethyl-3-(4-chloro-phenyl)-5-methylsulfanyl-[1,2,4]triazole-1-carboxamide
Example 126
N-(4-Chlorophenyl)-3-(4-chlorophenyl)-5-(3-hydroxypropyl)-pyrazole-1-carboxamide.
Example 127
5-Morpholin-4-yl-3-(4-phenoxyphenyl)-pyrazole-1-carboxylic acid Phenethylamide
Example 128
N-Phenyl-4-(4-chlorobenzenesulfonyl)-5-(4-chlorophenyl)-pyrazole-1-carboxamide
Example 129
N-(3,4-Dichlorophenyl)-2-phenyl-benzimidazole-1-carboxamide
Example 130
Dimethyl-carbamic acid 5-isopropylsulfanyl-4-(3-trifluoromethyl-phenyl)-4H-[1,2,4]triazol-3-yl ester
Example 131
Dimethyl carbamic acid 1-benzyl-2-oxo-3,5-diphenyl-1,2-dihydro-pyridin-4-yl ester
Example 132
Dimethyl-carbamic acid 7-methoxy-1-methyl-2-oxo-1,2-dihydro-quinolin-4-yl ester
Example 133
Dimethyl carbamic acid 4-(3-chloro-phenyl)-5-(4-methyl-benzylsulfanyl)-4H-[1,2,4]triazol-3-yl ester
Example 134
General Procedure 7
4-Methyl-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 1-methylpiperazine. White solid, m.p. 249-250° C. (decomp.); HPLC-MS m/z=458 (M+H), Rt: 3.15 min.; 1H NMR (DMSO-d6): δ 11.56 (br, 1H, NH), 8.61-8.54 (br, 1H, py-H6), 8.30-8.20 (m, 1H, py-H4), 7.32-7.19 (d+br s, 5H, py-H3+C6H 4), 4.5-3.0 (br, 10H, 8 CH+H2O), 2.79 (s, 3H, CH3); IR (KBr): ν 1713 (C═O).
Example 135
General Procedure 7
4-Benzyl-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 1-benzylpiperazine. White solid, m.p. 229-231° C.; HPLC-MS m/z=458 (M+H), Rt: 3.15 min.; 1H NMR (DMSO-d6): δ 11.17 (br, 1H, NH), 8.61-8.54 (br, 1H, py-H6), 8.30-8.20 (m, 1H, py-H4), 7.74-7.59 (m, 2H, arom.), 7.52-7.41 (m, 3H, arom.), 7.31-7.17 (d+br s, 5H, py-H3+C6H4), 4.5-4.0 (br, 4H, CH2+2 CH), 3.8-3.0 (br, 8H, 6 CH+H2O); IR (KBr): ν 1720 (C═O).
Example 136
General Procedure 7
4-(2-Hydroxyethyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 1-(2-hydroxyethyl)-piperazine. White solid, m.p. 255° C.; HPLC-MS m/z=412 (M+H), Rt: 2.12 min.; 1H NMR (DMSO-d6): δ 10.66 (br, 1H, NH), 8.61-8.54 (br, 1H, py-H6), 8.30-8.20 (m, 1H, py-H4), 7.32-7.20 (d+br s, 5H, py-H3+C6H4), 5.39 (br, 1H, OH), 4.18 (br, 2H), 3.87-3.70 (brt, 2H), 3.70-3.02 (br, 8H+water); IR (KBr): ν 1714 (C═O).
Example 137
General Procedure 7
4-(2-Oxo-2-pyrrolidin-1-yl-ethyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 1-(pyrrolidinocarbonylmethyl)-piperazine. White solid, m.p. 224° C.; HPLC-MS m/z=479 (M+H), Rt: 2.73 min.; 1H NMR (DMSO-d6): δ 10.43 (br, 1H, NH), 8.62-8.52 (br, 1H, py-H6), 8.31-8.20 (m, 1H, py-H4), 7.34-7.18 (d+br s, 5H, py-H3+C6H4), 4.40-3.05 (br, CH2 at 4.26+water at 3.37+N—C—H), 2.03-1.72 (m, 4H, CH2).
Example 138
General Procedure 7
4-Phenyl-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 1-phenyl-piperazine (0.5 mmol). The crude product (0.15 g) was partitioned between ethyl acetate (4 ml) and ethyldiisopropylamine (0.04 ml) dissolved in water (4 ml). The organic layer was washed with water (2×5 ml), dried over sodium sulfate. The drying agent was filtered off, and the solvent was removed from the filtrate in vacuo to give the title compound (0.095 g). White crystals, m.p. 117° C.; HPLC-MS m/z=444 (M+H), Rt: 5.12 min.; 1H NMR (DMSO-d6): δ 8.61-8.55 (br, 1H, py-H6), 8.29-8.20 (m, 1H, py-H4), 7.32-7.14 (m, 7H, py-H3+C6H4+2 arom.), 7.05-6.71 (m, 3H, arom.), 3.83-3.51 (br, 4H, 2 CH2), 3.28-2.99 (m, 4H, 2 CH2).
Example 139
General Procedure 8
Methyl-phenyl-carbamic acid pyrazol-1-yl ester
The title compound was prepared from 1-hydroxypyrazole and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to flash chromatography (Quad flash 25, EtOAc-heptane) (79%, oil which slowly crystallizes). HPLC-MS m/z=218.1 (M+1), Rt: 2.82 min. Mp 63-67° C.
δH(300 MHz; CDCl3): 3.45 (bs, 3H), 6.28 (s, 3H), 7.30-7.47 (m, 7H).
Example 140
General Procedure 8
Methyl-phenyl-carbamic acid 4-bromo-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-4-bromopyrazole and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to flash chromatography (Quad flash 25, EtOAc-heptane) (89%, oil). HPLC-MS m/z=298.0 (M+1), Rt: 3.77 min.
δH(300 MHz; CDCl3): 3.44 (bs, 3H), 7.32-7.47 (m, 7H).
Example 141
General Procedure 8
Methyl-phenyl-carbamic acid 3,4,5-tribromo-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-3,4,5-bromopyrazole and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to flash chromatography (Quad flash 25, EtOAc-heptane) (93%, colorless crystals). HPLC-MS m/z=455.8 (M+1), Rt: 4.88 min. Mp 115-119° C.
δH(300 MHz; CDCl3): 3.44 (bs, 3H), 7.36-7.48 (m, 5H).
Example 142
General Procedure 8
Methyl-phenyl-carbamic acid 3-(4-methoxy-phenyl)-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-3-(4-methoxyphenyl)pyrazole and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to flash chromatography (Quad flash 25, EtOAc-heptane) (93%, oil). HPLC-MS m/z=346.1 (M+Na), Rt: 4.21 min. δH(300 MHz; CDCl3): 3.45 (bs, 3H), 3.84 (s, 3H), 6.50 (d, 1H), 6.91 (d, 2H), 7.30-7.48 (m, 6H), 7.70 (d, 2H).
Example 143
General Procedure 8
Methyl-phenyl-carbamic acid imidazol-1-yl ester
The title compound was prepared from 1-hydroxyimidazole and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to flash chromatography (Quad flash 25, EtOAc-heptane) (68%, oil). HPLC-MS m/z=218.1 (M+1), Rt: 1.53 min.
δH(300 MHz; CDCl3): 3.45 (bs, 3H), 7.00 (bs, 1H), 7.05 (bs, 1H), 7.32-7.49 (m, 5H), 7.55 (bs, 1H).
Example 144
General Procedure 8
Methyl-phenyl-carbamic acid [1,2,3]triazol-1-yl ester
The title compound was prepared from 1-hydroxy-1,2,3-triazole and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to flash chromatography (Quad flash 25, EtOAc-heptane) (80%, oil). HPLC-MS m/z=219.1 (M+1), Rt: 2.50 min. Mp 105-106° C.
δH(300 MHz; CDCl3): 3.46 (bs, 3H), 7.00 (bs, 1H), 7.05 (bs, 1H), 7.31-7.48 (m, 5H), 7.62 (bs, 1H), 7.74 (s, 1H).
Example 145
General Procedure 7
4-(Isopropylcarbamoyl-methyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 1-methyl-piperazine. White solid, m.p. 234-235° C.; HPLC-MS m/z=466 (M+H), Rt: 2.75 min.; 1H NMR (DMSO-d6): δ 10.50 (br, 1H, NH), 8.66-8.54 (br, 2H, NH+py-H6), 8.30-8.20 (dd, 1H, py-H4), 7.31-7.20 (d+br s, 5H, py-H3+C6H4), 4.00-3.82 (br m, 5H, methin+4 CH), 3.70-3.09 (br, 9H, 6H+water), 1.11 (d, 6H, CH3).
Example 146
General Procedure 9
4-Cyclopentyl-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester.
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-cyclopentyl-piperazine. White solid, m.p. 294-295° C.; HPLC-MS m/z=436 (M+H), Rt: 2.92 min.; 1H NMR (DMSO-d6): δ 11.15 (br, 1H, NH), 8.60-8.55 (br, 1H, py-H6), 8.29-8.20 (m, 1H, py-H4), 7.32-7.21 (d+br s, 5H, py-H3+C6H4), 4.35-3.98 (br, 2H), 3.72-3.37 (br m, 5H), 3.29-2.97 (br, 2H), 2.12-1.45 (br m, 8H).
Example 147
General Procedure 9
4-Butyl-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-butyl-piperazine. White solid, m.p. 221-222° C.; HPLC-MS m/z=424 (M+H), Rt: 2.94 min.; 1H NMR (DMSO-d6): δ 10.86 (br, 1H, NH), 8.60-8.55 (br, 1H, py-H6), 8.29-8.21 (m, 1H, py-H4), 7.31-7.22 (d+br s, 5H, py-H3+C6H4), 4.32-4.03 (br, 2H), 3.65-3.44 (br m, 4H), 3.28-2.97 (br, 4H), 1.81-1.60 (brm, 2H), 1.45-1.22 (br, 4H), 0.92 (t, 3H, CH3).
Example 148
General Procedure 1
4-(Methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester
The title product was prepared from 4-Hydroxy-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester and N-methyl-N-phenylcarbamoyl chloride. The crude product was recrystallized from methanol (74%, white crystals).
1H NMR (CDCl3): 8.13 (d, 2H), 7.38-7.55 (m, 6H), 7.30 (t, 1H), 3.37 (s, 3H), 2.89 (s, 4H).
Example 149
General Procedure 10
4-Hydroxymethyl-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from 4-(5-trifluoromethyl-pyridin)-2-yloxy)-phenol and 4-hydroxymethylpiperidine. The crude product was subjected to flash chromatography (ethyl acetate/heptane, 1:2→2:1) (78%, light yellow oil). The purified product was crystallized from ethyl acetate/heptane (51%, white solid). HPLC-MS: m/z=397.1 (M+1); Rt: 4.08 min.
1H NMR (CDCl3): δ 8.44 (s, 1H), 7.88 (dd, 1H), 7.17 (d, 2H), 7.13 (d, 2H) 7.00 (d, 2H). 4.45-4.20 (bs, 2H), 3.55 (t, 2H), 3.10-2.75 (m, 2H), 1.95-1.65 (m, 3H), 1.47 (t, 1H), 1.29 (dq, 2H).
Example 150
General Procedure 10
4-Oxo-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from 4-(5-trifluoromethyl-pyridin)-2-yloxy)-phenol and 4-piperidone monohydrate. The solvent used was a mixture of dichloromethane and dimethyl-formamide (1:1). The crude product was subjected to preparative HPLC (7%, oil). HPLC-MS: m/z=381.1 (M+1); Rt: 4.17 min.
Example 151
General Procedure 10
4-[5-(4-Dimethylamino-phenyl)-1H-pyrazol-3-yl]-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from 4-(5-trifluoromethyl-pyridin)-2-yloxy)-phenol and N,N-dimethyl-4-[3-(4-piperidinyl)-1H-pyrazol-5-yl]aniline. The solvent used was a mixture of dichloromethane and dimethylformamide (1:2). The crude product was subjected to preparative HPLC (4%, oil). HPLC-MS: m/z=552.2 (M+1); Rt: 4.17 min.
1H NMR (CDCl3): 8.44 (d, 1H), 7.89 (dd, 1H), 7.53 (d, 2H), 7.22-7.10 (m, 4H), 7.00 (d, 1H). 6.73 (d, 2H), 6.27 (s, 1H), 4.45-4.20 (ds, 2H), 3.25-2.95 (m, 3H), 2.88 (s, 6H), 2.15-2.00 (m, 2H), 1.90-1.70 (dq, 2H).
Example 152
General Procedure 10
4-(5-Furan-2-yl-1H-pyrazol-3-yl)-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from 4-(5-trifluoromethyl-pyridin)-2-yloxy)-phenol and 4-[3-(2-furyl)-1H-pyrazol-5-yl]piperidine. The solvent used was a mixture of dichloromethane and dimethylformamide (1:2). The crude product was subjected to preparative HPLC (4%, oil).
HPLC-MS: m/z=499.1 (M+1); Rt: 4.60 min.
1H NMR (CDCl3): 8.44 (d, 1H), 7.89 (dd, 1H), 7.45 ((dd, 1H), 7.24-7.10 (m, 4H), 6.99 (d, 1H), 6.62 (d, 1H), 6.48 (dd, 1H), 6.34 (s, 1H), 4.40-4.25 (bs, 2H), 3.25-2.85 (m, 3H), 2.08 (d, 2H), 1.79 (dq, 2H).
Example 153
General Procedure 10
4-Benzylamino-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from 4-(5-trifluoromethyl-.pyridin)-2-yloxy)-phenol and benzyl-piperidin-4-yl-amine. The crude product was subjected to preparative HPLC (20%, oil).
HPLC-MS: m/z=472.2 (M+1); Rt: 3.34 min.
Example 154
General Procedure 10
4-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from 4-(5-trifluoromethyl-pyridin)-2-yloxy)-phenol and 2-Piperidin-4-ylmethyl-1,2,3,4-tetrahydro-isoquinoline. The crude product was subjected to preparative HPLC (12%, oil). HPLC-MS: m/z=512.2 (M+1); Rt: 3.21 min.
Example 155
General Procedure 1
Methyl-phenyl-carbamic acid 4-(1,3,5-trimethyl-1H-pyrazol-4-ylmethyl)-phenyl ester
The title product was prepared from 4-[(1,3,5-trimethyl-1H-pyrazol-4-yl)methyl]phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (88%, oil). HPLC-MS: m/z=350.0 (M+1); Rt: 3.52 min. (66% purity).
Example 156
General Procedure 10
3-Hydroxymethyl-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from 4-(5-trifluoromethyl-pyridin)-2-yloxy)-phenol and 3-hydroxymethyl-piperidine. The crude product was subjected to flash chromatography (Quad Flash 12, ethyl acetate/heptane 1:2). (56%, colourless oil). HPLC-MS: m/z=397.1 (M+1); Rt: 4.19 min.
1H NMR (DMSO-d6, 90° C.): 8.37 (s, 1H), 8.00 (dd, 1H), 6.95-7.10 (m, 5H), 4.09 (bs, 1H), 3.91 (dd, 1H), 3.78 (d, 1H), 3.21 (m, 1H), 3.15 (t, 1H), 2.80-2.90 (m, 1H), 2.65 (t, 1H), 1.45-1.70 (m, 3H), 1.25-1.45 (m, 1H), 1.08 (q, 1H).
Example 157
General Procedure 10
3-Hydroxy-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from 4-(5-trifluoromethyl-pyridin)-2-yloxy)-phenol and 3-hydroxy-piperidine. The-crude product-was-subjected to flash chromatography (Quad Flash 12, ethyl acetate/heptane (1:2) (56%, colourless oil). HPLC-MS:,m/z=383.0 (M+1); Rt: 3.98 min.
1H NMR (CDCl3): 8.43 (s, 1H), 7.89 (dd, 1H), 7.23-7.10 (m, 4H), 7.00 (d, 1H), 3.80-4.00 (m, 2H), 3.60-3.80 (m, 1H), 3.25-3.50 (m, 2H), 1.80-2.05 (m, 2H), 1.50-1.70 (m, 3H).
Example 158
General Procedure 10
4-Benzyl-4-hydroxy-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from 4-(5-trifluoromethyl-pyridin)-2-yloxy)-phenol and 4-benzyl-4-hydroxypiperidine. The crude product was subjected to flash chromatography (Quad Flash 12, ethyl acetate/heptane (1:2) (48%, colourless oil). HPLC-MS: m/z=473.0 (M+1); Rt: 5.04 min.
1H NMR (CDCl3): 8.44 (s, 1H), 7.89 (dd, 1H), 7.28-7.45 (m, 3H), 7.10-7.24 (m, 6H), 7.00 (d, 1H), 4.00-4.14 (bs, 2H), 3.15-3.45 (dt, 2H), 2.81 (s, 2H), 1.66-1.85 (dt, 2H), 1.55-1.65 (m, 2H), 1.27 (s, 1H).
Example 159
General Procedure 1
Methyl-phenyl-carbamic acid 4-(2-cyano-ethyl)-phenyl ester
The title product was prepared from 3-(4-hydroxyphenyl)proprionitrile and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (11%, colourless oil). HPLC-MS: m/z=281.2 (M+1); Rt: 3.75 min, purity 80%.
1H NMR (CDCl3): 7.26-7.50 (m, 7H), 7.00-7.15 (m, 2H), 3.42 (s, 3H), 2.94 (t, 2H), 2.59 8t, 2H).
Example 160
General Procedure 1
Methyl-phenyl-carbamic acid 4-([1,2,3,4]thiatriazol-5-ylamino)-phenyl ester
The title product was prepared from 4-(1,2,3,4-thiatriazol-5-ylamino)phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (10%, light brown solid material). HPLC-MS: m/z=328.0 (M+1); Rt: 3.69 min, purity 81%.
1H NMR (CDCl3): 7.61 (d, 2H), 7.38-7.52 (m, 4H), 7.19-7.35 (m, 2H), 6.86-6.95 (m, 3.35 (s, 3H), 3.33 (s, 1H).
Example 161
General Procedure 1
Methyl-phenyl-carbamic acid 4-pentyl-phenyl ester
The title product was prepared from 4-pentylphenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (4%, light brown oil). HPLC-MS: m/z=298.2 (M+1); Rt: 5.61 min.
1H NMR (CDCl3): 7.31-7.50 (m, 4H), 7.18-7.30 (m, 1H), 7.13 (d, 2H), 7.00 d, 2H), 3.42 (s, 3H), 2.57 (t, 2H), 1.58 (qi, 2H), 1.20-1.40 (m, 4H), 0.87 (t, 3H).
Example 162
General Procedure 1
Methyl-phenyl-carbamic acid 4-(2-methoxy-ethyl)-phenyl ester
The title product was prepared from 4-(2-methoxyethyl)phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (4%, light yellow oil). HPLC-MS: m/z=286.1 (M+1); Rt: 4.01 min.
1H NMR (CDCl3): 7.30-7.48 (m, 4H), 7.12-7.30 (m, 3H), 7.03 (d, 2H), 3.56 (t, 2H), 3.42 (s, 3H), 3.33 (s, 3H), 2.85 (t, 2H).
Example 163
General Procedure 10
4-Hydroxy-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from 4-(5-trifluoromethyl-pyridin)-2-yloxy)-phenol and 4-hydroxypiperidine. The crude product was subjected to flash chromatography (ethyl acetate/heptane (1:1) (48%, light yellow oil). HPLC-MS: m/z=383.0 (M+1); Rt: 3.88 min. purity 93%.
1H NMR (CDCl3): 8.44 (s, 1H), 7.89 (dd, 1H), 7.08-7.20 (m, 4H), 6.99 (d, 1H), 3.85-4.10 (m, 3H), 3.20-3.45 (m, 2H), 1.85-2.02 (m, 2H), 1.50-1.70 (m, 3H).
Example 164
General Procedure 1
Methyl-phenyl-carbamic acid 4-acetyl-phenyl ester
The title product was prepared from 4′-hydroxyacetophenone and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (78%, colourless oil). HPLC-MS: m/z=270.1 (M+1); Rt: 3.62 min.
1H NMR (CDCl3): 7.96 (d, 2H), 7.15-7.7.48 (m, 7H), 3.43 (s, 3H), 2.58 (s, 3H).
Example 165
General Procedure 1
Methyl-phenyl-carbamic acid pyridin-4-yl ester
The title product was prepared from 4-hydroxypyridine and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (11%, yellow solid). HPLC-MS: m/z=229.2 (M+1); Rt: 1.66 min, purity: 67%.
Example 166
General Procedure 1
Methyl-phenyl-carbamic acid pyridin-3-yl ester
The title product was prepared from 3-hydroxypyridine and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (94%, colourless oil).
HPLC-MS: m/z=229.2 (M+1); Rt: 2.54 min.
1H NMR (CDCl3): 10.70 (bs, 1H), 8.50 (d, 1H), 8.45-8.65 (m, 1H), 7.70-7.90 (m, 1H), 7.51 (dd, 1H), 7.42 (d, 2H), 7.34 (d, 2H), 7.28-7.37 (m, 1H), 3.43 (s, 3H).
Example 167
General Procedure 1
Methyl-phenyl-carbamic acid 6-methyl-pyridin-3-yl ester
The title product was prepared from 3-hydroxy-6-methyl-pyridine and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (79%, colourless oil). HPLC-MS: m/z=243.1 (M+1); Rt: 2.24 min.
1H NMR (CDCl3): 10.8 (bs, 1H), 8.54 (m, 1H), 7.76 (m, 1H), 7.26-7.50 (m, 6H), 3.42 (s, 3H), 2.69 (s, 3H).
Example 168
General Procedure 1
Methyl-phenyl-carbamic acid isoquinolin-1-yl ester
The title product was prepared from and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (15%, colourless oil). HPLC-MS: m/z=279.1 (M+1); Rt: 3.67 min.
Example 169
General Procedure 1
Methyl-phenyl-carbamic acid 3-phenoxy-phenyl ester
The title product was prepared from 3-phenoxyphenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (79%, colourless oil). HPLC-MS: m/z=320.1 (M+1); Rt: 5.16 min.
1H NMR (CDCl3): 7.20-7.50 (m, 8H), 7.11 (t, 1H), 6.95-7.06 (m, 2H), 6.70-6.93 (m, 3H), 3.40 (s, 3H).
Example 170
General Procedure 1
Methyl-phenyl-carbamic acid 3-acetyl-phenyl ester
The title product was prepared from m-hydroxyacetophenone and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (62%, colorless oil). HPLC-MS: m/z=270.1 (M+1); Rt: 3.56 min.
1H NMR (CDCl3): 7.78 (d, 1H), 7.68 (s, 1H), 7.22-7.50 (m, 7H), 3.43 (s, 3H), 2.58 (s, 3H).
Example 171
General Procedure 1
Methyl-phenyl-carbamic acid 4-acetyl-2-carbamoyl-phenyl ester
The title product was prepared from 5-acetylsalicylamide and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (87%, white solid). HPLC-MS: m/z=313.1 (M+1); Rt: 2.51 min.
1H NMR (CDCl3): 8.47 (bs, 1H), 8.08 (dd, 1H), 7.30-7.52 (m, 6H), 6.05 (bs, 1H), 5.38 (bs, 1H), 3.43 (s, 3H), 2.61 (s, 3H).
Example 172
General Procedure 1
Methyl-phenyl-carbamic acid 4-acetyl-3-methyl-phenyl ester
The title product was prepared from 4′-hydroxy-2′-methylacetophenone and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (76%, white crystals). HPLC-MS: m/z=284.2 (M+1); Rt: 3.95 min.
1H NMR (CDCl3): 7.72 (d, 1H), 7.22-7.47 (m, 5H), 6.90-7.12 (m, 2H), 3.43 (s, 3H), 2.55 (s, 3H), 2.52 (s, 3H).
Example 173
General Procedure 1
Methyl-phenyl-carbamic acid 1-oxo-indan-4-yl ester
The title product was prepared from 4-hydroxyindanone and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (77%, light yellow oil). HPLC-MS: m/z=282.1 (M+1); Rt: 3.54 min.
1H NMR (CDCl3): 7.61 (d, 1H), 7.27-7.50 (m, 7H), 3.45 (s, 3H), 3.00 (ds, 2H), 2.67 (t, 2H).
Example 174
General Procedure 1
Methyl-phenyl-carbamic acid benzothiazol-2-yl ester
The title product was prepared from 2-benzothiazolol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (70%, white crystals). HPLC-MS: m/z=307.1 (M+1); Rt: 4.24 min, purity 85%.
1H NMR (CDCl3): 7.78 (m, 2H), 7.28-7.50 (m, 7H), 3.40-3.70 (d, 3H).
Example 175
General Procedure 1
Methyl-phenyl-carbamic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester
The title product was prepared from 6-hydroxy-1-tetralone and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (49%, colorless oil). HPLC-MS: m/z=296.2 (M+1); Rt: 3.90 min.
1H NMR (CDCl3): 8.04 (d, 2H), 7.27-7.50 (m, 5H), 7.00-7.10 (m, 2H), 3.42 (s, 3H), 2.94 (t, 2H), 2.63 (t, 2H), 2.12 (qu, 2H).
Example 176
General Procedure 1
Methyl-phenyl-carbamic acid benzo[d]isoxazol-3-yl ester
The title product was prepared from benzo[d]isoxazol-3-ol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (53%, colorless oil). HPLC-MS: m/z=291.1 (M+23); Rt: 4.05 min.
1H NMR (CDCl3): 7.60-7.75 (m, 1H), 7.49-7.60 (m, 2H), 7.38-7.48 (m, 4H), 7.28-7.36 (m, 2H), 3.46 (s, 3H).
Example 177
General Procedure 1
Methyl-phenyl-carbamic acid pyridin-2-yl ester
The title product was prepared from 2-hydroxypyridine and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (57%, colorless oil). HPLC-MS: m/z=229.1 (M+23); Rt: 2.80 min.
1H NMR (CDCl3): 8.38 (d, 1H), 7.75 (t, 1H), 7.35-7.45 (m, 4H), 7.22-7.34 (m, 1H), 7.14-7.21 (t, 1H), 6.99-7.15 (bs, 1H), 3.44 (s, 3H).
Example 178
General Procedure 1
Methyl-phenyl-carbamic acid 1-(methyl-phenyl-carbamoyl)-1H-benzimidazol-2-yl ester
The title product was prepared from 2-hydroxybenzimidazole and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (14%, white crystals). HPLC-MS: m/z=401.2 (M+1); Rt: 3.88 min, purity: 83%.
1H NMR (CDCl3): 7.32 (dd, 2H), 7.24-7.28 (m, 2H), 7.21-7.24 (m, 2H), 7.29 (t,1H), 7.12-7.19 (m, 5H), 7.09-7.15 m, 2H), 3.28 (s, 6H).
Example 179
General Procedure 1
Methyl-phenyl-carbamic acid 4-[(pyridine-3-carbonyl)-amino]-phenyl ester
The title product was prepared from N-(4-Hydroxy-phenyl)-nicotinamide and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (1%, light yellow crystals). HPLC-MS: m/z=348.1 (M+1); Rt: 2.96 min.
Example 180
General Procedure 11
4-Pyrrolidin-1-yl-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from 4-(5-trifluoromethyl-pyridin)-2-yloxy)-phenol and 4-(1-pyrrolidinyl)piperidine. The crude product was used without further purification (68%, white solid). HPLC-MS: m/z=436.2 (M+1); Rt: 2.98 min.
1H NMR (DMSO-d6): 10.90 (bs, 1H), 8.57 (s, 1H), 8.24 (dd, 1H), 7.15-7.30 (m, 5H), 4.00-4.40 (m, 2H), 3.45-3.60 (m, 2H), 2.75-3.25 (m, 4H), 2.05-2.25 (d, 2H), 1.80-2.05 (m, 5H), 1.60-1.80 (m, 2H).
Example 181
General Procedure 12
Methyl-o-tolyl-carbamic acid 4-(trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from −4-(5-trifluoromethyl-pyridin)-2-yloxy)-phenol and N-methyl-o-toluidine. The crude product was subjected to preparative HPLC (51%, colorless oil). HPLC-MS: m/z=403.2 (M+1); Rt: 4.89 min.
1H NMR (CDCl3): 8.40 (s, 1H), 7.87 (dd, 1H), 7.05-7.18 (m, 4H), 6.96 (d, 1H), 3.30 (s, 3H), 2.36 (s, 3H).
Example 182
General Procedure 12
Methyl-pyridin-2-yl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from 4-(5-trifluoromethyl-pyridin)-2-yloxy)-phenol and 2-(methylamino)pyridine. The crude product was subjected to preparative HPLC (55%, white solid). HPLC-MS: m/z=390.1 (M+1); Rt: 4.31 min.
Example 183
General Procedure 12
Methyl-m-tolyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from 4-(5-trifluoromethyl-pyridin)-2-yloxy)-phenol and N-methyl-m-toluidine. The crude product was subjected to preparative HPLC (51%, colorless oil). HPLC-MS: m/z=403.2 (M+1); Rt: 4.98 min.
1H NMR (CDCl3): 8.42 (s, 1H), 7.88 (dd, 1H), 7.28 (d, 1H), 7.05-7.25 (m, 7H), 6.97 (d, 1H), 3.41 (s, 3H), 2.38 (s, 3H).
Example 184
General Procedure 12
3-Chloro-phenyl)-methyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from 4-(5-trifluoromethyl-pyridin)-2-yloxy)-phenol and 3-chloro-N-methylaniline. The crude product was subjected to preparative HPLC (54%, colorless oil). HPLC-MS: m/z=423.1 (M+1); Rt: 5.07 min.
1H NMR (CDCl3): 8.42 (m, 1H), 7.88 (dd, 1H), 7.39 (m, 1H), 7.33 (t, 1H), 7.22-7.30 (m, 2H), 7.10-7.7.22 (m, 4H), 6.99 (d, 1H), 3.43 (s, 3H).
Example 185
General Procedure 12
Methyl-p-tolyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from 4-(5-trifluoromethyl-pyridin)-2-yloxy)-phenol and N-methyl-p-toluidine. The crude product was subjected to preparative HPLC (54%, white solid). HPLC-MS: m/z=403.2 (M+1); Rt: 4.99 min.
1H NMR (CDCl3): 8.42 (s, 1H), 7.87 (dd, 1H), 7.05-7.30 (m, 8H), 6.98 (d, 1H), 3.40 (s, 3H), 2.36 (s, 3H).
Example 186
General Procedure 14
Methyl-phenyl-carbamic acid 4-(3-pyridin-3-yl-acryloyl)-phenyl ester
The title product was prepared from 1-(4-hydroxy-phenyl)-3-pyridin-3-yl-prop-2-en-1-one and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (56%, off-white solid). HPLC-MS: m/z=359.0 (M+1); Rt: 3.27 min.
1H NMR (CDCl3): 8.87 (d, 1H), 8.65 (dd, 1H), 8.03 (d, 2H), 7.97 (dt, 1H), 7.79 (d, 1H), 7.57 (d, 1H), 7.33-7.47 (m, 5H), 7.27-7.33 (m, 3H), 3.44 (s, 3H), 3.49 (t, 1H), 1.21 (t, 1H).
Example 187
General Procedure 14
Methyl-phenyl-carbamic acid 4-[3-(3,4,5-trimethoxy-phenyl)-acryloyl]-phenyl ester
The title product was prepared from 1-(4-hydroxyphenyl)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (82%, yellow solid). HPLC-MS: m/z=448.2 (M+1); Rt: 4.61 min.
1H NMR (CDCl3): 8.01 (d, 2H), 7.70 (d, 1H), 7.33-7.47 (m, 4H), 7.28-7.33 (m, 2H), 6.86 (s, 1H), 3.92 (s, 6H), 3.90 (s, 3H), 3.45 (s, 3H).
Example 188
General Procedure 14
Methyl-phenyl-carbamic acid 4-diethylcarbamoyl-2-methoxy-phenyl ester
The title product was prepared from N,N-diethyl-4-hydroxy-3-methoxy-benzamide and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (58%, colorless oil). HPLC-MS: m/z=357.1 (M+1); Rt: 3.64 min.
1H NMR (CDCl3): 7.34-7.44 (m, 4H), 7.21-7.28 (m, 1H), 7.03-7.09 (d, 1H), 6.99 (d, 1H), 6.90 (dd, 1H), 3.87 (s, 3H), 3.15-3.65 (bs, 4H), 3.43 (s, 3H), 1.05-1.35 (m, 6H).
Example 189
General Procedure 14
Methyl-phenyl-carbamic acid 3-phenylcarbamoyl-phenyl ester
The title product was prepared from 3-hydroxy-N-phenyl-benzamide and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (54%, white solid). HPLC-MS: m/z=347.2 (M+1); Rt: 4.01 min.
1H NMR (CDCl3): 7.76 (s, 1H), 7.68 (d, 1H), 7.58-7.65 (m, 3H), 7.27-7.51 (m, 8H), 7.15 (t, 1H), 3.44 (s, 3H).
Example 190
General Procedure 14
Methyl-phenyl-carbamic acid quinolin-7-yl ester
The title product was prepared from 7-hydroxyquinoline and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (28%, white solid). HPLC-MS: m/z=279.1 (M+1); Rt: 2.55 min.
1H NMR (CDCl3): 8.93 (dd, 1H), 8.18 (d, 1H), 7.83-7.86 (m, 1H), 7,82 (d, 1H), 7.35-7.50 (m, 6H), 7.27-7.32 (m, 1H), 3.47 (s, 1H).
Example 191
General Procedure 14
Methyl-phenyl-carbamic acid 4-(4-methyl-piperazine-1-carbonyl)-phenyl ester
The title product was prepared from 1-(4-hydroxybenzoyl)-4-methyl-piperazine and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (22%, colorless oil). HPLC-MS: m/z=354.1 (M+1); Rt: 2.07 min.
1H NMR (CDCl3): 7.37-7.49 (m, 4H), 7.28-7.37 (m, 3H), 7.16-7.25 (m, 2H), 4.60-4.00 (bs, 2H), 3.43 (s, 3H), 3.35-3.90 (bs, 4H), 2.82 (s, 3H) 2.55-2.90 (bs, 2H).
Example 192
General Procedure 14
Methyl-phenyl-carbamic acid 3-acetylamino-phenyl ester
The title product was prepared from 3-acetamidophenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (66%, white solid). HPLC-MS: m/z=285.1 (M+1); Rt: 3.09 min.
1H NMR (CDCl3): 7.40-7.49 (m, 1H), 7.31-7.40 (m, 5H), 7.25-7.30 (m, 1H), 7.22 (d, 1H), 7.14 (d, 1H), 6-84 (bd, 1H), 3.42 (s, 3H), 2.10 (s, 3H).
Example 193
General Procedure 14
Methyl-phenyl-carbamic acid 4-benzoyl-phenyl ester
The title product was prepared from (4-hydroxy-phenyl)-phenyl-methanone and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (36%, colorless oil). HPLC-MS: m/z=332.2 (M+1); Rt: 4.42 min.
1H NMR (CDCl3): 7.75-7.85 (m, 4H), 7.58 (ft, 1H), 7.33-7.52 (m, 6H), 7.27-7.32 (m, 1H), 7.18-7.25 (m, 2H), 3.44 (s, 3H).
Example 194
General Procedure 14
Methyl-phenyl-carbamic acid biphenyl-3-yl ester
The title product was prepared from 3-phenylphenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (52%, colorless oil). HPLC-MS: m/z=304.2 (M+1); Rt: 4.75 min.
1H NMR (CDCl3): 7.52-7.67 (m, 2H), 7.22-7.52 (m, 11H), 7.03-7.22 (m, 1H), 3.45 (s, 3H).
Example 195
General Procedure 14
Methyl-phenyl-carbamic acid 1H-indol-4-yl ester
The title product was prepared from 4-hydroxyindole and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (48%, off-white solid). HPLC-MS: m/z=267.1 (M+1); Rt: 3.57 min.
1H NMR (CDCl3): 8.20 (ds, 1H), 7.36-7.50 (m, 4H), 7.17-7.35 (m, 2H), 7.08-7.17 (m, 2H), 6.94 (d, 1H), 6.44 (s, 1H), 3.48 (s, 3H).
Example 196
General Procedure 14
Methyl-phenyl-carbamic acid 5,6,7,8-tetrahydro-naphthalen-1-yl ester
The title product was prepared from 5,6,7,8-tetrahydro-1-naphthol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (42%, colorless oil). HPLC-MS: m/z=282.1 (M+1); Rt: 4.77 min.
1H NMR (CDCl3): 7.33-7.45 (m, 4H), 7.22-7.32 (m, 1H), 7.02-7.13 (t, 1H), 6.82-7.96 (m, 2H), 3.42 (s, 3H), 2.70-2.82 (m, 2H), 2.50-2.65 (m, 2H), 1.62-1.83 (m, 4H).
Example 197
General Procedure 14
Methyl-phenyl-carbamic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl ester
The title product was prepared from 5,6,7,8-tetrahydro-1-naphthol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (60%, colorless oil). HPLC-MS: m/z=296.1 (M+1); Rt: 3.81 min.
1H NMR (CDCl3): 7.91 (dd, 1H), 7.21-7.50 (m, 7H), 3.44 (s, 3H), 2.60-2.93 (bs, 2H), 2.62 (t, 2H), 2.02-2.20 (m, 2H).
Example 198
General Procedure 14
Methyl-phenyl-carbamic acid 1,3-dioxo-1,3-dihydro-isobenzofuran-4-yl ester
The title product was prepared from 4-hydroxy-isobenzofuran-1,3-dione and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (50%, white solid). HPLC-MS: m/z=298.1 (M+1); Rt: 2.58 min, purity: 85%.
1H NMR (CDCl3): 7.90 (d, 1H), 7.48-7.62 (m, 2H), 7.28-7.45 (m, 5H), 3.38 (s, 3H).
Example 199
General Procedure 1
Methyl-phenyl-carbamic acid 4-(5-chloro-pyridin-2-yloxy)-phenyl ester
The title product was prepared from 4-(5-chloro-pyridin-2-yloxy)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to column chromatography (ethyl acetate/heptane (1:5) (85%, white solid). HPLC-MS: m/z=355.1 (M+1); Rt: 4.56 min.
1H NMR (CDCl3): 8.10 (d, 1H), 7.62 (dd, 1H), 7.31-7.44 (m, 4H), 7.25-7.30 (m, 1H), 7.05-7.20 (m, 4H), 6.84 (d, 1H), 3.43 (s, 3H).
Example 200
General Procedure 14
3-Fluoro-phenyl)-methyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from 4-(5-Trifluoromethyl-pyridin-2-yloxy)-phenol and 3-fluoro-N-methylaniline. The crude product was subjected to preparative HPLC (31%, white solid). HPLC-MS: m/z=407.0 (M+1); Rt: 4.93 min.
1H NMR (CDCl3): 8.42 (s, 1H), 7.88 (dd, 1H), 7.36 (q, 1H), 7.07-7.24 (m, 6H), 7.00 (d, 1H), 7.92-7.05 (m, 1H), 3.44 (s, 3H).
Example 201
General Procedure 11
4-Benzyl-piperazine-1-carboxylic acid 4-(5-chloro-pyridin-2-yloxy)-phenyl ester
The title product was prepared from 4-(5-chloro-pyridin-2-yloxy)-phenol and 1-benzylpiperazine. The title product precipitated from the reaction mixture and was collected by filtration (88%, off-white solid). HPLC-MS: m/z=424.1 (M+1); Rt: 2.91 min.
1H NMR (CDCl3): 13.86 (bs, 1H), 8.11 (d, 1H), 7.60-7.70 (m, 3H), 7.45-7.55 (m, 3H), 7.05-7.20 (m, 4H), 6.98 (d, 1H), 4.26-4.40 (m, 2H, 4.15-4.25 (m, 2H), 3.38-3.53 (m, 2H), 3.60-4.15 (m,-2H), 2.72-2.92 (m, 2H).
Example 202
General Procedure 11
4-Pyridin-3-ylmethyl-piperazine-1-carboxylic acid 4-(5-chloro-pyridin-2-yloxy)-phenyl ester
The title product was prepared from 4-(5-chloro-pyridin-2-yloxy)-phenol and (3-pyridylmethyl)piperazine. The title product precipitated from the reaction mixture and was collected by filtration and recrystallized from ethanol (35%, off-white solid). HPLC-MS: m/z=425.2 (M+1); Rt: 2.39 min.
1H NMR (CDCl3): 13.00-14.50 (bs, 1H), 8.72 (d, 2H), 8.50 (bs, 1H), 8.11 (d, 1H), 7.64 (dd, 1H), 7.56 (bs, 1H), 7.06-7.14 (m, 4H), 6.88 (d, 1H), 3.6-4.4 (m, 6H), 2.70-3.50 (m, 4H).
Example 203
General Procedure 14
4-Hydroxymethyl-piperidine-1-carboxylic acid 4-(5-chloro-pyridin-2-yloxy)-phenyl ester
The title product was prepared from 4-(5-chloro-pyridin-2-yloxy)-phenol and 4-hydroxymethyl-piperidine. The crude product was subjected to column chromatography (ethyl acetate/heptane, 1:1) (75%, colorless oil). HPLC-MS: m/z=363.1 (M+1); Rt: 3.58 min.
1H NMR (CDCl3): 8.12 (d, 1H), 7.64 (dd, 1H), 7.05-7.24 (m, 4H), 6.85 (d, 1H), 4.33 (ds, 2H), 3.56 (t, 2H), 2.75-3.10 (m, 2H), 1.69-1.95 (m, 3H), 1.56 (s, 1H), 1.19-1.45 (m, 2H).
Example 204
General Procedure 1
Methyl-phenyl-carbamic acid 4-morpholin-4-yl-phenyl ester
The title product was prepared from and 4-morpholin-4-yl-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was extracted with dichloromethane from citric acid (5%). The combined organic phases were evaporated and the product crystallized from ethanol (22%, crystals). HPLC-MS: m/z=313.2 (M+1); Rt: 3.75 min.
1H NMR (DMSO-d6): 7.35-7.50 (m, 4H), 7.22-7.32 (m, 1H), 7.00 (d, 2H), 6.92 (d, 2H), 3.72 (t, 4H), 3.32 (s, 3H), 3.05 (t, 4H).
Example 205
General Procedure 1
1,4-Dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from 4-(5-trifluoromethyl-pyridin)-2-yloxy)-phenol and 4-piperidone ethylene ketal. The crude product was extracted with dichloromethane from citric acid (5%). The combined organic phases were evaporated and the product crystallized from ethanol (61%, crystals). HPLC-MS: m/z=425.2 (M+1); Rt: 4.45 min.
Example 206
General Procedure 14
The title product was prepared from 2-(4-hydroxy-phenyl)-indan-1,3-dione and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (1%, oil). HPLC-MS: m/z=372.1 (M+1); Rt: 4.80 min.
Example 207
General Procedure 14
Methyl-phenyl-carbamic acid 4-(5,6-dichloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-phenyl ester
The title product was prepared from 5,6-dichloro-2-(4-hydroxy-phenyl)-isoindole-1,3-dione and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (2%,). HPLC-MS: m/z=441.1 (M+1); Rt: 5.00 min.
Example 208
General Procedure 14
Methyl-phenyl-carbamic acid 4-(2-phenoxy-acetylamino)-phenyl ester
The title product was prepared from N-(4-hydroxy-phenyl)-2-phenoxy-acetamide and N-methyl-N-phenylcarbamoyl chloride. The crude product was purified by preparative HPLC (54%, oil). HPLC-MS: m/z=277.2 (M+1); Rt: 4.19 min.
Example 209
General Procedure 14
Methyl-phenyl-carbamic acid 4-[2-(4-chloro-phenyl)-ethyl]-phenyl ester
The title product was prepared from 4-(4-chlorophenethyl)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (57%, white crystals). HPLC-MS: m/z=366.1 (M+1); Rt: 5.58 min.
1H NMR (CDCl3): 7.31-7.45 (m, 4H), 7.17-7.30 (m, 3H), 6.96-7.12 (m, 6H), 3.41 (s, 3H), 2.85 (s, 4H).
Example 210
General Procedure 14
Methyl-phenyl-carbamic acid 4-[(pyridine-2-carbonyl)-amino]-phenyl ester
The title product was prepared from pyridine-2-carboxylic acid (4-hydroxy-phenyl)-amide and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (41%,). HPLC-MS: m/z=348.1 (M+1); Rt: 4.00 min.
1H NMR (CDCl3): 7.32-7.47 (m, 4H), 7.24-7.31 (m, 3H), 7.10-7.23 (m, 4H), 7.79 (d, 2H), 3.41 (m, 6H).
Example 211
General Procedure 14
Methyl-phenyl-carbamic acid 4-[methyl-(thiophene-2-carbonyl)-amino]-phenyl ester
The title product was prepared from thiophene-2-carboxylic acid (4-hydroxy-phenyl)-methyl-amide and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (16%, oil). HPLC-MS: m/z=367.2 (M+1); Rt: 3.97 min.
Example 212
General Procedure 14
Methyl-phenyl-carbamic acid 4-butyrylamino-phenyl ester
The title product was prepared from 4′-hydroxybutyranilide and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (60%, white solid). HPLC-MS: m/z=313.2 (M+1); Rt: 3.58 min.
Example 213
General Procedure 14
Methyl-phenyl-carbamic acid 4-(4,6-dimethyl-pyrimidin-2-ylsulfanyl)-phenyl ester
The title product was prepared from 4-(4,6-dimethylpyrimidin-2-ylsulfanyl)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (59%, white solid). HPLC-MS: m/z=366.1 (M+1); Rt: 4.50 min.
1H NMR (CDCl3): 7.59 (d, 2H), 7.32-7.45 (m, 4H), 7.23-7.31 (m, 1H), 7.16 (d, 2H), 6.68 (s, 1H), 3.43 (s, 1H), 2.32.
Example 214
General Procedure 14
Methyl-phenyl-carbamic acid 4-methanesulfonyl-phenyl ester
The title product was prepared from 4-methylsulfonylphenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (50%, white solid). HPLC-MS: m/z=306.1 (M+1); Rt: 3.22 min.
Example 215
General Procedure 14
Methyl-phenyl-carbamic acid 4-[2-(3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl)-acetylamino]-phenyl ester
The title product was prepared from N-(4-hydroxyphenyl)-2-(3-oxo-1,2,3,4-tetrahydro-2-quinoxalinyl)acetamide and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (20%, yellow solid). HPLC-MS: m/z=431.2 (M+1); Rt: 3.55 min.
Example 216
General Procedure 14
Methyl-phenyl-carbamic acid 4-phenylacetyl-phenyl ester
The title product was prepared from benzyl 4-hydroxyphenyl ketone and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (68%, light yellow oil). HPLC-MS: m/z=431.2 (M+1); Rt: 3.55 min.
Example 217
General Procedure 12
4-Benzoyl-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from 4-(5-trifluoromethyl-pyridin)-2-yloxy)-phenol and 4-benzoylpiperidine (29%, white solid). HPLC-MS: m/z=471.3 (M+1); Rt: 5.12 min.
Example 218
General Procedure 11
[1,4′]Bipiperidinyl-1′-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from 4-(5-trifluoromethyl-pyridin)-2-yloxy)-phenol and 4-piperidinopiperidine. The crude product was filtered from the reaction mixture and washed with diethyl ether to give the title product (50%, off-white solid). HPLC-MS: m/z=450.1 (M+1); Rt: 3.12 min.
Example 219
General Procedure 12
4-(2-Oxo-2,3-dihydro-benzimidazol-1-yl)-piperidine-1-carboxylic acid 4-(5-trifluoromethyl -pyridin-2-yloxy)-phenyl ester
The title product was prepared from 4-(5-Trifluoromethyl-pyridin-2-yloxy)-phenol and 1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (44%, oil). HPLC-MS: m/z=499.1 (M+1); Rt: 4.35 min.
1H NMR (CDCl3): 10.15 (s, 1H), 8.44 (s, 1H), 7.90 (dd, 1H), 7.23 (t, 1H), 7.13-7.20 (m, 4H), 7.06-7.13 (m, 2H), 7.02 (d, 1H), 4.40-4.70 (m, 3H), 2.95-3.30 (m, 2H), 2.40-2.63 (m, 2H), 1.86 (d, 2H).
Example 220
General Procedure 12 
3-Diethylcarbamoyl-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from 4-(5-Trifluoromethyl-pyridin-2-yloxy)-phenol and N,N-diethylnipecotamide (56%, oil). HPLC-MS: m/z=466.1 (M+1); Rt: 4.51 min.
Example 221
General Procedure 12
4-Carbamoyl-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from 4-(5-Trifluoromethyl-pyridin-2-yloxy)-phenol and piperidine-4-carboxylic acid amide. The crude product was subjected to preparative HPLC (47%, white solid). HPLC-MS: m/z=410.2 (M+1); Rt: 3.45 min.
Example 222
General Procedure 12
3-Carbamoyl-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from 4-(5-Trifluoromethyl-pyridin-2-yloxy)-phenol and nipecotamide. The crude product was purified by preparative HPLC (60%, white solid). HPLC-MS: m/z=410.2 (M+1); Rt: 3.45 min.
Example 223
General Procedure 14
Methyl-phenyl-carbamic acid 4-{[4-(methyl-phenyl-carbamoyloxy)-2-oxo-1,2-dihydro-quinoline-3-carbonyl]-amino}-phenyl ester
The title product was prepared from 4-hydroxy-2-oxo-1,2-dihydro-quinoline-3-carboxylic acid (4-hydroxyphenyl)-amide and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (6.6%, oil). HPLC-MS: m/z=563.2 (M+1); Rt: 4.46 min.
1H NMR (CDCl3): 8.38 (d, 1H), 7.75 (t, 1H), 7.35-7.45 (m, 4H), 7.22-7.34 (m, 1H), 7.14-7.21 (t, 1H), 6.99-7.15 (bs, 1H), 3.44 (s, 3H).
Example 224
General Procedure 14
Methyl-phenyl-carbamic acid 4-[(4-hydroxy-2-oxo-1,2-dihydro-quinoline-3-carbonyl)-amino]-phenyl  ester
The title product was prepared from 4-hydroxy-2-oxo-1,2-dihydro-quinoline-3-carboxylic acid (4-hydroxy-phenyl)-amide and N-methyl-N-phenylcarbamoyl chloride (5%,). HPLC-MS: m/z=430.1 (M+1); Rt: 4.80 min, purity: 70%.
Example 225
General Procedure 14
Methyl-phenyl-carbamic acid 4-(4-hydroxy-benzyl)-phenyl ester
The title compound was prepared from 4,4′-dihydroxydiphenylmethane and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (21%, white crystals which turn red after standing). HPLC-MS: m/z=324.2 (M+1); Rt: 4.21 min.
Example 226
General Procedure 13
Methyl-phenyl-carbamic acid 4-(4-trifluoromethyl-benzylcarbamoyl)-phenyl ester
The title product was prepared from 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester and 4-trifluoromethyl-benzylamine (94%, white crystals). HPLC-MS: m/z=429.2 (M+1); Rt: 4.35 min.
Example 227
General Procedure 13
Methyl-phenyl-carbamic acid 4-(butyl-methyl-carbamoyl)-phenyl ester
The title product was prepared from 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester and n-butyl-methyl-amine. The crude product was subjected to preparative HPLC (20%, oil). HPLC-MS: m/z=341.2 (M+1); Rt: 3.96 min.
Example 228
General Procedure 13
Methyl-phenyl-carbamic acid 4-(methyl-phenethyl-carbamoyl)-phenyl ester
The title product was prepared from 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester and methyl-phenethyl-amine. The crude product was subjected to preparative HPLC (29%, oil). HPLC-MS: m/z=389.2 (M+1); Rt: 4.15 min.
Example 229
General Procedure 13
Methyl-phenyl-carbamic acid 4-[(pyridin-2-ylmethyl)-carbamoyl]-phenyl ester
The title product was prepared from 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester and 2-aminomethylpyridine. The crude product was used without further purification (57%, oil). HPLC-MS: m/z=362.2 (M+1); Rt: 2.43 min.
1H NMR (MeOH-d4): 8.50 (d, 1H), 7.92 (d, 2H), 7.83 (dt, 1H), 7.38-7.50 (m, 5H), 7.26-7.37 (m, 2H), 7.15-7.26 (m, 2H), 4.69 (s, 2H), 3.41 (s, 3H).
Example 230
General Procedure 13
Methyl-phenyl-carbamic acid 4-(2-pyridin-2-yl-ethylcarbamoyl)-phenyl ester
The title product was prepared from 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester and 2-aminoethylpyridine. The crude product was used without further purification (26%, oil). HPLC-MS: m/z=376.2 (M+1); Rt: 2.25 min.
1H NMR (MeOH-d4): 8.51 (d, 1H), 7.87 (dt, 1H), 7.78 (d, 2H), 7.33-7.50 (m, 6H), 7.25-7.33 (m, 1H), 7.18 (d, 2H), 3.74 (t, 2H), 3.41 (bs, 3H), 3.13 (t, 2H).
Example 231
General Procedure 13
Methyl-phenyl-carbamic acid 4-(2-phenylamino-ethylcarbamoyl)-phenyl ester
The title product was prepared from 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester and N-phenylethylenediamine. The crude product was used without further purification (80%, off-white foam). HPLC-MS: m/z=390.2 (M+1); Rt: 3.51 min.
1H NMR (MeOH-d4): 7.82 (d, 2H), 7.36-7.48 (m, 4H), 7.22-7.34 (m, 1H), 7.15-7.22 (d, 2H), 7.10 (t, 2H), 6.69 (d, 2H), 6.62 (t, 1H), 3.72 (t, 2H), 3.57 (t, 2H), 3.40 (s, 3H), 3.20 (s, 1H).
Example 232
General Procedure 13
Methyl-phenyl-carbamic acid 4-(3-methyl-butylcarbamoyl)-phenyl ester
The title product was prepared from 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester and iso-amylamine. The crude product was used without further purification (95%, oil). HPLC-MS: m/z=341.2 (M+1); Rt: 3.99 min.
1H NMR (MeOH-d4): 7,82 (d, 2H), 7.36-7.50 (m, 4H), 7.26-7.35 (m, 1H), 7.15-7.24 (d, 2H), 3.34-3.46 (m, 5H), 1.67 (sept, 1H), 1.50 (q, 2H), 0.96 (d, 6H).
Example 233
General Procedure 13
Methyl-phenyl-carbamic acid 4-(3,3-dimethyl-butylcarbamoyl)-phenyl ester
The title product was prepared from 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester and 3,3-dimethylbutylamine. The crude product was used without further purification (88%, oil). HPLC-MS: m/z=355.1 (M+1); Rt: 3.10 min.
1H NMR (MeOH-d4): 7.82 (d, 2H), 7.36-7.50 (m, 4H), 7.25-7.35 (m, 1H), 7.15-7.25 (d, 2H), 3.33-3.47 (m, 5H), 1.49-1.57 (m, 2H), 0.97 (s, 9H).
Example 234
General Procedure 13
Methyl-phenyl-carbamic acid 4-[(tetrahydro-furan-2-ylmethyl)-carbamoyl]-phenyl ester
The title product was prepared from 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester and C-(tetrahydro-furan-2-yl)methylamine. The crude product was used without further purification (86%, oil). HPLC-MS: m/z=(M+1); Rt: min.
1H NMR (MeOH-d4): 7.84 (d, 2H), 7.35-7.50 (m, 4H), 7.25-7.35 (m, 1H), 7.12-7.25 (d, 2H), 4.10 (qui, 1H), 3.87 (q, 1H), 3.68-3.82 (m, 1H), 3.41 (s, 3H), 3.35-3.54 (m, 2H), 1.82-2.10 (m, 3H), 1.58-1.72 (m, 1H).
Example 235
General Procedure 13
Methyl-phenyl-carbamic acid 4-cyclohexylcarbamoyl-phenyl ester
The title product was prepared from 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester and cyclohexylamine. The crude product was used without further purification (79%, off-white crystals). HPLC-MS: m/z=353.2 (M+1); Rt: 3.98 min.
1H NMR (MeOH-d4): 8.18 (d, 1H), 7.85 (d, 2H), 7.36-7.52 (m, 4H), 7.25-7.33 (m, 1H), 7.20 (d, 2H), 3.74 (m, 1H), 1.77-1.88 (m, 2H), 1.65-1.77 (m, 2H), 1.60 (d, 1H), 1.24-1.40 (m, 4H), 1-07-1.23 (m, 1H).
Example 236
General Procedure 13
Methyl-phenyl-carbamic acid 4-cyclopropylcarbamoyl-phenyl ester
The title product was prepared from 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester and cyclopropylamine. The crude product was used without further purification (97%, oil). HPLC-MS: m/z=311.2 (M+1); Rt: 3.21 min.
1H NMR (MeOH-d4): 7.81 (d, 2H), 7.36-7.50 (m, 4H), 7.25-7.36 (m, 1H), 7.18 (d, 2H), 3.40 (bs, 3H), 2.78-2.87 (m, 1H), 0.75-0.85 (m, 2H), 0.57-0.65 (m, 2H).
Example 237
General Procedure 13
Methyl-phenyl-carbamic acid 4-(cyclohexylmethyl-carbamoyl)-phenyl ester
The title product was prepared from 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester and C-cyclohexyl-methylamine. The crude product was used without further purification (84%, oil). HPLC-MS: m/z=367.3 (M+1); Rt: 4.28 min.
1H NMR (MeOH-d4): 7.81 (d, 2H), 7.36-7.49 (m, 4H), 7.25-7.32 (m, 1H), 7.19 (d, 2H), 3.40 (bs, 3H), 3.20 (d, 2H), 1.55-1.82 (m, 5H), 1.13-1.35 (m, 4H), 0.90-1.10 (m, 2H).
Example 238
Methyl-phenyl-carbamic acid 5-nitro-pyridin-2-yl ester
A solution of 2-hydroxy-5-nitropyridine (1.40 g, 10.0 mmol), 1-methyl-3-(methyl-phenyl -carbamoyl)-3H-imidazol-1-ium iodide (3.43 g, 10.0 mmol) and triethylamine (0.42 ml, 10.0 mmol) in acetonitrile (25 ml) was heated at 50° C. for 5 h. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate: heptane (25:75)) followed by crystallisation from ethyl acetate:heptane yielding the title compound (1.13 g, 41% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ 3.44 (br.s, 3H), 7.17 (br.d, 1H), 7.27-7.45 (m, 5H), 8.49 (br.d, 1H), 9.19 (br.s, 1H); HPLC-MS (Method A): m/z=296 (M+Na); Rt=3.45 min.
Example 239
Methyl-phenyl-carbamic acid pyrimidin-2-yl ester
A solution of 2-hydroxypyrimidine hydrochloride (0.40 g, 3.00 mmol), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.83 ml, 6.00 mmol) in acetonitrile (15 ml) was stirred at room temperature overnight. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate) followed by crystallisation from ethyl acetate:heptane yielding the title compound (0.08 g, 12% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ 3.43 (br.s, 3H), 7.14-7.31 (m, 2H), 7.39 (m, 4H), 8.68 (d, 2H); HPLC-MS (Method A): m/z=252 (M+Na); Rt=2.32 min.
Example 240
Methyl-phenyl-carbamic acid 7-chloro-quinolin-4-yl ester
A solution of 7-chloro-4-hydroxyquinoline (0.54 g, 3.00 mmol), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (40:60)) yielding the title compound (0.87 g, 93% yield) as a colourless oil which solidified upon standing.
1H NMR (300 MHz, CDCl3): δ 3.47 (br.s, 3H), 7.28-7.58 (m, 8H), 8.05 (br.s, 1H), 8.85 (d, 1H); HPLC-MS (Method A): m/z=313 (M+H); Rt=3.79 min.
Example 241
Methyl-phenyl-carbamic acid quinolin-4-yl ester
A mixture of 4-hydroxyquinoline (0.44 g, 3.00 mmol)), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (50:50)) yielding the title compound (0.75 g, 90% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ3.49 (br.s, 3H), 7.37 (br.t, 1H), 7.41-7.62 (m, 7H), 7.69 (br.t, 1H), 8.08 (br.d, 1H), 8.87 (d, 1H); HPLC-MS (Method A): m/z=279 (M+H); Rt=2.56 min.
Example 242
Methyl-phenyl-carbamic acid 5-methyl-isoxazol-3-yl ester
A mixture of 3-hydroxy-5-methylisoxazole (0.30 g, 3.00 mmol)), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (25:75)) yielding the title compound (0.67 g, 96% yield) as a colourless oil.
1H NMR (300 MHz, CDCl3): δ 2.40 (s, 3H), 3.40 (br.s, 3H), 6.14 (br.s, 1H), 7.28-7.44 (m, 5H); HPLC-MS (Method A): m/z=255 (M+Na); Rt=3.31 min.
Example 243
Methyl-phenyl-carbamic acid quinoxalin-2-yl ester
A mixture of 2-hydroxyquinoxaline (0.44 g, 3.00 mmol)), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours followed by heating at 40° C. for 24 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (30:70)) yielding the title compound (0.65 g, 77% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ 3.48 (br.s, 3H), 7.29 (m, 1H), 7.41 (m, 4H), 7.72 (m, 2H), 8.00 (m, 1H), 8.10 (m, 1H), 8.67 (br.s, 1H); HPLC-MS (Method A): m/z=280 (M+H); Rt=3.66 min.
Example 244
Methyl-phenyl-carbamic acid 4-methyl-quinolin-2-yl ester
A mixture of 2-hydroxy-4-methylquinoline (0.48 g, 3.00 mmol)), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours followed by heating at 50° C. for 4 days. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (30:70)) yielding the title compound (0.24 g, 27% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ2.70 (s, 3H), 3.49 (br.s, 3H), 7.08 (m, 1H), 7.27 (m, 1H), 7.40 (m, 4H), 7.53 (t, 1H), 7.69 (t, 1H), 7.96 (d, 1H), 8.00 (d, 1H); HPLC-MS (Method A): m/z=293 (M+H); Rt=3.88 min.
Example 245
Methyl-phenyl-carbamic acid 3-methyl-quinoxalin-2-yl ester
A mixture of 2-hydroxy-3-methylquinoxaline (0.48 g, 3.00 mmol)), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours followed by heating at 50° C. for 3 days. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (50:50)) yielding the title compound (0.59 g, 67% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ2.61 (br.s, 3H), 3.48 (br.s, 3H), 7.30 (m, 1H), 7.42 (m, 4H), 7.69 (m, 2H), 7.99 (m, 2H); HPLC-MS (Method A): m/z=294 (M+H); Rt=3.92 min.
Example 246
Methyl-phenyl-carbamic acid 4,6-dimethyl-pyrimidin-2-yl ester
A solution of 4,6-dimethyl-2-hydroxypyrimidine (0.37 g, 3.00 mmol)), 1-methyl-3-(methyl-phenyl -carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (50:50)) yielding the title compound (0.46 g, 60% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ2.48 (s, 6H), 3.43 (br.s, 3H), 6.92 (br.s, 1H), 7.22 (m, 1H), 7.37 (m, 4H); HPLC-MS (Method A): m/z=258 (M+H); Rt=2.77 min.
Example 247
Methyl-phenyl-carbamic acid isoquinolin-6-yl ester
A solution of 6-hydroxyquinoline (0.44 g, 3.00 mmol), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified-by-flash column-chromatography (SiO2, ethyl acetate:heptane (50:50)) yielding the title compound (0.80 g, 96% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ3.47 (s, 3H), 7.28 (m, 1H), 7.33-7.54 (m, 6H), 7.59 (s, 1H), 8.08 (d, 2H), 8.86 (m, 1H); HPLC-MS (Method A): m/z=279 (M+H); Rt=2.63 min.
Example 248
Methyl-phenyl-carbamic acid quinolin-2-yl ester
A solution of 2-hydroxyquinoline (0.44 g, 3.00 mmol), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours. More acetonitrile (60 ml) was added and the solution was heated at 50° C. for 3 days. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (40:60)) yielding the title compound (0.33 g, 40% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ3.50 (br.s, 3H), 7.14-7.30 (m, 2H), 7.42 (m, 4H), 7.52 (t, 1H); 7.71 (t, 1H), 7.82 (d, 1H), 8.00 (d, 1H), 8.19 (d, 1H); HPLC-MS (Method A): m/z=279 (M+H); Rt=3.91 min.
Example 249
Methyl-phenyl-carbamic acid isoquinolin-3-yl ester
A solution of 3-hydroxyisoquinoline (0.44 g, 3.00 mmol), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (50:50)) yielding the title compound (0.82 g, 99% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ3.49 (br.s, 3H), 7.24 (m, 1H), 7.33-7.47 (m, 5H), 7.51 (t, 1H), 7.63 (t, 1H), 7.77 (d, 1H), 7.94 (d, 1H), 9.06 (s, 1H); HPLC-MS (Method A): m/z=279 (M+H); Rt=3.68 min.
Example 250
Methyl-phenyl-carbamic acid 4-trifluoromethyl-pyrimidin-2-yl ester
A solution of 4-(trifluoromethyl)-2-pyrimidol (0.49 g, 3.00 mmol), 1-methyl-3-(methyl-phenyl -carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 3 days. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (30:70)) yielding the title compound (0.35 g, 39% yield) as a colourless oil.
1H NMR (300 MHz, CDCl3): δ3.45 (br.s, 3H), 7.28 (m, 1H), 7.38 (m, 4H), 7.52 (br.s, 1H), 8.93 (br.s, 1H); HPLC-MS (Method A): m/z=320 (M+Na); Rt=3.58 min.
Example 251
Morpholine-4-carboxylic acid 4-trifluoromethyl-pyrimidin-2-yl ester
A solution of 4-(trifluoromethyl)-2-pyrimidol (0.49 g, 3.00 mmol), 4-morpholinecarbonyl chloride (0.45 g, 3.00 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.51 g, 3.00 mmol) in N,N-dimethylformamide (15 ml) was stirred at room temperature for 2 hours. Water was added and the solution was extracted twice with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo, The residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (30:70→50:50)) yielding the title compound (0.66 g, 80% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ3.57-3.81 (m, 8H), 7.57 (d, 1H), 8.97 (d, 1H); HPLC-MS (Method A): m/z=300 (M+Na); Rt=2.36 min.
Example 252
Methyl-phenyl-carbamic acid 3-nitro-pyridin-2-yl ester
A solution of 2-hydroxy-3-nitropyridine (0.42 g, 3.00 mmol), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 3 days. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (40:60)) yielding the title compound (0.41 g, 50% yield) as a yellow solid.
1H NMR (300 MHz, CDCl3): δ3.41+3.58 (2×br.s, 3H), 7.30 (m, 1H), 7.42 (m, 5H), 8.45 (br.d, 1H), 8.49 (br.s, 1H); HPLC-MS (Method A): m/z=296 (M+Na); Rt=3.22 min.
Example 253
Methyl-phenyl-carbamic acid 5-chloro-pyridin-2-yl ester
A solution of 5-chloro-2-pyridol (0.39 g, 3.00 mmol), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 3 days. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (30:70)) yielding the title compound (0.78 g, 99% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ3.44 (br.s, 3H), 7.00 (br.s, 1H), 7.27 (m, 1H), 7.39 (m, 4H), 7.69 (d, 1H), 8.30 (d, 1H); HPLC-MS (Method A): m/z=285 (M+Na); Rt=3.47 min.
Example 254
Methyl-phenyl-carbamic acid 5-(2-nitro-phenyl)-pyrimidin-2-yl ester
A solution of 5-(2-nitrophenyl)-pyrimidin-2-ol (0.35 g, 1.61 mmol), 1-methyl-3-(methyl-phenyl -carbamoyl)-3H-imidazol-1-ium iodide (0.55 g, 1.61 mmol) and triethylamine (0.22 ml, 1.61 mmol) in acetonitrile (15 ml) was heated at 50° C. for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (50:50)) yielding the title compound (0.18 g, 32% yield) as a yellow oil.
1H NMR (300 MHz, CDCl3): δ3.47 (br.s, 3H), 7.29 (m, 1H), 7.40 (m, 5H), 7.63 (dt, 1H), 7.72 (dt, 1H), 8.10 (d, 1H), 8.61 (br.s, 2H); HPLC-MS (Method A): m/z=351 (M+H), 373 (M+Na), 723 (2M+Na).; Rt=3.65 min.
Example 255
Methyl-phenyl-carbamic acid 5-trifluoromethyl-pyridin-2-yl ester
A solution of 2-hydroxy-5-(trifluoromethyl)pyridine (0.49 g, 3.00 mmol), 1-methyl-3-(methyl -phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (15:85)) yielding the title compound (0.59 g, 66% yield) as a white solid.
1H NMR (300 MHz, CDCl3): t3.43 (br.s, 3H), 7.23 (br.s, 1H), 7.28 (m, 1H), 7.37 (m, 4H), 7.94 (br.d, 1H), 8.62 (br.s, 1H); HPLC-MS (Method A): m/z=319 (M+Na); Rt=3.85 min.
Example 256
Methyl-phenyl-carbamic acid 3-chloro-5-trifluoromethyl-pyridin-2-yl ester
A solution of 3-chloro-5-(trifluoromethyl)-2-pyridinol (0.59 g, 3.00 mmol), 1-methyl-3-(methyl -phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (15:85)) yielding the title compound (146 mg, 15% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ3.43 (br.s, 3H), 7.30 (m, 1H), 7.40 (d, 4H), 8.00 (br.s, 1H), 8.52 (br.s, 1H).; HPLC-MS (Method A): m/z=353 (M+Na); Rt=4.29 min.
Example 257
Methyl-phenyl-carbamic acid 5-nitro-3-trifluoromethyl-pyridin-2-yl ester
A solution of 2-hydroxy-5-nitro-3-(trifluoromethyl)pyridine (0.36 g, 1.73 mmol), N-methyl-N-phenylcarbamoyl chloride (0.44 g, 2.59 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.29 g, 2.59 mmol) in tetrahydrofuran (15 ml) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (15:85)) yielding the title compound (0.55 g, 92% yield) as an orange solid.
1H NMR (300 MHz, CDCl3): δ3.46 (br.s, 3H), 7.23-7.46 (m, 5H), 8.70 (br.s, 1H), 9.37 (br.s, 1H); HPLC-MS (Method A): m/z=364 (M+H); Rt=4.08 min.
Example 258
(3-Chloro-phenyl)-methyl-carbamic acid 4-trifluoromethyl-pyrimidin-2-yl ester
At 0° C. diphosgene (0.99 g, 5.00 mmol) was added to a stirred solution of 4-trifluoromethyl-2-hydroxypyrimidine (1.64 g, 10.0 mmol) in tetrahydrofuran (25 ml). The cooling bath was removed and stirring was continued at room temperature for 1 hour. (3-Chlorophenyl)-methylamine (0.35 g, 2.50 mmol) was added to one-fourth of the solution. After stirring overnight at room temperature the solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (20:80)) followed by preparative HPLC, yielding the title compound (332 mg, 40%) as a colourless oil.
1H NMR (300 MHz, CDCl3): δ3.45 (br.s, 3H), 7.23-7.44 (m, 4H), 7.56 (d, 1H), 8.94 (d, 1H); HPLC-MS (Method A): m/z=354 (M+H); Rt=4.03 min.
Example 259
Methyl-m-tolyl-carbamic acid 4-trifluoromethyl-pyrimidin-2-yl ester
At 0° C. diphosgene (0.99 g, 5.00 mmol) was added to a stirred solution of 4-trifluoromethyl-2-hydroxypyrimidine (1.64 g, 10.0 mmol) in tetrahydrofuran (25 ml). The cooling bath was removed and stirring was continued at room temperature for 1 hour. Methyl-m-tolyl-amine (0.30 g, 2.50 mmol) was added to one-fourth of the solution. After stirring overnight at room temperature the solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (20:80)) followed by preparative HPLC, yielding the title compound (51 mg, 7%) as a colourless oil.
1H NMR (300 MHz, CDCl3): (2.37 (s, 3H), 3.42 (br.s, 3H), 7.07-7.31 (m, 4H), 7.52 (br.s, 1H), 8.92 (br.s, 1H); HPLC-MS (Method A): m/z=334 (M+Na); Rt=3.92 min.
Example 260
Morpholine-4-carboxylic acid 4-trifluoromethyl-pyrimidin-2-yl ester
A solution of 4-trifluoromethyl-2-hydroxypyrimidine (0.49 g, 3.00 mmol), 4-morpholinecarbonyl chloride (0.45 g, 3.00 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.34 g, 3.00 mmol) in dimethylformamide (15 ml) was stirred at room temperature for 1 hour. Water and brine were added and the solution was extracted twice with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (30:70→50:50)) yielding the title compound (0.66 g, 80% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ3.45 (br.s, 3H), 7.23-7.44 (m, 4H), 7.56 (d, 1H), 8.94 (d, 1H); HPLC-MS (Method A): m/z=354 (M+H); Rt=4.03 min.
Example 261
Methyl-phenyl-carbamic acid 4,5-dichloro-pyridazin-3-yl ester
A solution of 4,5-dichloro-3-hydroxypyridazine (0.49 g, 3.00 mmol), N-methyl-N-phenylcarbamoyl chloride (0.51 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in tetrahydrofuran (15 ml) was stirred at room temperature for 3 days. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (20:80)) yielding the title compound (0.12 g, 14% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ3.50 (s, 3H), 7.18-7.32 (m, 5H), 7.63 (s, 1H); HPLC-MS (Method A): m/z=320 (M+Na); Rt=2.91 min.
Example 262
Methyl-phenyl-carbamic acid 5-benzoylamino-pyridin-2-yl ester
A solution of N-(6-hydroxy-pyridin-3-yl)-benzamide (0.64 g, 3.00 mmol), N-methyl-N-phenylcarbamoyl chloride (0.51 g, 3.00 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.34 g, 3.00 mmol) in dimethylformamide (15 ml) was stirred at room temperature for 1 hour. Water was added and the precipitates were collected by suction. The solids were dissolved in dichloromethane and the solution was dried over sodium sulphate, filtered and evaporated in vacuo. The residue was dissolved in ethyl acetate and filtered over a short pad of silica. Evaporation of the solvent in vacuo yielded the title compound (0.70 g, 68% yield) as a thick oil.
1H NMR (300 MHz, CDCl3): δ3.40 (br.s, 3H), 6.90 (br.s, 1H), 7.26 (m, 1H), 7.31-7.44 (m, 6H), 7.50 (m, 1H), 7.88 (d, 2H), 8.08 (dd, 1H), 8.37 (d, 1H), 8.79 (br.s, 1H); HPLC-MS (Method A): m/z=348 (M+H); Rt=3.49 min.
Example 263
Methyl-phenyl-carbamic acid 5-(cyclohexanecarbonyl-amino)-pyridin-2-yl ester
A solution of cyclohexanecarboxylic acid (6-hydroxy-pyridin-3-yl)-amide (0.66 g, 3.00 mmol), N-methyl-N-phenylcarbamoyl chloride (0.51 g, 3.00 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.34 g, 3.00 mmol) in dimethylformamide (20 ml) was stirred at room temperature for 18 hours. Water was added and the precipitates were collected by suction. The solids were dissolved in dichloromethane and the solution was dried over sodium sulphate, filtered and evaporated in vacuo. The residue was crystallised from ethyl acetate:heptane yielding the title compound (0.75 g, 71% yield) as a slightly coloured solid.
1H NMR (300 MHz, CDCl3): δ1.18-1.33 (m, 3H), 1.42-1.59 (m, 2H), 1.60 (m, 1H), 1.77-1.94 (m, 4H), 2.20 (m, 1H), 3.45 (br.s, 3H), 6.91 (br.s, 1H), 7.28 (m, 1H), 7.39 (m, 4H), 7.94 (br.s, 1H), 8.00 (dd, 1H), 8.20 (d, 1H); HPLC-MS (Method A): m/z=354 (M+H); Rt=3.74 min.
Example 264
Methyl-phenyl-carbamic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-yl ester
A solution of 6′-hydroxy-4,4-dimethyl-4;5-dihydro-3H-[1,3′]bipyridinyl-2,6-dione (0.70 g, 300 mmol), N-methyl-N-phenylcarbamoyl chloride (0.51 g, 3.00 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.34 g, 3.00 mmol) in dimethylformamide (20 ml) was stirred at room temperature for 18 hours. Water was added and the precipitates were collected by suction and subsequently dried in a vacuum oven yielding the title compound (0.75 g, 71% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ1.20 (s, 6H), 2.68 (s, 4H), 3.44 (br.s, 3H), 7.14 (br.s, 1H), 7.25 (m, 1H), 7.37 (m, 4H), 7.48 (br.d, 1H), 8.08 (d, 1H); HPLC-MS (Method A): m/z=368 (M+H); Rt=3.41 min.
Example 265
Methyl-phenyl-carbamic acid 5-(2,2-dimethyl-propionylamino)-pyridin-2-yl ester
A solution of N-(6-hydroxy-pyridin-3-yl)-2,2-dimethyl-propionamide (0.58 g, 3.00 mmol), N -methyl-N-phenylcarbamoyl chloride (0.51 g, 3.00 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.34 g, 3.00 mmol) in dimethylformamide (20 ml) was stirred at room temperature for 1 hour. Water was added and a thick oil was being formed. The water was decanted and the residue was dissolved in dichloromethane. The solution was dried over sodium sulphate, filtered and evaporated in vacuo yielding the title compound (0.55 g, 56% yield) as a brown oil that solidified upon standing.
1H NMR (300 MHz, CDCl3): δ1.29 (s, 9H), 3.43 (br.s, 3H), 6.97 (br.s, 1H), 7.26 (m, 1H), 7.38 (m, 4H), 7.64 (br.s, 1H), 8.10 (dd, 1H), 8.28 (br.s, 1H); HPLC-MS (Method A): m/z=348 (M+H); Rt=3.49 min.
Example 266
Methyl-phenyl-carbamic acid 5-(2-cyclohexyl-acetylamino)-pyridin-2-yl ester
A solution of 2-cyclohexyl-N-(6-hydroxy-pyridin-3-yl)-acetamide (0.70 g, 3.00 mmol), N -methyl-N-phenylcarbamoyl chloride (0.51 g, 3.00 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.34 g, 3.00 mmol) in dimethylformamide (15 ml) was stirred at room temperature for 1 hour. Water was added and the precipitates were collected by suction. The solids were dissolved in dichloromethane and the solution was dried over sodium sulphate, filtered and evaporated in vacuo. The residue was crystallised from ethyl acetate:heptane yielding the title compound (0.79 g, 72% yield) as a brown solid.
1H NMR (300 MHz, CDCl3): δ0.86-1.01 (m, 2H), 1.05-1.37 (m, 3H), 1.60-1.78 (m, 5H), 1.83 (m, 1H), 2.13 (d, 2H), 3.46 (br.s, 3H), 6.90 (br.s, 1H), 7.27 (m, 1H), 7.39 (m, 4H), 7.98 (d, 1H), 8.12 (s+br.s, 2H, CH+NH); HPLC-MS (Method A): m/z=368 (M+H); Rt=4.04 min.
Example 267
Methyl-phenyl-carbamic acid 5-(4-methoxy-phenoxy)-pyrimidin-2-yl ester
A solution of 5-(4-methoxy-phenoxy)-pyrimidin-2-ol (0.44 g, 2.00 mmol), N-methyl-N-phenylcarbamoyl chloride (0.34 g, 2.00 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.22 g, 2.00 mmol) in dimethylformamide (15 ml) was stirred at room temperature for 1 hour. Water was added and the precipitates were collected by suction. The solids were dissolved in dichloromethane and the solution was dried over sodium sulphate, filtered and evaporated in vacuo. The residue was crystallised from ethyl acetate:heptane yielding the title compound (0.55 g, 79% yield) as an off-white solid.
1H NMR (300 MHz, CDCl3): δ3.43 (br.s, 3H), 3.82 (s, 3H), 6.91+7.00 (AB-system, 2×2H), 7.26 (m, 1H), 6.39 (m, 4H), 8.33 (s, 2H); HPLC-MS (Method A): m/z=352 (M+H); Rt=4.02 min.
Example 268
Methyl-phenyl-carbamic acid 5-(3,4-dichloro-phenoxy)-pyrimidin-2-yl ester
A solution of 5-(3,4-dichloro-phenoxy)-pyrimidin-2-ol (0.51 g, 2.00 mmol), N-methyl-N-phenylcarbamoyl chloride (0.34 g, 2.00 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.22 g, 2.00 mmol) in dimethylformamide (15 ml) was stirred at room temperature for 1 hour. Water was added and the precipitates were collected by suction. The solids were dissolved in dichloromethane and the solution was dried over sodium sulphate, filtered and evaporated in vacuo. The residue was crystallised from ethyl acetate:heptane yielding the title compound (0.51 g, 65% yield) as an off-white solid.
1H NMR (300 MHz, CDCl3): δ3.44 (br.s, 3H), 6.89 (dd, 1H), 7.14 (d, 1H), 7.27 (m, 1H), 7.39 (m, 4H), 7.44 (d, 1H), 8.42 (s, 2H); HPLC-MS (Method A): m/z=390 (M+H); Rt=4.66 min.
Example 269
Methyl-phenyl-carbamic acid 6-pyridin-2-ylmethyl-pyridazin-3-yl ester
A solution of 6-(2-pyridinylmethyl)-3-pyridazinol (100 mg, 0.53 mmol), N-methyl-N-phenylcarbamoyl chloride (91 mg, 0.53 mmol) and 1,4-diazabicyclo[2.2.2]octane (60 mg, 0.53 mmol) in dimethylformamide (10 ml) was stirred at room temperature for 2 hours. Water was added and the solution was extracted twice with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate) yielding the title compound (70 mg, 41% yield) as a yellow oil.
1H NMR (300 MHz, CDCl3): δ3.42 (br.s, 3H), 4.50 (s, 2H), 7.11-7.33 (m, 4H), 7.39 (d, 4H), 7.60 (m, 2H), 8.52 (d, 1H); HPLC-MS (Method A): m/z=321 (M+H); Rt=1.98 min.
Example 270
Methyl-phenyl-carbamic acid 6-(4-methoxy-benzyl)-pyridazin-3-yl ester
A solution of 6-(2-pyridinylmethyl)-3-pyridazinol (97 mg, 0.45 mmol), N-methyl-N-phenylcarbamoyl chloride (76 mg, 0.45 mmol) and 1,4-diazabicyclo[2.2.2]octane (50 mg, 0.45 mmol) in dimethylformamide (10 ml) was stirred at room temperature for 2 hours. Water was added and the solution was extracted twice with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (50:50)) yielding the title compound (117 mg, 41% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ3.43 (br.s, 3H), 3.79 (s, 3H), 4.28 (s, 2H), 6.83 (d, 2H), 7.17 (d, 2H), 7.27 (m, 3H), 7.40 (d, 4H); HPLC-MS (Method A): m/z=350 (M+H); Rt=3.60 min.
Example 271
Methyl-phenyl-carbamic acid 6-(2,4-dichloro-benzyl)-pyridazin-3-yl ester
A solution of 6-(2,4-dichlorobenzyl)-3-pyridazinol (98 mg, 0.38 mmol), N-methyl-N-phenylcarbamoyl chloride (65 mg, 0.38 mmol) and 1,4-diazabicyclo[2.2.2]octane (43 mg, 0.38 mmol) in dimethylformamide (10 ml) was stirred at room temperature for 2 hours. Water was added and the solution was extracted twice with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (40:60)) yielding the title compound (119 mg, 80% yield) as a yellow oil.
1H NMR (300 MHz, CDCl3): δ3.43 (br.s, 3H), 4.42 (s, 2H), 7.17-7.44 (m, 10H); HPLC-MS (Method A): m/z=388 (M+H); Rt=4.44 min.
Example 272
General Procedure 15
4-Pyridin-2-yl-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)phenyl chloroformate and 1-pyridin-2-yl-piperazine. White crystals, yield 87%; m.p. 247-248° C.; HPLC-MS: m/z=445 (M+H); IR (KBr): ν 1713 (C═O) cm−1.
Example 273
General Procedure 15
4-(1,3-Benzodioxol-5-yl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(1,3-benzodioxol-5-yl)-piperazine. The crude product was partitioned between dichlorormethane and 1 M aqueous sodium carbonate. The organic layer was washed with water, dried and evaporated. The residue was triturated with ethyl acetate—heptane (1:4) and the precipitate was collected by filtration and dried to give the title compound. Yield 39%; m.p. 146-147° C.; 1H NMR (DMSO-d6): δ8.60-8.56 (br, 1H), 8.29-8.20 (dd-like, 1H), 7.31-7.20 (m, 5H), 6.84-6.72 (d-like, 1H), 6.76-6.72 (d-like, 1H), 6.45-6.36 (dd-like, 1H), 3.81-3.47 (br m, 4H), 3.16-3.00 (br, m, 4H); HPLC-MS: m/z=488 (M+H); IR (KBr): ν 1719 (C═O) cm−1.
Example 274
General Procedure 15
4-[2-(2-Hydroxyethoxy)ethyl]-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 2-(2-hydroxyethoxy)ethyl-piperazine. Yield 13%; 1H NMR (DMSO-d6): δ10.8 (br), 8.61-8.54 (br, 1H), 8.30-8.21 (dd-like, 1H), 7.32-7.19 (m, 5H), 4.3-3.9 (br, 2H), 3.9-3.0 (br m, alicyclics and aliphatics+water); HPLC-MS: m/z=456(M+H); IR (KBr): ν 1724 (C═O) cm−1.
Example 275
General Procedure 15
4-(Diphenylmethyl)piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl  ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(diphenylmethyl)piperazine, white crystals, yield 74%; m.p. 168-169° C.;
1H NMR (DMSO-d6): δ12.4 (br, 1H), 8.60-8.54 (d-like m, 1H), 8.28-8.20 (dd-like m, 1H), 7.98-7.82 (br, 2H), 7.55-7.15 (br m, 13H), 5.6 (br, 1H), 4.35-3.48 (br, 3H), 3.35-3.0 (br, 5H); IR (KBr): ν 1723 (C═O) cm−1.
Example 276
General Procedure 15
4-(4-tert-Butylbenzyl)piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(4-tert-butylbenzyl)diphenylmethyl)piperazine, white crystals, yield 56%; m.p. 274-275° C.; HPLC-MS: m/z=514 (M+H); IR (KBr): ν 1721 (C═O) cm−1.
Example 277
General Procedure 15
4-(4-Fluorobenzyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(4-fluorobenzyl)piperazine, white crystals, yield 69%; m.p. 240-243° C.; HPLC-MS: m/z=476 (M+H), 498 (M+Na); IR (KBr): ν 1720 (C═O) cm−1.
Example 278
General Procedure 15
4-(2-Thienylethyl)piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(2-thienylethyl)piperazine, white crystals, yield 62%; m.p. 236-237° C.; 1H NMR (DMSO-d6): δ11.51 (br s, 1H), 8.61-8.54 (br m, 1H), 7.48-7.17 (m, 6H), 7.06-6.89 (m, 2H), 4.4-3.9 (br, 2H), 3.9-2.6 (br m, 16.5H ̃12H+water); HPLC-MS: m/z=478 (M+H); IR (KBr): ν 1714 (C═O) cm−1.
Example 279
General Procedure 15
4-(1-Phenylethyl)piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)phenyl ester
The crude hydrochloride of the title compound was prepared from 4-(5-trifluoromethylpyridin-2-yloxy)-phenyl chloroformate and 1-(1-phenylethyl)piperazine. Trituration with water, filtering and drying of the residue gave white crystals, yield 31%; m.p. 242° C.; 1H NMR (DMSO-d6): δ11.56 (brs, 1H), 8.61-8.52 (brm, 1H), 8.30-8.19 (dd-like m, 1H), 7.77-7.31 (br m, 5H), 7.31-7.13 (m, 5H), 4.60-3.27 (br m, 6H+water), 3.27-2.57 (br, 3H), 1.73 (br d, 3H); IR (KBr): ν 1712 (C═O) cm−1.
Example 280
General Procedure 15
4-Octylpiperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)phenyl ester
The crude hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(1-phenylethyl)piperazine. Trituration with water, filtering and drying of the residue gave white crystals, yield 31%; m.p. 244-245° C.; 1H NMR (DMSO-d6): δ11.16 (brs, 1H), 8.61-8.57 (br m, 1H), 8.30-8.20 (dd-like m, 1H), 7.32-7.18 (m, 5H), 4.39-3.96 (br, 2H), 3.77-3.38 (br, 4H), 3.25-2.88 (br, 4H), 1.84-1.58 (br, 2H), 1.42-1.12 (br s, 10H), 0.87 (br t, 3H); IR (KBr): ν 1731, 1713 (C═O) cm−1.
Example 281
General Procedure 15
4-(3-Dimethylamino-propyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The crude hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(3-dimethylaminopropyl)piperazine. A suspension of the product in ether was stirred with an excess of HCl in ether and the precipitate was washed with ether and dried to give the dihydrochloride of the title compound as white crystals, m.p. 292-293° C.; 1H NMR (DMSO-d6): δ11.35 (br s, 1H), 10.46 (br s, 1H), 8.61-8.52 (br m, 1H), 8.31-8.17 (m, 1H), 7.35-7.16 (m, 5H), 4.45-4.00 (br, 2H), 3.80-3.45 (br, 4H), 3.30-3.01 (br, 6H), 2.78 (brs, 6H), 2.31-2.07 (br, 2H); IR (KBr): ν 1731, 1713 (C═O) cm −1.
Example 282
General Procedure 15
4-Pyrimidin-2-yl-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(pyrimidin-2-yl)piperazine. The crude product was dried in vacuo at 50° C. for 80 min and extracted with ether. The ether phase was evaporated and the residue was purified by flash chromatography on silica eluted with ethyl acetate—heptane 1:1 to give the title compound as white needles. Yield 14%; m.p. 120-121° C.; 1H NMR (DMSO-d6): δ8.61-8.56 (br, 1H), 8.41 (d, J=4.8 Hz, 2H), 8.29-8.20 (dd-like, 1H), 7.31-7.20 (m, 5H), 6,69 (t-like m, J ̃4.8 Hz, 1H), 3.94-3.78 (br s, 4H), 3.78-3.45 (br d, 4H); HPLC-MS: m/z=446 (M+H); IR (KBr): ν 1719 (C═O) cm−1.
Example 283
General Procedure 15
4-Cyclopropylmethyl-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-cyclopropylpiperazine, yield 62%. Recrystallisation from 0.2 M HCl gave white crystals, m.p. 238-239° C.; 1H NMR (DMSO-d6): δ11.51 (br s, 1H), 8.61-8.55 (m, 1H), 8.30-8.20 (m, dd, 1H), 7.32-7.19 (m, d+s, 5H), 4.44-4.00 (br, 2H), 3.80-3.40 (br m, 4H), 3.29-2.93 (br m, 4H), 1.28-1.05 (br m, 1H), 0.75-0.58 (m, 2H), 0.50-0.35 (m, 2H).IR (KBr): ν 1730, 1713 (C═O) cm−1.
Example 284
General Procedure 15
4-Methyl-1,4-diazepane-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-methylhomopiperazine; white crystals, m.p. 210-211° C.; 1H NMR (DMSO-d6): δ1.27 (br s, 1H), 8.61-8.54 (m, 1H), 8.30-8.20 (dd-like m, 1H), 7.34-7.18 (m, 5H), 4.13-3.08 (br, 11H, 8H+water), 2.80 (br s, 3H), 2.47-1.98 (br m, 2H); IR (KBr): ν 1723, 1711 (C═O) cm−1.
Example 285
General Procedure 15
4-Phenethyl-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-phenethylpiperazine, yield 54%. Recrystallisation from 99% EtOH gave white crystals, m.p. 245-247° C.; 1H NMR (DMSO-d6): δ11.72 (br, 1H), 8.63-8.53 (br, 1H), 8.31-8.19 (dd-like m, 1H), 7.44-7.16 (m, 10H), 4.44-4.01 (br, 2H), 3.83-3.45 (br, 4H), 3.45-2.95 (br,  ̃8H, 6H+water); IR (KBr): ν 1713 (C═O) cm−1.
Example 286
General Procedure 15
4-Pyridin-2-ylmethyl-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-pyridin-2-ylmethyl-piperazine. White crystals, yield 64%; m.p. 189-190° C.; 1H NMR (DMSO-d6):, δ8.72-8.63 (m, 1H), 8.60-8.55 (br, 1H), (br, 1H), 8.29-8.20 (dd-like, 1H), 8.02-7.90 (m, 1H), 7.80-7.65 (m, 1H), 7.56-7.45 (m, 1H), 7.31-7.22 (m, 5H), 4.52 (br s, 2H), 4.06-3.68 (br s, 4H), 3.68-2.93 (br, 4H+NH+water); HPLC-MS: m/z=459 (M+H); IR (KBr): ν 1717 (C═O) cm−1.
Example 287
General Procedure 15
4-Pyridin-3-ylmethyl-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-pyridin-3-ylmethyl-piperazine. Trituration with water, filtering and drying of the residue gave white crystals. 1H NMR (DMSO-d6): δ8.78-8.51 (m, 3H), 8.30-8.18 (dd-like, 1H), 8.12-8.00 (br d, 1H), 7.57-7.46 (m, 1H), 7.32-7.17 (m, 5H), 4.65-4.11 (br, 2H), 4.11-2.78 (br m, 6H+water); HPLC-MS: m/z=459 (M+H); IR (KBr): ν 1723 (C═O) cm−1.
Example 288
General Procedure 15
4-(3-Phenylpropyl)piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(3-phenylpropyl)piperazine, yield 68%. m.p. 235-238° C.; 1H NMR (DMSO-d6): δ11.51 (br, 1H), 8.61-8.55 (br, 1H), 8.29-8.20 (dd-like m, 1), 7.38-7.16 (m, 10H), 4.38-3.96 (br, 2H), 3.83-3.40 (br, 4H), 3.30-2.91(br, 4H), 2.75-2.57 (t-like m, 2H), 2.20-1.94 (m, 2H); IR (KBr): ν 1715 (C═O) cm−1.
Example 289
General Procedure 15
4-(4-Phenylbutyl)piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(4-phenylbutyl)piperazine, yield 71%. m.p. 232-234° C.;
1H NMR (DMSO-d6): δ11.32 (br s, 1H), 8.61-8.55 (br, 1H), 8.29-8.20 (dd-like m, 1H), 7.36-7.13 (m, 10H), 4.40-3-97 (br, 2H), 3.81-3.39 (br m, 4H), 3.26-2.91 (br, 4H), 2.71-2.55 (t-like m, 2H), 1.88-1.51 (br m, 4H); IR (KBr): ν 1728, 1713 (C═O) cm−1.
Example 290
General Procedure 15
4-Benzyl-1,4-diazepane-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-benzylhomopiperazine, crude yield 70%. 0.20 g Of the crude product was heated with 3 ml of water, cooled at 0° C., the precipitate filtered off and dried; m.p. 231-233° C.; 1H NMR (DMSO-d6): δ11.38 (br s, 1H), 8.62-8.55 (br, 1H), 8.30-8.20 (dd-like m, 1H), 7.76-7.60 (br, 2H), 7.52-7.41 (br m, 3H), 7.32-7.19 (m, 5H), 4.38 (br s, 2H), 4.18-3.01 (br m, 8H+water), 2.6-2.0 (br, 2H+DMSO); IR (KBr): ν 1726, 1710 (C═O) cm−1.
Example 291
General Procedure 15
4-(3,4-Dichlorophenyl)piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(3,4-dichlorophenyl)piperazine. The crude product was partitioned between dichlorormethane and 2 M aqueous sodium carbonate. The organic layer was washed with water, dried and evaporated. The residue was triturated with ethyl acetate—heptane (1:4) and the precipitate was collected by filtration and dried to give the title compound as white crystals. Yield 28%; m.p. 115-116° C.; 1H NMR (DMSO-d6): δ8.61-8.55 (br, 1H), 8.30-8.20 (dd-like, 1H), 7.48-7.40 (d-like, 1H), 7.31-7.16 (m, 6H), 7.04-6.94 (dd-like, 1H), 3.83-3.47 (br m, 4H), 3.36-3.24 (br s, 4H+water); HPLC-MS: m/z=512 (M+H); IR (KBr): ν 1724,1706 cm−1.
Example 292
General Procedure 15
4-(4-Fluorophenyl)piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(4-fluorophenyl)piperazine. White crystals, yield 20%; m.p. 131-132° C.; 1H NMR (DMSO-d6): δ8.61-8.53 (br, 1H), 8.30-8.19 (dd-like, 1H), 7.33-7.17 (m, 5H), 7.17-6.95 (m, 4H), 3.85-3.47 (br d, 4H), 3.25-3.07 (br m, 4H); HPLC-MS: m/z=462 (M+H); IR (KBr): ν 1739,1714 cm−1.
Example 293
General Procedure 15
4-(2-Chlorophenyl)piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)phenyl ester
The the hydrochloride of title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(2-chlorophenyl)piperazine. Drying in vacuo at 50° C. for 31⁄2 h gave the title compound; 1H NMR (DMSO-d6): δ8.61-8.55 (br, 1H), 8.29-8.20 (dd-like, 1H), 7.53-7.41 (m, 1H), 7.39-7.17 (m, 7H), 7.14-7.03 (m, 1H), 4.58 (br s, NH+water), 3.85-3.55 (br m, 4H), 3.12-2.99 (br m, 4H); HPLC-MS: m/z=478 (M+H); IR (KBr): ν 1733 (C═O) cm−1.
Example 294
General Procedure 15
(2-Dimethylamino-ethyl)methylcarbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and N,N,N′-trimethylethylenediamine; m.p. 139-140° C.; 1H NMR (MeOH-d6): δ8.45-8.38 (br, 1H), 8.15-8.05 (dd-like m, 1H), 7.31-7.11 (m, 5H), 3.84-3.73 (br m, 2H), 3.54-3.38 (br m, 3H), 3.19 (br s, 2H), 2.99 (br s, 6H); traces of impurities at 3.9 (br) and 3.1 (br); IR (KBr): ν 2695, 1705 cm (C═O) cm−1.
Example 295
General Procedure 15
4-Methylpiperazine-1-carboxylic acid 4-chlorophenyl ester
The hydrochloride of the title compound was prepared from 4-chlorophenyl chloroformate and 1-methylpiperazine, yield 81%. White crystals, m.p. 237-240° C.; 1H NMR (DMSO-d6): δ11.67 (br s, 1H), 7.50, 7.45, 7.24, 7.20 (AB-system, d=7.47 and 7.22; J=8.84 Hz, 4H), 4.40-3.91 (br, 2H, 3.77-2.92 (br m, 6H+water), 2.77 (s, 3H); IR (KBr): ν 1717 (C═O) cm −1.
Example 296
General Procedure 15
4-(4-Phenylbutyl)piperazine-1-carboxylic acid 4-chlorophenyl ester
The hydrochloride of the title compound was prepared from 4-chlorophenyl chloroformate and 1-(4-phenylbutyl)piperazine, yield 86%. White crystals, m.p. 230-232° C.; 1H NMR (DMSO-d6): δ11.43 (br, 1H), 7.51-7.43 (d-like m, 2H), 7.33-7.15 (m, 7H), 4.33-3.95 (br, max at 4.21 and 4.10 ppm; 2H), 3.72-3.36 (br m, 4H), 3.22-2.96 (br, max at 3.10 ppm, 4H), 2.62 (t, J=7.54 Hz, 2H), 1.84-1.69 (m, 2H), 1.69-1.54 (m, 2H) ppm; IR (KBr): ν 1736, 1720 (C═O) cm−1.
Example 297
General Procedure 15
4-[2-(2-Hydroxyethoxy)ethyl]piperazine-1-carboxylic acid 4-(4-trifluoromethylphenoxy)phenyl ester
The hydrochloride of the title compound was prepared from 4-(4-trifluoromethylphenoxy)phenyl chloroformate and 2-(2-hydroxyethoxy)ethyl-piperazine. Pale powder, m.p. 176-178° C.; 1H NMR (MeOH-d4): δ Two AB-systems: 7.68-7.58 (d-like, 2H) and 7.29-7.04 (m, 6H); 4.74-3.18 (complex, 16H, partly overlapping with MeOH-d4); HPLC-MS m/z=455 (M+H), 477 (M+Na), Rt=3.08 min.; IR (KBr): ν 1718 (C═O) cm−1.
Example 298
General Procedure 15
4-(1-Ethylpropyl)piperazine-1-carboxylic acid 4-(4-trifluoromethylphenoxy)phenyl ester
The hydrochloride of the title compound was prepared from 4-(4-trifluoromethylphenoxy)phenyl chloroformate and 1-(1-ethylpropyl)piperazine, yield 74%. White crystals, 1H NMR (DMSO-d6): δ10.59 (br s, 1H), 2 AB-systems: 7.81-7.70 (d-like, 2H) and 7.31-7.09 (m, 6H); 4.38-3.99 (br s, 2H), 3.90-3.38 (br, 4H), 3.33-2.99 (br, 3H), 2.01-1.77 (m, 2H), 1.77-1.49 (m, 2H), 0.98 (t, 6H); HPLC-MS m/z=437 (M+H).
Example 299
General Procedure 15
4-Cycloheptylpiperazine-1-carboxylic acid 4-(4-trifluoromethyl-phenoxy)phenyl ester
The hydrochloride of the title compound was prepared from 4-(4-trifluoromethylphenoxy)phenyl chloroformate and 1-cycloheptylpiperazine. The crude product was partitioned between dichlorormethane and aqueous sodium carbonate. The organic layer was washed with water, dried and evaporated. The residue was triturated with ethyl acetate—heptane (1:4) and the precipitate was collected by filtration and dried to give the title compound. White crystals, 1H NMR (MeOH-d4): δ Two AB-systems: 7.68-7.58 (d-like, 2H) and 7.23-7.04 (m, 6H); 3.86-3.50 (br d, 4H), 2.98-2.66 (br, 5H), 2.04-1.37 (m, 12H); HPLC-MS m/z=463 (M+H); IR (KBr): ν 1730, 1707 cm−1.
Example 300
General Procedure 15
4-Cyclohexylpiperazine-1-carboxylic acid 4-(4-trifluoromethyl-phenoxy)phenyl ester
The hydrochloride of the title compound was prepared from 4-(4-trifluoromethylphenoxy)phenyl chloroformate and 1-cyclohexylpiperazine, yield 80%. White crystals, m.p. 290-291° C., 1H NMR (DMSO-d6): δ10.82 (br s, 1H), 2 AB-systems: 7.83-7.69 (d-like, 2H) and 7.32-7.10 (m, 6H); 4.40-4.02 (br, 2H), 3.75-3.39 (br, 4H), 3.31-2.98 (br, 3H), 2.23-2.02 (m, 2H), 1.92-1.74 (m, 2H), 1.70-0.97 (m, 6H); HPLC-MS m/z=449 (M+H); IR (KBr): ν 1717 (C═O) cm−1.
Example 301
General Procedure 15
4-(4-Chlorobenzyl)piperazine-1-carboxylic acid 4-(4-trifluoromethylphenoxy)phenyl ester
The hydrochloride of the title compound was prepared from 4-(4-trifluoromethylphenoxy)phenyl chloroformate and 1-(4-chlorobenzyl)piperazine, yield 86% White crystals, m.p. 232-234° C.; 1H NMR (DMSO-d6): δ11.92 (br s, 1H), 3 AB-systems: 7.83-7.62 (t-like, 4H) and 7.62-7.48 (d-like, 2H), and 7.32-7.07 (m, 6H); 4.51-3.95 (br s at 4.37 ppm overlapping with br signal at 4.2 ppm, 4H), 3.95-2.95 (br m, 9H: 6H+water); IR (KBr): ν 1717 (C═O) cm−1.
Example 302
General Procedure 15
4-(4-Methylbenzyl)piperazine-1-carboxylic acid 4-(4-trifluoromethylphenoxy)phenyl ester
The hydrochloride of the title compound was prepared from 4-(4-trifluoromethylphenoxy)phenyl chloroformate and 1-(4-methylbenzyl)piperazine, yield 96%. White crystals, m.p. 250-252° C.; HPLC-MS m/z=472 (M+H); IR (KBr): ν 1720 (C═O) cm−1.
Example 303
General Procedure 15
4-(4-Methoxybenzyl)piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(4-methoxybenzyl)piperazine, yield 78%. White crystals, m.p. 237-238° C.; HPLC-MS m/z=488 (M+H); IR (KBr): ν 1719 (C═O) cm−1.
Example 304
General Procedure 15
4-(2-Chloro-6-fluoro-benzyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(2-chloro-6-fluorobenzyl)piperazine. White crystals, m.p. 204-205° C. (from ethanol); HPLC-MS m/z=510 (M+H); IR (KBr): ν 1726 (C═O) cm−1;
Example 305
General Procedure 15
4-(3-Methoxyphenyl)piperazine-1-carboxylic acid 4-(4-trifluoromethylphenoxy)phenyl ester
The hydrochloride of the title compound was prepared from 4-(4-trifluoromethylphenoxy)phenyl chloroformate and 1-(3-methoxyphenyl)piperazine. White crystals, m.p. 168-171° C. (sinters at 160° C.); HPLC-MS m/z=473(M+1); IR (KBr): ν 1739, 1716 (C═O) cm−1.
Example 306
General Procedure 15
4-Benzyl-piperazine-1-carboxylic acid 4-(3-chloro-5-trifluoromethyl-pyridin-2-yloxy)phenyl ester
The hydrochloride of the title compound was prepared from 4-(3-chloro-5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-benzyl-piperazine, yield 94%. White crystals; m.p. 111-113° C. (resolidifies) and 114-115° C.; HPLC-MS m/z=492 (M+H).
Example 307
General Procedure 8
Methyl-phenyl-carbamic acid 4-iodo-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-4-iodopyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (98%, oil).
1H NMR (300 MHz; CDCl3): δ3.44 (bs, 3H), 7.30-7.48 (m, 7H).; HPLC-MS: m/z=343.9 (M+1); Rt=4.12 min.
Example 308
General Procedure 8
Methyl-phenyl-carbamic acid benzotriazol-1-yl ester
The title compound was prepared from 1-hydroxybenzotriazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (98%, crystallizes slowly).
1H NMR (300 MHz; CDCl3): δ3.50 (bs, 3H), 7.37-7.57 (m, 8H), δ8.04 (d, 1H),; HPLC-MS : m/z=269.0 (M+1); Rt=3.69 min.
Example 309
General Procedure 8
Methyl-phenyl-carbamic acid [1,2,3]triazolo[4,5-b]pyridin-3-yl ester
The title compound was prepared from [1,2,3]Triazolo[4,5-b]pyridin-3-ol and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (99%, oil).
1H NMR (300 MHz; CDCl3): δ3.50 (bs, 3H), 7.30-7.60 (m, 6H), 8.40 (d, 1H), 8.75 (d, 1H); HPLC-MS: m/z=270.0 (M+1); Rt=3.18 min.
Example 310
General Procedure 8
Methyl-phenyl-carbamic acid 3-(2-nitro-phenyl)-pyrazol-1-yl  ester
The title compound was prepared from 1-hydroxy-3-(2-nitrophenyl)pyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (94%, oil).
1H NMR (300 MHz; CDCl3): δ3.45 (bs, 3H), 6.44 (bs, 1H), 7.30-7.50 (m, 7H), 7.58 (dt, 1H), 7.72-7.78 (m, 2H); HPLC-MS: m/z=339.1 (M+1); Rt=4.15 min.
Example 311
General Procedure 8
Methyl-phenyl-carbamic acid 3-(4-nitro-phenyl)-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-3-(4-nitrophenyl)pyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (99%, yellow crystals).
1H NMR (300 MHz; CDCl3): δ3.47 (bs, 3H), 6.70 (bd, 1H), 7.32-7.50 (m, 6H), 7.94 (d, 2H), 8.26 (d, 2H); HPLC-MS: m/z=339.1 (M+1); Rt=4.41 min.
Example 312
General Procedure 8
Methyl-phenyl-carbamic acid 3-pyridin-2-yl-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-3-(2-pyridyl)pyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (90%, oil).
1H NMR (300 MHz; CDCl3): δ3.48 (bs, 3H), 6.95 (d, 1H), 7.20 (dd, 1H), 7.30-7.48 (m, 6H), 7.70 (dt, 1H), 7.93 (d, 1H), 8.61 (d, 1H); HPLC-MS: m/z=295.1 (M+1); Rt=2.75 min.
Example 313
General Procedure 8
Methyl-phenyl-carbamic acid 3-thiophen-2-yl-pyrazol-1-yl  ester
The title compound was prepared from 1-hydroxy-3-(2-thienyl)pyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (66%, oil).
1H NMR (300 MHz; CDCl3): δ3.46 (bs, 3H), 6.48 (bd, 1H), 7.03 (dd, 1H), 7.25 (dd, 1H), 7.30-7.48 (m, 7H); HPLC-MS: m/z=300.1 (M+1); Rt=4.16 min.
Example 314
General Procedure 8
Methyl-phenyl-carbamic acid 3-(2-fluoro-phenyl)-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-3-(2-fluorophenyl)pyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (97%, oil).
1H NMR (300 MHz; CDCl3): δ3.48 (bs, 3H), 6.75 (bt, 1H), 7.07-7.47 (m, 9H), 7.97 (dt, 1H); HPLC-MS: m/z=312.1 (M+1); Rt=4.45 min.
Example 315
General Procedure 8
Methyl-phenyl-carbamic acid 3-bromo-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-3-bromopyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (63%, oil).
1H NMR (300 MHz; CDCl3): δ3.43 (bs, 3H), 6.31 (d, 1H), 7.26-7.48 (m, 6H); HPLC-MS : m/z=298.0 (M+1); Rt=3.97 min.
Example 316
General Procedure 8
Methyl-phenyl-carbamic acid 5-iodo-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-5-iodopyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (64%, oil).
1H NMR (300 MHz; CDCl3): δ3.48 (bs, 3H), 6.42 (d, 1H), 7.28-7.47 (m, 6H),; HPLC-MS : m/z=343.9 (M+1); Rt=3.81 min.
Example 317
General Procedure 8
Methyl-phenyl-carbamic acid 2-chloro-imidazol-1-yl ester
The title compound was prepared from 1-hydroxy-2-chloroimidazole, hydrochloride and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (77%, oil).
1H NMR (300 MHz; CDCl3): δ 3.45 (bs, 3H), 6.90 (bs, 1H), 7.07 (bs, 1H), 7.35-7.40 (m, 3H), 7.46 (bt, 2H); HPLC-MS: m/z=251.9 (M+1); Rt=3.29 min.
Example 318
General Procedure 8
Methyl-phenyl-carbamic acid 4-(4-methoxy-phenyl)-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-4-(4-methoxyphenyl)pyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (6%, oil).
1H NMR (300 MHz; CDCl3): δ 3.45 (bs, 3H), 3.82 (s, 3H), 6.90 (d, 2H), 7.30-7.48 (m, 7H), 7.54 (bs, 2H); HPLC-MS: m/z=346.1 (M+23); Rt=4.16 min.
Example 319
General Procedure 8
Methyl-phenyl-carbamic acid 5-benzoyl-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-5-benzoylpyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (30%, crystals).
1H NMR (300 MHz; CDCl3): δ 3.48 (bs, 3H), 6.69 (bs, 1H), 7.27-7.52 (m, 8H), 7.63 (t, 1H), 7.79 (d, 2H); HPLC-MS: m/z=344.0 (M+23); Rt=4.41 min.
Example 320
General Procedure 8
Methyl-phenyl-carbamic acid 5-(4-methoxy-phenyl)-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-5-(4-methoxyphenyl)pyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (38%, yellow crystals).
1H NMR (300 MHz; CDCl3): δ 3.33 (bs, 3H), 3.86 (s, 3H), 6.34 (d, 1H), 6.95 (d, 2H), 7.25-7.45 (m, 8H); HPLC-MS: m/z=324.1 (M+1); Rt=4.27 min.
Example 321
General Procedure 8
Methyl-phenyl-carbamic acid 5-(4-dimethylamino-phenyl)-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-5-(4-dimethylaminophenyl)-pyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (27%, crystals).
1H NMR (300 MHz; CDCl3): δ 3.02 (s, 6H), 3.35 (bs, 3H), 6.30 (d, 1H), 6.72 (d, 2H), 7.30-7.46 (m, 8H); HPLC-MS: m/z=337.1 (M+1); Rt=4.11 min.
Example 322
General Procedure 8
Methyl-phenyl-carbamic acid 4,5-diiodo-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-4,5-diiodopyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (76%, crystals).
1H NMR (300 MHz; CDCl3): δ 3.45 (bs, 3H), 7.30-7.50 (m, 6H).; HPLC-MS: m/z=369.9 (M+1); Rt=4.56 min.
Example 323
General Procedure 8
Methyl-phenyl-carbamic acid 5-thiophen-2-yl-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-5-(2-thienyl)pyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (51%, crystals).
1H NMR (300 MHz; CDCl3): δ 3.44 (bs, 3H), 6.45 (bs, 1H), 7.09 (dd, 1H), 7.26 (bs, 1H), 7.28-7.49 (m, 7H); HPLC-MS: m/z=300.1 (M+1); Rt=4.18 min.
Example 324
General Procedure 8
Methyl-phenyl-carbamic acid 2-(4-methoxy-phenyl)-imidazol-1-yl ester
The title compound was prepared from 1-hydroxy-2-(4-methoxyphenyl)imidazole, hydrochloride and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (89%, crystals).
1H NMR (300 MHz; CDCl3): δ 3.33 (bs, 3H), 3.86 (s, 3H), 6.92 (d, 2H), 7.04 (d, 1H), 7.10 (bs, 1H), 7.28 (d, 2H), 7.34-7.50 (m, 3H), 7.60 (bd, 2H); HPLC-MS: m/z=324.1 (M+1); Rt=2.87 min.
Example 325
General Procedure 8
Methyl-phenyl-carbamic acid 2-methylsulfanyl-imidazol-1-yl ester
The title compound was prepared from 1-hydroxy-2-methylsulfanyl-imidazole hydrochloride and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (97%, oil).
1H NMR (300 MHz; CDCl3): δ 2.56 (s, 3H), 3.44 (bs, 3H), 7.00 (bs, 1H), 7.08 (bs, 1H), 7.32-7.49 (m, 5H); HPLC-MS: m/z=264.1 (M+1); Rt=2.99 min.
Example 326
General Procedure 8
Methyl-phenyl-carbamic acid 3,5-bis-(4-methoxy-phenyl)-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-3,5-bis-(4-methoxyphenyl)pyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (29%, beige crystals).
1H NMR (300 MHz; CDCl3): δ 3.35 (bs, 3H), 3.84 (s, 3H), 3.88 (s, 3H), 6.57 (s, 1H), 6.92 (d, 2H), 6.97 (d, 2H), 7.25-7.48 (m, 7H), 7.74 (d, 2H); HPLC-MS: m/z=881.2 (2M+23); Rt=5.26 min.
Example 327
General Procedure 8
Methyl-phenyl-carbamic acid 4-(4-fluoro-phenyl)-5-(4-methoxy-phenyl)-3-(4-methylphenyl)-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-4-(4-fluorophenyl)-5-(4-methoxyphenyl)-3-(4-methylphenyl)pyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (11%, crystals).
1H NMR (300 MHz; CDCl3): δ 2.32 (s, 3H), 3.32 (bs, 3H), 3.83 (s, 3H), 6.87 (d, 2H), 6.93 (d, 2H), 7.12-7.48 (m, 13H); HPLC-MS: m/z=530.2 (M+23); Rt=6.04 min.
Example 328
General Procedure 8
Methyl-phenyl-carbamic acid 4-benzyl-5-(4-methoxy-phenyl)-3-(methylphenyl)-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-4-benzyl-5-(4-methoxyphenyl)-3-(4-methylphenyl)pyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (14%, oil).
1H NMR (300 MHz; CDCl3): δ 2.31 (s, 3H), 3.31 (bs, 3H), 3.83 (s, 3H), 3.95 (s, 2H), 6.89 (d, 2H), 7.08-7.39 (m, 13H), 7.43 (d, 2H); HPLC-MS: m/z=504.2 (M+1); Rt=6.11 min.
Example 329
General Procedure 8
Methyl-phenyl-carbamic acid 4-acetyl-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-4-acetylpyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (89%, oil).
1H NMR (300 MHz; CDCl3): δ 2.44 (s, 3H), 3.44 (bs, 3H), 7.32-7.48 (m, 5H), 7.78 (bs, 1H), 7.85 (bs, 1H).
Example 330
General Procedure 8
Methyl-phenyl-carbamic acid 2-(4-nitro-phenyl)-imidazol-1-yl ester
The title compound was prepared from 1-hydroxy-2-(4-nitrophenyl)imidazole, hydrochloride and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (90%, yellow crystals).
1H NMR (300 MHz; CDCl3): δ 3.38 (bs, 3H), 7.16 (s, 1H), 7.20 (s, 1H), 7.31 (d, 2H), 7.38-7.61 (m, 3H), 7.86 (bs, 2H), 8.25 (d, 2H).
Example 331
General Procedure 8
Methyl-phenyl-carbamic acid 2-chloro-5-(4-methylphenyl)-imidazol-1-yl ester
The title compound was prepared from 1-hydroxy-2-chloro-5-(4-methylphenyl)imidazole, hydrochloride and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (80%, oil).
1H NMR (300 MHz; CDCl3): δ 2.40 (s, 3H), 3.33 (bs, 3H), 7.00 (s, 1H), 7.19-7.29 (m, 6H), 7.35-7.50 (m, 3H).
Example 332
General Procedure 8
Methyl-phenyl-carbamic acid 4-formyl-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-4-formylpyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (73%, oil).
1H NMR (300 MHz; CDCl3): δ 3.45 (bs, 3H), 7.29-7.50 (m, 5H), 7.84 (bs, 1H), 7.90 (bs, 1H), 9.83 (s, 1H).
Example 333
General Procedure 8
Methyl-phenyl-carbamic acid 4-hydroxymethyl-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-4-hydroxymethylpyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (62%, oil).
1H NMR (300 MHz; CDCl3): δ 2.33 (bs, 1H), 3.40 (bs, 3H), 4.50 (s, 2H), 7.28-7.46 (m, 7H).
Example 334
General Procedure 8
Methyl-phenyl-carbamic acid 4-phenylethynyl-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-4-phenylethynylpyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (40%, yellow crystals).
1H NMR (300 MHz; CDCl3): δ 3.42 (bs, 3H), 7.30-7.58 (m, 12H).
Example 335
General Procedure 8
Methyl-phenyl-carbamic acid 2-bromo-imidazol-1-yl ester
The title compound was prepared from 1-hydroxy-2-bromoimidazole, hydrochloride and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (63%, oil).
1H NMR (300 MHz; CDCl3): δ 3.45 (bs, 3H), 6.98 (bd, 1H), 7.11 (bs, 1H), 7.33-7.50 (m, 5H); HPLC-MS: m/z=296.0 (M+1); Rt=2.90 min.
Example 336
General Procedure 8
Methyl-phenyl-carbamic acid 2-phenylsulfanyl-imidazol-1-yl ester
The title compound was prepared from 1-hydroxy-2-phenylsulfanylimidazole hydrochloride and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (61%, oil).
1H NMR (300 MHz; CDCl3): δ 3.35 (s, 3H), 7.12 (bd, 1H), 7.17-7.39 (m, 11H); HPLC-MS: m/z=326.0 (M+1); Rt=3.65 min.
Example 337
General Procedure 8
Morpholine-4-carboxylic acid imidazol-1-yl ester
The title compound was prepared from 1-hydroxyimidazole and 4-morpholine carbonyl chloride applying the general procedure 8. The crude product was purified by preparative HPLC (water-acetonitrile-0.1% TFA) (36%, crystals).
1H NMR (300 MHz; CDCl3): δ 3.57 (bs, 2H), 3.66 (bs, 2H), 3.78 (t, 4H), 7.12 (bs, 1H), 7.15 (bt, 1H), 7.90 (s, 1H); HPLC-MS: m/z=198.1 (M+1); Rt=0.36 min.
Example 338
General Procedure 8
Morpholine-4-carboxylic acid 2-bromo-imidazol-1-yl ester
The title compound was prepared from 1-hydroxy-2-bromoimidazole, hydrochloride and 4-morpholine carbonyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc) (98%, crystals).
1H NMR (300 MHz; CDCl3): δ 3.60 (bs, 2H), 3.71 (bs, 2H), 3.80 (t, 4H), 7.02 (d, 1H), 7.18 (d, 1H); HPLC-MS: m/z=276.0 (M+1); Rt=1.73 min.
Example 339
General Procedure 8
Morpholine-4-carboxylic acid 2-chloro-imidazol-1-yl ester
The title compound was prepared from 1-hydroxy-2-chloroimidazole, hydrochloride and 4-morpholine carbonyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc) (54%, oil).
1H NMR (300 MHz; CDCl3): δ 3.58 (bs, 2H), 3.68 (bs, 2H), 3.69 (t, 4H), 6.94 (d, 1H), 7.10 (d, 1H); HPLC-MS: m/z=232.0 (M+1); Rt=1.69 min.
Example 340
General Procedure 8
Morpholine-4-carboxylic acid 2-phenylsulfanyl-imidazol-1-yl ester
The title compound was prepared from 1-hydroxy-2-phenylsulfanylimidazole, hydrochloride and 4-morpholine carbonyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc) (98%, oil).
1H NMR (300 MHz; CDCl3): δ 3.46 (bs, 4H), 3.66 (bs, 4H), 7.15 (d, 1H), 7.18-7.31 (m, 6H); HPLC-MS: m/z=306.1 (M+1); Rt=2.75 min.
Example 341
General Procedure 8
Morpholine-4-carboxylic acid 2-(4-methoxy-phenyl)-imidazol-1-yl ester
The title compound was prepared from 1-hydroxy-2-(4-methoxyphenyl)imidazole, hydrochloride and 4-morpholine carbonyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc) (49%, crystals).
1H NMR (300 MHz; CDCl3): δ 3.51 (bs, 2H), 3.62-3.76 (m, 6H), 3.86 (s, 3H), 6.96 (d, 2H), 7.08 (d, 1H), 7.11 (d, 1H), 7.70 (d, 2H); HPLC-MS: m/z=304.1 (M+1); Rt=1.81 min.
Example 342
General Procedure 8
Morpholine-4-carboxylic acid 4-bromo-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-4-bromopyrazole and 4-morpholine carbonyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (85%, crystals).
1H NMR (300 MHz; CDCl3): δ 3.57 (bs, 2H), 3.68 (bs, 2H), 3.79 (t, 4H), 7.35 (d, 1H), 7.43 (d, 1H); HPLC-MS: m/z=298.0 (M+23); Rt=2.46 min.
Example 343
General Procedure 8
Morpholine-4-carboxylic acid 4-iodo-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-4-iodopyrazole and 4-morpholine carbonyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (99%, crystals).
1H NMR (300 MHz; CDCl3): δ 3.56 (bs, 2H), 3.66 (bs, 2H), 3.77 (t, 4H), 7.41 (d, 1H), 7.44 (d, 1H); HPLC-MS: m/z=324.0 (M+1); Rt=2.65 min.
Example 344
General Procedure 8
Morpholine-4-carboxylic acid 3,4,5-tribromo-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-3,4,5-tribromopyrazole and 4-morpholine carbonyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (90%, crystals).
1H NMR (300 MHz; CDCl3): δ 3.59 (bs, 2H), 3.69 (bs, 2H), 3.79 (t, 4H); HPLC-MS m/z=455.6 (M+23); Rt=3.91 min.
Example 345
General Procedure 8
Morpholine-4-carboxylic acid 3-(4-methoxy-phenyl)-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-3-(4-methoxyphenyl)pyrazole and 4-morpholine carbonyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (62%, crystals).
1H NMR (300 MHz; CDCl3): δ 3.58 (bs, 2H), 3.71 (bs, 2H), 3.79 (t, 4H), 3.84 (s, 3H), 6.53 (d, 1H), 6.92 (d, 2H), 7.40 (d, 1H), 7.71 (d, 2H); HPLC-MS: m/z=326.0 (M+23); Rt=3.21 min.
Example 346
General Procedure 8
Morpholine-4-carboxylic acid 3-thiophen-2-yl-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-3-(2-thienyl)pyrazole and 4-morpholine carbonyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (75%, crystals).
1H NMR (300 MHz; CDCl3): δ 3.57 (bs, 2H), 3.69 (bs, 2H), 3.79 (t, 4H), 6.51 (d, 1H), 7.04 (dd, 1H), 7.26 (dd, 1H), 7.34 (dd, 1H), 7.40 (d, 1H); HPLC-MS: m/z=280.0 (M+1); Rt=3.12 min.
Example 347
General Procedure 8
Morpholine-4-carboxylic acid pyrazol-1-yl ester
The title compound was prepared from 1-hydroxypyrazole and 4-morpholine carbonyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (94%, crystals).
1H NMR (300 MHz; CDCl3): δ 3.57 (bs, 2H), 3.69 (bs, 2H), 3.79 (t, 4H), 6.32 (t, 1H), 7.38 (dd, 1H), 7.41 (dd, 1H); HPLC-MS: m/z=198.0 (M+1); Rt=1.18 min.
Example 348
General Procedure 16 
4-Methyl-piperazine-1-carboxylic acid pyrazol-1-yl ester
The title compound was prepared from 1-hydroxypyrazole and N-methylpiperazine applying the general procedure 16. The crude product was purified by preparative HPLC (water-acetonitrile-0.1% TFA) (17%, salt with TFA).
1H NMR (300 MHz; CDCl3): δ 2.36 (s, 3H), 2.50 (bt, 4H), 3.59 (bs, 2H), 3.71 (bs, 2H), 6.31 (t, 1H), 7.38 (dd, 1H), 7.40 (dd, 1H); HPLC-MS: m/z=211.0 (M+1); Rt=0.40 min.
Example 349
General Procedure 16 
4-Cyclopentyl-piperazine-1-carboxylic acid pyrazol-1-yl ester
The title compound was prepared from 1-hydroxypyrazole and N-cyclopentylpiperazine applying the general procedure 16. The crude product was purified by preparative HPLC (water-acetonitrile-0.1% TFA) (34%, salt with TFA).
1H NMR (300 MHz; CDCl3): δ 1.45-2.01 (m, 8H), 2.70 (bs, 4H), 2.92 (bs, 1H), 3.55 (bt, 1H), 3.63 (bs, 2H), 3.77 (bs, 2H), 6.31 (t, 1H), 7.38 (dd, 1H), 7.41 (dd, 1H); HPLC-MS: m/z=265.1 (M+1); Rt=0.54 min.
Example 350
General Procedure 16 
4-Phenyl-piperazine-1-carboxylic acid pyrazol-1-yl ester
The title compound was prepared from 1-hydroxypyrazole and N-phenylpiperazine applying the general procedure 16. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (48%, crystals).
1H NMR (300 MHz; CDCl3): δ 3.25 (bt, 4H), 3.72 (bs, 2H), 3.85 (bs, 2H), 6.33 (t, 1H), 6.92-6.98 (m, 3H), 7.27-7.33 (m, 2H), 7.38 (dd, 1H), 7.41 (dd, 1H); HPLC-MS: m/z=273.1 (M+1); Rt=3.06 min.
Example 351
General Procedure 16 
4-Pyridin-2-yl-piperazine-1-carboxylic acid pyrazol-1-yl ester
The title compound was prepared from 1-hydroxypyrazole and 1-(2-pyridyl)piperazine applying the general procedure 16. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (59%, crystals).
1H NMR (300 MHz; CDCl3): δ 3.62-3.85 (m, 8H), 6.32 (t, 1H), 6.66-6.72 (m, 2H), 7.39 (dd, 1H), 7.42 (dd, 1H), 7.53 (dt, 1H), 8.21 (d, 1H); HPLC-MS: m/z=274.1 (M+1); Rt=0.63 min.
Example 352
General Procedure 16 
4-Pyrimidin-2-yl-piperazine-1-carboxylic acid pyrazol-1-yl ester
The title compound was prepared from 1-hydroxypyrazole and 1-(2-pyrimidyl)piperazine applying the general procedure 16. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (57%, crystals).
1H NMR (300 MHz; CDCl3): δ 3.65 (bs, 2H), 3.78 (bs, 2H), 3.95 (bs, 4H), 6.32 (t, 1H), 6.58 (t, 2H), 7.38 (dd, 1H), 7.42 (dd, 1H), 8.35 (d, 1H); HPLC-MS: m/z=275.2 (M+1); Rt=2.14 min.
Example 353
General Procedure 16 
4-Benzo[1,3]dioxol-5-yl-piperazine-1-carboxylic acid pyrazol-1-yl ester
The title compound was prepared from 1-hydroxypyrazole and 1-Benzo[1,3]dioxol-5-ylpiperazine applying the general procedure 16. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (92%, crystals).
1H NMR (300 MHz; CDCl3): δ 3.11 (bt, 4H), 3.71 (bs, 2H), 3.83 (bs, 2H), 5.93 (s, 2H), 6.32 (t, 1H), 6.39 (dd, 1H), 6.57 (d, 1H), 6.74 (d, 1H), 7.37 (dd, 1H), 7.41 (dd, 1H); HPLC-MS: m/z=317.2 (M+1); Rt=2.96 min.
Example 354
General Procedure 16 
4-Benzyl-piperazine-1-carboxylic acid 4-iodo-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-4-iodopyrazole and 1-benzylpiperazine applying the general procedure 16. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (32%, oil).
1H NMR (300 MHz; CDCl3): δ 2.53 (bs, 4H), 3.57 (bs, 4H), 3.67 (bs, 2H), 7.28-7.38 (m, 5H), 7.40 (d, 1H), 7.43 (d, 1H); HPLC-MS: m/z=413.0 (M+1); Rt=1.75 min.
Example 355
General Procedure 16 
4-Cyclopentyl-piperazine-1-carboxylic acid 4-iodo-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-4-iodopyrazole and N-cyclopentylpiperazine applying the general procedure 16. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane-3% Et3N) (61%, crystals).
1H NMR (300 MHz; CDCl3): δ 1.33-1.94 (m, 8H), 2.46-2.61 (m, 5H), 3.57 (bt, 2H), 3.67 (bt, 2H), 3.63 (bs, 2H), 3.77 (bs, 2H), 7.40 (d, 1H), 7.44 (d, 1H); HPLC-MS: m/z=391.1 (M+1); Rt=1.31 min.
Example 356
General Procedure 16 
4-(4-Fluoro-benzyl)-piperazine-1-carboxylic acid 4-iodo-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-4-iodopyrazole and 1-(4-fluorobenzyl)piperazine applying the general procedure 16. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (48%, crystals).
1H NMR (300 MHz; CDCl3): δ 2.50 (t, 4H), 3.51 (s, 2H), 3.57 (bt, 2H), 3.66 (bt, 2H), 7.02 (t, 2H), 7.29 (dd, 2H), 7.40 (d, 1H), 7.43 (d, 1H); HPLC-MS: m/z=431.0 (M+1); Rt=1.79 min.
Example 357
General Procedure 16 
4-Phenyl-piperazine-1-carboxylic acid 4-iodo-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-4-iodopyrazole and N-phenylpiperazine applying the general procedure 16. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (52%, crystals).
1H NMR (300 MHz; CDCl3): δ 3.25 (t, 4H), 3.72 (bs, 2H), 3.81 (bs, 2H), 6.90-6.97 (m, 3H), 7.30 (t, 2H), 7.41 (d, 1H), 7.47 (d, 1H); HPLC-MS: m/z=399.1 (M+1); Rt=3.91 min.
Example 358
General Procedure 16 
4-Pyridin-2-yl-piperazine-1-carboxylic acid 4-iodo-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-4-iodopyrazole and 1-(2-pyridyl)piperazine applying the general procedure 16. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (45%, crystals).
1H NMR (300 MHz; CDCl3): δ 3.62-3.82 (m, 8H), 6.66-6.72 (m, 2H), 7.42 (d, 1H), 7.47 (d, 1H), 7.54 (dt, 1H), 8.22 (d, 1H); HPLC-MS: m/z=400.0 (M+1); Rt=1.47 min.
Example 359
General Procedure 16 
4-Pyrimidin-2-yl-piperazine-1-carboxylic acid 4-iodo-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-4-iodopyrazole and 1-(2-pyrimidyl)piperazine applying the general procedure 16. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (10%, crystals).
1H NMR (300 MHz; CDCl3): δ 3.62 (bs, 2H), 3.72 (bs, 2H), 3.95 (bs, 4H), 6.58 (t, 2H), 7.41 (d, 1H), 7.46 (d, 1H), 8.36 (d, 1H); HPLC-MS: m/z=401.0 (M+1); Rt=3.09 min.
Example 360
General Procedure 16 
4-Benzo[1,3]dioxol-5-yl-piperazine-1-carboxylic acid 4-iodo-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-4-iodopyrazole and 1-Benzo[1,3]dioxol-5-ylpiperazine applying the general procedure 16. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (59%, crystals).
1H NMR (300 MHz; CDCl3): δ 3.11 (t, 4H), 3.69 (bs, 2H), 3.80 (bs, 2H), 5.92 (s, 2H), 6.38 (dd, 1H), 6.56 (d, 1H), 6.73 (d, 1H), 7.41 (d, 1H), 7.45 (d, 1H); HPLC-MS: m/z=443.0 (M+1); Rt=3.79 min.
Example 361
4-(1-Ethylpropyl)piperazine-1-carboxylic acid 3-trifluoromethylphenyl ester hydrochloride salt
To a stirred mixture of 1-(1-ethylpropyl)piperazine (175p1, 1.0 mmol) and dry DCM (10 ml) was added 3-trifluoromethylphenyl chloroformate (250 mg, 1.1 mmol). The mixture was stirred overnight at room temperature and then diluted with DCM (50 ml). The reaction mixture was washed with 1 N NaOH (3×25 ml) and water (2×25 ml). The organic solution was concentrated and the residue was dissolved in a 0.5 N HCl solution (15 ml) and a small portion of acetonitrile. The acidic solution was concentrated and stirred with ethyl acetate (15 ml). The solid was isolated and dried to give 330 mg (86%) of the title compound as a solid. M.p. 260-261° C.
1H NMR (400 MHz, DMSO-d6): δ 0.98 (t, 6H), 1.63 (hept, 2H), 1.86-1.98 (m, 2H), 3.03-3.12 (m, 1H), 3.12-3.31 (m, 2H), 3.41-3.49 (m, 2H), 3.52-3.85 (m, 2H), 4.05-4.35 (m, 2H), 7.47-7.70 (m, 4H), 11.0 (brs, 1H).
Example 362
4-(1-Ethylpropyl)piperazine-1-carboxylic acid naphthalen-1-yl ester hydrochloride salt
To a stirred mixture of 1-(1-ethylpropyl)piperazine (175 μl 1.0 mmol) and dry DCM (10 ml) was added 1-napthalenyl chloroformate (225 mg, 1.1 mmol). The mixture was stirred overnight at room temperature and then diluted with DCM (50 ml). The reaction mixture was washed with 1 N NaOH (3×25 ml) and water (2×25 ml). The organic solution was concentrated and the residue was dissolved in a 0.5 N HCl solution (15 ml) and a small portion of acetonitrile. The acidic solution was concentrated and stirred with ethyl acetate (15 ml). The solid was isolated and dried to give 310 mg (85%) of the title compound as a solid.
M.p. 288-290° C.
1H NMR (400 MHz, DMSO-d6): δ 1.00 (t, 6H), 1.63 (hept, 2H), 1.86-2.02 (m, 2H), 3.07-3.18 (m, 1H), 3.18-3.42 (m, 2H), 3.42-3.55 (m, 2H), 3.55-3.73 (m, 1H), 3.78-3.95 (m, 1H), 4.05-4.25 (m, 1H), 4.35-4.55 (m, 1H), 7.35 (d, 1H), 7.53 (t, 1H), 7.56-7.7.61 (m, 2H), 7.85 (d, 1H), 7.90-8.05 (m, 2H), 10.75 (brs, 1H).
Example 363
4-(1-Ethylpropyl)piperazine-1-carboxylic acid 4-fluorophenyl ester hydrochloride salt
To a stirred mixture of 1-(1-ethylpropyl)piperazine (350 μl, 2.0 mmol) and dry DCM (15 ml) was added 4-fluorophenyl chloroformate (350 mg, 2.0 mmol). The mixture was stirred overnight at room temperature and then diluted with DCM (50 ml). The reaction mixture was washed with 1 N NaOH (3×25 ml) and water (2×25 ml). The organic solution was concentrated and the residue was re-evaporated twice with acetonitrile to give 590 mg of the free base. The hydrochloride salt was prepared from 465 mg free base by addition of a 0.5 N HCl solution (15 ml) and a small portion of acetonitrile. The acidic solution was concentrated and stirred with ethyl acetate (15 ml). The solid was isolated and dried to give 470 mg (90%) of the title compound as a solid.
M.p. 275-277° C.
1H NMR (400 MHz, DMSO-d6): δ 0.98 (t, 6H), 1.64 (hept, 2H), 1.85-1.95 (m, 2H), 3.02-3.11 (m, 1H), 3.11-3.28 (m, 2H), 3.38-3.46 (m, 2H), 3.50-3.80 (m, 2H), 4.00-4.30 (m, 2H), 7.18-7.26 (m, 4H), 10.85 (brs, 1H).
Example 364
4-(1-Ethylpropyl)piperazine-1-carboxylic acid 2-nitrophenyl ester hydrochloride salt
To a stirred mixture of 1-(1-ethylpropyl)piperazine (175,μl, 1.0 mmol) and dry DCM (10 ml) was added 2-nitrophenyl chloroformate (201 mg, 1.0 mmol). The mixture was stirred overnight at room temperature and then diluted with DCM (50 ml). The reaction mixture was washed with 1 N NaOH (3×25 ml) and water (2×25 ml). The organic solution was concentrated and the residue was dissolved in a 0.5 N HCl solution (15 ml). The acidic solution was concentrated and stirred with ethyl acetate (15 ml). The solid was isolated and dried to give 310 mg (86%) of the title compound as a solid.
M.p. 251-253° C.
1H NMR (400 MHz, DMSO-d6): δ 0.96 (t, 6H), 1.65 (hept, 2H), 1.83-1.95 (m, 2H), 3.06-3.25 (m, 3H), 3.42-3.53 (m, 2H), 3.53-3.83 (m, 2H), 4.02-4.13 (m, 1H), 4.20-4.34 (m, 1H), 7.50-7.55 (m, 2H), 7.83 (t, 1H), 8.13 (d, 1H), 10.9 (brs, 1H).
Example 365
4-(1-Ethylpropyl)piperazine-1-carboxylic acid 4-methoxycarbonylphenyl ester hydrochloride salt
To a stirred mixture of 1-(1-ethylpropyl)piperazine (350 μl, 2.0 mmol) and dry DCM (15 ml) was added 4-methoxycarbonylphenyl-chloroformate (430 mg, 2.0 mmol). The mixture was stirred overnight at room temperature and then diluted with DCM (50 ml). The reaction mixture was washed with 1 N NaOH (3×25 ml) and water (2×25 ml). The organic solution was concentrated and re-evaporated twice with acetonitrile. The residue was dissolved in a 0.5 N HCl solution (15 ml) and a small portion of acetonitrile. The acidic solution was concentrated and stirred with ethyl acetate (15 ml). The solid was isolated and dried to give 670 mg (90%) of the title compound as a solid.
M.p. 248° C. decomp.
1H NMR (400 MHz, DMSO-d6): δ 0.97 (t, 6H), 1.63 (hept, 2H), 1.85-1.95 (m, 2H), 3.02-3.11 (m, 1H), 3.11-3.30 (m, 2H), 3.40-3.48 (m, 2H), 3.50-3.80 (m, 2H), 3.85 (s, 3H), 4.05-4.33 (m, 2H), 7.33 (d, 2H), 8.00 (d, 2H)), 10.7 (brs, 1H).
Example 366
Methyl-phenyl-carbamic acid 5-(3,3-dimethyl-butyrylamino)-pyridin-2-yl ester
A solution of N-(6-hydroxy-pyridin-3-yl)-3,3-dimethyl-butyramide (0.42 g, 2.00 mmol), N-methyl-N-phenylcarbamoyl chloride (0.37 g, 2.20 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.25 g, 2.20 mmol) in tetrahydrofuran (20 mL) was stirred at room temperature for 2.5 hours. Water was added and the solution was extracted three times with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo. The residue was redissolved in ethyl acetate and the solution was filtered over a short pad of silicagel. Evaporation of the solvent and crystallisation of the solid from ethyl acetate:heptane yielded the title compound (0.54 g, 79% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ=1.03 (s, 9H), 2.15 (s, 2H), 3.47 (br.s, 3H), 6.91 (br.s, 1H), 7.27 (m, 1H), 7.38 (m, 4H), 7.99 (br.s+dd, 2H), 8.13 (d, 1H); HPLC-MS (Method A): m/z=342 (M+H)+; Rt=3.67 min.
Example 367
Methyl-phenyl-carbamic acid 5-[(pyridine-2-carbonyl)-amino]-pyridin-2-yl ester
A solution of pyridine-2-carboxylic acid (6-hydroxy-pyridin-3-yl)-amide hydrochloride (0.50 g, 1.99 mmol), N-methyl-N-phenylcarbamoyl chloride (0.44 g, 2.59 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.54 g, 4.81 mmol) in dimethylformamide (15 mL) was stirred at room temperature for 1 hour. Water was added and the solids were isolated by suction, redissolved in dichloromethane. The solution was dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 50:50) yielding the title compound (0.38 g, 55% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ=3.45 (br.s, 3H), 7.11 (br.s, 1H), 7.26 (m, 1H), 7.40 (d, 4H), 7.51 (m, 1H), 7.92 (dt, 1H), 8.28 (d, 1H), 8.45 (dd, 1H), 8.60 (m, 2H), 10.10 (s, 1H); HPLC-MS (Method A): m/z=349 (M+H)+; Rt=3.31 min.
Example 368
Methyl-phenyl-carbamic acid 2-(4,4-dimethyl-2,6-dioxo-piperidin-1-yl)-pyrimidin-5-yl ester
A solution of 1-(5-hydroxy-pyrimidin-2-yl)-4,4-dimethyl-piperidine-2,6-dione (0.60 g, 2.55 mmol), N-methyl-N-phenylcarbamoyl chloride (0.48 g, 2.81 mmol) and 1,4-diazabicyclo-[2,2,2]octane (0.31 g, 2.81 mmol) in dichloromethane (25 mL) was stirred at room temperature for 15 minutes. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 50:50), yielding the title compound as a white solid.
1H NMR (300 MHz, CDCl3): δ=1.22 (s, 6H), 2.65 (s, 4H), 3.44 (br.s, 3H), 7.28-7.48 (m, 5H), 8.68 (br.s, 2H); HPLC-MS (Method A): m/z=369 (M+H)+; Rt=3.45 min.
Example 369
Methyl-phenyl-carbamic acid 5-bromo-pyrimidin-2-yl ester
A mixture of 4-bromo-2-hydroxypyrimidine (0.96 g, 5.49 mmol), N-methyl-N-phenylcarbamoyl chloride (1.02 g, 6.04 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.68 g, 6.04 mmol) in dry tetrahydrofuran (15 mL) was stirred at room temperature for 1 hour. Dichloromethane was added and the solution was extracted twice with water. The organic layer was dried over sodium sulphate, filtered and evaporated in vacuo yielding the title compound (1.70 g, 100% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ=3.43 (br.s, 3H), 7.27 (m, 1H), 7.38 (m, 4H), 8.68 (br.s, 2H); HPLC-MS (Method A): m/z=330 and 332 (M+H)+; Rt=3.33 min.
Example 370
Methyl-phenyl-carbamic acid 5-[(6-chloro-pyridine-3-carbonyl)-amino]-pyridin-2-yl ester
A mixture of 4-chloro-N-(6-hydroxy-pyridin-3-yl)-nicotinamide (0.56 g, 2.25 mmol), N-methyl-N-phenylcarbamoyl chloride (0.51 g, 3.00 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.67 g, 6.00 mmol) in dry tetrahydrofuran (15 mL) was stirred at room temperature for 1 hour. Dichloromethane was added and the solution was extracted twice with water. The organic layer was dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 70:30) followed by crystallised from ethyl acetate:heptane, yielding the title compound (44 mg, 5% yield) HPLC-MS (Method A): m/z=383 (M+H)+; Rt=3.40 min.
Example 371
Methyl-phenyl-carbamic acid 5-(2,2-dimethyl-propylcarbamoyl)-pyridin-2-yl ester
A solution of N-(2,2-dimethyl-propyl)-6-hydroxy-nicotinamide (0.50 g, 2.40 mmol), N-methyl-N-phenylcarbamoyl chloride (0.41 g, 2.40 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.27 g, 2.40 mmol) in tetrahydrofuran (15 mL) was stirred at room temperature for 3 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (first column: SiO2, dichloromethane:ethyl acetate 95:5, second column: SiO2, ethyl acetate), yielding the title compound (0.43 g, 52% yield).
1H NMR (300 MHz, CDCl3): δ=0.97 (s, 9H), 3.26 (d, 2H), 3.44 (br.s, 3H), 6.26 (br.s, 1H), 7.08 (br.s, 1H), 7.29 (m, 1H), 7.39 (m, 4H), 8.13 (br.d, 1H), 8.70 (br.s, 1H); HPLC-MS (Method A): m/z=383 (M+H)+; Rt=3.40 min.
Example 372
[Methyl-phenyl-carbamic acid 6-(3,4-dichloro-phenoxy)-pyridazin-3-yl ester
A solution of 6-(3,4-dichloro-phenoxy)-pyridazin-3-ol (0.51 g, 2.00 mmol), N-methyl-N-phenylcarbamoyl chloride (0.36 g, 2.10 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.24 g, 2.10 mmol) in tetrahydrofuran (15 mL) was stirred at room temperature for 2 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 30:70), yielding the title compound (0.34 g, 44% yield).
1H NMR (300 MHz, CDCl3): δ=3.43 (br.s, 3H), 7.10 (dd, 1H), 7.20-7.51 (m, 9H); HPLC-MS (Method A): m/z=389 (M+H)+; Rt=4.56 min.
Example 373
4-(tert-Butyl-dimethyl-silanyloxy)-piperidine-1-carboxylic acid 5-benzoylamino-pyridin-2-yl ester
A solution of N-(6-hydroxy-pyridin-3-yl)-benzamide (214 mg, 1.00 mmol), 3-[4-(tert-butyl-dimethyl-silanyloxy)-piperidine-1-carbonyl]-1-methyl-3H-imidazol-1-ium iodide (451 mg, 1.00 mmol) and 1,4-diazabicyclo[2,2,2]octane (112 mg, 1.00 mmol) in dimethylformamide (10 mL) was stirred for 18 hours at room temperature followed by heating for 3 days at 40° C. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 40:60), yielding the title compound (364 mg, 77% yield)
1H NMR (300 MHz, CDCl3): δ=0.08 (s, 6H), 0.91 (s, 9H), 1.59 (m, 2H), 1.78 (m, 2H), 3.50 (m, 1H), 3.62 (m, 2H), 3.76 (m, 1H), 4.00 (m, 1H), 6.87 (d, 1H), 7.41 (m, 2H), 7.50 (m, 1H), 7.90 (d, 2H), 8.01 (dd, 1H), 8.36 (d, 1H), 9.03 (s, 1H, NH); HPLC-MS (Method A): m/z=456 (M+H)+; Rt=5.23 min.
Example 374
4-hydroxy-piperidine-1-carboxylic acid 5-benzoylamino-pyridin-2-yl ester
hydrofluoric acid (min. 40% in water, 0.50 mL) was added to a stirred solution of 4-(tert-butyl-dimethyl-silanyloxy)-piperidine-1-carboxylic acid 5-benzoylamino-pyridin-2-yl ester (364 mg, 0.77 mmol) in acetonitrile. After stirring overnight at room temperature the solvent was evaporated in vacuo. The residue was redissolved in dichloromethane. After addition of triethylamine (1 mL) the solution was filtered over a short pad of silicagel and washed with ethyl acetate:acetone 50:50. Evaporation of the solvent yielded the title compound (180 mg, 68% yield) as a white solid.
1H NMR (400 MHz, CDCl3+DMSO-d6): δ=1.60 (m, 2H), 1.91 (m, 2H), 3.25 (m, 2H), 4.02 (m, 1H), 4.41 (d, 1H), 7.07 (d, 1H), 7.44-7.61 (m, 3H), 7.99 (m, 2H), 8.35 (dd, 1H), 8.72 (d, 1H), 10.19 (s, 1H, NH); HPLC-MS (Method A): m/z=342 (M+H)+; Rt=2.37 min.
Example 375
4-Hydroxy-piperidine-1-carboxylic acid 5-trifluoromethyl-pyridin-2-yl ester
A solution of 2-hydroxy-5-trifluoromethylpyridine (0.32 g, 2.00 mmol), 4-(tert-butyl-dimethyl-silanyloxy)-piperidine-1-carboxylic acid 5-benzoylamino-pyridin-2-yl ester (0.90 g, 2.00 mmol) and triethylamine (0.20 g, 2.00 mmol) in acetonitrile (10 mL) was stirred at room temperature for three days. Hydrofluoric acid (min. 40% in water, 0.50 mL) was added and stirring was continued for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 75:25), followed by crystallisation from ethyl-acetate:heptane, yielding the title compound (0.27 g, 47% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ=1.64 (m, 3H, 2×CH+OH), 1.96 (m, 2H), 3.33 (m, 1H), 3.45 (m, 1H), 4.00 (m, 3H), 7.27 (d, 1H), 8.00 (dd, 1H), 8.64 (d, 1H); HPLC-MS (Method A): m/z=313 (M+Na)+; Rt=2.45 min.
Example 376
4-Hydroxy-piperidine-1-carboxylic acid 5-(4-chloro-benzoylamino)-pyridin-2-yl ester
A solution of 4-chloro-N-(6-hydroxy-pyridin-3-yl)-benzamide (0.50 g, 2.00 mmol), 4-(tert-butyl-dimethyl-silanyloxy)-piperidine-1-carboxylic acid 5-benzoylamino-pyridin-2-yl ester (0.90 g, 2.00 mmol) and triethylamine (0.20 g, 2.00 mmol) in dimethylformamide (10 mL) was stirred overnight at room temperature. The solvent was evaporated in vacuo. The residue was dissolved in dichloromethane, filtered over a short pad of silicagel and washed with ethyl acetate:heptane 50:50. The solvent was evaporated in vacuo and the residue was redissolved in acetonitrile and hydrofluoric acid (min. 40% in water, 0.50 mL) was added. After stirring overnight at room temperature the solvent was evaporated in vacuo. Dichloromethane and triethylamine (1 mL) were added and the solution was extracted twice with water, dried over sodium sulphate, filtered and evaporated in vacuo. Crystallisation from ethyl acetate:heptane yielded the title compound (321 mg, 43% yield).
1H NMR (300 MHz, DMSO-d6): δ=1.50 (m, 2H), 1.80 (m, 2H), 3.16 (m, 1H), 3.31 (m, 1H), 3.75 (m, 2H), 3.88 (m, 1H), 4.81 (d, 1H), 7.18 (d, 1H), 7.62 (d, 2H), 8.01 (d, 2H), 8.24 (dd, 1H), 8.66 (d, 1H), 10.58 (s, 1H).; HPLC-MS (Method A): m/z 376 (M+H)+; Rt=2.81 min.
Example 377
4-Hydroxy-piperidine-1-carboxylic acid 5-(3-methoxy-benzoylamino)-pyridin-2-yl ester
Starting from N-(6-hydroxy-pyridin-3-yl)-3-methoxy-benzamide (0.49 g, 2.00 mmol) and using the procedure as described in Example 376 yielded the title compound (347 mg, 47% yield).
1H NMR (300 MHz, CDCl3+DMSO-d6): δ=1.51 (m, 2H), 1.82 (m, 2H), 3.16 (m, 1H), 3.30 (m, 1H), 3.79 (s, 3H+m, 2H), 3.92 (m, 1H), 4.28 (br.s, 1H), 6.98 (m, 2H), 7.30 (t, 1H), 7.47 (m, 2H), 8.24 (dd, 1H), 8.64 (d, 1H), 10.04 (s, 1H); HPLC-MS (Method A): m/z=372 (M+H)+; Rt=2.58 min.
Example 378
4-Hydroxy-piperidine-1-carboxylic acid 5-(4-methoxy-benzoylamino)-pyridin-2-yl ester
Starting from N-(6-hydroxy-pyridin-3-yl)-4-methoxy-benzamide (0.49 g, 2.00 mmol) and using the procedure as described in Example 376 yielded the title compound (297 mg, 40% yield).
1H NMR (300 MHz, CDCl3): δ=1.61 (m, 2H), 1.92 (m, 2H), 3.25 (m, 1H), 3.39 (m, 1H), 3.89 (s, 3H+m, 3H), 4.03 (m, 1H), 6.96 (d, 2H), 7.06 (d, 1H), 7.98 (d, 2H), 8.34 (dd, 1H), 8.67 (d, 1H), 9.72 (s, 1H); HPLC-MS (Method A): m/z=372 (M+H)+; Rt=2.53 min.
Example 379
4-Hydroxy-piperidine-1-carboxylic acid 5-(2,4-dichloro-benzoylamino)-pyridin-2-yl ester
Starting from 2,4-dichloro-N-(6-hydroxy-pyridin-3-yl)-benzamide (0.49 g, 2.00 mmol) and using the procedure as described in Example 376 yielded the title compound (367 mg, 45% yield).
1H NMR (300 MHz, CDCl3): δ=1.62 (m, 2H), 1.90 (m, 2H), 3.24 (m, 1H), 3.39 (m, 1H), 3.88 (m, 3H), 4.01 (m, 1H), 7.03 (d, 1H), 7.32 (d, 1H), 7.47 (s, 1H), 7.53 (d, 1H), 8.28 (dd, 1H), 8.58 (d, 1H), 10.1 (s, 1H); HPLC-MS (Method A): m/z=410 and 412 (M+H)+; Rt=2.99 min.
Example 380
4-Hydroxy-piperidine-1-carboxylic acid 5-(4-trifluoromethyl-benzoylamino)-pyridin-2-yl ester
Starting from N-(6-hydroxy-pyridin-3-yl)-4-trifluoromethyl-benzamide (0.56 g, 2.00 mmol) and using the procedure as described in Example 376 yielded the title compound (367 mg, 45% yield).
1H NMR (300 MHz, CDCl3): δ=1.61 (m, 2H), 1.93 (m, 2H), 3.27 (m, 1H), 3.41 (m, 1H), 3.67 (br.s, 1H), 3.91 (m, 2H), 4.05 (m, 1H), 7.08 (d, 1H), 7.74 (d, 2H), 8.14 (d, 2H), 8.37 (dd, 1H), 8.67 (d, 1H), 10.11 (s, 1H); HPLC-MS (Method A): m/z=410 (M+H)+; Rt=3.18 min.
Example 381
4-Hydroxy-piperidine-1-carboxylic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-yl ester
A solution of 6′-hydroxy-4,4-dimethyl-4,5-dihydro-3H-[1,3′]bipyridinyl-2,6-dione (468 mg, 2.00 mmol), 4-(tert-butyl-dimethyl-silanyloxy)-piperidine-1-carboxylic acid 5-benzoylamino-pyridin-2-yl ester (0.90 g, 2.00 mmol) and triethylamine (0.20 g, 2.00 mmol) in dimethylformamide (10 mL) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate, filtered over a short pad of silicagel and washed with ethyl acetate. The solvent was evaporated in vacuo and the residue was dissolved in 1 N HCl in ethyl acetate (10 mL, 10.0 mmol). After stirring for 1.5 hours at room temperature the solvent was evaporated in vacuo. The white solid was washed with a small amount of ethyl acetate and diethyl ether and dissolved in a few milliliters of dichloromethane and triethylamine (1 mL). Purification by flash column chromatography (SiO2, ethyl acetate:acetone 90:10) yielded the title compound (182 mg, 25% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ=1.22 (s, 6H), 1.61 (m, 2H), 1.92 (m, 2H), 2.70 (s, 4H), 3.28 (m, 1H), 3.40 (m, 1H), 3.63 (d, 1H), 3.84-4.08 (m, 3H), 7.21 (d, 1H), 7.51 (dd, 1H), 8.07 (d, 1H); HPLC-MS (Method A): m/z=362 (M+H)+; Rt=2.25 min.
Example 382
Methyl-phenyl-carbamic acid 2,6-dioxo-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-yl ester
A solution of N-methyl-N-phenyl carbamoyl chloride (170 mg, 1.00 mmol), 6′-hydroxy-4,5-dihydro-3H-[1,3]bipyridinyl-2,6-dione (206 mg, 1.00 mmol) and 1,4-diazabicyclo[2,2,2]octane (112 mg, 1.00 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, first ethyl acetate:heptane 75:25 followed by pure ethyl acetate). Evaporation of the solvent yielded the title compound (260 mg, 77% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ=2.10 (quintet, 2H), 2.81 (t, 4H), 3.53 (br.s, 3H), 7.12 (br.s, 1H), 7.27 (m, 1H), 7.38 (m, 4H), 7.50 (d, 1H), 8.09 (s, 1H); HPLC-MS (Method A): m/z=340 (M+H)+; Rt=2.89 min.
Example 383
Methyl-phenyl-carbamic acid 5-(2,5-dioxo-pyrrolidin-1-yl)-pyridin-2-yl ester
A solution of N-methyl-N-phenyl carbamoyl chloride (170 mg, 1.00 mmol), 1-(6-hydroxy-pyridin-3-yl)-pyrrolidine-2,5-dione (192 mg, 1.00 mmol) and 1,4-diazabicyclo[2,2,2]octane (112 mg, 1.00 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature for4 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 80:20) yielding the title compound (275 mg, 85% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ=2.89 (s, 4H), 3.44 (br.s, 3H), 7.14 (br.s, 1H), 7.27 (m, 1H), 7.39 (m, 4H), 7.74 (br.d, 1H), 8.38 (s, 1H); HPLC-MS (Method A): m/z=326 (M+H)+; Rt=2.78 min.
Example 384
Methyl-phenyl-carbamic acid 5-(4-trifluoromethyl-benzoylamino)-pyridin-2-yl ester
A solution of N-(6-hydroxy-pyridin-3-yl)-4-trifluoromethyl-benzamide (1.41 g, 5.00 mmol), N-methyl-N-phenylcarbamoyl chloride (0.85 g, 5.00 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.56 g, 5.00 mmol) in dimethylformamide (10 mL) was stirred at room temperature overnight. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 50:50) yielding the title compound (1.34 g, 64% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ=3.35+3.51 (2×br.s, 3H), 6.83 (br.s, 1H), 7.24-7.42 (m, 5H), 7.60 (d, 2H), 7.98 (d, 3H), 8.33 (s, 1H), 9.03+9.18 (2×br.s, 1H, NH); HPLC-MS (Method A): m/z=416 (M+H)+; Rt=4.14 min.
Example 385
Methyl-phenyl-carbamic acid quinolin-6-yl ester
A solution of 6-hydroxyquinoline (1.00 g, 6.89 mmol), N-methyl-N-phenylcarbamoyl chloride (1.17 g, 6.89 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.77 g, 6.89 mmol) in dichloromethane (20 mL) was stirred at room temperature for 1.25 hours. More dichloromethane was added and the solution was extracted with water. The organic layer was dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 50:50). Evaporation of the solvent and recrystalllised from ethylacetate/heptane yielded the title compound (1.33 g, 69% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ=3.48 (s, 3H), 7.22-7.64 (m, 8H), 8.09 (d, 2H), 8.87 (m, 1H); HPLC-MS (Method A): m/z=279 (M+H)+; Rt=2.56 min.
Example 386
4-Hydroxy-piperidine-1-carboxylic acid 5-(5-trifluoromethyl-pyridin-2-yloxy)-pyridin-2-yl ester
A solution of 5-(5-trifluoromethyl-pyridin-2-yloxy)-pyridin-2-ol (180 mg, 0.70 mmol), 3-[4-(tert-butyl-dimethyl-silanyloxy)-piperidine-1-carbonyl]-1-methyl-3H-imidazol-1-ium iodide (317 mg, 0.70 mmol) and triethylamine (98 μL) in acetonitrile (10 mL) was stirred at room temperature overnight. The solvent was evaporated in vacuo. The residue was redissolved in some dichloromethane, filtered over a short pad of silicagel and washed with ethyl acetate:heptane 50:50. The solvent was evaporated in vacuo and the residue was dissolved in 3.2N HCl in ether (10 mL). After stirring for 1 hour at room temperature the solvent was evaporated in vacuo and the residue was dissolved in dichloromethane. Triethylamine (0.5 mL) was added and the solution was extracted with water. The organic layer was dried over sodium sulphate, filtered and evaporated in vacuo to yield the title compound (174 mg, 65% yield) as a thick oil.
1H NMR (300 MHz, CDCl3): δ 1.63 (m, 2H), 1.79 (br.s, 1H, OH), 1.97 (m, 2H), 3.31 (m, 1H), 3.43 (m, 1H), 3.89-4.12 (m, 3H), 7.09 (d, 1H), 7.18 (d, 1H), 7.62 (dd, 1H), 7.94 (dd, 1H), 8.23 (d, 1H), 8.39 (d, 1H); HPLC-MS (Method A): m/z=384 (M+H)+; Rt=3.00 min.
Example 387
4-Hydroxy-piperidine-1-carboxylic acid 5-(3,5-dichloro-pyridin-2-yloxy)-pyridin-2-yl ester
Starting from 5-(3,5-dichloro-pyridin-2-yloxy)-pyridin-2-ol (265 mg, 1.03 mmol) and using the procedure as described in Example 386 yielded the title compound (121 mg, 54% yield) as a thick oil.
1H NMR (300 MHz, CDCl3): δ=1.62 (m, 2H), 1.94 (m, 2H), 3.06 (br.s, 1H), 3.28 (m, 1H), 3.41 (m, 1H), 3.90 (m, 2H), 4.01 (m, 1H), 7.18 (d, 1H), 7.62 (dd, 1H), 7.79 (d, 1H), 7.94 (d, 1H), 8.22 (d, 1H).; HPLC-MS (Method A): m/z=384 (M+H)+; Rt=3.35 min.
Example 388
Methyl-phenyl-carbamic acid 5-(4-chloro-benzoylamino)-pyridin-2-yl ester
A solution of 4-chloro-N-(6-hydroxy-pyridin-3-yl)-benzamide (0.50 g, 2.01 mmol), N-methyl-N-phenylcarbamoyl chloride (0.34 g, 2.01 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.22 g, 0.34 mmol) in dimethylformamide (10 mmol) was stirred at room temperature for 2 hours. Water (100 mL) was added and a thick oil was being formed. The water was decanted and the residue dissolved in dichloromethane, dried over sodium sulphate, filtered and evaporated in vacuo. Ethyl acetate was added and the solution was heated briefly (some of the compound does not dissolve). The solvent was decanted and heptane was added to it. After standing overnight, the crystals were isolated by suction, washed with heptane and dried in a vacuum oven at 45° C. Further purification by flash column chromatography (SiO2, ethyl acetate:heptane 50:50), yielded the title compound (0.41 g, 53% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ=3.38 (br.s, 3H), 6.84 (br.s, 1H), 7.20-7.42 (m, 7H), 7.80 (d, 2H), 7.97 (dd, 1H), 8.32 (d, 1H), 9.09 (br.s, 1H); —HPLC-MS (Method A): m/z=382 (M+H)+; Rt=3.63 min.
Example 389
4 Methyl-phenyl-carbamic acid 5-(4-methoxy-benzoylamino)-pyridin-2-yl ester
A solution of N-(6-hydroxy-pyridin-3-yl)-4-methoxy-benzamide (1.22 g, 5.00 mmol), N-methyl-N-phenylcarbamoyl chloride (0.85 g, 5.00 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.56 g, 5.00 mmol) in dimethylformamide (20 mL) was stirred at room temperature for 2 hours. Water (100 mL) was added. The solids were isolated by suction and washed with water. Crystallisation from ethyl acetate:heptane yielded the title compound (1.08 g, 57% yield).
1H NMR (300 MHz, CDCl3): δ=3.42 (br.s, 3H), 3.86 (s, 3H), 6.89 (d, 2H+br.s, 1H), 7.27 (m, 1H), 7.39 (m, 4H), 7.84 (d, 2H), 8.11 (dd, 1H), 8.34 (d, 1H), 8.51 (br.s, 1H); HPLC-MS (Method A): m/z=378 (M+H)+; Rt=3.55 min.
Example 390
Methyl-phenyl-carbamic acid 4,4-dimethyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-yl ester
A solution of 4,4-dimethyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ol (0.86 g, 4.17 mmol), N-methyl-N-phenylcarbamoyl chloride (0.71 g, 4.17 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.47 g, 4.17 mmol) in dichloromethane (10 mL) was stirred at room temperature for 2 hours. Extra dichloromethane was added and the solution was washed with water, dried over sodium sulphate, filtered and evaporated in vacuo. Crystallisation from ethyl acetate:heptane yielded the title compound (0.58 g, 41% yield)
1H NMR (300 MHz, CDCl3): δ=0.99 (s, 6H), 1.52 (m, 4H), 3.16 (m, 4H), 3.43 (br.s, 3H), 6.92 (br.d, 1H), 7.20-7.41 (m, 6H), 7.98 (d, 1H); HPLC-MS (Method A): m/z=340 (M+H)+; Rt=4.21 min.
Example 391
Methyl-phenyl-carbamic acid 2-methyl-quinolin-6-yl ester
A solution of 2-methylquinolin-6-ol (1.00 g, 6.28 mmol), N-methyl-N-phenylcarbamoyl chloride (1.07 g, 6.28 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.70 g, 6.28 mmol) in dichloromethane (10 mL) was stirred at room temperature for 18 hours. Extra dichloromethane was added and the solution was extracted twice with water, dried over sodium sulphate and filtered. Some ethyl acetate and heptane were added and the solution was slowly evaporated in vacuo yielding the title compound (1.64 g, 89% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ=2.71 (s, 3H), 3.45 (br.s, 3H), 7.25 (m, 2H), 7.40 (m, 5H), 7.54 (s, 1H), 7.98 (t, 2H); HPLC-MS (Method A): m/z=293 (M+H)+; Rt=2.16 min.
Example 392
General Procedure 17 
{2-[4-(Methyl-phenyl-carbamoyloxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester
Tyramin was N-Boc protected as described in J. Org. Chem, 49,1984,1016. To a solution of the N-Boc protected tyramin (10 mmol) in CH2Cl2 (50 mL) was added N-methyl-N-phenylcarbamoyl chloride (15 mmol) and DABCO (15 mmol) at room temperature. The reaction mixture was stirred for 16 hours at rt, added CH2Cl2 (20 mL) and washed with aqueous citric acid (5%) and brine. The organic phase was separated, dried (MgSO4) and evaporated to give the crude product which was purified by FC (Quad flash 40 MeOH—CH2Cl2 5:95) to give 3.45 g (93%) of the title compound as colorless crystals.
HPLC-MS: m/z=393.4 (M+Na); Rt=4.44 min.
Example 393
General Procedure 17
Methyl-phenyl-carbamic acid 4-(2-amino-ethyl)phenyl ester
{2-[4-(Methyl-phenyl-carbamoyloxy)-phenyl]-ethyl}-carbamic acid tertbutyl ester(3.7 g; 10 mmol) from above was dissolved in CH2Cl2 (90 mL). Addition of TFA (6 mL) and stirring for 4 h. The reaction mixture was evaporated to dryness and dried in vacuo at 50° C. overnight producing the title compound as a TFA salt in quantitative yield as yellow hygroscopic crystals.
HPLC-MS: m/z=271.1 (M+1); Rt=2.17 min.
Example 394
General Procedure 17
Methyl-phenyl-carbamic acid 4-[2-(toluene-4-sulfonylamino)-ethyl]-phenyl ester
The title compound was prepared in 39% yield as a clear oil using toluenesulfonyl chloride as the aryl sulfonyl chloride.
HPLC-MS: m/z=425.2 (M+1); Rt=4.33 min.
Example 395
General Procedure 17
Methyl-phenyl-carbamic acid 4-[2-(5-dimethylamino-naphthalene-1-sulfonylamino)-ethyl]-phenyl ester
The title compound was prepared in 29% yield as a yellow fluorescent oil using 5-dimethylamino-naphthalene-1-sulfonyl chloride as the aryl sulfonyl chloride.
HPLC-MS: m/z=505.1 (M+1); Rt=4.58 min.
Example 396
General Procedure 17
Methyl-phenyl-carbamic acid 4-[2-(3,4-difluoro-benzenesulfonylamino)-ethyl]-phenyl ester
The title compound was prepared in 40% yield as a clear oil using 3,4-difluoro-benzenesulfonyl chloride as the aryl sulfonyl chloride.
HPLC-MS: m/z=447.1 (M+1); Rt=4.47 min.
Example 397
General Procedure 17
2-{2-[4-(Methyl-phenyl-carbamoyloxy)-phenyl]-ethylsulfamoyl}-benzoic acid methyl ester
The title compound was prepared in 30% yield as an oil using 2-chlorosulfonyl-benzoic acid methyl ester as the aryl sulfonyl chloride.
HPLC-MS: m/z=469.1 (M+1); Rt=4.37 min.
Example 398
General Procedure 17
Methyl-phenyl-carbamic acid 4-[2-(2,5-dichloro-thiophene-3-sulfonylamino)-ethyl]-phenyl ester
The title compound was prepared in 39% yield as an oil using 2,5-dichloro-thiophene-3-sulfonyl chloride as the aryl sulfonyl chloride.
HPLC-MS: m/z=487.0 (M+1); Rt=4.80 min.
Example 399
General Procedure 17
Methyl-phenyl-carbamic acid 4-[2-(5-pyridin-2-yl-thiophene-2-sulfonylamino)-ethyl]-phenyl ester
The title compound was prepared in 12% yield as crystals using 5-pyridin-2-yl-thiophene-2-sulfonyl chloride as the aryl sulfonyl chloride.
HPLC-MS: m/z=494.0 (M+1); Rt=4.42 min.
Example 400
General Procedure 17
Methyl-phenyl-carbamic acid 4-[2-(1-methyl-1H-imidazole-4-sulfonylamino)-ethyl]-phenyl ester
The title compound was prepared in 42% yield as a yellow oil using 1-methyl-1H-imidazole-4-sulfonyl chloride as the aryl sulfonyl chloride.
HPLC-MS: m/z=415.1 (M+1); Rt=3.31 min.
Example 401
General Procedure 17
Methyl-phenyl-carbamic acid 4-[2-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonylamino)-ethyl]-phenyl
The title compound was prepared in 22% yield as an oil using 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride as the aryl sulfonyl chloride.
HPLC-MS: m/z=463.1 (M+1); Rt=3.91 min.
Example 402
General Procedure 17
Methyl-phenyl-carbamic acid 4-[2-(4-nitro-benzenesulfonylamino)-ethyl]-phenyl ester
The title compound was prepared in 25% yield as a yellow oil using 4-nitro-benzenesulfonyl chloride as the aryl sulfonyl chloride.
HPLC-MS: m/z=456.0 (M+1); Rt=4.19 min.
Example 403
General Procedure 17
Methyl-phenyl-carbamic acid 4-[2-(6-chloro-imidazo[2,1-b]thiazole-5-sulfonylamino)-ethyl]-phenyl ester
The title compound was prepared in 18% yield as an oil using 6-chloro-imidazo[2,1-b]thiazole-5-sulfonyl chloride as the aryl sulfonyl chloride.
HPLC-MS: m/z=490.9 (M+1); Rt=3.90 min.
Example 404
General Procedure 17
Methyl-phenyl-carbamic acid 4-[2-(2-trifluoromethoxy-benzenesulfonylamino)-ethyl]-phenyl ester
The title compound was prepared in 38% yield as an oil using 2-trifluoromethoxy-benzenesulfonyl chloride as the aryl sulfonyl chloride.
HPLC-MS: m/z=495.1 (M+1); Rt=4.49 min.
Example 405
General Procedure 17
Methyl-phenyl-carbamic acid 4-(2-dimethylaminosulfonylamino-ethyl)-phenyl ester
The title compound was prepared in 32% yield as an oil using dimethylaminosulfamoyl chloride as the sulfonyl chloride.
HPLC-MS: m/z=378.1 (M+1); Rt=3.62 min.
Example 406
General Procedure 17
Methyl-phenyl-carbamic acid 4-(2-methanesulfonylamino-ethyl)-phenyl ester
The title compound was prepared in 22% yield as an oil using methanesulfonyl chloride as the sulfonyl chloride.
HPLC-MS: m/z=349.0 (M+1); Rt=3.26 min.
Example 407
General Procedure 17
Methyl-phenyl-carbamic acid 4-[2-(6-morpholin-4-yl-pyridine-3-sulfonylamino)-ethyl]-phenyl ester
The title compound was prepared in 55% yield as crystals using 6-morpholin-4-yl-pyridine-3-sulfonyl chloride as the aryl sulfonyl chloride.
HPLC-MS: m/z=497.0 (M+1); Rt=3.90 min.
Example 408
General Procedure 17
Methyl-phenyl-carbamic acid 4-[2-(6-phenoxy-pyridine-3-sulfonylamino)-ethyl]-phenyl ester
The title compound was prepared in 54% yield as crystals using 6-phenoxy-pyridine-3-sulfonyl chloride as the aryl sulfonyl chloride.
HPLC-MS: m/z=504.4 (M+1); Rt=4.45 min.
Example 409
Methyl-phenyl-carbamic acid 4-{2-[4-(4-methyl-piperazin-1-yl)-benzenesulfonylamino]-ethyl}-phenyl ester
To a stirred solution of 1-(4-bromophenyl)-4-methylpiperazine (2.05 g, 8.0 mmol) in THF (10 mL) was added dropwise 1.57 M solution in hexanes n-BuLi (4.6 mL, 7.2 mmol) over a 5-min period at −78° C. The mixture was stirred at −78° C. for 15 min. Then gaseous sulphur dioxide (ca. 5 g) was added causing an immediate precipitation. The mixture was allowed to warm to room temperature and stirred for 1 h. The precipitated lithium; 4-(4-methyl-piperazin-1-yl)-benzenesulfinate was isolated by filtration under N2 (g), washed with THF (20 mL) and dried in vacuo providing 1.83 g (96%) of the lithium sulfinate as a solid. This lithium sulfinate (83 mg, 0.34 mmol) was suspended in CH2Cl2 (1 mL) and stirred with NCS (45 mg, 0.34 mmol) for 10 min at rt. A solution of N-methyl-N-phenyl-carbamic acid 4-(2-amino-ethyl)phenyl ester as its TFA salt (0.26 mmol) in CH2Cl2 (1.5 mL) was added together with DIPEA (0.90 mmol). The mixture was stirred at rt for 16 h and quenched with HOAc (2 mL) and water (2 mL). Extraction with CH2Cl2 and drying of the combined organic extracts gave the crude product which was purified by preparative HPLC (Gilson). This gave 54 mg (33%) of the title compound as its TFA salt as colorless crystals.
HPLC-MS: m/z=509.0 (M+1); Rt=2.88 min.
Example 410
Methyl-phenyl-carbamic acid 4-[2-(4-dimethylamino-benzenesulfonylamino)-ethyl]-phenyl ester
To a stirred solution of (4-bromo-phenyl)-dimethylamine (4.02 g, 20 mmol) in THF (25 mL) was added dropwise 1.57 M solution in hexanes n-BuLi (11.5 mL, 18 mmol) over a 5-min period at −78° C. The mixture was stirred at −78° C. for 15 min. Then gaseous sulphur dioxide (ca. 5 g) was added causing an immediate precipitation. The mixture was allowed to warm to room temperature and stirred for 1 h. The precipitated lithium sulfinate was isolated by filtration under N2 (g), washed with THF (20 mL) and dried in vacuo providing 2.99 g (87%) of lithium; 4-dimethylamino-benzenesulfinate as a bluegreen solid. This lithium sulfinate (65 mg, 0.34 mmol) was suspended in CH2Cl2 (1 mL) and stirred with NCS (45 mg, 0.34 mmol) for 10 min at rt. A solution of N-methyl-N-phenyl-carbamic acid 4-(2-amino-ethyl)phenyl ester as its TFA salt (0.26 mmol) in CH2Cl2 (1.5 mL) was added together with DIPEA (0.90 mmol). The mixture was stirred at rt for 16 h and quenched with HOAc (2 mL) and water (2 mL). Extraction with CH2Cl2 and drying of the combined organic extracts gave the crude product which was purified by preparative HPLC (Gilson). This gave 37 mg (31%) of the title compound as an oil.
HPLC-MS: m/z=454.5 (M+1); Rt=4.16 min.
Example 411
Methyl-phenyl-carbamic acid 4-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-benzenesulfonylamino]-ethyl}-phenyl ester
To a stirred solution of 1-[2-(4-bromo-phenoxy)-ethyl]-pyrrolidine (6.72 g, 25 mmol) in THF (45 mL) was added dropwise 1.6 M solution in hexanes n-BuLi (14 mL, 22.4 mmol) over a 5-min period at −78° C. The mixture was stirred at −78° C. for 15 min. Then gaseous sulphur dioxide (ca. 6 g) was added causing an immediate precipitation. The mixture was allowed to warm to room temperature and stirred for 1 h. The precipitated lithium sulfinate was isolated by filtration under N2 (g), washed with THF (40 mL) and dried in vacuo providing 5.04 g (78%) of lithium; 4-(2-pyrrolidin-1-yl-ethoxy)-benzenesulfinate as a solid. This lithium sulfinate (179 mg, 0.69 mmol) was suspended in CH2Cl2 (2 mL) and stirred with NCS (80 mg, 0.60 mmol) for 10 min at rt. A solution of N-methyl-N-phenyl-carbamic acid 4-(2-amino-ethyl)phenyl ester as its TFA salt (0.55 mmol) in CH2Cl2 (3 mL) was added together with DIPEA (2.0 mmol). The mixture was stirred at rt for 16 h and evaporated to dryness. It was then redissolved in MeCN and purified by preparative HPLC (Gilson). This gave 89 mg (25%) of the title compound as its TFA salt as a crystals.
HPLC-MS: m/z=524.5 (M+1); Rt=3.04 min.
Example 412
General Procedure 15
4-(Tetrahydrofuran-2-ylmethyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(tetrahydrofuran-2-ylmethyl)-piperazine, crude yield 0.28 g (89%). The crude product was stirred with a mixture of ethyl acetate (10 ml) and a solution of sodium bicarbonate (0.05 g) in water (5 ml). The aqueous layer was extracted with ethyl acetate (10+5 ml), the combined organic phases were washed with brine (5 ml), dried over sodium sulfate, filtered and evaporated. The residue was triturated with heptane (3 ml), filtered and dried to give the title compound, White crystals, m.p. 98-100° C.; 1H NMR (CDCl3) δ 8.52-8.37 (br, 1H), 7.98-7.83 (dd, 1H), 7.25-7.06 (m, 4H), 7.00 (d, J=8.5 Hz), 4.18-3.47 (m, 7H), 2.76-2.36 (m, 6H), 2.13-1.74 (m, 3H), 1.64-1.40 (m, 1H); IR (KBr): ν 1715 (C═O) cm−1.
Example 413
General Procedure 15
4-Cyclopropylmethyl-piperazine-1-carboxylic acid 4-(3-chloro-5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-phenyl chloroformate and 1-cyclopropylmethyl-piperazine, yield 83%. White crystals, m.p. 254-255° C.; IR (KBr): ν 1728 (C═O) cm−1.
Example 414
General Procedure 15
4-(Tetrahydro-furan-2-yl methyl)-piperazine-1-carboxylic acid 4-(4-trifluoromethylphenoxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(4-trifluoromethyl-phenoxy)-phenyl chloroformate and 1-(tetrahydro-furan-2-ylmethyl)-piperazine, yield 93%. White crystals, m.p. 216-217° C.; IR (KBr): ν 1730 (C═O) cm−1.
Example 415
General Procedure 15
4-Cyclohexylmethyl-piperazine-1-carboxylic acid 4-(4-trifluoromethyl-phenoxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(4-trifluoromethyl-phenoxy)-phenyl chloroformate and 1-cyclohexylmethyl-piperazine, yield 93%. White crystals, m.p. 256-258° C.; IR (KBr): ν 1715 (C═O) cm−1.
Example 416
General Procedure 15
4-Cyclohexylmethyl-piperazine-1-carboxylic acid 4-(3-chloro-5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(3-chloro-5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-cyclohexylmethyl-piperazine, yield 76%. White crystals, m.p. 265-266° C.; IR (KBr): ν 1732 (C═O) cm−1.
Example 417
General Procedure 15
4-Cyclopropylmethyl-piperazine-1-carboxylic acid 4-(4-trifluoromethyl-phenoxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(4-trifluoromethyl-phenoxy)-phenyl chloroformate and 1-cyclopropylmethyl-piperazine, yield 43%. White crystals, m.p. 238-239° C.; IR (KBr): ν 1725 (C═O) cm−1.
Example 418
General Procedure 15
4-(Tetrahydrofuran-2-ylmethyl)-piperazine-1-carboxylic acid 4-(3-chloro-5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(3-chloro-5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(tetrahydrofuran-2-ylmethyl)-piperazine, yield 23%. White crystals, m.p. 98-100° C.; IR (KBr): ν 1731 (C═O) cm−1.
Example 419
General Procedure 15
4-Naphthalen-1-ylmethyl-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-naphthalen-1-ylmethyl-piperazine, yield 71%. White crystals, m.p. 218-219° C.; IR (KBr): ν 1713 (C═O) cm−1.
Example 420
General Procedure 15
4-(2-Cyclohexyl-ethyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(2-cyclohexyl-ethyl)-piperazine, yield 90%. White crystals, m.p. 274-276° C.; IR (KBr): ν 1715 (C═O) cm−1.
Example 421
General Procedure 15
4-(3-Methoxy-phenyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(3-methoxy-phenyl)-piperazine, yield 96%. White solid, m.p. 109-111° C.; IR (KBr): ν 1721 (C═O) cm−1.
Example 422
General Procedure 15
4-Cyclopropylmethyl-piperazine-1-carboxylic acid 4-[2-(4-chloro-phenyl)-ethylcarbamoyl]-phenyl ester
The title compound was prepared from 4-[2-(4-chloro-phenyl)-ethylcarbamoyl]-phenyl chloroformate and 1-cyclopropylmethyl-piperazine, yield 18%. White crystals, m.p. 225-226° C.; IR (KBr): ν 1710 (ester C═O), 1661 (amide C═O) cm−1.
Example 423
General Procedure 15
4-(Tetrahydro-furan-2-ylmethyl)-piperazine-1-carboxylic acid 4-[2-(4-chloro-phenyl)-ethylcarbamoyl]-phenyl ester
The title compound was prepared from 4-[2-(4-chloro-phenyl)-ethylcarbamoyl]-phenyl chloroformate and 1-(tetrahydrofuran-2-ylmethyl)-piperazine, yield 12%. White crystals, m.p. 220-221° C.; IR (KBr): ν 1708 (ester C═O), 1660 (amide C═O) cm−1.
Example 424
General Procedure 15
4-(3,4-Dichloro-benzyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(3,4-dichloro-benzyl)-piperazine, yield 86%. White crystals, m.p. 229-230° C.; IR (KBr): ν 1717 (C═O) cm−1.
Example 425
General Procedure 15
4-Cyclopropylmethyl-[1,4]diazepane-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-cyclopropylmethyl-[1,4]diazepane, yield 61%. White crystals, m.p. 208-209° C.; IR (KBr): ν 1711 (C═O) cm−1.
Example 426
General Procedure 15
4-(2-Pyridin-2-yl-ethyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(2-pyridin-2-yl-ethyl)-piperazine, yield 81%. White crystals, m.p. 281-282° C.; IR (KBr): ν 1713 (C═O) cm−1.
Example 427
General Procedure 18
4-(Pyrazin-2-yl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(pyrazin-2-yl)-piperazine White crystals, m.p. 160-161° C.; HPLC-MS: m/z=446 (M+1) at Rt=4.0 min.; 1H NMR (DMSO-d6): δ 8.60-8.57 (m, 1H), 8.39-8.36 (m, 1H), 8.27-8.22 (dd-like, 1H), 8.14-8.11 (m, 1H) 7.91-7.87 (d-like, 1H), 7.29-7.21 (m, 5H), 3.80-3.64 (br, 6H), 3.64-3.50 (br, 2H); IR (KBr): ν 1737, 1714 (C═O) cm−1.
Example 428
General Procedure 15
4-(Benzo-isothiazol-3-yl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(benzo-isothiazol-3-yl)-piperazine. Drying on a rotary evaporator of the crude product gave the title compound as the free base. Purification by flash chromatography (silica, ethyl acetate—heptane 1:4) gave white crystals, m.p. 132-133° C.; IR (KBr): ν 1726 (C═O) cm−1.
Example 429
General Procedure 15
4-(5-Chloro-thiophen-2-ylmethyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(5-chloro-thiophen-2-ylmethyl)-piperazine, yield 48%. White crystals, m.p. 225-226° C. (from EtOH); 1H NMR (DMSO-d6): δ 12.00 (br, 1H), 8.60-8.55 (1H), 8.27-8.21 (dd-like, 1H), 7.33-7.20 (m, 6H), 7.20-7.15 (d, 1H), 4.55 (br s, 2H), 4.40-4.00 (br, 2H), 3.74-3.27 (br, 4H+H2O); 3.27-2.97 (br, 2H); IR (KBr): ν 1723 (C═O) cm1.
Example 430
General Procedure 15
4-(3-Trifluoromethyl-phenyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(3-trifluoromethyl-phenyl)-piperazine. The crude product was converted to the free base, yield 56%. White crystals, m.p. 87-88° C.; IR (KBr): ν 1719 (C═O) cm−1.
Example 431
General Procedure 15
4-(5-Chloro-2-methyl-phenyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(5-chloro-2-methyl-phenyl)-piperazine The crude product was converted to the free base, yield 26%. White crystals; HPLC-MS:m/z=492(M+H) at Rt=5.5 min.; IR (KBr): ν 1722 (C═O) cm−1.
Example 432
General Procedure 15
4-(1-Methyl-piperidin-4-ylmethyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The dihydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(1-methyl-piperidin-4-ylmethyl)-piperazine, yield 6%. White crystals, m.p. 305-306° C.; IR (KBr): ν 1713 (C═O) cm−1.
Example 433
General Procedure 15
4-Biphenyl-4-ylmethyl-[1,4]diazepane-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-biphenyl-4-ylmethyl-[1,4]diazepane. The crude product was converted to the free base, yield 17%. White crystals, m.p. 143° C.; HPLC-MS: m/z=548(M+H) at Rt=3.6 min.; IR (KBr): ν 1711 (C═O) cm−1.
Example 434
General Procedure XX
4-(5-Dimethylamino-naphthalene-1-sulfonyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(5-dimethylamino-naphthalene-1-sulfonyl)-piperazine and purified by flash chromatography (ethyl acetate—heptane 1:4), yield 32%. Pale crystals, HPLC-MS: m/z: 601(M+1) at Rt=5.2 min.; m.p. ° C.; IR (KBr): ν 1723 (C═O) cm−1.
Example 435
General Procedure 15
4-(3-Methoxy-benzyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(3-methoxy-benzyl)-piperazine, yield 99%. White crystals, m.p. 214-215° C.; HPLC-MS: m/z: 489(M+1) at Rt=2.8 min.; IR (KBr): ν 1712 (C═O) cm−1.
Example 436
General Procedure 15
4-(3-Fluoro-benzyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(3-fluoro-benzyl)-piperazine, yield 77%. White crystals, m.p. 138-139° C.; HPLC-MS: m/z: 476 (M+1) at Rt=3.0 min.; IR (KBr): ν 1714 (C═O) cm−1.
Example 437
General Procedure 18
4-(3-Trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(3-trifluoromethyl-pyridin-2-yl)-piperazine, yield 25%. White crystals, m.p. 131-132° C.; HPLC-MS: m/z: 513 (M+1) at Rt=5.0 min.; IR (KBr): ν 1722 (C═O) cm−1.
Example 438
General Procedure 15
4-(3-Fluorobenzyl)-piperazine-1-carboxylic acid 4-(4,6-dimethyl-pyrimidin-2-ylsulfanyl)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(4,6-dimethyl-pyrimidin-2-ylsulfanyl)-phenyl chloroformate and 1-(3-fluorobenzyl)-piperazine. The crude product was converted to the free base, yield 48%. White crystals, m.p. 117-118° C.; HPLC-MS: m/z: 453 (M+1) at Rt=2.6 min.; IR (KBr): ν 1714 (C═O) cm−1.
Example 439
General Procedure 15
5-(4-Trifluoromethoxybenzyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid 4-(5-trifluoromethylpyridin-2-yloxy)-phenyl ester
The hydrochloride of the title-compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 2-(4-trifluoromethoxybenzyl)-2,5-diazabicyclo[2.2.1]heptane. The crude product was converted to the free base, yield 20%. Oil; HPLC-MS: m/z: 554 (M+1) at Rt=3.1 min.; IR (KBr): ν 1723 (C═O) cm−1.
Example 440
General Procedure 18
1-Oxo-1λ4-thiomorpholine-4-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and thiomorpholine 1-oxide and purified by flash chromatography (ethyl acetate), yield 37%. White crystals, m.p. 156-157° C.; 1H NMR (CDCl3)δ 8.47-8.40 (s-like, 1H), 7.94-7.87 (dd-like, 1H), 7.24-7.13 (m, 4H), 7.06-6.99 (d-like), 4.31-3.91 (m, 4H), 2.97-2.87-2.75 (m, 2H+2H); IR (KBr): ν 1710 (C═O) cm−1.
Example 441
General Procedure 18
4-(2,4-Dimethoxyphenyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(2,4-dimethoxyphenyl)-piperazine. Purified by flash chromatography (ethyl acetate—heptane 1:4), yield 69%. White crystals, m.p. 98-99° C.; HPLC-MS: m/z=504 (M+1) at Rt=4.0 min.; IR (KBr): ν 1733, 1712 (C═O) cm−1.
Example 442
General Procedure 15
5-Benzyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid 4-(5-trifluoromethylpyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 2-benzyl-2,5-diazabicyclo[2.2.1]heptane. The crude product was converted to the free base and further purified by flash chromatography (ethyl acetate—heptane 1:4), yield 16%. White crystals, m.p. 114-115° C.; HPLC-MS: m/z: 470 (M+1) at Rt=2.6 min.; IR (KBr): ν 1718 (C═O) cm−1.
Example 443
General Procedure 10
4-Aminomethyl-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 4-aminomethylpiperidine. The crude product was purified by preparative HPLC (Method C) (32%, off-white crystals). HPLC-MS m/z=396.1 (M+1), Rt: 2.65 min. purity: 86%.
Example 444
General Procedure 10
4-Pyrimidin-2-yl-piperazine-1-carboxylic acid 4-(5-chloro-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(2-pyrimidinyl)-piperazine, two equivalent of diisopropylethylamine was added. The crude product was obtained by filtration of the reaction mixture. The crude product was washed with diethyl ether and subjected to column chromatography, ethyl acetate/heptane (1:3) (18%, white crystals). HPLC-MS m/z=412.1 (M+1), Rt: 4.12 min.
Example 445
General Procedure 12
4-Cyclopropylmethyl-piperazine-1-carboxylic acid 4-(4,4-dimethyl-2,6-dioxo-piperidin-1-yl)-phenyl ester
The title compound was prepared from 4-(4,4-dimethyl-2,6-dioxo-piperidin-1-yl)-phenyl chloroformate and 1-cyclopropylmethyl-piperazine, preparative HPLC (Method C) (45%, off-white crystals). HPLC-MS m/z=400.3 (M+1), Rt: 1.83 min.
Example 446
General Procedure 12
4-(4-Methoxy-benzyl)-piperazine-1-carboxylic acid 4-(4,4-dimethyl-2,6-dioxo-piperidin-1-yl)-phenyl ester
The title compound was prepared from 4-(4,4-dimethyl-2,6-dioxo-piperidin-1-yl)-phenyl chloroformate and 1-(4-methoxybenzyl)-piperazine, preparative HPLC (Method C) (54%, white crystals). HPLC-MS m/z=466.3 (M+1), Rt: 2.26 min.
Example 447
General Procedure 12
4-Pyridin-3-ylmethyl-piperazine-1-carboxylic acid 4-(4,4-dimethyl-2,6-dioxo-piperidin-1-yl)-phenyl ester
The title compound was prepared from 4-(4,4-dimethyl-2,6-dioxo-piperidin-1-yl)-phenyl chloroformate and 1-pyridin-3-ylmethyl-piperazine, hydrochloride, preparative HPLC (Method C) (75%, colourless oil). HPLC-MS m/z=437.2 (M+1), Rt: 1.70 min.
Example 448
General Procedure 12
4-(4-Methoxy-benzyl)-piperazine-1-carboxylic acid 4-(2-cyclohexyl-acetylamino)-phenyl ester
The title compound was prepared from 4-(2-cyclohexyl-acetylamino)-phenyl chloroformate and 1-(4-methoxybenzyl)-piperazine, preparative HPLC (Method C) (49%, white crystals). HPLC-MS m/z=466.3 (M+1), Rt: 2.85 min.
Example 449
General Procedure 12
4-Cyclopropylmethyl-piperazine-1-carboxylic acid 4-(2-cyclohexyl-acetylamino)-phenyl ester
The title compound was prepared from 4-(2-cyclohexyl-acetylamino)-phenyl chloroformate and 1-cyclopropylmethyl-piperazine, preparative HPLC (method C (60%, off-white crystals). HPLC-MS m/z=400.3 (M+1), Rt: 2.42 min.
Example 450
General Procedure 12
4-Pyridin-3-ylmethyl-piperazine-1-carboxylic acid 4-(2-cyclohexyl-acetylamino)-phenyl ester
The title compound was prepared from 4-(2-cyclohexyl-acetylamino)-phenyl chloroformate and 1-pyridin-3-ylmethyl-piperazine, hydrochloride, preparative HPLC (method C) (64%, white crystals). HPLC-MS m/z=437.4 (M+1), Rt: 2.38 min.
Example 451
General Procedure 14
Methyl-phenyl-carbamic acid 4-(2-cyclohexyl-ethylsulfamoyl)-phenyl ester
The title compound was prepared from N-(2-cyclohexyl-ethyl)-4-hydroxy-benzenesulfonamide and N-methyl-N-phenyl carbamoylchloride, preparative HPLC (Method C) (14%, light yellow oil). HPLC-MS m/z=417.3 (M+1), Rt: 4.89 min.
Example 452
General Procedure 14
Methyl-phenyl-carbamic acid 4-(3-methyl-butylsulfamoyl)-phenyl ester
The title compound was prepared from 4-hydroxy-N-(3-methyl-butyl)-benzenesulfonamide and N-methyl-N-phenyl carbamoylchloride, preparative HPLC (Method C) (11%, light yellow oil). HPLC-MS m/z=377.2 (M+1), Rt: 4.32 min.
Example 453
General Procedure 12
(6-Methoxy-pyridin-2-yl)-methyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The crude product was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and and 2-methoxy-6-methylaminopyridine. The reaction mixture was evaporated to dryness, dissolved in dichloromethane (100 ml) and extracted with a aqueous phosphate buffer, pH 7. The aqueous phase was extracted with dichloromethane (100 ml×2) and the combined organic phases were dried and evaporated to dryness. The product was subjected to flash chromatography, ethyl acetate/heptane (1:7) to give the titlew product (86%, white crystals). HPLC-MS m/z=420.4 (M+1), Rt: 5.23 min.
Example 454
General Procedure 12
4-Benzimidazol-1-yl-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The crude product was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-piperidine-4-yl-1H-benzimidazole, 5 equivalent of diisopropylamine was added, preparative HPLC (method C) (23%, colourless crystals). HPLC-MS m/z=483.3 (M+1), Rt: 3.14 min.
Example 455
General Procedure 12
4-Hydroxymethyl-piperidine-1-carboxylic acid 4-(2-cyclohexyl-acetylamino)-phenyl ester
The title compound was prepared from 4-(2-cyclohexyl-acetylamino)-phenyl chloroformate and 4-hydroxymethyl-piperidine, preparative HPLC (Method C) (37%, off-white crystals). HPLC-MS m/z=375.2 (M+1), Rt: 3.41 min.
Example 456
General Procedure 12
4-(4-Amino-phenyl)-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 4-(4-aminophenyl)piperidine, hydrochloride, preparative HPLC (Method C) (30%, light yellow crystals). HPLC-MS m/z=458.2 (M+1), Rt: 3.42 min.
Example 457
General Procedure 12
4-(Methyl-pyridin-3-ylmethyl-amino)-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and methyl-piperidin-4-yl-pyridin-3-ylmethyl-amine, hydrochloride, preparative HPLC (Method C) (31%, orange oil). HPLC-MS m/z=487.1 (M+1), Rt: 2.64 min.
Example 458
General Procedure 12
4-(2-Oxo-pyrrolidin-1-yl)-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-piperidin-4-yl-pyrrolidine-2-one, hydrochloride, preparative HPLC (Method C) (55%, semi-crystaline oil). HPLC-MS m/z=450.1 (M+1), Rt: 3.81 min.
Example 459
General Procedure 12
4-(Methyl-phenethyl-amino)-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and methyl-phenethyl-piperidin-4-yl-amine, hydrochloride, preparative HPLC (Method C) (37%, colourless oil). HPLC-MS m/z=500.1 (M+1), Rt: 3.26 min.
Example 460
4-[(Benzyl-ethyl-amino)-methyl]-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
Benzyl-ethyl-piperidin-4-ylmethyl-amine (1.42 mmol) was dissolved in dichloromethane. 4-(5-Trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate (1.42 mmol, 0.451 g) (prepared from the corresponding, phenol by conventional methods) was added at room temperature. The reaction mixture was stirred overnight and evaporated to dryness. The crude product was subjected to column chromatography, ethyl acetate/heptane (1:3)→Triethylamine/ethyl acetate 1:9). The fractions containing the title product, was evaporated to dryness and HCl (g) in ethyl acetate was added and stirred for 16 hours. The solution was evaporated to dryness and dried in vacuum for 16 h. to give the title product. (58%, light yellow crystals). HPLC-MS m/z=514.1 (M+1), Rt: 3.27 min.
Example 461
General Procedure 12
4-[Methyl-phenethyl-amino)-methyl]-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and methyl-phenethyl-piperidin-4-ylmethyl-amine, hydrochloride, 5 equivalent of diisopropylamine was added, preparative HPLC (Method C) (46%, colourless crystals). HPLC-MS m/z=514.1 (M+1), Rt: 3.31 min.
Example 462
General Procedure 12
4-[(Cyclohexyl-methyl-amino)-methyl]-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and cyclohexyl-methyl-piperidine-4-ylmethyl-amine, hydrochloride, 5 equivalent of diisopropylamine was added, preparative HPLC (Method C) (43%, white crystals). HPLC-MS m/z=492.3 (M+1), Rt: 3.22 min.
Example 463
General Procedure 12
4-[(Ethyl-pyridin-4-ylmethyl-amino)-methyl]-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and ethyl-piperidin-4-ylmethyl-pyridin-4-ylmethyl-amine, hydrochloride, 5 equivalent of diisopropylamine was added, preparative HPLC (Method C) (25%, off-white crystals). HPLC-MS m/z=515.2 (M+1), Rt: 2.77 min.
Example 464
General Procedure 12
4-[(Benzyl-methyl-amino)-methyl]-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and benzyl-methyl-piperidin-4-ylmethyl-amine, hydrochloride, 5 equivalent of diisopropylamine was added, preparative HPLC (Method C) (56%, colourless crystals). HPLC-MS m/z=500.2 (M+1), Rt: 3.18 min.
Example 465
General Procedure 12
4-[(Methyl-pyridin-3-ylmethyl-amino)-methyl]-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and methyl-piperidine-4-ylmethyl-pyridine-4-ylmethyl-amine, hydrochloride, 5 equivalent of diisopropylamine was added, preparative HPLC (Method C) (36%, colourless crystals). HPLC-MS m/z=501.1 (M+1), Rt: 2.74 min.
Example 466
General Procedure 12
4-(1,3-Dihydro-isoindol-2-ylmethyl)-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 2-piperidin-4-ylmethyl-2,3-dihydro-1H-isoindole, hydrochloride, 5 equivalent of diisopropylamine was added, preparative HPLC (Method C) (63%, colourless crystals). HPLC-MS m/z=498.1 (M+1), Rt: 3.07 min.
Example 467
4-Benzotriazol-1-yl-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-piperidin-4-yl-1 H-benzotriazole, hydrochloride, 5 equivalent of diisopropylamine was added, preparative HPLC (Method C) (7%, colourless crystals). HPLC-MS m/z=506.2 (M+1), Rt: 4.56 min.
Example 468
General Procedure 12
4-[(Cyclopropylmethyl-amino)-methyl]-piperidine-1-carboxylic acid 4-(5-trifluoromthyl-pyridin-2-yloxy)-phenyl ester
Cyclopropylmethyl-piperidine-4-ylmethyl-amine (0.65 mmol, 110 mg) was dissolve in dichloromethane. 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate (0.65 mmol, 0.208 g) (prepared from the corresponding phenol by conventional methods) was added at −15° C. for 15 min and stirred at room temperature overnight and evaporated to dryness. The crude product was purified by preparative HPLC (Method C) (16%, colourless crystals). HPLC-MS m/z=450.1 (M+1), Rt: 2.98 min.
Example 469
General Procedure 12
4-[Methyl-(2-pyridin-2-yl-ethyl)-amino]-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from methyl-piperidin-4-yl-(2-pyridin-2-yl-ethyl)-amine and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, 5 equivalent of diisopropylamine was added, preparative HPLC (method C) (48%, colourless oil). HPLC-MS m/z=501.1 (M+1), Rt: 2.77 min.
Example 470
General Procedure 12
4-(Cyclohexyl-methyl-amino)-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from cyclohexyl-methyl-piperidin-4-yl-amine, dihydrochloride and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, 2 equivalent of diisopropylamine; dimethylformamide/tetrahydrofuran (2:1). The reaction mixture was evaporated to dryness and the crude product extracted with ethyl acetate from an aqueous HCl solution saturated with sodium chloride, pH 1-2. The title product was crystallized from ethyl acetate during evaporation of the solvent, filtered and dried in vacuum (45%, white crystals). HPLC-MS m/z=478.2 (M+1), Rt: 3.10 min.
Example 471
General Procedure 12
4-(Isopropyl-methyl-amino)-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from isopropyl-methyl-piperidin-4-yl-amine, dihydrochloride and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate; dimethylformamide as solvent, preparative HPLC (method C) (77%, light yellow oil). HPLC-MS m/z=438.3 (M+1), Rt: 2.77 min.
Example 472
General Procedure 12
(4-Methoxy-phenyl)-methyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from N-methyl-p-anisidine and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, preparative HPLC (method C) (61%, off-white crystals). HPLC-MS m/z=419.2 (M+1), Rt: 4.67 min.
Example 473
General Procedure 12
(2-Methoxy-phenyl)-methyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from 2-methoxy-N-methylamine and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, preparative HPLC (method C) (63%, colourless oil). HPLC-MS m/z=419.2 (M+1), Rt: 4.75 min.
Example 474
General Procedure 12
(2-Carbamoyl-4-chloro-phenyl)-methyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester.
The title product was prepared from 5-chloro-2-(methylamino)-benzamide and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, preparative HPLC (method C) (31%, light yellow oil). HPLC-MS m/z=466.1 (M+1), Rt: 3.99 min.
Example 475
General Procedure 12
(2-Carbamoyl-phenyl)-methyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from 2-(methylamino)benzamide and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, preparative HPLC (method C) (57%, light yellow oil). HPLC-MS m/z=454.2 (M+Na), Rt: 3.66 min.
Example 476
General Procedure 12
(2-Chloro-phenyl)-methyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from 2-chlor-N-methylaniline and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, preparative HPLC (method C) (48%, light yellow oil). HPLC-MS m/z=423.1 (M+1), Rt: 4.98 min.
Example 477
General Procedure 12
(2,4-Difluoro-phenyl)-methyl-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from 2,4-difluoro-N-methylaniline and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, preparative HPLC (method C) (37%, white crystals). HPLC-MS m/z=425.1 (M+1), Rt: 4.90 min.
Example 478
General Procedure 12
Methyl-(2-trifluoromethoxy-phenyl)-carbamic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from N-methyl-2-(trifluoromethoxy)-aniline and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, preparative H PLC (method C) (49%, colourless oil). HPLC-MS m/z=473.2 (M+1), Rt: 5.18 min.
Example 479
General Procedure 13
Methyl-phenyl-carbamic acid 4-(1,1,3,3-tetramethyl-butylcarbamoyl)-phenyl ester
The title product was prepared from tert-octylamine and 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester, preparative HPLC (method C) (26%, white crystals). HPLC-MS m/z=383.5 (M+1), Rt: 4.67 min.
Example 480
General Procedure 13
Methyl-phenyl-carbamic acid 4-[(2-dimethylamino-ethyl)-methyl-carbamoyl]-phenyl ester
The title product was prepared from N,N,N′-trimethylethylendiamine and 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester, preparative HPLC (method C) (2%, colourless oil). HPLC-MS m/z=356.2 (M+1), Rt: 2.17 min.
Example 481
General Procedure 13
Methyl-phenyl-carbamic acid 4-(cyclopropylmethyl-carbamoyl)-phenyl ester
The title product was prepared from cyclopropylmethylamine and 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester. The crude product was used without further purification (100%, semi-crystal oil). HPLC-MS m/z=325.1 (M+1), Rt: 3.40 min.
Example 482
General Procedure 13
Methyl-phenyl-carbamic acid 4-(methyl-pyridin-3-ylmethyl-carbamoyl)-phenyl ester
The title product was prepared from methyl-pyridin-3-ylmethyl-amine and 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester. The crude product was subjected to preparative HPLC (method C) (48%, clear colourless oil). HPLC-MS m/z=376.2 (M+1), Rt: 2.37 min.
Example 483
General Procedure 13
Methyl-phenyl-carbamic acid 4-[(1H-benzimidazol-2-ylmethyl)-carbamoyl]-phenyl ester
The title product was prepared from C-(1H-benzimidazol-2-yl)-methylamine and 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester. The crude product was subjected to preparative HPLC (method C) (8%, off-white crystals). HPLC-MS m/z=401.1 (M+1), Rt: 2.56 min.
Example 484
General Procedure 13
Methyl-phenyl-carbamic acid 4-[2-(4-chloro-phenyl)-ethylcarbamoyl]-phenyl ester
The title product was prepared from 2-(4-chloro-phenyl)-ethylamine and 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester. The crude product was subjected to preparative HPLC (method C) (39%, off-white crystals). HPLC-MS m/z=409.2 (M+1), Rt: 4.27 min.
Example 485
4-Cyclopropylmethyl-piperazine-1-carboxylic acid 4-(3,3-dimethyl-butylcarbamoyl)-phenyl ester
The title product was prepared from 1-cyclopropylmethylpiperazine (0.35 mmol) dissolved in dichloromethane (5 ml). 4-(3,3-dimethyl-butylcarbamoyl)-phenyl chloroformate (0.35 mmol) was added at room temperature. The reaction mixture was stirred for 16 h and evaporated to dryness and subjected to preparative HPLC (method C) (5%, white crystals). HPLC-MS m/z=388.2 (M+1), Rt: 2.43 min.
Example 486
4-Hydroxymethyl-piperidine-1-carboxylic acid 4-(3,3-dimethyl-butylcarbamoyl)-phenyl ester ester
The title product was prepared from 4-hydroxymethylpiperidine (0.35 mmol) was dissolved in dichloromethane (5 ml). Diisopropylethylamine (0.35 mmol was added together with 4-(3,3-dimethyl-butylcarbamoyl)-phenyl chloroformate (0.35 mmol) at room temperature. The reaction mixture was stirred for 16 h and evaporated to dryness and subjected to preparative HPLC (method C). (25%, white crystals). HPLC-MS m/z=363.3 (M+1), Rt: 3.27 min.
Example 487
4-Pyridin-3-ylmethyl-piperazine-1-carboxylic acid 4-(3,3-dimethyl-butylcarbamoyl)-phenyl ester
The title product was prepared from 1-pyridin-3-ylmethyl-piperazine was dissolved in dichloromethane (5 ml). 4-(3,3-Dimethyl-butylcarbamoyl)-phenyl chloroformate (0.35 mmol) was added at room temperature. The reaction mixture was stirred for 16 h and evaporated to dryness and subjected to preparative HPLC (method C) (88%, light yellow oil). HPLC-MS m/z=425.4 (M+1), Rt: 2.33 min.
Example 488
4-(4-Methoxy-benzyl)-piperazine-1-carboxylic acid 4-(3,3-dimethyl-butylcarbamoyl)-phenyl ester
The title product was prepared from 1-(4-methoxy-benzyl)-piperazine (0.35 mmol) was dissolved in dichloromethane (5 ml). 4-(3,3-Dimethyl-butylcarbamoyl)-phenyl chloroformate (0.35 mmol) was added at room temperature. The reaction mixture was stirred for 16 h and evaporated to dryness and subjected to preparative HPLC (method C). (54%, colourless semicrystaline oil). HPLC-MS m/z=454.3 (M+1), Rt: 2.78 min.
Example 489
4-(2-Pyridin-2-yl-acetyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
a) Piperazine-1,4-dicarboxylic acid tert-butyl ester 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester (General procedure 18)
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-tert-butoxycarbonyl-piperazin, yield 59% (recrystallized from EtOAc—heptane 1:1). White crystals, m.p. 165-166° C.; 1H NMR (CDCl3) □ 8.45-8.42 (m, 1H), 7.92-7.87 (m, dd-like, 1H), 7.21-7.12 (AB-system, 4H), 7.03-6.98 (m, d-like, 1H), 3.72-3.45 (br m, 8H), 1.49 (s, 9H); 13C-NMR (CDCl3) □ (ref. CDCl3 77.00 ppm):165.71, 154.56, 153.51, 150.21, 148.34, 145.43 (q, J=4.4 Hz), 136.701 (q, J=3 Hz), 123.65 (q, J=271.5 Hz), 122.86, 122.24, 121.62 (q, J=33 Hz), 11.20, 80.32, 44.38, 43.78, 44.6-42.3 (br), 28.36 ppm; IR (KBr) □ 1722 (C═O), 1691 (C═O) cm−1.
b) Piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester hydrochloride
Piperazine-1,4-dicarboxylic acid tert-butyl ester 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester (0.12 g, 0.26 mmol) was stirred at 100° C. for 10 min in a mixture of ethanol (3 ml) and concentrated hydrochloric acid (1 ml). The solvent was removed in vacuum. The residue was stirred with toluene (10 ml) and evaporated, then stirred with ethanol and evaporated to dryness to give white crystals (0.10 g). Recrystallization from absolute ethanol gave the title compound. White crystals, 0.068 g (65%); m.p. 279-282° C. (decomp.); 1H-NMR (DMSO) □ 9.62 (br, 2H, NH2+), 8.61-8.55 (m, 1H), 8.29-8.21 (m, dd-like, 1H), 7.30-7.20 (m, 5H), 3.86 and 3.70 (br s, 4H), 3.19 (brs, 4H); 13C-NMR (DMSO) □ (ref DMSO 39.50 ppm): 165.51, 152.71, 149.98, 148.04, 145.20 (J=4.4 Hz), 137.62 (J=3.7 Hz), 123.87 (J=271.5 Hz), 123.11, 123.39, 120.39 (J=32.2 Hz), 111.80, 42.15 and a broad signal partly overlapping with the DMSO signal. IR (KBr) □ 1731, 1709 (C═O) cm−1.
c) 4-(2-Pyridin-2-yl-acetyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
Triethylamine (0.026 ml) was added to a stirred solution of (pyridin-2-yl)acetic acid hydrochloride (0.033 g, 0.19 mmol) in DMF (2.5 ml) at 0° C. 1-Hydroxy-benzotriazole containing 8% of water (0.034 g) and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.044 g) was added and the mixture was stirred for 50 min. Piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester hydrochloride (0.070 g) in a mixture of DMF (1 ml) and triethylamine (0.032 ml) was added and stirring was continued over night at room temperature. The solvent was removed in vacuum and the residue was partitioned between dichloromethane (10 ml) and water (10 ml). The organic phase was washed with water (10 ml), dried over sodium sulfate, filtered and evaporated. The residue was triturated with ether-petroleumsether 1:1 and the (2+1 ml). The residue was dried to give the title compound. White solid, m.p. 143-146° C.; HPLC-MS m/z: IR (KBr) □ 1732 (C═O), 1643 (C═O).
Example 490
General Procedure 15
4-(2-Pyridin-4-yl-ethyl)-piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(4-pyridin-2-yl-ethyl)-piperazine. White crystals, m.p. 268-271° C. (decomp); IR (KBr) □ 2680, 2579, 2456 (N+−H), 1731, 1713 (C═O) cm−1; HPLC-MS m/z: 473 (M+H) Rt=2.3 min.
Example 491
Methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester
A solution of methyl-phenyl-carbamic acid 5-nitro-pyridin-2-yl ester (10.41 g, 38.1 mmol) in tetrahydrofuran (100 mL) was hydrogenated in a Parr apparatus with wet 5% palladium on carbon and 20 psi hydrogen pressure. After 2 hours the solution was filtered over a short pad of Celite, washed thoroughly with ethyl acetate and evaporated in vacuo, yielding title compound (9.51 g, 103% yield) as a thick oil, which solidified upon standing.
1H NMR (300 MHz, CDCl3): δ=3.40 (br.s, 3H), 3.70 (br.s, 2H), 6.80 (br.d, 1H), 6.97 (dd, 1H), 7.22 (m, 1H), 7.36 (m, 4H), 7.72 (d, 1H); HPLC-MS (Method A): m/z=244 (M+H)+; Rt=2.28 min.
Example 492
Methyl-phenyl-carbamic acid 5-benzenesulfonylamino-pyridin-2-yl ester
Benzenesulphonyl chloride (0.18 g, 1.00 mmol), dissolved in a small amount of dichloromethane, was added dropwise to a stirred solution of methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (0.24 g, 1.00 mmol) and triethylamine (0.10 g, 1.00 mmol) in dichloromethane (10 mL). After stirring for 4 hours the solution was extracted with water and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 40:60 followed by 50:50) yielding the title compound (108 mg, 23% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ=3.46 (br.s, 3H), 6.82 (br.s, 1H), 7.24-7.52 (m, 9H), 7.63 (m, 3H), 7.84 (br.s, 1H); HPLC-MS (Method A): m/z=384 (M+H)+; Rt=3.26 min.
Example 493
3,3-Dimethyl-4-[6-(methyl-phenyl-carbamoyloxy)-pyridin-3-ylcarbamoyl]-butyric acid
A solution of methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (243 mg, 1.00 mmol) and 3,3-dimethylglutaric anhydride (142 mg, 1.00 mmol) in dichloromethane (10 mL) was stirred at room temperature for 48 hours. Evaporation of the solvent yielded the title compound as a thick oil.
HPLC-MS (Method A): m/z=386 (M+H)+; Rt=2.76 min.
Example 494
Piperidine-1-carboxylic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-yl
1-Piperidinecarbonyl chloride (63 microL, 0.50 mmol) was added to a solution of 6′-hydroxy-4,4-dimethyl-4,5-dihydro-3H-[1,3′]bipyridinyl-2,6-dione (117 mg, 0.50 mmol) and DABCO (56 mg, 0.50 mmol) in dimethylformamide (10 mL). After stirring for 1 hour at room temperature water was added and the solution was extracted twice with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo. The residue was crystallised from ethyl acetate:heptane yielding the title compound (0.12 g, 69% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ=1.21 (s, 6H), 1.64 (s, 6H), 2.69 (s, 4H), 3.53 (m, 2H), 3.63 (m, 2H), 7.22 (d, 1H), 7.49 (dd, 1H), 8.09 (d, 1H); HPLC-MS (Method A): m/z=346 (M+H)+; Rt=3.12 min.
Example 495
2,2-Dimethyl-N-[6-(methyl-phenyl-carbamoyloxy)-pyridin-3-yl]-succinamic acid
A solution of methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (0.49 g, 2.00 mmol) and 2,2-dimethylsuccinic anhydride (0.26 g, 2.00 mmol) in dichloromethane (10 mL) was stirred at room temperature overnight. Evaporation of the solvent in vacuo yielded the title compound.
HPLC-MS (Method A): m/z=372 (M+H)+; Rt=2.84 min.
Example 496
Methyl-phenyl-carbamic acid 5-(3,3-dimethyl-2,5-dioxo-pyrrolidin-1-yl)-pyridin-2-yl ester
A mixture of thionyl chloride (0.726 mL, 10.00 mmol) and 2,2-dimethyl-N-[6-(methyl-phenyl-carbamoyloxy)-pyridin-3-yl]-succinamic acid (0.74 g, 2.00 mmol) in dichloromethane (25 mL) was stirred at room temperature for 18 hours. The solvent and excess thionyl chloride were evaporated in vacuo. The crude product was redissolved in dichloromethane (25 mL) and pyridine (316 mg, 4.00 mmol) was added. The solution was extracted with water, dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 50:50), yielding the title compound (490 mg, 69% yield) as a white solid.
1H NMR (300 MHz, CDCl3): δ=1.43 (s, 6H), 2.74 (s, 2H), 3.45 (br.s, 3H), 7.1 (br, 1H), 7.26 (m, 1H), 7.38 (m, 4H), 7.76 (br.d, 1H), 8.39 (s, 1H); HPLC-MS (Method A): m/z=354 (M+H)+; Rt=3.35 min.
Example 497
Methyl-phenyl-carbamic acid 5-[3,3-dimethyl-5-(4-methyl-piperazin-1-yl)-5-oxo-pentanoylamino]-pyridin-2-yl ester
Thionyl chloride (56 microL, 0.78 mmol) was added to a stirred solution of 3,3-dimethyl-4-[6-(methyl-phenyl-carbamoyloxy)-pyridin-3-ylcarbamoyl]-butyric acid (0.15 g, 0.39 mmol) in dichloromethane (5 mL) and 2 drops of dimethylformamide. After stirring for 10 minutes N-methylpiperazine (1 mL) was added and stirring was continued for 2 hours. The solvent was evaporated in vacuo. The residue was redissolved in dichloromethane and extracted with water, dried over sodium sulphate, filtered and evaporated in vacuo. The crude product was purified by filtration over a short column (SiO2, ethyl acetate followed by acetone) yielding the title compound (93 mg, 51% yield) as a thick oil.
1H NMR (300 MHz, CDCl3): δ=1.11 (s, 6H), 2.32 (s, 3H), 2.43 (m, 8H), 3.42 (br.s 3H), 3.61 (m, 2H), 3.74 (m, 2H), 7.00 (br.s, 1H), 7.38 (d, 4H), 8.21 (dd, 1H), 8.47 (d, 1H), 10.90 (s, 1H); HPLC-MS (Method A): m/z=468 (M+H)+; Rt=2.20 min.
Example 498
Methyl-phenyl-carbamic acid 5-[3,3-dimethyl-4-(pyridin-3-ylcarbamoyl)-butyrylamino]-pyridin-2-yl ester
Thionylchloride (237 microL, 3.27 mmol) was added to a stirred solution of 3,3-dimethyl-4-[6-(methyl-phenyl-carbamoyloxy)-pyridin-3-ylcarbamoyl]-butyric acid (0.63 g, 1.63 mmol) in dichloromethane (10 mL). After stirring for 10 minutes the solution was divided into 4 equal portions of acid chloride. To one portion was added 2-aminopyridine (0.5 mL) and after stirring for 2 hours at room temperature the crude product was purified by flash column chromatography (SiO2, ethyl acetate followed by ethyl acetate:acetone 90:10), yielding the title compound (105 mg, 56% yield).
1H NMR (300 MHz, CDCl3): δ=1.09 (s, 6H), 2.36 (s, 2H), 2.38 (s, 2H), 3.44 (br.s 3H), 6.95 (br.s, 1H), 7.26 (m, 2H), 7.38 (m, 4H), 8.05 (dd, 1H), 8.10 (dt, 1H), 8.30 (m, 2H), 8.67 (d, 1H); HPLC-MS (Method A): m/z=462 (M+H)+; Rt=2.52 min.
Example 499
Methyl-phenyl-carbamic acid 5-(3,3-dimethyl-5-morpholin-4-yl-5-oxo-pentanoylamino)-pyridin-2-yl ester
Thionylchloride (237 microL, 3.27 mmol) was added to a stirred solution of 3,3-dimethyl-4-[6-(methyl-phenyl-carbamoyloxy)-pyridin-3-ylcarbamoyl]-butyric acid (0.63 g, 1.63 mmol) in dichloromethane (10 mL). After stirring for 10 minutes the solution was divided into 4 equal portions of acid chloride. To one portion was added morpholine (0.5 mL) and after stirring for 2 hours at room temperature the crude product was purified by flash column chromatography (SiO2), yielding the title compound (117 mg, 63% yield).
1H NMR (300 MHz, CDCl3): δ=1.11 (s, 6H), 2.44 (s, 4H), 3.42 (br.s, 3H), 3.59 (m, 2H), 3.70 (m, 6H), 7.00 (br.s, 1H), 7.24 (m, 1H), 7.38 (d, 4H), 8.21 (dd, 1H), 8.45 (d, 1H), 10.76 (s, 1H); HPLC-MS (Method A): m/z=455 (M+H)+; Rt=2.87 min.
Example 500
Methyl-phenyl-carbamic acid 5-[4-(2-dimethylamino-ethylcarbamoyl)-3,3-dimethylbutyrylamino]-pyridin-2-yl ester
Thionylchloride (237 microL,-3.27 mmol) was added to a stirred solution of 3,3-dimethyl-4-[6-(methyl-phenyl-carbamoyloxy)-pyridin-3-ylcarbamoyl]-butyric acid (0.63 g, 1.63 mmol) in dichloromethane (10 mL). After stirring for 10 minutes the solution was divided into 4 equal portions of acid chloride. To one portion was added N,N-dimethylethylenediamine (0.5 mL) and after stirring for 2 hours at room temperature the crude product was purified by flash column chromatography (SiO2), yielding the title compound (74 mg, 39% yield).
1H NMR (300 MHz, CDCl3): δ=1.10 (s, 6H), 2.22 (s, 2H), 2.27 (s, 6H), 2.44 (m, 4H), 3.37 (m, 2H), 3.43 (br.s, 3H), 6.60 (br.t, 1H), 7.00 (br.s, 1H), 7.25 (m, 1H), 7.38 (d, 4H), 8.21 (dd, 1H), 8.46 (d, 1H), 10.70 (s, 1H); HPLC-MS (Method A): m/z=456 (M+H)+; Rt=1.93 min.
Example 501
General Procedure 12
4-[Methyl-(2-pyridin-4-yl-ethyl)-amino]-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from methyl-piperidine-4-yl-(2-pyridin-4-yl-ethyl)-amine and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, 3 equivalent of diisopropylamine was added, preparative HPLC (method C) (15%, colourless oil). HPLC-MS m/z=501.4 (M+1), Rt: 2.04 min.
Example 502
General Procedure 12
4-(Cyclopropyl-pyridin-4-ylmethyl-amino)-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from cyclopropyl-piperidine-4-yl-pyridin-4-ylmethyl-amine and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, 3 equivalent of diisopropylamine was added, solvent: dimethylformamide. The crude reaction mixture was evaporated without addition of acetic acid, preparative HPLC (method C) (19%, yellow oil). HPLC-MS m/z=(M+1), Rt: 2.82 min.
Example 503
General Procedure 12
4-[Cyclopropyl-(2-fluoro-benzyl)-amino]-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from cyclopropyl-(2-fluoro-benzyl)-piperidin-4-yl-amine and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, 3 equivalent of diisopropylamine was added, solvent: dimethylformamide. The crude reaction mixture was evaporated without addition of acetic acid, preparative HPLC (method C) (60%, colourless oil). HPLC-MS m/z=(M+1), Rt: 3.02 min.
Example 504
General Procedure 12
4-(Cyclopropyl-pyridin-3-ylmethyl-amino)-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from cyclopropyl-piperidin-4-yl-pyridin-3-ylmethyl-amine and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, 3 equivalent of diisopropylamine was added, solvent: dimethylformamide. The crude reaction mixture was evaporated without addition of acetic acid, preparative HPLC (method C) (26%, light brown solid). HPLC-MS m/z=(M+1) 513.3, Rt: 2.64 min.
Example 505
General Procedure 12
4-(Cyclopropylmethyl-pyridin-3-ylmethyl-amino)-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from cyclopropylmethyl-piperidin-4-yl-pyridin-3-ylmethylamine and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, 3 equivalent of diisopropylamine was added, solvent: dimethylformamide. The crude reaction mixture was evaporated without addition of acetic acid, preparative HPLC (method C) (47%, off-white solid. HPLC-MS m/z=(M+1) 513.3, Rt: 2.70 min.
Example 506
General Procedure 12
4-(Cyclopropylmethyl-pyridin-3-ylmethyl-amino)-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from cyclopropylmethyl-piperidin-4-yl-pyridin-4-ylmethylamine and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, 3 equivalent of diisopropylamine was added, solvent: dimethylformamide. The crude reaction mixture was evaporated without addition of acetic acid, preparative HPLC (method C) (22%, off-white solid. HPLC-MS m/z=(M+1) 513.3, Rt: 2.70 min.
Example 507
General Procedure 12
4-(4-Hydroxy-piperidin-1-ylmethyl)-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from 1-piperidin-4-ylmethyl-piperidine-4-ol (released form the correspondent hydrochloride by a standard procedure) and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, preparative HPLC (method C) (reaction performed in a mixture of dichloromethane and dimethylformamide). 1.7 M HCl in ethyl acetate was added to the pooled fractions containing the title product, and the fractions was evaporated to dryness (92%, white solid. HPLC-MS m/z=(M+1) 480.4, Rt: 2.38 min.
Example 508
General Procedure 11
4-{3-[1-(2-Hydroxy-ethyl)-piperidin-4-yl]-propyl}-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from 2-[4-(3-piperidin-4-yl-propyl)-piperidin-1-yl]-ethanol and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate. The reaction mixture was evaporated, diethyl ether (30 ml) was added and the title product isolated by filtration, washed with diethyl ether and dried to give (67%, white solid. HPLC-MS m/z=(M+1) 536.2, Rt: 3.39 min.
Example 509
General Procedure 12
4-(2-Pyrrolidin-1-yl-ethyl)-piperidine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester
The title product was prepared from 2-[4-(3-piperidin-4-yl-propyl)-piperidin-1-yl]-ethanol and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, preparative HPLC (method C). 1.7 M HCl in ethyl acetate was added to the pooled fractions containing the title product, and the fractions was evaporated to dryness (65%, white solid). HPLC-MS m/z=(M+1) 464.1, Rt: 2.99 min.
Example 510
General Procedure 16
Methyl-o-tolyl-carbamic acid 4-iodo-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-4-iodopyrazole and methyl-o-tolylamine.
The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (40%, oil).
HPLC-MS: m/z=380.1 (M+23); Rt=4.05 min.
Example 511
General Procedure 16
Methyl-m-tolyl-carbamic acid 4-iodo-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-4-iodopyrazole and methyl-m-tolylamine. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (44%, oil).
HPLC-MS: m/z=380.1 (M+23); Rt=4.13 min.
Example 512
General Procedure 16
Methyl-p-tolyl-carbamic acid 4-iodo-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-4-iodopyrazole and methyl-p-tolylamine. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (55%, oil).
HPLC-MS: m/z=380.1 (M+23); Rt=4.13 min.
Example 513
General Procedure 16
(3-Chloro-phenyl)-methyl-carbamic acid 4-iodo-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-4-iodopyrazole and 3-chlorophenylmethylamine. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (54%, oil).
HPLC-MS: m/z=399.9 (M+23); Rt=4.28 min.
Example 514
General Procedure 16
(3-Fluoro-phenyl)-methyl-carbamic acid 4-iodo-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-4-iodopyrazole and 3-fluorophenyl-methylamine. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (51%, oil).
HPLC-MS: m/z=384.0 (M+23); Rt=4.00 min.
Example 515
General Procedure 16
4-(3-Trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic acid 4-iodo-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-4-iodopyrazole and 1-(3-trifluoromethylpyridin-2-yl)piperazine. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (13%, oil).
HPLC-MS: m/z=468.1 (M+1); Rt=4.38 min.
Example 516
General Procedure 16
2,6-Dimethyl-morpholine-4-carboxylic acid 4-iodo-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-4-iodopyrazole and 2,6-dimethylmorpholin. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (11%, oil).
HPLC-MS: m/z=374.0 (M+23); Rt=3.24 min.
Example 517
General Procedure 16
Thiomorpholine-4-carboxylic acid 4-iodo-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-4-iodopyrazole and thiomorpholin. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (27%, oil).
HPLC-MS: m/z=340.0 (M+1); Rt=3.22 min.
Example 518
General Procedure 16
3,5-Dimethyl-morpholine-4-carboxylic acid 4-iodo-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-4-iodopyrazole and 3,5-dimethylmorpholin. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (15%, oil).
HPLC-MS: m/z=352.0 (M+1); Rt=3.17 min.
Example 519
General Procedure 16
Piperidine-1-carboxylic acid 4-iodo-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-4-iodopyrazole and piperidine. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (46%, oil). HPLC-MS: m/z=322.0 (M+1); Rt=3.38 min.
Example 520
General Procedure 16
Methyl-o-tolyl-carbamic acid 2-chloro-imidazol-1-yl ester
The title compound was prepared from 1-hydroxy-2-chloroimidazole, hydrochloride and methyl-o-tolylamine. The crude product was purified by preparative HPLC (Gilson) (4%, red oil).
HPLC-MS: m/z=266.0 (M); Rt=3.28 min.
Example 521
General Procedure 16
(3-Fluoro-phenyl)-methyl-carbamic acid 2-chloro-imidazol-1-yl ester
The title compound was prepared from 1-hydroxy-2-chloroimidazole, hydrochloride and 3-fluorophenyl-methylamine. The crude product was purified by preparative HPLC (Gilson) (2%, oil).
HPLC-MS: m/z=270.1 (M); Rt=3.08 min.
Example 522
Methyl-phenyl-carbamic acid 4-iodo-phenyl ester
To a solution of 4-iodophenol (30 mmol) in CH2Cl2 (100 mL) was added N-methyl-N-phenylcarbamoyl chloride (27 mmol) and diisopropylethylamine (60 mmol) at room temperature. The reaction mixture was stirred for 16 hours at rt, added CH2Cl2 (20 mL) and washed with aqueous citric acid (5%), aqueous Na2CO3 and brine. The organic phase was dried (MgSO4) and evaporated to give the crude product which was purified by FC (Quad flash 40 EtOAc-Heptane) to give 6.55 g (69%) of the title compound as light brown crystals.
1H NMR (300 MHz; CDCl3): δ 3.38 (br s, 3H), 6.88 (d, 2H), 7.22-7.46 (m, 5H), 7.62 (d, 2H); HPLC-MS: m/z=354.0 (M+1); Rt=4.54 min.
Example 523
General Procedure 20
Methyl-phenyl-carbamic acid 4′-trifluoromethyl-biphenyl-4-yl ester
The title compound was prepared from methyl-phenyl-carbamic acid 4-iodo-phenyl ester and 4-trifluoromethylphenylboronic acid. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane 1:9) (42%, light brown crystals).
HPLC-MS: m/z=372.1 (M+1); Rt=5.19 min.
Example 524
General Procedure 20
Methyl-phenyl-carbamic acid 4′-trifluoromethoxy-biphenyl-4-yl ester
The title compound was prepared from methyl-phenyl-carbamic acid 4-iodo-phenyl ester and 4-trifluoromethoxyphenylboronic acid. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane 1:9) (17%, brown oil).
HPLC-MS: m/z=388.1 (M+1); Rt=5.27 min.
Example 525
General Procedure 20
Methyl-phenyl-carbamic acid 4-pyridin-3-yl-phenyl ester
The title compound was prepared from methyl-phenyl-carbamic acid 4-iodo-phenyl ester and pyridine-3-boronic acid. The crude product was purified by preparative HPLC (Gilson) (5%, brown oil).
1H NMR (300 MHz; CDCl3): δ 3.46 (brs, 3H), 7.29-7.46 (m, 7H), 7.61 (d, 2H), 7.88 (dd, 1H), 8.41 (d, 1H), 8.78 (d, 1H); HPLC-MS: m/z=305.1 (M+1); Rt=2.99 min.
Example 526
General Procedure 20
Methyl-phenyl-carbamic acid 4-(5-chloro-thiophen-2-yl)-phenyl ester
The title compound was prepared from methyl-phenyl-carbamic acid 4-iodo-phenyl ester and 5-chloro-2-thiopheneboronic acid. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane 1:9) (53%, pink crystals).
1H NMR (300 MHz; CDCl3): δ 3.43 (br s, 3H), 6.87/d, 1H), 7.00 (d, 1H), 7.13 (br d, 2H), 7.26-7.48 (m, 7H); HPLC-MS: m/z=344.0 (M+1); Rt=5.16 min.
Example 527
General Procedure 20
Methyl-phenyl-carbamic acid 4′-benzylsulfamoyl-biphenyl-4-yl ester
The title compound was prepared from methyl-phenyl-carbamic acid 4-iodo-phenyl ester and 4-benzylsulfamoylbenzeneboronic acid. The crude product was purified by preparative HPLC (Gilson) (35%, pink crystals).
HPLC-MS: m/z=473.0 (M+1); Rt=4.80 min.
Example 528
Methyl-phenyl-carbamic acid 4-styryl-phenyl ester
Styrene (1.2 mmol), N-methyldicyclohexylamine (1.2 mmol), Pd2(dba)3 (0.03 mmol), Pd(P(t-Bu)3)2 (0.06 mmol) and methyl-phenyl-carbamic acid 4-iodo-phenyl ester (1.0 mmol) were added to a Schlenk tube under nitrogen. The Schlenk tube was evacuated and refilled with nitrogen five times. Then dioxane (2 mL) was added and the reaction mixture was stirred at 70° C. for 8 h. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) giving the title compound in 17% yield as colorless crystals.
HPLC-MS: m/z=330.1 (M+1); Rt=5.08 min.
Example 529
Methyl-phenyl-carbamic acid 4-phenylethynyl-phenyl ester
Phenylacetylene (1.2 mmol), diisopropylamine (1.2 mmol), CuI (0.03 mmol), Pd2(dba)3 (0.03 mmol), Pd(P(t-Bu)3)2 (0.06 mmol) and methyl-phenyl-carbamic acid 4-iodo-phenyl ester (1.0 mmol) were added to a Schlenk tube under nitrogen. The Schlenk tube was evacuated and refilled with nitrogen five times. Then dioxane (2 mL) was added and the reaction mixture was stirred at 70° C. for 8 h. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) giving the title compound in 41% yield as brown oil.
HPLC-MS: m/z=328.1 (M+1); Rt=5.07 min.
Example 530
3-[4-(Methyl-phenyl-carbamoyloxy)-phenyl]-acrylic acid methyl ester
Methylacrylate (1.2 mmol), N-methyldicyclohexylamine (1.2 mmol), Pd2(dba)3 (0.03 mmol), Pd(P(t-Bu)3)2 (0.06 mmol) and methyl-phenyl-carbamic acid 4-iodo-phenyl ester (1.0 mmol) were added to a Schlenk tube under nitrogen. The Schlenk tube was evacuated and refilled with nitrogen five times. Then dioxane (2 mL) was added and the reaction mixture was stirred at 70° C. for 8 h. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) giving the title compound in 70% yield as a yellow solid.
HPLC-MS: m/z=312.1 (M+1); Rt=4.19 min.
Example 531
General Procedure 8
Methyl-phenyl-carbamic Acid 5-phenylsulfanyl-pyrazol-1-yl ester
The title compound was prepared from 1-hydroxy-5-phenylsulfanylpyrazole and N-methyl-N-phenylcarbamoyl chloride. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (80%, oil).
1H NMR (300 MHz; CDCl3): δ 3.36 (br s, 3H), 6.47 (d, 1H) 7.16-7.32 (m, 10H), 7.40 (d, 1H);
HPLC-MS: m/z=326.0 (M+1); Rt=4.42 min.
Example 532
General Procedure 21
Methyl-phenyl-carbamic acid 4-(toluene-4-sulfonylamino)-phenyl ester
The title compound was prepared in 8% yield as a clear oil using toluenesulfonyl chloride as the aryl sulfonyl chloride.
HPLC-MS: m/z=397.1 (M+1); Rt=4.13 min
Example 533
General Procedure 21
Methyl-phenyl-carbamic acid 4-(5-pyridin-2-yl-thiophene-2-sulfonylamino)-phenyl ester
The title compound was prepared in 7% yield as an oil using 5-pyridin-2-yl-thiophene-2-sulfonyl chloride as the aryl sulfonyl chloride.
HPLC-MS: m/z=466.1 (M+1); Rt=4.23 min.
Example 534
General Procedure 21
Methyl-phenyl-carbamic acid 4-(1-methyl-1H-imidazole-4-sulfonylamino)-phenyl ester
The title compound was prepared in 21% yield as crystals using 1-methyl-1H-imidazole-4-sulfonyl chloride as the aryl sulfonyl chloride.
HPLC-MS: m/z=387.1 (M+1); Rt=3.14 min.
Example 535
General Procedure 21
Methyl-phenyl-carbamic acid 4-(2,5-dichloro-thiophene-3-sulfonylamino)-phenyl ester
The title compound was prepared in 2% yield as an oil using 2,5-dichloro-thiophene-3-sulfonyl chloride as the aryl sulfonyl chloride.
HPLC-MS: m/z=458.6 (M+1); Rt=4.38 min.
Example 536
General Procedure 21
Methyl-phenyl-carbamic acid 4-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonylamino)-phenyl ester
The title compound was prepared in 3% yield as an oil using 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride as the aryl sulfonyl chloride.
HPLC-MS: m/z=435.1 (M+1); Rt=3.74 min.
Example 537
General Procedure 21
Methyl-phenyl-carbamic acid 4-(5-dimethylamino-naphthalene-1-sulfonylamino)-phenyl ester
The title compound was prepared in 14% yield as orange crystals using 5-dimethylamino-naphthalene-1-sulfonyl chloride as the aryl sulfonyl chloride.
HPLC-MS: m/z=476.0 (M+1); Rt=4.48 min.
Example 538
General Procedure 21
2-[4-(Methyl-phenyl-carbamoyloxy)-phenylsulfamoyl]-benzoic acid methyl ester
The title compound was prepared in 48% yield as a yellow oil using 2-chlorosulfonyl-benzoic acid methyl ester as the aryl sulfonyl chloride.
HPLC-MS: m/z=441.1 (M+1); Rt=4.19 min.
Example 539
General Procedure 21
Methyl-phenyl-carbamic acid 4-(3,4-difluoro-benzenesulfonylamino)-phenyl ester
The title compound was prepared in 1% yield as a clear oil using 3,4-difluoro-benzenesulfonyl chloride as the aryl sulfonyl chloride.
HPLC-MS: m/z=419.1 (M+1); Rt=4.23 min.
Example 540
General Procedure 22 and 1
Methyl-phenyl-carbamic acid 4-pyridin-2-ylmethyl-phenyl ester
4-Pyridin-2-ylmethyl-phenol was prepared following general procedure PVe3 using pyridine-2-carboxaldehyde. Subsequent carbamoylation using general procedure 1 (CH2Cl2 was used as solvent) produced the crude product which was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (86%, oil).
1H NMR (400 MHz; CDCl3): δ 3.40 (br s, 3H), 4.14 (s, 2H), 7.04-7.12 (m, 4H), 7.21-7.26 (m, 3H), 7.32-7.40 (m, 4H), 7.55 (t, 1H), 8.52 (d, 1H).
Example 541
General Procedure 22 and 1
Methyl-phenyl-carbamic acid 4-pyridin-3-ylmethyl-phenyl ester
4-Pyridin-3-ylmethyl-phenol was prepared following general procedure PVe3 using pyridine-3-carboxaldehyde. Subsequent carbamoylation using general procedure 1 (CH2Cl2 was used as solvent) produced the crude product which was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (50%, oil).
1H NMR (400 MHz; CDCl3): δ 3.42 (brs, 3H), 3.96 (s, 2H), 7.03-7.42 (m, 11H), 8.46 (d, 1H), 8.49 (d, 1H).
Example 542
General Procedure 22 and 1
Methyl-phenyl-carbamic acid 4-(4-trifluoromethyl-benzyl)-phenyl ester
4-(4-Trifluoromethyl-benzyl)-phenol was prepared following general procedure PVe3 using 4-trifluoromethylbenzaldehyde. Subsequent carbamoylation using general procedure 1 (CH2Cl2 was used as solvent) produced the crude product which was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (92%, oil).
1H NMR (400 MHz; CDCl3): δ 3.42 (br s, 3H), 4.00 (s, 2H), 7.06 (br s, 2H), 7.13 (d, 2H), 7.24-7.40 (m, 7H), 7.52 (d, 2H).
Example 543
General Procedure 22 and 1
Methyl-phenyl-carbamic acid 4-thiophen-3-ylmethyl-phenyl ester
4-Thiophen-3-ylmethyl-phenol was prepared following general procedure PVe3 using thiophene-3-carboxaldehyde. Subsequent carbamoylation using general procedure 1 (CH2Cl2 was used as solvent) produced the crude product which was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (83%, oil).
1H NMR (400 MHz; CDCl3): δ 3.42 (bs, 3H), 3.95 (s, 2H), 6.86-7.39 (m, 12H).
Example 544
General Procedure 22 and 1
Methyl-phenyl-carbamic acid 4-thiophen-2-ylmethyl-phenyl ester
4-Thiophen-2-ylmethyl-phenol phenol was prepared following general procedure PVe3 using thiophene-3-carboxaldehyde. Subsequent carbamoylation using general procedure 1 (CH2Cl2 was used as solvent) produced the crude product which was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (83%, oil).
1H NMR (400 MHz; CDCl3): δ 3.40 (br s, 3H), 4.13 (s, 2H), 6.78 (dd, 1H), 6.90 (dd, 1H), 7.04 (br d, 2H), 7.13 (dd, 1H), 7.20-7.39 (m, 7H). HPLC-MS: m/z=324.1 (M+1); Rt=4.82 min.
Example 545
4-Hydroxy-piperidine-1-carboxylic acid 4-[2-(toluene-4-sulfonylamino)-ethyl]-phenyl ester
N-Boc protected tyramin (10 mmol), triethylamine (10 mmol) and 3-[4-(tert-Butyl-dimethylsilanyloxy)-piperidine-1-carbonyl]-1-methyl-3H-imidazol-1-ium; iodide (10 mmol) in MeCN (25 mL) was stirred at room temperature for 16 hours. Acetonitrile was removed by evaporation and the crude product was purified by flash chromatography (Quad flash 40, EtOAc-heptane 1:2) providing 72% 4-tert-butylsilanyloxy-piperidine-1-carboxylic acid 4-(2-tert-butoxycarbonylamino-ethyl)-phenyl ester. This was deprotected by stirring with a 3.2 M solution of HCl in Et2O (50 mL) for 3 h at rt and subsequently washed with ether to give 91% of 4-(4-hydroxy-piperidine-1-carbonyloxy)-phenyl-ammonium; chloride as a solid. This compound was N-tosylated as described for methyl-phenyl-carbamic acid 4-[2-(toluene-4-sulfonylamino)-ethyl]-phenyl ester to give the title compound in 26% yield as yellow crystals after purification by flash chromatography (Quad flash 12, CH2Cl2-MeOH 95:5).
HPLC-MS: m/z=391.0 (M+1); Rt=3.04 min.
Example 546
4-Hydroxy-piperidine-1-carboxylic acid 4-[2-(5-pyridin-2-yl-thiophene-2-sulfonylamino)-ethyl]-phenyl
4-(4-Hydroxy-piperidine-1-carbonyloxy)-phenyl-ammonium; chloride (see above) was N-sulfonylated as described for methyl-phenyl-carbamic acid 4-[2-(5-pyridin-2-yl-thiophene-2-sulfonylamino)-ethyl]-phenyl ester to give the title compound in 59% yield as an oil after purification by preparative HPLC (Gilson).
HPLC-MS: m/z=488.0 (M+1); Rt=3.10 min.
Example 547
4-Hydroxy-piperidine-1-carboxylic acid 4-(5-pyridin-2-yl-thiophene-2-sulfonylamino)-phenyl ester
N-Boc protected 4-aminophenol (10 mmol), triethylamine (10 mmol) and 3-[4-(tert-Butyl-dimethyl-silanyloxy)-piperidine-carbonyl]-1-methyl-3H-imidazol-1-ium; iodide (10 mmol) in MeCN (25 mL) was stirred at room temperature for 16 hours. Acetonitrile was removed by evaporation and the crude product was purified by flash chromatography (Quad flash 40, EtOAc-heptane 1:2) providing 64% 4-tert-butylsilanyloxy-piperidine-1-carboxylic acid 4-tert-butoxycarbonylamino-phenyl ester. This was deprotected by stirring with a 3.2 M solution of HCl in Et2O (50 mL) for 3 h at rt and subsequently washed with ether to give 91% of 4-(4-Hydroxy-piperidine-1-carbonyloxy)-phenyl-ammonium; chloride as a hygroscopic solid. This compound was N-sulfonylated as described for methyl-phenyl-carbamic acid 4-[2-(5-pyridin-2-yl-thiophene-2-sulfonylamino)-ethyl]-phenyl ester to give the title compound in 1% yield as crystals after purification by preparative HPLC (Gilson).
HPLC-MS: m/z=482.8 (M+1); Rt=1.01 min.
Example 548
Methyl-phenyl-carbamic acid 4-[2-(4-amino-benzenesulfonylamino)-ethyl]-phenyl ester
Methyl-phenyl-carbamic acid 4-[2-(4-nitro-benzenesulfonylamino)-ethyl]-phenyl ester, 5% palladium on carbon, and ethanol were stirred under hydrogen at 1 bar and rt for 16 h. Filtration and removal of ethanol produced the title compound in 94% yield as an oil. HPLC-MS: m/z=426.1 (M+1); Rt=3.61 min.
Example 549
Methyl-phenyl-carbamic acid 4-{2-[(pyridine-3-carbonyl)-amino]-ethyl}-phenyl ester
A solution of 3-pyridinecarboxylic acid (0.3 mmol), EDAC (0.36 mmol) and triethylamine (0.36 mmol) in CH2Cl2 (10 mL) was added N-hydroxybenzoetriazole and N-methyl-N-phenyl-carbamic acid 4-(2-amino-ethyl)phenyl ester as its TFA salt (0.3 mmol). The mixture was stir-stirred 16 h at rt and purified by preparative HPLC (Gilson) to give the title compound in 15% yield as an oil.
HPLC-MS: m/z=376.1 (M+1); Rt=3.01 min.
Example 550
Methyl-phenyl-carbamic acid 4-[2-(2-dimethylamino-acetylamino)-ethyl]-phenyl ester
A solution of N,N-dimethylglycine, HCl (0.3 mmol), EDAC (0.36 mmol) and triethylamine (1.0 mmol) in CH2Cl2 (10 mL) was added N-hydroxybenzoetriazole and N-methyl-N-phenyl-carbamic acid 4-(2-amino-ethyl)phenyl ester as its TFA salt (0.3 mmol). The mixture was stirred 16 h at rt and purified by preparative HPLC (Gilson) to give the title compound in 66% yield as an oil.
HPLC-MS: m/z=356.4 (M+1); Rt=2.09 min.
Example 551
General Procedure 23
Methyl-phenyl-carbamic acid 2-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-isoquinolin-7-yl ester
The title compound was prepared using methyl-phenyl-carbamic acid 4-[2-(toluene-4-sulfonylamino)-ethyl]-phenyl ester as the sulfonamide. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane 2:3) (71%, yellow oil).
HPLC-MS: m/z=437.4 (M+1); Rt=4.43 min.
Example 552
Methyl-phenyl-carbamic acid 4-[4-(2-pyrrolidin-1-yl-ethoxy)-benzyl]-phenyl ester
To a stirred solution of 1-[2-(4-bromo-phenoxy)-ethyl]-pyrrolidine (2.89 g, 10.7 mmol) in THF (30 mL) was added dropwise 1.6 M solution in hexanes n-BuLi (7 mL, 10.2 mmol) over a 5-min period at −78° C. The mixture was stirred at −78° C. for 15 min before 4-trimethylsilyloxybenzaldehyde (2.08 g, 10.7 mmol) was added. The mixture was allowed to warm to rt during 20 min and quenched with water. Extraction with CH2Cl2, drying (MgSO4), filtration and evaporation provided the crude diarylmethanol which was dissolved in CH2Cl2 (30 mL) and stirred with triethylsilane (4 mL) and TFA (5 mL) for 16 h at rt. Evaporation gave 3.0 g (84%) 4-[4-(2-pyrrolidin-1-yl-ethoxy)-benzyl]-phenol. This was carbamoylated using general procedure 1 (CH2Cl2 was used as solvent) to give the title product after purification by preparative HPLC (Gilson) (35%, oil).
HPLC-MS: m/z=431.5 (M+1); Rt=2.93 min.
Example 553
General Procedure 24
4-Hydroxy-piperidine-1-carboxylic acid 4-pyridin-2-ylmethyl-phenyl ester
The title compound was prepared as its hydrochloride using 4-pyridin-2-ylmethyl-phenol as the phenol.
1H NMR (300 MHz; D2O): δ 1.50 (br s, 2H), 1.90 (d, 2H), 3.04-3.27 (m, 2H), 3.78-4.08 (m, 3H), 4.41 (s, 2H), 7.07 (d, 2H), 7.30 (d, 2H), 7.79-7.85 (m, 2H), 8.40 (dt, 1H), 8.55 (d, 1H).
Example 554
General Procedure 24
4-Hydroxy-piperidine-1-carboxylic acid 4-pyridin-3-ylmethyl-phenyl ester
The title compound was prepared as its hydrochloride using 4-pyridin-3-ylmethyl-phenol as the phenol.
1H NMR (300 MHz; D2O): δ 1.48 (br s, 2H), 1.90 (d, 2H), 3.03-3.26 (m, 2H), 3.80-4.05 (m, 3H), 4.18 (s, 2H), 7.03 (d, 2H), 7.25 (d, 2H), 7.40 (dd, 1H), 8.40 (d, 1H), 8.54-8.57 (m, 2H).
Example 555
General Procedure 24
4-Hydroxy-piperidine-1-carboxylic acid 4-(4-trifluoromethyl-benzyl)-phenyl ester
The title compound was prepared using 4-(4-trifluoromethyl-benzyl)-phenol as the phenol.
1H NMR (300 MHz; D2O): δ 1.43-1.55 (m, 2H), 1.76-1.88 (m, 2H), 3.10-3.29 (m, 2H), 3.79-3.94 (m, 5H), 6.97 (d, 2H), 7.08 (d, 2H), 7.20 (d, 1H), 7.45 (d, 2H).
Example 556
General Procedure 23
Methyl-phenyl-carbamic acid 2-[4-(2-pyrrolidin-1-yl-ethoxy)-benzenesulfonyl]-1,2,3,4-tetrahydro-isoquinolin-7-yl ester
The title compound was prepared using methyl-phenyl-carbamic acid 4-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-benzenesulfonylamino]-ethyl}-phenyl ester as the sulfonamide. The crude product was purified by preparative HPLC (Gilson) and isolated as its TFA salt (45%, foam).
HPLC-MS: m/z=536.2 (M+1); Rt=3.10 min.
Example 557
Methyl-phenyl-carbamic acid 4-{2-[(1-methyl-piperidine-4-carbonyl)-amino]-ethyl}-phenyl ester
A solution of 1-methylpiperidine-4-carboxylic acid (0.3 mmol), EDAC (0.36 mmol) and triethylamine (1.0 mmol) in CH2Cl2 (10 mL) was added N-hydroxybenzoetriazole and N-methyl-N-phenyl-carbamic acid 4-(2-amino-ethyl)phenyl ester as its TFA salt (0.3 mmol). The mixture was stirred 16 h at rt and purified by preparative HPLC (Gilson) to give the title compound in 5% yield as an oil.
HPLC-MS: m/z=396.4 (M+1); Rt=2.03 min.
Example 558
General Procedure 23
Methyl-phenyl-carbamic acid 2-(3,4-difluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-7-yl ester
The title compound was prepared using methyl-phenyl-carbamic acid 4-[2-(3,4-difluoro-benzenesulfonylamino)-ethyl]-phenyl ester as the sulfonamide. The crude product was purified by preparative HPLC (Gilson) (24%, oil).
HPLC-MS: m/z=481.0 (M+23); Rt=4.73 min.
Example 559
General Procedure 23
Methyl-phenyl-carbamic acid 1-methyl-2-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-isoquinolin-7-yl ester
The title compound was prepared using methyl-phenyl-carbamic acid 4-[2-(toluene-4-sulfonylamino)-ethyl]-phenyl ester as the sulfonamide and acetaldehyde in stead of formaldehyde. The crude product was purified by preparative HPLC (Gilson) (22%, brown oil).
HPLC-MS: m/z=451.5 (M+1); Rt=4.43 min.
Example 560
General Procedure 23
Methyl-phenyl-carbamic acid 2-[4-(4-methyl-piperazin-1-yl)-benzenesulfonyl]-1,2,3,4-tetrahydro-isoquinolin
The title compound was prepared using methyl-phenyl-carbamic acid 4-{2-[4-(4-methyl-piperazin-1-yl)-benzenesulfonylamino]-ethyl}-phenyl ester as the sulfonamide. The crude product was purified by preparative HPLC (Gilson) and isolated as its TFA salt (79%, crystals).
HPLC-MS: m/z=521.5 (M+1); Rt=2.65 min.
Example 561
General Procedure 23
Methyl-phenyl-carbamic acid 1-methyl-2-[4-(4-methyl-piperazin-1-yl)-benzenesulfonyl]-1,2,3,4-tetrahydro-isoquinolin-7-yl ester
The title compound was prepared using methyl-phenyl-carbamic acid 4-{2-[4-(4-methyl-piperazin-1-yl)-benzenesulfonylamino]-ethyl}-phenyl ester as the sulfonamide and acetaldehyde in stead of formaldehyde. The crude product was purified by preparative HPLC (Gilson) (12%, brown oil).
HPLC-MS: m/z=535.4 (M+1); Rt=2.69 min.
Example 562
3,3-Dimethyl-4-{2-[4-(methyl-phenyl-carbamoyloxy)-phenyl]-ethylcarbamoyl}-butyric acid
A solution of 3,3-dimethylglutaric anhydride (0.3 mmol), diisopropylethylamine (0.30 mmol) and N-methyl-N-phenyl-carbamic acid 4-(2-amino-ethyl)phenyl ester as its TFA salt (0.3 mmol) in CH2Cl2 (3 mL) was stirred 1 h at rt. The mixture was washed with water and brine, dried and evaporated to give the title compound in 95% yield as an oil. HPLC-MS: m/z=413.2 (M+1); Rt=3.20 min.
Example 563
Methyl-phenyl-carbamic acid 4-{2-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-ethyl}-phenyl ester
A solution of 4-(4-methylpiperazino)benzoic acid (0.3 mmol), EDAC (0.36 mmol) and triethylamine (1.0 mmol) in CH2Cl2 (10 mL) was added N-hydroxybenzoetriazole and N-methyl-N-phenyl-carbamic acid 4-(2-amino-ethyl)phenyl ester as its TFA salt (0.3 mmol). The mixture was stirred 16 h at rt and purified by preparative HPLC (Gilson) to give the title compound in 54% yield as its crystalline hydrochloride after treatment with HCl in diethyl ether.
HPLC-MS: m/z=473.2 (M+1); Rt=2.22 min.
Example 564
Methyl-phenyl-carbamic acid 4-{2-[4-(4-methyl-piperazin-1-ylmethyl)-benzoylamino]-ethyl}-phenyl ester
A solution of 4-(4-methylpiperazinyl)methyl benzoic acid (0.3 mmol), EDAC (0.36 mmol) and triethylamine (1.0 mmol) in CH2Cl2 (10 mL) was added N-hydroxybenzoetriazole and N-methyl-N-phenyl-carbamic acid 4-(2-amino-ethyl)phenyl ester as its TFA salt (0.3 mmol). The mixture was stirred 16 h at rt and purified by preparative HPLC (Gilson) to give the title compound in 25% yield as its crystalline hydrochloride after treatment with HCl in diethyl ether.
HPLC-MS: m/z=487.3 (M+1); Rt=2.13 min.
Example 565
Methyl-phenyl-carbamic acid 4-[2-(4,4-dimethyl-2,6-dioxo-piperidin-1-yl)-ethyl]-phenyl ester
A solution of 3,3-dimethylglutaric anhydride (0.3 mmol), diisopropylethylamine (0.30 mmol) and N-methyl-N-phenyl-carbamic acid 4-(2-amino-ethyl)phenyl ester as its TFA salt (0.3 mmol) in CH2Cl2 (3 mL) was stirred 1 h at rt. Thionylchloride (3 mmol) was added and the mixture was stirred for 2 h at rt. Addition of ethanol (5 mL) followed by evaporation to dryness gave a crude product which was purified by flash chromatography (Quad flash 12, EtOAc-heptane 1:1). This gave the title compound in 23% yield as crystals. Furthermore 3,3-dimethyl-4-{2-[4-(methyl-phenyl-carbamoyloxy)-phenyl]-ethylcarbamoyl}-butyric acid ethyl ester could be isolated in 27% yield as an oil (see characterization below)
1H NMR (400 MHz; CDCl3): δ 1.04 (s, 6H), 2.47 (s, 4H), 2.79 (t, 2H), 3.42 (br s, 3H), 3.97 (t, 2H), 7.03 (br d, 2H), 7.21-7.28 (m, 3H), 7.33-7.41 (m, 4H).
HPLC-MS: m/z=395.2 (M+1); Rt=4.23 min.
Example 566
3,3-Dimethyl-4-{2-[4-(methyl-phenyl-carbamoyloxy)-phenyl]-ethylcarbamoyl}-butyric acid ethyl ester
For experimental details, see preparation of methyl-phenyl-carbamic acid 4-[2-(4,4-dimethyl-2,6-dioxo-piperidin-1-yl)-ethyl]-phenyl ester.
1H NMR (400 MHz; CDCl3): δ 1.05 (s, 6H), 1.24 (t, 3H), 2.19 (s, 2H), 2.22 (s, 2H), 2.80 (t, 2H), 3.42 (br s, 3H), 3.50 (q, 2H), 4.1 (q, 2H), 6.53 (t, 1H), 7.03 (br d, 2H), 7.18 (d, 2H), 7.26 (t, 1H), 7.33-7.41 (m, 4H).
HPLC-MS: m/z=441.2 (M+1); Rt=4.11 min.
Example 567
Methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester
To a solution of 4-hydroxymethylphenol (10 mmol) and 4-diazabicyclo[2.2.2]octane (DABCO) (10 mmol) in CH2Cl2 (30 mL) was added N-methyl-N-phenylcarbamoyl chloride (10 mmol).
The reaction mixture was stirred for 16 hours at rt, added CH2Cl2 (20 mL) and washed with 1M aqueous HCl and brine. The organic phase was dried (MgSO4) and evaporated to give the crude product which was purified by FC (Quad flash 40 EtOAc-Heptane 1:1) to give 2.18 g (85%) of the title compound as an oil.
1H NMR (400 MHz; CDCl3): δ 1.70 (br s, 1H), 3.40 (br s, 3H), 4.66 (s, 2H), 7.08 (br d, 2H), 7.25-7.42 (m, 7H); HPLC-MS: m/z=258.1 (M+1); Rt=2.99 min.
Example 568
Methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester
To a solution of 4-(2-Hydroxyethyl)phenol (10 mmol) and 4-diazabicyclo[2.2.2]octane (DABCO) (10 mmol) in CH2Cl2 (30 mL) was added N-methyl-N-phenylcarbamoyl chloride (10 mmol). The reaction mixture was stirred for 16 hours at rt, added CH2Cl2 (20 mL), and washed with 1M aqueous HCl and brine. The organic phase was dried (MgSO4) and evaporated to give the 2.69 g (99%) of the title compound as crystals.
1H NMR (400 MHz; CDCl3): δ 1.52 (br s, 1H), 2.84 (t, 2H), 3.41 (br s, 3H), 3.81 (t, 2H), 7.04 (br d, 2H), 7.20 (d, 2H), 7.22-7.42 (m, 5H); HPLC-MS: m/z=272.1 (M+1); Rt=3.17 min.
Example 569
General Procedure 1
Methyl-phenyl-carbamic acid 4-(4-dimethylamino-pyridin-2-ylmethyl)-phenyl ester
A solution of 2-(dimethylamino)ethanol (32 mmol) in hexane (120 mL) was cooled to −5° C. and n-BuLi (64 mmol) was added. After 30 min 4-(dimethylamine=pyridine (16 mmol) was added and the red-orange mixture was stirred for further 1 h. The solution was cooled to −78° C. and 4-(trimethylsilyloxy)benzaldehyde (40 mmol) dissolved in hexane (80 mL) was added and the suspension was allowed to warm to rt over 20 min. The reaction mixture was quenched with water, and the aqueous phase was washed with CH2Cl2. The aqueous phase was evaporated to dryness, added Nal (96 mmol) and dissolved in MeCN (160 mL). Addition of trimethylsilylchloride (96 mmol) and stirring at rt for 16 h. The purple reaction mixture was evaporated to dryness and treated with an aqueous solution of Na2SO3 and pH was adjusted to 8. Extraction with CH2Cl2 gave after evaporation 560 mg (15%) slightly impure 4-(4-dimethylamino-pyridin-2-ylmethyl)phenol as yellow crystals. This was carbamoylated using general procedure 1 (CH2Cl2 was used as solvent) to give the title product as its hydrochloride after purification by preparative HPLC (Gilson) and treatment with HCl in Et2O (48%, light yellow crystals).
HPLC-MS: m/z=362.2 (M+1); Rt=2.27 min.
Example 570
General Procedure 25
Methyl-phenyl-carbamic acid 4-(4-imidazol-1-yl-phenoxymethyl)-phenyl ester
The title compound was prepared in 53% yield as light yellow crystals using and 4-imidazol-1-yl-phenol. 1H NMR (400 MHz; CDCl3): δ 3.42 (br s, 3H), 5.08 (s, 2H), 7.03 (d, 2H), 7.12-7.42 (m, 15H), 7.77 (s, 1H); HPLC-MS: m/z=400.1 (M+1); Rt=2.62 min.
Example 571
General Procedure 25
Methyl-phenyl-carbamic acid 4-[4-(2-dimethylamino-ethyl)-phenoxymethyl]-phenyl ester
The title compound was prepared in 52% yield as colorless crystals using methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester and 4-(2-dimethylaminoethyl)-phenol. 1H NMR (400 MHz; CDCl3): δ 2.85 (s, 6H), 2.98-3.02 (m, 2H), 3.17-3.21 (m, 2H), 3.42 (br s, 3H), 5.02 (s, 2H), 6.90 (d, 2H), 7.12 (d, 2H), 7.25-7.43 (m, 7H); HPLC-MS: m/z=405.2 (M+1); Rt=2.91 min.
Example 572
General Procedure 25
Methyl-phenyl-carbamic acid 4-(pyrazol-1-yloxymethyl)-phenyl ester
The title compound was prepared in 79% yield as an oil using and 1-hydroxypyrazole. 1H NMR (400 MHz; CDCl3): δ 3.42 (br s, 3H), 5.26 (s, 2H), 6.03 (t, 1H), 6.95 (dd, 1H), 7.11 (br s, 2H), 7.25-7.42 (m, 8H); HPLC-MS: m/z=324.1 (M+1); Rt=3.58 min.
Example 573
General Procedure 25
Methyl-phenyl-carbamic acid 4-(imidazol-1-yloxymethyl)-phenyl ester
The title compound was prepared as its TFA salt in 87% yield as a solid using methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester and 1-hydroxyimidazole, hydrochloride. 1H NMR (400 MHz; CDCl3): δ 3.42 (br s, 3H), 5.21 (s, 2H), 6.95 (s, 1H), 7.16-7.45 (m, 10H), 8.28 (br s, 1H); HPLC-MS: m/z=324.1 (M+1); Rt=1.92 min.
Example 574
General Procedure 25
Methyl-phenyl-carbamic acid 4-(2-oxo-2H-pyridin-1-ylmethyl)-phenyl ester
The title compound was prepared in 29% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and 2-hydroxypyridine. In addition 50% of the isomeric methyl-phenyl-carbamic acid 4-[2-(pyridin-2-yloxy)-ethyl]-phenyl ester was isolated, see characterization below. 1H NMR (400 MHz; CDCl3): δ 3.05 (t, 2H), 3.41 (br s, 3H), 4.14 (s, 2H), 6.08 (t, 1H), 6.66 (d, 1H), 6.90 (dd, 1H), 7.02 (br s, 2H), 7.10 (d, 2H), 7.25-7.42 (m, 6H); HPLC-MS: m/z=349.2 (M+1); Rt=3.04 min.
Example 575
General Procedure 25
Methyl-phenyl-carbamic acid 4-[2-(pyridin-2-yloxy)-ethyl]-phenyl ester
The title compound was prepared in 50% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and 2-hydroxypyridine. In addition 29% of the isomeric methyl-phenyl-carbamic acid 4-(2-oxo-2H-pyridin-1-ylmethyl)-phenyl ester was isolated, see characterization above. 1H NMR (400 MHz; CDCl3): δ 3.08 (t, 2H), 3.41 (br s, 3H), 4.49 (s, 2H), 6.73 (d, 1H), 6.88 (dd, 1H), 7.05 (br d, 2H), 7.22-7.42 (m, 7H), 7.61 (dt, 1H), 8.18 (dd, 1H); HPLC-MS: m/z=349.2 (M+1); Rt=3.97 min.
Example 576
General Procedure 25
Methyl-phenyl-carbamic acid 4-[2-(4-imidazol-1-yl-phenoxy)-ethyl]-phenyl ester
The title compound was prepared as its TFA salt in 62% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and 4-imidazol-1-yl-phenol.
1H NMR (400 MHz; CDCl3): δ 3.11 (t, 2H), 3.42 (br s, 3H), 4.22 (s, 2H), 7.00-7.10 (m, 5H), 7.25-7.42 (m, 9H), 7.52 (s, 1H), 8.81 (s, 1H); HPLC-MS: m/z=414.2 (M+1); Rt=2.73 min.
Example 577
General Procedure 25
Methyl-phenyl-carbamic acid 4-{2-[4-(2-dimethylamino-ethyl)-phenoxy]-ethyl}-phenyl ester
The title compound was prepared as its TFA salt in 92% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and 4-(2-dimethylaminoethyl)-phenol.
HPLC-MS: m/z=419.2 (M+1); Rt=2.77 min.
Example 578
General Procedure 25
Methyl-phenyl-carbamic acid 4-[2-(pyrazol-1-yloxy)-ethyl]-phenyl ester
The title compound was prepared in 62% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and 1-hydroxypyrazole.
1H NMR (400 MHz; CDCl3): δ 3.02 (t, 2H), 3.42 (br s, 3H), 4.50 (t, 2H), 6.16 (t, 1H), 7.05 (br d, 2H), 7.20-7.41 (m, 9H); HPLC-MS: m/z=338.2 (M+1); Rt=3.74 min.
Example 579
General Procedure 25
Methyl-phenyl-carbamic acid 4-[2-(imidazol-1-yloxy)-ethyl]-phenyl ester
The title compound was prepared as its TFA salt in 79% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and 1-hydroxyimidazole hydrochloride.
1H NMR (400 MHz; CDCl3): δ 3.06 (t, 2H), 3.42 (br s, 3H), 4.52 (t, 2H), 7.08-7.42 (m, 11H), 8.53 (s, 1H); HPLC-MS: m/z=338.2 (M+1); Rt=2.18 min.
Example 580
General Procedure 1
Methyl-phenyl-carbamic acid 4-(5-methyl-pyridin-2-ylmethyl)-phenyl ester
To a stirred solution of 2-bromo-5-methylpyridine (3.45 g, 20 mmol) in THF (10 mL) was added dropwise 1.6 M solution in hexanes n-BuLi (12 mL, 19.2 mmol) over a 10-min period at −78° C. The mixture was stirred at −78° C. for 2 min before 4-trimethylsilyloxybenzaldehyde (4.2 g, 21.6 mmol) dissolved in THF (10 mL) was added. The mixture was allowed to warm to −40° C. and quenched with water. The pH of the aqueous phase was adjusted to 7 which causes precipitation of 4-[hydroxy-(5-methyl-pyridin-2-yl)-methyl]phenol. This was isolated by filtration to give 1.13 g (27%) of 4-[hydroxy-(5-methyl-pyridin-2-yl)-methyl]phenol as crystals. This intermediate was dissolved in CH2Cl2 (15 mL) and stirred with triethylsilane (4 mL) and TFA (5 mL) for 16 h at 50° C. Evaporation gave 99% of 4-(5-methyl-pyridin-2-ylmethyl)phenol as a hygroscopic solid. This was carbamoylated using general procedure 1 (CH2Cl2 was used as solvent and N-phenyl-N-methyl carbamoyl chlorid) to give 99% of the title product as its crystalline hydrochloride after purification by flash chromatography (Quad flash 12, EtOAc-heptane) and treatment with HCl in Et2O.
1H NMR (400 MHz; CDCl3): δ 2.50 (s, 3H), 3.41 (br s, 3H), 4.57 (s, 2H), 7.10 (br s, 2H), 7.25-7.42 (m, 8H), 8.00 (dd, 1H), 8.46 (br s, 1H); HPLC-MS: m/z=333.1 (M+1); Rt=2.60 min.
Example 581
General Procedure 24
4-Hydroxy-piperidine-1-carboxylic acid 4-(5-methyl-pyridin-2-ylmethyl)-phenyl ester
The title compound was prepared as its hydrochloride using of 4-(5-methyl-pyridin-2-ylmethyl)phenol as the phenol.
1H NMR (300 MHz; CDCl3): δ 1.57-1.67 (m, 3H), 1.95 (d, 2H), 2.51 (s, 3H), 3.21-3.40 (m, 2H), 3.90-4.05 (m, 3H), 4.58 (s, 2H), 7.11 (d, 2H), 7.38 (d, 2H), 7.45 (d, 1H), 8.02 (d, 1H), 8.48 (br s, 1H).
Example 582
General Procedure 25
Methyl-phenyl-carbamic acid 4-(4-oxo-4H-pyridin-1-ylmethyl)-phenyl ester
The title compound was prepared in 33% yield as colorless crystals using methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester and 4-hydroxypyridine. 1H NMR (400 MHz; CDCl3): δ 3.43 (br s, 3H), 4.92 (s, 2H), 6.43 (d, 2H), 7.17 (br s, 4H), 7.22-7.42 (m, 9H); HPLC-MS: m/z=335.0 (M+1); Rt=2.55 min.
Example 583
General Procedure 25
Methyl-phenyl-carbamic acid 4-[2-(pyridin-3-yloxy)-ethyl]-phenyl ester
The title compound slightly contaminated with tributylphosphine oxide was prepared in 80% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and 3-hydroxypyridine.
1H NMR (400 MHz; CDCl3): δ 3.11 (t, 2H), 3.42 (br s, 3H), 4.23 (t, 2H), 7.07 (br d, 2H), 7.24-7.41 (m, 9H), 8.29 (br s, 1H), 8.40 (br s, 1H); HPLC-MS: m/z=349.2 (M+1); Rt=2.87 min.
Example 584
General Procedure 25
Methyl-phenyl-carbamic acid 4-(2-oxo-2H-pyridin-1-ylmethyl)-phenyl ester
The title compound was prepared in 66% yield as an oil using methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester and 2-hydroxypyridine. 1H NMR (400 MHz; CDCl3): δ 3.42 (br s, 3H), 5.12 (s, 2H), 6.13 (t, 1H), 6.60 (d, 1H), 7.10 (br s, 2H), 7.22-7.41 (m, 9H); HPLC-MS: m/z=335.2 (M+1); Rt=2.97 min.
Example 585
General Procedure 25
Methyl-phenyl-carbamic acid 4-(pyridin-3-yloxymethyl)-phenyl ester
The title compound was prepared in 43% yield as an oil using methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester and 3-hydroxypyridine. 1H NMR (400 MHz; CDCl3): δ 3.44 (br s, 3H), 5.12 (s, 2H), 7.17 (br s, 2H), 7.27-7.46 (m, 9H), 8.29 (br s, 1H), 8.49 (br s, 1H); HPLC-MS: m/z=335.0 (M+1); Rt=2.74 min.
Example 586
General Procedure 26
Methyl-phenyl-carbamic acid 4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethyl]-phenyl ester
The title compound was prepared in 85% yield as crystals using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and succinimide. 1H NMR (400 MHz; CDCl3): δ 2.65 (s, 4H), 2.86 (t, 2H), 3.41 (br s, 3H), 3.72 (t, 2H), 7.04 (br d, 2H), 7.19 (d, 2H), 7.26-7.42 (m, 5H); HPLC-MS: m/z=353.2 (M+1); Rt=3.17 min.
Example 587
General Procedure 26
Methyl-phenyl-carbamic acid 4-[2-(1,3-dioxo-1,3-dihydro-pyrrolo[3,4-]pyridin-2-yl)-ethyl]-phenyl ester
The title compound was prepared in 58% yield as crystals using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and 3,4-pyridinedicarboximide. 1H NMR (400 MHz; CDCl3): δ 2.98 (t, 2H), 3.40 (br s, 3H), 3.93 (t, 2H), 7.05 (br d, 2H), 7.20-7.42 (m, 7H), 7.73 (dd, 1H), 9.06 (d, 1H), 9.12 (d, 1H); HPLC-MS: m/z=402.1 (M+1); Rt=3.56 min.
Example 588
General Procedure 26
Methyl-phenyl-carbamic acid 4-(1-methyl-1H-imidazol-2-ylsulfanylmethyl)-phenyl ester
The title compound was prepared as its TFA salt in 22% yield as an oil using methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester and 2-mercapto-1-methylimidazole. 1H NMR (400 MHz; CDCl3): δ 3.34 (s, 3H), 3.40 (br s, 3H), 4.30 (s, 2H), 6.98 (br s, 2H), 7.08-7.11 (m, 3H), 7.27-7.42 (m, 5H), 7.48 (d, 1H); HPLC-MS: m/z=354.1 (M+1); Rt=2.12 min.
Example 589
General Procedure 26
Methyl-phenyl-carbamic acid 4-tetrazol-1-ylmethyl-phenyl ester
The title compound was prepared in 6% yield as an oil using methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester and tetrazole. 1H NMR (400 MHz; CDCl3): δ 3.42 (br s, 3H), 5.57 (s, 2H), 7.17 (br s, 2H), 7.26-7.42 (m, 7H), 8.52 (s, 1H); HPLC-MS: m/z=332.0 (M+23); Rt=3.24 min.
Example 590
General Procedure 26
Methyl-phenyl-carbamic acid 4-(2,5-dioxo-pyrrolidin-1-ylmethyl)-phenyl ester
The title compound was prepared in 57% yield as beige crystals using methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester and succinimide. 1H NMR (400 MHz; CDCl3): δ 2.68 (s, 4H), 3.41 (br s, 3H), 4.60 (s, 2H), 7.04 (br d, 2H), 7.23-7.41 (m, 7H); HPLC-MS: m/z=339.1 (M+1); Rt=3.40 min.
Example 590
General Procedure 26
Methyl-phenyl-carbamic acid 4-[2-(2-thioxo-2H-pyridin-1-yl)-ethyl]-phenyl ester
The title compound was prepared in 25% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and 2-mercaptopyridine. HPLC-MS: m/z=365.2 (M+1); Rt=4.08 min.
Example 591
General Procedure 26
Methyl-phenyl-carbamic acid 4-(1,3-dioxo-1,3-dihydro-pyrrolo[3,4]pyridin-2-ylmethyl)-phenyl ester
The title compound was prepared in 21% yield as an oil using methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester and 3,4-pyridinedicarboximide. 1H NMR (400 MHz; CDCl3): δ 3.40 (br s, 3H), 4.82 (s, 2H), 7.06 (d, 2H), 7.22-7.44 (m, 8H), 7.73 (d, 1H), 9.04 (d, 1H), 9.12 (s, 1H); HPLC-MS: m/z=388.0 (M+1); Rt=3.80 min.
Example 592
General Procedure 26
Methyl-phenyl-carbamic acid 4-[1,2,4]triazol-1-ylmethyl-phenyl ester
The title compound was prepared as its TFA salt in 27% yield as an oil using methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester and 1,2,4-triazole. 1H NMR (400 MHz; CDCl3): δ 3.42 (br s, 3H), 5.34 (s, 2H), 7.15 (br d, 2H), 7.26-7.43 (m, 7H), 8.10 (s, 1H), 8.38 (s, 1H); HPLC-MS: m/z=309.1 (M+1); Rt=2.74 min.
Example 593
General Procedure 26
Methyl-phenyl-carbamic acid 4-(2-thioxo-2H-pyridin-1-ylmethyl)-phenyl ester
The title compound was prepared in 14% yield as an oil using methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester and 2-mercaptopyridine. HPLC-MS: m/z=351.1 (M+1); Rt=3.95 min.
Example 594
General Procedure 26
Methyl-phenyl-carbamic acid 4-[2-(1-methyl-1H-imidazol-2-ylsulfanyl)-ethyl]-phenyl ester
The title compound was prepared as its TFA salt in 37% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and 2-mercapto-1-methylimidazole. NMR (400 MHz; CDCl3): δ 3.01 (t, 2H), 3.40 (br s, 3H), 3.47 (s, 1H), 3.64 (t, 2H), 6.92 (br d, 2H), 6.98 (s, 1H), 7.08 (d, 2H), 7.26-7.43 (m, 6H); HPLC-MS: m/z=368.2 (M+1); Rt=2.30 min.
Example 595
General Procedure 26
Methyl-phenyl-carbamic acid 4-(2-tetrazol-1-yl-ethyl)-phenyl ester
The title compound was prepared in 10% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and tetrazole. NMR (400 MHz; CDCl3): δ 3.19 (t, 2H), 3.40 (br s, 3H), 3.47 (s, 1H), 4.61 (t, 2H), 6.98-7.07 (m, 4H), 7.25-7.42 (m, 5H), 8.26 (s, 1H); HPLC-MS: m/z=324.1 (M+1); Rt=3.36 min.
Example 596
General Procedure 26
Methyl-phenyl-carbamic acid 4-[2-(pyrimidin-2-yloxy)-ethyl]-phenyl ester
The title compound was prepared in 24% yield as light yellow crystals using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and 2-hydroxypyrimidine. NMR (400 MHz; CDCl3): δ 3.11 (t, 2H), 3.42 (br s, 3H), 4.54 (t, 2H), 6.93 (t, 1H), 7.05 (d, 2H), 7.25-7.42 (m, 7H), 8.51 (d, 2H); HPLC-MS: m/z=350.2 (M+1); Rt=2.86 min.
Example 597
General Procedure 26
Methyl-phenyl-carbamic acid 4-[2-(pyridin-4-ylsulfanyl)-ethyl]-phenyl ester
The title compound was prepared as its TFA salt in 5% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and 4-mercaptopyridine. NMR (400 MHz; CDCl3): δ 3.07 (t, 2H), 3.36 (t, 2H), 3.44 (br s, 3H), 7.06 (br d, 2H), 7.20 (d, 2H), 7.25-7.43 (m, 7H), 8.51 (d, 2H); HPLC-MS: m/z=365.2 (M+1); Rt=2.53 min.
Example 598
General Procedure 12
4-(3-Amino-phenyl)-pipendine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin2-yloxy)-phenyl ester,
The title product was prepared from 4-(3-aminophenyl)piperidine (released form the correspondent hydrochloride by a standard procedure) and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, preparative HPLC (method C) (reaction performed in a mixture of dichloromethane and dimethylformamide, 5:3). 1.7 M HCl in ethyl acetate was added to the pooled fractions containing the title product, and the fractions was evaporated to dryness (7%, light yellow solid). HPLC-MS m/z=(M+1) 458.0, Rt: 3.09 min.
Example 599
General Procedure 26
Methyl-phenyl-carbamic acid 4-[2-(1-pyridin-3-yl-1H-imidazol-2-ylsulfanyl)-ethyl]-phenyl ester
The title compound was prepared as its TFA salt in 5% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and 3-(2thio-1H-imidazol-1-yl)pyridine. NMR (400 MHz; CDCl3): δ 2.95 (t, 2H), 3.42 (br s, 2H), 3.56 (t, 3H), 6.98 (br d, 2H), 7.05 (d, 2H), 7.15 (d, 1H), 7.23-7.43 (m, 5H), 7.48 (d, 1H), 7.53 (dd, 1H), 7.70 (ddd, 1H), 8.65 (d, 1H), 8.77 (dd, 1H); HPLC-MS: m/z=431.2 (M+1); Rt=2.79 min.
Example 600
General Procedure 26
Methyl-phenyl-carbamic acid 4-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-phenyl ester
The title compound was prepared in 39% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and isoindole-1,3-dione. NMR (400 MHz; CDCl3): δ 2.98 (t, 2H), 3.41 (br s, 2H), 3.89 (t, 3H), 7.04 (br d, 2H), 7.20-7.40 (m, 7H), 7.68-7.71 (m, 2H), 7.80-7.83 (m, 2H); HPLC-MS: m/z=401.1 (M+1); Rt=4.41 min.
Example 601
4-Phenyl-piperidine-1-carboxylic acid 4-(5-methyl-pyridin-2-ylmethyl)-phenyl ester
To a solution of 4-(5-methyl-pyridin-2-ylmethyl)phenol (0.8 mmol) prepared as described above and ethyldiisopropylamine (1.5 mmol) in CH2Cl2 (5 mL) at −30° C. was added trichloromethyl chloroformate (1.0 mmol). The solution was stirred at −30° C. for 10 min and at reflux temperature for 2 h. The solution was evaporated to dryness and redissolved in CH2Cl2 (5 mL) and cooled to 0° C. before addition of 4-phenylpiperidine (1.5 mmol). The solution was stirred at room temperature for 16 h evaporated to give the crude product which was purified by FC (Quad flash 40 CH2Cl2:Et2O:Heptane:Et3N 1:1:2:0.25->1:1:1:0.25) to give the title compound in 28% yield as an oil.
1H NMR (400 MHz; CDCl3): δ 1.70-1.80 (m, 2H), 1.91 (br d, 2H), 2.29 (s, 3H), 2.72 (tt, 1H), 2.94 (br t, 1H), 3.08 (br t, 1H), 4.10 (s, 2H), 4.42 (br s, 1H), 7.00 (d, 1H), 7.06 (d, 2H), 7.21-7.26 (m, 5H), 7.32 (d, 2H), 7.38 (dd, 1H), 8.37 (d, 1H); HPLC-MS: m/z=387.2 (M+1); Rt=2.95 min.
Example 602
4-(4-Methoxy-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid 4-(5-methyl-pyridin-2-ylmethyl)-phenyl ester
To a solution of 4-(5-methyl-pyridin-2-ylmethyl)phenol (0.8 mmol) prepared as described above and ethyldiisopropylamine (1.5 mmol) in CH2Cl2 (5 mL) at −30° C. was added trichloromethyl chloroformate (1.0 mmol). The solution was stirred at −30° C. for 10 min and at reflux temperature for 2 h. The solution was evaporated to dryness and redissolved in CH2Cl2 (5 mL) and cooled to 0° C. before addition of 4-(4-methoxyphenyl)-1,2,3,6-tetrahydro-pyridine (1.5 mmol). The solution was stirred at room temperature for 16 h evaporated to give the crude product which was purified by FC (Quad flash 40 CH2Cl2:Et2O:Heptane:Et3N 1:1:2:0.25->1:1:1:0.25) to give the title compound in 10% yield as colorless crystals.
1H NMR (400 MHz; CDCl3): δ 2.30 (s, 3H), 2.60 (br s, 2H), 3.75-3.88 (m, 5H), 4.12 (s, 2H), 4.20 (br s, 1H), 4.30 (br s, 1H), 5.98 (br s, 1H), 6.88 (d, 2H), 7.00 (d, 1H), 7.07 (d, 2H), 7.24 (d, 2H), 7.34 (d, 2H), 7.39 (dd, 1H), 8.38 (d, 1H); HPLC-MS: m/z=415.3 (M+1); Rt=2.95 min.
Pharmacological Methods
Compounds of formula I may be evaluated in vitro for their efficacy and potency to inhibit HSL, and such evaluation may be performed as described below.
Assays
Hormone-sensitive Lipase (HSL)
Materials. The Hormone-sensitive lipase was provided by Dr. Cecilia Holm, from Lund University Sweden or produced and purified by Novo Nordisk (NN) using the reagents and protocols used by Dr. Holm. The substrates used are: 3H-labeled triolein (TO) from Amersham, Buckinghamshire, U.K. cat No. TRA191; 5-20 Ci/mmol dissolved in toluene, triolein (Sigma, Cat. No. T-1740), fluorochrome-labeled triacylglyceride (cis-octadec-9-enoic acid 2-[12-(7-nitrobenzo[12,5]oxadiazol-4-ylamino)dodecanoyloxy]-1-cis-octadec-9-enoyloxymethyl-ethyl ester) prepared by Novo Nordisk (NN) by conventional methods, and 1,3-(di[3H]-stearin), 2-(PEG-Biotin)glycerol prepared in collaboration with Amersham Pharmacia Biotech, UK and described in WO 01/073442. Phosphatidyl choline (PC) and phosphatidyl inositol (PI) are from Sigma (St Luis MO cat. Nos. P-3556 and P-5954 respectively). All other reagents are of commercial grade and obtained from various commercial sources.
Methods.
3180.1: Assay for determination of inhibitor IC50 values.
A lipid emulsion with 3H-Triolein and phospholipid is used as substrate with a standard cencentration of highly purified HSL. BSA is added as product receptor. The substrate is prepared as follows:
30 μl PC:PI (20 mg/ml solution of PC:PI 3:1 prepared in chloroform)+128 μl cold TO+15 μl 3H-TO are mixed and then evaporated under a gentle stream of N2 followed by 20-30 minutes in a Speedvac to ensure the absence of residual solvent.
Compound and HSL are incubated for 30 min at 25° C. before addition of substrate. Reaction is stopped after 30 min at 25° C. by adding a mixture of methanol, chloroform and heptane at high pH. Formed product is separated from substrate by phase separation.
Standard concentrations of compound are 100 μM, 20 μM, 4 μM, 0.8 μM, 0.16 μM and 0.032 μM (sample concentrations).
Results are given as IC50 values after 4PL fit of obtained activity data.
3180.2: Assay for determination of percent inhibition by compound at 10 μM concentration. A lipid emulsion with 3H-Triolein and phospholipid is used as substrate with a standard cencentration of highly purified HSL. BSA is added as product receptor. The substrate is prepared as follows:
30 μl PC:PI (20 mg/ml solution of PC:PI 3:1 prepared in chloroform)+128 μl cold TO+15 μl 3H-TO are mixed and then evaporated under a gentle stream of N2 followed by 20-30 minutes in a Speedvac to ensure the absence of residual solvent.
Compound and HSL are incubated for 30 min at 25° C. before addition of substrate. Reaction is stopped after 30 min at 25° C. by adding a mixture of methanol, chloroform and heptane at high pH. Formed product is separated from substrate by phase separation.
Results are given as percent activity relative to an un-inhibited sample (no compound).
3190.1: Assay for determination of percent inhibition of hormone sensitive lipase by compound at 10 μM sample concentration.
A lipid emulsion with fluorochrome-labeled triacylglyceride and phospholipid is used as substrate with a standard concentration 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 the fluorochrome from the lipid phase to the water (BSA) phase changes the fluorescent properties of the fluorochrome. The changes can be monitored on a fluorimeter with an excitation wavelength of 450 nm and an emission wavelength of 545 nm.
Compound and HSL (20 μL compound, 10 μL enzyme and 70 μL PED-BSA buffer) is preincubated for 30 min at 25° C. before addition of substrate (100 μL). Amount of formed product is measured after 120 min incubation at 37° C.
Results are given as percent activity relative to a non-inhibited sample (no compound).
3190.2: Assay for determination of IC50 value for the inhibition of hormone sensitive lipase by compound. Standard concentrations of compound are 100 μM and 5-fold dilutions (initial concentration corresponding to 10 μM final concentration and 5-fold).
A lipid emulsion with fluorochrome-labeled triacylglyceride and phospholipid is used as substrate with a standard concentration 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 the fluorochrome from the lipid phase to the water (BSA) phase changes the fluorescent properties of the fluorochrome. The changes can be monitored on a fluorimeter with an excitation wavelength of 450 nm and an emission wavelength of 545 nm.
Compound and HSL (20 μL compound, 10 μL enzyme and 70 μL PED-BSA buffer) is preincubated for 30 min at 25° C. before addition of substrate (100 μL). Amount of formed product is measured after 120 min incubation at 37° C.
Results are given as IC50 values after 4PL fit of obtained activity data.
2848.2: This high-volume screening assay uses para-nitrophenyl butyrate (p-NPB) as substrate for HSL.HSL cleaves p-NPB and the reaction is monitored as an increase in the concentration of para-nitrophenol (p-NP). p-NP can be monitored as an increase in UV-absorbance at 405 nm. The reaction is carried out at room-temp. for 20 min. The action is not stopped, but instead UV-abs is measured at a fixed time (20 min.) Due to autohydrolysis of the substrate the reaction is read at t=0 min. too and t=20 min. and the increase in Abs is calculated as the difference-between the two readings; When a compound that inhibits HSL is present, it results in a relative decrease in UV-absorbance.

% Eff(% Inhibition)=(S−S0Eff)/(SmaxEff−S0Eff)×100

Where S=signal in UV-abs., S0Eff=assaybuffer alone, SmaxEff=Assaybuffer with the lipase inhibitor.

2898.2: This method is an enzyme assay based upon SPA (scintillation proximity assay) particles. The substrate, 1,3-(di-[3H]-stearin), 2-(PEG-Biotin)-glycerol, is marked with 3H in both fatty acid moieties in the tri-glyceride. The third moiety of the tri-glyceride is a PEG linked Biotin. The substrate binds through Biotin to streptavidin in the SPA particles and the proximity between the radioactive tritium in the stearic acid moiety and the SPA particle results in emission of light from the SPA particles. The assay is an on-bead assay where HSL degrades the substrate, where after 3H-stearin acid is released from the bead. The amount of light emitted is proportional to the amount of substrate bound to the receptor. When a compound that inhibits the activity of HSL is present it results in a decrease in degradation of the substrate and thus an increase in the amount of light emitted and a concomitant increase in % Eff.

% Eff(% Inhibition)=(S−S0Eff)/(SmaxEff−S0Eff)×100

Where S=signal in dpm., SOEff=no inhibitor added, SmaxEff=with maximum concentration of inhibitor.

Results

With these methods the following results were obtained for the compounds of the examples.















Test 3190.1
Test 3180.2
Test 2898.2
Test 2848.2


Compound
HSL_FL 
HSL %
HSL-2
HSL


according to
% ACTIVITY
ACTIVITY
% Inhibition
% Inhibition


example #
All
All
All
All



















120

40




122

14


123

22


121

24


118

24


119

10


47
42


46
43


11
17


87
48


81
36


48
15


61
23


6
49


85
88


90
24


54
52


62
88


59
16


24
30


20
51


92

62


73
39


109



15.9


106



23.8


108



37.2


114



42.4


126



33


110



18.8


111



36.2


107



59.9


105



26.8


104



19.8


127



58.7


128



33.8


103

2
101.4


115

85
73.6


113


18.3


129



27


112


86


116



23.5


124


75.1


117

2


130



30.1


131



21.6


132



19.6


133


15.8


144
25

## Claims

1. A compound of formula



wherein E is selected from the group consisting of —S—, —S(═O)—, —S(═O)2—, —NR16ae— and —CR17aeR18ae—; and
R4ae, R5ae, R6ae, R7ae, R8ae, R9ae, R10ae, R11ae, R12ae, R13ae, R14ae, and R15ae are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaxyl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyolyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, suifanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cyeloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
R16ae is independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
R7ae and R18ae are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalamethoxy; or
a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein at least one of R8ae, R9ae, R10ae, R11ae, R12ae, R13ae, R14ae and R15ae is selected from F, Cl, C1-6-alkyl, C1-6-alkoxy, C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.

3. A compound of formula




wherein R4af, R5af, R6af, R7af, R8af, R9af, R10af, R11af, R12af, R13af, R14af and R15af are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
R16af is selected from hydrogen, hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; with the proviso that R16af is not methyl; or
a pharmaceutically acceptable salt thereof.

4. The compound according to claim 3, wherein at least one of R8af, R9af, R10af, R11af, R12af, R13af, R14af and R15af is selected from F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.

5. A compound of the general formula



wherein E is selected from the group consisting of —S—, —S(═O)—, —S(═O)2— and —CR16agR17ag—; and
R4ag, R5ag, and R6ag, are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; with the proviso that R4ag is not —CH2—N(CH3)2; and
R7ag is selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy;
R8ag, R9ag, R14ag and R15ag are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
R10ag, R11ag, R12ag, and R13ag are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituenis independently selected from hydroxy, sulfhnyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; and
R16ag and R17ag are independently selected from hydrogen, hydroxy, sulfanyl, sulfo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, C3-8-heterocyclyl, and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, C3-8-heterocyclyl, C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heteracyclyl and C3-10-cycloalkyl, wherein each of the hydroxy, sulfanyl, amino, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, and C3-10-cycloalkyl may optionally be substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano, nitro, sulfo, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl, C3-10-cycloalkyl, perhalomethyl and perhalomethoxy; or
a pharmaceutically acceptable salt thereof.

6. The compound according to claim 5, wherein at least one of R8ag, R9ag, R10ag, R11ag, R12ag, R13ag, R14ag and R15ag are selected from F, Cl, C1-6-alkyl, C1-6-alkoxy, —C(═O)NH2, —NHC(═O)—OH, —S(═O)2—NH2, —NH—S(═O)2—OH, hydroxy, amino and perhalomethyl.

7. A compound selected from the group consisting of
4-(tert-Butyl-dimethyl-silanyloxy)-piperidine-1-carboxylic acid 5-benzoylamino-pyridin-2-yl ester,
4-Hydroxy-piperidine-1-carboxylic acid 5-benzoylamino-pyridin-2-yl ester,
4-Hydroxy-piperidine-1-carboxylic acid 5-trifluoromethyl-pyridin-2-yl ester,
4-Hydroxy-piperidine-1-carbaxylic acid 5-(4-chloro-benzoylamino)-pyridin-2-yl ester,
4-Hydroxy-piperidine-1-carboxylic acid 5-(3-methoxy-benzoylamino)-pyridin-2-yl ester,
4-Hydroxy-piperidine-1-carboxylic acid 5-(4-methoxy-benzoylamino)-pyridin-2-yl ester,
4-Hydroxy-piperidine-1-carboxylic acid 5-(2,4-dichloro-benzoylamino)-pyridin-2-yl ester,
4-Hydroxy-piperidine-1-carboxylic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-yl ester,
4-Hydroxy-piperidine-1-carboxylic acid 5-(5-trifluoromethyl-pyridin-2-yloxy)-pyridin-2-yl ester,
4-Hydroxy-piperidine-1-carboxylic acid 5-(3,5-dichloro-pyridin-2-yloxy)-pyridin-2-yl ester, and
Piperidine-1-carboxylic acid 4,4-dimethyl-2,6-dioxo-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-yl ester; or
a pharmaceutically acceptable salt thereof.

8. The compound according to any one of claims 1, 3, 5, or 7, which has a solubility in water of at least 0.5 mg/L as determined at 25° C. and pH 7.0.

9. The compound according to any one of claims 1, 3, 5, or 7, which has a solubility in water of at least 0.5 mg/L as determined at 25° C. and pH 2.0.

10. The compound according to any one of claims 1, 3, 5, or 7, which has an IC50 value of no greater than 5 μM.

11. The compound according to claim 10, which has an IC50 value of less than 1 μM.

12. The compound according to any one of claims 1, 3, 5, or 7, which is ionized at pH 7.0

13. The compound according to claim 12, which has a pKa in the range from 8 to 12.

14. The compound according to any one of claims 1, 3, 5, or 7, which has a molar weight of no greater than 1000 D.

15. The compound according to claim 14, which has a molar weight of less than 750 D.

16. A process for the preparation of a compound according to any one of claims 1, 3, 5, or 7, or its pharmaceutically acceptable salt, which comprises reacting the appropriate alcohol, Rz-OH, with the appropriate carbamoylating reagent, Lv-C(═O)—NRxRy, in a solvent according to the reaction scheme P1



and isolating the disubstituted carbamate product.

17. The process according to claim 16, wherein said carbamoylating reagent



is selected from the group consisting of

18. The process according to any one of claim 16, wherein said solvent is selected from the group consisting of tetrahydrofurane, dimethylformamide and N-methylpyrolidone.

19. The process according to any one of claim 16, wherein said base is selected from the group consisting of triethylamine, N,N-diisopropyl-N-ethylamine and DABCO.

20. A process for the preparation of a compound according to formula



wherein R1 is selected from C1-6-alkyl, C2-6-alkenyl and C3-10-cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, oxo, halogen, amino, cyano and nitro; and
R2 is selected from C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, each of which is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, perhalomethyl and perhalomethoxy; and
wherein R2 is optionally covalently bound to R1 by an ether, thioether, C—C or C—N bond, to form a ring system with the N-atom to which R1 and R2 are bound; and
R3 is —O-pyridyl, which is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl, wherein each of hydroxy, sulfanyl, sulfo, amino, C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl, C3-8-heterocyclyl and C3-10-cycloalkyl is optionally substituted with one or more substituents independently selected from hydroxy, sulfanyl, sulfo, oxo, halogen, amino, cyano, nitro, C1-6-alkyl, C2-6-alkenyl, perhalomethyl and perhalomethoxy; and
X is O;
and wherein the compound is a compound according to any one of claims 1, 3, 5, or 7; or
a pharmaceutically acceptable salt thereof;
said process comprising the treatment of the appropriate amine, R1—NH—R2, with the appropriate acylating reagent, Y—C(═X)—R3, in a solvent and in the presence of a base according to the reaction scheme P2

21. The process according to claim 20, wherein Y is Cl.

22. The process according to claim 19, wherein R3 is an aryloxy group.

23. The process according to claim 20, wherein said solvent is selected from the group consisting of diethyl ether, tetrahydrofuran and dichloromethane.

24. The process according to claim 20, wherein said base is selected from the group consisting of trimethylamine, triethylamine, ethyl-diisopropyl-amine and 1,4-diazabicyclo[2.2.2]octane.

25. The process according to claim 20, wherein said base is present as a functionality in one or both of the substituents R1 and R2, thus forming a salt with the acid H—Y.

26. A pharmaceutical composition comprising a compound as defined in any one of claims 1, 3, 5, or 7, or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.

27. The composition according to claim 26, wherein said composition is in unit dosage form, comprising from about 0.05 to about 2000 mg of the compound or pharmaceutically acceptable salt thereof.

28. A method of treating a disorder of a patient where modulation of the activity of hormone-sensitive lipase is desired, wherein said disorder is selected from the group consisting of insulin resistance, diabetes type 1 and 2, metabolic syndrome X, impaired glucose tolerance, hyperglycemia, dyslipidemia, obesity, abnormalities of lipoprotein metabolism and any combination thereof, the method comprising administering to said patient an effective amount of a compound according to any one of claims 1, 3, 5, or 7, or a pharmaceutically acceptable salt thereof.

29. The method according to claim 28, wherein said administration is carried out by the oral, nasal, transdermal, pulmonal, or parenteral route.

30. The method according to claim 28, wherein a further antidiabetic, antiobesity, antihypertensive or appetite regulating drug is administered to the patient.

31. The composition according to claim 26, wherein said composition is in unit dosage form, comprising from about 0.1 to about 500 mg of the compound or pharmaceutically acceptable salt thereof.

32. The composition according to claim 26, wherein said composition is in unit dosage form, comprising from about 1.0 to about 100 mg of the compound or pharmaceutically acceptable salt thereof.

33. The compound according to any one of claims 1, 3, 5, or 7, which has a solubility in water of at least 2 mg/L as determined at 25° C. and pH 7.0.

34. The compound according to any one of claims 1, 3, 5, or 7, which has a solubility in water of at least 10 mg/L as determined at 25° C. and pH 7.0.

35. The compound according to any one of claims 1, 3, 5, or 7, which has a solubility in water of at least 50 mg/L as determined at 25° C. and pH 7.0.

36. The compound according to any one of claims 1, 3, 5, or 7, which has a solubility in water of at least 200 mg/L as determined at 25° C. and pH 7.0.

37. The compound according to any one of claims 1, 3, 5, or 7, which has a solubility in water of at least 2 mg/L as determined at 25° C. and pH 2.0.

38. The compound according to any one of claims 1, 3, 5, or 7, which has a solubility in water of at least 10 mg/L as determined at 25° C. and pH 2.0.

39. The compound according to any one of claims 1, 3, 5, or 7, which has a solubility in water of at least 50 mg/L as determined at 25° C. and pH 2.0.

40. The compound according to any one of claims 1, 3, 5, or 7, which has a solubility in water of at least 200 mg/L as determined at 25° C. and pH 2.0.

41. The compound according to claim 10, which has an IC50 value of less than 500 nM.

42. The compound according to claim 10, which has an IC50 value of less than 100 nM.

43. The compound according to claim 10, which has an IC50 value of less than 50 nM.

44. The compound according to claim 10, which has an IC50 value of less than 25 nM.

45. The compound according to claim 10, which has an IC50 value of less than 10 nM.

46. The compound according to claim 10, which has an IC50 value of less than 5 nM.

47. The compound according to claim 12, which has a pKa in the range from 9 to 12.

48. The compound according to claim 12, which has a pKa in the range from 10 to 12.

49. The compound according to claim 14, which has a molar weight of less than 500 D.

50. The compound according to claim 14, which has a molar weight of less than 400 D.

51. The compound according to claim 14, which has a molar weight of less than 300D.

52. The compound according to claim 14, which has a molar weight of less than 250 D.