# Patent

## Title
Substituted tetrahydroimidazopyridine compounds and the use thereof in the treatment of pain and other conditions

## Abstract

Substituted tetrahydroimidazopyridine compounds corresponding to formula I:




in which R1, R2 and R3 have defined meanings, processes for preparing such compounds, pharmaceutical compositions containing such compounds, and the use of such compounds for treating or inhibiting pain, epilepsy, migraine, anxiety or urinary incontinence.

## Background
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims priority from European patent application no. EP 008001093.7, filed Jan. 22, 2008, the entire disclosure of which is incorporated herein by reference.
BACKGROUND OF THE INVENTION
The present invention relates to substituted tetrahydroimidazopyridine compounds, processes for the preparation thereof, pharmaceutical compositions containing these compounds, and the use of these compounds for the preparation of medicinal products and the treatment or inhibition of pain and other conditions.
The treatment of pain, in particular neuropathic pain, is of great importance in medicine. There is a worldwide need for effective pain therapies. The urgent need for action to find targeted, patient-appropriate treatment for chronic and non-chronic pain conditions, this being understood as the successful and satisfactory treatment of pain for the patient, is also documented in the large number of scientific works that have been published in recent times in the field of applied analgesics and basic research into nociception.
A pathophysiological feature of chronic pain is the overexcitability of neurons. Neuronal excitability is decisively influenced by the activity of K+ channels, since these significantly determine the resting potential of the cell and hence the excitability threshold. Heteromeric K+ channels of the molecular subtype KCNQ2/3 (Kv7.2/7.3) are expressed in neurons of various regions of the central (hippocampus, amygdala) and peripheral (dorsal root ganglia) nervous system and regulate the excitability thereof. Activation of KCNQ2/3 K+ channels leads to a hyperpolarisation of the cell membrane and, accompanying this, to a decrease in the electrical excitability of these neurons. KCNQ2/3-expressing neurons of the dorsal root ganglia are involved in the transmission of nociceptive stimuli from the periphery into the spinal cord (Passmore et al., J. Neurosci. 2003; 23(18):7227-36). It has accordingly been possible to detect an analgesic activity in preclinical neuropathic and inflammatory pain models for the KCNQ2/3 agonist retigabine (Blackburn-Munro and Jensen, Eur J. Pharmacol. 2003; 460(2-3):109-16; post et al., Naunyn Schmiedeberg's Arch Pharmacol 2004; 369(4): 382-390). The KCNQ2/3 K+ channel thus represents a suitable starting point for the treatment of pain; in particular pain chosen from the group consisting of chronic pain, neuropathic pain, inflammatory pain and muscular pain (Nielsen et al., Eur J. Pharmacol. 2004; 487(1-3): 93-103), in particular neuropathic and inflammatory pain.
Moreover, the KCNQ2/3 K+ channel is a suitable target for therapy of a large number of further diseases, such as, for example, migraine (US2002/0128277), cognitive diseases (Gribkoff, Expert Opin Ther Targets 2003; 7(6): 737-748), anxiety states (Korsgaard et al., J Pharmacol Exp Ther. 2005, 14(1): 282-92), epilepsy (Wickenden et al., Expert Opin Ther Pat 2004; 14(4): 457-469) and urinary incontinence (Streng et al., J Urol 2004; 172: 2054-2058).
SUMMARY OF THE INVENTION
An object of the present invention was therefore to provide novel compounds which are suitable in particular as pharmacological active ingredients in medicinal products, preferably in medicinal products for the treatment of disorders or diseases which are at least partly mediated by KCNQ2/3 K+ channels.
Surprisingly it has now been found that substituted tetrahydroimidazopyridine compounds having the general formula I given below are suitable for the treatment of pain and also have an excellent affinity for the KCNQ2/3 K+ channel and are therefore suitable for the treatment of disorders or diseases which are at least partly mediated by KCNQ2/3 K+ channels.
WO 2006/015737 discloses a large number of compounds, among them substituted tetrahydroimidazopyridines. These compounds are dopamine receptor ligands; in these compounds, however, the amide-nitrogen is always bound to a phenyl-substituted piperazine via an alkyl or cycloalkyl bridge.
The invention therefore provides substituted tetrahydroimidazopyridine compounds having the general formula I,




wherein

    R1 and R2 each independently denote H; C1-10 alkyl, C1-4 alkyl aryl, C1-4 alkyl heteroaryl, C1-4 alkyl C3-8 cycloalkyl, C1-4 alkyl heterocyclyl or C3-8 cycloalkyl, wherein the alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl groups may each be unsubstituted or mono- or polysubstituted, and R1 and R2 do not simultaneously denote H; or
    R1 and R2 together with the nitrogen to which they are bound form a four- to eight-membered heterocyclic ring, optionally bridged by a C1 or C2 alkyl chain, which may contain a further heteroatom and may be substituted or unsubstituted; and
    R3 denotes unsubstituted or mono- or polysubstituted phenyl;
    with the proviso that if one of R1 or R2 denotes H, alkyl or phenyl alkyl, the other one of R1 or R2 does not denote a group having the formula X1






    wherein the phenyl group in formula X1 may be unsubstituted or substituted, and
    Y denotes a C2-5 alkyl chain or —(CH2)o-Z-(CH2)p—,
    wherein Z denotes cyclopentyl, cyclohexyl or cycloheptyl, and
    o and p are each 0, 1, 2 or 3, with the sum of o and p being less than or equal to 3; in the form of the racemate; the enantiomers, diastereomers, mixtures of enantiomers or diastereomers or a single enantiomer or diastereomer; the bases and/or salts of physiologically compatible acids.


Within the meaning of this invention the expressions “C1-4 alkyl” and “C1-10 alkyl” include acyclic saturated or unsaturated hydrocarbon groups, which can be branched or straight-chain and unsubstituted or mono- or polysubstituted, having respectively 1 to 4 C atoms or 1 to 10 C atoms, i.e. C1-4 alkanyls, C2-4 alkenyls and C2-4 alkynyls or C1-10 alkanyls, C2-10 alkenyls and C2-10 alkynyls. Alkenyls have at least one C—C double bond and alkynyls have at least one C—C triple bond. Alkyl is advantageously selected from the group comprising methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, ethylenyl (vinyl), ethynyl, propenyl (—CH2CH═CH2, —CH═CH—CH3, —C(═CH2)—CH3), propynyl (—CH—C≡CH, —C≡C—CH3), butenyl, butynyl, pentenyl, pentynyl, hexenyl and hexynyl. Methyl, ethyl, n-propyl and n-butyl are particularly advantageous.
For the purposes of this invention the expression “cycloalkyl” or “C3-8 cycloalkyl” denotes cyclic hydrocarbons having 3, 4, 5, 6, 7 or 8 carbon atoms, which can optionally also be bridged, wherein the hydrocarbons can be saturated or unsaturated (but not aromatic), unsubstituted or mono- or polysubstituted. C3-8 cycloalkyl is advantageously selected from the group including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
The term “heterocyclyl” comprises saturated or unsaturated (but not aromatic) cycloalkyls having three to ten, preferably four to eight, ring members, which can optionally also be bridged, in which one or two carbon atoms are replaced by an S, N or O heteroatom. Heterocyclyl groups are advantageously selected from the group consisting of tetrahydropyranyl, azabicyclo[3.2.1]octane, dioxanyl, dioxolanyl, morpholinyl, piperidinyl, pyrazolinonyl and pyrrolidinyl.
Within the meaning of this invention, the expression “aryl” denotes aromatic hydrocarbons having up to 14 ring members, inter alia phenyls and naphthyls. The aryl groups can also be fused to other saturated, (partially) unsaturated or aromatic ring systems. Each aryl group can be present in unsubstituted or mono- or polysubstituted form, wherein the aryl substituents can be identical or different and can be at any desired and possible position of the aryl. Aryl is advantageously selected from the group including phenyl, 1-naphthyl, 2-naphthyl, each of which can be unsubstituted or mono- or polysubstituted.
The expression “heteroaryl” denotes a 5-, 6- or 7-membered cyclic aromatic group containing at least 1, optionally also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms can be identical or different and the heterocyclic compound can be unsubstituted or mono- or polysubstituted; if the heterocyclic compound is substituted, the substituents can be identical or different and can be at any desired and possible position of the heteroaryl. The heterocyclic compound can also be part of a bicyclic or polycyclic system having up to 14 ring members. Preferred heteroatoms are nitrogen, oxygen and sulfur. It is preferable for the heteroaryl group to be selected from the group including pyrrolyl, indolyl, furyl (furanyl), benzofuranyl, thienyl (thiophenyl), benzothienyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, phthalazinyl, pyrazolyl, imidazolyl, thiazolyl, oxadiazolyl, isoxazolyl, oxazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indazolyl, purinyl, indolizinyl, quinolinyl, isoquinolinyl, quinazolinyl, carbazolyl, phenazinyl, wherein the bond to the compounds having the general structure I can be made via any desired and possible ring member of the heteroaryl group. Pyridyl, furyl and thienyl are particularly preferred.
For the purposes of the present invention the expression “aryl, heteroaryl, heterocyclyl or cycloalkyl bound by C1-4 alkyl” means that C1-4 alkyl and aryl or heteroaryl or heterocyclyl or cycloalkyl have the meanings defined above and the aryl or heteroaryl or heterocyclyl or cycloalkyl group is bound to the compound having the general structure I by a C1-4 alkyl group. The alkyl chain can in all cases be saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted. It is advantageous for the alkyl chain to be unsubstituted or substituted with a methyl group. Phenyl, benzyl and phenethyl are particularly advantageous within the meaning of this invention.
In connection with “alkyl”, “heterocyclyl” and “cycloalkyl” the term “substituted” within the meaning of this invention is understood to mean the substitution of a hydrogen group with F, Cl, Br, I, —CN, NH2, NH—C1-6 alkyl, NH—C1-6 alkyl-OH, C1-6 alkyl, N(C1-6 alkyl)2, N(C1-6 alkyl-OH)2, NO2, SH, S—C1-6 alkyl, S-benzyl, O—C1-6 alkyl, OH, O—C1-6 alkyl-OH, ═O, O-benzyl, C(═O)C1-6 alkyl, C(═O)OC1-6 alkyl, phenyl or benzyl, wherein a substituent can optionally itself be substituted, but not with a further aryl or heteroaryl ring. Polysubstituted groups are understood to mean groups which are either substituted multiple times, e.g. twice or three times, at different or the same atoms, for example three times at the same C atom, as in the case of CF3 or —CH2CF3, or at different sites, as in the case of —CH(OH)—CH═CH—CHCl2. The polysubstitution can be performed with identical or different substituents.
With reference to “aryl”, “phenyl” and “heteroaryl”, within the meaning of this invention “mono- or polysubstituted” is understood to mean the mono- or poly- (i.e. di-, tri- or tetra-)substitution of one or more hydrogen atoms of the ring system with F, Cl, Br, I, CN, NH2, NH—C1-6 alkyl, NH—C1-6 alkyl-OH, N(C1-6 alkyl)2, N(C1-6 alkyl-OH)2, NO2, SH, S—C1-6 alkyl, OH, O—C1-6 alkyl, O—C1-6 alkyl-OH, C(═O)C1-6 alkyl, C(═O)NHC1-6 alkyl; C(═O) aryl; C(═O)—N-morpholine; C(═O)-piperidine; (C═O)-pyrrolidine; (C═O)-piperazine; NHSO2C1-6 alkyl, NHCOC1-6 alkyl, CO2H, CH2SO2 phenyl, CO2—C1-6 alkyl, OCF3, SCF3, CF3,




C1-6 alkyl, pyrrolidinyl, piperidinyl, morpholinyl, benzyloxy, phenoxy, phenyl, pyridyl, alkylaryl, thienyl or furyl; at one or optionally different atoms, wherein a substituent can optionally itself be substituted, but not with a further aryl or heteroaryl ring. The polysubstitution is performed with identical or with different substituents. Preferred substituents for “aryl” or “heteroaryl” are F, Cl, OCH3, CF3, OCF3, SCF3 and CH3.

Within the meaning of this invention the term “salt formed with a physiologically compatible acid” is understood to mean salts of the individual active ingredient with inorganic or organic acids which are physiologically—particularly when used in humans and/or mammals—compatible. Examples of physiologically compatible acids are: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, maleic acid, lactic acid, citric acid, glutamic acid, 1,1-dioxo-1,2-dihydro-1λ6-benzo[d]isothiazol-3-one (saccharinic acid), monomethyl sebacic acid, 5-oxoproline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, α-lipoic acid, acetylglycine, hippuric acid, phosphoric acid and/or aspartic acid. Citric acid and hydrochloric acid are particularly preferred.
Preferred within the meaning of this invention are substituted tetrahydroimidazopyridine compounds having the general formula I, wherein “alkyl substituted”, “heterocyclyl substituted” and “cycloalkyl substituted” denotes the substitution of a hydrogen group with F, Cl, Br, I, —CN, NH2, NH—C1-6 alkyl, NH—C1-6 alkyl-OH, C1-6 alkyl, N(C1-6 alkyl)2, N(C1-6 alkyl-OH)2, NO2, SH, S—C1-6 alkyl, S-benzyl, O—C1-6 alkyl, OH, O—C1-6 alkyl-OH, ═O, O-benzyl, C(═O)C1-6 alkyl, C(═O)OC1-6 alkyl, phenyl or benzyl, and “aryl substituted”, “phenyl substituted” and “heteroaryl substituted” denotes the single or multiple, e.g. two, three or four times, substitution of one or more hydrogen atoms in the ring system with F, Cl, Br, I, CN, NH2, NH—C1-6 alkyl, NH—C1-6 alkyl-OH, N(C1-6 alkyl)2, N(C1-6 alkyl-OH)2, NO2, SH, S—C1-6 alkyl, OH, O—C1-6 alkyl, O—C1-6 alkyl-OH, C(═O) aryl; C(═O)C1-6 alkyl, C(═O)NHC1-6 alkyl; C(═O)—N-morpholine; C(═O)-piperidine; (C═O)-pyrrolidine; (C═O)-piperazine; NHSO2C1-6 alkyl, NHCOC1-6 alkyl, CO2H, CH2SO2 phenyl, CO2—C1-6 alkyl, OCF3, CF3,




C1-6 alkyl, pyrrolidinyl, piperidinyl, morpholinyl, benzyloxy, phenoxy, phenyl, pyridyl, alkylaryl, thienyl or furyl.

The groups C1-6 alkyl, pyrrolidinyl, piperidinyl, morpholinyl, benzyloxy, phenoxy, phenyl, pyridyl, alkylaryl, thienyl or furyl can themselves be substituted with F, Cl, methoxy, ethoxy, CF3, CN, CH3, OH, OCF3, SCF3 or NO2.
Also preferred within the meaning of this invention are substituted tetrahydroimidazopyridine compounds having the general formula I, wherein

    R1 and R2 each independently denote C1-10 alkyl, C1-4 alkyl aryl, C1-4 alkyl heteroaryl, C1-4 alkyl C3-8 cycloalkyl or C3-8 cycloalkyl,
    
        wherein the alkyl, aryl, heteroaryl and cycloalkyl groups may each be unsubstituted or mono- or polysubstituted.
    
    


Also preferred are substituted tetrahydroimidazopyridine compounds having the general formula I, wherein R1 and R2 together with the nitrogen atom to which they are bound form a four- to eight-membered ring, optionally bridged by a C1 or C2 alkyl chain, which may contain a further heteroatom selected from the group consisting of O, N and S and which may be substituted or unsubstituted.
Particularly preferred are substituted tetrahydroimidazopyridine compounds having the general formula I, wherein R1 and R2 each independently denote H; benzyl, phenethyl, methylpyridyl, cyclopropyl, n-pentyl, n-butyl, n-hexyl, sec-butyl, propylethyl or methylcyclohexyl, each of which may be unsubstituted or mono- or polysubstituted with methoxy, F, CH3, CF3 or




in particular benzyl, phenethyl, methylpyridyl, cyclopropyl, 3,4-dimethoxyphenethyl, benzo[1,3]dioxol-5-yl, 4-fluorobenzyl, (1-methyl)propylphenyl, 3-trifluoromethylbenzyl, sec-butyl, (1-methyl)benzyl, methylcyclohexyl or (1-methyl)-3,4-dimethylbenzyl, n-butyl, n-pentyl or n-hexyl.

Also particularly preferred are substituted tetrahydroimidazopyridine compounds having the general formula I, wherein R1 and R2 together with the nitrogen atom to which they are bound form a five- to seven-membered ring which may contain a further nitrogen atom and which may be unsubstituted or mono- or polysubstituted with C(O)OC2H5; C(O)C1-6 alkyl; methyl, n-butyl or acetyl; phenyl or benzyl, each unsubstituted or substituted with phenyl F, Cl, Br, I, CN, CH3, C2H5, NH2, NO2, SH, CF3, OH, OCH3, OCF3, SCF3, SCH3, OC2H5 or N(CH3)2.
Most particularly preferred are substituted tetrahydroimidazopyridine compounds having the general formula I, wherein the NR1R2 grouping denotes




wherein R denotes H, phenyl F, Cl, Br, I, CN, CH3, C2H5, NH2, NO2, SH, CF3, OH, OCH3, OCF3, SCF3, SCH3, OC2H5 or N(CH3)2; in particular





Also preferred are tetrahydroimidazopyridine derivatives wherein R3 denotes phenyl, unsubstituted or mono- or polysubstituted with F, Cl, Br, I, CN, CH3, C2H5, NH2, NO2, SH, CF3, OH, OCH3, OCF3, SCF3, SCH3, phenoxy, OC2H5 or N(CH3)2; in particular phenyl mono- or polysubstituted with F, OCH3, CH3 or phenoxy.
Particularly preferred are tetrahydroimidazopyridine derivatives wherein R3 denotes




Most preferred are tetrahydroimidazopyridine compounds selected from the group consisting of:

    1 (4-Benzylpiperidin-1-yl)(6-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)methanone;
    2 N-Benzyl-N-phenethyl-6-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide;
    3 (6-Phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-yl)methanone;
    4 (6-(3-Fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-yl)methanone;
    5 N-Benzyl-6-(4-methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide;
    6 (4-(2-Fluorophenyl)piperazin-1-yl)(6-(4-methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)methanone;
    7 (6-(5-Fluoro-2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)methanone;
    8 (4-Benzylpiperidin-1-yl)(6-(5-fluoro-2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)methanone;
    9 (6-(5-Fluoro-2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-yl)methanone;
    10 (6-(4-Methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(2-methoxyphenyl)piperazin-1-yl)methanone;
    11 (4-Benzylpiperidin-1-yl)(6-(4-ethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)methanone;
    12 (6-(2,5-Dimethoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-yl)methanone;
    13 (6-(4-Fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(2-fluorophenyl)piperazin-1-yl)methanone;
    14 6-(4-Fluoro-3-methylphenyl)-N-(1-phenylethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide;
    15 6-(4-Methoxy-3,5-dimethylphenyl)-N-pentyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide;
    16 N-Hexyl-6-(4-methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide;
    17 6-(4-Methoxy-3,5-dimethylphenyl)-N-(3-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide;
    18 N-sec-Butyl-6-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide;
    19 N-Butyl-6-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide;
    20 Ethyl 1-(6-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carbonyl)piperidine-4-carboxylate;
    21 (4-Methylpiperidin-1-yl)(6-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)methanone;
    22 Ethyl 1-(6-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carbonyl)piperidine-3-carboxylate;
    23 1-(4-(6-(4-Phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carbonyl)piperazin-1-yl)ethanone;
    24 6-(4-Phenoxyphenyl)-N-(pyridin-3-ylmethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide;
    25 (6-(4-Phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(pyrrolidin-1-yl)methanone;
    26 N-Cyclopropyl-6-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide;
    27 N-(3,4-Dimethoxyphenethyl)-6-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide;
    28 N-Pentyl-6-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide;
    29 Pyrrolidin-1-yl(6-m-tolyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)methanone;
    30 (6-(3,5-Bis(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(pyrrolidin-1-yl)methanone;
    31 Pyrrolidin-1-yl(6-(3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)methanone;
    32 (4-(2-Fluorophenyl)piperazin-1-yl)(6-(3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)methanone;
    33 (6-(2,4-Dimethoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(pyrrolidin-1-yl)methanone;
    34 Pyrrolidin-1-yl(6-o-tolyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)methanone;
    35 (6-o-Tolyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-(trifluoromethyl)-phenyl)piperazin-1-yl)methanone;
    36 (6-(2,5-Difluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(pyrrolidin-1-yl)methanone;
    37 (6-(4-Ethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(pyrrolidin-1-yl)methanone;
    38 (6-(4-Fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-yl)methanone;
    39 6-(4-Methoxyphenyl)-N-(3-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide;
    40 6-(4-Ethylphenyl)-N-phenethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide;
    41 (4-Benzylpiperidin-1-yl)(6-(4-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)methanone;
    42 N-(Benzo[d][1,3]dioxol-5-ylmethyl)-6-(3,5-bis(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide;
    43 N-Benzyl-6-(3,5-bis(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide;
    44 (6-(4-Methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(4-methoxyphenyl)piperazin-1-yl)methanone;
    45 (4-(2-Ethoxyphenyl)piperazin-1-yl)(6-m-tolyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)methanone;
    46 (6-(2,4-Dimethoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)methanone;
    47 (6-(4-Fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)methanone;
    48 (6-(3-Fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)methanone;
    49 N-(4-Fluorobenzyl)-6-(4-methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo-[1,2-a]pyridine-2-carboxamide;
    50 (4-Benzylpiperidin-1-yl)(6-(3-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)methanone;
    51 6-(3-Fluorophenyl)-N-(4-phenylbutan-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide;
    52 6-(4-Ethylphenyl)-N-(4-phenylbutan-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide;
    53 (6-Phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)methanone;
    54 (6-(4-Methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)methanone;
    55 (4-Benzylpiperidin-1-yl)(6-(4-methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)methanone;
    56 (6-(4-Methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-yl)methanone;
    57 4-Benzylpiperidin-1-yl)(6-(4-fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo-[1,2-a]pyridin-2-yl)methanone;
    58 (6-(4-Fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)methanone;
    59 (4-Benzhydrylpiperazin-1-yl)(6-(4-methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)methanone;
    60 6-(3-Methoxyphenyl)-N-(4-phenylbutan-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide;
    61 (4-Benzylpiperidin-1-yl)(6-(3-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)methanone;
    62 (6-(4-Fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)methanone;
    63 (6-(4-Fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(4-fluorophenyl)piperazin-1-yl)methanone;
    64 (6-(4-Fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(4-methylphenyl)piperazin-1-yl)methanone;
    65 (6-(4-Fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-methylphenyl)piperazin-1-yl)methanone;
    66 (4-Butylpiperazin-1-yl)(6-(4-fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)methanone;
    67 (4-Benzhydrylpiperidin-1-yl)(6-(4-fluoro-3-methylphenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)methanone;
    68 N-(Cyclohexylmethyl)-6-(4-fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide;
    69 (6-(4-Methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)methanone;
    70 (4-Benzylpiperidin-1-yl)(6-m-tolyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)methanone;
    71 (6-(3-Methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)methanone;
    72 6-(4-Fluoro-3-methylphenyl)-N-(4-phenylbutan-2-yl)-5,6,7,8-tetrahydroimidazo-[1,2-a]pyridine-2-carboxamide;
    73 4-Benzylpiperidin-1-yl)(6-p-tolyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)methanone;
    74 (6-p-Tolyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-(trifluoromethyl)-phenyl)piperazin-1-yl)methanone;
    75 (6-m-Tolyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-(trifluoromethyl)-phenyl)piperazin-1-yl)methanone;
    76 (4-Benzylpiperidin-1-yl)(6-(4-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)methanone;
    77 (6-(3,5-Dimethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)methanone;
    78 N-(1-(3,5-Dimethylphenyl)ethyl)-6-(4-fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide;
    79 6-(3,4-Difluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)methanone;
    80 (4-Benzylpiperazin-1-yl)(6-(4-fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo-[1,2-a]pyridin-2-yl)methanone;
    81 (6-(4-Phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)methanone;
    82 6-(4-(Benzyloxy)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)methanone;
    83 (6-(4-Fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-fluorophenyl)piperazin-1-yl)methanone;
    84 (6-(4-Fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-yl)methanone;
    85 (6-(4-Fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;
    86 6-(4-Fluoro-3-methylphenyl)-N-(4-(3-(trifluoromethyl)phenyl)butan-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide;
    87 6-(4-Fluoro-3-methylphenyl)-N-methyl-N-(4-(3-(trifluoromethyl)phenyl)butan-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide; and
    88 N-(2-Cyclohexylethyl)-6-(4-fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide.


The substituted tetrahydroimidazopyridine compounds according to the invention and the corresponding acids, bases, salts and solvates are suitable as pharmaceutical active ingredients in medicinal products. The present invention therefore also provides a pharmaceutical composition containing at least one substituted tetrahydroimidazopyridine compound according to the invention having the general formula I, wherein the groups R1 to R3 have the meaning given above, and optionally one or more pharmaceutically compatible auxiliary substances.
These pharmaceutical compositions according to the invention are suitable for influencing KCNQ2/3 channels and exert an agonistic or antagonistic, in particular an agonistic, action.
The pharmaceutical compositions according to the invention are suitable for the treatment of disorders or diseases which are at least partly mediated by KCNQ2/3 channels. The pharmaceutical compositions according to the invention are particularly suitable for the treatment of one or more disorders or disease states selected from the group consisting of pain, preferably pain chosen from the group consisting of acute pain, chronic pain, neuropathic pain, muscular pain and inflammatory pain, migraine; epilepsy, anxiety states and urinary incontinence. The medicinal products according to the invention are particularly preferably suitable for the treatment of pain, most particularly preferably chronic pain, neuropathic pain, inflammatory pain and muscular pain. The compounds according to the invention are further preferably suitable for the treatment of epilepsy.
The present invention also provides the use of at least one substituted tetrahydroimidazopyridine compound according to the invention and optionally one or more pharmaceutically compatible auxiliary substances for the preparation of a medicinal product for the treatment of disorders or diseases which are at least partly mediated by KCNQ2/3 channels.
Preference is given to the use of at least one substituted tetrahydroimidazo-pyridine compound according to the invention and optionally one or more pharmaceutically compatible auxiliary substances for the preparation of a medicinal product for the treatment of pain, preferably pain chosen from the group consisting of acute pain, chronic pain, neuropathic pain, muscular pain and inflammatory pain; migraine; epilepsy, anxiety states and urinary incontinence.
Particularly preferred is the use of at least one substituted tetrahydroimidazopyridine compound according to the invention and optionally one or more pharmaceutically compatible auxiliary substances for the preparation of a medicinal product for the treatment of pain, most particularly preferably chronic pain, neuropathic pain, inflammatory pain and muscular pain. Also particularly preferred is the use of at least one substituted tetrahydroimidazopyridine compound according to the invention and optionally one or more pharmaceutically compatible auxiliary substances for the preparation of a medicinal product for the treatment of epilepsy.
The effectiveness against pain can be shown, for example, in the Bennett or Chung model described below. The effectiveness against epilepsy can be demonstrated, for example, in the DBA/2 mouse model (De Sarro et al., Naunyn-Schmiedeberg's Arch. Pharmacol. 2001, 363, 330-336).
The present invention also provides a process for preparing the substituted tetrahydroimidazopyridine compounds according to the invention. The chemicals and reaction components used in the reactions described above are available commercially or can be prepared by methods known to the person skilled in the art.




Starting from a correspondingly iodine-, bromine- or chlorine-substituted 2-aminopyridine, cyclisation is performed by reaction with 3-bromo-2-oxopropionic acid ethyl ester in an organic solvent, for example ethanol, methanol, THF, 1,2-dimethoxyethane, acetone, water or chloroform, at temperatures of between 0° C. and 80° C. for a reaction time of 2 to 48 h. Alternatively, the cyclisation reaction can also take place starting from the primarily formed 2-aminopyridinium bromide by heating in methanol.
The subsequent Suzuki reaction is performed by reacting the corresponding iodine-, bromine- or chlorine-substituted imidazole with phenylboric acids or phenylboric acid esters in solvents such as methanol, ethanol, 1-propanol, ethylene glycol, water, 1,2-dimethoxyethane, THF, dioxane, acetonitrile, DMF, benzene, toluene or xylene, which can also be present as blends, using a catalyst, a base and optionally an additive.
Catalysts which can be used are inter alia Pd(PPh3)4, Pd(dba)2, PdCl2(dppf)2, Pd(P(o-tolyl)3)4, PdCl2(PPh3)2, PdCl2(P(Cy)3)2, Pd(OAc)2(P(o-tolyl)3)2. In addition, a mixture of Pd(OAc)2/PPh3, Pd on activated carbon/PPh3 or (NH4)2PdCl4 can be used as catalyst. Tri-tert-butyl phosphine is suitable as a further ligand. Both organic and inorganic bases can be used as bases. TEA or sodium tert-butylate, for example, are suitable as organic bases. Sodium carbonate, sodium hydrogen carbonate, potassium carbonate, caesium carbonate or silver carbonate, barium hydroxide, sodium hydroxide or potassium hydroxide or potassium phosphate, for example, are suitable as inorganic bases. EDTA, tetrabutylammonium bromide, lithium chloride, potassium fluoride or methyl cyclohexane, for example, can be used as additives. The reaction temperature is between room temperature and 80° C., with a reaction time of 1.5 to 72 hours. The reaction can also be performed in the microwave.
Another reaction pathway starts from iodine-, bromine- or chlorine-substituted 2-aminopyridines, which are first converted to the phenyl-substituted aminopyridines in a Suzuki reaction. The Suzuki reaction is performed by reacting the corresponding iodine-, bromine- or chlorine-substituted 2-aminopyridine with boric acids or boric acid esters in solvents, for example methanol, ethanol, 1-propanol, ethylene glycol, water, 1,2-dimethoxyethane, THF, dioxane, acetonitrile, DMF, benzene, toluene or xylene, which can also be present as blends, using a catalyst, a base and optionally an additive.
Catalysts which can be used are inter alia Pd(PPh3)4, Pd(dba)2, PdCl2(dppf)2, Pd(P(o-tolyl)3)4, PdCl2(PPh3)2, PdCl2(P(Cy)3)2, Pd(OAc)2(P(o-tolyl)3)2. In addition, a mixture of Pd(OAc)2/PPh3, Pd on activated carbon/PPh3 or (NH4)2PdCl4 can be used as catalyst. Tri-tert-butyl phosphine is suitable as a further ligand.
Either organic or inorganic bases can be used as bases. TEA or sodium tert-butylate, for example, are suitable as organic bases. Sodium carbonate, sodium hydrogen carbonate, potassium carbonate, caesium carbonate or silver carbonate, barium hydroxide, sodium hydroxide or potassium hydroxide or potassium phosphate, for example, are suitable as inorganic bases. EDTA, tetrabutylammonium bromide, lithium chloride, potassium fluoride or methyl cyclohexane, for example, can be used as additives. The reaction temperature is between room temperature and 80° C., with a reaction time of 1.5 to 72 hours. The reaction can also be performed in the microwave.
Cyclization can be carried out by reacting the phenyl-substituted aminopyridine with 3-bromo-2-oxopropionic acid ethyl ester in an organic solvent, for example ethanol, methanol, THF, 1,2-dimethoxyethane, acetone, water or chloroform, at temperatures of between 0° C. and 80° C. for a reaction time of 2 to 48 h. Alternatively, the cyclisation reaction can also take place starting from the primarily formed 2-aminopyridinium bromide by heating in methanol.
The subsequent ester cleavage can be performed using organic acids, for example trifluoroacetic acid, or aqueous inorganic acids, for example hydrochloric acid, or using aqueous inorganic bases, for example lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, in organic solvents, for example methanol, dioxane, dichloromethane, THF, diethyl ether or in these solvents as blends.
The subsequent hydrogenation can be performed with Pd on activated carbon, Raney nickel, platinum or PtO2. Suitable solvents are, for example, ethanol, methanol, water, acetic acid, propionic acid, DCM, cyclohexane, methanolic KOH or blends of these solvents. TFA, for example, can be used as an additive. The reaction can be performed under normal pressure or elevated pressure. The reaction time can be between 1.5 and 72 hours.
The subsequent acylation can be performed both with acid chlorides or bromides, which can also be produced from carboxylic acids having the general formula II, and with carboxylic acids having the general formula II.
The carboxylic acids corresponding to formula II that are obtained can be converted into acid chlorides or bromides by methods known to persons skilled in the art. The carboxylic acid chlorides or bromides that are obtained can be reacted in solvents, for example DCM, benzene, toluene, THF, DMF, acetonitrile, pyridine, dioxane, water or 1-methylpyrrolidin-2-one or blends of these solvents, using bases, for example pyridine, DIEA, TEA, N-methylmorpholine or sodium hydrogen carbonate, optionally with addition of a coupling reagent, for example DCC, with primary or secondary amines. The reaction temperature can be varied between −20° C. and +110° C. The reaction times can be between 0.5 h and 24 hours.
The reaction of carboxylic acids having the general formula II with primary or secondary amines can be performed using bases and optionally coupling reagents in solvents, for example methanol, DMF or DCM. Sodium methanolate, TEA, DIEA or N-methylmorpholine, for example, can be used as bases. EDCI, HOBt, DCC, CDI, HBTU, DMAP or pentafluorophenyl diphenyl phosphinate, for example, are suitable as coupling reagents. The reaction time can vary between 1 and 3 days.


EXAMPLES




The following tetrahydroimidazopyridines were used for the syntheses:













S1
6-Phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid


S2
6-(4-Methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-



carboxylic acid


S3
6-(4-Fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-



carboxylic acid


S4
6-(3-Methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid


S5
6-(3-Fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid


S6
6-(4-Methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid


S7
6-(5-Fluoro-2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-



carboxylic acid


S8
6-(3,5-Dimethoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic



acid


S9
6-(4-Ethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid


S10
6-(4-Fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid


S11
6-(4-Phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid


S12
6-(3-Methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid


S13
6-(2,5-Difluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid


S14
6-(3,5-Bis(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-



carboxylic acid


S15
6-(3-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-



carboxylic acid


S16
6-2,4-Dimethoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic



acid


S17
6-(2-Methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid


S18
6-(4-Methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid


S19
6-(3,4-Difluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid


S20
6-(3,5-Dimethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid


S21
6-(4-(Benzyloxy)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic



acid














Starting





product for



structural unit
Name
Supplier







S1
Phenylboric acid
Acros



S2
3,5-Dimethyl-4-methoxyphenylboric acid
Aldrich



S3
4-Fluoro-3-methylphenylboric acid
Aldrich



S4
3-Methoxyphenylboric acid
Acros



S5
3-Fluorophenylboric acid
Acros



S6
4-Methoxyphenylboric acid
Acros



S7
5-Fluoro-2-methoxyphenylboric acid
Aldrich



S8
2,5-Dimethoxyphenylboric acid
Acros



S9
4-Ethylphenylboric acid
Acros



S10
4-Fluorophenylboric acid
Acros



S11
4-Phenoxyphenylboric acid
Acros



S12
3-Tolylboric acid
Acros



S13
2,5-Difluorophenylboric acid
Acros



S14
3,5-Bis-(trifluoromethyl)phenylboric acid
Acros



S15
3-Trifluoromethylphenylboric acid
Acros



S16
2,4-Dimethoxyphenylboric acid
Acros



S17
2-Tolylboric acid
Acros



S18
4-Tolylboric acid
Acros



S19
3,4-Difluorophenylboric acid
Acros



S20
3,5-Dimethylphenylboric acid
Aldrich



S21
4-(Benzyloxy)phenylboric acid
Interchim










6-Bromoimidazo[1,2-a]pyridine-2-carboxylic Acid Ethyl Ester




Ethylbromopyruvate (62.0 g; 318 mmol; 40.0 ml) was added to a solution of 5-bromo-2-aminopyridine (50.0 g; 289 mmol) in ethanol (500 ml) through a dropping funnel. The reaction batch was first stirred for 30 min at room temperature and then refluxed for 8 hours while stirring (DC control: DCE-ethanol 5:1). The solvent was removed under vacuum and the residue taken up in DCM. It was washed first with saturated common salt solution and then with saturated sodium hydrogen carbonate solution. The organic phase was dried over magnesium sulfate, filtered and concentrated to dryness. The residue was recrystallized from dry diethyl ether. Yield: 41 g (53%)
6-Phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic Acid S1




Stage 1. Phenylboric acid (2.13 g; 17.5 mmol) followed by KF solution (2M in water, 15 ml) and finally Pd(PPh3)4 (607 mg; 0.5 mmol; 3 mol %) were added under a nitrogen atmosphere to a solution of 6-bromoimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (4.71 g; 17.5 mmol) in acetonitrile (30 ml) in a Milestone 100 ml high-pressure vessel. The reaction vessel was rinsed with nitrogen, closed and irradiated in a microwave at 160° C. for 5 min. (DC control: n-hexane-ethyl acetate 1:1). Two batches of the same size were run in parallel and combined prior to processing. The precipitated product was filtered out and washed with diethyl ether. The black crystalline product was taken up in chloroform and filtered first over silica gel and then over celite. The clear filtrate was concentrated to dryness. Yield: 9.3 g (100%).

Stage 2. The 6-phenylimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (9.32 g, 17.5 mmol) was dissolved in ethanol (80 ml) and NaOH solution (20% in water, 7 ml) was added. The reaction batch was refluxed for 8 hours. On completion of the reaction the solvent was removed in a rotary evaporator and the residue taken up in a small amount of water. The solution was carefully adjusted to pH 3-4 with HCl solution (10% in water). The precipitated product was filtered and washed with water and used in the next stage without further purification. Yield: 7.90 g (95%).

Stage 3. Palladium on activated carbon (1.5 g) was added to a solution of 6-phenylimidazo[1,2-a]pyridine-2-carboxylic acid (6.3 g; 26.4 mmol) in a blend of HCl (4% in water, 100 ml) and ethanol (200 ml). The mixture was poured into an autoclave (stainless steel), the autoclave was closed and rinsed a few times with nitrogen. The autoclave was filled with hydrogen (8 bar) and the reaction batch stirred over the weekend at room temperature. The catalyst was filtered out over celite and the solvent drawn off in a rotary evaporator at room temperature. The product was crystallized out of acetonitrile. Yield: 4.1 g (56%).

6-(4-Methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic Acid Hydrochloride S2




Stage 1. 4-Methoxy-3,5-dimethylphenylboric acid (3.15 g; 17.5 mmol) followed by KF solution (2M in water, 15 ml) and finally Pd(PPh3)4 (607 mg; 0.525 mmol; 3 mol %) were added under a nitrogen atmosphere to a solution of 6-bromoimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (4.71 g; 17.5 mmol) in acetonitrile (30 ml) in a Milestone 100 ml high-pressure vessel. The reaction vessel was rinsed with nitrogen, closed and irradiated in a microwave at 160° C. for 5 min. (DC control: n-hexane-ethyl acetate 1:1). Four batches of the same size were run in parallel and combined prior to processing. The precipitated product was filtered out and washed with diethyl ether. The black crystalline product was taken up in chloroform and filtered over celite. The clear filtrate was concentrated to small volume and used for the next reaction without further purification. Yield: 22.7 g (quantitative).

Stage 2. The 6-(4-methoxy-3,5-dimethylphenyl)-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (22.7 g, 70 mmol) was dissolved in ethanol (300 ml) and NaOH solution (20% in water, 30 ml) was added. The reaction batch was refluxed for 24 hours. On completion of the reaction the solvent was removed in a rotary evaporator and the residue taken up in as small an amount of water as possible. The solution was carefully adjusted to pH 3-4 with HCl solution (10% in water). The precipitated product was filtered and washed with water. Yield: 21.2 (quantitative).

Stage 3. Palladium on activated carbon (1 g) was added to a solution of 6-(4-methoxy-3,5-dimethylphenyl)-imidazo[1,2-a]pyridine-2-carboxylic acid (4.74 g; 16 mmol) in a blend of HCl (4% in water, 70 ml) and ethanol (140 ml). The mixture was poured into an autoclave (stainless steel), the autoclave was closed and rinsed a few times with nitrogen. The autoclave was filled with hydrogen (8 bar) and the reaction batch stirred for 12 h at room temperature. On completion of the reaction the catalyst was filtered out over celite and the solvent drawn off in a rotary evaporator at room temperature. The product was crystallized out of acetonitrile. Yield: 2.3 g (43%).

6-(4-Fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic Acid S3




Stage 1. 4-Fluoro-3-methylphenylboric acid (4.62 g; 15 mmol) followed by KF solution (2M in water, 15 ml) and finally Pd(PPh3)4 (520 mg; 0.45 mmol; 3 mol %) were added under a nitrogen atmosphere to a solution of 6-bromoimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (4.04 g; 15 mmol) in acetonitrile (30 ml) in a Milestone 100 ml high-pressure vessel. The reaction vessel was rinsed with nitrogen, closed and irradiated in a microwave at 160° C. for 5 min. (DC control: n-hexane-ethyl acetate 1:1). Two batches of the same size were run in parallel and combined prior to processing. The precipitated product was filtered out and washed with diethyl ether. The black crystalline product was taken up in chloroform and filtered over celite. The clear filtrate was concentrated to small volume and crystallized out of diethyl ether. Yield: 4.5 g (50%).

Stage 2. The 6-(4-fluoro-3-methylphenyl)-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (3.0 g, 10.1 mmol) was dissolved in ethanol (50 ml) and NaOH solution (20% in water, 4 ml) was added. The reaction batch was refluxed for 2 hours. On completion of the reaction the solvent was removed in a rotary evaporator and the residue taken up in as small an amount of water as possible. The solution was carefully adjusted to pH 3-4 with HCl solution (10% in water). The precipitated product was filtered and washed with water. The crude product was used in the next stage without further purification. Yield: 1.69 g (62%).

Stage 3. Palladium on activated carbon (350 mg) was added to a solution of 6-(4-fluoro-3-methylphenyl)-imidazo[1,2-a]pyridine-2-carboxylic acid (1.69 g; 6.2 mmol) in a blend of HCl (4% in water, 20 ml) and ethanol (40 ml). The mixture was poured into an autoclave (stainless steel), the autoclave was closed and rinsed a few times with nitrogen. The autoclave was filled with hydrogen (8 bar) and the reaction batch stirred for 20 h at room temperature. The catalyst was filtered out over celite, and the solvent drawn off in a rotary evaporator at room temperature. The product was crystallized out of acetonitrile. As the reaction did not run to completion, the crude product mixture was dissolved again in a blend of HCl (4% in water, 15 ml) and ethanol (30 ml), palladium on activated carbon (260 mg) was added, and the mixture was poured into an autoclave (stainless steel), which was closed and rinsed a few times with nitrogen. The autoclave was filled with hydrogen (8 bar) and the reaction batch stirred for a further 12 hours at room temperature. The catalyst was filtered out over celite and the solvent drawn off in a rotary evaporator at room temperature. The product was crystallized out of acetonitrile. Yield: 609 mg (31%).

6-(3-Methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic Acid Hydrochloride S4




Stage 1. 3-Methoxyphenylboric acid (2.66 g; 17.5 mmol) followed by KF solution (2M in water, 15 ml) and finally Pd(PPh3)4 (606 mg; 0.525 mmol; 3 mol %) were added under a nitrogen atmosphere to a solution of 6-bromoimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (4.71 g; 17.5 mmol) in acetonitrile (30 ml) in a Milestone 100 ml high-pressure vessel. The reaction vessel was rinsed with nitrogen, closed and irradiated in a microwave at 160° C. for 5 min. (DC control: n-hexane-ethyl acetate 1:1). Four batches of the same size were run in parallel and combined prior to processing. The precipitated product was filtered out and washed with diethyl ether. The black crystalline product was taken up in chloroform and filtered over celite. The clear filtrate was concentrated to small volume and crystallized out of diethyl ether. Yield: 15.48 g (75%).

Stage 2. The 6-(3-methoxyphenyl)-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (15.48 g, 52 mmol) was dissolved in ethanol (150 ml) and NaOH solution (20% in water, 10 ml) was added. The reaction batch was refluxed for 8 hours. On completion of the reaction the solvent was removed in a rotary evaporator and the residue taken up in as small an amount of water as possible. The solution was carefully adjusted to pH 3-4 with HCl solution (10% in water). The precipitated product was filtered and washed with water. Yield: 7.93 g (57%).

Stage 3. Palladium on activated carbon (300 mg) was added to a solution of 6-(3-methoxyphenyl)-imidazo[1,2-a]pyridine-2-carboxylic acid (1.38 g; 5.15 mmol) in a blend of HCl (4% in water, 60 ml) and ethanol (90 ml). The mixture was poured into an autoclave (stainless steel), the autoclave was closed and rinsed a few times with nitrogen. The autoclave was filled with hydrogen (8 bar) and the reaction batch stirred for 5 h at room temperature. On completion of the reaction the catalyst was filtered out over celite and the solvent drawn off in a rotary evaporator at room temperature. The product was crystallized out of acetonitrile.

Yield: 1.30 g (82%)
Synthesis of Structural Units S5, S6, S10, S12, S18-S20




Stage 1. The corresponding boric acid (2.04 mmol) followed by K2CO3 (4.65 mmol), water (1.5 ml) and ethanol (3.5 ml) were added to a solution of 6-bromoimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (1.86 mmol) in toluene (7 ml). Argon was passed through the reaction solution for 15 min. Finally Pd(PPh3)4 (0.093 mmol) was added and the mixture was gassed with argon for a further 15 min. The mixture was then refluxed for 15 hours. On completion of the reaction (DC control) the reaction batch was diluted with ethyl acetate and washed first with water and then with saturated sodium chloride solution. The organic phase was dried over sodium sulfate and the solvent was drawn off completely. The products were crystallized out of a mixture of 25% diethyl ether in hexane, filtered and dried.

Stage 2. The Suzuki product was dissolved in ethanol and NaOH solution (20% in water) was added. The reaction batch was refluxed for 2 hours. On completion of the reaction the solvent was removed in a rotary evaporator and the residue taken up in as small an amount of water as possible. The solution was carefully adjusted to pH 3-4 with HCl solution (10% in water). The precipitated product was filtered and washed with water. The product was taken up in toluene, concentrated to small volume and then dried.

Stage 3. Palladium on activated carbon (1.53 g) was added to a solution of the free acid in a blend of HCl (3% in water, 175 ml) and ethanol (88 ml). The mixture was poured into an autoclave (stainless steel), the autoclave was closed and rinsed a few times with nitrogen. The autoclave was filled with hydrogen (8 bar) and the reaction batch stirred for 8 h at room temperature. On completion of the reaction the catalyst was filtered out over celite and the solvent drawn off in a rotary evaporator at 45° C. The product was crystallized out of methanol diethyl ether.




















Yield (over 3



R1
R2
R3
stages) (%)






















S5
F
H
H
25



S6
H
OCH3
H
18



S10
H
F
H
10



S12
CH3
H
H
36



S18
H
CH3
H
21



S19
F
F
H
33



S20
CH3
H
CH3
61










The following commercially available amines were used for the syntheses:















No.
Name
Supplier









A01
1-(2-Methoxyphenyl)piperazine
Aldrich



A02
Benzylamine
Aldrich



A03
2-Phenylethylamine
Aldrich



A04
3-Picolylamine
Aldrich



A05
4-Benzylpiperidine
Aldrich



A06
Cyclopropylamine
Aldrich



A07
Ethyl piperidine-4-carboxylate
Aldrich



A08
N-Benzyl-2-phenethylamine
Aldrich



A09
2-(3,4-Dimethoxyphenyl)ethanamine
Aldrich



A10
Ethyl piperidine-3-carboxylate
Aldrich



A11
1-(Piperazin-1-yl)ethanone
Aldrich



A12
Pyrrolidine
Aldrich



A13
4-(2-Fluorophenyl)piperazine
Aldrich



A14
Benzo[d][1,3]dioxol-5-ylmethanamine
Aldrich



A15
Butylamine
Aldrich



A16
4-Fluorobenzylamine
Aldrich



A17
1,3,3-Trimethyl-6-azabicyclo[3.2.1]octane
Acros



A18
Amylamine
Aldrich



A19
4-(3-Trifluoromethylphenyl)piperazine
Aldrich



A20
Hexylamine
Aldrich



A21
4-Methylpiperidine
Aldrich



A22
4-Phenylbutyl-2-amine
Aldrich



A23
(3-(Trifluoromethyl)phenyl)methanamine
Aldrich



A24
sec-Butylamine
Aldrich



A25
4-(4-Methoxyphenyl)piperazine
Aldrich



A26
a-Methylbenzylamine
Aldrich



A27
4-(2-Ethoxyphenyl)piperazine
Aldrich



A28
1-Benzhydrylpiperazine
Acros



A29
1-(4-(Trifluoromethyl)phenyl)piperazine
Acros



A30
4-(4-Fluorophenyl)piperazine
Acros



A31
4-(4-Methylphenyl)piperazine
Acros



A32
4-(3-Methylphenyl)piperazine
Acros



A33
Cyclohexylmethanamine
Lancaster



A34
1-Butylpiperazine
Fluka



A36
1-Benzylpiperazine
ACBBlocks



A37
1-(3-Fluorophenyl)piperazine
ABCR



A38
2-Cyclohexylethanamine
Alfa-Aesar



A39
4-(3-(Trifluoromethyl)phenyl)piperidine
Apollo










Synthesis of 1-(3,5-dimethylphenyl)ethanamine A35




3,5-Dimethylacetophenone (3.0 g, 20.2 mmol) was dissolved in ethanolic NH3 solution (2 M in ethanol, 50 ml), tetrapropylorthotitanate (11 ml, 40.4 ml) was added and the mixture was stirred for 6 h at room temperature. NaBH4 (1.16 g, 30.4 mmol) was then added carefully to the reaction solution and the mixture was stirred overnight at room temperature. The reaction mixture was poured into aqueous ammonia solution and filtered. The solid was washed twice more with ethyl acetate (50 ml). The phases were separated and the aqueous phase was extracted twice more with ethyl acetate. The combined organic phases were washed with HCl solution (2 N, 60 ml), the aqueous phase was adjusted to pH 11 with NaOH solution and extracted three times with ethyl acetate (100 ml). The organic phase was washed with saturated NaCl solution (100 ml), dried over MgSO4 and concentrated to small volume. The resulting crude product was used without further purification. Yield: 43%.
Synthesis of 4-(3-(trifluoromethyl)phenyl)butan-2-amine A40




The ketone and liquid ammonia (10 ml/mmol) were poured into the reaction vessel of a hydrogenator and Raney nickel (0.12 g/mmol) was added. The reaction batch was shaken at room temperature for 16 h under hydrogen pressure (50 psi). The reaction mixture was filtered over diatomaceous earth and rewashed three times with DCM. The combined organic phases were dried over Na2SO4 and concentrated to dryness. The crude product was taken up in dioxane saturated with HCl. The solvent was removed in a rotary evaporator and the remaining solid mass treated with diethyl ether. The product was obtained as HCl salt.
Synthesis of N-methyl-4-(3-(trifluoromethyl)phenyl)butan-2-amine A41




Stage 1. TEA (5 eq) was added to a solution of the amine (1 eq) in DCM at room temperature, followed dropwise by TFAA (2 eq). The reaction batch was stirred for 4 h at room temperature (DC control). The reaction mixture was washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over Na2SO4 and concentrated to dryness. The resulting crude product was purified by column chromatography (silica gel, 15% ethyl acetate in hexane).

Yield: 58%
Stage 2. KOtBu was added to a solution of the amide (1 eq) in DMF (2 ml/mmol) at room temperature, followed by methyl iodide (5 eq), and the mixture was stirred for 2 h at 0° C. (DC control). The reaction batch was poured onto ice and the product extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over Na2SO4 and concentrated to dryness. The resulting crude product was purified by column chromatography (silica gel, 5% ethyl acetate in hexane). Yield: 76%.

Stage 3. The methylated amide was dissolved in methanol (4 ml/mmol) and 1 N NaOH (4 ml/mmol) was added. The reaction batch was then stirred for 2 h at room temperature (DC control). The methanol was removed in a rotary evaporator and the product was extracted three times with ethyl acetate. The combined organic phases were dried over Na2SO4 and then concentrated to dryness. The resulting crude product was used without further purification. Yield: 78%.

Example Compounds
Automated Synthesis


    Preparation of the Stock Solutions:
    Solution A (Solution of the Acid Structural Unit in DMA):


The hydrochloride of the acid used was first dried in a vacuum drying oven before use. The corresponding compound was first mixed with 3 molar equivalents of 4-methylmorpholine in DMA at room temperature. Then sufficient solvent was added to produce a 0.15-0.2 molar solution.

    Solution B (Solution of TBTU in DMA):


Solution B was produced from TBTU in DMA (0.3 mol/l).

    Solution C (Solution of the Amine Structural Unit in DMA):


Solution C was produced from the corresponding amine in DMA (0.5 mol/l).
Solution A (100 μmol, 0.5-0.66 ml) and solution B (120 μmol, 0.4 ml) were poured into standard glass reaction vessels using a Cavro RSP9000 robotic system and reacted for 15 min. Then solution C (120 μmol, 0.24 ml) was added using a Cavro RSP9000 robotic system. The reaction batch was then stirred for 16-20 h at room temperature (DC control). The batches were processed by first removing the solvent under vacuum and then adding chloroform (2.5 ml) to the residue. The solution was then extracted first with water (1 ml), then with NaOH solution (10% in water, 1 ml) and subsequently with water (1 ml). The solvent was removed completely. The product was analysed by HPLC-MS and purified by preparative HPLC at a purity of <85%.
The following compounds were produced by automated synthesis.















Starting
Starting

MS


No.
product S
product A
Name
m/z [M + H]+



















1
S1
A05
(4-Benzylpiperidin-1-yl)(6-phenyl-
400.2





5,6,7,8-tetrahydroimidazo[1,2-





a]pyridin-2-yl)methanone


2
S1
A08
N-Benzyl-N-phenethyl-6-phenyl-
436.2





5,6,7,8-tetrahydroimidazo[1,2-





a]pyridine-2-carboxamide


3
S1
A17
(6-Phenyl-5,6,7,8-
378.2





tetrahydroimidazo[1,2-a]pyridin-2-





yl)(1,3,3-trimethyl-6-





azabicyclo[3.2.1]octan-6-yl)methanone


4
S5
A17
(6-(3-Fluorophenyl)-5,6,7,8-
396.2





tetrahydroimidazo[1,2-a]pyridin-2-





yl)(1,3,3-trimethyl-6-





azabicyclo[3.2.1]octan-6-yl)methanone


5
S2
A02
N-Benzyl-6-(4-methoxy-3,5-
390.2





dimethylphenyl)-5,6,7,8-





tetrahydroimidazo[1,2-a]pyridine-2-





carboxamide


6
S2
A13
(4-(2-Fluorophenyl)piperazin-1-yl)(6-(4-
463.2





methoxy-3,5-dimethylphenyl)-5,6,7,8-





tetrahydroimidazo[1,2-a]pyridin-2-





yl)methanone


7
S7
A19
(6-(5-Fluoro-2-methoxyphenyl)-5,6,7,8-
503.2





tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-





(3-(trifluoromethyl)phenyl)piperazin-1-





yl)methanone


8
S7
A05
(4-Benzylpiperidin-1-yl)(6-(5-fluoro-2-
448.2





methoxyphenyl)-5,6,7,8-





tetrahydroimidazo[1,2-a]pyridin-2-





yl)methanone


9
S7
A17
(6-(5-Fluoro-2-methoxyphenyl)-5,6,7,8-
426.2





tetrahydroimidazo[1,2-a]pyridin-2-





yl)(1,3,3-trimethyl-6-





azabicyclo[3.2.1]octan-6-yl)methanone


10
S2
A01
(6-(4-Methoxy-3,5-dimethylphenyl)-
475.3





5,6,7,8-tetrahydroimidazo[1,2-





a]pyridin-2-yl)(4-(2-





methoxyphenyl)piperazin-1-





yl)methanone


11
S9
A05
(4-Benzylpiperidin-1-yl)(6-(4-
428.3





ethylphenyl)-5,6,7,8-





tetrahydroimidazo[1,2-a]pyridin-2-





yl)methanone


12
S8
A17
(6-(2,5-Dimethoxyphenyl)-5,6,7,8-
438.3





tetrahydroimidazo[1,2-a]pyridin-2-





yl)(1,3,3-trimethyl-6-





azabicyclo[3.2.1]octan-6-yl)methanone


13
S3
A13
(6-(4-Fluoro-3-methylphenyl)-5,6,7,8-
437.2





tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-





(2-fluorophenyl)piperazin-1-





yl)methanone


14
S3
A26
6-(4-Fluoro-3-methylphenyl)-N-(1-
378.2





phenylethyl)-5,6,7,8-tetrahydroimidazo-





[1,2-a]pyridine-2-carboxamide


15
S2
A18
6-(4-Methoxy-3,5-dimethylphenyl)-N-
370.2





pentyl-5,6,7,8-tetrahydroimidazo[1,2-





a]pyridine-2-carboxamide


16
S2
A20
N-Hexyl-6-(4-methoxy-3,5-
384.3





dimethylphenyl)-5,6,7,8-





tetrahydroimidazo[1,2-a]pyridine-2-





carboxamide


17
S2
A23
6-(4-Methoxy-3,5-dimethylphenyl)-N-
458.2





(3-(trifluoromethyl)benzyl)-5,6,7,8-





tetrahydroimidazo[1,2-a]pyridine-2-





carboxamide


18
S11
A24
N-sec-Butyl-6-(4-phenoxyphenyl)-
390.2





5,6,7,8-tetrahydroimidazo[1,2-





a]pyridine-2-carboxamide


19
S11
A15
N-Butyl-6-(4-phenoxyphenyl)-5,6,7,8-
390.2





tetrahydroimidazo[1,2-a]pyridine-2-





carboxamide


20
S11
A07
Ethyl 1-(6-(4-phenoxyphenyl)-5,6,7,8-
474.2





tetrahydroimidazo[1,2-a]pyridine-2-





carbonyl)piperidine-4-carboxylate


21
S11
A21
(4-Methylpiperidin-1-yl)(6-(4-
416.2





phenoxyphenyl)-5,6,7,8-





tetrahydroimidazo[1,2-a]pyridin-2-





yl)methanone


22
S11
A10
Ethyl 1-(6-(4-phenoxyphenyl)-5,6,7,8-
474.2





tetrahydroimidazo[1,2-a]pyridine-2-





carbonyl)piperidine-3-carboxylate


23
S11
A11
1-(4-(6-(4-Phenoxyphenyl)-5,6,7,8-
445.2





tetrahydroimidazo[1,2-a]pyridine-2-





carbonyl)piperazin-1-yl)ethanone


24
S11
A04
6-(4-Phenoxyphenyl)-N-(pyridin-3-
425.2





ylmethyl)-5,6,7,8-tetrahydroimidazo-





[1,2-a]pyridine-2-carboxamide


25
S11
A12
(6-(4-Phenoxyphenyl)-5,6,7,8-
388.2





tetrahydroimidazo[1,2-a]pyridin-2-





yl)(pyrrolidin-1-yl)methanone


26
S11
A06
N-Cyclopropyl-6-(4-phenoxyphenyl)-
374.2





5,6,7,8-tetrahydroimidazo[1,2-





a]pyridine-2-carboxamide


27
S11
A09
N-(3,4-Dimethoxyphenethyl)-6-(4-
498.2





phenoxyphenyl)-5,6,7,8-





tetrahydroimidazo[1,2-a]pyridine-2-





carboxamide


28
S11
A18
N-Pentyl-6-(4-phenoxyphenyl)-5,6,7,8-
404.2





tetrahydroimidazo[1,2-a]pyridin-2-





carboxamide


29
S12
A12
Pyrrolidin-1-yl(6-m-tolyl-5,6,7,8-
310.2





tetrahydroimidazo[1,2-a]pyridin-2-





yl)methanone


30
S14
A12
(6-(3,5-Bis(trifluoromethyl)phenyl)-
432.1





5,6,7,8-tetrahydroimidazo[1,2-





a]pyridin-2-yl)(pyrrolidin-1-





yl)methanone


31
S15
A12
Pyrrolidin-1-yl(6-(3-(trifluoromethyl)-
364.2





phenyl)-5,6,7,8-tetrahydroimidazo[1,2-





a]pyridin-2-yl)methanone


32
S15
A13
(4-(2-Fluorophenyl)piperazin-1-yl)(6-(3-
473.2





(trifluoromethyl)phenyl)-5,6,7,8-





tetrahydroimidazo[1,2-a]pyridin-2-





yl)methanone


33
S16
A12
(6-(2,4-Dimethoxyphenyl)-5,6,7,8-
356.2





tetrahydroimidazo[1,2-a]pyridin-2-





yl)(pyrrolidin-1-yl)methanone


34
S17
A12
Pyrrolidin-1-yl(6-o-tolyl-5,6,7,8-
310.2





tetrahydroimidazo[1,2-a]pyridin-2-





yl)methanone


35
S17
A19
(6-o-Tolyl-5,6,7,8-tetrahydroimidazo-
469.2





[1,2-a]pyridin-2-yl)(4-(3-





(trifluoromethyl)phenyl)piperazin-1-





yl)methanone


36
S13
A12
(6-(2,5-Difluorophenyl)-5,6,7,8-
332.1





tetrahydroimidazo[1,2-a]pyridin-2-





yl)(pyrrolidin-1-yl)methanone


37
S9
A12
(6-(4-Ethylphenyl)-5,6,7,8-
324.2





tetrahydroimidazo[1,2-a]pyridin-2-





yl)(pyrrolidin-1-yl)methanone


38
S10
A17
(6-(4-Fluorophenyl)-5,6,7,8-
396.2





tetrahydroimidazo[1,2-a]pyridin-2-





yl)(1,3,3-trimethyl-6-





azabicyclo[3.2.1]octan-6-yl)methanone


39
S6
A23
6-(4-Methoxyphenyl)-N-(3-
430.2





(trifluoromethyl)benzyl)-5,6,7,8-





tetrahydroimidazo[1,2-a]pyridine-2-





carboxamide


40
S9
A03
6-(4-Ethylphenyl)-N-phenethyl-5,6,7,8-
374.2





tetrahydroimidazo[1,2-a]pyridine-2-





carboxamide


41
S10
A05
(4-Benzylpiperidin-1-yl)(6-(4-
418.2





fluorophenyl)-5,6,7,8-





tetrahydroimidazo[1,2-a]pyridin-2-





yl)methanone


42
S14
A14
N-(Benzo[d][1,3]dioxol-5-ylmethyl)-6-
512.1





(3,5-bis(trifluoromethyl)phenyl)-5,6,7,8-





tetrahydroimidazo[1,2-a]pyridine-2-





carboxamide


43
S14
A02
N-Benzyl-6-(3,5-
468.1





bis(trifluoromethyl)phenyl)-5,6,7,8-





tetrahydroimidazo[1,2-a]pyridine-2-





carboxamide


44
S2
A25
(6-(4-Methoxy-3,5-dimethylphenyl)-
475.3





5,6,7,8-tetrahydroimidazo[1,2-





a]pyridin-2-yl)(4-(4-methoxyphenyl)-





piperazin-1-yl)methanone


45
S12
A27
(4-(2-Ethoxyphenyl)piperazin-1-yl)(6-
445.3





m-tolyl-5,6,7,8-tetrahydroimidazo[1,2-





a]pyridin-2-yl)methanone


46
S16
A19
(6-(2,4-Dimethoxyphenyl)-5,6,7,8-
515.2





tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-





(3-(trifluoromethyl)phenyl)piperazin-1-





yl)methanone


47
S10
A19
(6-(4-Fluorophenyl)-5,6,7,8-
473.2





tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-





(3-(trifluoromethyl)phenyl)piperazin-1-





yl)methanone


48
S5
A19
(6-(3-Fluorophenyl)-5,6,7,8-
473.2





tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-





(3-(trifluoromethyl)phenyl)piperazin-1-





yl)methanone


49
S2
A16
N-(4-Fluorobenzyl)-6-(4-methoxy-3,5-
408.2





dimethylphenyl)-5,6,7,8-tetrahydro-





imidazo[1,2-a]pyridine-2-carboxamide


50
S4
A05
(4-Benzylpiperidin-1-yl)(6-(3-
430.2





methoxyphenyl)-5,6,7,8-tetrahydro-





imidazo[1,2-a]pyridin-2-yl)methanone


51
S5
A22
6-(3-Fluorophenyl)-N-(4-phenylbutan-
392.2





2-yl)-5,6,7,8-tetrahydroimidazo[1,2-





a]pyridine-2-carboxamide


52
S9
A22
6-(4-Ethylphenyl)-N-(4-phenylbutan-2-
402.2





yl)-5,6,7,8-tetrahydroimidazo[1,2-





a]pyridine-2-carboxamide









Equipment:

    Waters 1525 HPLC system: high-pressure binary HPLC pump with integrated splitter, MUX-UV 2488 detector (Waters Corp.) and in-house-developed autosampler based on a Cavro RSP 9452 (Cavro Scientific Inst., Inc.) robot workstation.
    ZQ2000 MS instrument (Waters Corp.) with ESI interface integrated with MUX (Waters Corp.)












Method:















HPLC column:


LiChroCART 30-4 Purospher STAR RP-18, end-capped, 3 μm (Merck)


Gradient:








Eluent (A):
Acetonitrile-H2O = 5:95 with 20 mM



HCOONH4/NH4OH buffer, pH 7.4


Eluent (B):
Acetonitrile-H2O = 80:20 with 20 mM



HCOONH4/NH4OH buffer, pH 7.4







Gradient program:












Min.
A %
B %



Column temperature:
0.0
95
5


Flow rate:
2.5
5
95


Sample concentration:
4.3
5
95



4.4
95
5


Solvent samples:
5.0
95
5








Injection volume:
2.5 μl


Detection:
UV 220 nm









Solid Substances

(6-Phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)methanone 53




TBTU (276 mg; 0.86 mmol) and N-methylmorpholine (237 μl; 218 mg; 2.15 mmol) were added to a solution of 6-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid hydrochloride (200 mg; 0.72 mmol) in DMF (1 ml). The reaction mixture was stirred vigorously for 30 min at room temperature and then 1-(3-trifluoromethylphenyl)piperazine (162 μl; 198 mg; 0.86 mmol) was added. The reaction mixture was stirred for 4 h at room temperature, then poured onto water and extracted with chloroform. The organic phase was dried over MgSO4, filtered and concentrated to small volume. The raw product was purified by column chromatography on silica gel (chloroform). Yield: 191 mg (59%).
1H NMR (600 MHz, DMSO-d6) d ppm 2.02-2.14 (m, 2H) 2.21 (s, 6H) 2.46-2.55 (m, 3H) 2.79-2.97 (m, 2H) 3.06-3.19 (m, 1H) 3.23-3.35 (m, 5H) 3.64 (s, 3H) 3.92 (t, J=11.71 Hz, 1H) 4.22 (dd, J=12.46, 4.91 Hz, 1H) 7.01 (s, 2H) 7.09 (d, J=6.80 Hz, 1H) 7.21 (br. s., 1H) 7.25 (d, J=8.31 Hz, 1H) 7.43 (t, J=7.93 Hz, 1H) 7.56 (br. s., 1H); MS: m/z 455.2 [M+H]+
(6-(4-Methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)methanone 54




TBTU (240 mg; 0.75 mmol) and N-methylmorpholine (206 μl; 189 mg; 1.87 mmol) were added to a solution of 6-(4-methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid hydrochloride (210 mg; 0.63 mmol) in DMF (1 ml). The reaction mixture was stirred vigorously for 30 min at room temperature and then 1-(3-trifluoromethylphenyl)piperazine (140 μl; 172 mg; 0.75 mmol) was added. The reaction mixture was stirred for 4 h at room temperature, then poured onto water and extracted with chloroform. The organic phase was dried over MgSO4, filtered and concentrated to small volume. The raw product was purified by column chromatography on silica gel (chloroform). Yield: 198 mg (62%).
1H NMR (600 MHz, DMSO-d6) d ppm 2.00-2.14 (m, 2H) 2.21 (s, 6H) 2.78-2.97 (m, 2H) 3.08-3.20 (m, 1H) 3.24-3.30 (m, 8H) 3.64 (s, 3H) 3.92 (t, J=11.71 Hz, 1H) 4.22 (dd, J=12.46, 4.91 Hz, 1H) 7.01 (s, 2H) 7.09 (d, J=6.80 Hz, 1H) 7.21 (br. s., 1H) 7.25 (d, J=8.31 Hz, 1H) 7.43 (t, J=7.93 Hz, 1H) 7.56 (s, 1H); MS: m/z 513.2 [M+H]+
(4-Benzylpiperidin-1-yl)(6-(4-methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo-[1,2-a]pyridin-2-yl)methanone 55




TBTU (212 mg; 0.66 mmol) and N-methylmorpholine (181 μl; 167 mg; 1.65 mmol) were added to a solution of 6-(4-methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid hydrochloride (165 mg; 0.49 mmol) in DMF (1 ml). The reaction mixture was stirred vigorously for 30 min at room temperature and then 4-benzylpiperidine (116 μl; 116 mg; 0.7 mmol) was added. The reaction mixture was stirred for 4 h at room temperature and then poured onto water. The precipitated solid was filtered out. Yield: 182 mg (81%)
1H NMR (600 MHz, DMSO-d6) d ppm 0.97-1.28 (m, 2H) 1.51-1.69 (m, 2H) 1.72-1.87 (m, 1H) 1.97-2.11 (m, 2H) 2.21 (s, 6H) 2.50-2.56 (m, 4H) 2.71-2.99 (m, 4H) 3.01-3.21 (m, 1H) 3.63 (s, 3H) 3.77-3.99 (m, 1H) 4.10-4.26 (m, 1H) 7.00 (s, 2H) 7.09-7.22 (m, 3H) 7.28 (t, J=7.18 Hz, 2H) 7.45 (br. s., 1H); MS: m/z 458.3 [M+H]+
(6-(4-Methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-yl)methanone 56




TBTU (212 mg; 0.66 mmol) and N-methylmorpholine (181 μl; 167 mg; 1.65 mmol) were added to a solution of 6-(4-methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid hydrochloride (165 mg; 0.49 mmol) in DMF (1 ml). The reaction mixture was stirred vigorously for 30 min at room temperature and then 1,3,3-trimethyl-6-azabicyclo[3.2.1.]octane (112 μl; 101 mg; 0.7 mmol) was added. The reaction mixture was stirred for 4 h at room temperature and then poured onto water. The precipitated solid was filtered.
Yield: 180 mg (84%) mixture of diastereomers. ESI-MS: m/z 436.3 [M+H]+.
(4-Benzylpiperidin-1-yl)(6-(4-fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)methanone 57




TBTU (295 mg; 0.92 mmol) and N-methylmorpholine (253 μl; 232 mg; 2.3 mmol) were added to a solution of 6-(4-fluoro-3-methylphenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-2-carboxylic acid hydrochloride (210 mg; 0.68 mmol) in DMF (1 ml). The reaction mixture was stirred vigorously for 30 min at room temperature and then 4-benzylpiperidine (162 μl; 161 mg; 0.9 mmol) was added. The reaction mixture was stirred for 4 h at room temperature and then poured onto water. The precipitated solid was filtered out and washed with petroleum ether. Yield: 205 mg (72%)
1H NMR (600 MHz, DMSO-d6) d ppm 1.02-1.18 (m, 2H) 1.54-1.66 (m, 2H) 1.73-1.85 (m, 1H) 2.02-2.14 (m, 2H) 2.23 (s, 3H) 2.51-2.56 (m, 2H) 2.76-2.97 (m, 4H) 3.16-3.26 (m, 1H) 3.25-3.30 (m, 2H) 3.92 (t, J=11.71 Hz, 1H) 4.21 (dd, J=12.46, 4.91 Hz, 1H) 7.10 (t, J=9.06 Hz, 1H) 7.14-7.23 (m, 4H) 7.28 (t, J=6.80 Hz, 3H) 7.46 (s, 1H)); MS: m/z 432.2 [M+H]+
(6-(4-Fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)methanone 58




TBTU (295 mg; 0.92 mmol) and N-methylmorpholine (253 μl; 232 mg; 2.3 mmol) were added to a solution of 6-(4-fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid hydrochloride (210 mg; 0.68 mmol) in DMF (1 ml). The reaction mixture was stirred vigorously for 30 min at room temperature and then 1-(3-trifluoromethylphenyl)piperazine (173 μl; 212 mg; 0.92 mmol) was added. The reaction mixture was stirred for 4 h at room temperature and poured onto water. The precipitated solid was purified by column chromatography on silica gel (chloroform). Yield: 166 mg (50%)
1H NMR (600 MHz, DMSO-d6) d ppm 2.00-2.19 (m, 2H) 2.23 (s, 3H) 2.78-3.02 (m, 2H) 3.11-3.29 (m, 5H) 3.55-3.89 (m, 2H) 3.95 (t, J=11.71 Hz, 1H) 4.25 (dd, J=12.46, 4.91 Hz, 1H) 4.30-4.66 (m, 2H) 7.01-7.16 (m, 2H) 7.17-7.24 (m, 2H) 7.25 (d, J=9.06 Hz, 1H) 7.29 (d, J=7.55 Hz, 1H) 7.43 (t, J=7.93 Hz, 1H) 7.57 (s, 1H); MS: m/z 487.2 [M+H]+
(4-Benzhydrylpiperazin-1-yl)(6-(4-methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)methanone 59




TBTU (212 mg; 0.66 mmol) and N-methylmorpholine (181 μl; 167 mg; 1.65 mmol) were added to a solution of 6-(4-methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid hydrochloride (165 mg; 0.49 mmol) in DMF (1 ml). The reaction mixture was stirred vigorously for 30 min at room temperature and then diphenylmethylpiperazine (166 mg; 0.7 mmol) was added. The reaction mixture was stirred for 4 h at room temperature and poured onto water. The precipitated solid was filtered. Yield: 232 mg (88%).
1H NMR (600 MHz, DMSO-d6) d ppm 1.96-2.12 (m, 2H) 2.20 (s, 6H) 2.26-2.38 (m, 4H) 2.45-2.54 (m, 2H) 2.72-2.94 (m, 2H) 3.01-3.18 (m, 1H) 3.55-3.72 (m, 4H) 3.87 (t, J=111.71 Hz, 1H) 4.18 (dd, J=12.09, 4.53 Hz, 2H) 4.35 (s, 1H) 6.99 (s, 2H) 7.20 (t, J=7.18 Hz, 2H) 7.30 (t, J=7.55 Hz, 4H) 7.43 (d, J=7.55 Hz, 4H) 7.47 (s, 1H); MS: m/z 535.3 [M+H]+
6-(3-Methoxyphenyl)-N-(4-phenylbutan-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide 60




TBTU (310 mg; 0.97 mmol) and N-methylmorpholine (267 μl; 245 mg; 2.4 mmol) were added to a solution of 6-(3-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid hydrochloride (250 mg; 0.8 mmol) in DMF (1 ml). The reaction mixture was stirred vigorously for 30 min at room temperature and then 1-methyl-3-phenylpropylamine (157 μl; 145 mg; 1.0 mmol) was added. The reaction mixture was stirred for 4 h at room temperature, poured onto water and extracted with chloroform. The organic phase was dried over MgSO4, filtered and concentrated to small volume. The raw product was purified by column chromatography on silica gel (chloroform). Yield: 183 mg (56%)
1H NMR (600 MHz, DMSO-d6) d ppm 1.14 (d, J=6.04 Hz, 3H) 1.63-1.77 (m, 1H) 1.81-1.91 (m, 1H) 2.06-2.19 (m, 2H) 2.52-2.63 (m, 2H) 2.80-2.96 (m, 2H) 3.18-3.27 (m, 1H) 3.75 (s, 3H) 3.93-4.05 (m, 2H) 4.25 (dd, J=12.09, 4.53 Hz, 1H) 6.84 (d, J=8.31 Hz, 1H) 6.90-6.98 (m, 2H) 7.12-7.22 (m, 3H) 7.23-7.31 (m, 3H) 7.50 (s, 1H) 7.58 (d, J=8.31 Hz, 1H); MS: m/z 404.2 [M+H]+
Synthesis of Compounds 61 to 88
TBTU (1.5 eq) and N-methylmorpholine (3.5 eq) were added to a solution of carboxylic acid (500 mg) in DMF (2.5 ml). The reaction mixture was stirred vigorously for 30 min at room temperature and then the corresponding amine (1.1 eq) was added. The reaction mixture was stirred overnight at room temperature. On completion of the reaction the mixture was diluted with ethyl acetate and washed successively with saturated ammonium chloride solution, saturated sodium chloride solution, sodium hydrogen carbonate solution and saturated sodium chloride solution. The organic phase was dried over sodium sulfate and concentrated to small volume. The crude product was purified on silica gel by column chromatography using the mobile solvents specified in the following table.
















Yield
Mobile
MS m/z


No.
Structure
%
solvent
[M + H]+







61




80
80% ethyl acetate in hexane
418.2



(4-Benzylpiperidin-1-yl)(6-(3-fluorophenyl)-



5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-



yl)methanone


 


62




28
60% ethyl acetate in hexane
487.2



(6-(4-Fluoro-3-methylphenyl)-5,6,7,8-



tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(4-



(trifluoromethyl)phenyl)piperazin-1-



yl)methanone


 


63




32
5% methanol in DCM
437.2



(6-(4-Fluoro-3-methylphenyl)-5,6,7,8-



tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(4-



fluorophenyl)piperazin-1-yl)methanone


 


64




68
70% ethyl acetate in hexane
433.2



(6-(4-Fluoro-3-methylphenyl)-5,6,7,8-



tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(4-



methylphenyl)piperazin-1-yl)methanone


 


65




70
70% ethyl acetate in hexane
433.2



(6-(4-Fluoro-3-methylphenyl)-5,6,7,8-



tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-



methylphenyl)piperazin-1-yl)methanone


 


66




56
80% ethyl acetate in hexane
399.2



(4-Butylpiperazin-1-yl)(6-(4-fluoro-3-



methylphenyl)-5,6,7,8-



tetrahydroimidazo[1,2-a]pyridin-2-



yl)methanone


 


67




67
80% ethyl acetate in hexane
508.3



(4-Benzhydrylpiperidin-1-yl)(6-(4-fluoro-3-



methylphenyl)-5,6,7,8-



tetrahydroimidazo[1,2-a]pyridin-2-



yl)methanone


 


68




54
70% ethyl acetate in hexane
370.2



N-(Cyclohexylmethyl)-6-(4-fluoro-3-



methylphenyl)-5,6,7,8-



tetrahydroimidazo[1,2-a]pyridine-2-



carboxamide


 


69




40
70% ethyl acetate in hexane
485.2



(6-(4-Methoxyphenyl)-5,6,7,8-



tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-



(trifluoromethyl)phenyl)piperazin-1-



yl)methanone


 


70




58
80% ethyl acetate in hexane
414.2



(4-Benzylpiperidin-1-yl)(6-m-tolyl-5,6,7,8-



tetrahydroimidazo[1,2-a]pyridin-2-



yl)methanone


 


71




76
90% ethyl acetate in hexane
485.2



(6-(3-Methoxyphenyl)-5,6,7,8-



tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-



(trifluoromethyl)phenyl)piperazin-1-



yl)methanone


 


72




66
80% ethyl acetate in hexane
406.2



6-(4-Fluoro-3-methylphenyl)-N-(4-



phenylbutan-2-yl)-5,6,7,8-



tetrahydroimidazo[1,2-a]pyridine-2-



carboxamide


73




22
80% ethyl acetate in hexane
414.2



4-Benzylpiperidin-1-yl)(6-p-tolyl-5,6,7,8-



tetrahydroimidazo[1,2-a]pyridin-2-



yl)methanone


 


74




19
80% ethyl acetate in hexane
469.2



(6-p-Tolyl-5,6,7,8-tetrahydroimidazo[1,2-



a]pyridin-2-yl)(4-(3-



(trifluoromethyl)phenyl)piperazin-1-



yl)methanone


 


75




33
80% ethyl acetate in hexane
469.2



(6-m-Tolyl-5,6,7,8-tetrahydroimidazo[1,2-



a]pyridin-2-yl)(4-(3-



(trifluoromethyl)phenyl)piperazin-1-



yl)methanone


 


76




35
75% ethyl acetate in hexane
430.2



(4-Benzylpiperidin-1-yl)(6-(4-



methoxyphenyl)-5,6,7,8-



tetrahydroimidazo[1,2-a]pyridin-2-



yl)methanone


 


77




50
80% ethyl acetate in hexane
483.2



(6-(3,5-Dimethylphenyl)-5,6,7,8-



tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-



(trifluoromethyl)phenyl)piperazin-1-



yl)methanone


 


78




41
75% ethyl acetate in hexane
406.2



N-(1-(3,5-Dimethylphenyl)ethyl)-6-(4-fluoro-



3-methylphenyl)-5,6,7,8-



tetrahydroimidazo[1,2-a]pyridine-2-



carboxamide


 


79






491.2



(6-(3,4-Difluorophenyl)-5,6,7,8-



tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-



(trifluoromethyl)phenyl)piperazin-1-



yl)methanone


 


80






433.2



(4-Benzylpiperazin-1-yl)(6-(4-fluoro-3-



methylphenyl)-5,6,7,8-



tetrahydroimidazo[1,2-a]pyridin-2-



yl)methanone


 


81






547.2



(6-(4-Phenoxyphenyl)-5,6,7,8-



tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-



(trifluoromethyl)phenyl)piperazin-1-



yl)methanone


 


82






561.2



(6-(4-(Benzyloxy)phenyl)-5,6,7,8-



tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-



(trifluoromethyl)phenyl)piperazin-1-



yl)methanone


 


83




66
80% ethyl acetate in hexane
436.2



(6-(4-Fluoro-3-methylphenyl)-5,6,7,8-



tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-



fluorophenyl)piperazin-1-yl)methanone


 


84




86
80% ethyl acetate in hexane
409.3



(6-(4-Fluoro-3-methylphenyl)-5,6,7,8-



tetrahydroimidazo[1,2-a]pyridin-2-yl)(1,3,3-



trimethyl-6-azabicyclo[3.2.1]octan-6-



yl)methanone


 


85




62
80% ethyl acetate in hexane
485.2



(6-(4-Fluoro-3-methylphenyl)-5,6,7,8-



tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-



(trifluoromethyl)phenyl)piperidin-1-



yl)methanone


 


86




29
80% ethyl acetate in hexane
473.2



6-(4-Fluoro-3-methylphenyl)-N-(4-(3-



(trifluoromethyl)phenyl)butan-2-yl)-5,6,7,8-



tetrahydroimidazo[1,2-a]pyridine-2-



carboxamide


 


87




48
80% ethyl acetate in hexane
487.2



6-(4-Fluoro-3-methylphenyl)-N-methyl-N-(4-



(3-(trifluoromethyl)phenyl)butan-2-yl)-



5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-



carboxamide


 


88






383.2



N-(2-Cyclohexylethyl)-6-(4-fluoro-3-



methylphenyl)-5,6,7,8-



tetrahydroimidazo[1,2-a]pyridine-2-



carboxamide









N-(2-Cyclohexylethyl)-6-(4-fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide




Stage 1. TBTU (1.5 eq) and N-methylmorpholine (3.5 eq) were added to a solution of carboxylic acid (500 mg) in DMF (2.5 ml). The reaction mixture was stirred vigorously for 30 min at room temperature and then the corresponding amine (1.1 eq) was added. The reaction mixture was stirred overnight at room temperature. On completion of the reaction the mixture was diluted with ethyl acetate and washed successively with saturated ammonium chloride solution, saturated sodium chloride solution, sodium hydrogen carbonate solution and saturated sodium chloride solution. The organic phase was dried over sodium sulfate and concentrated to small volume. The crude product was crystallized out of hexane/diethyl ether. Yield: 53%.

Stage 2. The amide was dissolved in ethanol and Pd (10% on carbon, 90 mg/mmol) was added. The reaction batch was stirred for 24 h at room temperature under a hydrogen atmosphere. The reaction mixture was filtered over diatomaceous earth and concentrated to small volume. The product was used in a further process without further purification.

Biological Data
Fluorescence Assay Using a Voltage-Sensitive Dye
Human CHO-K1 cells expressing KCNQ2/3 channels are cultivated adherently at 37° C., 5% CO2 and 95% humidity in cell culture bottles (e.g. 80 cm2 TC flasks, Nunc) with MEM Alpha Medium (1×, liquid, Invitrogen, #22571), 10% foetal calf serum (FCS) (Invitrogen, #10270-106, heat-inactivated) and the necessary selection antibiotics. Before being spread out for the measurements, the cells are washed with a 1×DPBS buffer without Ca2+/Mg2+ (e.g. Invitrogen, #14190-094) and detached from the bottom of the culture vessel by means of Accutase (PAA Laboratories, #L11-007) (incubation with Accutase for 15 min at 37° C.). The cell count then present is determined using a CASYTM cell counter (TCC model, Schärfe System) in order subsequently to apply 20,000 cells/well/100 μl of the described nutrient medium to 96-well measuring plates of the CorningTM CellBINDTM type (flat clear-bottom black polystyrene microplates, #3340). Incubation is then carried out for one hour at room temperature, without gassing or adjusting the humidity, followed by incubation for 24 hours at 37° C., 5% CO2 and 95% humidity.
The voltage-sensitive fluorescent dye from the Membrane Potential Assay Kit (Red bulk format part R8123 for FLIPR, Molecular DevicesTM) is prepared by dissolving the contents of a vessel of Membrane Potential Assay Kit Red Component A in 200 ml of extracellular buffer (ES buffer, 120 mM NaCl, 1 mM KCl, 10 mM HEPES, 2 mM CaCl2, 2 mM MgCl2, 10 mM glucose; pH 7.4). After removal of the nutrient medium, the cells are washed with 200 μl of ES buffer, then covered with a layer of 100 μl of the dye solution prepared above and incubated for 45 min at room temperature with exclusion of light.
The fluorescence measurements are carried out with a BMG Labtech FLUOstarTM or BMG Labtech POLARstarTM instrument (525 nm excitation, 560 nm emission, bottom-read mode). After incubation of the dye, 50 μl of the substances to be tested in the desired concentrations, or 50 μl of ES buffer for control purposes, are introduced into separate cavities of the measuring plate and incubated for 30 min at room temperature whilst being shielded from light. The fluorescence intensity of the dye is then measured for 5 min and the fluorescence value F1 of each well is thus determined at a given, constant time. 15 μl of a 100 mM KCl solution (final concentration 92 mM) are then added to each well. The change in fluorescence is subsequently measured until all relevant measured values have been obtained (mainly 5-30 min). At a given time after KCl application, a fluorescence value F2 is determined, in this case at the time of the fluorescence peak.
For calculation, the fluorescence intensity F2 is compared with the fluorescence intensity F1, and the agonistic activity of the target compound on the potassium channel is determined therefrom. F2 and F1 are calculated as follows:




  
    
      (
      
        
          
            F
            2
          
          -
          
            F
            1
          
        
        
          F
          1
        
      
      )
    
    ×
    100
  
  =
  
    
      
        Δ
        ⁢
        
          
        
        ⁢
        F
      
      F
    
    ⁢
    
      (
      %
      )
    
  




In order to determine whether a substance has an agonistic activity,





  
    
      Δ
      ⁢
      
        
      
      ⁢
      F
    
    F
  
  ,




for example, can be compared with





  
    (
    
      
        Δ
        ⁢
        
          
        
        ⁢
        F
      
      F
    
    )
  
  K




of control cells.





  
    (
    
      
        Δ
        ⁢
        
          
        
        ⁢
        F
      
      F
    
    )
  
  K




is determined by adding to the reaction batch only the buffer solution instead of the substance to be tested, determining the value F1K of the fluorescence intensity, adding the potassium ions as described above and measuring a value F2K of the fluorescence intensity. Then F2K and F1K are calculated as follows:





  
    
      (
      
        
          
            F
            
              2
              ⁢
              K
            
          
          -
          
            F
            
              1
              ⁢
              K
            
          
        
        
          F
          
            1
            ⁢
            K
          
        
      
      )
    
    ×
    100
  
  =
  
    
      
        (
        
          
            Δ
            ⁢
            
              
            
            ⁢
            F
          
          F
        
        )
      
      K
    
    ⁢
    
      (
      %
      )
    
  




A substance has an agonistic activity on the potassium channel when





  
    Δ
    ⁢
    
      
    
    ⁢
    F
  
  F




is greater than





  
    
      (
      
        
          Δ
          ⁢
          
            
          
          ⁢
          F
        
        F
      
      )
    
    K
  
  :








  
    
      
        Δ
        ⁢
        
          
        
        ⁢
        F
      
      F
    
    ⁢
    
      
    
    〉
  
  ⁢
  
    
  
  ⁢
  
    
      (
      
        
          Δ
          ⁢
          
            
          
          ⁢
          F
        
        F
      
      )
    
    K
  




Independently of the comparison of





  
    
      
        Δ
        ⁢
        
          
        
        ⁢
        F
      
      F
    
    ⁢
    
      
    
    ⁢
    with
    ⁢
    
      
    
    ⁢
    
      
        (
        
          
            Δ
            ⁢
            
              
            
            ⁢
            F
          
          F
        
        )
      
      K
    
  
  ,




it is also possible to conclude that a target compound has an agonistic activity if an increase in





  
    Δ
    ⁢
    
      
    
    ⁢
    F
  
  F




is to be observed as the dosage of the target compound increases. Calculations of EC50 and IC50 values are carried out with the aid of Prism 4 software (GraphPad SoftwareTM).














% Stimulation




[10 μmol]


No.
Average
EC50 [μM]

















1
16.2



2
20.0


3
16.7


4
20.7


5
15.5


6

7.4


7
30.0


8
29.1


9

11.92


10
15.7


11
38.5


12
51.8


13
18.0


14
24.7


15
16.8


16

3.95


17
18.5


18
18.6


19

6.21


20

11.61


21

8.4


22
18.0


23

5.81


24

6.14


25

2.33


26
17.4


27

6.35


28

9.38


29
26.2


30
20.9


31
17.6


32
21.2


33
24.5


34
32.2


35
20.9


36
21.7


37
15.5


38
25.9


39
17.8


40
16.6


41
29.4


42
18.1


43
16.3


44
27.5


45

7.98


46

3.98


47
63.5


48
33.0


49
15.1


50
25.7


51
16.2


52
34.2


53

8.34


54

2.45


55

5.42


56

11.31


57

9.71


58

4.46


59

8.4


60

6.4


61
82.180


62
40.840


63
96.670


64
46.720


65
131.557


66


67
33.307


68
25.127


69
30.060


70
123.123


71
115.307


72
103.377


73
88.763


74
51.927


75
126.850


76
65.087


77

0.08


78
29.653


79
125.493


80
33.123


81


82
32.733


83

6.5


84
37.873


85
120.005


86

1.2


87
48.435


88
47.930









List Of Abbreviations

    CDI 1,1′-carbonyl diimidazole
    d day(s)
    dba dibenzylidene acetone
    DCE 1,2-dichloroethane
    DCC N,N′-dicyclohexyl carbodiimide
    DCM dichloromethane
    DIEA diisopropylethylamine
    DMA N,N-dimethylacetamide
    DMAP 4-(dimethylamino)pyridine
    DMF dimethylformamide
    dppf 1,1′-bis(diphenylphosphinoferrocene)
    EDCI N-(3-dimethylaminopropyl)-N′-ethyl carbodiimide
    EDTA ethylenediamine-N,N,N′,N′-tetraacetic acid
    h hour(s)
    HBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
    HOBt 1-hydroxy-1H-benzotriazole
    M molar
    min minute(s)
    N normal
    OAc acetate
    P(Cy)3 tricyclohexylphosphine
    P(o-tolyl)3 tri-o-tolylphosphine
    PPh3 triphenylphosphine
    quant. quantitative
    TBTU O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluronium tetrafluoroborate
    TEA triethylamine
    TFA trifluoroacetic acid
    THF tetrahydrofuran


The foregoing description and examples have been set forth merely to illustrate the invention and are not intended to be limiting. Since modifications of the described embodiments incorporating the spirit and substance of the invention may occur to persons skilled in the art, the invention should be construed broadly to include all variations within the scope of the appended claims and equivalents thereof.

## Claims

1. A substituted tetrahydroimidazopyridine compound corresponding to formula I:




wherein
R1 and R2 each independently denote H, C1-10 alkyl, C1-4 alkyl aryl, C1-4 alkyl heteroaryl, C1-4 alkyl C3-8 cycloalkyl, C1-4 alkyl heterocyclyl or C3-8 cycloalkyl, with the proviso that R1 and R2 do not both denote H,
wherein
said alkyl and cycloalkyl groups may each be saturated or mono- or polyunsaturated; and
said alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl groups may each be unsubstituted or mono- or polysubstituted; or

R1 and R2 together with the nitrogen to which they are bound form a four- to eight-membered heterocyclic ring, optionally bridged by a C1 or C2 alkyl chain, which may contain a further heteroatom and may be substituted or unsubstituted; and
R3 denotes unsubstituted or mono- or poly-substituted phenyl;
wherein if one of R1 or R2 denotes H, alkyl or phenyl alkyl, the other one of R1 and R2 does not denote a group corresponding to formula X1:





wherein
the phenyl group in formula X1 may be unsubstituted or substituted, and
Y denotes a C2-5 alkyl chain or —(CH2)o—Z—(CH2)p—,
wherein
Z denotes cyclopentyl, cyclohexyl or cycloheptyl, and
o and p are each 0, 1, 2 or 3, and the sum of o and p is less than or equal to 3,



or a salt thereof with a physiologically acceptable acid.

2. A compound as claimed in claim 1, wherein said compound is in the form of an isolated stereoisomer.

3. A compound as claimed in claim 1, wherein said compound is in the form of a mixture of stereoisomers in any mixing ratio.

4. A compound as claimed in claim 3, wherein said mixture is a racemic mixture.

5. A compound as claimed in claim 1, wherein:
“alkyl substituted”, “heterocyclyl substituted” and “cycloalkyl substituted” denote the replacement of a hydrogen with F, Cl, Br, l, —CN , NH2, NH—C 1-6 alkyl, NH—C 1-6 alkyl-OH, C1-6 alkyl, N(C1-6 alkyl)2, alkyl-OH)2, NO2, SH, S—C1-6 alkyl, S-benzyl, O—C1-6 alkyl, OH, O—C1-6 alkyl-OH, ═O, O-benzyl, C(═O)C1-6 alkyl, C(═O)OC1-6 alkyl, phenyl or benzyl;
“aryl substituted”, “phenyl substituted” and “heteroaryl substituted” denote the single or multiple substitution of one or more hydrogen atoms in the ring system with F, Cl, Br, l, CN, NH2, NH—C1-6 alkyl, NH—C1-6 alkyl-OH, N(C1-6 alkyl)2, N(C1-6 alkyl-OH) 2, NO2, SH, S—C1-6 alkyl, OH, O—C1-6 alkyl, O-C1-6 alkyl-OH, C(═O) aryl;
C(═O)C1-6 alkyl, C(═O)NHC1-6 alkyl; C(═O)-N-morpholine; C(═O)-piperidine;

(C═O)-pyrrolidine; (C═O)-piperazine; NHSO2C1-6 alkyl, NHCOC1-6 alkyl, CO2H, CH2SO2 phenyl, CO2—C1-6 alkyl, OCF3, CF3,




 C1-6 alkyl, pyrrolidinyl, piperidinyl, morpholinyl, benzyloxy, phenoxy, phenyl, pyridyl, alkylaryl, thienyl or furyl; and
wherein said C1-6 alkyl, pyrrolidinyl, piperidinyl, morpholinyl, benzyloxy, phenoxy, phenyl, pyridyl, alkylaryl, thienyl and furyl groups may themselves be substituted with F, Cl, methoxy, ethoxy, CF3, CN, CH3, OH, OCF3, SCF3 or NO2.

6. A compound as claimed in claim 1, wherein R1 and R2 each independently denote C1-10 alkyl, C1-4 alkyl aryl, C1-4 alkyl heteroaryl, C1-4 alkyl C3-8 cycloalkyl or C3-8 cycloalkyl, wherein said alkyl, aryl, heteroaryl and cycloalkyl groups may each be unsubstituted or mono- or polysubstituted.

7. A compound as claimed in claim 6, wherein R1 and R2 each independently denote H, benzyl, phenethyl, methylpyridyl, cyclopropyl, n-pentyl, n-butyl, n-hexyl, sec-butyl, propylethyl or methylcyclohexyl, and each may be unsubstituted or mono- or polysubstituted with methoxy, F, CH3, CF3 or

8. A compound as claimed in claim 1, wherein R1 and R2 together with the nitrogen to which they are bound form a four- to eight-membered ring, optionally bridged by a C1 or C2 alkyl chain, which may contain a further heteroatom selected from the group consisting of O, N and S, and which may be substituted or unsubstituted.

9. A compound as claimed in claim 8, wherein R1 and R2 together with the nitrogen atom to which they are bound form a five- to seven-membered ring which may contain a further nitrogen atom and which may be unsubstituted or mono- or polysubstituted with C(O)OC2H5; C(O)C1-6 alkyl; methyl, n-butyl or acetyl; phenyl or benzyl, which each may be unsubstituted or substituted with phenyl F, Cl, Br, l, CN, CH3, C2H5, NH2, NO2, SH, CF3, OH, OCH3, OCF3, SCF3, SCH3, OC2H5 or N(CH3)2.

10. A compound as claimed in claim 1, wherein R3 denotes a phenyl group, which may be unsubstituted or mono- or polysubstituted with F, Cl, Br, l, CN, CH3, C2H5, NH2, NO2, SH, CF3, OH, OCH3, OCF3, SCF3, SCH3, phenoxy, OC2H5 or N(CH3)2.

11. A compound as claimed in claim 1, selected from the group consisting of:
1 (4-Benzylpiperidin-1-yl)(6-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl) methanone;
2 N-Benzyl-N-phenethyl-6-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide;
3 (6-Phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(1,3,3-trimethyl-6-azabicyclo [3.2.1]octan-6-yl)methanone;
4 (6-(3-Fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-yl)methanone;
5 N-Benzyl-6-(4-methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a ]pyridine-2-carboxamide;
6 (4-(2-Fluorophenyl)piperazin-1-yl)(6-(4-methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo [1,2-a]pyridin-2-yl)methanone;
7 (6-(5-Fluoro-2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-(trifluoromethyl) phenyl)piperazin-1-yl)methanone;
8 (4-Benzylpiperidin-1-yl)(6-(5-fluoro-2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo [1,2-a]pyridin-2-yl)methanone;
9 (6-(5-Fluoro-2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-y 1)(1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-yl)methanone;
10 (6-(4-Methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-y 1)(4-(2-methoxyphenyl)piperazin-1-yl)methanone;
11 (4-Benzylpiperidin-1-yl)(6-(4-ethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a ]pyridin-2-yl)methanone;
12 (6-(2,5-Dimethoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(1,3,3-trimethyl -6-azabicyclo[3.2.1]octan-6-yl)methanone;
13 (6-(4-Fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(2-fluorophenyl) piperazin-1-yl)methanone;
14 6-(4-Fluoro-3-methylphenyl)-N-(1-phenylethyl)-5,6,7,8-tetrahydroimidazo[1,2-a ]pyridine-2-carboxamide;
15 6-(4-Methoxy-3,5-dimethylphenyl)-N-pentyl-5,6,7,8-tetrahydroimidazo[1,2-a ]pyridine-2-carboxamide;
16 N-Hexyl-6-(4-methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a ]pyridine-2-carboxamide;
17 6-(4-Methoxy-3,5-dimethylphenyl)-N-(3-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydroimidazo [1,2-a]pyridine-2-carboxamide;
18 N-sec-Butyl-6-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide;
19 N-Butyl-6-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide;
20 Ethyl 1-(6-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carbonyl) piperidine-4-carboxylate;
21 (4-Methylpiperidin-1-yl)(6-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a ]pyridin-2-yl)methanone;
22 Ethyl 1-(6-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carbonyl) piperidine-3-carboxylate;
23 1-(4-(6-(4-Phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carbonyl) piperazin-1-ypethanone;
24 6-(4-Phenoxyphenyl)-N-(pyridin-3-ylmethyl)-5,6,7,8-tetrahydroimidazo[1,2-a ]pyridine-2-carboxamide;
25 (6-(4-Phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(pyrrolidin-1-yl) methanone;
26 N-Cyclopropyl-6-(4-phenoxyphenyl)-5,617,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide;
27 N-(3,4-Dimethoxyphenethyl)-6-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a ]pyridine-2-carboxamide;
28 N-Pentyl-6-(4-phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide;
29 Pyrrolidin-1-yl(6-m-tolyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)methanone;
30 (6-(3,5-Bis(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl) (pyrrolidin-1-yl)methanone;
31 Pyrrolidin-1-yl(6-(3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a ]pyridin-2-yl)methanone;
32 (4-(2-Fluorophenyl)piperazin-1-yl)(6-(3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroimidazo [1,2-a]pyridin-2-yl)methanone;
33 (6-(2,4-Dimethoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(pyrrolidin-1-yl)methanone;
34 Pyrrolidin-1-yl(6-o-tolyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)methanone;
35 (6-o-Tolyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-(trifluoromethyl)-phenyl) piperazin-1-yl)methanone;
36 (6-(2,5-Difluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(pyrrolidin-1-yl methanone;
37 (6-(4-Ethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(pyrrolidin-1-yl) methanone;
38 (6-(4-Fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-yl)methanone;
39 6-(4-Methoxyphenyl)-N-(3-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydroimidazo[1,2-a ]pyridine-2-carboxamide;
40 6-(4-Ethylphenyl)-N-phenethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide;
41 (4-Benzylpiperidin-1-yl)(6-(4-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a ]pyridin-2-yl)methanone;
42 N-(Benzo[d][1,3]dioxo1-5-ylmethyl)-6-(3,5-bis(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroimidazo [1,2-a]pyridine-2-carboxamide;
43 N-Benzyl-6-(3,5-bis(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a ]pyridine-2-carboxamide;
44 (6-(4-Methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl) (4-(4-methoxyphenyl)piperazin-1-yl)methanone;
45 (4-(2-Ethoxyphenyl)piperazin-1-yl)(6-m-tolyl-5,6,7,8-tetrahydroimidazo[1,2-a ]pyridin-2-yl)methanone;
46 (6-(2,4-Dimethoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-(trifluoromethyl) phenyl)piperazin-1-yl)methanone;
47 (6-(4-Fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-(trifluoromethyl) phenyl)piperazin-1-yl)methanone;
48 (6-(3-Fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-(trifluoromethyl) phenyl)piperazin-1-yl)methanone;
49 N-(4-Fluorobenzyl)-6-(4-methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroirnidazo-[1,2-a]pyridine-2-carboxamide;
50 (4-Benzylpiperidin-1-yl)(6-(3-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a ]pyridin-2-yl)methanone;
51 6-(3-Fluorophenyl)-N-(4-phenylbutan-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a ]pyridine-2-carboxamide;
52 6-(4-Ethylphenyl)-N-(4-phenylbutan-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a ]pyridine-2-carboxamide;
53 (6-Phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-(trifluoromethyl) phenyl)piperazin-1-yl)methanone;
54 (6-(4-Methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl) (4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)methanone;
55 (4-Benzylpiperidin-1-yl)(6-(4-methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydro-imidazo [1,2-a]pyridin-2-yl)methanone;
56 (6-(4-Methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-y) (1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-yl)methanone;
57 4-Benzylpiperidin-1-yl)(6-(4-fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo [1,2-a]pyridin-2-yl)methanone;
58 (6-(4-Fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-(trifluoromethyl) phenyl)piperazin-1-yl)methanone;
59 (4-Benzhydrylpiperazin-1-yl)(6-(4-methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo [1,2-a]pyridin-2-yl)methanone;
60 6-(3-Methoxyphenyl)-N-(4-phenylbutan-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a ]pyridine-2-carboxamide;
61 (4-Benzylpiperidin-1-yl)(6-(3-fluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a ]pyridin-2-yl)methanone;
62 (6-(4-Fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(4-(trifluoromethyl) phenyppiperazin-1-yl)methanone;
63 (6-(4-Fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(4-fluorophenyl) piperazin-1-yl)methanone;
64 (6-(4-Fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(4-methylphenyl) piperazin-1-Arnethanone;
65 (6-(4-Fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-methylphenyl) piperazin-1-yl)methanone;
66 (4-Butylpiperazin-1-yl)(6-(4-fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo [1,2-a]pyridin-2-ylynethanone;
67 (4-Benzhydrylpiperidin-1-yl)(6-(4-fluoro-3-methylphenyl)-5,6,7,8-tetrahydro-imidazo [1,2-a]pyridin-2-yl)methanone;
68 N-(Cyclohexylmethyl)-6-(4-fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a ]pyridine-2-carboxamide;
69 (6-(4-Methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-(trifluoromethyl) phenyl)piperazin-1-yl)methanone;
70 (4-Benzylpiperidin-1-yl)(6-m-tolyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl) methanone;
71 (6-(3-Methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-(trifluoromethyl) phenyppiperazin-1-yl)methanone;
72 6-(4-Fluoro-3-methylphenyl)-N-(4-phenylbutan-2-yl)-5,6,7,8-tetrahydroimidazo-[1,2-a]pyridine-2-carboxamide;
73 4-Benzylpiperidin-1-yl)(6-p-tolyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl) methanone;
74 (6-p-Tolyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-(trifluoromethyl)-phenyl) piperazin-1-Amethanone;
75 (6-m-Tolyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-(trifluoromethyl)-phenyl) piperazin-1-yl)methanone;
76 (4-Benzylpiperidin-1-yl)(6-(4-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a ]pyridin-2-yl)methanone;
77 (6-(3,5-Dimethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-(trifluoromethypphenyl) piperazin-1-yl)methanone;
78 N-(1-(3,5-Dimethylphenypethyl)-6-(4-fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo [1,2-a]pyridine-2-carboxamide;
79 6-(3,4-Difluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-(trifluoromethyl) phenyl)piperazin-1-yl)methanone;
80 (4-Benzylpiperazin-1-yl)(6-(4-fluoro-3-methylphenyl)-5,6,7,8-tetrahydro-imidazo [1,2-a]pyridin-2-yl)methanone;
81 (6-(4-Phenoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-(trifluoromethyl) phenyppiperazin-1-yDrnethanone;
82 6-(4-(Benzyloxy)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-(trifluoromethyl) phenyppiperazin-1-yl)methanone;
83 (6-(4-Fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-fluorophenyl) piperazin-1-yl)methanone;
84 (6-(4-Fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-yl)methanone;
85 (6-(4-Fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)(4-(3-(trifluoromethyl) phenyl)piperidin-1-yl)methanone;
86 6-(4-Fluoro-3-methylphenyl)-N-(4-(3-(trifluoromethyl)phenyl)butan-2-yO-5,6,7,8-tetrahydroimidazo [1,2-a]pyridine-2-carboxamide;
87 6-(4-Fluoro-3-methylphenyl)-N-methyl-N-(4-(3-(trifluoromethyl)phenyl)butan-2-yl) -5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide; and
88 N-(2-Cyclohexylethyl)-6-(4-fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a ]pyridine-2-carboxamide.

12. A pharmaceutical composition comprising a compound as claimed in claim 1, and at least one pharmaceutically acceptable carrier or auxiliary substance.

13. A method of treating pain in a subject, said method comprising administering to said subject a pharmacologically effective amount of a compound as claimed in claim 1.

14. A method as claimed in claim 13, wherein said pain is selected from the group consisting of acute pain, chronic pain, neuropathic pain, muscular pain and inflammatory pain.

15. A method of treating a condition selected from the group consisting of pain, epilepsy, migraine, anxiety and urinary incontinence in a subject, said method comprising administering to said subject a pharmacologically effective amount of a compound as claimed in claim 1.

16. A process for preparing a compound as claimed in claim 1, according to the following reaction scheme:




said process comprising:
a) reacting an iodine-, bromine- or chlorine-substituted 2-aminopyridine with 3-bromo -2-oxopropionic acid in an organic solvent at a temperature between 0° C. and 80° C. for 2 to 48 hours to yield an iodine-, bromine- or chlorine-substituted imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester;
b) reacting the iodine-, bromine- or chlorine-substituted imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester from a) with a phenylboric acid or phenylboric acid ester in a solvent using a catalyst, a base and optionally an additive;
c) cleaving the carboxylic acid ester using an organic or aqueous inorganic acid or an aqueous inorganic base in an organic solvent to yield a substituted imidazopyridine carboxylic acid;
d) hydrogenating the substituted imidazopyridine carboxylic acid from c) with a hydrogenation catalyst in a solvent under normal pressure or elevated pressure to yield a tetrahydroimidazopyridine carboxylic acid; and
e) reacting the tetrahydroimidazopyridine carboxylic acid from d) with a primary or secondary amine using a base, and optionally a coupling reagent, in a solvent.

17. A process as claimed in claim 16, wherein:
said solvents are independently selected from the group consisting of methanol, ethanol, 1-propanol, ethylene glycol, water, THF, 1,2-dimethoxyethane, acetone, chloroform, dioxane, acetonitrile, DMF, benzene, toluene, xylene, dichloromethane, diethyl ether, acetic acid, propionic acid, DCM, cyclohexane or methanolic KOH;
said carboxylic acid ester is cleaved with trifluoroacetic acid or aqueous hydrochloric acid or an aqueous based selected from the group consisting of lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, sodium hydrogen carbonate or potassium carbonate;
said hydrogenation catalyst is selected from the group consisting of Pd on activated carbon, Raney nickel, platinum or PtO2;
said base is selected from the group consisting of sodium methanolate, TEA, DIEA or N-methylmorpholine; and
said coupling reagent is selected from the group consisting of EDCI, HOBt, DCC, CDI, HBTU, DMAP or pentafluorophenyl diphenyl phosphinate.