3-aryl-substituted imidazo[1,2-A]pyridines and their use

Abstract

The present application relates to novel 3-aryl-substituted imidazo[1,2-a]pyridines, to processes for preparation thereof, to the use thereof, alone or in combinations, for treatment and/or prophylaxis of diseases, and to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases, especially for treatment and/or prophylaxis of cardiovascular disorders.

Claims

1. A compound having the structure of formula (I) ##STR00263## in which A represents CH.sub.2, R.sup.1 represents cyclohexyl or phenyl, where phenyl is substituted by 1 to 3 fluorine substituents, or represents a pyridyl group of the formula ##STR00264## where # is the attachment site to A, and R.sup.10 represents fluorine, R.sup.2 represents methyl or ethyl, R.sup.3 represents phenyl, where phenyl is optionally substituted by 1 or 2 substituents selected from the group consisting of fluorine, bromine, chlorine, cyano, trifluoromethyl, difluoromethyl, methyl, ethyl, —(C═O)NR.sup.7R.sup.8, amino, hydroxycarbonyl, methylsulphonyl, ethylsulphonyl, methoxy, ethoxy, trifluoromethoxy, difluoromethoxy and cyclobutyl, in which methyl and ethyl is optionally substituted by 1 or 2 substituents selected from the group consisting of trifluoromethoxy, —(C═O)NR.sup.7R.sup.8, methoxy, ethoxy, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, hydroxy and amino, in which amino is optionally substituted by 1 or 2 substituents independently of one another selected from the group consisting of (C.sub.1-C.sub.4)-alkyl, methylcarbonyl, ethylcarbonyl, methylsulphonyl, ethylsulphonyl and methoxyethyl, in which cyclobutyl is optionally substituted by amino or hydroxy, in which amino is optionally substituted by 1 or 2 substituents independently of one another selected from methyl, ethyl, methylcarbonyl, ethylcarbonyl, methylsulphonyl or ethylsulphonyl, and in which R.sup.7 and R.sup.8 independently of one another represent hydrogen, methyl, ethyl or cyclopropyl, or represent represents a group of the formula ##STR00265## ##STR00266## where * represents the point of attachment to the imidazopyridine, n represents a number 1 or 2, R.sup.9a represents (C.sub.1-C.sub.6)-alkyl, phenyl, pyridyl or cyclopropyl, where (C.sub.1-C.sub.6)-alkyl is optionally substituted by 1 or 2 substituents selected from the group consisting of fluorine, cyano, trifluoromethyl, difluoromethyl, methylcarbonyl, methoxycarbonyl, ethoxycarbonyl, hydroxycarbonyl, —(C═O)NR.sup.7R.sup.8, —O(C═O)NR.sup.7R.sup.8, methylsulphonyl, ethylsulphonyl, methoxy, phenyl, pyridyl, 1H-pyrazolyl, 1H-tetrazolyl, 1,2-oxazolyl, hydroxy, amino, (C.sub.3-C.sub.5)-cycloalkyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, thiomorpholinyl 1,1-dioxide and azetidine, in which 1H-pyrazolyl, 1H-tetrazolyl and 1,2-oxazolyl is optionally substituted by 1 or 2 methyl or ethyl substituents, in which piperidinyl is optionally substituted by 1 to 2 fluorine substituents, in which azetidine is optionally substituted by hydroxyl, and in which piperazinyl is optionally substituted by methyl, where cyclopropyl is optionally substituted by 1 to 2 substituents independently selected from the group consisting of methyl, ethyl, methoxycarbonyl, ethoxycarbonyl and hydroxycarbonyl, where phenyl and pyridyl is optionally substituted by 1 or 2 fluorine substituents, and in which R.sup.7 and R.sup.8 independently of one another represent hydrogen, methyl, ethyl or cyclopropyl, R.sup.9b represents hydrogen or (C.sub.1-C.sub.4)-alkyl, R.sup.9c represents hydrogen or (C.sub.1-C.sub.4)-alkyl, R.sup.9d represents hydrogen, (C.sub.1-C.sub.6)-alkyl, trifluoromethyl, methoxy, ethoxy, amino, methoxycarbonyl, ethoxycarbonyl, hydroxycarbonyl, —(C═O)NR.sup.7R.sup.8, phenyl, pyridyl, pyrimidyl, 1,3-thiazolyl, tetrahydrothiophenyl 1,1-dioxide or cyclopropyl, where (C.sub.1-C.sub.6)-alkyl is optionally substituted by 1 or 2 substituents selected from the group consisting of trifluoromethyl, difluoromethyl, (C.sub.1-C.sub.4)-alkoxy, 2-oxopyrrolidin-1-yl, phenyl, pyridyl, pyrimidyl, 1H-1,2,4-triazolyl, hydroxy and amino, in which 1H-1,2,4-triazolyl is optionally substituted by 1 or 2 methyl or ethyl substituents, and in which amino is optionally substituted by (C.sub.1-C.sub.4)-alkyl, where amino is optionally substituted by (C.sub.1-C.sub.4)-alkyl, where phenyl, pyridyl, pyrimidyl and 1,3-thiazolyl can each be substituted by 1 or 2 methyl or ethyl substituents, and where R.sup.7 and R.sup.8 each independently of one another represent hydrogen, methyl, ethyl or cyclopropyl, R.sup.4 represents hydrogen, R.sup.5 represents hydrogen, chlorine, fluorine, methyl, ethyl, difluoromethyl or cyclopropyl, R.sup.6 represents hydrogen, and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides or salts thereof.

2. The compound according to claim 1 in which A represents CH.sub.2, R.sup.1 represents cyclohexyl, or represents a phenyl group of the formula ##STR00267## where ## represents the point of attachment to A, and R.sup.11, R.sup.12 and R.sup.13 independently of one another represent hydrogen or fluorine, with the proviso that at least two of the radicals R.sup.11, R.sup.12, R.sup.13 are different from hydrogen, or represents a pyridyl group of the formula ##STR00268## where # represents the attachment site to A, and R.sup.10 represents fluorine, R.sup.2 represents methyl or ethyl, R.sup.3 represents phenyl, where phenyl is optionally substituted by 1 or 2 substituents selected from the group consisting of fluorine, chlorine, cyano, amino, trifluoromethyl, difluoromethyl, methyl, —(C═O)NR.sup.7R.sup.8, methoxy, piperidinyl and cyclobutyl, in which methyl is optionally substituted by 1 or 2 substituents selected from the group consisting of —(C═O)NR.sup.7R.sup.8, methoxy, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, hydroxy and amino, in which amino is optionally substituted by 1 or 2 substituents independently of one another selected from methyl, ethyl and methoxyethyl, in which amino is optionally substituted by 1 or 2 substituents independently of one another selected from methyl, ethyl, methylcarbonyl, ethylcarbonyl, methylsulphonyl or ethylsulphonyl, in which cyclobutyl is substituted by amino, and in which R.sup.7 and R.sup.8 each independently of one another represent hydrogen, methyl, ethyl or cyclopropyl, or represents a group of the formula ##STR00269## where * represents the point of attachment to the imidazopyridine, R.sup.9a represents (C.sub.1-C.sub.6)-alkyl, phenyl, pyridyl or cyclopropyl, where (C.sub.1-C.sub.6)-alkyl is optionally substituted by fluorine, cyano, trifluoromethyl, difluoromethyl, methylcarbonyl, methoxycarbonyl, ethoxycarbonyl, hydroxycarbonyl, —(C═O)NR.sup.7R.sup.8, —O(C═O)NR.sup.7R.sup.8, methylsulphonyl, ethylsulphonyl, methoxy, ethoxy, trifluoromethoxy, difluoromethoxy, phenyl, pyridyl, 1H-pyrazolyl, 1H-tetrazolyl, 1,2-oxazolyl, hydroxy, amino, cyclopropyl, cyclobutyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, thiomorpholinyl 1,1-dioxide or azetidine, in which 1H-pyrazolyl, 1H-tetrazolyl and 1,2-oxazolyl is optionally substituted by 1 or 2 methyl or ethyl substituents, in which piperidinyl is optionally substituted by 1 to 2 fluorine substituents, in which azetidine is optionally substituted by hydroxyl, and in which piperazinyl is optionally substituted by methyl, where cyclopropyl is optionally substituted by methoxycarbonyl, ethoxycarbonyl or hydroxycarbonyl, where phenyl and pyridyl is optionally substituted by 1 or 2 fluorine substituents, and in which R.sup.7 and R.sup.8 independently of one another represent hydrogen, methyl, ethyl or cyclopropyl, R.sup.9b represents hydrogen or methyl, R.sup.9c represents hydrogen or methyl, R.sup.9d represents hydrogen, (C.sub.1-C.sub.6)-alkyl, trifluoromethyl, methoxy, ethoxy, amino, methoxycarbonyl, ethoxycarbonyl, hydroxycarbonyl, —(C═O)NR.sup.7R.sup.8, phenyl, pyridyl, pyrimidyl, 1,3-thiazolyl, tetrahydrothiophenyl 1,1-dioxide or cyclopropyl, where (C.sub.1-C.sub.6)-alkyl is optionally substituted by 1 or 2 substituents selected from the group consisting of trifluoromethyl, difluoromethyl, (C.sub.1-C.sub.4)-alkoxy, 2-oxopyrrolidin-1-yl, phenyl, pyridyl, pyrimidyl, 1H-1,2,4-triazolyl, hydroxy and amino, in which 1H-1,2,4-triazolyl is optionally substituted by 1 or 2 methyl or ethyl substituents, and in which amino is optionally substituted by (C.sub.1-C.sub.4)-alkyl, where amino is optionally substituted by (C.sub.1-C.sub.4)-alkyl, where phenyl, pyridyl, pyrimidyl and 1,3-thiazolyl may each be substituted by 1 or 2 methyl or ethyl substituents, and in which R.sup.7 and R.sup.8 each independently of one another represent hydrogen, methyl, ethyl or cyclopropyl, R.sup.4 represents hydrogen, R.sup.5 represents hydrogen, chlorine, fluorine, methyl, ethyl, difluoromethyl or cyclopropyl, R.sup.6 represents hydrogen, and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides or salts thereof.

3. A process for preparing the compound according to claim 1, comprising [A] converting a compound of the formula (II) ##STR00270## in which A, R.sup.1, R.sup.2, R.sup.4, R.sup.5 and R.sup.6 are each as defined in claim 1 and T.sup.1 represents (C.sub.1-C.sub.4)-alkyl or benzyl, in an inert solvent in the presence of a suitable base or acid to a carboxylic acid of the formula (III) ##STR00271## in which A, R.sup.1, R.sup.2, R.sup.4, R.sup.5 and R.sup.6 each have the meanings given above, and converting the carboxylic acid of the formula (Ill) in the presence of a suitable acid into an imidazo[1,2-a]-pyridine of the formula (IV) ##STR00272## in which A, R.sup.1, R.sup.2, R.sup.4, R.sup.5 and R.sup.6 each have the meanings given above, and converting the imidazo[1,2-a]-pyridine of the formula (IV) with a halogen equivalent into a compound of the formula (V) ##STR00273## in which A, R.sup.1, R.sup.2, R.sup.4, R.sup.5 and R.sup.6 are each as defined above and X.sup.1 represents chlorine, bromine or iodine, and reacting the compound of the formula (V) in an inert solvent, in the presence of a suitable transition metal catalyst, with a compound of the formula (VI) ##STR00274## in which R.sup.3A has the meanings given in claim 1 for R.sup.3 and T.sup.2 represents hydrogen or (C.sub.1-C.sub.4)-alkyl, or the two T.sup.2 radicals together form a —C(CH.sub.3).sub.2—C(CH.sub.3).sub.2— bridge, to give a compound of the formula (I-A) ##STR00275## and if R.sup.3A represents ##STR00276## reacting the compound of the formula (I-A) in an inert solvent in the presence of a suitable base with a compound of the formula (VIII)
R.sup.14 —X.sup.1  (VIII), in which X.sup.1 represents a suitable leaving group, and R.sup.14 represents (C.sub.1-C.sub.6)-alkyl, where (C.sub.1-C.sub.6)-alkyl can be substituted by 1 to 3 substituents selected from the group consisting of fluorine, cyano, trifluoromethyl, difluoromethyl, (C.sub.1-C.sub.4)-alkylcarbonyl, (C.sub.1-C.sub.4)-alkoxycarbonyl, hydroxycarbonyl, —(C═O)NR.sup.7R.sup.8, —O(C═O)NR.sup.7R.sup.8, (C.sub.1-C.sub.4)-alkylsulphonyl, (C.sub.1-C.sub.4)-alkoxy, trifluoromethoxy, difluoromethoxy, phenyl, 1H-pyrazolyl, 1H-1,2,4-triazolyl, 1H-tetrazolyl, 1,2-oxazolyl, tetrahydrothiophenyl 1,1-dioxide, hydroxy, amino, (C.sub.3-C.sub.7)-cycloalkyl, morpholinyl, piperidinyl, pyrrolidinyl, 2-oxopyrrolidin-1-yl, piperazinyl, tetrahydrothiophenyl 1,1-dioxide, thiomorpholinyl 1,1-dioxide and azetidine, in which 1H-pyrazolyl, 1H-1,2,4-triazolyl, 1H-tetrazolyl and 1,2-oxazolyl is optionally substituted by 1 or 2 methyl or ethyl substituents, in which piperidinyl is optionally substituted by 1 or 2 fluorine substituents, in which phenyl is optionally substituted by 1 or 2 fluorine substituents, in which piperazinyl is optionally substituted by methyl, and in which R.sup.7 and R.sup.8 each independently of one another represent hydrogen, methyl or cyclopropyl, or R.sup.7 and R.sup.8 together with the carbon atom to which they are attached form a 3- to 5-membered carbocycle, to give a compound of the formula (I-B) ##STR00277## in which A, R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6 and R.sup.14 each have the meanings given above and removing any protecting groups present, and optionally converting the resulting compounds of the formula (I-B) with the appropriate (i) solvents and/or (ii) acids or bases into the solvates, salts and/or solvates of the salts thereof, or [B] converting the compound of the formula (II) in the presence of hydrazine hydrate into a compound of the formula (IX) ##STR00278## in which A, R.sup.1, R.sup.2, R.sup.4, R.sup.5 and R.sup.6 each have the meanings given above, and subsequently reacting the compound of the formula (IX) in an inert solvent under amide coupling conditions with a carboxylic acid of the formula (X) ##STR00279## in which R.sup.15 represents (C.sub.1-C.sub.6)-alkyl, where (C.sub.1-C.sub.6)-alkyl is optionally substituted by 1 to 3 substituents selected from the group consisting of trifluoromethyl, difluoromethyl, hydroxy and amino, to give a compound of the formula (XI) ##STR00280## in which A, R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6 and R.sup.15 each have the meanings given above, and converting the compound of the formula XI with 2,4-bis(4-methoxyphenyI)-1,3,2,4-dithiadiphosphetane-2,4-disulphide [Lawesson's reagent] into a compound of the formula (I-C) ##STR00281## in which A, R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6 and R.sup.15 each have the meanings given above, then detaching any protecting groups present, and optionally converting the resulting compounds of the formula (I) with the appropriate (i) solvents and/or (ii) acids or bases to the solvates, salts and/or solvates of the salts thereof.

4. A medicament comprising the compound according to claim 1 in combination with an inert, non-toxic, pharmaceutically suitable excipient.

5. A medicament comprising the compound according to claim 1 in combination with a further active ingredient selected from the group consisting of organic nitrates, NO donors, cGMP-PDE inhibitors, antithrombotic agents, hypotensive agents and lipid metabolism modifiers.

6. A method for treatment of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders and arteriosclerosis in humans and animals comprising administering an effective amount of at least one compound according to claim 1 to a patient in need thereof.

7. A method for treatment of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders and arteriosclerosis in humans and animals comprising administering an effective amount of the medicament according to claim 4 to a patient in need thereof.

8. A method for treatment of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders and arteriosclerosis in humans and animals comprising administering an effective amount of the medicament according to claim 5 to a patient in need thereof.

Description

A. EXAMPLES

Abbreviations and Acronyms

(1) aq. aqueous solution calc. calculated br. broad signal (NMR coupling pattern) CAS No. Chemical Abstracts Service number δ shift in the NMR spectrum (stated in) d doublet (NMR coupling pattern) TLC thin-layer chromatography DCI direct chemical ionization (in MS) DMAP 4-N,N-dimethylaminopyridine DMF dimethylformamide DMSO dimethyl sulphoxide EDCI N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide eq. equivalent(s) ESI electrospray ionization (in MS) Et ethyl h hour(s) HATU N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]-pyridin-3-yloxy)methylene]-N-methylmethanaminium hexafluorophosphate HOBT 1H-benzotriazol-1-ol HPLC high-pressure, high-performance liquid chromatography HRMS high-resolution mass spectrometry ID internal diameter conc. concentrated LC-MS liquid chromatography-coupled mass spectrometry LiHMDS lithium hexamethyldisilazide m multiplet Me methyl min minute(s) MS mass spectrometry NMR nuclear magnetic resonance spectrometry PDA photodiode array detector Pd.sub.2dba.sub.3 tris(dibenzylideneacetone)dipalladium Ph phenyl q quartet (NMR coupling pattern) quint. quintet (NMR coupling pattern) R.sub.F retention factor (in thin-layer chromatography) RT room temperature R.sub.t retention time (in HPLC) s singlet (NMR coupling pattern) t triplet (NMR coupling pattern) THF tetrahydrofuran TBTU (benzotriazol-1-yloxy)bisdimethylaminomethylium fluoroborate UPLC-MS ultra-pressure liquid chromatography-coupled mass spectrometry UV ultraviolet spectrometry v/v ratio by volume (of a solution) Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene XPHOS dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine

(2) Unless stated otherwise, the percentages in the tests and examples which follow are percentages by weight; parts are parts by weight. Solvent ratios, dilution ratios and concentration data for the liquid/liquid solutions are based in each case on volume. Details given for coupling patterns in NMR spectra are of a descriptive nature; coupling patterns of a higher order are not described as such.

(3) LC/MS and HPLC Methods:

(4) Method 1 (LC-MS):

(5) Instrument: Waters ACQUITY SQD UPLC system; column: Waters Acquity UPLC HSS T3 1.8 μ50×1 mm; mobile phase A: 1 l of water+0.25 ml of 99% strength formic acid, mobile phase B: 1 l of acetonitrile+0.25 ml of 99% strength formic acid; gradient: 0.0 min 90% A.fwdarw.1.2 min 5% A.fwdarw.2.0 min 5% A; oven: 50° C.; flow rate: 0.40 ml/min; UV detection: 210-400 nm.

(6) Method 2 (LC-MS):

(7) Instrument: Micromass Quattro Premier with Waters UPLC Acquity; column: Thermo Hypersil GOLD 1.9μ 50 mm×1 mm; mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid, mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min 90% A.fwdarw.0.1 min 90% A.fwdarw.1.5 min 10% A.fwdarw.2.2 min 10% A; flow rate: 0.33 ml/min; oven: 50° C.; UV detection: 210 nm.

(8) Method 3 (LC-MS):

(9) MS instrument type: Waters Micromass Quattro Micro; HPLC instrument type: Agilent 1100 series; column: Thermo Hypersil GOLD 3μ 20 mm×4 mm; mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid, mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min 100% A.fwdarw.3.0 min 10% A.fwdarw.4.0 min 10% A.fwdarw.4.01 min 100% A (flow rate 2.5 ml/min).fwdarw.5.00 min 100% A; oven: 50° C.; flow rate: 2 ml/min; UV detection: 210 nm.

(10) Method 4 (LC-MS):

(11) MS instrument: Waters SQD; HPLC instrument: Waters UPLC; column: Zorbax SB-Aq (Agilent), 50 mm×2.1 mm, 1.8 μm; mobile phase A: water+0.025% formic acid, mobile phase B: acetonitrile (ULC)+0.025% formic acid; gradient: 0.0 min 98% A—0.9 min 25% A—1.0 min 5% A—1.4 min 5% A—1.41 min 98% A—1.5 min 98% A; oven: 40° C.; flow rate: 0.600 ml/min; UV detection: DAD; 210 nm.

(12) Method 5 (LC-MS):

(13) MS instrument: Waters ZQ 2000; HPLC instrument: Agilent 1100, 2-column system, autosampler: HTC PAL; column: YMC-ODS-AQ, 50 mm×4.6 mm, 3.0 μm; mobile phase A: water+0.1% formic acid, mobile phase B: acetonitrile+0.1% formic acid; gradient: 0.0 min 100% A—0.2 min 95% A—1.8 min 25% A—1.9 min 10% A—2.0 min 5% A—3.2 min 5% A—3.21 min 100% A—3.35 min 100% A; oven: 40° C.; flow rate: 3.0 ml/min; UV detection: 210 nm.

(14) Method 6 (Preparative HPLC):

(15) Column: Macherey-Nagel VP 50/21 Nucleosil 100-5 C18 Nautilus. Flow rate: 25 ml/min. Gradient: A=acetonitrile, B=water+0.1% formic acid, 0 min 10% A; 2.00 min 10% A; 6.00 min 90% A; 7.00 min 90% A; 7.10 min 10% A; 8 min 10% A; UV detection: 220 nm

(16) Method 7 (Preparative HPLC):

(17) Column: Phenomenex Gemini C18; 110A, AXIA, 5 μm, 21.2×50 mm 5 micron; gradient: A=water+0.1% conc. ammonia, B=acetonitrile, 0 min=10% B, 2 min=10% B, 6 min=90% B, 7 min=90% B, 7.1 min=10% B, 8 min=10% B, flow rate 25 ml/min, UV detection 220 nm.

(18) Method 8 (Preparative HPLC):

(19) Column: Axia Gemini 5μ C18 110 A, 50×21.5 mm, P/NO: 00B-4435-P0-AX, S/NO: 35997-2, gradient: A=water+0.1% conc. aq. ammonia, B=acetonitrile, 0 min=30% B, 2 min=30% B, 6 min=100% B, 7 min=100% B, 7.1 min=30% B, 8 min=30% B, flow rate 25 ml/min, UV detection 220 nm.

(20) Method 9 (Preparative HPLC):

(21) Column: Macherey-Nagel VP 50/21 Nucleosil 100-5 C18 Nautilus. Flow rate: 25 ml/min. Gradient: A=water+0.1% formic acid, B=methanol, 0 min=30% B, 2 min=30% B, 6 min=100% B, 7 min=100% B, 7.1 min=30% B, 8 min=30% B, flow rate 25 ml/min, UV detection 220 nm.

(22) Method 10 (Preparative HPLC):

(23) Column: Macherey-Nagel VP 50/21 Nucleosil 100-5 C18 Nautilus. Flow rate: 25 ml/min. Gradient: A=water+0.1% conc. aq. ammonia, B=methanol, 0 min=30% B, 2 min=30% B, 6 min=100% B, 7 min=100% B, 7.1 min=30% B, 8 min=30% B, flow rate 25 ml/min, UV detection 220 nm.

(24) Method 11 (Preparative HPLC):

(25) MS instrument: Waters; HPLC instrument: Waters (column Waters X-Bridge C18, 18 mm×50 mm, 5 Ξm, mobile phase A: water+0.05% triethylamine, mobile phase B: acetonitrile (ULC)+0.05% triethylamine; gradient: 0.0 min 95% A—0.15 min 95% A—8.0 min 5% A—9.0 min 5% A; flow rate: 40 ml/min; UV detection: DAD; 210-400 nm).

(26) and

(27) MS instrument: Waters; HPLC instrument: Waters (column Phenomenex Luna 5μ C18(2) 100A, AXIA Tech. 50×21.2 mm, mobile phase A: water+0.05% formic acid, mobile phase B: acetonitrile (ULC)+0.05% formic acid; gradient: 0.0 min 95% A—0.15 min 95% A—8.0 min 5% A—9.0 min 5% A; flow rate: 40 ml/min; UV detection: DAD; 210-400 nm).

(28) Method 12 (LC-MS):

(29) MS instrument: Waters SQD; HPLC instrument: Waters UPLC; column: Zorbax SB-Aq (Agilent), 50 mm×2.1 mm, 1.8 μm; mobile phase A: water+0.025% formic acid, mobile phase B: acetonitrile (ULC)+0.025% formic acid; gradient: 0.0 min 98% A—0.9 min 25% A—1.0 min 5% A—1.4 min 5% A—1.41 min 98% A—1.5 min 98% A; oven: 40° C.; flow rate: 0.600 ml/min; UV detection: DAD; 210 nm.

(30) When compounds according to the invention are purified by preparative HPLC by the above-described methods in which the eluents contain additives, for example trifluoroacetic acid, formic acid or ammonia, the compounds according to the invention may be obtained in salt form, for example as trifluoroacetate, formate or ammonium salt, if the compounds according to the invention contain a sufficiently basic or acidic functionality. Such a salt can be converted to the corresponding free base or acid by various methods known to the person skilled in the art.

(31) Method 13 (DCI-MS):

(32) Instrument: DSQ II; Thermo Fisher-Scientific; DCI with NH.sub.3, flow rate: 1.1 ml/min; source temperature: 200° C.; ionization energy 70 eV; DCI filament heated to 800° C.; mass range 80-900.

(33) Method 14 (GC-MS):

(34) Instrument: Micromass GCT, GC6890; column: Restek RTX-35, 15 m×200 μm×0.33 μm; constant helium flow rate: 0.88 ml/min; oven: 70° C.; inlet: 250° C.; gradient: 70° C., 30° C./min.fwdarw.310° C. (maintained for 3 min).

(35) Method 15 (MS):

(36) Instrument: Waters ZQ; ionization type: ESI (+); mobile phase: acetonitrile/water.

(37) Method 16 (LCMS):

(38) Instrument: Waters ACQUITY SQD UPLC system; column: Waters Acquity UPLC HSS T3 1.8μ 30×2 mm; mobile phase A: 1 l of water+0.25 ml of 99% strength formic acid; mobile phase B: 1 l of acetonitrile+0.25 ml of 99% strength formic acid; gradient: 0.0 min 90% A.fwdarw.1.2 min 5% A.fwdarw.2.0 min 5% A oven: 50° C.; flow rate: 0.60 ml/min; UV detection: 208-400 nm.

(39) Method 17 (LC-MS):

(40) Instrument: Micromass Quattro Premier with Waters UPLC Acquity; column: Thermo Hypersil GOLD 1.9μ 50×1 mm; mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid; mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min 97% A.fwdarw.0.5 min 97% A.fwdarw.3.2 min 5% A.fwdarw.4.0 min 5% A; oven: 50° C.; flow rate: 0.3 ml/min; UV detection: 210 nm.

(41) Method 18 (Preparative HPLC):

(42) Chromatorex C18 10μ 250×20 mm gradient: A=water+0.5% formic acid, B=acetonitrile, 0 min=5% B, 3 min=5% B pre-rinse without substance, then injection, 5 min=5% B, 25 min=30% B, 38 min=30% B, 38.1 min=95% B, 43 min=95% B, 43.01 min=5% B, 48.0 min=5% B flow rate 20 ml/min, wavelength 210 nm.

(43) Method 19 (Preparative HPLC):

(44) Chromatorex C18 10μ 250×20 mm gradient: A=water+0./5% formic acid, B=acetonitrile, 0 min=5% B, 3 min=5% B pre-rinse without substance, then injection, 5 min=5% B, 25 min=50% B, 38 min=50% B, 38.1 min=95% B, 43 min=95% B, 43.01 min=5% B, 48.0 min=5% B flow rate 20 ml/min, wavelength 210 nm.

(45) Method 20 (Preparative HPLC):

(46) XBridge Prep. C18 5μ 50×19 mm gradient: A=water+0.5% ammonium hydroxide, B=acetonitrile, 0 min=5% B, 3 min=5% B pre-rinse without substance, then injection, 5 min=5% B, 25 min=50% B, 38 min=50% B, 38.1 min=95% B, 43 min=95% B, 43.01 min=5% B, 48.0 min=5% B flow rate 15 ml/min, wavelength 210 nm.

(47) Method 21 (Preparative HPLC):

(48) Chromatorex 10 Ξ 250×20 mm gradient: A=water, B=acetonitrile, 0 min=5% B, 3 min=5% B pre-rinse without substance, then injection, 5 min=5% B, 25 min=95% B, 38 min=95% B, 38.1 min=5% B, 40 min=5% B, flow rate 20 ml/min, wavelength 210 nm.

(49) Method 22 (LC-MS):

(50) Instrument: Acquity UPLC coupled with Quattro Micro mass spectrometer; column: Acquity UPLC BEH C18 (50 mm×2.1 mm ID, 1.7 Ξm packing diameter); mobile phase A: 10 mM aqueous ammonium bicarbonate solution (adjusted with ammonia to a pH of 10), mobile phase B: acetonitrile; gradient: 0.0 min 97% A, 3% B, flow rate 1 ml/min; 1.5 min 100% B, flow rate 1 ml/min; 1.9 min 100% B, flow rate 1 ml/min; 2.0 min 97% A, 3% B, flow rate 0.05 ml/min; column temperature: 40° C.; UV detection: from 210 nm to 350 nm; MS conditions: ionization mode: alternating scans positive and negative electrospray (ES+/ES−); scan range: 100 to 1000 AMU.

(51) Method 23 (LC-MS):

(52) Instrument: Acquity UPLC coupled with Quattro Micro mass spectrometer; column: Acquity UPLC BEH C18 (50 mm×2.1 mm ID, 1.7 μm packing diameter); mobile phase A: 0.1% formic acid in water, mobile phase B: 0.1% formic acid in acetonitrile; gradient: 0.0 min 97% A, 3% B, flow rate 1 ml/min; 1.5 min 100% B, flow rate 1 ml/min; 1.9 min 100% B, flow rate 1 ml/min; 2.0 min 97% A, 3% B, flow rate 0.05 ml/min; column temperature: 40° C.; UV detection: from 210 nm to 350 nm; MS conditions: ionization mode: alternating scans positive and negative electrospray (ES+/E−); scan range: 100 to 1000 AMU.

(53) Method 24 (LC-MS):

(54) Instrument: Waters 2690, PDA detector Waters 2996 coupled with Quattro Micro mass MS detector; column: Waters SunFire C18 3.5 μm, 2.1×50 mm; mobile phase A: 10 mM aqueous ammonium bicarbonate solution (adjusted with ammonia to a pH of 10), mobile phase B: acetonitrile; gradient: 0.0 min 95% A, 5% B, flow rate 0.5 ml/min; 3.0 min 95% A, 5% B, flow rate 0.5 ml/min; 17.50 min 5% A, 95% B, flow rate 0.5 ml/min; 19.00 min 5% A, 95% B, flow rate 0.5 ml/min; 19.50 min 95% A, 5% B, flow rate 0.5 ml/min; 20.00 min 95% A, 5% B, flow rate 0.5 ml/min; column temperature: 30° C.; UV detection: from 210 nm to 400 nm; MS conditions: ionization mode: scans positive and negative electrospray (ES+/ES−); scan range: 130 to 1100 AMU.

(55) Method 25 (LC-MS):

(56) Instrument: Waters 2690, PDA detector Waters 2996 coupled with Quattro Micro mass MS detector; column: Waters SunFire C18 3.5 μm, 2.1×50 mm; mobile phase A: 0.1% formic acid in water, mobile phase B: 0.1% formic acid in acetonitrile; gradient: 0.0 min 95% A, 5% B, flow rate 0.5 ml/min; 3.0 min 95% A, 5% B, flow rate 0.5 ml/min; 17.50 min 5% A, 95% B, flow rate 0.5 ml/min; 19.00 min 5% A, 95% B, flow rate 0.5 ml/min; 19.50 min 95% A, 5% B, flow rate 0.5 ml/min; 20.00 min 95% A, 5% B, flow rate 0.5 ml/min; column temperature: 30° C.; UV detection: from 210 nm to 400 nm; MS conditions: ionization mode: scans positive and negative electrospray (ES+/ES−); scan range: 130 to 1100 AMU.

(57) Method 26 (prep. HPLC):

(58) Instrument: Waters 2690, PDA detector Waters 2996 coupled with Quattro Micro mass MS detector; column: XBridge Prep. MS C18 OBD (150 mm×30 mm ID 5 μm particle size) at room temperature; mobile phase A: 10 mM NH.sub.4HCO.sub.3, adjusted with ammonia to a pH of 10, mobile phase B: acetonitrile; gradient: 0.0 min 97% A, 3% B; 1.0 min 97% A, 3% B; 30 min 0% A, 100% B; 35 min 0% A, 100% B, flow rate 50 ml/min; column temperature: 30° C.; UV detection: from 210 nm to 400 nm; MS conditions: ionization mode: scans positive and negative electrospray (ES+/ES−); scan range: 100 to 1000 AMU.

Starting Materials and Intermediates

Example 1A

(59) 3-[(2,6-Difluorobenzyl)oxy]pyridine-2-amine

(60) ##STR00039##

(61) At RT, 51 g of sodium methoxide (953 mmol, 1.05 equivalents) were initially charged in 1000 ml of methanol, 100 g of 2-amino-3-hydroxypyridine (908 mmol, 1 equivalent) were added and the mixture was stirred at RT for 15 min. The reaction mixture was concentrated under reduced pressure, the residue was taken up in 2500 ml of DMSO and 197 g of 2,6-difluorobenzyl bromide (953 mmol, 1.05 equivalents) were added. After 4 h at RT, the reaction mixture was added to 20 l of water, the mixture was stirred for 15 min and the solid was filtered off with suction. The solid was washed with 1 l of water and 100 ml of isopropanol and 500 ml of petroleum ether and dried under high vacuum. This gave 171 g of the title compound (78% of theory).

(62) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=5.10 (s, 2 H), 5.52 (br. s, 2 H), 6.52 (dd, 1 H), 7.16-7.21 (m, 3 H), 7.49-7.56 (m, 2 H).

Example 2A

Ethyl 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate

(63) ##STR00040##

(64) 170 g of 3-[(2,6-difluorobenzyl)oxy]pyridine-2-amine (Example 1A; 719 mmol, 1 equivalent) were initially charged in 3800 ml of ethanol, and 151 g of powdered molecular sieve 3 Å and 623 g of ethyl 2-chloroacetoacetate (3.6 mol, 5 equivalents) were added. The reaction mixture was heated at reflux for 24 h and then filtered off through silica gel and concentrated under reduced pressure. The mixture was kept at RT for 48 h and the solid formed was filtered off. The solid was stirred with a little isopropanol and then filtered off three times, and washed with diethyl ether. This gave 60.8 g (23% of theory) of the title compound. The combined filtrates of the filtration steps were concentrated and the residue was chromatographed on silica gel using the mobile phase cyclohexane/diethyl ether. This gave a further 46.5 g (18% of theory, total yield: 41% of theory) of the title compound.

(65) LC-MS (Method 1): R.sub.t=1.01 min

(66) MS (ESpos): m/z=347 (M+H).sup.+

(67) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=1.36 (t, 3 H), 2.54 (s, 3 H; obscured by DMSO signal), 4.36 (q, 2 H), 5.33 (s, 2 H), 7.11 (t, 1 H), 7.18-7.27 (m, 3 H), 7.59 (quint, 1 H), 8.88 (d, 1 H).

Example 3A

8-[(2,6-Difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid

(68) ##STR00041##

(69) 107 g of ethyl 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate (Example 2A; 300 mmol, 1 equivalent) were dissolved in 2.8 l of THF/methanol (1:1), 1.5 l of 1 N aqueous lithium hydroxide solution (1.5 mol, 5 equivalents) were added and the mixture was stirred at RT for 16 h. The organic solvents were removed under reduced pressure and the resulting aqueous solution was, in an ice bath, adjusted to pH 3-4 using 1 N aqueous hydrochloric acid. The resulting solid was filtered off, washed with water and isopropanol and dried under reduced pressure. This gave 92 g (95% of theory) of the title compound.

(70) LC-MS (Method 1): R.sub.t=0.62 min

(71) MS (ESpos): m/z=319.1 (M+H).sup.+

(72) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=2.55 (s, 3 H; superposed by DMSO signal), 5.32 (s, 2 H); 7.01 (t, 1 H), 7.09 (d, 1 H), 7.23 (t, 2 H), 7.59 (quint, 1 H), 9.01 (d, 1 H).

Example 4A

3-(Cyclohexylmethoxy)pyridine-2-amine

(73) ##STR00042##

(74) At RT, 96 g of sodium hydroxide, 45% strength in water (1081 mmol, 1 equivalent), were initially charged in 1170 ml of methanol, 119 g of 2-amino-3-hydroxypyridine (1080 mmol, 1 equivalent) were added and the mixture was stirred at RT for another 10 min. The reaction mixture was concentrated under reduced pressure, the residue was taken up in 2900 ml of DMSO and 101 g of cyclohexylmethyl bromide (1135 mmol, 1.05 equivalents) were added. After 16 h at RT, the reaction mixture was slowly added to 6 l of water and the aqueous solution was extracted twice with in each case 2 l of ethyl acetate. The combined organic phases were washed with in each case 1 l of saturated aqueous sodium bicarbonate solution and water, dried, filtered and concentrated. The residue was stirred with 500 ml of n-pentane, filtered and dried under reduced pressure. This gave 130 g (58% of theory) of the title compound.

(75) LC-MS (Method 3): R.sub.t=1.41 min

(76) MS (ESpos): m/z=207.1 (M+H).sup.+

Example 5A

Ethyl 8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylate

(77) ##STR00043##

(78) 130 g of 3-(cyclohexylmethoxy)pyridine-2-amine (Example 4A; 630 mmol, 1 equivalent) were initially charged in 3950 ml of ethanol, and 436 ml of ethyl 2-chloroacetoacetate (3.2 mol, 5 equivalents) were added. The mixture was heated at reflux for 24 h and then concentrated under reduced pressure. The crude product thus obtained was chromatographed on silica gel using the mobile phase cyclohexane/diethyl ether, giving 66.2 g (33% of theory) of the title compound.

(79) LC-MS (Method 1): R.sub.t=1.17 min

(80) MS (ESpos): m/z=317.1 (M+H).sup.+

(81) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=1.02-1.31 (m, 5 H), 1.36 (t, 3 H), 1.64-1.77 (m, 3 H), 1.79-1.90 (m, 3 H), 2.60 (s, 3 H), 3.97 (d, 2 H), 4.35 (q, 2 H), 6.95 (d, 1 H), 7.03 (t, 1 H), 8.81 (d, 1 H).

Example 6A

8-(Cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid

(82) ##STR00044##

(83) 50 g of ethyl 8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylate (Example 5A; 158 mmol, 1 equivalent) were dissolved in 600 ml of 1,4-dioxane, 790 ml of 2 N aqueous sodium hydroxide solution (1.58 mol, 10 equivalents) were added and the mixture was stirred at RT for 16 h. 316 ml of 6 N aqueous hydrochloric acid were added and the mixture was concentrated to about ⅕ of the total volume. The resulting solid was filtered off, washed with water and tert-butyl methyl ether and dried under reduced pressure. This gave 35 g (74% of theory) of the title compound.

(84) LC-MS (Method 1): R.sub.t=0.81 min

(85) MS (ESpos): m/z=289.0 (M+H).sup.+

(86) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=1.03-1.44 (m, 5 H), 1.64-1.78 (m, 3 H), 1.81-1.92 (m, 3 H), 2.69 (s, 3 H), 4.07 (d, 2 H), 7.30-7.36 (m, 2 H), 9.01 (d, 1 H).

Example 7A

5-Chloro-2-nitropyridin-3-ol

(87) ##STR00045##

(88) With ice cooling, 30 g of 5-chloropyridin-3-ol (232 mmol, 1 equivalent) were dissolved in 228 ml of concentrated sulphuric acid, and 24 ml of concentrated nitric acid were added slowly at 0° C. The mixture was warmed to RT, stirred overnight and then stirred into an ice/water mixture and stirred for another 30 min. The solid was filtered off, washed with cold water and air-dried. This gave 33 g (82% of theory) of the title compound which was used without further purification for the next reaction.

(89) LC-MS (Method 1): R.sub.t=0.60 min

(90) MS (ESneg): m/z=172.9/174.9 (M−H).sup.−

(91) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=7.71 (d, 1 H), 8.10 (d, 1 H), 12.14 (br. 1 H).

Example 8A

5-Chloro-3-[(2,6-difluorobenzyl)oxy]-2-nitropyridine

(92) ##STR00046##

(93) 33 g of 5-chloro-2-nitropyridin-3-ol (Example 7A; 189 mmol, 1 equivalent) and 61.6 g of caesium carbonate (189 mmol, 1 equivalent) were initially charged in 528 ml of DMF, 40.4 g of 2,6-difluorobenzyl bromide (189 mmol, 1 equivalent) were added and the mixture was stirred at RT overnight. The reaction mixture was stirred into water/1N aqueous hydrochloric acid. The solid was filtered off, washed with water and air-dried. This gave 54.9 g (97% of theory) of the title compound.

(94) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=5.46 (s, 2 H), 7.22 (t, 2 H), 7.58 (q, 1 H), 8.28 (d, 1 H), 8.47 (d, 1 H).

Example 9A

5-Chloro-3-[(2,6-difluorobenzyl)oxy]pyridine-2-amine

(95) ##STR00047##

(96) 59.7 g of 5-chloro-3-[(2,6-difluorobenzyl)oxy]-2-nitropyridine (Example 8A; 199 mmol, 1 equivalent) were initially charged in 600 ml of ethanol, 34.4 g of iron powder (616 mmol, 3.1 equivalents) were added and the mixture was heated to reflux. 152 ml of concentrated hydrochloric acid were slowly added dropwise, and the mixture was boiled at reflux for a further 30 min. The reaction mixture was cooled and stirred into an ice/water mixture. The resulting mixture was adjusted to pH 5 used sodium acetate. The solid was filtered off, washed with water and air-dried and then dried under reduced pressure at 50° C. This gave 52.7 g (98% of theory) of the title compound.

(97) LC-MS (Method 1): R.sub.t=0.93 min

(98) MS (ESpos): m/z=271.1/273.1 (M+H).sup.+

(99) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=5.14 (s, 2 H), 5.82 (br. s, 2 H); 7.20 (t, 2 H), 7.35 (d, 1 H), 7.55 (q, 1 H), 7.56 (d, 1 H).

Example 10A

Ethyl 6-chloro-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate

(100) ##STR00048##

(101) 40 g of 5-chloro-3-[(2,6-difluorobenzyl)oxy]pyridine-2-amine (Example 9A; 147.8 mmol, 1 equivalent) were initially charged in 800 ml of ethanol, 30 g of powdered molecular sieve 3 Å and 128 g of ethyl 2-chloroacetoacetate (739 mmol, 5 equivalents) were added and the mixture was heated at reflux overnight. The reaction mixture was concentrated, and the residue was taken up in ethyl acetate and filtered. The ethyl acetate phase was washed with water, dried, filtered and concentrated. This gave 44 g (78% of theory) of the title compound.

(102) LC-MS (Method 1): R.sub.t=1.27 min

(103) MS (ESpos): m/z=381.2/383.2 (M+H).sup.+

(104) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=1.36 (t, 3 H), 2.54 (s, 3 H; obscured by DMSO signal); 4.37 (q, 2 H), 5.36 (s, 2 H), 7.26 (t, 2 H), 7.38 (d, 1 H), 7.62 (q, 1 H), 8.92 (d, 1 H).

Example 11A

6-Chloro-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid

(105) ##STR00049##

(106) 44 g of ethyl 6-chloro-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate (Example 10A; 115 mmol, 1 equivalent) were dissolved in 550 ml of THF and 700 ml of methanol, 13.8 g of lithium hydroxide (dissolved in 150 ml of water; 577 mmol, 5 equivalents) were added and the mixture was stirred at RT overnight. 1 N aqueous hydrochloric acid was added and the mixture was concentrated under reduced pressure. The solid obtained was filtered off and washed with water. This gave 34 g of the title compound (84% of theory).

(107) LC-MS (Method 2): R.sub.t=1.03 min

(108) MS (ESpos): m/z=353.0/355.0 (M+H).sup.+

(109) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=2.54 (s, 3 H; superimposed by DMSO signal), 5.36 (s, 2 H), 7.26 (t, 2 H), 7.34 (d, 1 H), 7.61 (q, 1 H), 8.99 (d, 1 H), 13.36 (br. s, 1 H).

Example 12A

5-Bromo-3-[(2,6-difluorobenzyl)oxy]pyridine-2-amine

(110) ##STR00050##

(111) 32.6 g of 3-[(2,6-difluorobenzyl)oxy]pyridine-2-amine (Example 1A; 138 mmol, 1 equivalent) were suspended in 552 ml of 10% strength sulphuric acid, and the mixture was cooled to 0° C. 8.5 ml of bromine (165 mmol, 1.2 equivalents) were dissolved in 85 ml of acetic acid and then, over 90 min, added dropwise to the reaction solution, cooled with ice. After the addition had ended, the mixture was stirred at 0° C. for 90 min and then diluted with 600 ml of ethyl acetate, and the aqueous phase was separated off. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated aqueous sodium bicarbonate solution, dried and concentrated. The residue was dissolved in dichloromethane and chromatographed on silica gel (petroleum ether/ethyl acetate gradient as mobile phase). This gave 24 g (55% of theory) of the title compound.

(112) LC-MS (Method 1): R.sub.t=0.96 min

(113) MS (ESpos): m/z=315.1/317.1 (M+H).sup.+

(114) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=5.14 (s, 2 H), 5.83 (br. s, 2 H), 7.20 (t, 2 H), 7.42 (d, 1 H), 7.54 (q, 1 H), 7.62 (d, 1 H).

Example 13A

Ethyl 6-bromo-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate

(115) ##STR00051##

(116) 16 g of powdered molecular sieve 3 Å and 52.7 ml of ethyl 2-chloroacetoacetate (380.8 mmol, 5 equivalents) were added to 24 g of 5-bromo-3-[(2,6-difluorobenzyl)oxy]pyridine-2-amine (Example 12A; 76.2 mmol, 1 equivalent) in 400 ml of ethanol, and the mixture was heated at reflux overnight. 8 g of molecular sieve were added and the mixture was heated at reflux for a further 24 h. The reaction mixture was concentrated under reduced pressure, and the residue was taken up in dichloromethane and chromatographed on silica gel (mobile phase: dichloromethane/methanol 20:1). The product-containing fractions were concentrated and the residue was stirred with 100 ml of diethyl ether for 30 min. The solid was then filtered off, washed with a little diethyl ether and dried. This gave 15 g (45% of theory) of the title compound.

(117) LC-MS (Method 2): R.sub.t=1.43 min

(118) MS (ESpos): m/z=414.9/416.8 (M+H).sup.+

(119) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=1.36 (t, 3 H), 2.54 (s, 3H; obscured by DMSO signal), 4.37 (q, 2 H), 5.36 (s, 2 H), 7.25 (t, 2 H), 7.42 (d, 1 H), 7.61 (q, 1 H), 9.00 (d, 1 H).

Example 14A

6-Bromo-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid

(120) ##STR00052##

(121) 1.5 g of ethyl 6-bromo-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate (Example 13A; 3.5 mmol, 1 equivalent) were dissolved in 72 ml of THF/methanol 5:1, 17.6 ml of 1N aqueous lithium hydroxide solution (17.6 mmol, 5 equivalents) were added and the mixture was warmed to 40° C. and stirred at this temperature for 6 h. Using 6 N aqueous hydrochloric acid, the mixture was adjusted to pH 4 and concentrated under reduced pressure. Water was added to the solid formed, the mixture was stirred and the product was filtered off, washed with water and dried under reduced pressure. This gave 1.24 g of the title compound (88% of theory).

(122) LC-MS (Method 1): R.sub.t=0.93 min

(123) MS (ESpos): m/z=397.0/399.1 (M+H).sup.+

(124) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=2.54 (s, 3 H; superimposed by DMSO signal); 5.36 (s, 2 H); 7.25 (t, 2 H); 7.40 (d, 1 H); 7.61 (q, 1 H); 9.06 (d, 1 H); 13.35 (br. s, 1 H).

Example 15A

Ethyl 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate

(125) ##STR00053##
Method 1:

(126) 600 mg of ethyl 6-bromo-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate (Example 13A; 1.4 mmol, 1 equivalent) and 230 mg of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride/dichloromethane complex (0.282 mmol, 20 mol %) were dissolved in 25 ml of THF, and 0.88 ml (1.76 mmol, 1.2 equivalents) of a 2 M solution of methylzinc chloride in THF was added. In a microwave oven, the reaction mixture was heated at 100° C. for 40 min. The reaction mixture was filtered through Celite and then concentrated under reduced pressure. The residue was chromatographed (Biotage Isolera Four; cyclohexane:ethyl acetate). This gave 225 mg (38% of theory) of the title compound.

(127) Method 2:

(128) 20.00 g (85.38 mmol) of ethyl 8-hydroxy-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate from Example 20A, 19.44 g (93.91 mmol) of 2,6-difluorobenzyl bromide and 61.20 g (187.83 mmol) of caesium carbonate in 1.18 l of DMF were stirred at 60° C. for 5 h. The reaction mixture was then added to 6.4 l of 10% strength aqueous sodium chloride solution and then twice extracted with ethyl acetate. The combined organic phases were washed with 854 ml of a 10% strength aqueous sodium chloride solution, dried, concentrated and dried at RT under high vacuum overnight. This gave 28.2 g (92% of theory, purity: 90%) of the title compound.

(129) LC-MS (Method 1): R.sub.t=1.05 min

(130) MS (ESpos): m/z=361.1 (M+H).sup.+

(131) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=1.38 (t, 3 H), 2.36 (s, 3 H), 4.35 (q, 2 H), 5.30 (s, 2 H), 7.10 (s, 1 H), 7.23 (t, 2 H), 7.59 (q, 1 H), 8.70 (s, 1 H).

Example 16A

8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylic acid

(132) ##STR00054##

(133) 220 mg of ethyl 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate (Example 15A; 0.524 mmol, 1 equivalent) were dissolved in 7 ml of THF/methanol (1:1), 2.6 ml of 1 N aqueous lithium hydroxide solution (2.6 mmol, 5 equivalents) were added and the mixture was stirred at RT for 16 h. The mixture was concentrated under reduced pressure and the residue was acidified with 1N aqueous hydrochloric acid and stirred for 15 min. The solid was filtered off, washed with water and dried under reduced pressure. This gave 120 mg of the title compound (60% of theory).

(134) LC-MS (Method 1): R.sub.t=0.68 min

(135) MS (ESpos): m/z=333.1 (M+H).sup.+

(136) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=2.34 (s, 3 H), 5.28 (s, 2 H), 7.09 (s, 1 H), 7.23 (t, 2 H), 7.58 (q, 1 H), 8.76 (s, 1 H), 13.1 (br. s, 1 H).

Example 17A

3-(Benzyloxy)-5-bromopyridine-2-amine

(137) ##STR00055##

(138) The target compound is known from the literature and described: 1) Palmer, A. M. et al. J Med. Chem. 2007, 50, 6240-6264. 2) ALTANA WO2005/58325 3) ALTANA WO2005/90358 4) Cui, J. T. et al. J Med. Chem. 2011, 54, 6342-6363
Further Preparation Method:

(139) 200 g (1 mol) of 2-amino-3-benzyloxypyridine were initially charged in 4 l of dichloromethane, and at 0° C. a solution of 62 ml (1.2 mol) of bromine in 620 ml of dichloromethane was added over 30 min. After the addition had ended, the reaction solution was stirred at 0° C. for 60 min. About 4 l of saturated aqueous sodium bicarbonate solution were then added to the mixture. The organic phase was removed and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 6:4) and the product fractions were concentrated. This gave 214 g (77% of theory) of the title compound.

(140) LC-MS (Method 1): R.sub.t=0.92 min

(141) MS (ESpos): m/z=279 (M+H).sup.+

(142) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=5.16 (s, 2H), 5.94-6.00 (m, 2H), 7.26-7.29 (m, 1H), 7.31-7.36 (m, 1H), 7.37-7.43 (m, 2H), 7.47-7.52 (m, 2H), 7.57-7.59 (m, 1H).

Example 18A

Ethyl 8-(benzyloxy)-6-bromo-2-methylimidazo[1,2-a]pyridine-3-carboxylate

(143) ##STR00056##

(144) Under argon, 200 g (0.72 mol) of 3-(benzyloxy)-5-bromopyridine-2-amine from Example 17A, 590 g (3.58 mol) of ethyl 2-chloroacetoacetate and 436 g of 3 A molecular sieve were suspended in 6 l of ethanol, and the suspension was stirred at reflux for 72 h. The reaction mixture was filtered off through silica gel and concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate 9:1, then 6:4) and the product fractions were concentrated. This gave 221 g (79% of theory) of the target compound.

(145) LC-MS (Method 16): R.sub.t=1.31 min

(146) MS (ESpos): m/z=389 (M+H).sup.+

(147) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=1.36 (t, 3 H), 2.58 (s, 3 H), 4.32-4.41 (m, 2 H), 5.33 (s, 2 H), 7.28-7.32 (m, 1 H), 7.36-7.47 (m, 3 H), 7.49-7.54 (m, 2 H), 8.98 (d, 1 H).

Example 19A

Ethyl 8-(benzyloxy)-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate

(148) ##STR00057##

(149) Under argon, 105 g (270 mmol) of ethyl 8-(benzyloxy)-6-bromo-2-methylimidazo[1,2-a]pyridine-3-carboxylate from Example 18A were suspended in 4.2 l of 1,4-dioxane, and 135.4 g (539 mmol, purity 50%) of trimethylboroxine, 31.2 g (27 mmol) of tetrakis(triphenylphosphine)palladium(0) and 78.3 g (566 mmol) of potassium carbonate were added in succession and the mixture was stirred under reflux for 8 h. The reaction mixture was cooled to RT and, using silica gel, freed from the precipitate, and the filtrate was concentrated. The residue was dissolved in dichloromethane and purified by silica gel chromatography (dichloromethane:ethyl acetate=9:1). This gave 74 g (84.6% of theory, purity 100%) of the target compound.

(150) LC-MS (Method 16): R.sub.t=1.06 min

(151) MS (ESpos): m/z=325 (M+H).sup.+

(152) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=1.35 (t, 3 H), 2.34 (br. s, 3 H), 2.56 (s, 3 H), 4.31-4.38 (m, 2 H), 5.28 (br. s, 2 H), 6.99-7.01 (m, 1 H), 7.35-7.47 (m, 3 H), 7.49-7.54 (m, 2 H), 8.68-8.70 (m, 1 H).

Example 20A

Ethyl 8-hydroxy-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate

(153) ##STR00058##

(154) 74 g (228 mmol) of ethyl 8-(benzyloxy)-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate from Example 19A were initially charged in 1254 ml of dichloromethane and 251 ml of ethanol, and 20.1 g of 10% strength palladium on activated carbon (moist with water, 50%) were added. Overnight, the reaction mixture was hydrogenated at RT and under atmospheric pressure. The reaction mixture was filtered off through silica gel and concentrated. The crude product was purified by silica gel chromatography (dichloromethane:methanol=95:5). This gave 50.4 g (94% of theory) of the target compound.

(155) DCI-MS: (Method 13) (ESpos): m/z=235.2 (M+H).sup.+

(156) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=1.35 (t, 3 H), 2.27 (s, 3 H), 2.58 (s, 3 H), 4.30-4.38 (m, 2 H), 6.65 (d, 1 H), 8.59 (s, 1 H), 10.57 (br. s, 1H).

Example 21A

Ethyl 2,6-dimethyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine-3-carboxylate

(157) ##STR00059##

(158) 3.00 g (12.81 mmol) of ethyl 8-hydroxy-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate Example 20A, 3.27 g (14.1 mmol) of 2-(bromomethyl)-1,3,4-trifluorobenzene and 9.18 g (28.17 mmol) of caesium carbonate were initially charged in 183 ml of dry DMF, and the mixture was heated in an oil bath at 60° C. for 30 min. About 1.81 of water were then added, and the mixture was stirred for 30 min. The solid was filtered off, washed with water and dried under reduced pressure. This gave 5.07 g of the title compound (99% of theory).

(159) LC-MS (Method 1): R.sub.t=1.14 min

(160) MS (ESpos): m/z=379 (M+H).sup.+

(161) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=1.35 (t, 3 H), 2.36 (s, 3 H); 2.55 (s, 3 H; superimposed by DMSO signal), 4.36 (q, 2 H), 5.35 (s, 2 H), 7.09 (s, 1 H), 7.22-7.32 (m, 1 H), 7.60-7.73 (m, 1 H), 8.72 (s, 1 H).

Example 22A

2,6-Dimethyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine-3-carboxylic acid

(162) ##STR00060##

(163) 5.07 g (12.87 mmol) of ethyl 2,6-dimethyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine-3-carboxylate Example 21A were dissolved in 275 ml of THF/methanol (5/1), 64.4 ml of 1 N aqueous lithium hydroxide solution were added and the mixture was stirred at 40° C. for 3.5 h. At 0° C., the reaction was brought to a pH of about 4 using 6 N aqueous hydrochloric acid and then concentrated. The solid obtained was filtered off, washed with water and dried under reduced pressure. This gave 4.77 g (98% of theory, purity about 93%) of the title compound.

(164) LC-MS (Method 1): R.sub.t=0.72 min

(165) MS (ESpos): m/z=351 (M+H).sup.+

(166) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=2.37 (s, 3 H), 2.54 (s, 3 H; superimposed by DMSO signal), 5.36 (s, 2 H), 7.11 (s, 1 H), 7.25-7.33 (m, 1 H), 7.61-7.73 (m, 1 H), 8.78 (s, 1 H), 13.10 (br. s, 1 H).

Example 23A

Ethyl 8-[(3-fluoropyridin-2-yl)methoxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate

(167) ##STR00061##

(168) 16.92 g (72.2 mmol) of ethyl 8-hydroxy-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate from Example 20A were initially charged in 956 ml of DMF, and 15.78 g (86.7 mmol) of 2-(chloromethyl)-3-fluoropyridine hydrochloride (described in: U.S. Pat. No. 5,593,993 A1, 1997; WO2007/2181 A2, 2007) and 94.06 g (288.9 mmol) of caesium carbonate were added. The reaction mixture was stirred at 60° C. overnight. The reaction mixture, cooled to RT, was filtered, the filter cake was washed with ethyl acetate and the filtrate was concentrated. About 500 ml of water were added to the residue, and the solid was filtered off and dried under high vacuum. This gave 24.1 g (93% of theory) of the target compound.

(169) LC-MS (Method 1): R.sub.t=0.84 min

(170) MS (ESpos): m/z=344 (M+H).sup.+

(171) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=1.35 (t, 3H), 2.35 (s, 3H), 2.54 (s, 3H, obscured by DMSO signal), 4.35 (q, 2H), 5.40 (s, 2H), 7.08 (s, 1H), 7.55-7.62 (m, 1H), 7.82-7.89 (m, 1H), 8.48-8.52 (m, 1H), 8.70 (s, 1H).

Example 24A

8-[(3-Fluoropyridin-2-yl)methoxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylic acid

(172) ##STR00062##

(173) 24.06 g (70.1 mmol) of ethyl 8-[(3-fluoropyridin-2-yl)methoxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate from Example 23A were initially charged in 1.5 l of THF/methanol (5:1), 350.4 ml (350.4 mmol) of 1 N aqueous lithium hydroxide solution were added and the mixture was stirred at 40° C. for 2.5 h. After cooling, the mixture was adjusted to a pH of about 4 using 1 N aqueous hydrochloric acid, and the solution was freed from THF/methanol under reduced pressure. The residue was cooled and the solid was filtered off and dried under reduced pressure. This gave 22.27 g (100% of theory) of the title compound.

(174) LC-MS (Method 1): R.sub.t=0.55 min

(175) MS (ESpos): m/z=316 (M+H).sup.+

(176) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=2.34 (s, 3H), 2.53 (s, 3H, obscured by DMSO signal), 5.38-5.42 (m, 2H), 7.06 (s, 1H), 7.56-7.62 (m, 1H), 7.82-7.89 (m, 1H), 8.48-8.52 (m, 1H), 8.74 (s, 1H), 13.02 (br. s, 1H).

Example 25A

8-[(2,6-Difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carbonyl chloride hydrochloride

(177) ##STR00063##

(178) 4 drops of DMF and then 3.19 g of oxalyl chloride (25.14 mmol, 4 equivalents) were added dropwise to 2.0 g of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid (6.28 mmol, 1 equivalent) from Example 3A in 25 ml of dry THF. The reaction mixture was stirred at RT for 3 h. Another 0.80 g of oxalyl chloride (6.28 mmol, 1 equivalent) was added and the reaction was stirred at RT for a further 4 h. The reaction mixture was concentrated and evaporated three times with toluene, and the residue was dried under high vacuum. This gave 2.43 g of the title compound (103% of theory).

(179) DCI-MS (Method 13): MS (ESpos): m/z=437 (M-HCl+H).sup.+

Example 26A

8-(Cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carbonyl chloride

(180) ##STR00064##

(181) 2.8 g of 8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid (Example 6A, 9.6 mmol) were dissolved in 60 ml of thionyl chloride, and the mixture was stirred at 80° C. overnight. The mixture was then concentrated under reduced pressure, dissolved in toluene and concentrated again. The residue was dried under high vacuum. This gave 2.9 g (98% of theory) of the title compound. The crude product obtained was reacted further without purification.

Example 27A

8-[(2,6-Difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine

(182) ##STR00065##

(183) 12 g of 3-[(2,6-difluorobenzyl)oxy]pyridine-2-amine (Example 1A, 50.8 mmol, 1 equivalent) and 8 g of 1-chloroacetone (86.4 mmol, 1.7 equivalents) in 90 ml of ethanol were stirred at 80° C. overnight. Silica gel was added and the reaction mixture was concentrated. The residue was purified by silica gel chromatography (mobile phase mixture dichloromethane/ethanol=50:1). The product mixture obtained was then purified by silica gel chromatography (mobile phase mixture dichloromethane/ethanol/diethylamine=50:1:0.1, 40:1:0.5, 30:1:0.5). This gave 6.3 g (45% of theory) of the title compound.

(184) LC-MS (Method 1): R.sub.t=0.58 min

(185) MS (ESpos): m/z=274 (M+H).sup.+

(186) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=2.27 (s, 3 H), 5.27 (s, 2 H), 6.69-6.80 (m, 2 H), 7.23 (s, 2 H), 7.51-7.62 (m, 1 H), 7.65 (s, 1 H), 8.03-8.12 (m, 1 H).

Example 28A

3-Bromo-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine

(187) ##STR00066##

(188) 193 g of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine (Example 27A, 0.7 mmol, 1 equivalent) were initially charged in 2.2 l of ethanol, and 150.3 g of N-bromosuccinimide (0.8 mmol, 1.2 equivalents) were added. After 1.5 h at RT, the mixture was concentrated under reduced pressure at RT. The residue was then diluted with ethyl acetate, and the organic phase was washed with saturated aqueous sodium hydrogencarbonate solution, dried over sodium sulphate, filtered and concentrated by rotary evaporation. The residue was purified by silica gel chromatography (mobile phase mixture cyclohexane/ethyl acetate=98:2, 96:4, 92:8, 9:1, 8:2 and 7:3). The product obtained was stirred with 600 ml of ethyl acetate and decanted off. The residue was dried under reduced pressure. This gave 23.4 g (9% of theory) of the title compound. The filtrate was concentrated under reduced pressure and the residue was stirred with 100 ml of ethyl acetate. The ethyl acetate phase was decanted off and the residue was dried under reduced pressure. This gave a further 6.1 g (2.3% of theory) of the title compound.

(189) LC-MS (Method 1): R.sub.t=0.90 min

(190) MS (ESpos): m/z=353 (M+H).sup.+

(191) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=2.27 (s, 3 H), 5.27 (s, 2 H), 6.70-6.80 (m, 2 H), 7.23 (t, 2 H), 7.52-7.62 (m, 1 H), 7.65 (s, 1 H), 8.09 (d, 1 H).

Example 29A

8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine

(192) ##STR00067##

(193) 10.0 g (30.09 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylic acid from Example 16A were initially charged in 228 ml of dioxane, 25.1 ml of 6 N aqueous hydrochloric acid solution were added and the mixture was stirred at 100° C. for 2 h. After cooling, the dioxane was removed under reduced pressure and the aqueous residue was adjusted to pH 8 using 2 N aqueous sodium hydroxide solution. The solid obtained was filtered off, washed with water and dried under high vacuum. This gave 8.97 g of the target compound (97% of theory, purity 94%).

(194) LC-MS (Method 1): R.sub.t=0.70 min

(195) MS (ESpos): m/z=289 (M+H).sup.+

(196) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=2.22-2.30 (m, 6 H); 5.27 (s, 2 H); 6.67 (s, 1 H); 7.21 (t, 2 H); 7.53-7.63 (m, 2 H); 7.89 (s, 1 H).

Example 30A

3-Bromo-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine

(197) ##STR00068##

(198) Under argon and with exclusion of light, 3.865 g (13.41 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine from Example 29A were initially charged in 42 ml of ethanol, 2.625 g (14.75 mmol) of N-bromosuccinimide were added and the mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated. The residue was stirred with about 100 ml of water, and the resulting suspension was then stirred at RT for 30 min. The precipitate formed was filtered off, washed with water and dried under high vacuum. This gave 4.48 g of the target compound (91% of theory, purity 100%).

(199) LC-MS (Method 1): R.sub.t=0.93 min

(200) MS (ESpos): m/z=267 (M+H).sup.+

(201) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=2.28 (s, 3H), 2.33 (s, 3 H); 5.30 (s, 2 H); 6.89 (s, 1 H); 7.22 (t, 2 H); 7.53-7.63 (m, 1 H); 7.75 (s, 1 H).

Example 31A

2,6-Dimethyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine

(202) ##STR00069##

(203) 6.48 g (18.50 mmol) of 2,6-dimethyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine-3-carboxylic acid from Example 22A were initially charged in 140 ml of dioxane, 15.4 ml of 6 N aqueous hydrochloric acid solution were added and the mixture was stirred at 100° C. for 4 h. After cooling, the dioxane was removed under reduced pressure and the aqueous residue was adjusted to pH 8 using 1 N aqueous sodium hydroxide solution. The solid formed was filtered off, washed with water and dried under high vacuum. This gave 5.57 g of the target compound (96% of theory).

(204) LC-MS (Method 1): R.sub.t=0.65 min

(205) MS (ESpos): m/z=307 (M+H).sup.+

(206) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=2.20-2.29 (m, 6 H), 5.29 (s, 2 H), 6.69 (s, 1 H), 7.23-7.33 (m, 1 H), 7.57 (s, 1 H), 7.60-7.73 (m, 1 H), 7.91 (s, 1 H).

Example 32A

3-Bromo-2,6-dimethyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine

(207) ##STR00070##

(208) Under argon and with exclusion of light, 2.28 g (7.45 mmol) of 2,6-dimethyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine from Example 31A were initially charged in 23.4 ml of ethanol, 1.46 g (8.20 mmol) of N-bromosuccinimide were added and the mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure. The residue was stirred with 200 ml of water, and the resulting suspension was then stirred at RT for 2 h. The precipitate formed was filtered off, washed with water and dried under high vacuum. 2.47 g of the target compound were obtained (86% of theory).

(209) LC-MS (Method 1): R.sub.t=0.97 min

(210) MS (ESpos): m/z=385 (M+H).sup.+

(211) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=2.28 (s, 3 H), 2.33 (s, 3 H); 5.32 (s, 2 H); 6.87 (s, 1 H); 7.24-7.33 (m, 1 H); 7.62-7.73 (m, 1 H); 7.76 (s, 1 H).

Example 33A

8-[(3-Fluoropyridin-2-yl)methoxy]-2,6-dimethylimidazo[1,2-a]pyridine

(212) ##STR00071##

(213) 2.30 g (7.29 mmol) of 8-[(3-fluoropyridin-2-yl)methoxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylic acid from Example 24A were initially charged in 55.2 ml of dioxane, 12.2 ml of 6 N aqueous hydrochloric acid solution were added and the mixture was stirred at 100° C. overnight. After cooling, the dioxane was removed under reduced pressure and the aqueous residue was adjusted to pH 8 using 2 N aqueous sodium hydroxide solution. The solid formed was filtered off, washed well with water and dried under high vacuum. 2.53 g of the target compound were obtained (125% of theory).

(214) LC-MS (Method 1): R.sub.t=0.58 min

(215) MS (ESpos): m/z=272 (M+H).sup.+

(216) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=2.24 (s, 3 H), 2.26 (s, 3 H), 5.40 (s, 2 H), 6.87 (s, 1 H), 7.54-7.70 (m, 2 H), 7.85 (t, 1 H), 7.99 (s, 1 H), 8.47-8.53 (m, 1 H).

Example 34A

3-Bromo-8-[(3-fluoropyridin-2-yl)methoxy]-2,6-dimethylimidazo[1,2-a]pyridine trifluoroacetate

(217) ##STR00072##

(218) Under argon, 916 mg (3.38 mmol) of 8-[(3-fluoropyridin-2-yl)methoxy]-2,6-dimethylimidazo[1,2-a]pyridine from Example 33A were initially charged in 10.6 ml of dichloromethane, the mixture was cooled to −78° C., 631 mg (3.55 mmol) of N-bromosuccinimide were added and the mixture was stirred at −78° C. for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was taken up in acetonitrile, water/TFA was added and the mixture was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). This gave 508 mg of the target compound (30% of theory, purity 94%).

(219) LC-MS (Method 1): R.sub.t=0.71 min

(220) MS (ESpos): m/z=350 (M+H).sup.+

(221) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=2.29 (s, 3 H), 2.34 (s, 3 H); 5.39 (s, 2 H); 6.85 (s, 1 H); 7.54-7.62 (m, 1 H); 7.72 (s, 1H), 7.85 (t, 1 H), 8.49 (d, 1 H).

Example 35A

8-[(2,6-Difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide

(222) ##STR00073##

(223) Under argon, 5 g of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid (Example 3A, 15.7 mmol, 1 equivalent) were initially charged in 300 ml of dichloromethane, 4.5 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (23.6 mmol, 1.5 equivalents) and 3.6 g of 1-hydroxy-1H-benzotriazole hydrate (HOBT, 23.6 mmol, 1.5 equivalents) were added successively at RT and the mixture was stirred at RT for 10 min. 4.2 g of ammonium chloride (78.5 mmol, 5 equivalents) and 19.2 ml of N,N-diisopropylethylamine (109.9 mmol, 7 equivalents) were then added, and the mixture was stirred at RT overnight. The mixture was concentrated by rotary evaporation, dichloromethane was added to the residue, the mixture was filtered, the filter cake was washed with dichloromethane and the product was dried under reduced pressure overnight. This gave 5.38 g (108% of theory) of the title compound which was reacted further without purification.

(224) LC-MS (Method 1): R.sub.t=0.65 min

(225) MS (ESpos): m/z=318.2 (M+H).sup.+

Example 36A

8-[(2,6-Difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carbonitrile

(226) ##STR00074##

(227) 912 mg of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide (Example 35A, 2.9 mmol, 1 equivalent) were initially charged in 13 ml of THF, and 0.6 ml of pyridine (7.4 mmol, 2.56 equivalents) was added. Subsequently, 1.04 ml (7.4 mmol, 2.56 equivalents) of trifluoroacetic anhydride were added dropwise and the mixture was stirred at RT overnight. Subsequently, the mixture was added to water and extracted three times with ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium bicarbonate solution, once with 1 N aqueous hydrochloric acid and once with saturated sodium chloride solution, dried over sodium sulphate and concentrated on a rotary evaporator. The residue was dried under reduced pressure overnight. This gave 787 mg (91% of theory) of the title compound.

(228) LC-MS (Method 1): R.sub.t=0.97 min

(229) MS (ESpos): m/z=300.1 (M+H).sup.+

(230) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=2.44 (s, 3 H), 5.33 (s, 2 H), 7.10-7.16 (m, 1 H), 7.18-7.28 (m, 3 H), 7.54-7.64 (m, 1 H), 8.22 (d, 1 H).

Example 37A

8-[(2,6-Difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboximidamide

(231) ##STR00075##

(232) Under argon, 135 mg (2.5 mmol, 2.52 equivalents) of ammonium chloride were initially charged in 3.9 ml of toluene, and the mixture was cooled to 0° C. At this temperature, 1.26 ml of 2 M trimethylaluminium in toluene (2.5 mmol, 2.52 equivalents) were added, and the solution was stirred at RT for 2 h. In another flask, 300 mg of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carbonitrile (Example 36A, 1.0 mmol, 1 equivalent) were initially charged in 3.3 ml of toluene, 2 ml of the solution prepared beforehand were added at RT and the mixture was stirred at 110° C. for 1 h. This procedure was repeated four times. The mixture was then cooled, silica gel and a 1:1 mixture of dichloromethane/methanol were added at RT and the mixture was stirred at RT for 30 min. The silica gel was filtered off over a frit. The silica gel was washed with methanol and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (mobile phase: dichloromethane; dichloromethane:methanol=10:2). This gave 137.5 mg (43% of theory) of the title compound.

(233) LC-MS (Method 1): R.sub.t=0.51 min

(234) MS (ESpos): m/z=317.1 (M+H).sup.+

(235) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=2.46 (s, 3 H), 5.32 (s, 2 H), 7.04 (t, 1 H), 7.14 (d, 1 H), 7.24 (t, 2 H), 7.53-7.66 (m, 1 H), 8.17 (d, 1 H), 9.31 (d, 3 H).

Example 38A

8-[(2,6-Difluorobenzyl)oxy]-N-hydroxy-2-methylimidazo[1,2-a]pyridine-3-carboximidamide

(236) ##STR00076##

(237) 50.0 g (148.9 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carbonitrile from Example 36A were suspended in ethanol (1.5 l), 51.75 g (744.6 mmol) of hydroxylamine hydrochloride and 103.0 ml (744.6 mmol) of triethylamine were added and the mixture was stirred at RT overnight. The mixture was then concentrated under reduced pressure, water (2.0 l) and ethanol (100 ml) were added and the mixture was stirred for 1 h. The solid formed was filtered off, washed with water and dried under high vacuum overnight. This gave 38.5 g (78% of theory) of the title compound.

(238) LC-MS (Method 1): R.sub.t=0.56 min

(239) MS (ESpos): m/z=333.2 (M+H).sup.+

Example 39A

8-[(2,6-Difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboximidamide hydrochloride

(240) ##STR00077##

(241) 37.5 g (98.4 mmol, purity 87%) of 8-[(2,6-difluorobenzyl)oxy]-N-hydroxy-2-methylimidazo[1,2-a]pyridine-3-carboximidamide from Example 38A were initially charged in acetic acid (1.0 l), and 11.14 ml (118.08 mmol) of acetic anhydride were added. 7.5 g of palladium/carbon (10%, moist) were then added, and the mixture was hydrogenated at atmospheric pressure for 16 h. The mixture was filtered through kieselguhr and washed with ethanol. After concentration, three times in each case 500 ml of toluene were added to the residue, and the mixture was concentrated under reduced pressure. The residue was stirred with 200 ml of ethyl acetate, filtered and dried under high vacuum. This gave 22.0 g (59% of theory) of the title compound.

(242) LC-MS (Method 1): R.sub.t=0.51 min

(243) MS (ESpos): m/z=317.2 (M+H).sup.+

(244) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=1.82 (s, 3H), 2.46 (s, 3 H), 5.31 (s, 2 H), 6.93 (t, 1 H), 7.01 (d, 1 H), 7.21-7.25 (m, 2 H), 7.55-7.63 (m, 1 H), 8.55 (br d, 1 H).

Example 40A

8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide

(245) ##STR00078##

(246) 7.0 g (21.07 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylic acid from Example 16A were initially charged in 403 ml of dichloromethane, 6.06 g (31.60 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 4.27 g (31.60 mmol) of 1-hydroxy-1H-benzotriazole hydrate were added and the mixture was stirred at room temperature for 10 min. Subsequently, 5.63 g (105.32 mmol) of ammonium chloride and 25.68 ml (147.5 mmol) of N,N-diisopropylethylamine were added and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the solid present was filtered off, then stirred with water at 50° C. for 30 min, filtered off again and washed with water. This gave 4.59 g (65% of theory) of the title compound. The combined filtrate fractions (dichloromethane/water) were separated into the phases. The dichloromethane phase was washed in each case once with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was triturated with a little acetonitrile and filtered off. This gave a further 1.29 g (17% of theory, purity: 93%) of the title compound.

(247) LC-MS (Method 1): R.sub.t=0.64 min

(248) MS (ESpos): m/z=332 (M+H).sup.+

(249) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=2.31 (s, 3H), 2.50 (s, 3 H; hidden under DMSO signal), 5.28 (s, 2 H), 6.92 (s, 1 H), 7.22 (t, 2 H), 7.35 (br. s, 2 H), 7.53-7.63 (m, 1 H); 8.62 (s, 1 H).

Example 41A

8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carbonitrile

(250) ##STR00079##

(251) 5.7 g (17.20 mol) of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide Example 40A were initially charged in 77 ml of THF, and 3.56 ml (44.0 mmol) of pyridine were added. At RT, 6.22 ml (44.0 mmol) of trifluoroacetic anhydride were added dropwise, and the reaction mixture was stirred at RT for 3 h. After the reaction had ended, the mixture was added to water and extracted three times with ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium bicarbonate solution, once with 1 N aqueous hydrochloric acid and once with saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The residue was dried under reduced pressure overnight. This gave 5.47 g (90% of theory) of the title compound.

(252) LC-MS (Method 1): R.sub.t=1.12 min

(253) MS (ESpos): m/z=314 (M+H).sup.+

(254) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=2.37 (s, 3 H), 2.41 (s, 3 H), 5.31 (s, 2 H), 7.12 (s, 1 H), 7.23 (t, 2 H), 7.54-7.63 (m, 1 H), 8.09 (s, 1 H).

Example 42A

8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboximidamide

(255) ##STR00080##

(256) 5.47 g (17.46 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carbonitrile from Example 41A were reacted analogously to Example 37A. This gave 1.28 g (22% of theory) of the title compound.

(257) LC-MS (Method 1): R.sub.t=0.60 min

(258) MS (ESpos): m/z=331.3 (M+H).sup.+

(259) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=2.35 (s, 3 H), 2.43 (s, 3 H), 5.31 (s, 2 H), 7.06 (s, 1 H), 7.24 (t, 2 H), 7.54-7.65 (m, 1 H), 8.02 (s, 1 H), 9.25 (br. s, 3 H).

Example 43A

8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboximidohydrazide

(260) ##STR00081##

(261) 600 mg (1.82 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboximidamide from Example 42A were initially charged in ethanol (15 ml), and 2.025 ml (14.53 mmol) of triethylamine and then 220 μl (3.63 mmol) of hydrazine hydrate (80%) were added. The mixture was stirred at 50° C. overnight and then concentrated under reduced pressure. This gave 681 mg of crude product.

(262) LC-MS (Method 1): R.sub.t=0.55 min

(263) MS (ESpos): m/z=346.2 (M+H).sup.+

Example 44A

8-[(2,6-Difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carbohydrazide

(264) ##STR00082##

(265) At RT, 3 g of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid (Example 16A, 9.4 mmol), 5.4 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (28.3 mmol, 3 equivalents) and 3.8 g of 1H-benzotriazol-1-ol (28.3 mmol, 3 equivalents) were initially charged in DMF. After 30 min, 1.4 ml of hydrazine hydrate (28.3 mmol, 1.4 g, 3 equivalents) and 3.9 ml of triethylamine (28.3 mmol, 2.9 g, 3 equivalents) were added and the mixture was stirred at RT for 6 h. Water and ethyl acetate were then added to the reaction mixture. The organic phase was separated off, washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. This gave 3.1 g (85% of theory, purity: 85%) of the title compound.

(266) LC-MS (Method 1): R.sub.t=0.58 min

(267) MS (ESpos): m/z=333 (M+H).sup.+

Example 45A

5-{8-[(2,6-Difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}-1,3,4-oxadiazol-2(3H)-one

(268) ##STR00083##

(269) At RT, 3.1 g of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carbohydrazide (Example 44A, 7.9 mmol, 1 equivalent) were initially charged in 23.7 ml of DMF, and 1.35 g of di-1H-imidazol-1-ylmethanone (CDI; 8.3 mmol, 1.05 equivalents) were added. The mixture was stirred at RT overnight, and water was then added. The solid formed was filtered off and dried under reduced pressure. This gave 0.71 g (23% of theory) of the title compound.

(270) LC-MS (Method 2): R.sub.t=1.01 min

(271) MS (ESpos): m/z=359 (M+H).sup.+

(272) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=2.55 (s, 3 H; obscured by DMSO signal), 5.32 (s, 2 H), 7.09-7.15 (m, 2 H), 7.24 (t, 2 H), 7.54-7.64 (m, 1 H), 8.60 (d, 1 H), 12.61 (br. s, 1 H).

Example 46A

6-Chloro-8-[(2,6-difluorobenzyl)oxy]-N-[(2R)-1-hydroxyhexan-2-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide

(273) ##STR00084##

(274) Successively, 37.2 mg of (2R)-2-aminohexan-1-ol (0.32 mmol, 1.4 equivalents), 112 mg HATU (0.3 mmol, 1.3 equivalents) and 0.112 ml of N,N-diisopropylethylamine (0.68 mmol, 3 equivalents) were added to 80 mg of 6-chloro-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid (Example 11 A, 0.23 mmol, 1 equivalent) in 0.72 ml of DMF, and the mixture was stirred at RT overnight. The solid formed was filtered off, washed with water and dried under reduced pressure. This gave 88 mg (82% of theory) of the title compound.

(275) LC-MS (Method 1): R.sub.t=1.05 min

(276) MS (ESpos): m/z=452.1 (M+H).sup.+

(277) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=0.88 (s, 3 H), 1.25-1.40 (m, 4 H), 1.42-1.53 (m, 1 H), 1.54-1.67 (m, 1 H), 3.39-3.56 (m, 2 H), 3.92-4.04 (m, 1 H), 4.67-4.79 (m, 1 H), 5.35 (s, 2 H), 7.13-7.32 (m, 3 H), 7.53-7.66 (m, 2 H), 8.59-8.67 (m, 1 H), [further signals hidden under the solvent peaks].

Example 47A

6-Chloro-N-[(2R)-1-chlorohexan-2-yl]-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide hydrochloride

(278) ##STR00085##

(279) 270 mg of 6-chloro-8-[(2,6-difluorobenzyl)oxy]-N-[(2R)-1-hydroxyhexan-2-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide (Example 46A, 0.6 mmol, 1 equivalent) were initially charged in 2.5 ml of dichloromethane. At 0° C., 0.13 ml of thionyl chloride (1.79 mmol, 3 equivalents) was added dropwise, and the mixture was stirred at 0° C. for 1 h and then at RT overnight. The mixture was then concentrated under reduced pressure, three times, dichloromethane was added and removed again under reduced pressure, and the product was then dried under reduced pressure. This gave 295 mg (97% of theory) of the title compound.

(280) LC-MS (Method 1): R.sub.t=1.33 min

(281) MS (ESpos): m/z=470.3 (M+H).sup.+

Example 48A

3-[(4R)-4-Butyl-4,5-dihydro-1,3-oxazol-2-yl]-6-chloro-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine

(282) ##STR00086##

(283) 393 mg of 6-chloro-N-[(2R)-1-chlorohexan-2-yl]-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide hydrochloride (Example 47A, 0.78 mmol, 1 equivalent) were initially charged in 79 ml of DMF, 1 g of sodium azide (15.5 mmol, 20 equivalents) was added and the mixture was stirred at 60° C. for 6 h. 65 ml of water were then added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (cyclohexane/ethyl acetate=9:1, 7:3). This gave 167 mg (50% of theory) of the title compound.

(284) LC-MS (Method 1): R.sub.t=1.52 min

(285) MS (ESpos): m/z=434.3 (M+H).sup.+

(286) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=0.91 (t, 3 H), 1.21-1.50 (m, 5 H), 1.52-1.70 (m, 2 H), 4.01 (m, 7.90 Hz, 1 H), 4.21-4.36 (m, 1 H), 4.43-4.57 (m, 1 H), 5.36 (s, 2 H), 7.16-7.35 (m, 3 H), 7.52-7.70 (m, 1 H), 9.29 (s, 1 H); [further signals hidden under the solvent peaks].

Example 49A

8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethyl-3-[(trimethylsilyl)ethynyl]imidazo[1,2-a]pyridine

(287) ##STR00087##

(288) 2.0 g (5.27 mmol) of 3-bromo-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine from Example 30A were initially charged in 16 ml of acetonitrile, 1.04 g (10.55 mmol) of ethynyl(trimethyl)silane, 152 mg (0.13 mmol) of bis(triphenylphosphine)palladium(II) chloride, 36 mg (0.19 mmol) of copper(I) iodide and 1.04 ml (7.38 mmol) of diisopropylamine were added and the mixture was stirred under reflux overnight. The mixture was concentrated under reduced pressure and the residue was taken up in ethyl acetate and extracted with water. There was no phase separation. The mixture was filtered off through Celite, and a little saturated aqueous sodium chloride solution was added to the filtrate. The two phases were then separated. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (mobile phase: cyclohexane/ethyl acetate 5/1 to 7/3). This gave 1.1 mg of the target compound (35% of theory, purity about 64%).

(289) LC-MS (Method 1): R.sub.t=1.25 min

(290) MS (ESpos): m/z=385 (M+H).sup.+

Example 50A

8-[(2,6-Difluorobenzyl)oxy]-3-ethynyl-2,6-dimethylimidazo[1,2-a]pyridine

(291) ##STR00088##

(292) 1.1 g (1.83 mmol; purity 64%) of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethyl-3-[(trimethylsilyl)ethynyl]imidazo[1,2-a]pyridine from Example 49A were initially charged in 9.3 ml of methanol, 25 mg (0.18 mmol) of potassium carbonate were added and the mixture was stirred at RT for 1 h. The residue was filtered off and washed with methanol. The filtrate was concentrated under reduced pressure and the residue was dried under high vacuum. This gave 0.97 mg of the target compound (99% of theory, purity about 60%).

(293) LC-MS (Method 1): R.sub.t=0.91 minpo

(294) MS (ESpos): m/z=313 (M+H).sup.+

Example 51A

2-Methyl-2-nitropropyl trifluoromethanesulphonate

(295) ##STR00089##

(296) 1.0 g (8.40 mmol) of 2-methyl-2-nitropropan-1-ol was initially charged in 20 ml of dichloromethane, 1.0 ml (12.59 mmol) of pyridine was added, the mixture was cooled to 0° C. and 1.85 ml (10.91 mmol) of trifluoromethanesulphonic anhydride was added slowly. The mixture was then stirred at 0° C. for 1 h. The course of the reaction was monitored by TLC (cyclohexane/ethyl acetate 7/3, staining reagent: potassium permanganate stain). The reaction solution was washed in each case once with water and saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate and filtered and the filtrate was concentrated. 2.18 g of the target compound were obtained (99% of theory). The target compound was stored at −18° C. and used without further purification.

(297) MS (Method 13):

(298) MS (ESpos): m/z=269 (M+NH.sub.4).sup.+

(299) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=1.64 (s, 6 H), 5.13 (s, 2 H).

Example 52A

8-[(2,6-Difluorobenzyl)oxy]-2-methyl-3-[1-(2-methyl-2-nitropropyl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyridine

(300) ##STR00090##

(301) 479 mg (1.47 mmol) of caesium carbonate and 435 mg (1.73 mmol) of 2-methyl-2-nitropropyl trifluoromethanesulphonate Example 51A were added to 417 mg (1.23 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2-methyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine from Example 45 in 7.5 ml of DMF, and the mixture was stirred at 100° C. overnight. 242 mg (0.96 mmol) of 2-methyl-2-nitropropyl trifluoromethanesulphonate Example 51A were then added, and the mixture was stirred at 100° C. for 6 h. The reaction solution was filtered, the solid was washed with ethyl acetate and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). Saturated aqueous sodium bicarbonate solution was added to the crude product, and the mixture was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulphate and filtered. The filtrate was concentrated and the residue was dried under high vacuum and purified by silica gel chromatography (mobile phase: first cyclohexane/ethyl acetate 1/1, then dichloromethane/2 N methanolic ammonia solution 20/1). This gave 193 mg of the target compound (33% of theory, purity 93%).

(302) LC-MS (Method 1): R.sub.t=0.79 min

(303) MS (ESpos): m/z=442 (M+H).sup.+

(304) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=1.58 (s, 6 H), 2.31 (s, 3 H), 4.79 (s, 2 H), 5.31 (s, 2 H), 6.80-6.89 (m, 2 H), 7.23 (t, 2 H), 7.55-7.64 (m, 1 H), 7.82-7.86 (m, 2 H), 8.08 (s, 1 H).

Example 53A

8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethyl-3-[1-(2-methyl-2-nitropropyl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyridine

(305) ##STR00091##

(306) 1.30 g (3.67 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine from Example 88 were initially charged in 22.5 ml of DMF, 1.43 g (4.40 mmol) of caesium carbonate and 2.53 g (10.07 mmol) of 2-methyl-2-nitropropyl trifluoromethanesulphonate Example 51A were added and the mixture was stirred at 100° C. overnight. The reaction mixture was filtered, the precipitate was washed with ethyl acetate and the filtrate was concentrated under reduced pressure. Water and ethyl acetate were added to the residue, the aqueous phase was extracted twice with ethyl acetate and the combined organic phases were dried over sodium sulphate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (mobile phase: dichloromethane/methanol 60/1). The crude product was purified once more by silica gel chromatography (mobile phase: dichloromethane/methanol 80/1). This gave 412 mg of the target compound (24% of theory).

(307) LC-MS (Method 1): R.sub.t=0.82 min

(308) MS (ESpos): m/z=456 (M+H).sup.+

(309) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=1.57 (s, 6 H), 2.25-2.32 (m, 6 H), 4.78 (s, 2 H), 5.28 (s, 2 H), 6.73 (s, 1 H), 7.22 (t, 2 H), 7.54-7.64 (m, 1 H), 7.68 (s, 1 H), 7.82 (s, 1 H), 8.06 (s, 1 H).

Example 54A

2,6-Dimethyl-3-[1-(2-methyl-2-nitropropyl)-1H-pyrazol-4-yl]-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine

(310) ##STR00092##

(311) 100 mg (0.27 mmol) of 2,6-dimethyl-3-(1H-pyrazol-4-yl)-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine from Example 86 were initially charged in 3.8 ml of THF, 12 mg (0.32 mmol) of sodium hydride (65%) were added, the mixture was stirred at room temperature for 5 min and 213 mg (0.81 mmol) of 2-methyl-2-nitropropyl trifluoromethanesulphonate Example 51A in 0.3 ml of DMF were then added. The reaction mixture was stirred at room temperature for 1 h. The mixture was then diluted with ethyl acetate and washed twice with water. The organic phase was dried over sodium sulphate and filtered, the filtrate was concentrated and the residue was purified by silica gel chromatography (mobile phase dichloromethane/methanol 80/1 to 40/1). This gave 94 mg of the target compound (65% of theory, purity 89%).

(312) LC-MS (Method 1): R.sub.t=0.87 min

(313) MS (ESpos): m/z=474 (M+H).sup.+

(314) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=1.58 (s, 6 H), 2.39 (s, 3 H), 2.43 (s, 3 H), 4.82 (s, 2 H), 5.49 (s, 2 H), 6.78-6.87 (m, 1 H), 7.59 (br. s, 1 H), 7.65-7.76 (m, 1 H), 7.93 (s, 1 H), 8.02 (s, 1 H), 8.22 (s, 1 H).

Example 55A

8-[(3-Fluoropyridin-2-yl)methoxy]-2,6-dimethyl-3-[1-(2-methyl-2-nitropropyl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyridine

(315) ##STR00093##

(316) 95 mg (0.28 mmol) of 8-[(3-fluoropyridin-2-yl)methoxy]-2,6-dimethyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine from Example 84 were initially charged in 1.73 ml of THF, 8.5 mg (0.34 mmol) of sodium hydride (95%) were added, the mixture was stirred at room temperature for 5 min and 185 mg (0.70 mmol) of 2-methyl-2-nitropropyl trifluoromethanesulphonate Example 51A were then added. The reaction mixture was stirred at room temperature for 1 h. Another 2 mg (0.09 mmol) of sodium hydride (95%) were then added and the mixture was stirred at room temperature for 15 min. 74 mg (0.28 mmol) of 2-methyl-2-nitropropyl trifluoromethanesulphonate were added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed twice with water. The organic phase was dried over sodium sulphate and filtered, the filtrate was concentrated and the residue was purified by silica gel chromatography (mobile phase dichloromethane/2 N methanolic ammonia solution (60/1)). This gave 66 mg of the target compound (50% of theory, purity 93%).

(317) LC-MS (Method 1): R.sub.t=0.75 min

(318) MS (ESpos): m/z=439 (M+H).sup.+

Example 56A

8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethyl-3-[2-(2-methyl-2-nitropropyl)-2H-1,2,3-triazol-4-yl]imidazo[1,2-a]pyridine trifluoroacetate

(319) ##STR00094##

(320) 6.1 mg (0.15 mmol) of sodium hydride (60%) were added to 70 mg (0.13 mmol; purity about 84%) of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethyl-3-(2H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine from Example 82 in 1.8 ml of THF and 0.45 ml DMF, and the mixture was stirred at room temperature for 10 min. 95 mg (0.38 mmol) of 2-methyl-2-nitropropyl trifluoromethanesulphonate from Example 51A were then added, and the mixture was stirred at room temperature for 1.5 h. A little water/TFA was added and the mixture was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). This gave 46 mg of the target compound (48% of theory, purity about 75%) which were converted further without further purification.

(321) LC-MS (Method 1): R.sub.t=0.93 min

(322) MS (ESpos): m/z=457 (M+H).sup.+

Example 57A

2-(4-{8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1H-pyrazol-1-yl)ethyl methanesulphonate

(323) ##STR00095##

(324) Under argon, 780 mg (1.72 mmol; purity about 90%) of 2-(4-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1H-pyrazol-1-yl)ethanol from Example 91 were dissolved in 4.0 ml of dichloromethane, and 0.72 ml (5.17 mmol) of triethylamine was added. With ice-cooling, 0.16 ml (2.08 mmol) of methansulphonyl chloride was added dropwise and the reaction mixture was stirred for 30 min while slowly warming to room temperature. 0.08 ml (1.04 mmol) of methanesulphonyl chloride was added at RT, and the mixture was then stirred for 30 min. The reaction mixture was diluted with dichloromethane and washed once with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate and filtered and the filtrate was concentrated and purified by silica gel chromatography (solvent: ethyl acetate/cyclohexane=2/1). This gave 608 mg (74% of theory) of the target compound.

(325) LC-MS (Method 1): R.sub.t=0.78 min

(326) MS (ESpos): m/z=477 (M+H).sup.+

(327) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=2.27-2.35 (m, 6 H), 3.12 (s, 3 H), 4.52-4.69 (m, 4 H), 5.28 (s, 2 H), 6.73 (s, 1 H), 7.22 (t, 2 H), 7.53-7.65 (m, 1 H), 7.72 (s, 1 H), 7.83 (s, 1 H), 8.20 (s, 1 H).

Example 58A

8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethyl-N-(prop-2-yn-1-yl)imidazo[1,2-a]pyridine-3-carboxamide

(328) ##STR00096##

(329) 1.49 g of HATU (3.91 mmol) were added to a mixture of 1.00 g of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylic acid (3.01 mmol) from Example 16A, 0.29 ml of propargylamine (4.5 mmol) and 2.6 ml of N,N-diisopropylethylamine (15.0 mmol) in 6.0 ml of DMF, and the mixture was stirred at room temperature for 1 h. 70 ml of water were then added and the precipitated solid was stirred, filtered off, washed with water and dried under high vacuum. This gave 933 mg (81% of theory) of the title compound.

(330) LC-MS (Method 1): R.sub.t=0.79 min

(331) MS (ESpos): m/z=370 (M+H).sup.+

(332) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=2.32 (s, 3 H), 2.49 (s, 3 H), 3.13-3.17 (m, 1 H), 4.08 (dd, 2 H), 5.28 (s, 2 H), 6.94 (s, 1 H), 7.20-7.28 (m, 2 H), 7.53-7.65 (m, 1 H), 8.21-8.28 (m, 1 H), 8.48 (s, 1 H).

Example 59A

8-[(2,6-Difluorobenzyl)oxy]-N-methoxy-N,2,6-trimethylimidazo[1,2-a]pyridine-3-carboxamide

(333) ##STR00097##

(334) 2.16 g of EDCI (11.3 mmol) and 1.73 g of HOBT (11.3 mmol) were added to a solution of 2.50 g of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylic acid (7.52 mmol) from Example 16A in 100 ml of dichloromethane, and the mixture was stirred at room temperature for 10 min. 9.2 ml of N,N-diisopropylethylamine (52.7 mmol) and 3.67 g of N,O-dimethylhydroxylamine hydrochloride (37.6 mmol) were then added and the mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was stirred initially with 200 ml of water and then with 150 ml of tert-butyl methyl ether and then filtered off. The solid was taken up in ethyl acetate and washed three times with saturated aqueous sodium bicarbonate solution, and with water and saturated aqueous sodium chloride solution, dried with magnesium sulphate, filtered and concentrated. The crude product was stirred with diisopropyl ether, filtered off and dried under high vacuum. This gave 1.75 g (61% of theory) of the title compound.

(335) LC-MS (Method 1): R.sub.t=0.79 min

(336) MS (ESpos): m/z=376 (M+H).sup.+

(337) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=2.31 (s, 3 H), 2.33 (s, 3 H), 3.31 (s, 3 H), 3.50 (s, 3 H), 5.28 (s, 2 H), 6.90-6.92 (m, 1 H), 7.20-7.29 (m, 2 H), 7.55-7.65 (m, 1 H), 7.96-7.99 (m, 1 H).

Example 60A

1-{8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}ethanone

(338) ##STR00098##

(339) 1.97 ml of 3 N methylmagnesium bromide solution in THF (5.9 mmol) were slowly added dropwise to a solution, cooled to 0° C., of 1.70 g of 8-[(2,6-difluorobenzyl)oxy]-N-methoxy-N,2,6-trimethylimidazo-[1,2-a]pyridine-3-carboxamide (4.53 mmol) from Example 59A in 45 ml of THF. The mixture was then stirred at 0° C. for 15 min and then at RT for 2 h. 150 ml of water were added dropwise and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated. The residue was triturated with n-pentane and the solid formed was filtered off and dried under high vacuum. This gave 1.24 g (78% of theory) of the title compound.

(340) TLC (cyclohexane/ethyl acetate 1:1): R.sub.F=0.32

(341) LC-MS (Method 1): R.sub.t=0.96 min

(342) MS (ESpos): m/z=331 (M+H).sup.+

(343) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=2.37 (s, 3 H), 2.56 (s, 3 H), 2.65 (s, 3 H), 5.31 (s, 2 H), 7.16 (s, 1 H), 7.20-7.29 (m, 2 H), 7.54-7.65 (m, 1 H), 9.11 (s, 1 H).

Example 61A

2-Bromo-1-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}ethanone

(344) ##STR00099##

(345) At room temperature, 170 μl of bromine (3.30 mmol) were added dropwise to a suspension of 990 mg of 1-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}ethanone (3.00 mmol) from Example 60A in 10 ml of hydrogen bromide (33% in acetic acid), and the mixture was stirred at room temperature for 1 h. 40 ml of diisopropyl ether were then added, the mixture was stirred and the solid was then filtered off. The solid was purified using Biotage Isolera (100 g silica gel cartridge, cyclohexane/ethyl acetate gradient followed by dichloromethane/methanol 5:1). This gave 317 mg (23% of theory, purity 90%) and 819 mg (47% of theory, purity 70%) of the title compound.

(346) LC-MS (Method 1): R.sub.t=1.13 min

(347) MS (ESpos): m/z=409 (M+H).sup.+

Example 62A

Ethyl 4-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-2,4-dioxobutanoate

(348) ##STR00100##

(349) At −40° C., 2.66 ml of 1 N lithium hexamethylsilazane solution in THF (2.66 mmol) were added dropwise to a solution of 800 mg of 1-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}ethanone (2.42 mmol) from Example 61A and 493 μl of ethyl oxalate (3.63 mmol) in 80 ml of THF, and the mixture was stirred at −40° C. for 30 min and at room temperature for 1.5 h. 250 ml of water were then added dropwise and the mixture was extracted repeatedly with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried with magnesium sulphate, filtered and concentrated. This gave 814 mg (62% of theory; purity 80%) of the title compound.

(350) LC-MS (Method 1): R.sub.t=1.25 min

(351) MS (ESpos): m/z=431 (M+H).sup.+

Example 63A

8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carbohydrazide

(352) ##STR00101##

(353) 1.474 g (4.09 mmol) of ethyl 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate from Example 15A were initially charged in ethanol (30 ml), and 7.60 ml (195.11 mmol) of hydrazine hydrate (80%) were added. The mixture was stirred at reflux for 2 days, 3.80 ml (97.5 mmol) of hydrazine hydrate (80%) were then added and the mixture was stirred under reflux for 6 h. Water was added and the reaction mixture was cooled in an ice bath. The solid was filtered off, washed thoroughly with water and dried under high vacuum overnight. This gave 998 mg (70% of theory) of the title compound.

(354) LC-MS (Method 1): R.sub.t=0.60 min

(355) MS (ESpos): m/z=347 (M+H).sup.+

(356) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=2.31 (s, 3 H), 2.44 (s, 3 H), 4.50-4.54 (m, 2 H), 5.28 (s, 2 H), 6.91 (s, 1 H), 7.23 (t, 2 H), 7.54-7.64 (m, 1 H), 8.38 (s, 1 H), 9.18 (br. s, 1 H).

Example 64A

tert-Butyl {4-[2-({8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}carbonyl)hydrazino]-2-methyl-4-oxobutan-2-yl}carbamate

(357) ##STR00102##

(358) 125.5 mg (0.58 mmol) of 3-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid from Example 63A were initially charged in 4 ml of DMF, 266 mg (1.39 mmol) of EDCI and 212 mg (1.39 mmol) of HOBT were added and the mixture was stirred at RT for 30 min. 200 mg (0.58 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carbohydrazide from Example 63A and 0.24 ml (1.39 mmol) of N,N-diisopropylethylamine were then added and the mixture was stirred at RT overnight. The reaction mixture was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.05% formic acid). This gave 128 mg (40% of theory) of the title compound.

(359) LC-MS (Method 1): R.sub.t=0.95 min

(360) MS (ESpos): m/z=546 (M+H).sup.+

(361) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=1.34 (s, 6 H), 1.38 (s, 9 H), 2.32 (s, 3 H), 5.29 (s, 2 H), 5.76 (s, 1 H), 6.57 (br. s, 1 H), 6.97 (s, 1 H), 7.24 (t, 2 H), 7.54-7.64 (m, 1 H), 8.37 (br. s, 1 H), 9.74 (br. s, 1 H), 10.00 (br. s, 1 H) [further signals under solvent signals].

Example 65A

tert-Butyl[1-(5-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1,3,4-thiadiazol-2-yl)-2-methylpropan-2-yl]carbamate

(362) ##STR00103##

(363) 77 mg (0.19 mmol) of 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulphide [Lawesson's reagent] were added to 126 mg (0.13 mmol; purity 55%) of tert-butyl {4-[2-({8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}carbonyl)hydrazino]-2-methyl-4-oxobutan-2-yl}carbamate from Example 64A in 3 ml of THF, and the mixture was stirred in a microwave oven at 100° C. for 2 h. 77 mg (0.19 mmol) of 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulphide [Lawesson's reagent] were added and the mixture was stirred initially in the microwave at 100° C. for 8 h and then in the microwave at 120° C. for 11 h. The reaction mixture was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.05% formic acid). This gave 12 mg (18% of theory) of the title compound.

(364) LC-MS (Method 1): R.sub.t=1.28 min

(365) MS (ESpos): m/z=544 (M+H).sup.+

Example 66A

tert-Butyl[1-(5-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1,3,4-oxadiazol-2-yl)-2-methylpropan-2-yl]carbamate

(366) ##STR00104##

(367) 129 mg (0.24 mmol) of tert-butyl {4-[2-({8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}carbonyl)hydrazino]-2-methyl-4-oxobutan-2-yl}carbamate from Example 64A were initially charged in 4 ml of THF, 169 mg (0.71 mmol) of 3,3,3-triethyl-1-(methoxycarbonyl)diazathian-3-ium-1-ide 2,2-dioxide (Burgess reagent) were added and the reaction mixture was stirred in a microwave oven at 80° C. for 15 min. Concentration under reduced pressure gave 125 mg of the target compound (quantitative yield).

(368) LC-MS (Method 1): R.sub.t=1.23 min

(369) MS (ESpos): m/z=528 (M+H).sup.+

Example 67A

8-[(2,6-Difluorobenzyl)oxy]-N-hydroxy-2,6-dimethylimidazo[1,2-a]pyridine-3-carboximidamide

(370) ##STR00105##

(371) 500 mg (1.43 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carbonitrile from Example 41A were initially charged in 15 ml of ethanol, 0.43 ml (7.15 mmol) of 50% strength hydroxylamine solution in water was added and the mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure and 20 ml of water and 1 ml of ethanol were added to the residue. The solid formed was filtered off, washed with 10 ml of water and dried under high vacuum overnight. This gave 512 mg of the target compound (90% of theory, purity 87%).

(372) LC-MS (Method 1): R.sub.t=0.58 min

(373) MS (ESpos): m/z=347 (M+H).sup.+

(374) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=2.28 (s, 3 H), 2.36 (s, 3 H), 5.27 (s, 2 H), 5.87 (s, 2 H), 6.78 (s, 1 H), 7.19-7.28 (m, 2 H), 7.54-7.64 (m, 1 H), 8.15 (s, 1 H), 9.77 (s, 1 H).

Example 68A

tert-Butyl[4-({[(Z)-amino{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}methylene]amino}oxy)-2-methyl-4-oxobutan-2-yl]carbamate

(375) ##STR00106##

(376) 121 mg (0.63 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 96.4 mg (0.63 mmol) of 1-hydroxy-1H-benzotriazole hydrate were added to 137 mg (0.63 mmol) of Boc-3-amino-3-methylbutyric acid, initially charged in 5 ml DMF, and the mixture was stirred at RT for 30 min. 250 mg (0.63 mmol, 87%) of 8-[(2,6-difluorobenzyl)oxy]-N′-hydroxy-2,6-dimethylimidazo[1,2-a]pyridine-3-carboximidamide from Example 67A were suspended in 3 ml of DMF and added to the reaction mixture, and the mixture was stirred at RT for 48 hours. The mixture was then purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.05% formic acid), and the product fractions were concentrated on a rotary evaporator. This gave 168 mg of the target compound (49% of theory).

(377) LC-MS (Method 1): R.sub.t=0.99 min

(378) MS (ESpos): m/z=546 (M+H).sup.+

(379) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=1.32 (s, 6 H), 1.39 (s, 9 H), 2.29 (s, 3 H), 2.39 (s, 3 H), 2.83-2.89 (m, 2 H), 5.26-5.31 (m, 2 H), 6.76-6.81 (m, 2 H), 6.84-6.88 (m, 1 H), 7.19-7.28 (m, 2 H), 7.54-7.64 (m, 1 H), 8.25-8.30 (m, 1 H).

Example 69A

tert-Butyl[1-(3-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1,2,4-oxadiazol-5-yl)-2-methylpropan-2-yl]carbamate

(380) ##STR00107##

(381) 0.092 ml (0.09 mmol) of tetra-n-butylammonium fluoride solution (1 M in THF) were added to 50 mg (0.09 mmol) of tert-butyl[4-({[(Z)-amino{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}methylene]amino}oxy)-2-methyl-4-oxobutan-2-yl]carbamate from Example 68A in 3 ml of THF, and the mixture was stirred at RT overnight. The reaction mixture was concentrated to dryness and dried under high vacuum. 54 mg of the target compound were obtained. The product was used further without further purification.

(382) LC-MS (Method 1): R.sub.t=1.26 min

(383) MS (ESpos): m/z=528 (M+H).sup.+

Example 70A

Benzyl [4-(hydroxyamino)-2-methylpentan-2-yl]carbamate

(384) ##STR00108##

(385) 1.58 ml (25.83 mmol) of 50% strength aqueous hydroxylamine solution were added to 1.20 g (5.17 mmol) of benzyl (1-cyano-2-methylpropan-2-yl)carbamate in 10 ml of ethanol, and the mixture was stirred at RT overnight. Another 1.58 ml (25.83 mmol) of 50% strength aqueous hydroxylamine solution were added and the mixture was stirred for 5 days. The reaction mixture was concentrated and the residue was taken up in 20 ml of ethyl acetate and washed three times with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate, filtered off and concentrated under reduced pressure. This gave 1.39 g of the target compound (quantitative). The product was used further without further purification.

(386) LC-MS (Method 1): R.sub.t=0.60 min

(387) MS (ESpos): m/z=266 (M+H).sup.+

(388) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=1.27 (s, 6 H), 2.24 (s, 2 H), 4.97 (s, 2 H), 5.36 (s, 2 H), 6.89-6.95 (m, 1 H), 7.28-7.40 (m, 5 H), 8.96 (s, 1 H).

Example 71A

Benzyl [(4Z)-4-amino-4-{[({8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}carbonyl)oxy]imino}-2-methylbutan-2-yl]carbamate

(389) ##STR00109##

(390) 180.6 mg (0.9 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 144 mg (0.94 mmol) of 1-hydroxy-1H-benzotriazole hydrate were added to 313 mg (0.94 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylic acid from Example 16A in 5 ml of DMF, and the reaction mixture was stirred at RT for 30 min. 250 mg (0.94 mmol) of benzyl [4-(hydroxyamino)-2-methylpentan-2-yl]carbamate from Example 70A were suspended in 3 ml of DMF and added dropwise, and the reaction mixture was stirred at RT overnight. The reaction solution was then purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.05% formic acid), and the product fractions were concentrated on a rotary evaporator. This gave 317 mg of the target compound (58% of theory).

(391) LC-MS (Method 1): R.sub.t=1.15 min

(392) MS (ESpos): m/z=580 (M+H).sup.+

(393) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=1.37 (s, 6 H), 2.36 (s, 3 H), 2.58 (s, 3 H), 5.01 (s, 2 H), 5.31 (s, 2 H), 6.33 (s, 2 H), 7.06-7.13 (m, 2 H), 7.21-7.27 (m, 2 H), 7.28-7.40 (m, 5 H), 7.55-7.65 (m, 1 H), 8.71 (s, 1 H).

Example 72A

Benzyl [1-(5-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1,2,4-oxadiazol-3-yl)-2-methylpropan-2-yl]carbamate

(394) ##STR00110##

(395) 0.09 ml (0.09 mmol) of tetra-n-butylammonium fluoride solution (1 M in THF) were added to 50 mg (0.09 mmol) of benzyl [(4Z)-4-amino-4-{[({8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}carbonyl)oxy]imino}-2-methylbutan-2-yl]carbamate from Example 71A in 3 ml of THF, and the mixture was stirred at RT overnight. The reaction mixture was concentrated under reduced pressure and dried under high vacuum. This gave 58 mg of the target compound (quantitative). The product was used further without further purification.

(396) LC-MS (Method 1): Rt=1.36 min

(397) MS (ESpos): m/z=562 (M+H).sup.+

Example 73A

5-Methyl-1-(2-methyl-2-nitropropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

(398) ##STR00111##

(399) 69 mg (1.72 mmol) of 60% sodium hydride were added to 300 mg (1.44 mmol) of 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in 4 ml of THF and 2 ml of DMF, the mixture was stirred at RT for 10 min and 435 mg (1.73 mmol) of 2-methyl-2-nitropropyl trifluoromethanesulphonate from Example 51A were added. The reaction mixture was then stirred at RT for 5 days. 29 mg (0.72 mmol) of 60% sodium hydride were then added, the mixture was stirred at RT for 5 min and 181 mg (0.72 mmol) of 2-methyl-2-nitropropyl trifluoromethanesulphonate from Example 51A were then added. The mixture was stirred at RT overnight. 1 ml of saturated aqueous ammonium chloride solution was added to the reaction mixture. Acetonitrile and water were added and the mixture was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.05% formic acid). The product fractions were concentrated and dried under high vacuum. This gave 174 mg of the target compound (39% of theory).

(400) LC-MS (Method 1): R.sub.t=1.10 min

(401) MS (ESpos): m/z=310 (M+H).sup.+

(402) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=1.24 (s, 18 H), 2.18 (s, 3 H), 4.58 (s, 2 H), 7.70 (s, 1 H).

Example 74A

8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethyl-3-[3-methyl-1-(2-methyl-2-nitropropyl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyridine

(403) ##STR00112##

(404) Under argon, 30 mg (0.04 mmol) of bis(diphenylphosphino)ferrocenepalladium(II) chloride/dichloromethane complex and 2 ml (2.0 mmol) of aqueous 1 M potassium carbonate solution were added to 186 mg (0.51 mmol) of 3-bromo-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine from Example 30A and 172 mg (0.56 mmol) of 5-methyl-1-(2-methyl-2-nitropropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole from Example 73A in 10 ml of acetonitrile, and the mixture was heated at 90° C. overnight. The mixture was filtered, 3 drops of water were added to the filtrate and the filtrate was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.05% formic acid). The product fractions were concentrated on a rotary evaporator. This gave 74 mg of the target compound (31% of theory).

(405) LC-MS (Method 1): R.sub.t=0.92 min

(406) MS (ESpos): m/z=470 (M+H).sup.+

(407) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=1.54-1.61 (m, 6 H), 1.96 (s, 3 H), 2.11-2.16 (m, 3 H), 2.25 (s, 3 H), 4.66-4.71 (m, 2 H), 5.28 (s, 2 H), 6.74 (s, 1 H), 7.24 (m, 2 H), 7.29-7.33 (m, 1 H), 7.55-7.64 (m, 1 H), 7.82 (s, 1 H).

Example 75A

8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethyl-3-[1-(2-methyl-2-nitropropyl)-1H-1,2,4-triazol-3-yl]imidazo[1,2-a]pyridine

(408) ##STR00113##

(409) 27 mg of 60% sodium hydride (0.68 mmol) were added to 200 mg (0.56 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethyl-3-(1H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine from Example 128 in 8 ml of THF and 2 ml of DMF. The reaction mixture was stirred at RT for 10 min. 424 mg (1.69 mmol) of 2-methyl-2-nitropropyl trifluoromethanesulphonate from Example 51A were then added, and the reaction was stirred at RT for 30 min. Saturated aqueous ammonium chloride solution and 2 ml of water were added to the reaction mixture and the THF was distilled off on a rotary evaporator. 5 ml of acetonitrile were added and the solid formed was filtered off, washed with acetonitrile and dried under high vacuum. The filtrate was concentrated and stirred in 10 ml of water and 2 ml of acetonitrile, and the residue was filtered off, washed with acetonitrile and dried under high vacuum. This gave 287 mg of the target compound (quantitative).

(410) LC-MS (Method 1): R.sub.t=0.86 min

(411) MS (ESpos): m/z=457 (M+H).sup.+

(412) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=1.59 (s, 6 H), 2.43 (s, 3 H), 2.64 (s, 3 H), 4.95 (s, 2 H), 5.38 (s, 2 H), 7.21-7.30 (m, 3 H), 7.61 (quin, 1 H), 8.75-8.86 (m, 2 H).

Example 76A

8-[(2,6-Difluorobenzyl)oxy]-2-methyl-3-[(trimethylsilyl)ethinyl]imidazo[1,2-a]pyridine

(413) ##STR00114##

(414) 2 ml (14.15 mmol) of trimethylsilylacetylene were slowly added dropwise to 2.60 g (7.08 mmol, purity 96%) of 3-bromo-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine from Example 28A, 202 mg (1.06 mmol) of copper(I) iodide, 0.50 g (0.71 mmol) of bis(triphenylphosphine)palladium(II) chloride and 3.12 ml (22.41 mmol) of triethylamine in 3.1 ml of THF, and the reaction mixture was stirred under argon at reflux for 8 hours. The mixture was concentrated and the residue was taken up in dichloromethane and purified by silica gel chromatography (mobile phase: dichloromethane). The product fractions were concentrated and dried under high vacuum. 1.46 g of the target compound were obtained (56% of theory).

(415) LC-MS (Method 1): R.sub.t=1.23 min

(416) MS (ESpos): m/z=371 (M+H).sup.+

(417) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=0.29 (s, 9 H), 2.34 (s, 3 H), 5.30 (s, 2 H), 6.93-7.03 (m, 2 H), 7.23 (quin, 2 H), 7.54-7.63 (m, 1 H), 7.90-7.97 (m, 1 H).

Example 77A

8-[(2,6-Difluorobenzyl)oxy]-3-ethynyl-2-methylimidazo[1,2-a]pyridine

(418) ##STR00115##

(419) 1.46 g (3.93 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2-methyl-3-[(trimethylsilyl)ethinyl]imidazo[1,2-a]pyridine from Example 76A and 54 mg (0.39 mmol) of potassium carbonate in 20 ml of methanol were stirred under argon at RT for 30 min. The reaction mixture was then filtered, the residue was washed with methanol, and the filtrate was concentrated and dried under high vacuum. 1.31 g of the target compound were obtained (84% of theory, 76% purity).

(420) LC-MS (Method 1): R.sub.t=0.86 min

(421) MS (ESpos): m/z=299 (M+H).sup.+

(422) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=2.30 (s, 1 H), 2.35 (s, 3 H), 5.30 (s, 2 H), 6.93-7.02 (m, 2 H), 7.23 (quin, 2 H), 7.54-7.64 (m, 1 H), 8.00 (dd, 1 H).

Example 78A

Pyrimidine-2-carbohydrazide

(423) ##STR00116##

(424) The title compound can be prepared using the following procedures: 1.) WOCKHARDT RESEARCH CENTRE; TRIVEDI, Bharat Kalidas; PATEL, Mahesh Vithalbhai, WO2010/136971 A1, 2010 or 2.) GLAXO GROUP LIMITED; DEAN, David Kenneth; MUNOZ-MURIEDAS, Jorge; SIME, Mairi; STEADMAN, Jon Graham Anthony; THEWLIS, Rachel Elizabeth Anne; TRANI, Giancarlo; WALTER, Daryl Simon, WO2010/125102 A1, 2010.

Example 79A

tert-Butyl (6-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-2-methyl-4,6-dioxohexan-2-yl)carbamate

(425) ##STR00117##

(426) A mixture of 98.6 mg (0.454 mmol) of 3-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (CAS 129765-95-3) and 73.6 mg (0.454 mmol) of 1,1′-carbonyldiimidazole in 2 ml of dry THF was stirred at room temperature for 3 h. The solution obtained was added dropwise to a freshly prepared solution of 150 mg (0.454 mmol) of 1-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}ethanone Example 60A and 0.454 ml (0.454 mmol) of lithium hexamethyldisilazide (1M in tetrahydrofuran) in 5 ml of dry tetrahydrofuran which was stirred under argon at −40° C. After 30 min at −40° C. and 30 min at room temperature, the reaction mixture was partitioned between water (20 ml) and ethyl acetate (30 ml). The phases were separated and the aqueous phase was additionally extracted with ethyl acetate (2×15 ml). The combined organic phases were concentrated under reduced pressure, giving 200 mg of crude material comprising the target product in a yield of 8.4% as by-product in a mixture with starting material. Used in the next step without further purification.

(427) LC-MS (Method 23): R.sub.t=1.39 min; m/z=530.36 (M+H).sup.+

Example 80A

tert-Butyl[1-(3-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1H-pyrazol-5-yl)-2-methylpropan-2-yl]carbamate

(428) ##STR00118##

(429) Under microwave irradiation, a mixture of 200 mg (0.032 mmol, 8.4% yield in a mixture) of tert-butyl (6-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-2-methyl-4,6-dioxohexan-2-yl)carbamate Example 79A and 21.7 mg (0.317 mmol) of hydrazine monohydrochloride in 5 ml of ethanol was heated at 120° C. for 30 min. The reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate (15 ml) and water (10 ml). The phases were separated and the organic phases were concentrated under reduced pressure, giving 120 mg of crude material comprising the target product in a yield of 8% as by-product in a mixture with starting material from the previous step. The crude mixture was used without further purification.

(430) LC-MS (Method 23): R.sub.t=1.00 min; m/z=526.38 (M+H).sup.+

Working Examples

Example 1

3-(1-Benzyl-1H-pyrazol-4-yl)-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine

(431) ##STR00119##

(432) 35 mg of 3-bromo-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine (Example 28A), 5.8 mg of tetrakis(triphenylphosphine)palladium(0) (0.005 mmol, 0.05 equivalent), 21 mg of sodium carbonate (0.2 mmol, 2 equivalents) and 0.2 ml of water were added to 28 mg of 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.1 mmol, 1 equivalent) in 0.6 ml of 1,4-dioxane, and the mixture was shaken at 85° C. overnight. After the reaction had ended, the reaction solution was filtered, the 1,4-dioxane was removed under reduced pressure and the residue was dissolved in a little DMSO and purified by preparative HPLC (Method 11). This gave 0.6 mg (1.4% of theory) of the title compound.

(433) LC-MS (Method 12): R.sub.t=0.90 min

(434) MS (ESpos): m/z=431 (M+H).sup.+

(435) Analogously to Example 1, the example compounds shown in Table 1 were prepared by reacting 3-bromo-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine (Example 28A) with the appropriate boronic acids or boronic esters.

(436) TABLE-US-00001 TABLE 1 IUPAC name Example Structure No. (Yield) Analytical data 2 1-(3-{8-[(2,6-difluorobenzyl)oxy]-2- LC-MS (Method 12): R.sub.t = 0.87 min methylimidazo[1,2-a]pyridin-3-yl}phenyl)ethanone MS (ESpos): m/z = 393.2 (M + H).sup.+ 0 3 8-[(2,6-difluorobenzyl)oxy]-2-methyl-3-(2- LC-MS (Method 12): R.sub.t = 0.77 min methylpyridin-4-yl)imidazo[1,2-a]pyridine MS (ESpos): m/z = 366.1 (M + H).sup.+ 4 N-(3-{8-[(2,6-difluorobenzyl)oxy]-2- LC-MS (Method 12): R.sub.t = 0.83 min methylimidazo[1,2-a]pyridin-3-yl}phenyl)acetamide MS (ESpos): m/z = 408.1 (M + H).sup.+ 5 N-(3-{8-[(2,6-difluorobenzyl)oxy]-2- LC-MS (Method 12): R.sub.t = 0.64 min methylimidazo[1,2-a]pyridin-3-yl}benzyl)-N- MS (ESpos): m/z = 422.3 (M + H).sup.+ methylethanamine 6 8-[(2,6-difluorobenzyl)oxy]-3-[3- LC-MS (Method 12): R.sub.t = 0.85 min (ethylsulphonyl)phenyl]-2-methylimidazo[1,2- MS (ESpos): m/z = 443.1 (M + H).sup.+ a]pyridine 3-{8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2- LC-MS (Method 12): R.sub.t = 0.78 min a]pyridin-3-yl}benzamide MS (ESpos): m/z = 394.1 (M + H).sup.+ 8 3-{8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2- LC-MS (Method 12): R.sub.t = 0.83 min a]pyridin-3-yl}phenol MS (ESpos): m/z = 367.1 (M + H).sup.+ 9 N-cyclopropyl-4-{8-[(2,6-difluorobenzyl)oxy]-2- LC-MS (Method 12): R.sub.t = 0.84 min methylimidazo[1,2-a]pyridin-3-yl}benzamide MS (ESpos): m/z = 434.2 (M + H).sup.+ 10 8-[(2,6-difluorobenzyl)oxy]-3-(4-ethoxyphenyl)-2- LC-MS (Method 12): R.sub.t = 0.93 min methylimidazo[1,2-a]pyridine MS (ESpos): m/z = 395.2 (M + H).sup.+ 11 8-[(2,6-difluorobenzyl)oxy]-2-methyl-3-(1-methyl-1H- LC-MS (Method 12): R.sub.t = 0.94 min pyrazol-5-yl)imidazo[1,2-a]pyridine MS (ESpos): m/z = 355.0 (M + H).sup.+ 12 3-(6-chloro-5-methylpyridin-3-yl)-8-[(2,6- LC-MS (Method 12): R.sub.t = 0.94 min difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine MS (ESpos): m/z = 400.1 (M + H).sup.+ 0 13 3-(3-bromophenyl)-8-[(2,6-difluorobenzyl)oxy]-2- LC-MS (Method 12): R.sub.t = 0.86 min methylimidazo[1,2-a]pyridine MS (ESpos): m/z = 430.0 (M + H).sup.+ 14 8-[(2,6-difluorobenzyl)oxy]-2-methyl-3-(3- LC-MS (Method 12): R.sub.t = 0.87 min thienyl)imidazo[1,2-a]pyridine MS (ESpos): m/z = 357.0 (M + H).sup.+ 15 8-[(2,6-difluorobenzyl)oxy]-2-methyl-3-[3-(pyrrolidin- LC-MS (Method 12): R.sub.t = 0.65 min 1-ylmethyl)phenyl]imidazo[1,2-a]pyridine MS (ESpos): m/z = 434.3 (M + H).sup.+ 16 8-[(2,6-difluorobenzyl)oxy]-3-(4-fluorophenyl)-2- LC-MS (Method 12): R.sub.t = 0.89 min methylimidazo[1,2-a]pyridine MS (ESpos): m/z = 369.1 (M + H).sup.+ 17 4-{8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2- LC-MS (Method 12): R.sub.t = 0.89 min a]pyridin-3-yl}benzonitrile MS (ESpos): m/z = 376.1 (M + H).sup.+ 18 Ethyl 3-{8-[(2,6-difluorobenzyl)oxy]-2- LC-MS (Method 12): R.sub.t = 0.93 min methylimidazo[1,2-a]pyridin-3-yl}benzoate MS (ESpos): m/z = 423.2 (M + H).sup.+ 19 3-{8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2- LC-MS (Method 12): R.sub.t = 0.93 min a]pyridin-3-yl}quinoline MS (ESpos): m/z = 423.2 (M + H).sup.+ 20 LC-MS (Method 12): R.sub.t = 0.94 min MS (ESpos): m/z = 353.0/356.0 (M + H).sup.+ 21 8-[(2,6-difluorobenzyl)oxy]-2-methyl-3-[3- LC-MS (Method 12): R.sub.t = 0.96 min (morpholin-4-ylmethyl)phenyl]imidazo[1,2-a]pyridine MS (ESpos): m/z = 419.1 (M + H).sup.+ 22 8-[(2,6-difluorobenzyl)oxy]-2-methyl-3-(6- LC-MS (Method 12): R.sub.t = 0.94 min propoxypyridin-3-yl)imidazo[1,2-a]pyridine MS (ESpos): m/z = 410.1(M + H).sup.+ 0 23 5-{8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2- LC-MS (Method 12): R.sub.t = 0.85 min a]pyridin-3-yl}-2-benzofuran-1(3H)-one MS (ESpos): m/z = 407.0 (M + H).sup.+ 24 8-[(2,6-difluorobenzyl)oxy]-2-methyl-3-[3- LC-MS (Method 12): R.sub.t = 0.97 min (trifluormethoxy)phenyl]imidazo[1,2-a]pyridine MS (ESpos): m/z = 435.0 (M + H).sup.+ 25 8-[(2,6-difluorobenzyl)oxy]-3-(4-methoxyphenyl)-2- LC-MS (Method 12): R.sub.t = 0.89 min methylimidazo[1,2-a]pyridine MS (ESpos): m/z = 400.1 (M + H).sup.+ 26 1-(4-{8-[(2,6-difluorobenzyl)oxy]-2- methylimidazo[1,2-a]pyridin-3-yl}phenyl)-N,N- LC-MS (Method 12): R.sub.t = 0.90 min dimethylmethanamine MS (ESpos): m/z = 381.2 (M + H).sup.+ 27 N-(5-{8-[(2,6-difluorobenzyl)oxy]-2- LC-MS (Method 12): R.sub.t = 0.67 min methylimidazo[1,2-a]pyridin-3-yl}-2-methoxybenzyl)- MS (ESpos): m/z = 482.3(M + H).sup.+ 2-methoxy-N-methylethanamine 28 N-(3-{8-[(2,6-difluorobenzyl)oxy]-2- LC-MS (Method 12): R.sub.t = 0.65 min methylimidazo[1,2-a]pyridin-3-yl}-4-methoxybenzyl)- MS (ESpos): m/z = 452.2 (M + H).sup.+ N-methylethanamine 29 8-[(2,6-difluorobenzyl)oxy]-2-methyl-3-(pyridin-4- LC-MS (Method 12): R.sub.t = 0.79 min yl)imidazo[1,2-a]pyridine MS (ESpos): m/z = 352.2 (M + H).sup.+ 30 8-[(2,6-difluorobenzyl)oxy]-2-methyl-3-(4- LC-MS (Method 12): R.sub.t = 0.92 min methylphenyl)imidazo[1,2-a]pyridine MS (ESpos): m/z = 365.1 (M + H).sup.+ 31 8-[(2,6-difluorobenzyl)oxy]-2-methyl-3-(4- LC-MS (Method 12): R.sub.t = 1.01 min phenoxyphenyl)imidazo[1,2-a]pyridine MS (ESpos): m/z = 443.2 (M + H).sup.+ 32 8-[(2,6-difluorobenzyl)oxy]-2-methyl-3-(4- LC-MS (Method 12): R.sub.t = 0.95 min vinylphenyl)imidazo[1,2-a]pyridine MS (ESpos): m/z = 377.1 (M + H).sup.+ 0 33 8-[(2,6-difluorobenzyl)oxy]-2-methyl-3-[3- LC-MS (Method 12): R.sub.t = 0.93 min (methylsulphanyl)phenyl]imidazo[1,2-a]pyridine MS (ESpos): m/z = 397.1 (M + H).sup.+ 34 3-(3-chlorophenyl)-8-[(2,6-difluorobenzyl)oxy]-2- LC-MS (Method 12): R.sub.t = 0.93 min methylimidazo[1,2-a]pyridine MS (ESpos): m/z = 385.1 (M + H).sup.+ 35 3-(1-benzothiophen-3-yl)-8-[(2,6-difluorobenzyl)oxy]- LC-MS (Method 12): R.sub.t = 0.94 min 2-methylimidazo[1,2-a]pyridine MS (ESpos): m/z = 407.1 (M + H).sup.+ 36 8-[(2,6-difluorobenzyl)oxy]-2-methyl-3-(1-methyl-1H- LC-MS (Method 12): R.sub.t = 0.94 min indol-5-yl)imidazo[1,2-a]pyridine MS (ESpos): m/z = 404.1 (M + H).sup.+ 37 8-[(2,6-difluorobenzyl)oxy]-3-(2,3-dihydro-1,4- LC-MS (Method 12): R.sub.t = 0.90 min benzodioxin-6-yl)-2-methylimidazo[1,2-a]pyridine MS (ESpos): m/z = 409.1 (M + H).sup.+ 38 8-[(2,6-difluorobenzyl)oxy]-2-methyl-3-[3-(piperidin- LC-MS (Method 12): R.sub.t = 0.92 min 1-yl)phenyl]imidazo[1,2-a]pyridine MS (ESpos): m/z = 434.2 (M + H).sup.+ 39 8-[(2,6-difluorobenzyl)oxy]-3-[3-fluoro-4-(morpholin- LC-MS (Method 12): R.sub.t = 0.65 min 4-ylmethyl)phenyl]-2-methylimidazo[1,2-a]pyridine MS (ESpos): m/z = 468.2 (M + H).sup.+ 40 4-{8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2- LC-MS (Method 12): R.sub.t = 0.77 min a]pyridin-3-yl}benzamide MS (ESpos): m/z = 394.2 (M + H).sup.+ 41 8-[(2,6-difluorobenzyl)oxy]-3-[4-methoxy-3- LC-MS (Method 12): R.sub.t = 0.66 min (morpholin-4-ylmethyl)phenyl]-2-methylimidazo[1,2- MS (ESpos): m/z = 480.4 (M + H).sup.+ a]pyridine 42 8-[(2,6-difluorobenzyl)oxy]-2-methyl-3-[3-(piperidin- LC-MS (Method 12): R.sub.t = 0.69 min 1-ylmethyl)phenyl]imidazo[1,2-a]pyridine MS (ESpos): m/z = 448.2 (M + H).sup.+ 0 43 N-(4-{8-[(2,6-difluorobenzyl)oxy]-2- LC-MS (Method 12): R.sub.t = 0.66 min methylimidazo[1,2-a]pyridin-3-yl}-2-fluorobenzyl)-N- MS (ESpos): m/z = 454.3 (M + H).sup.+ ethylethanamine 44 8-[(2,6-difluorobenzyl)oxy]-3-[4-fluoro-3-(morpholin- LC-MS (Method 12): R.sub.t = 0.65 min 4-ylmethyl)phenyl]-2-methylimidazo[1,2-a]pyridine MS (ESpos): m/z = 468.2 (M + H).sup.+

(437) Boronic acids and boronic esters not commercially available can be prepared according to the following literature procedures: [1] Preparation analogously to Leblanc, Catherine; Pulz, Robert Alexander; Stiefl, Nikolaus Johannes
patent: US2009/181941 A1, 2009 from N-(3-bromobenzyl)-N-methylethanamine. [2] SIRTRIS PHARMACEUTICALS, INC.; Rebecca, L.;
patent: WO2010/101949 A1, 2010. [3] Florentin et al., Journal of Heterocyclic Chemistry, 1976, Vol. 13, p. 1265, 12664268, 1271. [4] ELI LILLY AND COMPANY; Patent: WO2005/73205 A1, 2005. [5] Leblanc, Catherine; Pulz, Robert Alexander; Stiefl, Nikolaus Johannes; Patent: US2009/181941 A1, 2009. [6] Preparation analogously to Leblanc, Catherine; Pulz, Robert Alexander; Stiefl, Nikolaus Johannes
patent: US2009/181941 A1, 2009 from N-(5-bromo-2-methoxybenzyl)-2-methoxy-N-methylethanamine. [7] Preparation analogously to Leblanc, Catherine; Pulz, Robert Alexander; Stiefl, Nikolaus Johannes
patent: US2009/181941 A1, 2009 from N-(3-bromo-4-methoxybenzyl)-2-methoxy-N-methylethanamine. [8] Preparation analogously to Leblanc, Catherine; Pulz, Robert Alexander; Stiefl, Nikolaus Johannes
patent: US2009/181941 A1, 2009 from 1-(3-bromophenyl)piperidine. [9] Preparation analogously to NOVARTIS AG; patent: WO2008/148867 A2, 2008 from 4-(4-bromo-2-fluorobenzyl)morpholine. [10] Preparation analogously to NOVARTIS AG; patent. WO2008/148867 A2, 2008 from 4-(5-bromo-2-methoxybenzyl)morpholine. [11] Preparation analogously to ASTRAZENECA AB; patent: WO2008/32191 A2, 2008 from N-(4-bromo-2-fluorobenzyl)-N-ethylethanamine. [12] Preparation analogously to NOVARTIS AG; patent: WO2008/148867 A2, 2008 from 4-(5-bromo-2-fluorobenzyl)morpholine.

Example 45

8-[(2,6-Difluorobenzyl)oxy]-2-methyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine

(438) ##STR00163##

(439) Under argon, 95 mg of 1H-pyrazol-4-ylboronic acid (0.85 mmol, 3 equivalents), 180 mg of potassium phosphate and 15 mg of bis(tri-tert-butylphosphine)palladium(0) (0.85 mmol, 3 equivalents) were added to 100 mg of 3-bromo-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine (Example 28A, 0.28 mmol, 1 equivalent) in a mixture of 2 ml of ethanol, 1 ml of water and 1 ml of toluene. The suspension was degassed with argon and stirred for 30 seconds and then stirred in a CEM Discover microwave at 120° C. for 15 min. After the reaction had ended, the reaction mixture was applied to diatomaceous earth and purified using Isolera (column: Biotage SNAP Cartridge KP-Sil 10 g, mobile phase: gradient: 100% cyclohexane to ethyl acetate 100%). This gave 23 mg (24% of theory) of the title compound.

(440) LC-MS (Method 1): R.sub.t=0.65 min

(441) MS (ESpos): m/z=341 (M+H).sup.+

(442) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=2.32 (s, 3 H), 5.31 (s, 2 H), 6.75-6.87 (m, 3 H), 7.18-7.29 (m, 3 H), 7.53-7.65 (m, 2 H), 7.80 (s, 1 H), 7.87-7.92 (m, 2 H), 8.10-8.19 (m, 1 H), 13.25 (s, 1 H).

(443) Analogously to Example 45, the example compounds shown in Table 2 were prepared by reacting 3-bromo-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine (Example 28A) with the appropriate commercially available boronic acids or boronic esters.

(444) TABLE-US-00002 TABLE 2 46 LC-MS (Method 2): R.sub.t = 0.86 min MS (ESpos): m/z = 429.0 (M + H).sup.+ .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ = 2.35 (s, 3 H), 5.33 (s, 2 H), 6.83-6.89 (m, 1 H), 6.91- 6.96 (m, 1 H), 7.21-7.29 (m, 2 H), 7.55-7.65 (m, 1 H), 7.80-7.92 (m, 2 H), 7.93- 8.04 (m, 3 H) [further signal hidden under solvent peaks]. 47 LC-MS (Method 1): R.sub.t = 0.69 min MS (ESpos): m/z = 341.1 (M + H).sup.+ .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ = 5.32 (s, 2 H), 6.63 (s, 1 H), 6.81-6.96 (m, 2 H), 7.24 (t, 2 H), 7.50-7.69 (m, 1 H), 7.95 (d, 1 H), 8.85 (dd, 2.13 Hz, 1 H), 13.17 (br. s., 1 H) [further signal hidden under solvent peaks]. 48 LC-MS (Method 1): R.sub.t = 0.76 min MS (ESpos): m/z = 444.2 (M + H).sup.+ .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ = 2.33 (s, 3 H), 3.06 (s, 3 H), 5.32 (s, 2 H), 6.79-6.86 (m, 1 H), 6.87-6.92 (m, 1 H), 7.20-7.35 (m, 5 H), 7.49- 7.64 (m, 2 H), 7.93 (d, 1 H), 9.92 (s, 1 H). 49 LC-MS (Method 2): R.sub.t = 0.85 min MS (ESpos): m/z = 369.1 (M + H).sup.+ .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ = 1.45 (t, 3 H), 2.32 (s, 3 H), 4.23 (m, 2 H), 5.30 (s, 2 H), 6.74-6.89 (m, 2 H), 7.24 (s, 2 H), 7.50-7.66 (m, 1 H), 7.76 (d, 1 H), 7.89-7.97 (m, 1 H), 8.16 (s, 1 H). 50 LC-MS (Method 1): R.sub.t = 0.63 min MS (ESpos): m/z = 355.1 (M + H).sup.+ .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ = 2.31 (s, 3 H), 3.94 (s, 3 H), 5.29 (s, 2 H), 6.73-6.89 (m, 2 H), 7.14-7.29 (m, 2 H), 7.54-7.64 (m, 1 H), 7.74 (s, 1 H), 7.87-7.97 (m, 1 H), 8.10 (s, 1 H). 51 LC-MS (Method 1): R.sub.t = 0.72 min MS (ESpos): m/z = 391.1 (M + H).sup.+ .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ = 2.35 (s, 3 H), 5.29 (s, 2 H), 6.74-6.97 (m, 2 H), 7.14- 7.36 (m, 3 H), 7.53-7.69 (m, 2 H), 7.86-8.03 (m, 2 H), 8.16 (s, 1 H), 13.18 (s, 1 H). 52 0 LC-MS (Method 1): R.sub.t = 0.74 min MS (ESpos): m/z = 383.1 (M + H).sup.+ .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ = 1.49 (d, 6 H), 2.33 (s, 3 H), 4.54-4.65 (m, 1 H), 5.30 (s, 2 H), 6.78-6.86 (m, 2 H), 7.19-7.28 (m, 2 H), 7.54- 7.64 (m, 1 H), 7.76 (s, 1 H), 7.91-7.96 (m, 1 H), 8.18 (s, 1 H). 53 LC-MS (Method 1): R.sub.t = 0.72 min MS (ESpos): m/z = 391.1 (M + H).sup.+ .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ = 2.29 (s, 3 H), 5.32 (s, 2 H) 6.73-6.83 (m, 1 H), 6.88- 6.96 (m, 1 H), 7.21-7.35 (m, 3 H), 7.47-7.75 (m, 5 H), 13.34 (s, 1 H). 54 LC-MS (Method 2): R.sub.t = 0.87 min MS (ESpos): m/z = 391.0 (M + H).sup.+ .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ = 2.31 (s, 3 H), 5.32 (s, 2 H), 6.78 (t, 1 H), 6.87 (d, 1 H), 7.21-7.29 (m, 2 H), 7.41- 7.46 (m, 1 H), 7.55-7.65 (m, 1 H), 7.72 (d, 1 H), 7.85 (d, 1 H), 7.89-7.92 (m, 1 H), 8.16 (s, 1 H), 13.24 (s, 1 H). 55 LC-MS (Method 1): R.sub.t = 0.70 min MS (ESpos): m/z = 369.1 (M + H).sup.+ .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ = 1.98 (s, 3 H), 2.19 (s, 3 H), 3.85 (s, 3 H), 5.28 (s, 2 H), 6.70-6.88 (m, 2 H), 7.18- 7.29 (m, 2 H), 7.51-7.66 (m, 2 H), 7.87 (s, 1 H). 56 LC-MS (Method 1): R.sub.t = 0.71 min MS (ESpos): m/z = 369.2 (M + H).sup.+ .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ = 2.10 (s, 3 H), 2.19 (s, 3 H), 3.84 (s, 3 H), 5.29 (s, 2 H), 6.73-6.78 (m, 1 H), 6.84 (d, 1 H), 7.17-7.31 (m, 2 H), 7.53 (s, 1 H), 7.55-7.64 (m, 2 H).

Example 57

5-{8-[(2,6-Difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}-N-ethyl-1,3,4-oxadiazole-2-amine

(445) ##STR00175##

(446) At RT, 50 mg of 5-{8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}-1,3,4-oxadiazol-2(3 H)-one (Example 45A, 0.13 mmol, 1 equivalent) were suspended in 1.3 ml of ethanol, 0.19 ml of 2 M ethylamine in THF (0.4 mmol, 3 equivalents) were added and the mixture was stirred in a CEM Discover microwave at 80° C. for 2.5 h. The mixture was then concentrated under reduced pressure, the residue was subsequently dissolved in a mixture of 1 ml of acetonitrile and 3 ml of dichloromethane, and 0.09 ml of triethylamine (0.6 mmol, 5 equivalents) and 0.04 ml of carbon tetrachloride (0.4 mmol, 3 equivalents) were added in succession. The reaction mixture was stirred at 50° C. for 1.5 h and then concentrated under reduced pressure. The crude product was separated via Biotage using a mobile phase mixture of cyclohexane/ethyl acetate. The resulting product was re-purified by preparative HPLC (column: Sunfire C 18, 5 μm, 250×20 mm, mobile phase: 45% methanol+TFA). This gave 18 mg (36% of theory) of the title compound.

(447) LC-MS (Method 1): R.sub.t=0.82 min

(448) MS (ESpos): m/z=386.2 (M+H).sup.+

(449) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=1.21 (t, 3 H), 2.59 (s, 3 H), 3.22-3.36 (m, 2 H), 5.30-5.45 (s, 2 H), 7.19-7.34 (m, 4 H), 7.54-7.65 (m, 1 H), 7.83-7.96 (m, 1 H), 8.85-8.97 (d, 1 H).

Example 58

5-{8-[(2,6-Difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}-1,3,4-oxadiazole-2-amine

(450) ##STR00176##

(451) 2.3 ml of 0.1 M aqueous sodium carbonate solution (0.23 mmol, 1.1 equivalents) were added to 85 mg of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carbohydrazide (Example 44A, 0.2 mmol, 1 equivalent) and 43 mg of cyanogen bromide (0.4 mmol, 2 equivalents) in 2.25 ml of 1,4-dioxane. The mixture was stirred at RT overnight and then extracted with ethyl acetate and water. The organic phase was dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by preparative HPLC (Method 10). This gave 32 mg (44% of theory) of the title compound.

(452) LC-MS (Method 1): R.sub.t=0.70 min

(453) MS (ESpos): m/z=358.1 (M+H).sup.+

(454) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=2.57 (s, 3 H), 5.34 (s, 2 H), 7.07-7.13 (m, 2 H), 7.25 (t, 2 H), 7.31 (s, 2 H), 7.52-7.66 (m, 1 H), 8.85 (dd, 2.36 Hz, 1 H).

Example 59

8-[(2,6-Difluorobenzyl)oxy]-3-[2-(4-fluorophenyl)pyridin-4-yl]-2-methylimidazo[1,2-a]pyridine

(455) ##STR00177##

(456) 2.2 mg of palladium(II) acetate (0.01 mmol, 0.05 equivalent) and 8 mg of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-Phos, 0.02 mmol, 0.1 equivalent) in 0.35 ml of acetonitrile were stirred at RT for 15 min. First a solution of 82 mg of potassium carbonate (0.6 mmol, 3 equivalents) in 0.5 ml of water, then a solution of 77 mg of 2-(4-fluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.3 mmol, 1.3 equivalents) in 0.35 ml of acetonitrile and subsequently 70 mg of 3-bromo-8[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine (Example 28A, 0.2 mmol, 1 equivalent) were then added. The reaction mixture was stirred under reflux for 8 h. After cooling, the reaction mixture was filtered through a Millipore filter and the filtrate was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated, the residue was taken up in ethyl acetate and washed twice with aqueous saturated sodium bicarbonate solution and the organic phase was dried over sodium sulphate, filtered, concentrated and lyophilized. This gave 56 mg (63% of theory) of the title compound.

(457) LC-MS (Method 1): R.sub.t=0.95 min

(458) MS (ESpos): m/z=446.3 (M+H).sup.+

(459) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=2.43 (s, 3 H), 5.34 (s, 2 H), 6.88 (t, 1 H), 6.97 (d, 1 H), 7.25 (t, 2 H), 7.34 (t, 2 H), 7.50-7.54 (m, 1 H), 7.56-7.65 (m, 1 H), 8.08 (s, 1 H), 8.15 (d, 1 H), 8.19-8.26 (m, 2 H), 8.73-8.86 (m, 1 H).

Example 60

8-[(2,6-Difluorobenzyl)oxy]-2-methyl-3-(pyrazin-2-yl)imidazo[1,2-a]pyridine

(460) ##STR00178##

(461) 600 mg of 2-(tributylstannyl)pyrazine (1.6 mmol, 1.7 equivalents) and 60 mg of dichloropalladiumditriphenylphosphane (0.09 mmol, 0.125 equivalent) were added to 350 mg of 3-bromo-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine (Example 28A, 0.99 mmol, 1 equivalent) in 10.5 ml of DMF. The batch was divided into 4 batches and each was stirred at 120° C. in a CEM Discover microwave for 1 h. Then water was added, and the reaction mixture was extracted three times with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated using a rotary evaporator. The residue was absorbed on diatomaceous earth and purified using Isolera (column: Biotage SNAP Cartridge KP-Sil 50 g, mobile phase: gradient cyclohexane 100% to ethyl acetate 100%). The solid obtained was triturated with methanol, filtered off and dried under high vacuum. The filtrate was concentrated on a rotary evaporator and purified by preparative HPLC (Method 10). This gave 56 mg (16% of theory) of the title compound.

(462) LC-MS (Method 2): R.sub.t=0.93 min

(463) MS (ESpos): m/z=353.1 (M+H).sup.+

(464) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=2.58 (s, 3 H), 5.34 (s, 2 H), 6.95 (t, 1 H), 7.04 (d, 1 H), 7.25 (m, 2 H), 7.55-7.65 (m, 1 H), 8.59 (d, 1 H), 8.77-8.80 (m, 1 H), 8.85-8.90 (m, 1 H), 8.97 (d, Hz, 1 H).

Example 61

3-(4-Butyl-1,3-oxazol-2-yl)-6-chloro-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine trifluoroacetate

(465) ##STR00179##

(466) 44 mg of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 0.2 mmol, 1.8 equivalents) were added to 47 mg of 3-[(4S)-4-butyl-4,5-dihydro-1,3-oxazol-2-yl]-6-chloro-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine (Example 48A, 0.1 mmol, 1 equivalent) in 2.35 ml of toluene, and the mixture was stirred at 150° C. in a microwave oven for 45 min. This was followed by concentration under reduced pressure, and the residue was purified by preparative thin-layer chromatography (mobile phase: cyclohexane/ethyl acetate=7:3). The product obtained was re-purified by preparative HPLC (column: Nucleodur C 18, 5 μm, Gravity 21×100, mobile phase: acetonitrile/water+TFA 50% to 70%). This gave 6 mg (10% of theory) of the title compound.

(467) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=0.94 (s, 3 H), 1.32-1.48 (m, 2 H), 1.57-1.71 (m, 2 H), 2.58-2.65 (m, 5 H), 5.38 (s, 2 H), 7.16-7.37 (m, 3 H), 7.54-7.68 (m, 1 H), 7.95-8.06 (m, 1 H), 9.14-9.26 (m, 1 H).

Example 62

8-(Cyclohexylmethoxy)-2-methyl-3-[5-(pyrimidin-2-yl)-1,3,4-oxadiazol-2-yl]imidazo[1,2-a]pyridine

(468) ##STR00180##

(469) 15 mg of pyrimidine-2-carbohydrazide (Example 78A, 0.11 mmol, 1.1 equivalents) were initially charged, and 8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carbonyl chloride (Example 26A, 0.1 mmol, 1 equivalent), dissolved in 0.6 ml of methylene chloride, were added. 0.02 mg of pyridine (0.3 mmol, 3 equivalents) was then added, and this mixture was shaken at RT overnight. After this time the reaction was diluted with 0.6 ml of methylene chloride and, with ice bath cooling, 0.05 mg of pyridine (0.6 mmol, 6 equivalents) and 0.112 mg of trifluoromethanesulphonic acid (0.4 mmol, 4 equivalents) were added in succession and the mixture was shaken first at 0° C. for 1 h and then at RT overnight. The product formed was purified by preparative HPLC (Method 11). This gave 13 mg (30% of theory; purity 92%) of the title compound.

(470) LC-MS (Method 12): R.sub.t=1.15 min

(471) MS (ESpos): m/z=391.2 (M+H).sup.+

(472) Analogously to Example 62, the example compounds shown in Table 3 were prepared by reacting 8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carbonyl chloride (Example 26A) with the appropriate hydrazides.

(473) TABLE-US-00003 TABLE 3 IUPAC name Example Structure No. (Yield) Analytical methods 63 LC-MS (Method 12): R.sub.t = 1.16 min MS (ESpos): m/z = 319.2 (M + H).sup.+ 64 LC-MS (Method 12): R.sub.t = 1.25 min MS (ESpos): m/z = 390.2 (M + H).sup.+ 65 LC-MS (Method 12): R.sub.t = 1.03 min MS (ESpos): m/z = 357.2 (M + H).sup.+ 66 LC-MS (Method 12): R.sub.t = 1.18 min MS (ESpos): m/z = 371.2 (M + H).sup.+ 67 LC-MS (Method 12): R.sub.t = 1.14 min MS (ESpos): m/z = 357.2 (M + H).sup.+ 68 LC-MS (Method 12): R.sub.t = 1.12 min MS (ESpos): m/z = 371.2 (M + H).sup.+ 69 LC-MS (Method 12): R.sub.t = 1.23 min MS (ESpos): m/z = 410.2 (M + H).sup.+ 70 LC-MS (Method 12): R.sub.t = 1.25 min MS (ESpos): m/z = 369.2 (M + H).sup.+ 71 LC-MS (Method 12): R.sub.t = 1.07 min MS (ESpos): m/z = 410.2 (M + H).sup.+ 72 0 LC-MS (Method 12): R.sub.t = 1.12 min MS (ESpos): m/z = 422.2 (M + H).sup.+ 73 LC-MS (Method 12): R.sub.t = 1.08 min MS (ESpos): m/z = 431.2 (M + H).sup.+ 74 LC-MS (Method 12): R.sub.t = 1.18 min MS (ESpos): m/z = 353.2 (M + H).sup.+

Example 75

Ethyl 5-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}nicotinate trifluoroacetate

(474) ##STR00193##

(475) Under argon, 2.16 ml of 1 M aqueous potassium carbonate solution were added to 200 mg (0.55 mmol) of 3-bromo-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine from Example 30A, 166 mg (0.60 mmol) of ethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate and 33 mg (0.04 mmol) of bis(diphenylphosphino)ferrocenepalladium(II) chloride dichloromethane complex in 10.8 ml of acetonitrile, and the mixture was stirred at 90° C. overnight. Water and TFA were added and the reaction solution was purified in two portions by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). This gave 134 mg of the target compound (42% of theory, purity 94%).

(476) LC-MS (Method 1): R.sub.t=0.85 min

(477) MS (ESpos): m/z=438 (M-TFA+H).sup.+

(478) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=2.28 (s, 3 H), 2.33 (s, 3 H); 5.30 (s, 2 H); 6.89 (s, 1 H); 7.22 (t, 2 H); 7.53-7.63 (m, 1 H); 7.75 (s, 1 H).

Example 76

5-{8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}nicotinic acid trifluoroacetate

(479) ##STR00194##

(480) 1.38 ml of 1N aqueous lithium hydroxide solution were added to 152 mg (0.28 mmol) ethyl 5-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}nicotinate trifluoroacetate from Example 75 in 5.9 ml of THF/ethanol (5/1), and the mixture was stirred at room temperature for 4 h. With ice cooling, the mixture was adjusted to pH=4 using 1 N aqueous hydrochloric acid solution, and the solvent was then removed on a rotary evaporator. This gave 189 mg of the crude product. 80 mg of this crude product were taken up in acetonitrile/water/TFA and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). This gave 55 mg of the title compound.

(481) LC-MS (Method 1): R.sub.t=0.73 min

(482) MS (ESpos): m/z=410 (M-TFA+H).sup.+

(483) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=2.38 (s, 3 H), 2.40 (s, 3 H), 5.48 (s, 2 H), 7.29 (t, 2 H), 7.52-7.69 (m, 2 H), 8.09 (s, 1 H), 8.48 (s, 1 H), 8.98 (d, 1 H), 9.27 (d, 1 H), 13.78 (br. s, 1H).

Example 77

5-{8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}nicotinamide

(484) ##STR00195##

(485) 54 mg (0.28 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 38 mg (0.28 mmol) of 1-hydroxy-1H-benzotriazole hydrate were added to 50 mg (0.09 mmol) of 5-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}nicotinic acid trifluoroacetate from Example 76 in 1.8 ml of dichloromethane, and the mixture was stirred at room temperature for 10 min. Subsequently, 50 mg (0.94 mmol) of ammonium chloride and 158 mg (1.22 mmol) of N,N-diisopropylethylamine were added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was applied to silica gel and purified by silica gel chromatography (mobile phase: dichloromethane/2 N ammonia in methanol 50/1, 20/1). This gave 25 mg (66% of theory) of the title compound.

(486) LC-MS (Method 1): R.sub.t=0.69 min

(487) MS (ESpos): m/z=409 (M+H).sup.+

(488) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=2.29 (s, 3 H), 2.31 (s, 3 H), 5.30 (s, 2 H), 6.83 (s, 1 H), 7.23 (t, 2 H), 7.55-7.64 (m, 1 H), 7.72 (br. s, 1 H), 7.78 (s, 1 H), 8.26 (br. s, 1 H), 8.29-8.33 (m, 1 H), 8.82 (d, 1 H), 9.08 (d, 1 H).

Example 78

N-Cyclopropyl-5-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}nicotinamide trifluoroacetate

(489) ##STR00196##

(490) 0.012 m (0.12 mmol) of cyclopropylamine was added to 54 mg (0.10 mmol) of 5-{-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}nicotinic acid trifluoroacetate from Example 76, 49 mg (0.15 mmol) of (benzotriazol-1-yloxy)bisdimethylaminomethylium fluoroborate and 0.056 ml (0.51 mmol) of 4-methylmorpholine in 0.65 ml of DMF, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water and TFA and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). This gave 35 mg (60% of theory) of the title compound.

(491) LC-MS (Method 1): R.sub.t=0.75 min

(492) MS (ESpos): m/z=449 (M-TFA+H).sup.+

(493) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=0.58-0.62 (m, 2 H), 0.72-0.79 (m, 2 H), 2.37 (s, 3 H), 2.39 (s, 3 H), 2.85-2.93 (m, 1 H), 5.48 (s, 2 H), 7.29 (t, 2 H), 7.40-7.68 (m, 2 H), 8.04 (br. s, 1 H), 8.38 (s, 1 H), 8.79 (d, 1 H), 8.88 (d, 1 H), 9.17 (s, 1 H).

Example 79

Methyl 2-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}pyrimidine-4-carboxylate

(494) ##STR00197##

(495) Under reflux, 200 mg (0.61 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboximidamide from Example 42A were dissolved in 7 ml of ethanol. The mixture was then cooled to 50° C., and 51 mg (0.76 mmol) of sodium ethoxide were added. 207 mg (1.21 mmol) of ethyl 4-(dimethylamino)-2-oxobut-3-enoate, dissolved in 0.26 ml of ethanol, were then added, and the reaction solution was stirred at 50° C. for 4 days. Another 52 mg (0.24 mmol) of ethyl 3-(dimethylamino)-2-oxobut-3-enoate and 10 mg (0.15 mmol) of sodium ethoxide were then added, and the reaction solution was stirred at 50° C. for 3 days. The reaction mixture was filtered through molecular sieve, the molecular sieve was washed with ethanol and the filtrate was concentrated under reduced pressure. The filtrate was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). This gave 19 mg of the target compound (6% of theory, purity 80%).

(496) LC-MS (Method 17): R.sub.t=2.12 min

(497) MS (ESpos): m/z=425 (M+H).sup.+

Example 80

2-{8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}pyrimidine-4-carboxamide trifluoroacetate

(498) ##STR00198##

(499) 0.29 ml (2.05 mmol) of 7 N ammonia solution in methanol was added to 6.7 mg (0.016 mmol) of methyl 2-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}pyrimidine-4-carboxylate from Example 79, and the mixture was stirred at 50° C. overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by thick-layer chromatography (mobile phase: dichloromethane/methanol=20/1). The product-containing fractions were re-purified [column: Sunfire C18, 5 μm, 250×20 mm; mobile phase: 52% water, 35% acetonitrile+13% 1% strength aqueous TFA; flow rate: 25 ml/min; 40° C.; detection: 210 nm], concentrated and lyophilized. This gave 1.2 mg of the target compound (14% of theory).

(500) LC-MS (Method 1): R.sub.t=0.80 min

(501) MS (ESpos): m/z=410 (M+H).sup.+

(502) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=2.40 (s, 3 H), 2.74 (s, 3 H), 5.32 (s, 2 H), 7.03 (s, 1 H), 7.23 (t, 2 H), 7.53-7.65 (m, 1 H), 7.73 (d, 1 H), 7.98-8.10 (m, 2 H), 9.13 (d, 1 H), 9.30 (s, 1 H).

Example 81

N-Cyclopropyl-2-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}pyrimidine-4-carboxamide trifluoroacetate

(503) ##STR00199##

(504) 0.256 ml (3.70 mmol) of cyclopropylamine was added to 15 mg (0.028 mmol) of methyl 2-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}pyrimidine-4-carboxylate Example 79, and the mixture was stirred at 50° C. overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by thick-layer chromatography (mobile phase:

(505) dichloromethane/methanol=20/1). The product-containing fractions were re-purified [column: Shield RP18, 5 μm, 19×100 mm; mobile phase (gradient): water/acetonitrile/1% strength aqueous TFA; flow rate: 40 ml/min; 25° C.; detection: 210 nm], concentrated and lyophilized. This gave 1 mg of the target compound (6% of theory, purity 90%).

(506) LC-MS (Method 1): R.sub.t=0.89 min

(507) MS (ESpos): m/z=450 (M+H).sup.+

(508) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=0.59-0.65 (m, 2 H), 0.69-0.74 (2 H), 2.33 (s, 3 H), 2.70 (s, 3 H), 2.82-2.94 (m, 1 H), 5.30 (s, 2 H), 7.05-7.22 (m, 3 H), 7.51-7.62 (m, 1 H), 7.67-7.72 (m, 1 H), 8.53-8.62 (m, 1 H), 9.08 (d, 1 H), 9.30 (s, 1 H).

Example 82

8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethyl-3-(2H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine

(509) ##STR00200##

(510) 762 mg (1.44 mmol; purity about 60%) of 8-[(2,6-difluorobenzyl)oxy]-3-ethynyl-2,6-dimethylimidazo[1,2-a]pyridine from Example 77A were initially charged in a dry reaction flask in 1.44 ml of DMF/methanol (4/1), 14 mg (0.07 mmol) of copper(I) iodide and 249 mg (2.16 mmol) of azido(trimethyl)silane were added and the mixture was stirred under argon at 100° C. overnight. The reaction solution was diluted with water/acetonitrile/TFA and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). This gave 471 mg of the target compound as TFA salt (59% of theory, purity 84%). 20 mg of this fraction were purified by thick-layer chromatography (mobile phase: dichloromethane/2N ammonia in methanol 20/1). This gave 6.4 mg of the target compound.

(511) LC-MS (Method 1): R.sub.t=0.74 min

(512) MS (ESpos): m/z=356 (M+H).sup.+

(513) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=2.33 (s, 3 H), 2.43 (s, 3 H), 5.30 (s, 2 H), 6.83 (s, 1 H), 7.23 (t, 2 H), 7.54-7.66 (m, 1 H), 8.29 (br. s, 1 H), 8.45 (s, 1 H), 15.38 (br. s, 1 H).

Example 83

1-(4-{8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-2H-1,2,3-triazol-2-yl)-2-methylpropan-2-amine

(514) ##STR00201##

(515) About 80 mg of Raney nickel (50% aqueous suspension) were added to 46 mg (0.06 mmol; purity about 75%) of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethyl-3-[2-(2-methyl-2-nitropropyl)-2H-1,2,3-triazol-4-yl]imidazo[1,2-a]pyridine trifluoroacetate from Example 56A in 0.25 ml of ethanol, and the mixture was hydrogenated under atmospheric pressure at room temperature overnight. The reaction mixture was filtered through Celite and the filter cake was washed thoroughly with ethanol and a mixture of dichloromethane/2 N ammonia solution in methanol (20/1). The filtrate was concentrated under reduced pressure. The residue was purified by thick-layer chromatography (mobile phase: dichloromethane/2N ammonia in methanol 20/1). This gave 19 mg of the target compound (73% of theory).

(516) LC-MS (Method 1): R.sub.t=0.61 min

(517) MS (ESpos): m/z=427 (M+H).sup.+

(518) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=1.08 (s, 6 H), 1.68 (br. s, 2 H), 2.32 (s, 3 H), 2.45 (s, 3 H), 4.41 (s, 2 H), 5.31 (s, 2 H), 6.87 (s, 1 H), 7.22 (t, 2 H), 7.54-7.64 (m, 1 H), 8.18 (s, 1 H), 8.39 (s, 1 H).

Example 84

8-[(3-Fluoropyridin-2-yl)methoxy]-2,6-dimethyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine

(519) ##STR00202##

(520) Under argon, 1.08 g (5.08 mmol) of [1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl]boronic acid [can be prepared from the corresponding pinacol boronic acid ester by methods known from the literature, e.g. WO2009/155527; WO2012/6760], 1.29 g (6.09 mmol) of potassium phosphate and 104 mg (0.20 mmol) of bis(tri-tert-butyl-phosphine)palladium(0) were added to 0.943 g (2.03 mmol) of 3-bromo-8-[(3-fluoropyridin-2-yl)methoxy]-2,6-dimethylimidazo[1,2-a]pyridine trifluoroacetate from Example 34A in toluene/ethanol/water (7.2 ml/14.4 ml/7.2 ml), and the mixture was stirred in an oil bath, preheated to 120° C., for 30 min. The reaction mixture was concentrated and the residue was taken up in ethyl acetate/water. An insoluble solid formed. The solvent was decanted off from the solid and the solid was stirred in acetonitrile/water. The acetonitrile was then distilled off and the aqueous mixture was cooled. The precipitate was filtered off and dried under high vacuum. This gave 581 mg of the target compound (84% of theory).

(521) LC-MS (Method 1): R.sub.t=0.66 min

(522) MS (ESpos): m/z=338 (M+H).sup.+

(523) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=2.27 (s, 3 H), 2.30 (s, 3 H), 5.38 (s, 2 H), 6.72 (s, 1 H), 7.55-7.63 (m, 1 H), 7.70 (s, 1 H), 7.75-7.89 (m, 2 H), 8.12 (br. s, 1 H), 8.50 (d, 1 H), 13.28 (br. s, 1 H).

Example 85

1-(4-{8-[(3-Fluoropyridin-2-yl)methoxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1H-pyrazol-1-yl)-2-methylpropan-2-amine

(524) ##STR00203##

(525) About 197 mg of Raney nickel (50% aqueous suspension) were added to 65 mg (0.148 mmol) of 8-[(3-fluoropyridin-2-yl)methoxy]-2,6-dimethyl-3-[1-(2-methyl-2-nitropropyl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyridine from Example 55A in 1.5 ml of ethanol, and the mixture was hydrogenated under atmospheric pressure at room temperature overnight. The reaction mixture was filtered through Celite and the filter cake was washed with dichloromethane/2 N ammonia solution in methanol (20/1). The filtrate was concentrated and the residue was purified by preparative thick-layer chromatography (mobile phase: dichloromethane/2 N ammonia solution in methanol (20/1)). This gave 42 mg of the target compound (69% of theory).

(526) LC-MS (Method 1): R.sub.t=0.46 min

(527) MS (ESpos): m/z=409 (M+H).sup.+

(528) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=1.02 (s, 6 H), 1.61 (br. s, 2 H), 2.28 (s, 3 H), 2.31 (s, 3 H), 4.05 (s, 2 H), 5.38 (s, 2 H), 6.72 (s, 1 H), 7.55-7.62 (m, 1 H), 7.71 (s, 1 H), 7.78 (s, 1 H), 7.86 (t, 1 H), 8.10 (s, 1 H), 8.49 (d, 1 H).

Example 86

2,6-Dimethyl-3-(1H-pyrazol-4-yl)-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine

(529) ##STR00204##

(530) Under argon, 3.40 g (16.04 mmol) of [1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl]boronic acid [can be prepared from the corresponding pinacol boronic acid ester by methods known from the literature, e.g. WO2009/155527; WO2012/6760], 4.09 g (19.25 mmol) of potassium phosphate and 328 mg (0.64 mmol) of bis(tri-tert-butyl-phosphine)palladium(0) were added to 2.47 g (6.42 mmol) of 3-bromo-2,6-dimethyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine from Example 32A in toluene/ethanol/water (22.7 ml/45.3 ml/22.7 ml), and the mixture was stirred in an oil bath, preheated to 120° C., for 45 min. The reaction mixture was concentrated and the residue was taken up in dichloromethane/water. The insoluble solid was filtered off and dried under high vacuum. The aqueous phase was extracted twice with dichloromethane and the combined organic phases were dried over sodium sulphate and filtered. The filtrate was concentrated and the residue was, together with the solid, purified by silica gel chromatography (mobile phase: dichloromethane/methanol 50/1). 1.61 g of the target compound were obtained (66% of theory).

(531) LC-MS (Method 1): R.sub.t=0.67 min

(532) MS (ESpos): m/z=373 (M+H).sup.+

(533) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=2.29 (s, 3 H), 2.30 (s, 3 H), 5.32 (s, 2 H), 6.72 (s, 1 H), 7.27-7.34 (m, 1 H), 7.61-7.73 (m, 2 H), 7.80 (s, 1 H), 8.14 (s, 1 H), 13.28 (br. s, 1 H).

Example 87

1-(4-{2,6-Dimethyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo pyridin-3-yl}-1H-pyrazol-1-yl)-2-methylpropan-2-amine

(534) ##STR00205##

(535) About 349 mg of Raney nickel (50% aqueous suspension) were added to 140 mg (0.26 mmol) of 2,6-dimethyl-3-[1-(2-methyl-2-nitropropyl)-1H-pyrazol-4-yl]-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine from Example 54A in 1.1 ml of ethanol, and the mixture was hydrogenated under atmospheric pressure at room temperature overnight. The reaction mixture was filtered through Celite and the filter cake was washed with dichloromethane/2 N ammonia solution in methanol (20/1). The filtrate was concentrated and the residue was purified by silica gel chromatography (mobile phase: dichloromethane/2 N ammonia solution in methanol (60/1)). This gave 73 mg of the target compound (61% of theory).

(536) LC-MS (Method 1): R.sub.t=0.59 min

(537) MS (ESpos): m/z=444 (M+H).sup.+

(538) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=1.02 (s, 6 H), 1.61 (br. s, 2 H), 2.25-2.35 (m, 6 H), 4.05 (s, 2 H), 5.32 (s, 2 H), 6.72 (s, 1 H), 7.25-7.33 (m, 1 H), 7.62-7.72 (m, 1 H), 7.73 (s, 1 H), 7.78 (s, 1 H), 8.11 (s, 1 H).

Example 88

8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine

(539) ##STR00206##

(540) Under argon, 1.44 g (6.81 mmol) of [1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl]boronic acid [can be prepared from the corresponding pinacol boronic acid ester by methods known from the literature, e.g. WO2009/155527; WO2012/6760], 1.73 g (8.17 mmol) of potassium phosphate and 139 mg (0.27 mmol) of bis(tri-tert-butyl-phosphine)palladium(0) were added to 1.0 g (2.72 mmol) of 3-bromo-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine from Example 30A in toluene/ethanol/water (9.6 ml/19.2 ml/9.6 ml), and the mixture was stirred in an oil bath, preheated to 120° C., for 30 min. The reaction mixture was concentrated, the residue was taken up in ethyl acetate/water and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography (mobile phase: dichloromethane/methanol 50/1 to 20/1). This gave 889 mg of the target compound (89% of theory).

(541) LC-MS (Method 1): R.sub.t=0.73 min

(542) MS (ESpos): m/z=355 (M+H).sup.+

(543) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=2.26-2.30 (m, 6 H), 5.28 (s, 2 H), 6.72 (s, 1 H), 7.22 (t, 2 H), 7.54-7.63 (m, 1 H), 7.70 (s, 1 H), 7.80 (s, 1 H), 8.14 (s, 1 H), 13.28 (br. s, 1 H).

Example 89

1-(4-{8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1H-pyrazol-1-yl)-2-methylpropan-2-amine

(544) ##STR00207##

(545) About 1200 mg of Raney nickel (50% aqueous suspension) were added to 412 mg (0.91 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethyl-3-[1-(2-methyl-2-nitropropyl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyridine from Example 53A in 3.75 ml of ethanol, and the mixture was hydrogenated under atmospheric pressure at room temperature overnight. The reaction mixture was filtered through Celite and the filter cake was washed with ethanol, dichloromethane, ethanol and THF. The filtrate was concentrated and the residue was purified by silica gel chromatography (mobile phase: dichloromethane/2 N ammonia solution in methanol (60/1)). This gave 263 mg of the target compound (68% of theory).

(546) LC-MS (Method 1): R.sub.t=0.59 min

(547) MS (ESpos): m/z=426 (M+H).sup.+

(548) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=1.04 (s, 6 H), 1.59 (br. s, 2 H), 2.27-2.32 (m, 6 H), 4.07 (s, 2 H), 5.28 (s, 2 H), 6.72 (s, 1 H), 7.22 (t, 2 H), 7.54-7.64 (m, 1 H), 7.71 (s, 1 H), 7.78 (s, 1 H), 8.09 (s, 1 H).

Example 90

1-(4-{8-[(2,6-Difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}-1H-pyrazol-1-yl)-2-methylpropan-2-amine

(549) ##STR00208##

(550) About 150 mg of Raney nickel (50% aqueous suspension) were added to 151 mg (0.32 mmol; purity 93%) of 8-[(2,6-difluorobenzyl)oxy]-2-methyl-3-[1-(2-methyl-2-nitropropyl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyridine from Example 52A in 3.3 ml of DMF, and the mixture was hydrogenated under atmospheric pressure at room temperature overnight. 150 mg of Raney nickel (50% aqueous suspension) were added and the mixture was once more hydrogenated under atmospheric pressure overnight. The mixture was then filtered through Celite, the filter cake was washed with dichloromethane, the filtrate was concentrated and the residue was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). Dichloromethane and saturated aqueous sodium bicarbonate solution were added to the product fractions and the aqueous phase was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulphate and filtered and the filtrate was concentrated and lyophilized. The product was re-dissolved in dichloromethane, saturated aqueous sodium bicarbonate solution was added and the aqueous phase was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulphate and filtered and the filtrate was concentrated and lyophilized. This gave 28 mg of the target compound (21% of theory).

(551) LC-MS (Method 1): R.sub.t=0.48 min

(552) MS (ESpos): m/z=412 (M+H).sup.+

(553) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=1.04 (s, 6 H), 1.68 (br. s, 2 H), 2.31 (s, 3 H), 4.05 (s, 2 H), 5.31 (s, 2 H), 6.78-6.84 (m, 2 H), 7.22 (t, 2 H), 7.54-7.63 (m, 1 H), 7.78 (s, 1 H), 7.88-7.92 (m, 1 H), 8.11 (s, 1 H).

Example 91

2-(4-{8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1H-pyrazol-1-yl)ethanol

(554) ##STR00209##

(555) 3.35 g (10.27 mmol) of caesium carbonate, 66 mg (0.40 mmol) of potassium iodide and 0.40 ml (5.14 mmol) of iodoethanol were added to 1.40 g (3.95 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine from Example 88 in 21.6 DMF, and the mixture was stirred at 70° C. overnight. After cooling, the solid was filtered off and washed with dichloromethane/methanol (20/1), the filtrate was concentrated and the residue was purified by silica gel chromatography (solvents: dichloromethane/methanol=80/1). 962 mg of the target compound were obtained (54% of theory, about 90% purity). The mixed fractions of the silica gel chromatography were concentrated and the residue was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The concentrated product fractions were partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulphate and filtered and the filtrate was concentrated and lyophilized. This gave another 211 mg of the target compound (10% of theory, purity about 80%).

(556) LC-MS (Method 1): R.sub.t=0.71 min

(557) MS (ESpos): m/z=399 (M+H).sup.+

(558) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=2.25-2.33 (m, 6 H), 3.80 (q, 2 H), 4.23 (t, 2 H), 4.96 (t, 1 H), 5.28 (s, 2 H), 6.73 (s, 1 H), 7.22 (t, 2 H), 7.54-7.65 (m, 1 H), 7.72 (s, 1 H), 7.78 (s, 1 H), 8.10 (s, 1 H).

Example 92

8-[(2,6-Difluorobenzyl)oxy]-3-{1-[2-(4,4-difluoropiperidin-1-yl)ethyl]-1H-pyrazol-4-yl}-2,6-dimethylimidazo[1,2-a]pyridine

(559) ##STR00210##

(560) 0.07 ml (0.40 mmol) of N,N-diisopropylethylamine, 0.08 ml (0.60 mmol) of triethylamine, 2.4 mg (0.02 mmol) of 4-dimethylaminopyridine, 60 mg (0.40 mmol) of sodium iodide and 157 mg (1.0 mmol) of 4,4-difluoropiperidine hydrochloride in 2 ml THF were added to 106 mg (0.20 mmol; purity about 90%) of 2-(4-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1H-pyrazol-1-yl)ethyl methanesulphonate from Example 57A. The mixture was stirred at reflux overnight. After cooling, the reaction mixture was diluted with ethyl acetate and washed with water/saturated aqueous sodium chloride solution (1/1). The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were dried over sodium sulphate and filtered. The filtrate was concentrated and dried under high vacuum. The residue was purified by thick-layer chromatography (solvent: ethyl acetate/cyclohexane=4/1). This gave 16 mg of the target compound (16% of theory).

(561) LC-MS (Method 1): R.sub.t=0.67 min

(562) MS (ESpos): m/z=502 (M+H).sup.+

(563) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=1.85-2.00 (m, 4 H), 2.25-2.32 (m, 6 H), 2.50-2.64 (m, 4 H), 2.87 (t, 2 H), 4.30 (t, 2 H), 5.28 (s, 2 H), 6.73 (s, 1 H), 7.23 (t, 2 H), 7.54-7.63 (m, 1 H), 7.69 (s, 1 H), 7.76 (s, 1 H), 8.17 (s, 1 H).

Example 93

8-[(2,6-Difluorobenzyl)oxy]-3-{1-[2-(1,1-dioxidothiomorpholin-4-yl)ethyl]-1H-pyrazol-4-yl}-2,6-dimethylimidazo[1,2-a]pyridine

(564) ##STR00211##

(565) 135 mg (0.98 mmol) of thiomorpholine 1,1-dioxide were added to 130 mg (0.25 mmol; purity about 90%) of 2-(4-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1H-pyrazol-1-yl)ethyl methanesulphonate from Example 57A, 0.17 ml (0.98 mmol) of N,N-diisopropylethylamine, 3 mg (0.025 mmol) of 4-dimethylaminopyridine and 74 mg (0.49 mmol) of sodium iodide in 2.4 ml of THF. The mixture was stirred at reflux overnight. After cooling, the reaction mixture was diluted with ethyl acetate and washed with water/saturated aqueous sodium chloride solution (1/1). The aqueous phase was extracted twice with ethyl acetate, the combined organic phases were dried over sodium sulphate and filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (solvent: dichloromethane/methanol=80/1 to 40/1). This gave 85 mg of the target compound (64% of theory).

(566) LC-MS (Method 1): R.sub.t=0.76 min

(567) MS (ESpos): m/z=516 (M+H).sup.+

(568) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=2.25-2.32 (m, 6 H), 2.93-3.11 (m, 10 H), 4.30 (t, 2 H), 5.29 (s, 2 H), 6.69-6.81 (m, 1 H), 7.23 (t, 2 H), 7.54-7.64 (m, 1 H), 7.70 (br. s, 1 H), 7.78 (s, 1 H), 8.18 (s, 1 H).

Example 94

8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethyl-3-{1-[2-(4-methylpiperazin-1-yl)ethyl]-1H-pyrazol-4-yl}imidazo[1,2-a]pyridine

(569) ##STR00212##

(570) 77 mg (0.77 mmol) of 1-methylpiperazine were added to 106 mg (0.20 mmol; purity about 90%) of 2-(4-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1H-pyrazol-1-yl)ethyl methanesulphonate from Example 57A, 0.13 ml (0.77 mmol) of N,N-diisopropylethylamine, 2.4 mg (0.02 mmol) of 4-dimethylaminopyridine and 58 mg (0.39 mmol) of sodium iodide in 1.9 ml of THF. The mixture was stirred at reflux overnight. After cooling, the reaction mixture was diluted with ethyl acetate and washed with water/saturated aqueous sodium chloride solution (1/1). The aqueous phase was extracted twice with ethyl acetate, the combined organic phases were dried over sodium sulphate and filtered and the filtrate was concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane and the combined organic phases were dried over sodium sulphate and filtered. The filtrate was concentrated and the residue was purified by thick-layer chromatography (dichloromethane/methanol 10/1) (the silica gel of the TLC plate was extracted with dichloromethane/2 N ammonia solution in methanol (10/1)). This gave 19 mg of the target compound (20% of theory).

(571) LC-MS (Method 1): R.sub.t=0.53 min

(572) MS (ESpos): m/z=481 (M+H).sup.+

(573) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=2.18 (s, 3 H), 2.25-2.58 (m, 14 H), 2.75 (t, 2 H), 4.29 (t, 2 H), 5.28 (s, 2 H), 6.72 (m, 1 H), 7.22 (t, 2 H), 7.55-7.65 (m, 1 H), 7.70 (s, 1 H), 7.75 (s, 1 H), 8.13 (s, 1 H).

Example 95

1-[2-(4-{8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1H-pyrazol-1-yl)ethyl]azetidin-3-ol trifluoroacetate

(574) ##STR00213##

(575) 80 mg (0.15 mmol; purity about 90%) of 2-(4-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1H-pyrazol-1-yl)ethyl methanesulphonate from Example 57A, 0.13 ml (0.76 mmol) of N,N-diisopropylethylamine, 1.8 mg (0.015 mmol) of 4-dimethylaminopyridine and 45 mg (0.30 mmol) of sodium iodide were added to 56 mg (0.76 mmol) of azetidin-3-ol in 1.47 ml of abs. THF. The mixture was stirred at reflux overnight. Another 56 mg (0.76 mmol) of azetidin-3-ol were added and the mixture was stirred at reflux for 3 days. The reaction mixture was then concentrated, water/TFA was added to the residue and the mixture was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). This gave 6.2 mg (7% of theory) of the target compound.

(576) LC-MS (Method 1): R.sub.t=0.60 min

(577) MS (ESpos): m/z=454 (M-TFA+H).sup.+

(578) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=2.36-2.44 (m, 6 H), 3.69-3.96 (m, 4 H), 4.12-4.20 (m, 1 H), 4.28-4.38 (m, 1 H), 4.41-4.60 (m, 3 H), 5.46 (s, 2 H), 6.09-6.25 (m, 1 H), 7.27 (t, 2 H), 7.52-7.66 (m, 2 H), 7.97-8.08 (m, 2 H), 8.31 (d, 1 H).

Example 96

8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethyl-3-{1-[2-(methylsulphonyl)ethyl]-1H-pyrazol-4-yl}imidazo[1,2-a]pyridine

(579) ##STR00214##

(580) 130 mg (0.25 mmol; purity about 90%) of 2-(4-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1H-pyrazol-1-yl)ethyl methanesulphonate from Example 57A and 295 mg (2.46 mmol) of sodium methanesulphinate in 2.4 ml DMF were stirred at 100° C. overnight. The reaction mixture was diluted with ethyl acetate and washed once with saturated aqueous sodium chloride solution/water (1/1). The aqueous phase was extracted twice with ethyl acetate, the combined organic phases were concentrated and the residue was purified by silica gel chromatography (dichloromethane/methanol=40/1). The product fractions were re-purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated, the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulphate and filtered, the filtrate was concentrated and the residue was lyophilized. The crude product was purified once more by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated, the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulphate and filtered, the filtrate was concentrated and the residue was lyophilized. This gave 51 mg of the target compound (42% of theory, purity 94%).

(581) LC-MS (Method 1): R.sub.t=0.68 min

(582) MS (ESpos): m/z=461 (M+H).sup.+

(583) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=2.26-2.35 (m, 6 H), 2.97 (s, 3 H), 3.80 (t, 2 H), 4.68 (t, 1 H), 5.30 (s, 2 H), 6.83 (br. s, 1 H), 7.23 (t, 2 H), 7.55-7.64 (m, 1 H), 7.78 (br. s, 1 H), 7.85 (s, 1 H), 8.23 (s, 1 H).

Example 97

2-(4-{8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1H-pyrazol-1-yl)ethyl carbamate

(584) ##STR00215##

(585) At −15° C., 128 mg (0.90 mmol) of isocyanatosulphuryl chloride were added to 180 mg (0.45 mmol) of 2-(4-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1H-pyrazol-1-yl)ethanol from Example 91 in 4.6 ml of dichloromethane, and the mixture was stirred for 1 h whilst slowly warming to room temperature. The reaction mixture was concentrated and the residue was purified by preparative TLC (mobile phase: dichloromethane/methanol=10/1). The crude product was purified once more by preparative TLC (mobile phase: dichloromethane/2 N methanolic ammonia solution=20/1). This gave 19 mg of the target compound (9% of theory).

(586) LC-MS (Method 1): R.sub.t=0.73 min

(587) MS (ESpos): m/z=442 (M+H).sup.+

(588) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=2.25-2.32 (m, 6 H), 4.29-4.44 (m, 4 H), 5.27 (s, 2 H), 6.40-6.79 (m, 3 H), 7.23 (t, 2 H), 7.54-7.65 (m, 1 H), 7.73 (s, 1 H), 7.79 (s, 1 H), 8.12 (s, 1 H).

Example 98

8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethyl-3-{1-[(5-methyl-1,2-oxazol-3-yl)methyl]-1H-pyrazol-4-yl}imidazo[1,2-a]pyridine

(589) ##STR00216##

(590) 0.65 ml (0.65 mmol) of potassium tert-butoxide solution (1 N in THF) was added to 100 mg (0.28 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine from Example 88 in 1.4 ml of DMF, the mixture was stirred at room temperature for 5 min, 77 mg (0.42 mmol) of 3-(bromomethyl)-5-methyl-1,2-oxazole and 4.7 mg (0.03 mmol) of potassium iodide were then added and the mixture was stirred at 70° C. overnight. The reaction mixture was concentrated, and the residue was taken up in ethyl acetate and washed twice with water. The organic phase was dried over sodium sulphate and filtered, the filtrate was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA).

(591) The product-containing fractions were concentrated, and the residue was taken up in dichloromethane and washed once with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane, the combined organic phases were dried over sodium sulphate and filtered and the filtrate was concentrated. The crude product was purified once more by silica gel chromatography (mobile phase: dichloromethane/methanol=80/1). This gave 39 mg of the target compound (30% of theory).

(592) LC-MS (Method 1): R.sub.t=0.77 min

(593) MS (ESpos): m/z=450 (M+H).sup.+

(594) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=2.25-2.34 (m, 6 H), 2.39 (s, 3 H), 5.28 (s, 2 H), 5.48 (s, 2 H), 6.20 (s, 1 H), 6.77 (br. s, 1 H), 7.23 (t, 2 H), 7.54-7.64 (m, 1 H), 7.73 (s, 1 H), 7.85 (s, 1 H), 8.30 (s, 1 H).

Example 99

8-[(2,6-Difluorobenzyl)oxy]-3-{1-[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]-1H-pyrazol-4-yl}-2,6-dimethylimidazo[1,2-a]pyridine

(595) ##STR00217##

(596) 0.37 ml (0.37 mmol) of potassium tert-butoxide solution (1 N in THF) was added to 100 mg (0.28 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine from Example 88 in 1.4 ml of DMF, the mixture was stirred at room temperature for 5 min, 90 mg (0.42 mmol) of 4-(2-bromoethyl)-3,5-dimethyl-1H-pyrazole and 4.7 mg (0.03 mmol) of potassium iodide were then added and the mixture was stirred at 70° C. overnight. The reaction mixture was concentrated, and the residue was taken up in ethyl acetate and washed twice with water. The organic phase was dried over sodium sulphate and filtered, the filtrate was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated, and the residue was taken up in dichloromethane and washed once with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane, and the combined organic phases were dried over sodium sulphate and filtered, the filtrate was concentrated and the residue was lyophilized. This gave 85 mg of the target compound (62% of theory).

(597) LC-MS (Method 1): R.sub.t=0.73 min

(598) MS (ESpos): m/z=477 (M+H).sup.+

(599) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=1.93 (s, 6 H), 2.26 (s, 3 H), 2.31 (s, 3 H), 2.82 (t, 2 H), 4.23 (t, 2 H), 5.29 (s, 2 H), 6.83 (br. s, 1 H), 7.23 (t, 2 H), 7.53-7.66 (m, 2 H), 7.74-7.83 (m, 2 H), 12.08 (br. s, 1 H).

Example 100

4-(4-{8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1H-pyrazol-1-yl)butanonitrile

(600) ##STR00218##

(601) 0.37 ml (0.37 mmol) of potassium tert-butoxide solution (1 N in THF) was added to 100 mg (0.28 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine from Example 88 in 1.4 ml of DMF, the mixture was stirred at room temperature for 5 min, 63 mg (0.42 mmol) of 4-bromobutanonitrile and 4.7 mg (0.03 mmol) of potassium iodide were then added and the mixture was stirred at 70° C. overnight. The reaction mixture was concentrated and the residue was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated, and the residue was taken up in dichloromethane and washed once with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane, the combined organic phases were dried over sodium sulphate and filtered and the filtrate was concentrated. The crude product was purified by silica gel chromatography (mobile phase: dichloromethane/methanol=20/1). This gave 47 mg of the target compound (40% of theory).

(602) LC-MS (Method 1): R.sub.t=0.77 min

(603) MS (ESpos): m/z=422 (M+H).sup.+

(604) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=2.18 (q, 2 H), 2.25-2.32 (m, 6 H), 2.57 (t, 2 H; superimposed by DMSO signal), 4.29 (t, 2 H), 5.28 (s, 2 H), 6.73 (s, 1 H), 7.23 (t, 2 H), 7.55-7.65 (m, 1 H), 7.73 (s, 1 H), 7.79 (s, 1 H), 8.19 (s, 1 H).

Example 101

8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethyl-3-{1-[3-(1H-tetrazol-5-yl)propyl]-1H-pyrazol-4-yl}imidazo[1,2-a]pyridine

(605) ##STR00219##

(606) 12.3 mg (0.19 mmol) of sodium azide and 41 mg (0.76 mmol) of ammonium chloride were added to 20 mg (0.05 mmol) of 4-(4-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1H-pyrazol-1-yl)butanonitrile from Example 100 in 0.5 ml of DMF, and the mixture was irradiated in the microwave at 150° C. for 8 h. Water/TFA was added and the reaction mixture was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated, concentrated three times with dichloromethane/formic acid (10/1) and three times with dichloromethane and the residue was then lyophilized. This gave 8.4 mg of the target compound (35% of theory).

(607) LC-MS (Method 1): R.sub.t=0.69 min

(608) MS (ESpos): m/z=465 (M+H).sup.+

(609) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=2.22-2.38 (m, 8 H), 2.92 (t, 2 H), 4.30 (t, 2 H), 5.32 (s, 2 H), 6.93 (br. s, 1 H), 7.23 (t, 2 H), 7.55-7.64 (m, 1 H), 7.76-7.90 (m, 2 H), 8.18 (s, 1 H), 16.05 (br. s, 1 H).

Example 102

Methyl 3-(4-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1H-pyrazol-1-yl)propanoate

(610) ##STR00220##

(611) 520 mg (1.60 mmol) of caesium carbonate, 10.2 mg (0.06 mmol) of potassium iodide and 133 mg (0.80 mmol) of methyl 3-bromopropanoate were added to 218 mg (0.61 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine from Example 88 in 3.3 ml of DMF, and the mixture was stirred at 70° C. for 2.5 h. After cooling, the solid was filtered off and washed with THF/methanol, the filtrate was concentrated and the residue was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The concentrated product fractions were partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane, the combined organic phases were dried over sodium sulphate and filtered and the filtrate was concentrated. The crude product was purified by silica gel chromatography (solvent: dichloromethane/methanol=80/1). This gave 179 mg of the target compound (65% of theory).

(612) LC-MS (Method 1): R.sub.t=0.78 min

(613) MS (ESpos): m/z=441 (M+H).sup.+

(614) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=2.25-2.32 (m, 6 H), 2.98 (t, 2 H), 3.62 (s, 3 H), 4.44 (t, 2 H), 5.28 (s, 2 H), 6.74 (s, 1 H), 7.23 (t, 2 H), 7.55-7.65 (m, 1 H), 7.72 (s, 1 H), 7.78 (s, 1 H), 8.14 (s, 1 H).

(615) The examples shown in Table 4 were prepared analogously to Example 102 by reacting 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine from Example 88 with the appropriate commercially available bromides (1.1-2.5 equivalents), caesium carbonate (2-4 equivalents) and potassium iodide (0.1-0.5 equivalent) under the reaction conditions described (reaction time: 2-24 h; temperature: 70° C.).

(616) Illustrative Workup of the Reaction Mixture:

(617) After cooling, the solid was filtered off and washed well with THF/methanol, the filtrate was concentrated and the residue was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The concentrated product fractions were partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane, the combined organic phases were dried over sodium sulphate and filtered and the filtrate was concentrated. If required, the crude product was additionally purified by silica gel chromatography (solvent: dichloromethane/methanol=80/1 to 20/1).

(618) TABLE-US-00004 TABLE 4 Ex- IUPAC name/structure ample (Yield) Analytical data 103 LC-MS (Method 1): R.sub.t = 0.70 min MS (ESpos): m/z = 427 (M + H).sup.+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ = 2.26-2.32 (m, 6 H), 3.27 (s, 3 H), 5.18 (s, 2 H), 5.28 (s, 2 H), 6.75 (s, 1 H), 7.23 (t, 2 H), 7.55-7.65 (m, 1 H), 7.71 (s, 1 H), 7.83 (s, 1 H), 8.18 (s, 1 H). 104 LC-MS (Method 1): R.sub.t = 0.77 min MS (ESpos): m/z = 441 (M + H).sup.+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ = 1.74 (d, 3 H), 2.25-2.32 (m, 6 H), 3.70 (s, 3 H), 5.28 (s, 2 H), 5.38 (q, 1 H), 6.75 (s, 1 H), 7.23 (t, 2 H), 7.55- 7.65 (m, 1 H), 7.72 (s, 1 H), 7.83 (s, 1 H), 8.25 (s, 1 H). 105 LC-MS (Method 1): R.sub.t = 0.80 min MS (ESpos): m/z = 455 (M + H).sup.+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ = 1.52 (d, 3 H), 2.25-2.32 (m, 6 H), 2.88-2.97 (m, 1 H), 2.98-3.08 (m, 1 H), 3.58 (s, 3 H), 4.80-4.92 (m, 1 H), 5.28 (s, 2 H), 6.73 (s, 1 H), 7.23 (t, 2 H), 7.55-7.65 (m, 1 H), 7.72 (s, 1 H), 7.78 (s, 1 H), 8.18 (s, 1 H). 106 LC-MS (Method 1): R.sub.t = 0.77 min MS (ESpos): m/z = 453 (M + H).sup.+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ = 1.57-1.63 (m, 1 H), 1.95-2.02 (m, 1 H), 2.26-2.32 (m, 6 H), 2.33-2.40 (m, 1 H), 3.32 (s, 3 H), 4.23-4.30 (m, 1 H), 5.28 (s, 2 H), 6.73 (s, 1 H), 7.23 (t, 2 H), 7.55-7.65 (m, 1 H), 7.73 (s, 1 H), 7.79 (s, 1 H), 8.30 (s, 1 H).

Example 107

3-(4-{8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1H-pyrazol-1-yl)propanoic acid

(619) ##STR00225##

(620) 0.23 ml (0.23 mmol) of 1 N aqueous lithium hydroxide solution was added to 50 mg (0.11 mmol) of methyl 3-(4-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1H-pyrazol-1-yl)propanoate from Example 102 in 2.45 ml of THF/methanol (5/1), and the mixture was stirred at room temperature for 2 h. The reaction solution was adjusted to pH=2 using 1 N aqueous hydrochloric acid and concentrated and the residue was purified by silica gel chromatography (mobile phase: dichloromethane/methanol=10/1). The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated and the residue was concentrated three times with dichloromethane/formic acid (10/1) and then three times with dichloromethane. This gave 30.5 mg of the target compound (63% of theory).

(621) LC-MS (Method 1): R.sub.t=0.72 min

(622) MS (ESpos): m/z=427 (M+H).sup.+

(623) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=2.23-2.32 (m, 6 H), 2.88 (t, 2 H), 4.40 (t, 2 H), 5.27 (s, 2 H), 6.73 (s, 1 H), 7.23 (t, 2 H), 7.56-7.65 (m, 1 H), 7.72 (s, 1 H), 7.78 (s, 1 H), 8.13 (s, 1 H), 12.48 (br. s, 1 H).

(624) The examples shown in Table 5 were prepared analogously to Example 107 by reacting the corresponding carboxylic esters with lithium hydroxide (2-5 equivalents) under the reaction conditions described (reaction time: 2-5 h; temperature: RT)

(625) Illustrative Workup of the Reaction Mixture:

(626) The reaction solution was adjusted with aqueous hydrochloric acid (1 N to 6 N) or TFA to pH=2-4 and concentrated and the residue was purified by silica gel chromatography (mobile phase: dichloromethane/methanol=10/1). Additionally or alternatively, the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated and the residue was concentrated three times with dichloromethane/formic acid (10/1) and then three times with dichloromethane.

(627) TABLE-US-00005 TABLE 5 IUPAC name/structure Example (Yield) Analytical data 108 LC-MS (Method 1): R.sub.t = 0.70 min MS (ESpos): m/z = 413 (M + H).sup.+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ = 2.33-2.46 (m, 6 H), 5.12 (s, 2 H), 5.46 (s, 2 H), 7.27 (t, 2 H), 7.44-7.68 (m, 2 H), 7.92 (s, 1 H), 8.02 (br. s, 1 H), 8.31 (s, 1 H), 13.28 (br. s, 1 H). 109 LC-MS (Method 1): R.sub.t = 0.72 min MS (ESpos): m/z = 427 (M + H).sup.+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ = 1.73 (d, 3 H), 2.25-2.32 (m, 6 H), 5.22 (q, 1 H), 5.28 (s, 2 H), 6.74 (s, 1 H), 7.23 (t, 2 H), 7.55-7.65 (m, 1 H), 7.72 (s, 1 H), 7.80 (s, 1 H), 8.12 (s, 1 H), 3.12 (br. s, 1 H). 110 LC-MS (Method 1): R.sub.t = 0.78 min MS (ESpos): m/z = 441 (M + H).sup.+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ = 1.50 (d, 3 H), 2.25-2.32 (m, 6 H), 2.78-2.37 (m, 1 H), 2.89-2.99 (m, 1 H), 4.78-4.88 (m, 1 H), 5.28 (s, 2 H), 6.73 (s, 1 H), 7.23 (t, 2 H), 7.55-7.65 (m, 1 H), 7.72 (s, 1 H), 7.78 (s, 1 H), 8.18 (s, 1 H), 12.40 (br. s, 1 H). 111 LC-MS (Method 1): R.sub.t = 0.76 min MS (ESpos): m/z = 439 (M + H).sup.+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ = 1.53-1.60 (m, 1 H), 1.87-1.94 (m, 1 H), 2.20-2.39 (m, 7 H), 4.20-4.28 (m, 1 H), 5.33 (s, 2 H), 7.04 (br. s, 1 H), 7.22 (t, 2 H), 7.55-7.65 (m, 1 H), 7.81 (s, 1 H), 7.88 (br. s, 1 H), 8.37 (s, 1 H), 12.70 (br. s, 1 H).

Example 112

rac-N-[2-(Diethylamino)ethyl]-3-(4-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1H-pyrazol-1-yl)butanamide

(628) ##STR00230##

(629) 44 mg (0.10 mmol) of rac-3-(4-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1H-pyrazol-1-yl)butanoic acid from Example 110, 49.4 mg (0.13 mmol) of HATU and 0.07 ml (0.40 mmol) of N,N-diisopropylethylamine in 0.33 ml of DMF were stirred at RT for 10 min, 15 mg (0.13 mmol) of N,N-diethylethane-1,2-diamine were added and the mixture was stirred at RT overnight. 19 mg (0.05 mmol) of HATU, 0.035 ml (0.20 mmol) of N,N-diisopropylethylamine and 17.4 mg (0.15 mmol) of N,N-diethylethane-1,2-diamine were then added to the reaction mixture and the mixture was stirred at RT for 30 min. TFA was added and the reaction solution was then purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The concentrated product fractions were partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane, the combined organic phases were dried over sodium sulphate and filtered and the filtrate was concentrated and lyophilized. This gave 33 mg of the target compound (60% of theory).

(630) LC-MS (Method 1): R.sub.t=0.58 min

(631) MS (ESpos): m/z=539 (M+H).sup.+

(632) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=0.78-0.98 (m, 6 H), 1.50 (d, 3 H), 2.23-2.47 (m, 10 H), 2.58-2.69 (m, 1 H), 2.70-2.80 (m, 1 H), 2.98-3.14 (m, 2 H), 4.79-4.89 (m, 1 H), 5.28 (s, 2 H), 6.72 (s, 1 H), 7.23 (t, 2 H), 7.55-7.65 (m, 1 H), 7.72 (s, 1 H), 7.76 (s, 1 H), 7.84 (br. s, 1 H), 8.09 (s, 1 H).

Example 113

N-Cyclopropyl-2-(4-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1H-pyrazol-1-yl)acetamide

(633) ##STR00231##

(634) 55 mg (0.13 mmol) of (4-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1H-pyrazol-1-yl)acetic acid from Example 108, 56 mg (0.15 mmol) of HATU and 0.09 ml (0.53 mmol) of N,N-diisopropylethylamine in 0.85 ml of DMF were stirred at RT for 20 min, 9 mg (0.15 mmol) of cyclopropylamine were added and the mixture was stirred at RT overnight. The reaction solution was concentrated and then purified twice by preparative TLC (1. mobile phase:

(635) dichloromethane/methanol=10/1; 2. mobile phase: dichloromethane/2 N ammonia solution in methanol=20/1). This gave 5.1 mg of the target compound (8% of theory).

(636) LC-MS (Method 1): R.sub.t=0.76 min

(637) MS (ESpos): m/z=452 (M+H).sup.+

(638) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=0.42-0.48 (m, 2 H), 0.62-0.69 (m, 2 H), 2.25-2.34 (m, 6 H), 2.63-2.70 (m, 1 H), 4.80 (s, 2 H), 5.28 (s, 2 H), 6.73 (s, 1 H), 7.23 (t, 2 H), 7.55-7.65 (m, 1 H), 7.72 (s, 1 H), 7.78 (s, 1 H), 8.10 (s, 1 H), 8.34 (d, 1 H).

Example 114

N-Cyclopropyl-3-(4-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1H-pyrazol-1-yl)propanamide

(639) ##STR00232##

(640) 50 mg (0.11 mmol) of methyl 3-(4-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1H-pyrazol-1-yl)propanoate from Example 102 and 843 mg (14.76 mmol) of cyclopropylamine were stirred at 50° C. The reaction solution was concentrated and the residue was concentrated twice with dichloromethane and then purified by silica gel chromatography (solvent:

(641) pure dichloromethane; dichloromethane/methanol 100/1 to 40/1). The concentrated product fractions were re-purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated and the residue was concentrated three times with dichloromethane/formic acid (10/1) and then three times with dichloromethane. This gave 32 mg of the target compound (58% of theory).

(642) LC-MS (Method 1): R.sub.t=0.75 min

(643) MS (ESpos): m/z=466 (M+H).sup.+

(644) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=0.29-0.36 (m, 2 H), 0.55-0.62 (m, 2 H), 2.24-2.39 (m, 6 H), 2.54-2.72 (m, 3 H), 4.42 (t, 2 H), 5.32 (s, 2 H), 6.99 (br. s, 1 H), 7.23 (t, 2 H), 7.55-7.65 (m, 1 H), 7.73-7.88 (m, 2 H), 8.07 (d, 1 H), 8.10 (s, 1 H).

Example 115

2-(4-{8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1H-pyrazol-1-yl)acetamide

(645) ##STR00233##

(646) 29 mg (0.26 mmol) of potassium tert-butoxide, 3.3 mg (0.02 mmol) of potassium iodide and 44 mg (0.32 mmol) of 2-bromoacetamide were added to 70 mg (0.29 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine from Example 88 in 1.1 ml of DMF, and the mixture was stirred at 70° C. overnight. After cooling, the solid was filtered off and washed well with THF, the filtrate was concentrated and the residue was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The concentrated product fractions were partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane, the combined organic phases were dried over sodium sulphate and filtered and the filtrate was concentrated and lyophilized. This gave 32 mg of the target compound (37% of theory).

(647) LC-MS (Method 1): R.sub.t=0.66 min

(648) MS (ESpos): m/z=412 (M+H).sup.+

(649) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=2.25-2.32 (m, 6 H), 4.86 (s, 2 H), 5.29 (s, 2 H), 6.75 (s, 1 H), 7.23 (t, 2 H), 7.30 (br. s, 1 H), 7.48-7.65 (m, 2 H), 7.73 (s, 1 H), 7.79 (s, 1 H), 8.12 (s, 1 H).

Example 116

1-(4-{8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1H-pyrazol-1-yl)-2-methylpropan-2-ol

(650) ##STR00234##

(651) At 0° C. and under argon, 0.27 ml (0.82 mmol) of a methylmagnesium solution (3 M in diethyl ether) was added to 100 mg (0.24 mmol) of methyl (4-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1H-pyrazol-1-yl)acetate from Example 103 in 2.3 ml of dry THF, and the mixture was stirred at this temperature for 15 min. The mixture, slowly warming to RT, was then stirred at room temperature overnight. Saturated aqueous ammonium chloride solution was carefully added to the reaction mixture. Celite was added to the suspension, the solid was filtered off and washed well with THF, the filtrate was concentrated and the residue was purified by silica gel chromatography (mobile phase: dichloromethane/methanol 20/1). The product fractions were concentrated and purified by preparative TLC (mobile phase: dichloromethane/methanol=10/1). This gave 30.5 mg of the target compound (31% of theory).

(652) LC-MS (Method 1): R.sub.t=0.76 min

(653) MS (ESpos): m/z=427 (M+H).sup.+

(654) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=1.12 (s, 6 H), 2.26-2.32 (m, 6 H), 4.12 (s, 2 H), 4.77 (s, 1 H), 5.28 (s, 2 H), 6.73 (s, 1 H), 7.23 (t, 2 H), 7.55-7.65 (m, 1 H), 7.73 (s, 1 H), 7.77 (s, 1 H), 8.04 (s, 1 H).

Example 117

1-(4-{8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1H-pyrazol-1-yl)-2-methylpropan-2-amine hydrochloride

(655) ##STR00235##

(656) 0.1 ml (0.20 mmol) of hydrogen chloride solution (2 N in diethyl ether) was added to 70 mg (0.17 mmol) of 1-(4-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1H-pyrazol-1-yl)-2-methylpropan-2-amine from Example 89 in 1.3 ml of diethyl ether, and the mixture was stirred at room temperature for 30 min. The solvent was removed on a rotary evaporator. This gave 78 mg of the target compound (98% of theory).

(657) LC-MS (Method 1): R.sub.t=0.53 min

(658) MS (ESpos): m/z=426 (M+H).sup.+

(659) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=1.28 (s, 6 H), 2.26-2.32 (m, 6 H), 4.38 (s, 2 H), 5.28 (s, 2 H), 6.76 (s, 1 H), 7.22 (t, 2 H), 7.54-7.64 (m, 1 H), 7.80-8.12 (m, 4 H), 7.78 (s, 1 H), 8.20 (s, 1 H).

Example 118

8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethyl-3-{1-[2-(morpholin-4-yl)ethyl]-1H-pyrazol-4-yl}imidazo[1,2-a]pyridine

(660) ##STR00236##

(661) Under argon, 1.9 ml of a degassed 3:1 mixture of 1,2-dimethoxyethane and water were added to 125 mg (0.33 mmol) of 3-bromo-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine from Example 30A, 112 mg (0.36 mmol) of 4-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethyl}morpholine, 111 mg (1.32 mmol) of sodium bicarbonate and 13.5 mg (0.02 mmol) of bis(diphenylphosphino)ferrocenepalladium(II) chloride/dichloromethane complex. The reaction mixture was stirred at 80° C. overnight. The reaction mixture was diluted with water/TFA and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated, and the residue was taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane, and the combined organic phases were dried over sodium sulphate, filtered, concentrated and lyophilized. This gave 44 mg of the target compound (27% of theory, purity 94%).

(662) LC-MS (Method 1): R.sub.t=0.60 min

(663) MS (ESpos): m/z=468 (M+H).sup.+

(664) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=2.26-2.32 (m, 6 H), 2.38-2.50 (m, 4 H), 2.78 (t, 2 H), 3.48-3.60 (m, 4 H), 4.32 (t, 2 H), 5.28 (s, 2 H), 6.74 (s, 1 H), 7.23 (t, 2 H), 7.54-7.65 (m, 1 H), 7.71 (s, 1 H), 7.77 (s, 1 H), 8.16 (s, 1 H).

(665) The example compounds shown in Table 6 were prepared analogously to Example 118 by reacting 3-bromo-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine from Example 28A or 3-bromo-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine from Example 30A with the appropriate commercially available pinacol boronic acid esters, sodium bicarbonate or potassium carbonate (4 equivalents) and bis(diphenylphosphino)ferrocenepalladium(II) chloride/dichloromethane complex (0.02-0.1 equivalent) in 1,2-dimethoxyethane/water (3/1) or acetonitrile under the reaction conditions described (reaction time: 12-24 h; temperature: 80° C.).

(666) Illustrative Workup of the Reaction Mixture:

(667) The reaction mixture was diluted with water/TFA and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). Additionally or alternatively, the crude product was purified by silica gel chromatography (mobile phase: dichloromethane/methanol=20/1 to 10/1). The product-containing fractions were concentrated, and the residue was taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane, and the combined organic phases were dried over sodium sulphate, filtered, concentrated and lyophilized.

(668) TABLE-US-00006 TABLE 6 Example IUPAC name/structure No. (Yield) Analytical methods 119 LC-MS (Method 1): R.sub.t = 0.53 min MS (ESpos): m/z = 454 (M + H).sup.+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ = 2.32 (s, 3 H), 2.39-2.50 (m, 4 H), 2.78 (t, 2 H), 3.54-3.60 (m, 4 H), 4.32 (t, 2 H), 5.30 (s, 2 H), 6.79-6.85 (m, 2 H), 7.22 (t, 2 H), 7.54-7.64 (m, 1 H), 7.77 (s, 1 H), 7.90 (d, 1 H), 8.18 (s, 1 H). 120 LC-MS (Method 1): R.sub.t = 0.61 min MS (ESpos): m/z = 477 (M + H).sup.+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ = 2.18 (s, 3 H), 2.22-2.55 (m, 14 H), 3.57 (s, 2 H), 5.29 (s, 2 H), 6.78 (s, 1 H), 7.24 (t, 2 H), 7.32- 7.43 (m, 3 H), 7.52 (t, 1 H), 7.55- 7.65 (m, 1 H), 7.69 (s, 1 H). 121 LC-MS (Method 1): R.sub.t = 0.70 min MS (ESpos): m/z = 418 (M + H).sup.+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ = 2.40 (s, 3 H), 5.32 (s, 2 H), 6.83- 6.91 (m, 2 H), 7.23 (t, 2 H), 7.55- 7.64 (m, 2 H), 8.11 (d, 1 H), 8.20 (s, 1 H), 8.32-8.38 (m, 1 H), 8.58 (d, 1 H), 9.01 (s, 1 H), 9.24 (d, 1 H). 122 0 LC-MS (Method 1): R.sub.t = 0.77 min MS (ESpos): m/z = 436 (M + H).sup.+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ = 2.42 (s, 3 H), 5.33 (s, 2 H), 6.84- 6.91 (m, 2 H), 7.23 (t, 2 H), 7.55- 7.64 (m, 1 H), 8.11 (d, 1 H), 8.23 (s, 1 H), 8.33-8.39 (m, 1 H), 8.60 (d, 1 H), 9.06 (s, 1 H), 9.18 (s, 1 H).

Example 123

8-[(2,6-Difluorobenzyl)oxy]-3-[1-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-methylimidazo[1,2-a]pyridine

(669) ##STR00241##

(670) Under argon, 175 mg (6.81 mmol) of [1-(4-fluorophenyl)-1H-pyrazol-4-yl]boronic acid, 180 mg (0.85 mmol) of potassium phosphate and 14.5 mg (0.03 mmol) of bis(tri-tert-butylphosphine)palladium(0) were added to 100 mg (0.28 mmol) of 3-bromo-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine from Example 28A in the solvent mixture toluene/ethanol/water (1 ml/2 ml/1 ml), and the mixture was stirred in an oil bath, preheated to 120° C., for 15 min. The reaction mixture was concentrated and the crude product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product fraction was triturated with acetonitrile and the solid present was filtered off. This gave 62 mg of the target compound (50% of theory).

(671) LC-MS (Method 1): R.sub.t=0.92 min

(672) MS (ESpos): m/z=435 (M+H).sup.+

(673) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=2.39 (s, 3 H), 5.32 (s, 2 H), 6.81-6.89 (m, 2 H), 7.23 (t, 2 H), 7.40 (t, 2 H), 7.55-7.64 (m, 1 H), 7.96-8.05 (m, 2 H), 8.08-8.13 (m, 2 H), 8.88 (s, 1 H).

Example 124

5-{8-[(2,6-Difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}-1H-1,2,4-triazol-3-amine

(674) ##STR00242##

(675) 1.248 g (23.099 mmol) of sodium methoxide in 20 ml of methanol were cooled to 0° C. 2.844 g (11.549 mmol) of aminoguanidine hemisulphate were added and the mixture was stirred at RT for 10 min. 2.00 g (5.775 mmol) of ethyl 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate from Example 2A were suspended in 20 ml of methanol and the mixture was heated at reflux overnight. The mixture was then concentrated and the residue was purified by preparative HPLC (methanol:water:water (+1% trifluoroacetic acid)−55:40:5-isocratic). This gave 60 mg of the target compound (2.6% of theory).

(676) LC-MS (Method 1): R.sub.t=0.64 min

(677) MS (ESpos): m/z=357.2 (M+H).sup.+

(678) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=2.72 (s, 3 H), 5.46 (s, 2 H), 6.45 (s br, 2H), 7.23-7.29 (m, 2 H), 7.41-7.51 (br s, 1 H), 7.59-7.66 (m, 2H), 9.33 (d, 1 H), 12.63 (br s, 1H).

Example 125

3-{8-[(2,6-Difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-amine

(679) ##STR00243##

(680) 25 μl (0.152 mmol) of 2,2,2-trifluoroethyl trichloromethanesulphonate were added to 45 mg (0.127 mmol) of 5-{8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}-1H-1,2,4-triazole-3-amine from Example 124 and 49.5 mg (0.152 mmol) of caesium carbonate in DMF (2 ml). The mixture was stirred at RT for 3 days and another 20.6 mg (0.063 mmol) of caesium carbonate and 10 μl (0.063 mmol) of 2,2,2-trifluoroethyl trichloromethanesulphonate were then added and the mixture was stirred at RT overnight. The reaction solution was filtered and purified by preparative HPLC (mobile phase: acetonitrile/water with 0.05% formic acid, gradient). This gave 12 mg (21% of theory) of the target compound.

(681) LC-MS (Method 1): R.sub.t=0.76 min

(682) MS (ESpos): m/z=439.2 (M+H).sup.+

(683) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=2.60 (s, 3 H), 4.98-5.05 (dd, 2H), 5.31 (s, 2 H), 6.88 (s br, 2H), 6.96 (d, 2H), 7.22-7.26 (m, 2 H), 7.55-7.63 (m, 1 H), 9.02 (t, 1 H).

Example 126

8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethyl-3-[5-(trifluoromethyl)-1H-1,2,4-triazol-3-yl]imidazo[1,2-a]pyridine

(684) ##STR00244##

(685) 1 ml (7.080 mmol) of trifluoroacetic anhydride was added to 300 mg of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboximidohydrazide, the crude product from Example 43A, in dichloromethane (1 ml). The mixture was stirred at RT overnight. The reaction solution was purified by preparative HPLC (mobile phase: acetonitrile/water with 0.05% formic acid, gradient). This gave 34 mg (43% of theory) of the target compound.

(686) LC-MS (Method 1): R.sub.t=1.00 min

(687) MS (ESpos): m/z=424.2 (M+H).sup.+

(688) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=2.36 (s, 3 H), 5.32 (s, 2 H), 7.02 (s, 1H), 7.22-7.28 (m, 2 H), 7.57-7.64 (m, 1 H), 8.47 (br s, 1 H), 15.05 (br s, 1H), 1 signal probably under DMSO signal.

Example 127

1-(4-{8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-3-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-amine formate

(689) ##STR00245##

(690) Under argon, about 203 mg of Raney nickel (50% aqueous suspension) were added to 59 mg (0.13 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethyl-3-[3-methyl-1-(2-methyl-2-nitropropyl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyridine from Example 74A in 2 ml of ethanol, and the mixture was stirred at RT and under atmospheric pressure overnight with hydrogen. The reaction mixture was filtered through kieselguhr, the filter cake was washed well with ethanol and the filtrate was concentrated to dryness. The residue was separated by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.05% formic acid) and the product fractions were concentrated on a rotary evaporator. This gave 45 mg of the target compound (74% of theory).

(691) LC-MS (Method 17): R.sub.t=1.47 min

(692) MS (ESpos): m/z=440 (M+H).sup.+

(693) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=1.12-1.22 (m, 6 H), 2.01 (s, 3 H), 2.14-2.19 (m, 3 H), 2.25 (s, 3 H), 4.10-4.18 (m, 2 H), 5.28 (s, 2 H), 6.75 (s, 1 H), 7.20-7.30 (m, 2 H), 7.39 (s, 1 H), 7.55-7.65 (m, 1 H), 7.91 (s, 1 H), 8.25-8.32 (m, 2 H).

Example 128

8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethyl-3-(1H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine

(694) ##STR00246##

(695) 1.00 g (3.02 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide from Example 40A in 6.30 ml (47.58 mmol) of N,N-dimethylformamide dimethyl acetal was heated at 120° C. for 2 hours. The mixture was then cooled and concentrated on a rotary evaporator. 14.5 ml (252.6 mmol) of acetic acid and 0.135 ml (3.47 mmol) of hydrazine hydrate were added to the residue and the mixture was then stirred at 90° C. overnight. After cooling, the solvent was removed on a rotary evaporator. The residue was stirred vigorously with ethyl acetate and saturated aqueous sodium bicarbonate solution. The solid formed was filtered off, washed with water and diethyl ether and then dried under high vacuum. 1.04 g of the target compound were obtained (97% of theory).

(696) LC-MS (Method 1): R.sub.t=0.71 min

(697) MS (ESpos): m/z=356 (M+H).sup.+

(698) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=2.36 (s, 3 H), 2.62 (s, 3 H), 5.30 (s, 2 H), 6.89 (s, 1 H), 7.20-7.29 (m, 2 H), 7.55-7.65 (m, 1 H), 8.73 (s, 1 H), 8.91 (s, 1 H).

Example 129

1-(3-{8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1H-1,2,4-triazol-1-yl)-2-methylpropan-2-amine

(699) ##STR00247##

(700) Under argon, about 500 mg of Raney nickel (50% aqueous suspension) were added to 140 mg (0.31 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethyl-3-[1-(2-methyl-2-nitropropyl)-1H-1,2,4-triazol-3-yl]imidazo[1,2-a]pyridine from Example 75A in 5 ml of ethanol, and the mixture was stirred at RT and under atmospheric pressure with hydrogen. The reaction mixture was filtered through kieselguhr, the filter cake was washed well with ethanol and the filtrate was concentrated to dryness. The residue was separated by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.05% diethylamine) and the product fractions were concentrated on a rotary evaporator. This gave 63 mg of the target compound (48% of theory).

(701) LC-MS (Method 1): R.sub.t=0.54 min

(702) MS (ESpos): m/z=427 (M+H).sup.+

(703) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=1.07 (s, 6 H), 2.35 (s, 3 H), 2.61 (s, 3 H), 4.12-4.17 (m, 2 H), 5.30 (s, 2 H), 6.89 (s, 1 H), 7.21-7.29 (m, 2 H), 7.55-7.65 (m, 1 H), 8.66 (s, 1 H), 8.88 (s, 1 H).

Example 130

1-(5-{8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1,3,4-oxadiazol-2-yl)-2-methylpropan-2-amine

(704) ##STR00248##

(705) 1.0 ml of TFA was added dropwise to 125 mg (0.24 mmol) of tert-butyl[1-(5-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1,3,4-oxadiazol-2-yl)-2-methylpropan-2-yl]carbamate from Example 66A in 4 ml of dichloromethane, and the reaction mixture was stirred at RT for 30 min. The mixture was concentrated on a rotary evaporator and the residue was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.05% diethylamine). The product fractions were concentrated on a rotary evaporator. The residue was stirred with dichloromethane and saturated aqueous sodium bicarbonate solution. The phases were separated, the aqueous phase was washed twice with dichloromethane and the combined organic phases were dried over sodium sulphate. The mixture was filtered and the filtrate was concentrated on a rotary evaporator. The product-containing fractions were re-purified [column: Kromasil 100 C18, 5 μm, 250×20 mm; mobile phase: 56% water, 30% methanol+14% 1% strength aqueous TFA; flow rate: 24 ml/min; 40° C.; detection: 210 nm], concentrated and lyophilized. This gave 46 mg of the target compound (45% of theory).

(706) LC-MS (Method 1): R.sub.t=0.73 min

(707) MS (ESpos): m/z=428 (M+H).sup.+

(708) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=1.42 (s, 6 H), 2.43 (s, 3 H), 2.62 (s, 3 H), 5.35 (s, 2 H), 7.15 (s, 1 H), 7.21-7.30 (m, 2 H), 7.55-7.67 (m, 1 H), 8.10 (br. s., 2 H), 8.78 (s, 1 H).

Example 131

1-(3-{8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1,2,4-oxadiazol-5-yl)-2-methylpropan-2-amine

(709) ##STR00249##

(710) 1.0 ml of TFA was added dropwise to 160 mg (0.30 mmol) of tert-butyl[1-(3-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1,2,4-oxadiazol-5-yl)-2-methylpropan-2-yl]carbamate from Example 69A in 4 ml of dichloromethane, and the reaction mixture was stirred at RT for 1 h. The mixture was concentrated on a rotary evaporator and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.05% diethylamine) and the product fractions were concentrated on a rotary evaporator. Twice, 5 ml of toluene were added to the residue and the mixture was concentrated to dryness, and 5 ml of an acetonitrile/water mixture were then added. The residual acetonitrile was removed on a rotary evaporator and the aqueous residue was frozen in a dry-ice bath and lyophilized overnight. This gave 31 mg of the target compound (23% of theory, purity 95%).

(711) LC-MS (Method 1): R.sub.t=0.79 min

(712) MS (ESpos): m/z=428 (M+H).sup.+

(713) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=1.25 (s, 6 H), 2.39 (s, 3 H), 2.64 (s, 3 H), 3.17 (s, 2 H), 5.33 (s, 2 H), 7.06 (s, 1 H), 7.21-7.29 (m, 2 H), 7.56-7.65 (m, 1 H), 8.64 (s, 1 H).

Example 132

1-(5-{8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1,2,4-oxadiazol-3-yl)-2-methylpropan-2-amine formate

(714) ##STR00250##

(715) 5.2 mg of 10% palladium on carbon were added to 52 mg (0.09 mmol) of benzyl [1-(5-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1,2,4-oxadiazol-3-yl)-2-methylpropan-2-yl]carbamate from Example 72A in 5 ml of ethanol, and the reaction mixture was stirred under argon and at RT for 40 min. The reaction mixture was filtered off and the solvent was removed on a rotary evaporator. The crude product was separated by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.05% formic acid) and the product fractions were concentrated on a rotary evaporator. This gave 21 mg of the target compound (44% of theory, purity 95%).

(716) LC-MS (Method 1): R.sub.t=0.78 min

(717) MS (ESpos): m/z=428 (M+H).sup.+

(718) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=1.22 (s, 6 H), 2.32 (s, 3 H), 2.93 (s, 2 H), 5.29 (s, 2 H), 6.94-6.99 (m, 1 H), 7.20-7.28 (m, 2 H), 7.55-7.64 (m, 1 H), 8.36-8.41 (m, 1 H), 10.18-10.23 (m, 1 H).

Example 133

1-(5-{8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1,3,4-thiadiazol-2-yl)-2-methylpropan-2-amine formate

(719) ##STR00251##

(720) 0.5 ml of TFA were added to 12 mg (0.02 mmol; crude product) of tert-butyl[1-(5-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1,3,4-thiadiazol-2-yl)-2-methylpropan-2-yl]carbamate from Example 65A in 3 ml of dichloromethane, and the mixture was stirred at RT for 0.5 h. The reaction mixture was concentrated and then purified by preparative

(721) HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.05% formic acid). The product fractions were lyophilized. This gave 6 mg (62% of theory) of the title compound.

(722) LC-MS (Method 1): R.sub.t=0.78 min

(723) MS (ESpos): m/z=444 (M+H).sup.+

(724) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=1.15 (s, 6 H), 2.41 (s, 3 H), 2.56 (s, 3 H), 3.20 (br. s, 2 H), 5.34 (s, 2 H), 7.08 (s, 1 H), 7.24 (t, 2 H), 7.55-7.65 (m, 1 H), 9.17 (s, 1 H).

Example 134

8-[(2,6-Difluorobenzyl)oxy]-2-methyl-3-(2H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine

(725) ##STR00252##

(726) 1.30 g (4.36 mmol) of 8-[(2,6-difluorobenzyl)oxy]-3-ethynyl-2-methylimidazo[1,2-a]pyridine from Example 77A, 0.57 ml (4.36 mmol) of azidotrimethylsilane, 33 ml of water/ethanol (2/1), 345 mg (1.74 mmol) of (2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate and 152 mg (0.61 mmol) of copper(II) tetraoxosulphate(VI) pentahydrate were stirred at 50° C. overnight. 173 mg (0.87 mmol) of (2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate and 76 mg (0.31 mmol) of copper(II) tetraoxosulphate(VI) pentahydrate were added and stirring was continued at reflux overnight. 173 mg (0.87 mmol) of (2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate, 76 mg (0.31 mmol) of copper(II) tetraoxosulphate(VI) pentahydrate and 0.573 ml (4.36 mmol) of azidotrimethylsilane were added and stirring was continued at 85° C. overnight. The mixture was cooled, filtered and washed with water. The solid was washed with ethyl acetate. The filtrate was filtered off, washed with water and diethyl ether and dried under high vacuum. The two solids fractions were combined and re-purified [column: Sunfire C18, 5 μm, 250×20 mm; mobile phase: 56% water, 30% acetonitrile+14% 1% strength aqueous TFA; flow rate: 25 ml/min; 25° C.; detection: 210 nm]. This gave 293 mg of the target compound (19% of theory).

(727) LC-MS (Method 16): R.sub.t=0.62 min

(728) MS (ESpos): m/z=342 (M+H).sup.+

(729) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=2.56 (br. s., 3 H), 5.45 (s, 2 H), 7.22-7.31 (m, 2 H), 7.32-7.44 (m, 1 H), 7.45-7.57 (m, 1 H), 7.57-7.66 (m, 1 H), 8.30-8.93 (m, 2 H).

Example 135

8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethyl-3-(4-methylphenyl)imidazo[1,2-a]pyridine

(730) ##STR00253##

(731) A mixture of 100 mg of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylic acid (0.301 mmol, 1.0 eq.) from Example 16A, 56 μl of 4-bromotoluene (0.45 mmol, 1.5 eq.), 49.9 mg of potassium carbonate (0.361 mmol, 1.2 eq.), 11.5 mg of copper(I) iodide (0.060 mmol, 0.2 eq.) and 16.3 mg of 1,10-phenanthroline in 2.0 ml of N-methylpyrrolidone was degassed in a stream of argon, 3.4 mg of palladium(II) acetate (0.015 mmol, 0.05 eq.) were then added and the mixture was heated in a microwave oven at 200° C. for 30 min. The mixture was then filtered through kieselguhr, eluted with ethyl acetate and concentrated. Water was added, the mixture was extracted twice with ethyl acetate, and the combined organic phases were washed with saturated aqueous sodium chloride solution, dried with magnesium sulphate, filtered and concentrated. The residue was purified by Biotage Isolera (10 g silica gel cartridge, cyclohexane/ethyl acetate gradient, 10%->100% ethyl acetate). This gave 50.7 mg (44% of theory) of the title compound.

(732) TLC (cyclohexane/ethyl acetate 1:1): R.sub.F=0.66

(733) LC-MS (Method 17): R.sub.t=2.02 min

(734) MS (ESpos): m/z=379 (M+H).sup.+

(735) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=2.24 (s, 3 H), 2.26 (s, 3 H), 2.40 (s, 3 H), 5.29 (s, 2 H), 6.76 (br. s, 1 H), 7.25-7.30 (m, 2 H), 7.38 (s, 4 H), 7.55-7.64 (m, 1 H), 7.66 (br. s, 1 H).

Example 136

5-{[(2,6-Difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}pyridine-2-carbonitrile

(736) ##STR00254##

(737) A mixture of 100 mg of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylic acid (0.301 mmol, 1.0 eq.) from Example 16A, 82.6 mg of 5-bromo-2-pyridinecarbonitrile (0.45 mmol, 1.5 eq.), 49.9 mg of potassium carbonate (0.361 mmol, 1.2 eq.), 5.7 mg of copper(I) iodide (0.030 mmol, 0.1 eq.) and 8.1 mg of 1,10-phenanthroline (0.045 mmol, 0.015 eq.) in 1.0 ml of N-methylpyrrolidone was degassed in a stream of argon, 3.4 mg of palladium(II) acetate (0.015 mmol, 0.05 eq.) were then added and the mixture was heated in a microwave oven at 190° C. for 30 min. The mixture was then filtered through kieselguhr, eluted with ethyl acetate and concentrated. Water was added, the mixture was extracted twice with ethyl acetate, and the combined organic phases were washed with saturated aqueous sodium chloride solution, dried with magnesium sulphate, filtered and concentrated. The residue was purified by Biotage Isolera (10 g silica gel cartridge, cyclohexane/ethyl acetate gradient, 10%->66% ethyl acetate), giving 32.0 mg (purity: 53%) of the title compound. The impure product was purified together with the crude product of a further reaction by preparative HPLC (Method 19). The resulting crude product was recrystallized from a mixture of water, methanol and acetonitrile. This gave 20.3 mg of the title compound.

(738) TLC (cyclohexane/ethyl acetate 2:1): R.sub.F=0.17

(739) LC-MS (Method 1): R.sub.t=0.78 min

(740) MS (ESpos): m/z=391 (M+H).sup.+

(741) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=2.28 (s, 3 H), 2.34 (s, 3 H), 5.30 (s, 2 H), 6.89 (s, 1 H), 7.21-7.29 (m, 2 H), 7.55-7.65 (m, 1 H), 7.91 (s, 1 H), 8.18-8.27 (m, 2 H), 8.93 (d, 1 H).

Example 137

8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethyl-3-(5-methyl-1,3-oxazol-2-yl)imidazo[1,2-a]pyridine

(742) ##STR00255##

(743) 4.1 mg of gold(III) chloride (0.014 mmol, 0.05 eq.) were added to a suspension of 100 mg of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethyl-N-(prop-2-yn-1-yl)imidazo[1,2-a]pyridine-3-carboxamide (0.271 mmol, 1.0 eq.) from Example 58A in 5.0 ml of acetonitrile, and the mixture was stirred at 80° C. overnight. The mixture was then filtered through kieselguhr and eluted using a mixture of acetonitrile and dichloromethane. The filtrate was concentrated and purified using Biotage Isolera (10 g silica gel cartridge, cyclohexane/ethyl acetate gradient). This gave 59 mg (59% of theory) of the title compound.

(744) LC-MS (Method 1): R.sub.t=0.98 min

(745) MS (ESpos): m/z=370 (M+H).sup.+

(746) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=2.38 (s, 3 H), 2.42 (s, 3 H), 2.60 (s, 3 H), 5.31 (s, 2 H), 6.99-7.01 (m, 1 H), 7.09-7.11 (m, 1 H), 7.20-7.30 (m, 2 H), 7.53-7.65 (m, 1 H), 8.87-8.91 (m, 1 H).

Example 138

Ethyl 5-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1,3-thiazole-2-carboxylate

(747) ##STR00256##

(748) A mixture of 43.0 mg of 2-bromo-1-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}ethanone (0.105 mmol, 1.0 eq.) from Example 61A and 28.0 mg of ethyl thiooxamidate (0.210 mmol, 2.0 eq.) in 5.0 ml of ethanol was heated at reflux for 5 h. The mixture was then concentrated and purified using Biotage Isolera (25 g silica gel cartridge, cyclohexane/ethyl acetate gradient, and dichloromethane/methanol gradient). The isolated product mixture was purified by preparative HPLC (Method 21), giving 8.9 mg (19% of theory) of the title compound.

(749) LC-MS (Method 1): R.sub.t=0.92 min

(750) MS (ESpos): m/z=444 (M+H).sup.+

(751) .sup.1H-NMR (400 MHz, CDCl.sub.3): δ [ppm]=1.48 (t, 3 H), 2.35 (s, 3 H), 2.58 (s, 3 H), 4.53 (q, 2 H), 5.32 (s, 2 H), 6.60 (s, 1 H), 6.89-6.99 (m, 2 H), 7.29-7.40 (m, 1 H), 7.61 (s, 1 H), 8.37 (s, 1 H).

Example 139

5-{8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-3-ethoxythiophen-2-amine

(752) ##STR00257##

(753) The title compound was formed as a by-product in the synthesis of ethyl 5-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1,3-thiazole-2-carboxylate.

(754) LC-MS (Method 1): R.sub.t=1.01 min

(755) MS (ESpos): m/z=430 (M+H).sup.+

(756) .sup.1H-NMR (400 MHz, CDCl.sub.3): δ [ppm]=1.40 (t, 3 H), 2.38 (s, 3 H), 2.78 (s, 3 H), 4.38 (q, 2 H), 5.32 (s, 2 H), 6.53 (s, 1 H), 6.75 (s, 1 H), 6.89-6.98 (m, 2 H), 7.29-7.41 (m, 1 H), 9.18 (s, 1 H). (NH.sub.2 was not observed).

Example 140

8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethyl-3-(pyridin-3-yl)imidazo[1,2-a]pyridine

(757) ##STR00258##

(758) A mixture of 69.5 mg of 3-bromo-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine (0.185 mmol, 1.0 eq.) from Example 30A, 34.2 mg of pyridine-3-boronic acid (0.278 mmol, 1.5 eq.) and (2-aminobiphenyl-2-yl)(chloro)palladium-dicyclohexyl[2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphane (1:1) [CAS No: 1028206-56-5; Sigma Aldrich] (0.009 mmol, 0.05 eq.), 2.0 ml of acetonitrile and 1.1 ml of 0.5 M aqueous potassium phosphate solution (0.56 ml, 3.0 eq.) was stirred at 60° C. for 48 h. The mixture was then filtered through an Extrelute cartridge and eluted with ethyl acetate, and the filtrate was concentrated. The crude product was purified by preparative HPLC (Method 19), giving 32.7 mg (68% of theory) of the title compound.

(759) LC-MS (Method 1): R.sub.t=0.75 min

(760) MS (ESpos): m/z=366 (M+H).sup.+

(761) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=2.27 (s, 3 H), 2.29 (s, 3 H), 5.30 (s, 2 H), 6.83 (br. s, 1 H), 7.22-7.29 (m, 2 H), 7.55-7.65 (m, 2 H), 7.74 (br. s, 1 H), 7.94-8.01 (m, 1 H), 8.63-8.67 (m, 1 H), 8.69-8.74 (m, 1 H)

Example 141

Ethyl 5-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1,2-oxazole-3-carboxylate

(762) ##STR00259##

(763) A mixture of 815 mg of ethyl 4-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-2,4-dioxobutanoate (80%, 1.89 mmol) from Example 62A and 461 mg of hydroxylamine hydrochloride (6.63 mmol, 3.5 eq.) in 70 ml of ethanol was heated at reflux for 7 days. The reaction mixture was then concentrated and recrystallized from boiling water/acetonitrile. This gave 473 mg (51% of theory, purity 87%) of the title compound.

(764) TLC (cyclohexane/ethyl acetate 1:1): R.sub.F=0.51

(765) LC-MS (Method 1): R.sub.t=1.12 min

(766) MS (ESpos): m/z=428 (M+H).sup.+

(767) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=1.32-1.41 (m, 3 H), 2.39 (s, 3 H), 4.37-4.49 (m, 2 H), 5.32 (s, 2 H), 7.05 (s, 1 H), 7.16-7.29 (m, 2 H), 7.34 (s, 1 H), 7.55-7.65 (m, 1 H), 8.24 (s, 1 H), (further peak under solvent signal).

Example 142

(5-{8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1,2-oxazol-3-yl)methanol

(768) ##STR00260##

(769) 37.4 mg of sodium borohydride (0.990 mmol, 1.0 eq.) were added to a suspension of 470 mg of ethyl 5-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1,2-oxazole-3-carboxylate (0.990 mmol, 1.0 eq.) from Example 141 in 20 ml of ethanol, and the mixture was stirred at room temperature for 2 h and at reflux for 1 h. The mixture was then concentrated to half its original volume, water was added and the mixture was extracted repeatedly with dichloromethane. The combined organic phases were dried with magnesium sulphate, filtered and concentrated. The residue was purified using Biotage Isolera (50 g silica gel cartridge, dichloromethane/methanol gradient), giving 125 mg (32% of theory) of the title compound.

(770) TLC (dichloromethane/methanol 100:5): R.sub.F 0.33

(771) LC-MS (Method 1): R.sub.t=0.85 min

(772) MS (ESpos): m/z=386 (M+H).sup.+

(773) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=2.38 (br. s, 3 H), 2.49 (s, 3 H), 4.61 (d, 2 H), 5.31 (s, 2 H), 5.59 (t, 1 H), 6.88 (s, 1 H), 6.99 (br. s, 1 H), 7.20-7.30 (m, 2 H), 7.54-7.67 (m, 1 H), 8.18-8.21 (m, 1 H).

Example 143

1-(3-{8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1H-pyrazol-5-yl)-2-methylpropan-2-amine

(774) ##STR00261##

(775) 0.028 ml (0.365 mmol) of trifluoroacetic acid was added to a solution of 120 mg (0.018 mmol) of the mixture from Example 80A [tert-butyl 1-(3-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1H-pyrazol-5-yl)-2-methylpropan-2-yl]carbamate in 2 ml dichloromethane. The resulting solution was stirred at room temperature overnight. After the reaction had ended, the solvent was removed under reduced pressure and the residue that remained was purified by preparative HPLC chromatography (Method 26), which gave 5.3 mg (60% of theory, purity 88%) of the title compound (Example 149).

(776) LC-MS (Method 25): R.sub.t=7.26 min; m/z=426.19 (M+H).sup.+

(777) .sup.1H-NMR (600 MHz, DMSO-d.sub.6): δ [ppm]=1.13 (s, 6 H), 2.30 (s, 3 H), 2.42 (s, 3H), 2.79 (s, 2H), 5.28 (s. 2 H), 6.42 (s, 1 H), 6.79 (s, 1 H), 7.14-7.31 (m, 2 H), 7.53-7.66 (m, 1 H), 8.55-8.74 (m, 1H).

(778) .sup.13C-NMR (151 MHz, DMSO-d.sub.6): δ [ppm]=14.8, 18.3, 28.0, 38.7, 50.5, 58.1, 103.7, 105.9, 111.9, 115.2, 116.9, 121.0, 132.1, 136.4, 139.5, 140.2, 145.9, 160.6.

Example 144

1-(5-{8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-1,2-oxazol-3-yl)-2-methylpropan-2-amine

(779) ##STR00262##

(780) A mixture of 200 mg (0.238 mmol, purity 63%) of tert-butyl (6-{8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-yl}-2-methyl-4,6-dioxohexan-2-yl)carbamate (Example 79A) and 165.3 mg (2.38 mmol) of hydroxylamine hydrochloride in 10 ml of ethanol was heated in a microwave oven at 120° C. with stirring for 30 min. The reaction mixture was cooled to RT and concentrated under reduced pressure. Ethyl acetate (15 ml) and water (10 ml) were added to the residue, the mixture was shaken and the phases were then separated. The organic phase was concentrated to dryness under reduced pressure. The residue was then purified by preparative HPLC (Method 26). This gave 47 mg (46% of theory) of the title compound.

(781) LC-MS (Method 25): R.sub.t=7.71 min; m/z=427.09 (M+H).sup.+

(782) .sup.1H-NMR (600 MHz, DMSO-d.sub.6): δ [ppm]=1.12 (s, 6 H), 2.38 (s, 3 H), 2.49 (s, 3 H), 2.75 (s, 2 H), 5.32 (s, 2 H), 6.80 (s, 1 H), 6.98 (s, 1 H), 7.25 (t, 2 H), 7.60 (ddd, 1 H), 8.20 (s, 1 H)

(783) .sup.13C-NMR (151 MHz, DMSO-d.sub.6): δ [ppm]=15.0, 18.2, 30.3, 40.4, 49.4, 58.3, 102.1, 107.8, 111.3, 111.6, 111.9, 116.4, 123.2, 132.2, 138.0, 143.3, 146.0, 159.6, 161.3, 161.5.

(784) B. Assessment of Pharmacological Efficacy

(785) The following abbreviations are used: ATP adenosine triphosphate Brij35 polyoxyethylene(23) lauryl ether BSA bovine serum albumin DTT dithiothreitol TEA triethanolamine

(786) The pharmacological effect of the compounds according to the invention can be shown in the following assays:

(787) B-1. Measurement of sGC Enzyme Activity by Means of PPi Detection

(788) Soluble guanylyl cyclase (sGC) converts GTP to cGMP and pyrophosphate (PPi) when stimulated. PPi is detected with the aid of the method described in WO 2008/061626. The signal that arises in the assay increases as the reaction progresses and serves as a measure of the sGC enzyme activity. With the aid of a PPi reference curve, the enzyme can be characterized in a known manner, for example in terms of conversion rate, stimulability or Michaelis constant.

(789) Practice of the Test

(790) To conduct the test, 29 μl of enzyme solution (0-10 nM soluble guanylyl cyclase (prepared according to Hönicka et al., Journal of Molecular Medicine 77(1999)14-23), in 50 mM TEA, 2 mM magnesium chloride, 0.1% BSA (fraction V), 0.005% Brij 35, pH 7.5) were initially charged in the microplate, and 1 μl of the stimulator solution (0-10 μM 3-morpholinosydnonimine, SIN-1, Merck in DMSO) was added. The microplate was incubated at RT for 10 min. Subsequently, 20 μl of detection mix (1.2 nM firefly luciferase (Photinus pyralis Luziferase, Promega), 29 μM dehydroluciferin (prepared according to Bitler & McElroy, Arch. Biochem. Biophys. 72 (1957) 358), 122 μM luciferin (Promega), 153 μM ATP (Sigma) and 0.4 mM DTT (Sigma) in 50 mM TEA, 2 mM magnesium chloride, 0.1% BSA (fraction V), 0.005% Brij 35, pH 7.5) were added. The enzyme reaction was started by adding 20 μl of substrate solution (1.25 mM guanosine 5′-triphosphate (Sigma) in 50 mM TEA, 2 mM MgCl2, 0.1% BSA (fraction V), 0.005% Brij, pH 7.5) and analysed continuously in a luminometer.

(791) B-2. Effect on a Recombinant Guanylate Cyclase Reporter Cell Line

(792) The cellular effect of the inventive compounds is determined using a recombinant guanylate cyclase reporter cell line, as described in F. Wunder et al., Anal. Biochem. 339, 104-112 (2005).

(793) Representative MEC values (MEC=minimum effective concentration) for the inventive compounds are shown in the table below (in some cases as mean values for individual determinations):

(794) TABLE-US-00007 TABLE A Example No. MEC [μM] 1 0.065 2 0.1 3 0.1 4 0.2 5 0.2 6 0.1 7 0.1 8 0.1 9 0.3 10 1.0 11 3.0 12 0.1 13 0.3 14 0.3 15 0.065 16 1.0 17 1.0 18 1.0 19 1.0 20 1.0 21 1.0 22 1.0 23 1.0 24 1.0 25 1.0 26 1.0 27 1.0 28 1.0 29 1.0 30 3.0 31 3.0 32 3.0 33 3.0 34 3.0 35 3.0 36 3.0 37 3.0 38 3.0 39 3.0 40 3.0 41 3.0 42 3.0 43 3.0 44 3.0 45 0.1 46 0.2 47 0.3 48 0.2 49 0.3 50 0.3 51 0.3 52 0.3 53 1.0 54 1.0 55 1.0 56 3.0 57 1.0 58 3.0 59 1.0 60 3.0 61 3.0 62 3.0 63 3.0 64 3.0 65 3.0 66 3.0 67 3.0 68 3.0 69 3.0 70 3.0 71 3.0 72 3.0 73 3.0 74 3.0 75 — 76 3.0 77 0.1 78 0.1 79 — 80 0.3 81 3.0 82 0.1 83 0.3 84 1.0 85 3.0 86 0.03 87 0.1 88 0.01 89 0.03 90 0.3 91 0.1 92 0.03 93 0.1 94 0.3 95 0.3 96 0.065 97 0.3 98 0.03 99 0.03 100 0.03 98 3.0 99 0.1 100 0.03 101 0.1 102 0.1 103 0.03 104 0.3 105 0.01 106 0.3 107 0.065 108 0.3 109 0.3 110 1.0 111 1.0 112 1.0 113 0.03 114 0.3 115 0.1 116 0.01 117 0.1 118 0.03 119 0.1 120 0.3 121 1.0 122 3.0 123 0.3 124 3.0 125 3.0 126 3.0 127 0.3 128 1.0 129 1.0 130 3.0 131 1.0 132 0.3 133 0.3 134 1.0 135 3.0 136 0.3 137 3.0 138 3.0 139 0.1 140 0.1 141 1.0 142 0.1 143 1.0 144 0.3
B-3. Vasorelaxant Effect In Vitro

(795) Rabbits are stunned by a blow to the neck and exsanguinated. The aorta is removed, freed from adhering tissue and divided into rings of width 1.5 mm, which are placed individually under prestress into 5 ml organ baths with carbogen-sparged Krebs-Henseleit solution at 37° C. having the following composition (each mM): sodium chloride: 119; potassium chloride: 4.8; calcium chloride dihydrate: 1; magnesium sulphate heptahydrate: 1.4; potassium dihydrogenphosphate: 1.2; sodium bicarbonate: 25; glucose: 10. The contractile force is determined with Statham UC2 cells, amplified and digitalized using A/D transducers (DAS-1802 HC, Keithley Instruments Munich), and recorded in parallel on linear recorders. To obtain a contraction, phenylephrine is added to the bath cumulatively in increasing concentration. After several control cycles, the substance to be studied is added in increasing dosage each time in every further run, and the magnitude of the contraction is compared with the magnitude of the contraction attained in the last preceding run. This is used to calculate the concentration needed to reduce the magnitude of the control value by 50% (IC.sub.50 value). The standard administration volume is 5 μl; the DMSO content in the bath solution corresponds to 0.1%.

(796) B-4. Blood Pressure Measurement on Anaesthetized Rats

(797) Male Wistar rats having a body weight of 300-350 g are anaesthetized with thiopental (100 mg/kg i.p.). After tracheotomy, a catheter is introduced into the femoral artery to measure the blood pressure. The substances to be tested are administered as solutions, either orally by means of a gavage or intravenously via the femoral vein (Stasch et al. Br. J. Pharmacol. 2002; 135: 344-355).

(798) B-5. Radiotelemetry Measurement of Blood Pressure in Conscious, Spontaneously Hypertensive Rats

(799) A commercially available telemetry system from DATA SCIENCES INTERNATIONAL DSI, USA, is employed for the blood pressure measurement on conscious rats described below.

(800) The system consists of 3 main components: implantable transmitters (Physiotel® telemetry transmitter) receivers (Physiotel® receiver) which are linked via a multiplexer (DSI Data Exchange Matrix) to a data acquisition computer.

(801) The telemetry system makes it possible to continuously record blood pressure, heart rate and body motion of conscious animals in their usual habitat.

(802) Animal Material

(803) The studies are conducted on adult female spontaneously hypertensive rats (SHR Okamoto) with a body weight of >200 g. SHR/NCrl from the Okamoto Kyoto School of Medicine, 1963, were a cross of male Wistar Kyoto rats having greatly elevated blood pressure and female rats having slightly elevated blood pressure, and were handed over at F13 to the U.S. National Institutes of Health.

(804) After transmitter implantation, the experimental animals are housed singly in type 3 Makrolon cages. They have free access to standard feed and water.

(805) The day/night rhythm in the experimental laboratory is changed by the room lighting at 6.00 am and at 7.00 pm.

(806) Transmitter Implantation

(807) The TA11 PA-C40 telemetry transmitters used are surgically implanted under aseptic conditions in the experimental animals at least 14 days before the first experimental use. The animals instrumented in this way can be used repeatedly after the wound has healed and the implant has settled.

(808) For the implantation, the fasted animals are anaesthetized with pentobarbital (Nembutal, Sanofi: 50 mg/kg i.p.) and shaved and disinfected over a large area of their abdomens. After the abdominal cavity has been opened along the linea alba, the liquid-filled measuring catheter of the system is inserted into the descending aorta in the cranial direction above the bifurcation and fixed with tissue glue (VetBonD™, 3M). The transmitter housing is fixed intraperitoneally to the abdominal wall muscle, and the wound is closed layer by layer.

(809) An antibiotic (Tardomyocel COMP, Bayer, 1 ml/kg s.c.) is administered postoperatively for prophylaxis of infection.

(810) Substances and Solutions

(811) Unless stated otherwise, the substances to be studied are administered orally by gavage to a group of animals in each case (n=6). In accordance with an administration volume of 5 ml/kg of body weight, the test substances are dissolved in suitable solvent mixtures or suspended in 0.5% tylose.

(812) A solvent-treated group of animals is used as control.

(813) Experimental Outline

(814) The telemetry measuring unit present is configured for 24 animals. Each experiment is recorded under an experiment number (Vyear month day).

(815) Each of the instrumented rats living in the system is assigned a separate receiving antenna (1010 Receiver, DSI).

(816) The implanted transmitters can be activated externally by means of an incorporated magnetic switch. They are switched to transmission in the run-up to the experiment. The signals emitted can be detected online by a data acquisition system (Dataquest TM A.R.T. for WINDOWS, DSI) and processed accordingly. The data are stored in each case in a file created for this purpose and bearing the experiment number.

(817) In the standard procedure, the following are measured for 10-second periods in each case: systolic blood pressure (SBP) diastolic blood pressure (DBP) mean arterial pressure (MAP) heart rate (HR) activity (ACT).

(818) The acquisition of measurements is repeated under computer control at 5-minute intervals. The source data obtained as absolute values are corrected in the diagram with the currently measured barometric pressure (Ambient Pressure Reference Monitor; APR-1) and stored as individual data. Further technical details are given in the extensive documentation from the manufacturer company (DSI).

(819) Unless indicated otherwise, the test substances are administered at 9:00 am on the day of the experiment. Following the administration, the parameters described above are measured over 24 hours.

(820) Evaluation

(821) After the end of the experiment, the acquired individual data are sorted using the analysis software (DATAQUEST TM A.R.T. TM ANALYSIS). The blank value is assumed to be the time 2 hours before administration, and so the selected data set encompasses the period from 7:00 am on the day of the experiment to 9:00 am on the following day.

(822) The data are smoothed over a predefinable period by determination of the average (15-minute average) and transferred as a text file to a storage medium. The measured values presorted and compressed in this way are transferred to Excel templates and tabulated. For each day of the experiment, the data obtained are stored in a dedicated file bearing the number of the experiment. Results and test protocols are stored in files in paper form sorted by numbers.

LITERATURE

(823) Klaus Witte, Kai Hu, Johanna Swiatek, Claudia Müssig, Georg Ertl and Björn Lemmer: Experimental heart failure in rats: effects on cardiovascular circadian rhythms and on myocardial β-adrenergic signaling. Cardiovasc Res 47 (2): 203-405, 2000; Kozo Okamoto: Spontaneous hypertension in rats. Int Rev Exp Pathol 7: 227-270, 1969; Maarten van den Buuse: Circadian Rhythms of Blood Pressure, Heart Rate, and Locomotor Activity in Spontaneously Hypertensive Rats as Measured With Radio-Telemetry. Physiology & Behavior 55(4): 783-787, 1994.

(824) B-6. Determination of Pharmacokinetic Parameters Following Intravenous and Oral Administration

(825) The pharmacokinetic parameters of the inventive compounds are determined in male CD-1 mice, male Wistar rats and female beagles. Intravenous administration in the case of mice and rats is effected by means of a species-specific plasma/DMSO formulation, and in the case of dogs by means of a water/PEG400/ethanol formulation. In all species, oral administration of the dissolved substance is performed via gavage, based on a water/PEG400/ethanol formulation. The removal of blood from rats is simplified by inserting a silicone catheter into the right Vena jugularis externa prior to substance administration. The operation is effected at least one day prior to the experiment with isofluran anaesthesia and administration of an analgesic (atropine/rimadyl (3/1) 0.1 ml s.c.). The blood is taken (generally more than 10 time points) within a time window including terminal time points of at least 24 to a maximum of 72 hours after substance administration. The blood is removed into heparinized tubes. The blood plasma is then obtained by centrifugation; if required, it can be stored at −20° C. until further processing.

(826) An internal standard (which may also be a chemically unrelated substance) is added to the samples of the inventive compounds, calibration samples and qualifiers, and there follows protein precipitation by means of acetonitrile in excess. Addition of a buffer solution matched to the LC conditions, and subsequent vortexing, is followed by centrifugation at 1000 g. The supernatant is analysed by LC-MS/MS using C18 reversed-phase columns and variable mobile phase mixtures. The substances are quantified via the peak heights or areas from extracted ion chromatograms of specific selected ion monitoring experiments.

(827) The plasma concentration/time plots determined are used to calculate the pharmacokinetic parameters such as AUC, C.sub.max, t.sub.1/2 (terminal half-life), F (bioavailability), MRT (mean residence time) and CL (clearance), by means of a validated pharmacokinetic calculation program.

(828) Since the substance quantification is performed in plasma, it is necessary to determine the blood/plasma distribution of the substance in order to be able to adjust the pharmacokinetic parameters correspondingly. For this purpose, a defined amount of substance is incubated in heparinized whole blood of the species in question in a rocking roller mixer for 20 min. After centrifugation at 1000 g, the plasma concentration is measured (by means of LC-MS/MS; see above) and determined by calculating the ratio of the C.sub.blood/C.sub.plasma value.

(829) B-7. Metabolic Study

(830) To determine the metabolic profile of the inventive compounds, they are incubated with recombinant human cytochrome P450 (CYP) enzymes, liver microsomes or primary fresh hepatocytes from various animal species (e.g. rats, dogs), and also of human origin, in order to obtain and to compare information about a very substantially complete hepatic phase I and phase II metabolism, and about the enzymes involved in the metabolism.

(831) The inventive compounds were incubated with a concentration of about 0.1-10 μM. To this end, stock solutions of the inventive compounds having a concentration of 0.01-1 mM in acetonitrile were prepared, and then pipetted with 1:100 dilution into the incubation mixture. Liver microsomes and recombinant enzymes were incubated at 37° C. in 50 mM potassium phosphate buffer pH 7.4 with and without NADPH-generating system consisting of 1 mM NADP.sup.+, 10 mM glucose-6-phosphate and 1 unit glucose-6-phosphate dehydrogenase. Primary hepatocytes were incubated in suspension in Williams E medium, likewise at 37° C. After an incubation time of 0-4 h, the incubation mixtures were stopped with acetonitrile (final concentration about 30%) and the protein was centrifuged off at about 15 000×g. The samples thus quenched were either analysed directly or stored at −20° C. until analysis.

(832) The analysis is carried out by high-performance liquid chromatography with ultraviolet and mass spectrometry detection (HPLC-UV-MS/MS). To this end, the supernatants of the incubation samples are chromatographed with suitable C18 reversed-phase columns and variable eluent mixtures of acetonitrile and 10 mM aqueous ammonium formate solution or 0.05% formic acid. The UV chromatograms in conjunction with mass spectrometry data serve for identification, structural elucidation and quantitative estimation of the metabolites, and for quantitative metabolic reduction of the compound according to the invention in the incubation mixtures.

(833) B-8. Caco-2 Permeability Test

(834) The permeability of a test substance was determined with the aid of the Caco-2 cell line, an establish in vitro model for permeability prediction at the gastrointestinal barrier (Artursson, P. and Karlsson, J. (1991). Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. Biochem. Biophys. 175 (3), 880-885). The Caco-2 cells (ACC No. 169, DSMZ, Deutsche Sammlung von Mikroorganismen and Zellkulturen, Braunschweig, Germany) were sown in 24-well plates having an insert and cultivated for 14 to 16 days. For the permeability studies, the test substance was dissolved in DMSO and diluted to the final test concentration with transport buffer (Hanks Buffered Salt Solution, Gibco/Invitrogen, with 19.9 mM glucose and 9.8 mM HEPES). In order to determine the apical to basolateral permeability (P.sub.appA-B) of the test substance, the solution comprising the test substance was applied to the apical side of the Caco-2 cell monolayer, and transport buffer to the basolateral side. In order to determine the basolateral to apical permeability (P.sub.appB-A) of the test substance, the solution comprising the test substance was applied to the basolateral side of the Caco-2 cell monolayer, and transport buffer to the apical side. At the start of the experiment, samples were taken from the respective donor compartment in order to ensure the mass balance. After an incubation time of two hours at 37° C., samples were taken from the two compartments. The samples were analysed by means of LC-MS/MS and the apparent permeability coefficients (P.sub.app) were calculated. For each cell monolayer, the permeability of Lucifer Yellow was determined to ensure cell layer integrity. In each test run, the permeability of atenolol (marker for low permeability) and sulfasalazine (marker for active excretion) is also determined in each test run as quality control.

(835) B-9. hERG Potassium Current Assay

(836) The hERG (human ether-a-go-go related gene) potassium current makes a significant contribution to the repolarization of the human cardiac action potential (Scheel et al., 2011). Inhibition of this current by pharmaceuticals can in rare cases cause potentially lethal cardiac arrythmia, and is therefore studied at an early stage during drug development.

(837) The functional hERG assay used here is based on a recombinant HEK293 cell line which stably expresses the KCNH2(HERG) gene (Zhou et al., 1998). These cells are studied by means of the “whole-cell voltage-clamp” technique (Hamill et al., 1981) in an automated system (Patchliner™; Nanion, Munich, Germany), which controls the membrane voltage and measures the hERG potassium current at room temperature. The PatchControlHT™ software (Nanion) controls the Patchliner system, data capture and data analysis. The voltage is controlled by 2 EPC-10 quadro amplifiers controlled by the PatchMasterPro™ software (both: HEKA Elektronik, Lambrecht, Germany). NPC-16 chips with moderate resistance (˜2 MΩ; Nanion) serve as the planar substrate for the voltage clamp experiments.

(838) NPC-16 chips are filled with intra- and extracellular solution (cf. Himmel, 2007) and with cell suspension. After forming a gigaohm seal and establishing whole-cell mode (including several automated quality control steps), the cell membrane is clamped at the −80 mV holding potential. The subsequent voltage clamp protocol changes the command voltage to +20 mV (for 1000 ms), −120 mV (for 500 ms), and back to the −80 mV holding potential; this is repeated every 12 s. After an initial stabilization phase (about 5-6 minutes), test substance solution is introduced by pipette in rising concentrations (e.g. 0.1, 1, and 10 μl) (exposure about 5-6 minutes per concentration), followed by several washing steps.

(839) The amplitude of the upward “tail” current which is generated by a change in potential from +20 mV to −120 mV serves to quantify the hERG potassium current, and is described as a function of time (IgorPro™ Software). The current amplitude at the end of various time intervals (for example stabilization phase before first substance, first/second/third concentration of test substance) serves to establish a concentration/effect curve, from which the half-maximum inhibiting concentration IC.sub.50 of the test substance is calculated. Hamill O P, Marty A, Neher E, Sakmann B, Sigworth F J. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pfluegers Arch 1981; 391:85-100. Himmel H M. Suitability of commonly used excipients for electrophysiological in-vitro safety pharmacology assessment of effects on hERG potassium current and on rabbit Purkinje fiber action potential. J Pharmacol Toxicol Methods 2007; 56:145-158. Scheel O, Himmel H, Rascher-Eggstein G, Knott T. Introduction of a modular automated voltage-clamp platform and its correlation with manual human ether-a-go-go related gene voltage-clamp data. Assay Drug Dev Technol 2011; 9:600-607. Zhou Z F, Gong Q, Ye B, Fan Z, Makielski J C, Robertson G A, January C T. Properties of hERG channels stably expressed in HEK293 cells studied at physiological temperature. Biophys J 1998; 74:230-241.
C. Working Examples for Pharmaceutical Compositions

(840) The compounds according to the invention can be converted to pharmaceutical formulations as follows:

(841) Tablet:

(842) Composition:

(843) 100 mg of the compound according to the invention, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

(844) Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

(845) Production:

(846) The mixture of inventive compound, lactose and starch is granulated with a 5% solution (w/w) of the PVP in water. The granules are dried and then mixed with the magnesium stearate for 5 minutes. This mixture is compressed in a conventional tabletting press (see above for format of the tablet). The guide value used for the pressing is a pressing force of 15 kN.

(847) Suspension which can be Administered Orally:

(848) Composition:

(849) 1000 mg of the compound according to the invention, 1000 mg of ethanol (96%), 400 mg of Rhodigel® (xanthan gum from FMC, Pennsylvania, USA) and 99 g of water.

(850) 10 ml of oral suspension correspond to a single dose of 100 mg of the compound according to the invention.

(851) Production:

(852) The Rhodigel is suspended in ethanol; the compound according to the invention is added to the suspension. The water is added while stirring. The mixture is stirred for about 6 h before swelling of the Rhodigel is complete.

(853) Solution for Oral Administration:

(854) Composition:

(855) 500 mg of the compound according to the invention, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. 20 g of oral solution correspond to a single dose of 100 mg of the compound according to the invention.

(856) Production:

(857) The compound according to the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring operation is continued until dissolution of the compound according to the invention is complete.

(858) i.v. Solution:

(859) The compound according to the invention is dissolved in a concentration below the saturation solubility in a physiologically acceptable solvent (e.g. isotonic saline solution, glucose solution 5% and/or PEG 400 solution 30%). The resulting solution is subjected to sterile filtration and dispensed into sterile and pyrogen-free injection vessels.