HK1098948A

HK1098948A - Tricyclic imidazopyridines for use as gastric secretion inhibitors

Info

Publication number: HK1098948A
Application number: HK07105226.8A
Authority: HK
Inventors: Wilm Buhr; M. Vittoria Chiesa; Peter Jan Zimmermann; Christof Brehm; Wolfgang-Alexander Simon; Wolfgang Kromer; Stefan Postius; Andreas Palmer
Original assignee: Altana Pharma Ag
Priority date: 2003-12-19
Filing date: 2004-12-17
Publication date: 2007-08-03

Description

Tricyclic imidazopyridines as gastric secretion inhibitors

Technical Field

The present invention relates to the enantiomers of tricyclic imidazopyridine compounds, to a process for their preparation and to their use as active compounds in the pharmaceutical industry for the preparation of medicaments.

Prior Art

U.S. patent 4,468,400 describes tricyclic imidazo [1, 2] pyridine compounds having different ring systems fused to the parent imidazopyridine structure, which are useful in the treatment of peptic ulcer conditions. International patent applications WO 95/27714, WO 98/42707, WO 98/54188, WO 00/17200, WO 00/26217, WO 00/63211, WO 01/72756, WO01/72754, WO 01/72755, WO 01/72757, WO 02/34749, WO03/014120, WO 03/016310, WO03/014123, WO 03/068774 and WO03/091253 disclose tricyclic imidazopyridine compounds having specific substitution patterns, which compounds are described therein as being equally suitable for the treatment of gastrointestinal disorders.

Description of the invention

It has now been found that the compounds described in, for example, WO03/014123 as racemic mixtures can be separated into their enantiomers or the enantiomers can be prepared by stereoselective methods. It has also been unexpectedly found that the enantiomer of formula 1 has a significant activity of inhibiting gastric acid secretion compared to its optical enantiomer represented by formula 2.

Although enantiomerically pure tricyclic imidazo [1, 2-a ] pyridine derivatives are known, for example from international patent application WO 95/27714, it is unexpected that the compounds of formula 1 have a higher activity than the compounds of formula 2. So far, for any combination of substituents R1, R2, R3 and Arom, the enantiomer of formula 1 is preferred because it has more significant activity of inhibiting gastric acid secretion than its optical antipode shown in formula 2 has not been described.

Accordingly, the present invention provides a compound of formula 1:

wherein

R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 1-4C-alkoxy-1-4C-alkyl or 1-4C-alkoxycarbonyl;

r2 is hydrogen, 1-4C-alkyl, halogen, 2-4C-alkenyl, 2-4C-alkynyl, hydroxy-1-4C-alkyl, 3-7C-cycloalkyl, 1-4C-alkoxycarbonyl;

r3 is hydroxy-1-2C-alkyl, 1-4C-alkoxy-1-2C-alkyl, 1-4C-alkoxycarbonyl or a radical-CO-NR 31R32,

wherein

R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, and

r32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or wherein

R31 and R32 together with the nitrogen atom to which they are attached are pyrrolidino, piperidino, morpholino,

arom is a monocyclic or bicyclic aryl group substituted with R4, R5, R6, and R7 selected from: phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1, 2, 3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxazolyl, pyridyl, pyrimidinyl, quinolinyl and isoquinolinyl,

r4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, carboxyl, 1-4C-alkoxycarbonyl, carboxyl-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxyl, aryl-1-4C-alkyl, aryloxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono-or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,

r5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy,

r6 is hydrogen, 1-4C-alkyl or halogen, and

r7 is hydrogen, 1-4C-alkyl or halogen,

wherein

Aryl is phenyl or substituted phenyl having 1, 2 or 3 identical or different substituents selected from the group consisting of: 1-4C-alkyl, 1-4C-alkoxy, carboxyl, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano, and also the salts of these compounds.

1-4C-alkyl means straight-chain or branched alkyl having 1 to 4 carbon atoms. Examples which may be mentioned are butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl.

3-7C-cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, of which cyclopropyl, cyclobutyl and cyclopentyl are preferred.

1-4C-alkoxy means a group which, in addition to an oxygen atom, also contains a straight-chain or branched alkyl group having 1 to 4 carbon atoms. Examples which may be mentioned are butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy, and preferably ethoxy and methoxy.

1-4C-alkoxy-1-4C-alkyl means one of the above-mentioned 1-4C-alkyl groups substituted by 1 of the above-mentioned 1-4C-alkoxy groups. Examples which may be mentioned are the methoxymethyl, the methoxyethyl and the butoxyethyl radical.

1-4C-alkoxycarbonyl (-CO-1-4C-alkoxy) means a carbonyl group to which 1 of the above-mentioned 1-4C-alkoxy groups is attached. Examples which may be mentioned are methoxycarbonyl (CH)₃O-C (O) and ethoxycarbonyl (CH)₃CH₂O-C(O)-)。

For the purposes of the present invention, halogen is bromine, chlorine and fluorine.

2-4C-alkenyl means straight-chain or branched alkenyl having 2 to 4 carbon atoms. Examples which may be mentioned are 2-butenyl, 3-butenyl, 1-propenyl and 2-propenyl (allyl).

2-4C-alkynyl means straight-chain or branched alkynyl having 2 to 4 carbon atoms. Examples which may be mentioned are 2-butynyl, 3-butynyl, 2-propynyl (propargyl) and preferably 1-ethynyl, 1-propynyl and 1-butynyl.

hydroxy-1-4C-alkyl means the above-mentioned 1-4C-alkyl group substituted by hydroxy. Examples which may be mentioned are hydroxymethyl, 2-hydroxyethyl and 3-hydroxypropyl.

1-2C-alkyl means methyl or ethyl.

hydroxy-1-2C-alkyl means the above-mentioned 1-2C-alkyl group substituted by hydroxy. Examples which may be mentioned are hydroxymethyl and 2-hydroxyethyl.

1-4C-alkoxy-1-2C-alkyl means one of the above-mentioned 1-2C-alkyl groups substituted by one of the above-mentioned 1-4C-alkoxy groups. Examples which may be mentioned are the methoxymethyl, the methoxyethyl and the butoxyethyl radical.

1-4C-alkoxy-1-4C-alkoxy means one of the above-mentioned 1-4C-alkoxy groups substituted by another 1-4C-alkoxy group. Examples which may be mentioned are 2- (methoxy) ethoxy (CH)₃-O-CH₂-CH₂-O-) and 2- (ethoxy) ethoxy (CH)₃-CH₂-O-CH₂-CH₂-O-)。

1-4C-alkoxy-1-2C-alkyl means one of the above-mentioned 1-4C-alkoxy groups which is substituted by one 1-4C-alkoxy-1-2C-alkyl group. Examples which may be mentioned are 2- (methoxy) ethoxymethyl (CH)₃-O-CH₂-CH₂-O-CH₂-)。

1-7C-alkyl means straight-chain or branched alkyl having 1 to 7 carbon atoms. Examples which may be mentioned are heptyl, isoheptyl (5-methylhexyl), hexyl, isohexyl (4-methylpentyl), neohexyl (3, 3-dimethylbutyl), pentyl, neopentyl- (3-methylbutyl), neopentyl- (2, 2-dimethylpropyl), butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl.

carboxy-1-4C-alkyl means, for example, carboxymethyl (-CH)₂COOH) or carboxyethyl (-CH)₂CH₂COOH)。

1-4C-alkoxycarbonyl-1-4C-alkyl means one of the above-mentioned 1-4C-alkyl groups substituted by one of the above-mentioned 1-4C-alkoxycarbonyl groups. Examples which may be mentioned are ethoxycarbonylmethyl (CH)₃CH₂OC(O)CH₂-)。

aryl-1-4C-alkyl means 1-4C-alkyl substituted by aryl. Examples which may be mentioned are benzyl.

aryl-1-4C-alkoxy means 1-4C-alkoxy substituted by aryl. Benzyloxy can be mentioned as an example.

In addition to the nitrogen atom, the mono-or di-1-4C-alkylamino radical contains one or two of the abovementioned 1-4C-alkyl radicals. Di-1-4C-alkylamino and especially dimethylamino, diethylamino or diisopropylamino are preferred.

1-4C-alkylcarbonylamino means an amino group to which a 1-4C-alkylcarbonyl group is attached. As examples there may be mentioned propionylamino (C)₃H₇C (O) NH-) and acetylamino (acetylamino, CH)₃C(O)NH-)。

1-4C-Alkoxycarbonylamino means an amino group substituted by the above-mentioned 1-4C-alkoxycarbonyl group. Examples which may be mentioned are ethoxycarbonylamino and methoxycarbonylamino.

1-4C-alkoxy-1-4C-alkoxycarbonyl means a carbonyl group substituted by the above-mentioned 1-4C-alkoxy-1-4C-alkoxy group. Examples which may be mentioned are 2- (methoxy) ethoxycarbonyl (CH)₃-O-CH₂CH₂-O-CO-) and 2- (ethoxy) ethoxycarbonyl (CH)₃CH₂-O-CH₂CH₂-O-CO-)。

1-4C-alkoxy-1-4C-alkoxycarbonylamino means an amino group substituted by the above-mentioned 1-4C-alkoxy-1-4C-alkoxycarbonyl group. Examples which may be mentioned are 2- (methoxy) ethoxycarbonylamino and 2- (ethoxy) ethoxycarbonylamino.

The radicals Arom which may be mentioned are, for example, the following substituents: 4-acetoxyphenyl group, 4-acetylaminophenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 3-benzyloxyphenyl group, 4-benzyloxyphenyl group, 3-benzyloxy-4-methoxyphenyl group, 4-benzyloxy-3-methoxyphenyl group, 3, 5-bis (trifluoromethyl) phenyl group, 4-butoxyphenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2-chloro-6-fluorophenyl group, 3-chloro-4-fluorophenyl group, 2-chloro-5-nitrophenyl group, 4-chloro-3-nitrophenyl group, 3- (4-chlorophenoxy) phenyl group, 2, 4-dichlorophenyl group, 3, 4-difluorophenyl group, 2, 4-dihydroxyphenyl group, 2, 6-dimethoxyphenyl group, 3, 4-dimethoxy-5-hydroxyphenyl group, 2, 5-dimethylphenyl group, 3-ethoxy-4-hydroxyphenyl group, 2-fluorophenyl group, 4-hydroxyphenyl group, 2-hydroxy-5-nitrophenyl group, 3-methoxy-2-nitrophenyl group, 3-nitrophenyl group, 2, 3, 5-trichlorophenyl group, 2, 4, 6-trihydroxyphenyl group, 2, 3, 4-trimethoxyphenyl group, 2-hydroxy-1-naphthyl group, 2-methoxy-1-naphthyl group, 4-methoxy-1-naphthyl group, 1-methyl-2-pyrrolyl group, 2, 6-dimethoxyphenyl group, 2-hydroxy-5-nitrophenyl group, 3-methoxy-2-nitrophenyl group, 2, 3, 5-trichlorophenyl, 2-pyrrolyl, 3-methyl-2-pyrrolyl, 3, 4-dimethyl-2-pyrrolyl, 4- (2-methoxycarbonylethyl) -3-methyl-2-pyrrolyl, 5-ethoxycarbonyl-2, 4-dimethyl-3-pyrrolyl, 3, 4-dibromo-5-methyl-2-pyrrolyl, 2, 5-dimethyl-1-phenyl-3-pyrrolyl, 5-carboxy-3-ethyl-4-methyl-2-pyrrolyl, 3, 5-dimethyl-2-pyrrolyl, 2, 5-dimethyl-1- (4-trifluoromethylphenyl) -3-pyrrolyl, methyl-2-pyrrolyl, methyl-3-pyrrolyl, methyl-2-yl, methyl-2-hydroxy-3, 1- (2, 6-dichloro-4-trifluoromethylphenyl) -2-pyrrolyl, 1- (2-nitrobenzyl) -2-pyrrolyl, 1- (2-fluorophenyl) -2-pyrrolyl, 1- (4-trifluoromethoxyphenyl) -2-pyrrolyl, 1- (2-nitrobenzyl) -2-pyrrolyl, 1- (4-ethoxycarbonyl) -2, 5-dimethyl-3-pyrrolyl, 5-chloro-1, 3-dimethyl-4-pyrazolyl, 5-chloro-1-methyl-3-trifluoromethyl-4-pyrazolyl, 1- (4-chlorobenzyl) -5-pyrazolyl, and mixtures thereof, 1, 3-dimethyl-5- (4-chlorophenoxy) -4-pyrazolyl, 1-methyl-3-trifluoromethyl-5- (3-trifluoromethylphenoxy) -4-pyrazolyl, 4-methoxycarbonyl-1- (2, 6-dichlorophenyl) -5-pyrazolyl, 5-allyloxy-1-methyl-3-trifluoromethyl-4-pyrazolyl, 5-chloro-1-phenyl-3-trifluoromethyl-4-pyrazolyl, 3, 5-dimethyl-1-phenyl-4-imidazolyl, 4-bromo-1-methyl-5-imidazolyl, 2-butylimidazolyl, 1-phenyl-1, 2, 3-triazol-4-yl, 3-indolyl, 4-indolyl, 7-indolyl, 5-methoxy-3-indolyl, 5-benzyloxy-3-indolyl, 1-benzyl-3-indolyl, 2- (4-chlorophenyl) -3-indolyl, 7-benzyloxy-3-indolyl, 6-benzyloxy-3-indolyl, 2-methyl-5-nitro-3-indolyl, 4, 5, 6, 7-tetrafluoro-3-indolyl, 1- (3, 5-difluorobenzyl) -3-indolyl, 1-methyl-2- (4-trifluorophenoxy) -3-indolyl, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof, 1-methyl-2-benzimidazolyl, 5-nitro-2-furyl, 5-hydroxymethyl-2-furyl, 3-furyl, 5- (2-nitro-4-trifluoromethylphenyl) -2-furyl, 4-ethoxycarbonyl-5-methyl-2-furyl, 5- (2-trifluoromethoxyphenyl) -2-furyl, 5- (4-methoxy-2-nitrophenyl) -2-furyl, 4-bromo-2-furyl, 5-dimethylamino-2-furyl, 5-bromo-2-furyl, 5-sulfo-2-furyl, 2-benzofuranyl, 2-thienyl, 3-methyl-2-thienyl, 4-bromo-2-thienyl, 5-nitro-2-thienyl, 5-methyl-2-thienyl, 5- (4-methoxyphenyl) -2-thienyl, 4-methyl-2-thienyl, 3-phenoxy-2-thienyl, 5-carboxy-2-thienyl, 2, 5-dichloro-3-thienyl, 3-methoxy-2-thienyl, 2-benzothienyl, 3-methyl-2-benzothienyl, 2-bromo-5-chloro-3-benzothienyl, 2-thiazolyl, 2-amino-4-chloro-5-thiazolyl, 2, 4-dichloro-5-thiazolyl, 2-diethylamino-5-thiazolyl, 3-methyl-4-nitro-5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 6-methyl-2-pyridyl, 3-hydroxy-5-hydroxymethyl-2-methyl-4-pyridyl, 2, 6-dichloro-4-pyridyl, 3-chloro-5-trifluoromethyl-2-pyridyl, 4, 6-dimethyl-2-pyridyl, 4- (4-chlorophenyl) -3-pyridyl, 2-amino-4-chloro-5-thiazolyl, 2, 4-dichloro-5-thiazolyl, 3-pyridyl, 3-methyl-2-pyridyl, 4- (4-chloro phenyl) -2-pyridyl, 2-, 2-chloro-5-methoxy-carbonyl-6-methyl-4-phenyl-3-pyridyl, 2-chloro-3-pyridyl, 6- (3-trifluoromethylphenoxy) -3-pyridyl, 2- (4-chlorophenoxy) -3-pyridyl, 2, 4-dimethoxy-5-pyrimidyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 2-chloro-3-quinolyl, 2-chloro-6-methoxy-3-quinolyl, 8-hydroxy-2-quinolyl and 4-isoquinolyl.

Suitable salts (depending on the substitution) of the compounds of formula 1 are in particular all acid addition salts. Pharmaceutically acceptable salts of inorganic and organic acids commonly used pharmacologically can be mentioned in particular. Suitable are the water-soluble and water-insoluble acid addition salts formed with the following acids: hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2- (4-hydroxybenzoyl) benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, pamoic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, wherein the acids are used in equimolar proportions or in different proportions for the preparation of the salts, depending on whether the acid used is a mono-or polybasic acid and the salt desired.

Pharmacologically unacceptable salts, which are initially obtained as industrial products in the preparation of the compounds according to the invention, for example on an industrial scale, can be converted into pharmaceutically acceptable salts by methods known to the person skilled in the art.

It will be clear to the skilled person that if the compound of the invention and its salts are isolated, for example in crystalline form, they may contain various amounts of solvent. The invention therefore also includes all solvates, especially all hydrates, of the compounds of formula 1, and also all solvates, especially all hydrates, of the salts of the compounds of formula 1.

In particular, the present invention relates to a compound of formula 1 and/or a salt thereof of the present invention that is substantially free of a compound of formula 2 and/or a salt thereof.

In the context of the present invention, substantially free means that the compound of formula 1 and/or a salt thereof contains less than 10% by weight of the compound of formula 2 and/or a salt thereof. Preferably, "substantially free" means that the compound of formula 1 and/or salt thereof contains less than 5% by weight of the compound of formula 2 and/or salt thereof. In a most preferred embodiment, "substantially free" means that the compound of formula 1 and/or salt thereof contains less than 2% by weight of the compound of formula 2 and/or salt thereof.

Compounds which may be mentioned are the compounds of formula 1 as defined below, in which

R1 is 1-4C-alkyl or 3-7C-cycloalkyl,

r2 is 1-4C-alkyl, halogen, hydroxy-1-4C-alkyl, 2-4C-alkenyl or 3-7C-cycloalkyl,

wherein

R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,

and is

R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,

or therein

R31 and R32 together with the nitrogen atom to which they are attached are pyrrolidino, piperidino, pyrrolidino, piperidino, and pyrrolidino,

A morpholino group having a hydroxyl group and a carboxyl group,

arom is a monocyclic or bicyclic aryl group substituted with R4, R5, R6, and R7 selected from:

phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1, 2, 3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxazolyl, pyridyl, pyrimidinyl, quinolinyl and isoquinolinyl,

wherein

r6 is hydrogen, 1-4C-alkyl or halogen, and

r7 is hydrogen, 1-4C-alkyl or halogen,

wherein

Compounds which may also be mentioned are the compounds of formula 1 as defined below, in which

R1 is 1-4C-alkyl or 3-7C-cycloalkyl,

r2 is 1-4C-alkyl, halogen, hydroxy-1-4C-alkyl, 2-4C-alkenyl or 3-7C-cycloalkyl,

r3 is a group-CO-NR 31R32,

wherein

R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,

and is

R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,

or therein

A morpholino group having a hydroxyl group and a carboxyl group,

wherein

r6 is hydrogen, 1-4C-alkyl or halogen, and

r7 is hydrogen, 1-4C-alkyl or halogen,

wherein

Particular mention may be made of compounds of the formula 1 as defined below, in which

R1 is 1-4C-alkyl,

r2 is 1-4C-alkyl, halogen, hydroxy-1-4C-alkyl or 2-4C-alkenyl,

r3 is hydroxy-1-2C-alkyl, 1-4C-alkoxy-1-2C-alkyl or a radical-CO-NR 31R32,

wherein

R31 is hydrogen, 1-7C-alkyl,

r32 is hydrogen, 1-7C-alkyl,

or therein

arom is phenyl, furyl, thienyl, pyrrolyl or pyridyl substituted with R4 and R5,

wherein

R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, halogen or hydroxy,

r5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen or hydroxy, and also the salts of these compounds.

Also specifically mentioned are compounds of formula 1 as defined below, wherein

R1 is 1-4C-alkyl,

r2 is 1-4C-alkyl, halogen, hydroxy-1-4C-alkyl or 2-4C-alkenyl,

r3 is a group-CO-NR 31R32,

wherein

R31 is hydrogen or 1-7C-alkyl,

r32 is hydrogen or 1-7C-alkyl,

or therein

arom is phenyl, furyl, thienyl or pyridyl substituted by R4 and R5,

wherein

The compounds of formula 1 as defined below are particularly given, wherein

R1 is 1-4C-alkyl,

r2 is 1-4C-alkyl, halogen, hydroxy-1-4C-alkyl or 2-4C-alkenyl,

r3 is hydroxy-1-2C-alkyl, 1-4C-alkoxy-1-2C-alkyl or a radical-CO-NR 31R32,

wherein

R31 is hydrogen or 1-7C-alkyl,

r32 is hydrogen or 1-7C-alkyl,

or therein

arom is phenyl, furyl, thienyl, pyrrolyl or pyridyl substituted with R4 and R5,

wherein

The compounds of formula 1 as defined below are also emphasized, wherein

R1 is 1-4C-alkyl,

r2 is 1-4C-alkyl,

r3 is a group-CO-NR 31R32,

wherein

R31 is hydrogen or 1-7C-alkyl,

r32 is hydrogen or 1-7C-alkyl,

or therein

arom is phenyl, furyl, thienyl or pyridyl substituted by R4 and R5,

wherein

The compounds of formula 1 as defined below are also emphasized, wherein

R1 is 1-4C-alkyl,

r2 is halogen, hydroxy-1-4C-alkyl or 2-4C-alkenyl,

r3 is a group-CO-NR 31R32,

wherein

R31 is hydrogen or 1-7C-alkyl,

r32 is hydrogen or 1-7C-alkyl,

or therein

arom is phenyl, furyl, thienyl or pyridyl substituted by R4 and R5,

wherein

The compounds of the formula 1, in which the definitions are as follows, are particularly emphasized

R1 is 1-4C-alkyl,

r2 is 1-4C-alkyl, halogen or hydroxy-1-4C-alkyl,

r3 is 1-4C-alkoxy-1-2C-alkyl or a radical-CO-NR 31R32, wherein

R31 is hydrogen or 1-7C-alkyl,

r32 is hydrogen or 1-7C-alkyl,

or therein

R31 and R32 together with the nitrogen atom to which they are attached are pyrrolidino,

arom is phenyl or thienyl substituted with R4,

wherein

R4 is hydrogen, 1-4C-alkyl or halogen, and also the salts of these compounds.

The compounds of the formula 1, in which the definitions are as follows, are also particularly emphasized, are

R1 is 1-4C-alkyl,

r2 is 1-4C-alkyl,

r3 is a group-CO-NR 31R32,

wherein

R31 is hydrogen or 1-7C-alkyl,

r32 is hydrogen or 1-7C-alkyl,

arom is a phenyl group, which is,

and salts of these compounds.

As a particularly preferred example, the following exemplary compounds of formula 1 may be synthesized according to the general methods described in more detail below:

R1	R2	R3	Arom
R1	R2	R3	Arom	CH₃	CH₃	-C(O)-N(CH₃)₂	phenyl radical
CH₃	-CH₂OH	-C(O)-N(CH₃)₂	Phenyl radical	CH₃	CH₃	-C(O)-N(CH₃)₂	phenyl radical
CH₃	-CH₂OH	-C(O)-N(CH₃)₂	Phenyl radical	CH₃	Br	-C(O)-N(CH₃)₂	Phenyl radical
CH₃	-CH₂CH₃	-C(O)-N(CH₃)₂	Phenyl radical	CH₃	Br	-C(O)-N(CH₃)₂	Phenyl radical
CH₃	-CH₂CH₃	-C(O)-N(CH₃)₂	Phenyl radical	CH₃	CH₃	-C (O) -pyrrolidino	Phenyl radical
CH₃	CH₃	-C(O)-N(H)CH₃	Phenyl radical	CH₃	CH₃	-C (O) -pyrrolidino	Phenyl radical
CH₃	CH₃	-C(O)-N(H)CH₃	Phenyl radical	CH₃	CH₃	-C(O)-NH₂	Phenyl radical
CH₃	CH₃	-C(O)-N(CH₃)₂	2-methylphenyl radical	CH₃	CH₃	-C(O)-NH₂	Phenyl radical
CH₃	CH₃	-C(O)-N(CH₃)₂	2-methylphenyl radical	CH₃	CH₃	-C(O)-N(CH₃)₂	2-fluorophenyl group
CH₃	CH₃	-C(O)-N(CH₃)₂	4-fluorophenyl group	CH₃	CH₃	-C(O)-N(CH₃)₂	2-fluorophenyl group
CH₃	CH₃	-C(O)-N(CH₃)₂	4-fluorophenyl group	CH₃	CH₃	-C(O)-N(CH₃)₂	Thien-2-yl
CH₃	CH₃	CH₂OCH₃	Phenyl radical	CH₃	CH₃	-C(O)-N(CH₃)₂	Thien-2-yl

Other compounds of formula 1 not mentioned as examples may be prepared according to analogous methods known to the person skilled in the art.

The compounds of the invention can be prepared from the corresponding racemic mixtures by the following methods: the desired optical antipode of formula 1 is separated from the optical antipode of formula 2 according to techniques known to those skilled in the art. The separation can be achieved, for example, by crystallization of the diastereomeric salts after reaction of the racemic mixture of the free acid compounds of formula 1 and 2 with a suitable optically pure acid or by preparative chromatography using a chiral column.

For this purpose, racemic mixtures of compounds of formula 1 and compounds of formula 2, preferably of compounds of formula 1 and compounds of formula 2 wherein R2 is 1-4C-alkyl, can be prepared according to the methods described, for example, in WO03/014123 or by analogous reaction procedures (reaction scheme 1). 1-aryl-3- (imidazo [1, 2-a ] pyridin-7-yl) -propan-1-one of formula 4 is prepared by: 8-hydroxyimidazo [1, 2-a ] pyridines of formula 3 are aminomethylated with, for example, Eschenmoser's salt, and then reacted with a suitable enamine compound, such as 1- (1-aryl-vinyl) -pyrrolidine. The conversion of the ketone of formula 4 to a racemic mixture of the compound of formula 1 and the compound of formula 2 can be accomplished using a method similar to that described in WO03/014123 (reduction of the carbonyl function with, for example, sodium borohydride, followed by cyclization of the resulting diol of formula 5, for example, in the presence of an acid such as phosphoric acid). Racemic mixtures of compounds of formula 1 and compounds of formula 2 bearing, for example, a 6-amido substituent can be prepared from 7H-8, 9-dihydropyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid esters of formula 6 by a convenient method: cleavage of the ester function, for example by saponification with sodium hydroxide, gives the corresponding carboxylic acid of formula 7, which is then treated with a suitable coupling reagent, for example TBTU, before addition of a coupling component, for example an amine.

Reaction scheme 1

Alternatively, racemic mixtures of the compounds of formula 1 and of formula 2, preferably of the compounds of formula 1 and of formula 2 in which R2 is hydrogen, halogen, 1-4C-alkyl, 2-4C-alkenyl, 2-4C-alkynyl, hydroxy-1-4C-alkyl, 3-7C-cycloalkyl or 1-4C-alkoxycarbonyl, can be prepared by the following reaction schemes 2, 3 and 4.

Reaction scheme 2:

the compound of formula 8 can be directly converted to a racemic mixture of the compound of formula 1 and the compound of formula 2 by, for example, electrophilic aromatic substitution.

Alternatively, the compound of formula 8 may be first converted to a compound of formula 9 by, for example, Vilsmeier formylation, followed by additional derivatization reactions known to those skilled in the art (e.g., reduction of aldehyde groups, followed by etherification if desired, or oxidation of aldehyde groups, followed by esterification) to produce a racemic mixture of the compound of formula 1 and the compound of formula 2.

Another possible method of obtaining a racemic mixture of a compound of formula 1 and a compound of formula 2 is, for example, carried out by: racemic mixtures of compounds of formula 1 and 2, wherein R2 ═ halogen, are converted by, for example, C — C bond formation reactions such as Heck coupling, Suzuki coupling or Sonogashira coupling. The products of these coupling reactions may be further modified if desired, for example, by reducing the CC multiple bond. Racemic mixtures of compounds of formula 1 and compounds of formula 2, wherein R2 ═ halogen, can be prepared from compounds of formula 8 by, for example, halogenation reactions, e.g., bromination using a bromination reagent such as N-bromosuccinimide.

The compound of formula 8 (R2 ═ H) -or the racemic mixture of the compound of formula 1 and the compound of formula 2 can generally be prepared, for example, according to the reaction sequence depicted in reaction scheme 3.

Reaction scheme 3

The compound of formula 12 can be obtained, for example, from the compound of formula 3 by: o-alkylation is carried out and then the O-alkylated product of formula 11 is subjected to a thermally induced Claisen-rearrangement reaction. The alcohol function in the compound of formula 12 is protected using a suitable protecting group Prot, such as pivaloyl or dimethyl- (1, 1, 2-trimethyl-propyl) -siloxy using standard conditions to obtain the compound of formula 13, which may be subjected to, for example, a cross-metathesis reaction in the next reaction step, for example, using a suitable Grubbs catalyst suitable for introducing an Arom residue. The reaction product of formula 14 may be deprotected and ring closure may be carried out using methods known to those skilled in the art, for example using acidic conditions, to yield the desired compound of formula 8 or a racemic mixture of the compound of formula 1 and the compound of formula 2.

The compounds of formula 10 can be prepared in analogy to the methods described in WO03/014123, for example according to the exemplary method described in reaction scheme 4.

Reaction scheme 4

The preparation of the compounds of formula 16 from the compounds of formula 15 is carried out according to methods known per se to the person skilled in the art, for example according to reactions analogous to those described by way of example in international patent application WO 03/014123. The hydrogenation of the compound of formula 16 to the compound of formula 10 is carried out according to methods known per se to the person skilled in the art using standard reaction conditions, for example using hydrogen/Pd (0).

Alternatively, the compounds of formula 1 can be prepared by stereoselective methods following the reaction steps as generally depicted in scheme 5. Formula 1The compound of formula 7 can be prepared by subjecting the compound of formula 4 to asymmetric reduction. Various methods of performing asymmetric reduction of prochiral ketones are known (see e.g., e.n. jacobsen, a. pfaltz, y. yamamoto, comparative asymmetric Catalysis, vol. l-li, Springer, Berlin, 1999), including internal catalytic hydrogenation, catalytic transfer hydrogenation, chiral reducing agents (e.g., chiral boranes), achiral reducing agents in the presence of chiral promoters or chiral catalysts, hydrosilylation (achiral silanes used in combination with chiral catalysts), and enzymatic reduction. Using a chiral hydrogenation catalyst (RuCl) of the Noyori type₂[PP][NN]) Is the preferred method for synthesizing enantiomerically pure diols of formula 17. In the general formula RuCl₂[PP][NN]In (b), PP is used as an abbreviation of chiral diphosphine ligand, and NN is used as an abbreviation of chiral diamine ligand. For a detailed description of the process and specific examples of hydrogenation catalysts see, for example, Angew. chem.2001, 113, 40-75 and references cited therein. Conversion of a derivative of formula 17 to enantiomerically pure 7H-8, 9-dihydropyrano [2, 3-c ] of formula 1]Imidazo [1, 2-a ]]Pyridine can be synthesized by reacting at SN₂The method is carried out under the condition. For this purpose, the hydroxyl group in the α -position of the Arom group can be converted into a suitable leaving group LG, for example by esterification with an acid halide or sulfonyl chloride. To prepare the compound of formula 18a, the phenolic hydroxyl group may be temporarily protected. Suitable protecting groups are described, for example, in t.w.greene, p.g.m.wuts "organic synthesis, 3 rd edition, j.wiley&Sons, New York, 1999. Alternatively, the phenolic hydroxyl group in the compound of formula 17 may be converted to a suitable leaving group LG using, for example, the reagents described above to give the compound of formula 18 b. A related process is disclosed in international patent application WO 95/27714. Enantiomerically pure compounds of formula 1 may be prepared, for example, by heating a solution of these intermediates 18a or 18b in a dipolar aprotic solvent such as DMF or DMSO. The ring closure of the compound of formula 18b may be carried out, for example, in the presence of a base such as sodium hydride. More suitably, the ring closure of the diol of formula 17 may be effected under Mitsunobu conditions, for example using diisopropyl azodicarboxylate and triphenylphosphine.

Reaction scheme 5

The compounds of formula 4 are known, for example as described in WO03/014123, or they may be prepared in analogy to known methods for preparing known compounds (see, for example, reaction scheme 1). The purity of the compound of formula 4 has a major impact on the reaction conditions and results of the asymmetric hydrogenation to the compound of formula 17. In contrast to WO03/014123, further purification steps are required, for example a crystallization step in the presence of a suitable organic acid, as described in the examples in an exemplary manner. Suitable methods for converting compounds of formula 4 to other compounds of formula 4 bearing a different substituent R3 are shown in reaction scheme 6 and can be illustrated by the following examples: 7- (3-aryl-3-oxo-propyl) -8-hydroxy-imidazo [1, 2-a ] pyridine-6-carboxylic acid ester of formula 19, wherein R33 is e.g. 1-4C-alkyl, can be converted to the acetal of formula 20, which can be achieved e.g. by reaction with 2, 2-dimethoxypropane in the presence of an acid. Cleavage of the ester functionality, for example by saponification with sodium hydroxide, affords the corresponding carboxylic acid of formula 21, which is then treated with a suitable coupling reagent such as TBTU, followed by addition of a coupling component such as an amine to yield the derivative of formula 22. Alternatively, the ester of formula 20 can be reduced to the corresponding primary alcohol using, for example, lithium aluminum hydride, and the hydroxyl group can be activated, for example, by converting the hydroxyl group to a halide or sulfonate using, for example, thionyl chloride or methanesulfonyl chloride. Interconversion of the substituent R3 may then be accomplished by nucleophilic displacement reactions using nucleophiles such as alcoholates. Finally, the ketone of formula 4 is obtained by cleavage of the acetal of formula 22, for example in the presence of an acid such as hydrochloric acid.

Reaction scheme 6:

another method suitable for the synthesis of the compound of formula 1 is depicted in reaction scheme 7. The compound of formula 14 (see reaction scheme 3) can be converted into a chiral diol by hydrogenation of the double bond. Chiral reagents suitable for this conversion are described, for example, in Aldrich Acta 1987, 20(1), 9-24. One example which may be mentioned is isopinocampheylborane. Alternatively, an achiral reagent may be used in combination with a chiral catalyst. The conversion of the compound of formula 17 to the compound of formula 1 is described above.

Reaction scheme 7:

likewise, the optical antipodes of formula 2 can be made stereoselectively using the methods described above and illustrated in reaction schemes 5 and 7. For this purpose, the conversion must be carried out using the corresponding enantiomers of the chiral catalyst/chiral agent, respectively.

Derivatization of the compounds obtained according to the above-described reaction schemes 1 to 7 (for example conversion of one group R3 into another group R3 or conversion of one group R2 into another group R2) is likewise carried out, if desired, in a manner known to the person skilled in the art. For example, if a compound wherein R2 and/or R3 is-CO-1-4C-alkoxy or wherein R3 is-CO-NR 31R32 is desired, suitable derivatization (e.g. metal-catalyzed carbonylation of the corresponding halogenated compound or conversion of an ester to an amide) may be carried out in a manner known to those skilled in the art, e.g. at the stage of a compound of formula 4, 5, 6, 8 or 19 or more suitably at a later point in time, e.g. conversion of a compound of formula 1 to another compound of formula 1. Specific examples are given in reaction scheme 1 (conversion of the compound of formula 6 to a racemic mixture of the compound of formula 1 and the compound of formula 2) and reaction scheme 6 (conversion of the ketone of formula 19 to the ketone of formula 4).

The invention also relates to a process for the synthesis of compounds of formula 1, which comprises reacting a compound of formula 8, wherein R1, R3 and Arom have the meanings given initially

To a racemic mixture of the compound of formula 1 and its optical antipode of formula 2, in which R1, R2, R3 and Arom have the meanings given initially,

and

separating the compound of formula 1 from its optical antipode of formula 2, and

-if desired, further derivatizing the compound of formula 1 at the stage of racemic mixture of the compound of formula 1 with its optical antipode of formula 2 or after separation of the compound of formula 1 from its optical antipode of formula 2.

The invention also relates to a process for the synthesis of compounds of formula 1, which comprises converting a compound of formula 13, wherein R1, R2 and R3 have the meanings as given initially, into a compound of formula 14, wherein R1, R2, R3 and Arom have the meanings as given initially

And further converting the compound of formula 14 into a racemic mixture of the compound of formula 1 and its optical antipode represented by formula 2

And

The invention also relates to a method for synthesizing the compound of formula 1, which comprises

-asymmetric reduction of a compound of formula 4 to yield a compound of formula 17

Wherein R1, R2, R3 and Arom have the meanings given initially,

-and converting the compound of formula 17 to a compound of formula 1 or a salt thereof.

-converting the compound of formula 14 to the compound of formula 17

Wherein R1, R2, R3 and Arom have the meanings given initially,

The following examples are intended to illustrate the invention in more detail, but are not intended to limit the invention. Other compounds of formula 1, the preparation of which is not specifically described, may likewise be prepared in an analogous manner or in a manner known per se to those skilled in the art, using conventional processing techniques. The abbreviation ee stands for enantiomeric excess, RT for retention time, S/C for substrate to catalyst ratio, v for volume. For NMR signals, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), me (concentrated multiplet), b (broad). The following units were used: ml (ml), l (l), nm (nm), mm (mm), mg (mg), g (g), mmol (mmol), N (equivalent), M (mol), min (min), MHz (] MHz).

For a given chemical, the following abbreviations are also used:

(S) -BINAP (S) -2, 2 '-bis- (diphenylphosphino) -1, 1' -binaphthyl

(R) -BINAP (R) -2, 2 '-bis- (diphenylphosphino) -1, 1' -binaphthyl

(S) -DAIPEN (2S) - (+) -1, 1-bis (4-methoxyphenyl) -3-methyl-1, 2-butanediamine

(R) -DAIPEN (2R) - (-) -1, 1-bis (4-methoxyphenyl) -3-methyl-1, 2-butanediamine

(S, S) -DPEN (1S, 2S) - (-) -1, 2-diphenylethylenediamine

(S) - (+) -MTPACI (S) - (+) -a-methoxy-a- (trifluoromethyl) phenylacetyl chloride

DIAD diisopropyl azodicarboxylate

DMSO dimethyl sulfoxide

THF tetrahydrofuran

DMF dimethyl formamide

TBTU O-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium tetrafluoroborate

The optical purity of the compounds of formulae 1, 2 and 17 is determined by Capillary Electrophoresis (CE) and/or High Pressure Liquid Chromatography (HPLC). Each example gives experimental conditions for the separation of enantiomers by HPLC in the experimental section. The separation by CE was performed with one of the following experimental setups:

the device comprises the following steps: agilent CE-3D

Capillary tube: the method A comprises the following steps: 64.5cm X50 μm bubble chamber (Agilent)

The method B comprises the following steps: 64.5cm X75 μm bubble chamber (Agilent)

Buffer solution: two methods are as follows: 50mM sodium phosphate, pH 2.5(Agilent)

A chiral selector: two methods are as follows: seven (2, 3, 6-tri-O-methyl) -beta-cyclodextrin (Cyclolab) 40mM

Voltage: two methods are as follows: 30kV

Temperature: two methods are as follows: 10 deg.C

The number of methods used for the corresponding analysis is given in parentheses.

The purity of the prochiral ketone of formula 4 as substrate for the asymmetric catalytic hydrogenation reaction was also determined by HPLC. The following experimental procedures were used:

column: 150X 4.6mm XTerra RP 185 μm; a mobile phase; 0.01M KH₂PO₄(pH2.0)/acetonitrile/water 90: 10: 0(v/v/v) [0 min]To 15: 80: 5(v/v/v) [30 minutes](ii) a Flow rate: 1.0 ml/min; at 30 ℃. For each example, the retention times (measured at 237-245 nm) of the title compounds are given in the experimental section.

All HPLC columns used for preparation and analytical purposes are commercially available:

·CHIRALPAK^®AD，CHIRALPAK^®AD-H，CHIRALPAK^®AS-V，CHIRALPAK^®AS-H，CHIRAL-PAK^®50801，CHIRALCEL^®OJ，CHIRALCEL^®OD-H：DAICEL Chemical Industries Ltd，Tokyo orChiral Technologies-Europe SARL，Ilkirch，France

·Lichrochart^®240ChiraDex^®：Merck KgaA，Darmstadt，Germany

·XTerra RP 18：Waters Corporate，Milord，Massachusetts，USA。

if the melting point is determined after crystallization of the compound, the solvent/solvent mixtures which have been used for purification are given in brackets. If the NMR (nuclear magnetic resonance) chemical shifts given are not integrated, an overlap of the signal of the corresponding proton of the compound with the signal of the solvent, water or impurities is observed.

I. Compounds of formula 1

A compound of formula 1 obtained by separation of a racemic mixture of 7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine

(R, R) -tartrate salt of (9S) -2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

Racemic 2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (synthesis described in WO03/014123, 840mg, 2.40mmol) and L- (+) -tartaric acid (358mg, 2.39mmol) were dissolved in isopropanol (5ml) and water (5ml) by heating. The mixture was allowed to crystallize at room temperature for 2 days. The precipitate formed (700mg) was isolated and the enantiomeric excess was determined by chiral HPLC analysis (see below, 21% ee). The solid was recrystallized from a mixture of isopropanol and water [ 1: 1(v/v), 14mL ] to obtain three batches of crystals: first batch: 30mg, 73% ee; and (2) second batch: 120mg, 67% ee; first batch: yield and ee were not determined. The first two batches were combined and recrystallized from isopropanol/water [ 1: 1(v/v), 3mL ]. Isolated salt (60mg) was determined to have an ee of 88%. This sample was recrystallized again from isopropanol/water [ 1: 1(v/v), 2mL ] to give a pure sample of the title compound (4mg, 0.3% yield, 95% ee). The third crystalline material was added to the mother liquor and a further 23mg of the title compound (91% ee) was isolated by crystallization. Recrystallization of this sample from isopropanol/water [ 1: 1(v/v), 0.4mL ] gave the title compound with 96% ee (10mg, 0.8% yield).

The enantiomeric excess was determined by HPLC analysis using the following conditions: column: chiralcel oj; eluent: heptane/ethanol/diethylamine 90: 10: 0.2 (v/v/v); flow rate: 1.0 ml/min; temperature: at 40 ℃. (9R) -enantiomer showed a retention time of 15.5 min; the (9R) -enantiomer (the title compound) was eluted after 18.4 min.

¹H-NMR(dmso-d₆，400MHz)：d＝2.12(m_c，1H)，2.25(s，bs，4H)，2.34(s，3H)，2.49(bs)，2.75(m_c，1H)，2.86，3.00(2s，6H)，4.24(s，2H)，5.26(d，1H)，7.40(m_c，5H)，7.80(s，1H).

(9S) -2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

Racemic 2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ]]Imidazo [1, 2-a ]]Resolution of pyridine-6-carboxylic acid dimethylamide (synthesis described in WO03/014123, 3.00g, 8.6mmol) by using a 250X 110mm CHIRALPAK^®Preparative chromatography on an AD 20 μm column. The mobile phase consists of a mixture of ethanol, methanol and diethylamine [ 50: 0.1(v/v/v)]And (4) forming. The separation was carried out at room temperature at a flow rate of 500 ml/min. The product was detected at a wavelength of 300 nm. The second eluted product was identified as the title compound ((9S) -enantiomer) (1.38g, 46% yield, 98.7% ee).

Melting point: 254 deg.C

The settings for the analytical method for HPLC determination of optical purity were as follows: column: 250X 4.6mm CHIRALPAK^®AD and 250X 4.6mm CHIRALPAK^®A combination of AD-H; mobile phase: ethanol, methanol, diethylamine [ 50: 0.1(v/v/v)](ii) a Flow rate: 1 ml/min; and (4) room temperature. The title compound (detected at 240 nm) eluted after 9.0 minutes.

Optical rotation: [ a ] A]^D ₂₀-53 ° (c ═ 0.63, dichloromethane).

¹H-NMR(200MHz，dmso-d₆)：δ＝2.14(m_c，2H)，2.26，2.35(2s，6H)，2.42(m_c)，2.75(m_c，1H)，2.87，3.01(2s，6H)，5.27(dd，1H)，7.43(m_c，5H)，7.79(s，1H).

(9S) -3-hydroxymethyl-2-methyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

Racemic 3-hydroxymethyl-2-methyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ]]Imidazo [1, 2-a ]]Resolution of pyridine-6-carboxylic acid dimethylamide (example xii, 194mg, 0.53mmol) by Using 250X 20mm CHIRALPAK^®Preparative chromatography on an AD 10 μm column. The mobile phase consists of a mixture of n-heptane and ethanol [ 9: 1(v/v)]And (4) forming. The separation was carried out at room temperature at a flow rate of 20 ml/min. The product was detected at a wavelength of 330 nm. The second eluted enantiomer was identified as the title compound ((9S) -enantiomer) (90mg, 46% yield, 98.5-98.9% ee).

Melting point: 178 ℃ C. 181 ℃ C

Settings of the analytical method for HPLC determination of optical purity: column: 250X 4.6mm CHIRALPAK^®AD 10 μm; mobile phase: n-heptane/ethanol [ 9: 1(v/v)](ii) a Flow rate: 2 ml/min; at 30 ℃. The title compound (detected at 220 nm) eluted after 13.70 min (98.9% ee).

Determination of optical purity by CE: RT ═ 17.6 min/98.5% ee (a).

Optical rotation: [ a ] A]^D ₂₀-65 ° (c 56, chloroform).

¹H-NMR(dmso-d₆，200MHz)：d＝2.13m_c，1H)，2.25，2.30(m_c，s，4H)，2.44(m_c)，2.80，2.88(m_c，s，4H)，3.01(s，3H)，4.72(bs，2H)，5.06(bs，1H)，5.29dd，1H)，7.42m_c，5H)，7.89(s，1H).

(9S) -3-bromo-2-methyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

Racemic 3-bromo-2-methyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ]]Imidazo [1, 2-a ]]Resolution of-pyridine-6-carboxylic acid dimethylamide (example xiii, 186mg, 0.45mmol) by using 250X 20mm CHIRALPAK^®Preparative chromatography on an AD 10 μm column. The mobile phase consists of a mixture of ethanol and methanol [ 1: 1(v/v)]And (4) forming. The separation was carried out at room temperature at a flow rate of 20 ml/min. The product was detected at a wavelength of 330 nm. The second eluted enantiomer was identified as the title compound ((9S) -enantiomer) (90mg, 48% yield, 99.1-99.6% ee).

Melting point: 161 ℃ C. -

The settings for the analytical method for HPLC determination of optical purity were as follows: column: 250X 4.6mm CHIRALPAK^®AD 10 μm; mobile phase: ethanol/methanol [ 1: 1(v/v)](ii) a Flow rate: 1 ml/min; at 30 ℃. The title compound (detected at 220 nm) eluted after 6.24 min (99.1% ee).

Determination of optical purity by CE: RT ═ 17.7 min/99.6% ee (a).

Optical rotation: [ a ] A]^D ₂₀-54 ° (c ═ 0.51, chloroform).

¹H-NMR(dmso-d₆，200MHz)：d＝2.16(m_c，1H)，2.25，2.31(m_c，s，4H)，2.50(m_c)，2.80，2.87(m_c，s，4H)，3.02(s，3H)，5.31(dd，1H)，7.43(m_c，5H)，7.82(m_c，1H).

Elemental analysis: c₂₀H₂₀BrN₃O₂Measured value of (414.31): c57.98, H4.87, N10.14, Br 19.29; measured value: c57.21, H4.92, N9.90, Br 18.49.

(9S) -3-ethyl-2-methyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

Racemic 3-ethyl-2-methyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c]Imidazo [1, 2-a ]]Resolution of pyridine-6-carboxylic acid dimethylamide (example xv, 188mg, 0.52mmol) by using a 250X 50mm CHIRALPAK^®5080120 μm column. The mobile phase consisted of ethanol. The separation was carried out at room temperature at a flow rate of 120 ml/min. The product was detected at a wavelength of 250 nm. The first eluted enantiomer was identified as the title compound ((9S) -enantiomer) (90mg, 48% yield, 98.6-99.3% ee).

Melting point: 211 ℃ C. (213 ℃ C.)

The settings for the analytical method for HPLC determination of optical purity were as follows: column: 250X 4.6mm CHIRALPAK^®5080120 μm; mobile phase: ethanol; flow rate: 1 ml/min; at 30 ℃. The title compound (detected at 220 nm) eluted after 9.06 minutes (99.3% ee).

Determination of optical purity by CE: RT ═ 18.0 min/98.6% ee (a).

Optical rotation: [ a ] A]^D ₂₀-82 ° (c ═ 0.54, chloroform).

¹H-NMR(dmso-d₆，200MHz)：d＝1.10(t，3H)，2.14，2.26(m_c，s，5H)，2.40(m_c)，2.77，2.87，2.88(m_c，q，s，6H)，3.01(s，3H)，526(dd，1H)，7.42(m_c，5H)，7.88(s，1H).

Elemental analysis: c₂₂H₂₅N₃O₂·H₂Calculated O (363.46+ 18): c69.27, H7.13, N11.01; measured value: c69.95, H6.76, N10.69.

(9S) - (2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridin-6-yl) -pyrrolidin-1-yl-methanone

Racemic (2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c)]Imidazo [1, 2-a ]]Resolution of pyridin-6-yl) -pyrrolidin-1-yl-methanone (example xxv, 198mg, 0.53mmol) by Using 250X 50mm CHIRALPAK^®5080120 μm columnBy preparative chromatography. The mobile phase consisted of ethanol. The separation was carried out at room temperature at a flow rate of 120 ml/min. The product was detected at a wavelength of 250 nm. The first eluted enantiomer was identified as the title compound ((9S) -enantiomer) (90mg, 45% yield, 98.1-98.8% ee).

Melting point: 269, 271 deg.C

The settings for the analytical method for HPLC determination of optical purity were as follows: column: 250X 4.6mm CHIRALPAK^®5080120 μm; mobile phase: ethanol; flow rate: 1 ml/min; at 30 ℃. The title compound (detected at 220 nm) was eluted after 11.93 minutes (98.1% ee).

Determination of optical purity by CE: RT ═ 18.8 min/98.8% ee (a).

Optical rotation: [ a ] A]^D ₂₀-60 ° (c ═ 0.55, chloroform).

¹H-NMR(dmso-d₆，200MHz)：δ＝1.85(m_c，4H)，2.14，2.25，2.35(m_c，2s，8H)，2.56(m_c)，2.81(m_c，1H)，3.24(m_c)，3.48(t，2H)，5.26(dd，1H)，7.42(m_c，5H)，7.84(s，1H).

Elemental analysis: c₂₃H₂₅N₃O₂·H₂Calculated O (375.47+ 18): c70.21, H6.92, N10.68; measured value: c71.10, H6.55, N10.51.

(9S) -2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid methylamide

Racemic 2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ]]Imidazo [1, 2-a ]]Resolution of pyridine-6-carboxylic acid methylamide (example xxvi, 196mg, 0.58mmol) by Using a 250X 110mm CHIRALPAK^®Preparative chromatography on an ASV 20 μm column. The mobile phase consists of a mixture of acetonitrile and dimethylamine [ 100: 0.1(v/v)]And (4) forming. The separation was carried out at room temperature at a flow rate of 520 ml/min. At 300The product was detected at a wavelength of nm. The first eluted enantiomer was identified as the title compound ((9S) -enantiomer) (85mg, 43% yield, 98.7-100% ee).

Melting point: 253 deg.C

The settings for the analytical method for HPLC determination of optical purity were as follows: column: 250X 4.6mm CHIRALPAK^®ASH; mobile phase: acetonitrile/dimethylamine [ 100: 0.1(v/v)](ii) a Flow rate: 0.7 ml/min; at 25 ℃. The title compound (detected at 220 nm) eluted after 5.34 minutes (98.7% ee).

Determination of optical purity by CE: RT ═ 18.5 min/100.0% ee (a).

Optical rotation: [ a ] A]^D ₂₀-56 ° (c ═ 0.53, chloroform).

¹H-NMR(dmso-d₆，200MHz)：δ＝2.00(m_c，s)，2.26(m_c，s，4H)，2.37(s，3H)，2.78(m_c，d，4H)，3.00(m_c，1H)，5.24(dd，1H)，7.41(m_c，5H)，7.92(s，1H)，8.32(q，1H).

(9S) -2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid amide

Racemic 2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ]]Imidazo [1, 2-a ]]Resolution of pyridine-6-carboxylic acid amide (example xxvii, 189mg, 0.59mmol) by Using 250X 110mm CHIRALPAK^®Preparative chromatography on an AD 20 μm column. The mobile phase consists of a mixture of n-heptane and ethanol [ 1: 1(v/v)]And (4) forming. The separation was carried out at room temperature at a flow rate of 520 ml/min. The product was detected at a wavelength of 300 nm. The second eluted enantiomer was identified as the title compound ((9S) -enantiomer) (85mg, 45% yield, 98.2-98.6% ee).

Melting point: 349 and 350 DEG C

The settings for the analytical method for HPLC determination of optical purity were as follows: column: 250X 4.6mm CHIRALPAK^®AD 10 μm; mobile phase: n-heptane/ethanol [ 7: 3(v/v)](ii) a Flow rate: 1.0 ml/min; at 25 ℃. The title compound (detected at 220 nm) eluted after 6.38 minutes (98.2% ee).

Determination of optical purity by CE: RT ═ 18.8 min/98.6% ee (a).

¹H-NMR(dmso-d₆，200MHz)：δ＝2.09(m_c，1H)，2.26(m_c，s，4H)，2.38(s，3H)，2.97(m_c，2H)，5.24(dd，1H)，7.41(bs，m_c，6H)，7.85(bs，1H)，7.98(s，1H).

(9S) -2, 3-dimethyl-9- (2-methylphenyl) -7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

Resolution of racemic 2, 3-dimethyl-9- (2-methylphenyl) -7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (example xxix, 208mg, 0.57mmol) was accomplished by preparative chromatography using a 250X 20mm CHIRALPAK ® AD-H5 μm column. The mobile phase consisted of a mixture of n-heptane and ethanol [ 85: 15(v/v) ]. The separation was carried out at room temperature at a flow rate of 20 ml/min. The product was detected at a wavelength of 300 nm. The second eluted enantiomer was identified as the title compound ((9S) -enantiomer) (100mg foamy solid, 48% yield, > 99.5% ee).

The settings for the analytical method for HPLC determination of optical purity were as follows: column: 250X 4.6mm CHIRALPAK^®AD 10 μm; mobile phase: n-heptane/ethanol [ 85: 15(v/v)](ii) a Flow rate: 1.0 ml/min; at 25 ℃. The title compound (detected at 220 nm) eluted after 15.96 min (> 99.5% ee).

Optical rotation: [ a ] A]^D ₂₀-49 ° (c ═ 0.45, chloroform).

¹H-NMR(dmso-d_s，200MHz)：δ＝2.05(m_c，1H )，2.25(m_c，s，4H)，2.35，2.39(2s，6H)，2.56(m_c)，2.86，2.91(m_c，s，4H)，3.02(s，3H)，5.37(dd，1H)，7.28(m_c，3H)，7.47(m_c，1H)，7.79(s，1H).

(9S) -9- (2-fluorophenyl) -2, 3-dimethyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

Racemic 9- (2-fluorophenyl) -2, 3-dimethyl-7H-8, 9-dihydro-pyrano [2, 3-c]Imidazo [1, 2-a ]]Resolution of pyridine-6-carboxylic acid dimethylamide (example xxxi, 247mg, 0.67mmol) by using 250X 20mm CHIRALPAK^®The preparation chromatography of AD-H5 μm column. The mobile phase consists of a mixture of n-heptane and ethanol [ 85: 15(v/v)]And (4) forming. The separation was carried out at room temperature at a flow rate of 20 ml/min. The product was detected at a wavelength of 300 nm. The second eluted enantiomer was identified as the title compound ((9S) -enantiomer) (116mg, 47% yield, > 99.5% ee).

Melting point: 210 deg.C

The settings for the analytical method for HPLC determination of optical purity were as follows: column: 250X 4.6mm CHIRALPAK^®AD 10 μm; mobile phase: n-heptane/ethanol [ 85: 15(v/v)]；

Flow rate: 1.5 ml/min; at 25 ℃. The title compound (detected at 220 nm) eluted after 11.22 min (> 99.5% ee).

Determination of optical purity by CE: RT ═ 14.5 min/99.8% ee (b).

Optical rotation: [ a ] A]^D ₂₀-84 ° (c ═ 0.47, chloroform).

¹H-NMR(dmso-d₆，200MHz)：δ＝2.24，225(m_c，s，5H)，2.35(s，3H)，2.54(m_c)，2.84，2.90(m_c，s，4H)，3.02(s，3H)，5.48(dd，1H)，7.29(m_c，2H)，7.44(m_c，1H)，7.58(m_c，1H)，7.81(s，1H).

(9S) -9- (4-fluorophenyl) -2, 3-dimethyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

Racemic 9- (4-fluorophenyl) -2, 3-dimethyl-7H-8, 9-dihydro-pyrano [2, 3-c]Imidazo [1, 2-a ]]Resolution of pyridine-6-carboxylic acid dimethylamide (example xxxiii, 210mg, 0.57mmol) by using 250X 20mm CHIRALPAK^®The preparation chromatography of AD-H5 μm column. The mobile phase consists of a mixture of n-heptane and ethanol [ 85: 15(v/v)]And (4) forming. The separation was carried out at room temperature at a flow rate of 20 ml/min. The product was detected at a wavelength of 300 nm. The second eluted enantiomer was identified as the title compound ((9S) -enantiomer) (105mg, 50% yield, > 99.5% ee).

Melting point: 255 deg.C

Flow rate: 1.5 ml/min; 35 ℃ is carried out. The title compound (detected at 220 nm) eluted after 18.79 min (> 99.5% ee).

Determination of optical purity by CE: RT ═ 14.8 min/99.8% ee (b).

Optical rotation: [ a ] A]^D ₂₀-72 ° (c ═ 0.47, chloroform).

¹H-NMR(dmso-d₆，200MHz)：δ＝2.16，2.25(m_c，s，5H)，2.35(s，3H)，2.48(m_c)，2.79，2.88(m_c，s，4H)，3.01(s，3H)，5.27(dd，1H)，7.26(m_c，2H)，7.54(m_c，2H)，7.79(s，1H).

(9S) -2, 3-dimethyl-9-thiophen-2-yl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

The title compound can be obtained by resolution of racemic 2, 3-dimethyl-9-thiophen-2-yl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (example xxxv) in analogy to the above examples.

Melting point: 237-

Determination of optical purity by CE: RT [ (9R) -enantiomer ] ═ 15.7 min/8.0 area-%;

RT [ (9S) -enantiomer ] ═ 16.1 min/92.0 area-%; 84.0% ee (A).

Optical rotation: [ a ] A]^D ₂₀-18 ° (c ═ 0.61, chloroform).

¹H-NMR(dmso-d₆，200MHz)：d＝2.25，2.26，2.34(s，m_c，s，8H)，2.53(m_c)，2.73，2.87(m_c，s，4H)，3.01(s，3H)，5.56(dd，1H)，7.08(dd，1H)，7.23(bd，1H)，7.57(dd，1H)，7.79(s，1H).

(9S) -6-methoxymethyl-2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine

The title compound can be obtained by resolution of racemic 6-methoxymethyl-2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine in analogy to the above examples. The corresponding racemate can be prepared: 3- (8-hydroxy-6-methoxymethyl-2, 3-dimethyl-imidazo [1, 2-a ] pyridin-7-yl) -1-phenyl-propan-1-one (example li) was reduced with sodium borohydride, followed by cyclization of 7- (3-hydroxy-3-phenyl-propyl) -6-methoxymethyl-2, 3-dimethyl-imidazo [1, 2-a ] pyridin-8-ol using one of the following procedures.

Melting point: 146 deg.C (diethyl ether)

The settings for the analytical method for HPLC determination of optical purity were as follows: column: 250X 4.6mm CHIRALPAK^®AD-H5 μm; mobile phase: isopropanol/n-hexane 1: 9(v/v), containing 0.1% diethylamine; flow rate: 1 ml/min; detection was carried out at 237nm at 35 ℃. (9R) -enantiomer (0.7 area-%) after 12.9 minThe title compound eluted after 19.3 minutes (99.3 area-%). Optical purity: 98.6% ee.

Optical rotation: [ a ] A]^D ₂₀-98 ° (c ═ 0.61, chloroform).

¹H-NMR(dmso-d₆，200MHz)：d＝2.15，2.25，2.35(m_c，2s，8H)，2.83(m_c，2H)，3.30(s)，4.42(s，2H)，5.20(dd，1H)，7.43(m_c，5H)，7.76(s，1H).

Obtaining the compound of formula 1 by asymmetric synthesis

In a flame-dried flask filled with argon, (3R) -8-hydroxy-7- (3-hydroxy-3-phenyl-propyl) -2, 3-dimethyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (example liii, 9.10g, 24.8mmol, 85.9% ee) was suspended in anhydrous THF (330 ml). After addition of triphenylphosphine (19.50g, 74.3mmol) and dropwise addition of DIAD (15.20g, 75.1mmol), a dark green solution was obtained which was stirred at room temperature for 80 min. The reaction mixture was concentrated under reduced pressure, and the residue (50g of green oil) was purified by flash chromatography [250g silica gel, eluent: ethyl acetate, then ethyl acetate/methanol-20: 1(v/v) ]. A colourless solid (6.5g) was obtained, which was suspended in diethyl ether (30 ml). The precipitate was separated by filtration, washed with diethyl ether (20ml), and dried in vacuo to give 5.0g of the title compound (58% yield, optical purity: 85.2-85.4% ee).

Melting point: 258 ℃ C (diethyl ether)

The settings for the analytical method for HPLC determination of optical purity were as follows: column: 250X 4.6mm CHIRALPAK^®AD-H5 μm; mobile phase: ethanol/methanol 1: 1(v/v), containing 0.1% diethylamine; flow rate: 1 ml/min; detection was at 243nm at 35 ℃. (9R) -enantiomer (7.3 area-%) eluted after 4.0 min, the title compound was obtained inEluted after 4.4 min (92.7 area-%). Optical purity: 85.4% ee.

Determination of optical purity by CE: RT [ (9S) -enantiomer ] ═ 19.5 min/92.6 area-%;

RT [ (9R) -enantiomer ] ═ 20.3 min/7.4 area-%; 85.2% ee (A).

The optical purity of the title compound can be improved by crystallization in the presence of L- (+) tartaric acid: (9S) -2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (0.88g, 2.5mmol, 85% ee) and L- (+) -tartaric acid (0.37g, 2.5mmol) were dissolved in a hot mixture of isopropanol (5ml) and water (5 ml). Solid crystals (950mg) formed, which were removed by filtration and recrystallized from a mixture of isopropanol (8ml) and water (8ml) by HPLC analysis (91.5% ee). About 500mg of the salt of the title compound with L- (+) -tartaric acid with an optical purity of 96% ee were obtained, which was again dissolved in a mixture of isopropanol (4ml) and water (4 ml). A salt of the title compound with L- (+) -tartaric acid was formed and isolated by filtration (about 150mg, 12% yield). Optical purity (> 99% ee) was determined by HPLC.

In another experiment, the title compound (0.50g, 1.4mmol, 85% ee) was crystallized from a mixture of ethanol (4ml) and water (15ml) in the presence of L- (+) -tartaric acid (0.21g, 1.5 mmol). About 200mg of the salt of the title compound with L- (+) -tartaric acid were obtained (29% yield) with an optical purity of 96% ee.

The enantiomeric excess was determined by HPLC analysis using the following conditions: column: chiralcel OJ; eluent: heptane/ethanol/diethylamine 90: 10: 0.2 (v/v/v); flow rate: 1.0 ml/min; temperature: at 40 ℃. The (9R) -enantiomer showed a retention time of 15.5 min, and the (9S) -enantiomer (title compound) eluted after 18.4 min.

¹H-NMR(dmso-d₈，400MHz)：d＝2.12(m_c，1H)，2.25(s，bs，4H)，2.34(s，3H)，2.49(bs)，2.75(m_c，1H)，2.86，3.00(2s，6H)，4.24(s，2H)，5.26(d，1H)，7.40(m_c，5H)，7.80(s，1H).

In a flame-dried flask filled with argon, (3R) - [ 8-hydroxy-7- (3-hydroxy-3-phenyl-propyl) -2, 3-dimethyl-imidazo [1, 2-a ] pyridin-6-yl ] -pyrrolidin-1-yl-methanone (example liv, 750mg, 1.90mmol, 87.4% ee) was dissolved in anhydrous THF (20 ml). Triphenylphosphine (1.50g, 5.7mmol) was added and the suspension was stirred at room temperature for 10 min. After dropwise addition of DIAD (1.20g, 5.9mmol) a yellow solution was obtained which was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue (5g) was purified by flash chromatography [80g silica gel, eluent: ethyl acetate). A colourless solid (410mg) was obtained, which was suspended in diethyl ether (5 ml). The precipitate was separated by filtration, washed with diethyl ether (3ml), and dried in vacuo to give 360mg of the title compound (50% yield, optical purity: 87.1-87.5% ee).

Melting point: 268 ℃ C (diethyl ether)

The settings for the analytical method for HPLC determination of optical purity were as follows: column: 250X 4.6mm CHIRALPAK^®OD-H5 μm; mobile phase: n-hexane/isopropanol 9: 1(v/v), flow rate: 1 ml/min; detection was at 35 ℃ at 220 and 240 nm. The (9R) -enantiomer (6.3/6.3 area-%) eluted after 35.5 minutes, and the title compound eluted after 43.1 minutes (93.6/93.7 area-%). Optical purity: 87.4-87.5% ee.

Determination of optical purity by CE: RT [ (9S) -enantiomer ] ═ 19.7 min/93.6 area-%;

RT [ (9R) -enantiomer ] ═ 20.4 min/6.4 area-%; 87.2% ee (A).

¹H-NMR(dmso-d₆，200MHz)：d＝1.85(m_c，4H)，2.13(m_c，1H)，2.25(s，m_c，4H)，2.35(s，3H)，2.50(m_c)，2.81(m_c，1H)，3.26(m_c，2H)，3.48(t，2H)，5.25(dd，1H)，7.42(m_c，5H)，7.84(s，1H).

In a flame-dried flask filled with argon, (3R) -8-hydroxy-7- (3-hydroxy-3-phenyl-propyl) -2, 3-dimethyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid methylamide (example Iv, 900mg, 2.55mmol, 92.0% ee) was suspended in anhydrous THF (55 ml).

After addition of triphenylphosphine (2.00g, 7.6mmol) and dropwise addition of DIAD (1.55g, 7.6mmol), a brown solution was obtained which was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue (6g) was purified by flash chromatography [150g silica gel, eluent: dichloromethane/methanol 100: 1(v/v) ]. A colorless solid was obtained, which was suspended in diethyl ether. The precipitate was isolated by filtration and dried in vacuum to obtain 120mg of the title compound (14% yield, optical purity: 94.2% ee).

Melting point: 261 ℃ 263 (diethyl ether)

The settings for the analytical method for HPLC determination of optical purity were as follows: column: 250X 4.6mm CHIRALPAK^®AD-H5 μm; mobile phase: ethanol/methanol-1: 1(v/v), with 0.1% diethylamine; flow rate: 0.8 ml/min; detection was at 35 ℃ at 245 nm. The (9R) -enantiomer (2.9 area-%) eluted after 4.1 min, and the title compound eluted after 4.4 min (97.1 area-%). Optical purity: 94.2% ee.

Determination of optical purity by CE: RT [ (9S) -enantiomer ] ═ 18.6 min/97.1 area-%; RT [ (9R) -enantiomer ] ═ 19.9 min/2.9 area-%; 94.2% ee (A).

¹H-NMR(dmso-d₆，200MHz)：d＝2.07(m_c，1H)，2.26(s，m_c，4H)，2.37(s，3H)，2.74，2.77(m_c，d，4H)，3.00(m_c，1H)，5.24(dd，1H)，7.42(m_c，5H)，7.91(s，1H)，8.32(bq，1H).

I. A compound of formula 2

A compound of formula 2 obtained by separation of a racemic mixture of 7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine

(9R) -2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (S, S) -tartrate

Racemic 2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (synthesis described in WO03/014123, 840mg, 2.40mmol) and L- (+) -tartaric acid (358mg, 2.39mmol) were dissolved in isopropanol (5ml) and water (5ml) by heating. The mixture was allowed to crystallize at room temperature for 2 days. After removal of the precipitate, the mother liquor was concentrated, treated with 1N NaOH (40ml) and extracted with an ethyl acetate/methanol mixture [ 95: 5(v/v), 3X 150ml ]. The combined organic phases were washed with brine (75ml), dried over sodium sulphate and concentrated under reduced pressure. A sample of 2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (250mg, 31% ee) containing an excess of the (9R) -enantiomer was thus isolated and dissolved in isopropanol (4ml) and water (4 ml). D- (-) -tartaric acid (107mg, 0.71mmol) was added and the mixture was allowed to crystallize. The precipitate was isolated (75mg, 79% ee) and recrystallized from isopropanol/water [ 1: 1(v/v), 2ml ]. 14mg (1.1%) of the title compound are obtained (> 90% enantiomeric excess).

The enantiomeric excess was determined by HPLC analysis using the following conditions: column: chiralcel oj; eluent: heptane/ethanol/diethylamine 90: 10: 0.2 (v/v/v); flow rate: 1.0 ml/min; temperature: at 40 ℃. The (9R) -enantiomer (the title compound) showed a retention time of 15.5 minutes; the (9R) -enantiomer (example 1) was eluted after 19.1 minutes.

¹H-NMR(dmso-d₆，400MHz)：d ＝2.12(m_c，1H)，2.25(s，bs，4H)，2.34(s，3H)，2.49(bs)，2.75(m_c，1H)，2.86，3.00(2s，6H)，4.23(s，2H)，5.26(d，1H)，7.41(m_c，5H)，7.80(s，1H).

(9R) -2, 3-dimethyl-9-phenyl-7H-8 s 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

Resolution of racemic 2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (synthesis described in WO03/014123, 3.00g, 8.6mmol) was carried out as described in example 2. The first eluted enantiomer was identified as the title compound ((9R) -enantiomer) (1.40g, 47% yield, 98.2% ee).

Melting point: 254 deg.C

The analytical method for determining the optical purity by HPLC is described in example 2. The title compound (detected at 240 nm) eluted after 8.0 minutes (98.2% ee).

Optical rotation: [ a ] A]^D ₂₀53 ° (c 0.61, dichloromethane).

(9R) -3-hydroxymethyl-2-methyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, Scl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

Resolution of racemic 3-hydroxymethyl-2-methyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (example xii, 194mg, 0.53mmol) was performed as described in example 3. The first eluted enantiomer was identified as the title compound ((9R) -enantiomer) (90mg, 46% yield, 99.6-100% ee).

Melting point: 178 ℃ C. 181 ℃ C

The analytical method for determining the optical purity by HPLC is described in example 3. The title compound (detected at 220 nm) eluted after 9.50 minutes (99.6% ee).

Determination of optical purity by CE: RT ═ 18.0 min/100% ee (a).

Optical rotation: [ a ] A]^D ₂₀62 ° (c 0.53, chloroform).

¹H-NMR(dmso-d₆，200MHz)：d＝2.13(m_c，1H)，2.25，2.30(m_c，s，4H)，2.44(m_c)，2.80，2.88(m_c，s，4H)，3.01(s，3H)，4.72(bs，2H)，5.06(bs，1H)，5.29(dd，1H)，7.42m_c，5H)，7.89(s，1H).

(9R) -3-bromo-2-methyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

Resolution of racemic 3-bromo-2-methyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (example xiii, 186mg, 0.45mmol) was performed as described in example 4. The first eluted enantiomer was identified as the title compound ((9R) -enantiomer) (90mg, 48% yield, 99.7-99.8% ee).

Melting point: 162 ℃ C. & lt 164 ℃ C. & gt

The analytical method for determining the optical purity by HPLC is described in example 4. The title compound (detected at 220 nm) eluted after 4.76 min (99.8% ee).

Determination of optical purity by CE: RT ═ 18.0 min/99.7% ee (a).

Optical rotation: [ a ] A]^D ₂₀64 ° (c 0.45, chloroform, sample was filtered through a pad of silica gel before optical rotation was measured).

Elemental analysis: c₂₀H₂₀BrN₃O₂Calculated value of (414.31): c57.98, H4.87, N10.14, Br 19.29; measured value: c57.09, H4.91, N9.85, Br 18.78.

(9R) -3-Ethyl-2-methyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

Resolution of racemic 3-ethyl-2-methyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (example xv, 188mg, 0.52mmol) was carried out as described in example 5. The second eluted enantiomer was identified as the title compound ((9R) -enantiomer) (90mg, 48% yield, 99.4-100% ee).

Melting point: 212 deg.C and 214 deg.C

The analytical method for determining the optical purity by HPLC is described in example 5. The title compound (detected at 220 nm) eluted after 13.99 min (99.4% ee).

Determination of optical purity by CE: RT ═ 18.7 min/100.0% ee (a).

Optical rotation: [ a ] A]^D ₂₀58 ° (c 0.52, chloroform).

¹H-NMR(dmso-d₆，200MHz)：d＝1.10(t，3H)，2.14，2.26(m_c，s，5H)，2.40(m_c)，2.77，2.87，2.88(m_c，q，s，6H)，3.01(s，3H)，5.26(dd，1H)，7.42(m_c，5H)，7.88(s，1H).

Elemental analysis: c₂₂H₂₅N₃O₂·H₂Meter for O (363.46+18)Calculating the value: c69.27, H7.13, N11.01; measured value: c69.52, H6.74, N10.45.

(9R) - (2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridin-6-yl) -pyrrolidin-1-yl-methanone

Resolution of racemic (2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridin-6-yl) -pyrrolidin-1-yl-methanone (example xxv, 198mg, 0.53mmol) was carried out as described in example 6. The second eluted enantiomer was identified as the title compound ((9 e-enantiomer) (90mg, 45% yield, 98.6-98.9% ee).

Melting point: 246 deg.C

The analytical method for determining the optical purity by HPLC is described in example 6. The title compound (detected at 220 nm) eluted after 18.26 minutes (98.9% ee).

Determination of optical purity by CE: RT ═ 18.8 min/98.6% ee (a).

Optical rotation: [ a ] A]^D ₂₀45 ° (c 0.55, chloroform).

Elemental analysis: c₂₃H₂₅N₃O₂·H₂Calculated O (375.47+ 18): c70.21, H6.92, N10.68; measured value: c70.77, H6.58, N10.31.

(9R) -2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid methylamide

Resolution of racemic 2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid methylamide (example xxvi, 196mg, 0.58mmol) was carried out as described in example 7. The second eluted enantiomer was identified as the title compound ((91) -enantiomer) (85mg, 43% yield, 96.5-97.0% ee).

Melting point: 250 ℃ and 253 DEG C

The analytical method for determining the optical purity by HPLC is described in example 7. The title compound (detected at 220 nm) eluted after 6.11 minutes (96.5% ee).

Determination of optical purity by CE: RT ═ 19.4 min/97.0% ee (a).

Optical rotation: [ a ] A]^D ₂₀56(c 0.53, chloroform).

¹H-NMR(dmso-d₆，200MHz)：δ＝2.09(m_c，s)，2.26(m_c，s，4H)，2.37(s，3H)，2.78(m_c，d，4H)，3.00(m_c，1H)，5.24(dd，1H)，7.41(m_c，5H)，7.92(s，1H)，8.32(q，1H).

(9R) -2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid amide

Resolution of racemic 2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid amide (example xxvii, 189mg, 0.59mmol) was performed as described in example 8. The first eluted enantiomer was identified as the title compound ((9R) -enantiomer) (85mg, 45% yield, 98.5-100.0% ee).

Melting point: 349 and 350 DEG C

The analytical method for determining the optical purity by HPLC is described in example 8. The title compound (detected at 220 nm) eluted after 4.90 minutes (98.5% ee). Determination of optical purity by CE: RT ═ 18.8 min/100.0% ee (a).

(9R) -2, 3-dimethyl-9- (2-methylphenyl) -7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

Resolution of racemic 2, 3-dimethyl-9- (2-methylphenyl) -7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (example xxix, 208mg, 0.57mmol) was performed as described in example 9. The first eluted enantiomer was identified as the title compound ((gR) -enantiomer) (100mg foamy solid, 48% yield, > 99.5% ee).

The set-up of the analytical method for determining the optical purity by HPLC is described in example 9. The title compound (detected at 220 nm) eluted after 10.84 min (> 99.5% ee).

Optical rotation: [ a ] A]^D ₂₀39 ° (c 0.42, chloroform).

¹H-NMR(dmso-d₆，200MHz)：δ＝2.05(m_c，1H)，2.25(m_c，s，4H)，2.35，2.39(2s，6H)，2.56(m_c)，2.86，2.91(m_c，s，4H)，3.02(s，3H)，5.37(dd，1H)，7.28(m_c，3H)，7.47(m_c，1H)，7.79(s，1H).

(9R) -9- (2-fluorophenyl) -2, 3-dimethyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

Resolution of racemic 9- (2-fluorophenyl) -2, 3-dimethyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (example xxxi, 247mg, 0.67mmol) was carried out as described in example 10. The first eluted enantiomer was identified as the title compound ((9R) -enantiomer) (117mg, 47% yield, > 99.5% ee).

Melting point: 210 deg.C

The set-up of the analytical method for determining the optical purity by HPLC is described in example 10. The title compound (detected at 220 nm) eluted after 8.41 minutes (> 99.5% ee).

Determination of optical purity by CE: RT ═ 15.1 min/99.8% ee (b).

Optical rotation: [ a ] A]^D ₂₀75 ° (c 0.47, chloroform).

¹H-NMR(dmso-d₆，200MHz)：δ＝2，24，2.25(m_c，s，5H)，2.35(s，8H)，2.54(m_c)，2.84，2.90(m_c，s，4H)，3.02(s，3H)，5.48(dd，1H)，7.29(m_c，2H)，7.44(m_c，1H)，7.58(m_c，1H)，7.81(s，1H).

(9R) -9- (4-fluorophenyl) -2, 3-dimethyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

Resolution of racemic 9- (4-fluorophenyl) -2.3-dimethyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (example xxxiii, 210mg, 0.57mmol) was carried out as described in example 11. The first eluted enantiomer was identified as the title compound ((9R) -enantiomer) (105mg, 50% yield, > 99.5% ee).

Melting point: 255 deg.C

The set-up of the analytical method for determining the optical purity by HPLC is described in example 11. The title compound (detected at 220 nm) eluted after 10.59 minutes (> 99.5% ee).

Determination of optical purity by CE: RT ═ 15.1 min/98.2% ee (b).

Optical rotation: [ a ] A]^D ₂₀60(c 0.39, chloroform).

Obtaining the compound of formula 2 by asymmetric synthesis

L. (9R) -2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

In a flame-dried flask filled with argon, (3S) -8-hydroxy-7- (3-hydroxy-3-phenyl-propyl) -2, 3-dimethyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (example lii, 4.00g, 10.9mmol, 95.4% ee) was dissolved in anhydrous dichloromethane (80ml) and triphenylphosphine (4.30g, 16.4mmol) was added. DIAD (3.40g, 16.8mmol) was added over 3 minutes, at which time a yellow-green solution was obtained. Immediately after the addition was complete, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography [100g silica gel, eluent: dichloromethane/methanol 100: 1 followed by 20: 1(v/v) ]. A solid (4g) was obtained, which was suspended in acetone (20ml), and the precipitate was separated by filtration, washed with acetone (5ml) and diethyl ether (10ml), and dried in vacuo to obtain 1.6g of the title compound (42% yield, optical purity: 95.6-95.8% ee).

Melting point: 257 ℃ C (acetone)

The settings for the analytical method for HPLC determination of optical purity were as follows: column: 250X 4.6mm CHIRALPAK^®AD-H5 μm; mobile phase: ethanol/methanol 1: 1(v/v), containing 0.1% diethylamine; flow rate: 1 ml/min; detection was at 243nm at 35 ℃. The title compound (97.8 area-%) eluted after 3.9 minutes, the (9S) enantiomer eluted after 4.4 minutes (2.2 area-%). Optical purity: 95.6% ee.

Determination of optical purity by CE: RT [ (9S) -enantiomer ] ═ 18.3 min/2.1 area-%;

RT [ (9R) -enantiomer ] ═ 18.6 min/97.9 area-%; 95.8% ee (A).

¹H-NMR(dmso-d₆，200MHz)：d＝2.14(m_c，1H)，2.26(s，m_c，4H)，2.35(s，3H)，2.47(m_c)，2.78，2.87(m_c，s，4H)，3.01(s，3H)，5.26(dd，1H)，7.42(m_c，5H)，7.79(s，1H).

Starting materials and intermediates

Synthesis of racemic 7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine compounds by cross-metathesis reaction

2-amino-3-benzyloxy-5-bromo-pyridine

2-amino-3-benzyloxypyridine (85.0g, 0.42mol) was dissolved in 10% aqueous sulfuric acid (1000 ml). The yellow solution was cooled to 0-4 deg.C and a solution of bromine (80.5g, 0.50mol) in acetic acid (276g, 4.6mol) was added dropwise over 2 hours. A red suspension was obtained which was stirred at 0 ℃ for 2.5 hours and then poured into a mixture of ice water (500ml) and dichloromethane (1000 ml). The pH was adjusted to 8 by adding 25% aqueous ammonia solution (ca. 600ml) to the well stirred biphasic mixture. The phases were separated and the aqueous phase was extracted with dichloromethane (3X 500 ml). The combined organic phases were washed with water (400ml) and dried over sodium sulphate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography [1kg silica gel, eluent: petroleum ether/ethyl acetate 7: 3(v/v) ]. 96.0g of the title compound were thus isolated as a brown solid (81% yield).

Melting point: 109 ℃ and 110 DEG C

¹H-NMR(CDCl₃，200MHz)：δ＝4.73(bs，2H)，5.04(s，2H)，7.08(d，1H)，7.40(m_c，5H)，7.73(d，1H).

ii.8-benzyloxy-6-bromo-2-methyl-imidazo [1, 2-a ] pyridine

A well stirred solution of 2-amino-3-benzyloxy-5-bromo-pyridine (96.0g, 0.34mol) and chloroacetone (50ml, 58.0g, 0.63mol) in anhydrous THF (300ml) was heated to 60 ℃. After 3.5 days, the precipitate formed during the reaction was isolated by filtration, washed with THF (30ml) and dried in vacuo. The mother liquor was treated further with chloroacetone (50ml, 58.0g, 0.63mol) and the reaction mixture was stirred at 60 ℃ for a further 8 days. A precipitate formed again, which was separated again by filtration, washed with THF (30ml) and dried in vacuo. The two batches (55+48g) were combined and crystallized from hot isopropanol (800 ml). The colorless crystals obtained (55g) were dissolved in a biphasic mixture of water and dichloromethane. The mixture was neutralized by adding 6N aqueous sodium hydroxide solution. The phases were separated and the aqueous phase was extracted with dichloromethane (2X 50 ml). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The resulting solid was purified by flash chromatography [1.7kg silica gel, eluent: petroleum ether/ethyl acetate 8: 2(v/v) ]. The mother liquor of the crystallization step was concentrated and the residue was purified as described above (48 g). A total of 63.7g (59% yield) of a viscous yellow solid was isolated, which was pure by H-NMR analysis.

¹H-NMR(CDCl₃，200MHz)：δ＝2.43(s，3H)，5.28(s，2H)，6.52(d，1H)，7.37(m_c，6H)，7.79(d，1H).

iii 8-benzyloxy-2-methyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

Reacting 8-benzyloxy-6-bromo-2-methyl-imidazo [1, 2-a ]]A solution of pyridine (146.0g, 0.46mol) in dry THF (3l) was transferred to the autoclave. After addition of palladium acetate (11.5g, 0.05mol), triphenylphosphine (71.0g, 0.27mol), triethylamine (132ml, 0.94mol) and a solution of 2M dimethylamine in THF (1.2l, 2.4mol), the autoclave was pressurized with carbon monoxide (6 bar) and heated to 120 ℃. After 18 hours, the reaction mixture was cooled, filtered, and concentrated in vacuo. The residue was dissolved in dichloromethane (700ml) and water (300 ml). The phases were separated and the aqueous phase (100ml) was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. A viscous brown residue (219g) was obtained which was purified by flash chromatography (4.4kg silica gel, eluent: ethyl acetate, then ethyl acetateEster/methanol 9: 1). The title compound was isolated as a beige solid (110g, 77% yield) by¹The H-NMR spectrum showed that it was pure.

¹H-NMR(CDCl₃，200MHz)：δ＝2.47(s，3H)，2.95(bs，6H)，5.35(s，2H)，6.43(d，1H)，7.40(m_c，6H)，7.88(d，1H).

8-hydroxy-2-methyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

A solution of 8-benzyloxy-2-methyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (58.0g, 0.19mol) in methanol (500ml) was treated with a hydrogenation catalyst (10% palladium on charcoal, 7g) and a hydrogen pressure of 1 bar was applied. After stirring the suspension at room temperature for 18 hours, the catalyst was removed by filtration and the filtrate was concentrated in vacuo. The title compound was isolated (40.1g, 98% yield) as a beige solid.

¹H-NMR(CDCl₃，200MHz)：δ＝2.44(s，3H)，3.10(bs，6H)，6.74(d，1H)，7.31(s，1H)，7.89(d，1H)，8.96(bs，1H).

v.8-allyloxy-2-methyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

Alcohol 8-hydroxy-2-methyl-imidazo [1, 2-a]Pyridine-6-carboxylic acid dimethylamide (4.74g, 21.6mmol) was dissolved in anhydrous DMF (50ml), potassium carbonate (2.98g, 21.6mmol) and allyl bromide (3.14g, 25.9mmol) were added and the reaction mixture was stirred at room temperature for 18.5 h. The solvent was removed under reduced pressure and the residue was dissolved in saturated ammonium chloride solution (100ml) and chloroform (150 ml). The phases were separated and the aqueous phase was extracted with chloroform (2X 150 ml). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The resulting dark brown liquid (8.5g) was purified by flash chromatography [250g silica gel, eluent: ethyl acetate/methanol 4: 1(v/v)]. The title compound (5.05g) was isolated in 70% yield as a yellow oil. In that¹Traces of impurities (about 5 mol-%) were visible in the H-NMR spectrum.

¹H-NMR(CDCl₃，200MHz)：δ＝2.46(s，3H)，3.09(s，6H)，4.79(dt，2H)，5.33(dd，1H)，5.45(dd，1H)，6.15(ddt，1H)，6.48(d，1H)，7.33(s，1H)，7.87(d，1H).

vi.7-allyl-8-hydroxy-2-methyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

The flask, containing only 8-allyloxy-2-methyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (3.93g, 15.2mmol), is placed in an oil bath that has been previously heated to 160 ℃. After 50 minutes at 160 ℃, the reaction mixture solidified to form a dark brown solid. The crude product was cooled to room temperature and treated with a mixture of acetone and diethyl ether [ 1: 1(v/v), 20ml ]. A colourless solid precipitated out, was isolated by filtration, washed with diethyl ether (10ml) and dried in vacuo. 2.10g of pure title compound are thus isolated. The mother liquor was concentrated under reduced pressure and purified by flash chromatography (70g silica gel, eluent: ethyl acetate/methanol 9: 1 then 4: 1 (v/v)), yielding in turn 0.48g of the title compound (2.58g, 66% overall yield).

¹H-NMR(CDCl₃，200MHz)：δ＝2.43(s，3H)，2.88(s，3H)，3.11(s，3H)，3.55(bd，2H)，5.00，5.07(2dd，2H)，5.98(m_c，1H)，7.22(s，1H)，7.53(s，1H)，9.57(bs，1H).

Pivalic acid (7-allyl-6-dimethylcarbamoyl-2-methyl-imidazo [1, 2-a ] pyridin-8-yl) ester

To a suspension of alcohol 7-allyl-8-hydroxy-2-methyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (1.00g, 3.9mmol) in acetone (30ml) were added potassium carbonate (0.53g, 3.9mmol) and pivaloyl chloride (0.93g, 7.7 mmol). The yellow suspension was stirred at room temperature for 3 hours. After addition of saturated ammonium chloride solution (20ml) and water (10ml), the reaction mixture was extracted with dichloromethane (3X 50 ml). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The crude product (1.46g of anhydrous solid) was purified by flash chromatography (30g of silica gel, eluent: ethyl acetate). The title compound was obtained in a yield of 72% (0.96g anhydrous solid).

Melting point: 178-

¹H-NMR(CDCl₃，200MHz)：δ＝1.48(s，9H)，2.41(s，3H)，2.89(s，3H)，3.08(s，3H)，3.35(d，2H)，5.04(m_c，2H)，5.78(m_c，1H)，7.28(s，1H)，7.82(s，1H).

(E) -pivalic acid [ 6-dimethylcarbamoyl-2-methyl-7- (3-phenyl-allyl) -imidazo [1, 2-a ] pyridin-8-yl ] ester

The alkene pivalic acid (7-allyl-6-dimethylcarbamoyl-2-methyl-imidazo [1, 2-a)]Pyridin-8-yl) ester (9.30g, 27.1mmol) was dissolved in dichloromethane (140ml) which had been degassed with argon. Trans-stilbene (19.53g, 108.4mmol) and the second generation Grubbs catalyst (CAS 246047-72-3, 920mg, 1.08mmol, 4. mol-%) were added to give a red solution. The reaction mixture was heated to 40 ℃ and stirred at this temperature for 18 hours. The crude product obtained by concentrating the green solution was purified by flash chromatography [1.2kg silica gel, eluent: petroleum ether (to remove excess trans-stilbene) followed by ethyl acetate]. A pale green solid (6.6g) was isolated from the title compound (90 mol-%, 53% yield) and unconverted pivalic acid (7-allyl-6-dimethylcarbamoyl-2-methyl-imidazo [1, 2-a ])]Pyridin-8-yl ester (10 mol-%) in a ratio determined by¹H-NMR analysis).

Of the title compound from a 9: 1 mixture with unconverted starting material¹H-NMR data

(CDCl₃，200MHz)：δ＝1.49(s，9H)，2.42(s，3H)，2.79(s，3H)，3.01(s，3H)，3.53(d，2H)，6.12(dt，1H)，δ.43(d，1H)，7.24(m_c，6H)，7.81(s，1H).

The NMR signal of the starting material is reported above.

2-methyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

Comprises (E) -pivalic acid [ 6-dimethylcarbamoyl-2-methyl-7- (3-phenyl-allyl) -imidazo [1, 2-a]Pyridin-8-yl]Ester (6.05g, 14.4mmol) and pivalic acid (7-allyl-6-dimethylcarbamoyl-2-methyl-imidazo [1, 2-a)]Pyridin-8-yl) ester (0.55g, 1.6mmol) of the product of the above cross-metathesis reaction (6.6g) was treated with 200ml of orthophosphoric acid (85%). The resulting green solution was heated at 80 ℃ for 50 minutes. The reaction mixture was cooled to room temperature, diluted with dichloromethane (200ml) and neutralized with 6N sodium hydroxide solution at 0 ℃. The phases were separated and the aqueous phase was extracted with dichloromethane (2X 200 ml). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography [210g silica gel, eluent: ethyl acetate/methanol 9: 1(v/v)]. A colourless solid was obtained (4.4g, 91% yield),¹H-NMR analysis indicated that it was the pure title compound.

Melting point: 189 deg.C

¹H-NMR(CDCl₃，200MHz)：δ＝2.26(m_c，2H)，2.41(s，3H)，2.58，2.77(2m_c，2H)，2.94(s，3H)，3.12(s，3H)，5.31(dd，1H)，7.40(m_c，6H)，7.67(s，1H).

Synthesis of 2-methyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide by one-pot method

The title compound can also be obtained by a one-pot method: in a flame-dried flask filled with argon, pivalic acid (7-allyl-6-dimethylcarbamoyl-2-methyl-imidazo [1, 2-a)]Pyridin-8-yl) ester (4.80g, 14.0mmol) was dissolved in dichloromethane (100ml) which had been degassed with argon. After addition of trans-stilbene (10.10g, 56.0mmol) and the second generation Grubbs catalyst (CAS 246047-72-3, 475mg, 0.56mmol, 4 mol-%), the solution was heated to 40 ℃. The reaction mixture was stirred at this temperature for 18 hours and then concentrated under reduced pressure. A green solution was obtained which was treated with 100ml orthophosphoric acid (85%). The suspension was heated to 80 ℃. After 1 hour, a clear solution was obtained, which was cooled to room temperature and poured into a mixture of ice water (50ml) and dichloromethane (50 ml). The pH was adjusted to 8 by addition of 6N sodium hydroxide solution. The phases were separated and the aqueous phase was extracted with dichloromethane (2X 20 ml). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The residue 16g of green solid was purified by flash chromatography [320g silica gel, eluent: petroleum ether (to remove excess trans-stilbene) followed by ethyl acetate/methanol 100: 2(v/v)]. The title compound was isolated (3.0g, 64% yield) as a green foamy solid. By passing¹The H-NMR spectrum showed that it was pure.

xi.3-formyl-2-methyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

The flask containing anhydrous DMF (10ml) was cooled to 0 ℃ and phosphorus oxychloride (1.14g, 7.4mmol) was added. The cooling bath was removed and the solution was stirred at room temperature for 1 hour. The red reaction mixture was washed with 2-methyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ]]Imidazo [1, 2-a ]]A solution of pyridine-6-carboxylic acid dimethylamide (1.00g, 3.0mmol) in anhydrous DMF (10ml) was treated and heated to 60 ℃. After 3 hours, the reaction mixture was poured onto ice water (50ml), neutralized by addition of 2N sodium hydroxide solution and then removed with dichloromethane (3X 40 ml). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The title compound (1.0g, 92% yield) was obtained as a brown solid by¹The H-NMR spectrum showed it to be almost pure.

¹H-NMR(CDCl₃，200MHz)：δ＝2.31(m_c，2H)，2.72(s，m_c，4H)，2.80，2.95(m_c，s，4H)，3.15(s，3H)，5.34(dd，1H)，7.39(m_c，5H)，9.09(s，1H)，9.99(s，1H).

3-hydroxymethyl-2-methyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

A suspension of 3-formyl-2-methyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (1.00g, 2.8mmol) in anhydrous ethanol (30ml) was treated with sodium borohydride (52mg, 1.37 mmol). The reaction mixture was stirred at room temperature for 40 minutes. A clear solution was obtained which was poured onto water (20ml) and dichloromethane (50 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (2X 20 ml).

The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. A pale yellow foamy solid was obtained which was crystallized from acetone (5 ml). The colorless precipitate was isolated by filtration and dried in vacuo to yield 420mg of pure title compound (42% yield). The mother liquor was concentrated and the residue was purified by flash chromatography [ silica gel, eluent: ethyl acetate/methanol 10: 1(v/v)]. 160mg of the title compound (16% yield, yellow solid,¹H-NMR spectrum showed that it was pure).

Melting point: 186 ℃ (acetone)

¹H-NMR(CDCl₃，200MHz)：δ＝2.30，2.37(m_c，s，5H)，2.68(m_c，2H)，2.90，3.10(2s，6H)，4.85(s，2H)，5.30(dd，1H)，7.38(m_c，5H)，7.81(s，1H).

3-bromo-2-methyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

2-methyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ]]Imidazo [1, 2-a ]]Pyridine-6-carboxylic acid dimethylamide (example ix/x, 2.00g, 6.0mmol) dissolved in a mixture of chloroform (10ml) and dichloromethane (10ml)In the above-mentioned material. The solution was cooled to-78 deg.C and N-bromosuccinimide (1.06g, 6.0mmol) was added. The reaction mixture was stirred at-78 ℃ for 45 minutes. The cooling bath was removed and saturated sodium bicarbonate solution (15ml) was added. The phases were separated and the aqueous phase was extracted with dichloromethane (10 ml). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. A pale green foamy solid (2.7g) was isolated and purified by flash chromatography [80g silica gel, eluent: ethyl acetate/petroleum ether 6: 4(v/v)]. The title compound was isolated as a beige solid (1.75g, 71% yield),¹the H-NMR spectrum showed that it was pure. In addition, 0.5g of a mixture of the title compound (96% by weight) and succinimide (4% by weight) was isolated (yield 19%).

Melting point: 167 ℃ F. & 168 ℃ C. (R.)

¹H-NMR(CDCl₃，200MHz)：δ＝2.28(m_c，2H)，2.45(s，3H)，2.69(m_c，2H)，2.93，3.14(2s，6H)，5.32(dd，1H)，7.38(m_c，5H)，7.65(s，1H).

xiv.2-methyl-9-phenyl-3-vinyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

In a flame-dried flask filled with argon, 3-bromo-2-methyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (1.60g, 3.9mmol) was dissolved in anhydrous 1, 4-dioxane (50 ml). The solution was treated with tributyl (vinyl) stannane (1.48g, 4.7mmol) and bis (triphenylphosphino) palladium chloride (270mg, 0.38mmol) and stirred at a temperature of 100 ℃ (preheated oil bath). After 2 hours, an additional portion of tributyl (vinyl) stannane (0.70g, 2.2mmol) and bis (triphenylphosphino) palladium chloride (140mg, 0.20mmol) was added. The reaction was continued at 100 ℃ for 1 hour. The reaction mixture was cooled to room temperature and concentrated in the presence of silica gel (3 g). The crude product was purified by flash chromatography [120g silica gel, eluent: petroleum ether, then petroleum ether/ethyl acetate 1: 1(v/v), followed by petroleum ether/ethyl acetate 2: 8(v/v) ]. To achieve further purification, the title compound (1.3g) obtained was dissolved in ethyl acetate (20ml) and water (15ml) after chromatographic purification. The pH was adjusted to 1.5 by addition of 2N hydrochloric acid. The phases were separated and the aqueous phase was extracted with ethyl acetate (10 ml). The organic phase was discarded and methylene chloride (20ml) was added to the aqueous phase. The pH was adjusted to 8 by addition of 2N sodium hydroxide solution. The phases were separated and the aqueous phase was extracted with dichloromethane (2X 10 ml). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The residue, 1.0g yellow solid, was dried in vacuo and was determined to be the pure title compound (72% yield).

¹H-NMR(CDCl₃，200MHz)：δ＝2.30(m_c，2H)，2.54，2.63(s，m_c，4H)，2.79(m_c，1H)，2.92，3.13(2s，6H)，5.34(dd，1H)，5.42(d，1H)，5.56(d，1H)，6.78(dd，1H)，7.38(m_c，5H)，7.75(s，1H).

xv.3-ethyl-2-methyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

2-methyl-9-phenyl-3-vinyl-7H-8, 9-dihydro-pyrano [2, 3-c ]]Imidazo [1, 2-a ]]Pyridine-6-carboxylic acid dimethylamide (0.280g, 0.77mmol) was dissolved in dry methanol (20 ml). Adding Lindlar catalyst (Pd/CaCO)₃Pb, Aldrich 20, 573-7, 56mg, 20% by weight), 1 bar of hydrogen pressure is applied. The reaction mixture was stirred at room temperature for 2 hours, and 28mg (10% by weight) of the catalyst were added. Hydrogenation was continued for 2 hours.

The catalyst was removed by filtration, the filtrate was concentrated, and the remaining yellow solid was dried in vacuo. The title compound (250mg) was isolated in 89% yield.

Melting point: 230 deg.C

¹H-NMR(CDCl₃，200MHz)：δ＝1.20(t，3H)，2.26(m_c，2H)，2.41(s，3H)，2.57(m_c，1H)，2.73，2.84，2.92(m_c，q，s，6H)，3.13(s，3H)，5.32(dd，1H)，7.38(m_c，6H).

Elemental analysis: c₂H₂₅N₃O₂Calculated value of (363.46): c72.70, H6.93, N11.56;

measured value: c71.71, H6.86, N11.21.

2, 3-dimethyl-9- (2-methylphenyl) -7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

In a flame-dried flask filled with argon, 7-allyl-2, 3-dimethyl-8- [ dimethyl- (1, 1, 2-trimethyl-propyl) -siloxy ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (example xxi, 1.50g, 3.6mmol) is dissolved in dichloromethane (50ml) which has been degassed with argon. After addition of o-methylstyrene (2.13g, 18.0mmol) and the second generation Grubbs catalyst (CAS 246047-72-3, 122mg, 0.14mmol, 4 mol-%), the solution is heated to 40 ℃. The reaction mixture was stirred at this temperature for 4 days and then concentrated under reduced pressure. A suspension of the residue in 80ml of orthophosphoric acid (85%) was stirred at 80 ℃ (preheated oil bath). After 1.5 hours, a clear solution was obtained, which was poured onto ice water (100 ml). The pH was adjusted to 8 by addition of 6N sodium hydroxide solution. The aqueous phase was extracted with methylene chloride (3X 80 ml). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The solid residue (3.7g) was purified by flash chromatography [120g silica gel, eluent: petroleum ether (to remove 2, 2' -dimethylstilbene) followed by ethyl acetate/triethylamine 100: 1(v/v) ]. After removal of the solvent, two samples were obtained: (A) pure title compound (280mg foamy solid, 21% yield); (B) a mixture of the title compound and 2, 3, 8-trimethyl-7, 8-dihydro-furo [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (formed by ring closure of the deprotected starting material, 240mg as a foamy solid). The mixture was further purified by preparative HPLC, and 111mg of the pure title compound was obtained again (total yield: 29%).

¹H-NMR(CDCl₃，200MHz)：δ＝2.18(m_c，2H)，2.36，2.37，2.40(3s，9H)，2.78，2.99(m_c，s，5H)，3.15(s，3H)，5.42(dd，1H)，7.20(m_c，3H)，7.43(s，1H)，7.56(m_c，1H).

xvii.9- (2-fluorophenyl) -2, 3-dimethyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

In a flame-dried flask filled with argon, 7-allyl-2, 3-dimethyl-8- [ dimethyl- (1, 1, 2-trimethyl-propyl) -siloxy ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (example xxi, 2.00g, 4.8mmol) is dissolved in dichloromethane (50ml) which has been degassed with argon. 2-fluoro-styrene (2.94g, 24.1mmol) and a second generation Grubbs catalyst (CAS 246047-72-3, 162mg, 0.19mmol, 4 mol-%) were then added and the solution was heated to 40 ℃. The reaction mixture was stirred at this temperature for 17 hours and then concentrated under reduced pressure. A suspension of the residue in 25ml of orthophosphoric acid (85%) was stirred at 100 ℃ (preheated oil bath). After 2 hours, a clear solution was obtained, which was poured onto ice water (70ml) and dichloromethane (100 ml). The pH was adjusted to 8 by addition of 6N sodium hydroxide solution. The phases were separated and the aqueous phase was extracted with dichloromethane (2X 50 ml). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The black solid residue (5.6g) was purified by flash chromatography [225g silica gel, eluent: ethyl acetate/triethylamine 100: 1(v/v) ]. After removal of the solvent, the title compound was obtained pure (1.0g of colorless solid, 56% yield).

Melting point: 202 deg.C

¹H-NMR(CDCl₃，200MHz)：δ＝2.27(m_c，2H)，2.36，2.41(2s，6H)，2.61(m_c，1H)，2.82(m_c，1H)，2.95，3.14(2s，6H)，5.60(dd，1H)，7.09(m_c，2H)，7.27(m_c)，7.44(s，1H)，7.60(dt，1H).

xviii.9- (4-fluorophenyl) -2, 3-dimethyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

In a flame-dried flask filled with argon, 7-allyl-2, 3-dimethyl-8- [ dimethyl- (1, 1, 2-trimethyl-propyl) -siloxy ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (example xxi, 1.50g, 3.6mmol) is dissolved in dichloromethane (50ml) which has been degassed with argon. After addition of p-fluoro-styrene (2.20g, 18.0mmol) and the second generation Grubbs catalyst (CAS 246047-72-3, 122mg, 0.14mmol, 4 mol-%), the solution was heated to 40 ℃. The reaction mixture was stirred at this temperature for 5 days and then concentrated under reduced pressure. A suspension of the residue in 80ml of orthophosphoric acid (85%) was stirred at 80 ℃ (preheated oil bath). After 2 hours, the reaction mixture was poured onto ice water (100 ml). The pH was adjusted to 8 by addition of 6N sodium hydroxide solution. The aqueous phase was extracted with dichloromethane (3X 100 ml). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography [100g silica gel, eluent: petroleum ether (to remove 4, 4' -difluorostilbene) followed by ethyl acetate/methanol-10: 1(v/v) ]. After removal of the solvent, the pure title compound was isolated as a pale green solid (280mg, 21% yield).

¹H-NMR(CDCl₃，200MHz)：δ＝2.24(m_c，2H)，2.36，2.41(2s，6H)，2.68(m_c，2H)，2.93，3.13(2s，6H)，5.27(dd，1H)，7.04(t，2H)，7.43(m_c，3H).

Synthesis of intermediates for asymmetric hydrogenation by cross-metathesis reaction

xix.8-allyloxy-2, 3-dimethyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

Alcohol 8-hydroxy-2, 3-dimethyl-imidazo [1, 2-a ]]Pyridine-6-carboxylic acid dimethylamide (synthesis described in WO03/014123, 50.0g, 0.22mol) was dissolved in anhydrous DMF (1L). Potassium carbonate (29.7g, 0.22mol) and allyl bromide (31.2g,0.26mol) and the reaction mixture was stirred at room temperature for 18.5 hours. The solvent was removed under reduced pressure, and the residue was dissolved in a saturated ammonium chloride solution (250ml) and chloroform (500 ml). The phases were separated and the aqueous phase was extracted with chloroform (2 ×). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography [800g silica gel, eluent: ethyl acetate/methanol 9: 1(v/v)]. The title compound (40.0g) was isolated as a yellow solid in 67% yield. In that¹The presence of trace impurities (about 14 mol-%) can be seen by H-NMR spectroscopy.

¹H-NMR(CDCl₃，400MHz)：δ＝2.39，2.46(2s，6H)，3.10(s，6H)，4.80(dt，2H)，5.33(dd，1H)，5.47(dd，1H)，6.14(ddt，1H)，6.53(d，1H)，7.69(d，1H).

xx.7-allyl-2, 3-dimethyl-8-hydroxy-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

The flask, containing only 8-allyloxy-2, 3-dimethyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (40.0g, 0.15mol), is placed in an oil bath that has been previously heated to 160 ℃. After 50 minutes at 160 ℃, the reaction mixture solidified to form a dark brown solid. The crude product was cooled to room temperature and treated with a mixture of acetone and diethyl ether [ 1: 1(v/v), 200ml ] to precipitate a beige solid. After 20 minutes, the precipitate was isolated by filtration, washed with diethyl ether and dried in vacuo. 28.0g of pure title compound was thus isolated. The mother liquor was concentrated under reduced pressure and the residue (10g of brown solid) was purified by flash chromatography (300g of silica gel, eluent: ethyl acetate/methanol 9: 1 (v/v)), whereby 2.2g of the title compound (30.2g, total yield 76%) was obtained.

¹H-NMR(CDCl₃，200MHz)：δ＝2.35，2.44(2s，6H)，2.87，3.13(2s，3H)，3.55(d，2H)，5.02，5.07(2dd，2H)，5.97(m_c，1H)，7.36(s，1H)，10.76(bs，1H).

xxi.7-allyl-2, 3-dimethyl-8- [ dimethyl- (1, 1, 2-trimethylpropyl) siloxy ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

In a flame-dried flask filled with argon, 7-allyl-2, 3-dimethyl-8-hydroxy-imidazo [1, 2-a ] was charged]A suspension of pyridine-6-carboxylic acid dimethylamide (3.60g, 13.2mmol) in anhydrous DMF (50ml) was treated with imidazole (1.52g, 22.3mmol) and chloro (dimethyl) hexylsilane (4.40ml, 4.00g, 22.4mmol, added slowly). A brown solution was obtained, which was stirred at room temperature for 1 hour. The reaction mixture was poured onto a mixture of ice (20g), saturated ammonium chloride solution (30ml) and dichloromethane (50 ml). The biphasic mixture was stirred for a few minutes, the phases separated and the aqueous phase extracted with dichloromethane (2X 15 ml). The combined organic phases were washed with water (20ml), dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by flash chromatography 7.5g of a yellow-brown oil [150g silica gel, eluent: petroleum ether/Ethyl acetate 8: 2(v/v)]A colourless solid (5.10g) was isolated by¹The H-NMR spectrum confirmed that it was the pure title compound (93% yield).

Melting point: 93-95 deg.C

¹H-NMR(CDCl₃200 MHz): δ is 0.41(s, 6H), 0.96(d, 6H), 1.02(s, 6H), 1.83 (heptad, 1H), 2.31, 2.36(2s, 6H), 2.84, 3.08(2s, 6H), 3.50 (m)_c，2H)，4.96(m_c，2H)，5.84(m_c，1H)，7.36(s，1H).

xxii. (E) -2, 3-dimethyl-8- [ dimethyl- (1, 1, 2-trimethyl-propyl) -siloxy ] -7- (3-phenyl-allyl) -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

In a flame-dried flask filled with argon, 7-allyl-2, 3-dimethyl-8- [ dimethyl- (1, 1, 2-trimethyl-propyl) -siloxy ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (5.00g, 12.0mmol) is dissolved in anhydrous dichloromethane (200ml) which has been degassed with argon. Trans-stilbene (8.70g, 48.3mmol) and a second generation Grubbs catalyst (CAS 246047-72-3, 0.40g, 0.5mmol, 3.9 mol-%) were added and the resulting red solution heated to reflux for 19 h. The dark brown reaction mixture was concentrated to a volume of 89ml and loaded onto a column packed with 200g of silica gel. The title compound was eluted using a mixture of petroleum ether and ethyl acetate [ 7: 3(v/v) ]. The solvent was removed and the oily residue was dried in vacuo. A pale red foam (3.70g) was obtained which was analyzed to be a mixture of the title compound (93 wt-%, 58% yield) and dimethyl- (1, 1, 2-trimethyl-propyl) -silanol (7 wt-%). 400mg (8% yield) of starting material was also recovered from the column.

¹H-NMR(CDCl₃200 MHz): δ ═ 0.44(s, 6H), 0.97(d, 6H), 1.03(s, 6H), 1.88 (heptad, 1H), 2.31, 2.37(2s, 6H), 2.75, 3.03(2s, 6H), 3.69(bs, 2H), 6.20(dt, 1H), 6.37(d, J ═ 15.8Hz, 1H), 7.22(m, m)_c，5H)，7.34(s，1H)，

Dimethyl- (1, 1, 2-trimethyl-propyl) -silanol:

δ＝0.13(s，6H)，0.87(s，6H)，0.90(d，6H)，1.64(m_c).

xxiii. (E) -8-hydroxy-2, 3-dimethyl-7- (3-phenyl-allyl) -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

In an argon-filled flask, (E) -2, 3-dimethyl-8- [ dimethyl- (1, 1, 2-trimethyl-propyl) -siloxy ] -7- (3-phenyl-allyl) -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (1.10g, 2.2mmol) was dissolved in anhydrous THF (20 ml).

After slowly adding a 1M solution of tetrabutylammonium fluoride in THF (3.30ml, 3.3mmol), a dark green solution was obtained, which was stirred at room temperature for 30 minutes. The reaction mixture was poured onto a mixture of ice (10g), saturated ammonium chloride solution (15ml) and dichloromethane (30 ml). The biphasic mixture was stirred for a few minutes, the phases separated and the aqueous phase extracted with dichloromethane (3X 10 ml). The combined organic phases were washed with water (20ml), dried over sodium sulphate and concentrated under reduced pressure. The oily residue (1.5g) was purified by flash chromatography [15g silica gel, eluent: dichloromethane followed by dichloromethane/methanol 20: 1(v/v) ]. A green solid (900mg) was obtained, which was suspended in diethyl ether (10ml), isolated by filtration, washed with diethyl ether (10ml) and dried in vacuo. The pure title compound was isolated in 81% yield (630mg as a light grey solid).

Melting point: 183 temperature 185 deg.C (diethyl ether)

¹H-NMR(CDCl₃，200MHz)：δ＝2.32，2.35(2s，6H)，2.76，2.96(2s，6H)，3.48(d，2H)，5.26(bs)，6.23，6.34(m_c，d，2H)，7.27(m_c，5H)，7.69(s，1H)，

Elemental analysis: c₂₁H₂₃N₃O₂Calculated value of (349.43): c72.18, H6.63, N12.03;

measured value: c71.54, H6.53, N11.77.

Synthesis of racemic 7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid ethyl ester by saponification of 7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine:

xxiv.2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid

2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ]]Imidazo [1, 2-a ]]A suspension of pyridine-6-carboxylic acid ethyl ester (synthesis described in WO03/014123, 16.7g, 48mmol) in methanol (170ml) and water (35ml) was treated with potassium hydroxide (4.5g, 80mmol) and heated to 50 ℃. After 2 hours of reaction, the methanol was removed in vacuo. Water (400ml) and dichloromethane (300ml) were added and the pH adjusted to 4.8 (isoelectric point of the title compound) by addition of 6N hydrochloric acid and stirring was continued for 30 min. A precipitate formed which slowly dissolved upon addition of dichloromethane (100ml) and methanol (100 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (2X 50 ml). The combined organic phases were dried over sodium sulphate and concentrated to a volume of 50 ml.After addition of diethyl ether (100ml), a colorless precipitate formed. Stirring was continued at 0 ℃ for 30 minutes. The precipitate was isolated by filtration and dried in vacuo to afford 9.1g of pure title compound (58% yield). The aqueous phase was saturated with sodium chloride and extracted with chloroform (1X 400ml, 2X 100 ml). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Warp beam¹H-NMR confirmed that the residue (2.0g, 13% yield) was pure title compound.

Melting point: 18-320 ℃ (diethyl ether)

¹H-NMR(dmso-d₆，200MHz)：δ＝2.09(m_c，1H)，2.28(s，m_c，4H)，2.40(s，3H)，3.10(m_c，2H)，5.25(dd，1H)，7.43(m_c，5H)，8.32(s，1H)，

Exchangeable protons are not seen.

Elemental analysis: calculated value C₁₉H₁₈N₂O₃·(H2O)_0.5Calculated value of (322.37+ 9.0): c68.87, H5.78, N8.45; measured value: c68.95, H5.49, N8.40.

xxv. (2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridin-6-yl) -pyrrolidin-1-yl-methanone

A suspension of 2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid (1.00g, 3.1mmol) in dichloromethane (50ml) was treated with TBTU (1.08g, 3.4 mmol). After a reaction time of 45 min at room temperature, pyrrolidine (219mg, 253. mu.l, 3.08mmol) was added. A clear solution was obtained, which was stirred at room temperature for 2.5 hours. The reaction mixture was poured into saturated sodium bicarbonate solution (50ml), the phases were separated and the aqueous phase was extracted with dichloromethane (2X 20 ml). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue (1.8g) was treated with hot acetone (10 ml). The suspension was allowed to cool to room temperature and stirred for 1 hour. The precipitate was isolated by filtration (730mg), further purified by flash chromatography [ silica gel, eluent: ethyl acetate/methanol 90: 3(v/v) ]. The corresponding fractions were evaporated to give a residue, which was washed with diethyl ether (15ml) and isolated by filtration. The title compound (524mg) was obtained in 45% yield.

Melting point: 274 deg.C (diethyl ether)

¹H-NMR(CDCl₃，200MHz)：δ＝1.97(m_c，4H)，2.26，2.36，2.41(m_c，2s，8H)，2.62(m_c，1H)，2.84(m_c，1H)，3.24(m_c，2H)，3.65(t，2H)，5.31(dd，1H)，7.38(m_c，6H).

Elemental analysis: calculated value C₂₃H₂₅N₃O₂C73.58, H6.71, N11.19 of (375.47);

measured value: c73.43, H6.74, N11.19.

xxvi.2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid methylamide

2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid (example xxiv, 1.50g, 4.6mmol) and TBTU (1.40g, 4.4mmol) are suspended in dichloromethane (50 ml). After a reaction time of 1 hour at room temperature, methylamine (8.0M solution in ethanol, 2ml, 16mmol) was added. A clear solution was obtained within 30 minutes, which was stirred at room temperature for 2 hours. The reaction mixture was poured onto water (20ml), the phases were separated and the aqueous phase was extracted with dichloromethane (10 ml). The combined organic phases were washed with water (10ml), dried over sodium sulphate and concentrated in vacuo. The residue (1.1g) was purified by flash chromatography [ silica gel, eluent: dichloromethane/methanol 15: 1(v/v) ]. After evaporation of the corresponding fractions, a colourless solid was obtained which was dried in vacuo. The title compound (0.90g) was obtained in a yield of 58%.

Melting point: 234 deg.C

xxvii.2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid amide

2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ]]Imidazo [1, 2-a ]]A suspension of pyridine-6-carboxylic acid (example xxiv, 500mg, 1.54mmol) in dichloromethane (20ml) was treated with TBTU (504mg, 1.57 mmol). The reaction mixture was heated at 40 ℃ for 1 hour and then allowed to cool to room temperature. To this suspension was passed ammonia gas for 30 minutes. The reaction mixture was poured onto water (20ml), dichloromethane (30ml) was added and the pH was adjusted to 6 by addition of 2N hydrochloric acid. To aid in the separation of the phases, 10ml of methanol was added. The phases were separated and the aqueous phase was extracted with dichloromethane (2X 10 ml). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The title compound (310mg, 64% yield) was isolated as a colorless solid,¹H-NMR spectrum confirmed that it was pure.

Melting point: 303 ℃ 305-

Synthesis of racemic 7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridines by ketone reduction and acid-catalyzed cyclization/Mitsunobu cyclization

xxviii.8-hydroxy-7- [ 3-hydroxy-3- (2-methylphenyl) -propyl ] -2, 3-dimethyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

8-hydroxy-2, 3-dimethyl-7- [3- (2-methylphenyl) -3-oxo-propyl ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (example xxxvii, 2.00g, 5.3mmol) is dissolved in absolute ethanol (20ml) and sodium borohydride (240mg, 6.34mmol) is added in small portions. The reaction mixture was stirred at room temperature for 1 hour and treated with another portion of sodium borohydride (120mg, 3.17 mmol). Stirring was continued for 30 minutes and the reaction mixture was poured onto a mixture of ice (50g), saturated ammonium chloride solution (50ml) and dichloromethane (100 ml). The biphasic mixture was stirred for 20 minutes. The phases were separated and the aqueous phase was extracted with dichloromethane (2X 10 ml). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The crude product of the title compound (3.2g) was isolated as a yellow foam which was used directly as starting material for example xxix.

¹H-NMR(CDCl₃+ micro MeOD, 200 MHz): δ 2.00 (bm)_c，2H)，2.16(s，3H)，2.35(s，3H)，2.55(s，3H)，2.91，3.05，3.12(s，bm_c，s，8H)，4.81(dd，1H)，7.07(m_c，4H)，7.51(d，1H).

Orthophosphoric acid (85 wt-%, 15ml) was heated to 80 ℃ and 8-hydroxy-7- [ 3-hydroxy-3- (2-methylphenyl) -propyl ] -2, 3-dimethyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (3.2g, crude from example xxviii) was added dropwise. After a reaction time of 25 minutes, the hot solution was poured onto ice water (100ml) and dichloromethane (100 ml). The pH of the biphasic mixture was adjusted to 6.5 by addition of 6N sodium hydroxide solution. The phases were separated and the aqueous phase was extracted with dichloromethane (2X 50 ml). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography [ silica gel, eluent: 888mg of the title compound were isolated (46% yield in two steps) from ethyl acetate/methanol 9: 1 (v/v).

Melting point: 198 deg.C

xxx.7- [3- (2-fluorophenyl) -3-hydroxy-propyl ] -8-hydroxy-2, 3-dimethyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

7- [3- (2-fluorophenyl) -3-oxo-propyl ] -8-hydroxy-2, 3-dimethyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (example xxxviii, 2.00g, 5.2mmol) is suspended in absolute ethanol (70ml) and sodium borohydride (200mg, 5.3mmol) is added in small portions. The reaction mixture, a yellow solution, was stirred at room temperature for 30 minutes and then poured onto a mixture of saturated ammonium chloride solution (50ml) and dichloromethane (100 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (30 ml). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The crude product of the title compound was dried in vacuo (2.1g of a colorless solid) and used directly as starting material in example xxxi.

¹H-NMR(CDCl₃，200MHz)：δ＝1.90(m_c，2H)，2.35，2.56(2s，6H)，2.80，2.95(bs，s，4H)，3.14(s，3H)，3.35(m_c，1H)，4.90(dd，1H)，6.88(m_c，1H)，7.09，7.14(m_c，s，3H)，7.59(m_c，1H).

xxxi.9- (2-fluorophenyl) -2, 3-dimethyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

7- [3- (2-fluorophenyl) -3-hydroxy-propyl ] -8-hydroxy-2, 3-dimethyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (2.1g, crude from example xxx) is dissolved in orthophosphoric acid (85 wt-%, 20 ml). The suspension was heated at 80 ℃ (preheated oil bath). After 30 minutes, a clear solution was obtained. After a reaction time of 1 hour, the hot solution was poured onto ice water (100ml) and dichloromethane (100 ml). The pH of the biphasic mixture was adjusted to 8 by addition of 6N sodium hydroxide solution. The phases were separated and the aqueous phase was extracted with dichloromethane (2X 40 ml). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. A pale yellow foamy solid was obtained, which was dried in vacuo. The title compound (1.94g) was obtained in a yield of 94%.

Melting point: 203 deg.C

¹H-NMR(CDCl₃，200MHz)：δ＝2.23，2.36，2.41(m_c，2s，8H)，2.61(m_c，1H)，2.83，2.95(m_c，s，4H)，3.14(s，3H)，5.60(dd，1H)，7.09(m_c，2H)，7.27(m_c)，7.44(s，1H)，7.60(dt，1H).

xxxii.7- [3- (4-fluorophenyl) -3-hydroxy-propyl ] -8-hydroxy-2, 3-dimethyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

7- [3- (4-fluorophenyl) -3-oxo-propyl ] -8-hydroxy-2, 3-dimethyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (example xxxix, 2.24g, 5.8mmol) is dissolved in absolute ethanol (70ml) and sodium borohydride (220mg, 5.8mmol) is added in small portions. The reaction mixture was stirred at room temperature for 45 minutes and then poured onto a mixture of saturated ammonium chloride solution (50ml) and dichloromethane (100 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (50 ml). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The crude product of the title compound was dried in vacuo (2.4g of a colorless solid) and used directly as the starting material in example xxxiii.

¹H-NMR(CDCl₃+ micro MeOD, 200 MHz): δ 1.97 (bm)_c，2H)，2.35(s，3H)，2.56(s，3H)，2.92，3.14，3.20(2s，bm_c，8H)，4.55(dd，1H)，6.92(t，2H)，7.17(s，1H)，7.29(m_c，2H).

xxxiii.9- (4-fluorophenyl) -2, 3-dimethyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide 7- [3- (4-fluorophenyl) -3-hydroxy-propyl ] -8-hydroxy-2, 3-dimethyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (2.4g, crude product from example xxxii) is dissolved in orthophosphoric acid (85 wt-%, 20 ml). The suspension was heated at 80 ℃ (preheated oil bath). After 30 minutes, a clear solution was obtained. After a reaction time of 1 hour, the hot solution was poured onto ice water (100ml) and dichloromethane (100 ml).

The pH of the biphasic mixture was adjusted to 8 by addition of 6N sodium hydroxide solution. The phases were separated and the aqueous phase was extracted with dichloromethane (2X 40 ml). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. A colorless solid was obtained, which was dried in vacuo. The title compound (1.94g) was obtained in 85% yield.

Melting point: 260 deg.C

xxxiv.8-hydroxy-7- (3-hydroxy-3-thiophen-2-yl-propyl) -2, 3-dimethyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

8-hydroxy-2, 3-dimethyl-7- [ 3-oxo-3-thiophen-2-yl-propyl ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (example xl, 2.00g, 5.4mmol) is suspended in absolute ethanol (70ml) and sodium borohydride (250mg, 6.6mmol) is added in small portions. A brown solution was obtained which was stirred at room temperature for 2 hours and then poured onto a mixture of saturated ammonium chloride solution (50ml) and dichloromethane (100 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (30 ml). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The crude product of the title compound was dried in vacuo (2.0g of a beige solid) and used directly as starting material for example xxxv.

¹H-NMR(CDCl₃，200MHz)：δ＝2.09(bs，2H)，2.31(s，3H)，2.48(bs，4H)，2.91，3.14(2s，6H)，3.33(bs，1H)，4.80(t，1H)，6.70(bs)，6.89(m_c，2H)，7.11(m_c，2H).

xxxv.2, 3-dimethyl-9-thiophen-2-yl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

In a flame-dried flask filled with argon, 8-hydroxy-7- (3-hydroxy-3-thiophen-2-yl-propyl) -2, 3-dimethyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (2.0g, crude from example xxxiv) was suspended in anhydrous THF (25 ml). After addition of triphenylphosphine (2.80g, 10.7mmol) and dropwise addition of DIAD (1.63g, 8.1mmol), a brown solution was obtained which was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue (8g brown oil) was purified by flash chromatography [260g silica gel, eluent: ethyl acetate, then ethyl acetate/methanol 100: 1 and 100: 2(v/v) ].

A colorless solid was obtained (661mg of pure title compound, 35% yield).

Melting point: 241

Synthesis of prochiral ketones:

xxxvi.8-hydroxy-2, 3-dimethyl-7- (3-oxo-3-phenyl-propyl) -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

(A) In a flame-dried flask filled with argon, a suspension of the alcohol 8-hydroxy-2, 3-dimethyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (synthesis described in WO03/014123, 50.0g, 214mmol) in anhydrous dichloromethane (1.2L) was treated with N, N-dimethylmethyleneammonium iodide (40.3g, 218 mmol). The reaction mixture was stirred at room temperature for 1 hour. At the beginning, a clear solution was obtained, and after 10 minutes a precipitate was observed to form. The solvent was then removed under reduced pressure.

(B) Argon was charged to the rotary evaporator, and (7-dimethylaminomethyl-6-dimethylcarbamoyl-8-hydroxy-2, 3-dimethyl-imidazo [1, 2-a ] pyridin-1-ium iodide) was dried in vacuo and dissolved in anhydrous DMF (1.1L) which had been previously heated to 50 ℃. An almost clear solution was obtained which was treated with potassium carbonate (30.4g, 220mmol) and 1- (1-phenyl-vinyl) -pyrrolidine (CAS3433-56-5, 82.5g, purity: 90 wt-%, 428 mmol). The brown solution was stirred at 50 ℃ for 30 minutes in a preheated oil bath and then poured onto a stirred mixture of ammonium chloride (130g), water (200ml), ice (300g) and dichloromethane (600 ml). Stirring was continued for a few minutes and the pH was adjusted to 8 by addition of 6N hydrochloric acid. The phases were separated and the aqueous phase was extracted with dichloromethane (3X 100 ml). The combined organic phases were washed with water (2 × 100ml), dried over sodium sulphate and concentrated under reduced pressure (DMF was removed at 60 ℃). A dark brown oily residue (80g) was obtained which was dried in vacuo.

(C) The residue (crude product of the title compound) was purified by filtration through silica gel [500g, eluent: ethyl acetate (to remove acetophenone formed by cleavage of excess enamine) followed by ethyl acetate/methanol 8: 2(v/v)]. A red-brown solid (60g of the crude product of the title compound, HPLC-purity: 88.08%) was isolated, dried in vacuo, dissolved in methanol (200ml) and treated with fumaric acid (25.5g, 220 mmol). The brown suspension was stirred at 40 ℃ for 20 minutes to obtain a clear solution. The solution was concentrated under reduced pressure until a viscous suspension formed. Acetone (120ml) was added and the mixture was concentrated again until a viscous suspension formed. The slurry was diluted with acetone (150ml) and stirred at 40 deg.C (30 min), room temperature (19 h) and 0 deg.C (2 h). The precipitate formed was removed by filtration, washed with acetone (20ml) and diethyl ether (50ml) and dried in vacuo. A colorless solid was obtained (51g, 49% yield, melting point: 196 ℃ C.)¹The H-NMR spectrum showed that it was the salt of the title compound with fumaric acid in a molar ratio of 1: 1.

(D) The salt of the title compound with fumaric acid (50g, 104mmol) was added portionwise to sodium bicarbonate (42g, 500mmol), water(400ml) and dichloromethane (400 ml). The biphasic mixture was stirred for 5 minutes. The phases were separated and the aqueous phase was extracted with dichloromethane (2X 50 ml). The organic phase was washed with water (2X 100ml), dried over sodium sulphate and concentrated under reduced pressure. A colorless foamy solid was obtained which was identified as the title compound (37.7g, 99% yield, 49% overall yield).¹H-NMR spectroscopy indicated that the sample was pure and showed 99.07% HPLC purity (RT ═ 9.4 min). It was dried in vacuo (phosphorus pentoxide, 1 day).

Melting point: 115 ℃ and 117 DEG C

¹H-NMR(CDCl₃，200MHz)：δ＝2.32，2.37(2s，6H)，2.95(s)，3.05(bs)，3.14(s，∑8H)，3.42(m_c，2H)，7.29(s，1H)，7.47(m_c，3H)，8.00(m_c，2H).

xxxvii.8-hydroxy-2, 3-dimethyl-7- [3- (2-methylphenyl) -3-oxo-propyl ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

(A) In a flame-dried flask filled with argon, a suspension of alcohol 8-hydroxy-2, 3-dimethyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (15.0g, 64mmol) in anhydrous dichloromethane (500ml) was treated with N, N-dimethylmethyleneiminium iodide (11.9g, 64 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure and a yellow solid was isolated.

(B) Subjecting the 7-dimethylaminomethyl-6-dimethylcarbamoyl-8-hydroxy-2, 3-dimethyl-imidazo [1, 2-a ] produced in (A)]The crude product of pyridin-1-ium iodide was dissolved in anhydrous DMF (300 ml). After addition of potassium carbonate (8.9g, 64mmol), a clear solution is obtained which is taken up with 1- [1- (2-methylphenyl) -vinyl]Pyrrolidine (CAS 156004-72-7, 36.5g, 195 mmol). The brown solution was stirred at 50 ℃ for 4 hours in a preheated oil bath and then poured onto a mixture of ice water (400ml) and dichloromethane (400 ml). The pH was adjusted to pH 7 by addition of 6N hydrochloric acid. The phases were separated and the aqueous phase was extracted with dichloromethane (2X 200 ml). To be combinedThe organic phase was dried over sodium sulfate and concentrated under reduced pressure (DMF was removed at 60 ℃). A dark brown oily residue (45g) was obtained. (C) The residue (crude product of the title compound) was purified by filtration through silica gel [600g, eluent: ethyl acetate (to remove o-methylacetophenone formed by cleavage of excess enamine) and then ethyl acetate/methanol 8: 2(v/v)]. Two batches of the title compound (8.65g brown oil/19.81 g brown foamy solid) were isolated and purified separately. The material was dissolved in methanol (100ml/200ml) and stirred at 50 ℃ until a clear solution was obtained (about 10 minutes). A solution of fumaric acid (4.76g, 41.0mol/10.90g, 94.0mmol) in methanol (100ml/200ml) was added and stirring was continued for 10 minutes. The solution was concentrated under reduced pressure, acetone (50ml/100ml) was added to the brown crystalline residue, and the mixture was stirred at room temperature for 19 hours. The precipitate formed was removed by filtration, washed with diethyl ether (20ml/50ml) and dried in vacuo. A beige solid (6.10g/19.87g, 51+ 29% yield) was obtained by¹The H-NMR spectrum showed that it was the salt of the title compound with fumaric acid in a molar ratio of 1: 2.

(D) The salt of the title compound with fumaric acid (6.10, 18.8mol/19.87g, 32.5mmol) was added portionwise to a mixture of saturated sodium bicarbonate solution (100ml/200ml) and dichloromethane (100ml/200 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (50ml/100 ml). The organic phase was dried over sodium sulfate and concentrated under reduced pressure. A foamy solid was isolated and suspended in diethyl ether (50ml/100 ml). After 30 min/15 min, the precipitate was isolated by filtration, washed with diethyl ether (20ml/50ml) and dried in vacuo. 2 batches of the title compound were isolated: 2.63g of a colorless solid [ 11% yield, HPLC purity: 97.3% (RT ═ 10.7 min) ] and 10.4g of a colorless solid [ 43% yield, HPLC purity: 99.6% (RT ═ 10.7 minutes) ].

Melting point: 179 ℃ 180 ℃/182-

¹H-NMR(dmso-d₆，200MHz)：δ＝2.32，2.35，2.41(3s，9H)，2.79，2.88(m_c，s，5H)，3.01，3.08(s，m_c，5H)，5.45(bs)，7.37(m_c，3H)，7.71(m_c，2H).

xxxviii.7- [3- (2-fluorophenyl) -3-oxo-propyl ] -8-hydroxy-2, 3-dimethyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

(A) In an argon-filled flame-dried flask, a suspension of alcohol 8-hydroxy-2, 3-dimethyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (25.0g, 107mmol) in anhydrous dichloromethane (1L) was treated with N, N-dimethylmethyleneiminium iodide (19.8g, 107 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. At the beginning, a clear solution was obtained, and after 30 minutes a precipitate was observed to form. The solvent was then removed under reduced pressure.

(B) To a rotary evaporator was filled with argon and the light yellow solid (7-dimethylaminomethyl-6-dimethylcarbamoyl-8-hydroxy-2, 3-dimethyl-imidazo [1, 2-a ] pyridin-1-ium iodide) was dissolved in anhydrous DMF (600ml) which had been previously heated to 50 ℃. After addition of potassium carbonate (5.9g, 107mmol), a clear solution is obtained which is treated with 1- [1- (2-fluorophenyl) -vinyl ] -pyrrolidine (CAS 237436-15-6, 53.2g, 278mmol, purity: 80 mol-%). The brown solution was stirred at 50 ℃ for 2 hours in a preheated oil bath and then poured onto a mixture of ice water (600ml) and dichloromethane (500 ml). The pH was adjusted to pH 7 by addition of 6N hydrochloric acid. The phases were separated and the aqueous phase was extracted with dichloromethane (2X 300 ml). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure (DMF was removed at a temperature of 60 ℃). A dark brown oily residue (72g) was obtained.

(C) The residue (crude product of the title compound) was purified by filtration through silica gel [800g, eluent: ethyl acetate (to remove o-fluoroacetophenone formed by cleavage of excess enamine) and then ethyl acetate/methanol 8: 2(v/v)]. A brown solid (39g of the crude product of the title compound) was isolated, dissolved in methanol (800ml) and treated with a solution of fumaric acid (21.3g, 183mmol) in methanol (500 ml). The brown solution was stirred at 50 ℃ for 10 minutes. The solvent was evaporated and acetone (120ml) was addedTo the brown solid residue, the mixture was stirred at room temperature for 19 hours and at 0 ℃ for 2 hours. The precipitate was isolated by filtration, washed with diethyl ether (50ml) and dried in vacuo. A colorless solid was obtained (45.9g, 59% yield) by¹The H-NMR spectrum showed that it was the salt of the title compound with fumaric acid in a molar ratio of 1: 3.

(D) The salt of the title compound with fumaric acid (45.9g, 63mmol) was added portionwise to a stirred mixture of dichloromethane (500ml) and saturated sodium bicarbonate solution (400 ml). The biphasic mixture was stirred until the solids had completely dissolved (about 15 minutes). The phases were separated and the aqueous phase was extracted with dichloromethane (100 ml). The organic phase was dried over sodium sulfate and concentrated under reduced pressure. A green foamy solid (23g) was isolated and suspended in diethyl ether (200 ml). After stirring the suspension at room temperature for 2 hours, the precipitate was isolated by filtration and dried in vacuo. The title compound was isolated as a beige solid (21.0g, 51% overall yield).¹H-NMR spectroscopy indicated that the sample was pure and showed 98.12% HPLC purity (RT ═ 9.4 min).

Melting point: 196 deg.C

¹H-NMR(dmso-d₆，200MHz)：δ＝2.32，2.35(2s，6H)，2.89(bm_c，s，5H)，2.99(s，3H)，3.18(bm_c，2H)，5.48(bs)，7.33(m_c，2H)，7.65，7.69(m_c，s，2H)，7.81(dt，1H).

xxxix.7- [3- (4-fluorophenyl) -3-oxo-propyl ] -8-hydroxy-2, 3-dimethyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

(A) In a flame-dried flask filled with argon, a suspension of alcohol 8-hydroxy-2, 3-dimethyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (10.0g, 43mmol) in anhydrous dichloromethane (500ml) was treated with N, N-dimethylmethyleneiminium (7.9g, 43 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. At the beginning, a clear solution was obtained, and after 30 minutes a precipitate was observed to form. The solvent was then removed under reduced pressure.

(B) To a rotary evaporator was filled with argon and the light yellow solid (7-dimethylaminomethyl-6-dimethylcarbamoyl-8-hydroxy-2, 3-dimethyl-imidazo [1, 2-a ] pyridin-1-ium iodide) was dissolved in anhydrous DMF (300ml) which had been previously heated to 50 ℃. After addition of potassium carbonate (5.9g, 43mmol), a clear solution was obtained which was treated with 1- [1- (4-fluorophenyl) -vinyl ] -pyrrolidine (CAS 237436-54-3, 18.9g, 99 mmol). The brown solution was stirred at 50 ℃ for 2 hours in a pre-heated oil bath and then poured onto a mixture of ice water (300ml) and dichloromethane (300 ml). The pH was adjusted to pH 7 by addition of 6N hydrochloric acid. The phases were separated and the aqueous phase was extracted with dichloromethane (2X 200 ml). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure (DMF was removed at a temperature of 60 ℃). A dark brown oily residue (28.8g) was obtained.

(C) The residue (crude product of the title compound) was purified by filtration through silica gel [600g, eluent: ethyl acetate (to remove p-fluoroacetophenone formed by cleavage of excess enamine) and then ethyl acetate/methanol 7: 3(v/v) ]. A brown solid (15.2g of the crude product of the title compound) was isolated, dissolved in methanol (400ml) and treated with fumaric acid (8.3g, 72 mmol). The brown suspension was stirred at 50 ℃ for 15 minutes and methanol (400ml) was added. Stirring was continued at 50 ℃ for 30 minutes to obtain a clear solution. The solvent was evaporated, acetone (80ml) was added to the brown solid residue, and the mixture was stirred at room temperature for 19 hours and at 0 ℃ for 2 hours. The precipitate was isolated by filtration, washed with diethyl ether (30ml) and dried in vacuo. A colourless solid was obtained (16.2g, 52% yield) which, by 1H-NMR spectroscopy, was the salt of the title compound with fumaric acid in a molar ratio of 1: 3.

(D) The salt of the title compound with fumaric acid (16.2g, 22mmol) was treated with a mixture of dichloromethane (200ml) and saturated sodium bicarbonate solution (200 ml). The biphasic mixture was stirred until the solids had completely dissolved (about 15 minutes). The phases were separated and the aqueous phase was extracted with dichloromethane (2X 30 ml). Will haveThe organic phase is dried over sodium sulfate and concentrated under reduced pressure. A beige foamy solid (8.4g) was isolated and suspended in diethyl ether (100 ml). After stirring the suspension at room temperature for 1 hour, the precipitate was isolated by filtration and dried in vacuo. The title compound was isolated as a beige solid (7.53g, 46% overall yield).¹H-NMR spectroscopy indicated that the sample was pure and showed 97.83% HPLC purity (RT ═ 9.9 minutes).

Melting point: 221 deg.C

¹H-NMR(dmso-d₆，200MHz)：δ＝2.32，2.35(2s，6H)，2.85，2.88(m_c，s，5H)，3.00(s，3H)，3.19(t，2H)，6.42(bs，1H)，7.34(t，2H)，7.70(s，1H)，8.05(q，2H).

xi.8-hydroxy-2, 3-dimethyl-7- (3-oxo-3-thiophen-2-yl-propyl) -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

(A) 7-dimethylaminomethyl-8-hydroxy-2, 3-dimethyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide can be prepared as described above by reacting 8-hydroxy-2, 3-dimethyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide with N, N-dimethylmethyleneiminium iodide in dichloromethane, except that the reaction mixture is treated with saturated sodium bicarbonate solution rather than being evaporated to dryness.

(A) The crude product of 7-dimethylaminomethyl-8-hydroxy-2, 3-dimethyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide (18.8g, 65mmol) was dissolved in anhydrous DMF (400 ml). After addition of potassium carbonate (8.9g, 64mmol), a clear solution is obtained which is prepared from 1- [ 1-thiophen-2-yl-vinyl ] -pyrrolidine (prepared from 2-acetylthiophene and pyrrolidine by titanium tetrachloride-mediated condensation, see J.org.chem.1967, 32, 213-214, 27.1g, 151 mmol). The biphasic mixture was stirred at 50 ℃ for 4 hours in a pre-heated oil bath and then poured onto a mixture of ice water (500ml) and dichloromethane (400 ml). The pH was adjusted to pH 7 by addition of 6N hydrochloric acid. The phases were separated and the aqueous phase was extracted with dichloromethane (3X 200 ml). The combined organic phases were washed with water (200ml), dried over sodium sulphate and concentrated under reduced pressure (DMF was removed at 60 ℃). An oily residue (30g) was obtained.

(B) The residue (crude product of the title compound) was purified by filtration through silica gel [600g, eluent: ethyl acetate (to remove 2-acetylthiophene formed as a result of cleavage of excess enamine) and then ethyl acetate/methanol 8: 2(v/v)]. A light brown solid (14.5g of the crude product of the title compound) was isolated and dissolved in hot methanol (300 ml). After 10 min, a solution of fumaric acid (8.2g, 70mmol) in methanol (200ml) was added. Stirring was continued at 50 ℃ for 10 minutes and the solvent was evaporated. The solid residue was suspended in acetone (100ml) and the mixture was stirred at room temperature for 17 hours. The precipitate was isolated by filtration, washed with diethyl ether (30ml) and dried in vacuo. A colorless solid (18.7g, 53% yield) was obtained by¹The H-NMR spectrum showed that it was the salt of the title compound with fumaric acid in a molar ratio of 1: 1.5.

(C) The salt of the title compound with fumaric acid (18.7g, 34mmol) was added portionwise to a mixture of dichloromethane (250ml) and saturated sodium bicarbonate solution (100 ml). The biphasic mixture was stirred until the solids had completely dissolved. The phases were separated and the aqueous phase was extracted with dichloromethane (50 ml). The organic phase was dried over sodium sulfate and concentrated under reduced pressure. A light brown solid (11g) was isolated and suspended in diethyl ether (60 ml). After stirring the suspension at room temperature for 2 hours, the precipitate was isolated by filtration and dried in vacuo. The title compound was isolated as a beige solid (10.7g, 45% overall yield).¹H-NMR spectroscopy indicated that the sample was pure and showed 99.04% HPLC purity (RT ═ 8.3 minutes). Melting point: 234 deg.C (diethyl ether)

¹H-NMR(dmso-d₆，200MHz)：δ＝2.32，2.36(2s，6H)，2.81，2.89(m_c，s，5H)，3.01(s，3H)，3.14(t，2H)，5.85(bs)，7.24(dd，1H)，7.71(s，1H)，7.93(dd，1H)，8.00(dd，1H).

xli.8-hydroxy-2, 3-dimethyl-7- (3-oxo-3-phenyl-propyl) -imidazo [1, 2-a ] pyridine-6-carboxylic acid ethyl ester

(A) In a flame-dried flask filled with argon, a suspension of ethyl alcohol 8-hydroxy-2, 3-dimethyl-imidazo [1, 2-a ] pyridine-6-carboxylate (17.0g, 73mmol) in anhydrous dichloromethane (550ml) was treated with N, N-dimethylmethyleneiminium (13.5g, 73 mmol). The reaction mixture was stirred at room temperature for 70 minutes. At the beginning, a clear solution was obtained, and after 30 minutes a precipitate was observed to form. The solvent was then removed under reduced pressure.

(B) The rotary evaporator was filled with argon and the colourless solid (7-dimethylaminomethyl-6-ethoxycarbonyl-8-hydroxy-2, 3-dimethyl-imidazo [1, 2-a ] pyridin-1-ium iodide) was dissolved in anhydrous DMF (350ml) which had been previously heated to 50 ℃. After gradual addition of potassium carbonate (10.0g, 72mmol) and 1- (1-phenyl-vinyl) -pyrrolidine (CAS3433-56-5, 28.0g, purity: 90 wt-%, 145mmol), an almost clear solution was obtained. The brown solution was stirred at 50 ℃ for 90 minutes in a preheated oil bath and then poured onto a mixture of ice water (200ml) and dichloromethane (300 ml). The pH was adjusted to pH 7 by addition of 6N hydrochloric acid. The phases were separated and the aqueous phase was extracted with dichloromethane (3X 40 ml). The combined organic phases were washed with water (2 × 50ml), dried over sodium sulphate and concentrated under reduced pressure (DMF was removed at a temperature of 70 ℃). A dark brown oily residue (40g) was obtained.

(C) The residue (crude product of the title compound) was purified by filtration through silica gel [400g, eluent: ethyl acetate (to remove acetophenone formed by cleavage of excess enamine) and then ethyl acetate/methanol 8: 2(v/v)]. A brown solid (31g of the crude product of the title compound, HPLC-purity: 74.05%) was isolated, dried in vacuo, dissolved in methanol (300ml) and treated with fumaric acid (16.0g, 138 mmol). The brown suspension was stirred at 40 ℃ to give gradually a clear solution which was concentrated under reduced pressure to a volume of 20 ml. Acetone (200ml) was added and the mixture was again concentrated to a volume of 20 ml. The slurry was diluted with acetone (120ml), stirred at room temperature (19 hours) and 0 deg.C (2 hours),the precipitate was isolated by filtration, washed with acetone (20ml) and diethyl ether (25ml) and dried in vacuo. A colorless solid was obtained (20.0g, 65% yield, melting point: 192-¹The H-NMR spectrum showed that it was the salt of the title compound with fumaric acid in a molar ratio of 2: 1.

(D) The salt of the title compound with fumaric acid (19.5g, 46mmol) was added portionwise to a mixture of water (200ml), sodium bicarbonate (20.0g, 238mmol) and dichloromethane (250 ml). The biphasic mixture was stirred for 5 minutes. The phases were separated and the aqueous phase was extracted with dichloromethane (2X 20 ml). The organic phase was washed with water (2X 30ml), dried over sodium sulphate and concentrated under reduced pressure. A colorless solid was isolated and was determined to be the title compound (16.5g, 98% yield, 64% overall yield). A sample (HPLC purity: 94.26%) containing unconverted starting material was further purified by flash chromatography [400g silica gel, eluent: dichloromethane/methanol 100: 2(v/v) ]. The title compound (14.5g, 55% yield) was obtained as an almost colorless solid exhibiting an HPLC purity of 98.33% (RT ═ 14.1 min).

Melting point: 172 ℃ and 174 ℃.

¹H-NMR(dmso-d₆，200MHz)：δ＝1.29(t，3H)，2.34，2.41(2s，6H)，3.23(s，4H)，4.29(q，2H)，6.30(bs，1H)，7.51(t，2H)，7.64(t，1H)，7.98(d，2H)，8.19(s，1H).

xiii.9-methoxy-2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid ethyl ester

2, 2-Dimethoxypropane (8.6g, 10.1ml, 83mmol) was added to a solution of ethyl 8-hydroxy-2, 3-dimethyl-7- (3-oxo-3-phenyl-propyl) -imidazo [1, 2-a ] pyridine-6-carboxylate (2.00g, 5.5mmol) in anhydrous dichloromethane (25 ml). After slow addition of methanesulfonic acid (0.68g, 0.46ml, 7.1mmol) a dark brown solution was obtained, which was refluxed for 6 hours. The reaction mixture was cooled and poured into a stirred mixture of saturated sodium bicarbonate solution (25ml) and dichloromethane (20 ml). The biphasic mixture was stirred for a few minutes and the phases were separated. The aqueous phase was extracted with dichloromethane (2X 15 ml). The combined organic phases were washed with water (20ml), dried over sodium sulphate and concentrated under reduced pressure. The brown residue (3g) was treated with diethyl ether (15ml) and the resulting slurry was stirred for 15 minutes. The precipitate was isolated by filtration, washed with diethyl ether (5ml) and dried in vacuo. The title compound (1.85g of a colorless solid) was obtained in 88% yield.

Melting point: 184 ℃ and 186 DEG C

¹H-NMR(dmso-d₆，200MHz)：δ＝1.35(t，3H)，1.90(m_c，1H)，2.34，2.37，2.43(s，m_c，s，7H)，2.99，3.12(s，m_c，5H)，4.33(q，2H)，7.49(m_c，3H)，7.63(m_c，2H)，8.36(s，1H).

xliii.9-methoxy-2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid

To a suspension of ethyl 9-methoxy-2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylate (1.80g, 4.7mmol) in methanol (40ml) was added aqueous potassium hydroxide solution (solution of 0.56g, 10.0mmol in 5ml water). The resulting red suspension was heated to 55 ℃. After 30 minutes, a clear solution was obtained, which was kept at 55 ℃ for 90 minutes. The reaction mixture was cooled and concentrated under reduced pressure. The wet residue was dissolved in water (40ml) and 2N hydrochloric acid was added to the stirred solution until pH2. Stirring was continued at room temperature for 1 hour and the precipitate which had formed was removed by filtration. The filter cake was washed with water (until the filtrate showed a neutral pH) and acetone (5ml) and dried in vacuo. The title compound was isolated in 97% yield (1.6g anhydrous solid).

Melting point: 240 ℃ and 242 DEG C

¹H-NMR(dmso-d₆+ micro MeOD, 200 MHz): delta 1.99 (m)_c，1H)，2.51(m_c)，3.06(s，3H)，3.23(m_c，2H)，7.52(m_c，3H)，7.74(m_c，2H)，8.68(s，1H).

xliv (9-methoxy-2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridin-6-yl) -pyrrolidin-1-yl-methanone

In an argon-filled flask, a suspension of 9-methoxy-2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid (2.00g, 5.7mmol) in anhydrous dichloromethane (35ml) was treated with TBTU (2.10g, 6.5 mmol).

The reaction mixture was refluxed for 2 hours and then allowed to cool to room temperature. After addition of pyrrolidine (0.43g, 0.50ml, 6.0mmol) a yellow solution was obtained which was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water (30ml) and the stirred biphasic mixture was neutralized by the addition of saturated sodium bicarbonate solution. The phases were separated and the aqueous phase was extracted with dichloromethane (2X 10 ml). The combined organic phases were washed with water (20ml), dried over sodium sulphate and concentrated under reduced pressure. The residue (4g yellow oil) was purified by flash chromatography [90g silica gel, eluent: methylene chloride/methanol 100: 2(v/v)]. A foamy solid (1.9g, 83% yield) was isolated as a mixture of the title compound (67 mol-%), benzotriazol-1-ol (22 mol-%), and tetramethylurea (11 wt-%) [ by passing through%¹Determined by H-NMR spectroscopy]。

¹H-NMR(dmso-d₆，200MHz)：δ＝1.87，2.07(2m_c，5H)，2.36，2.42(2s，6H)，2.55(m_c) 2.69 (tetramethylurea), 2.86, 3.02 (m)_c，s，4H)，3.26(m_c)，3.50(t，2H)，7.48(m_c3H [ the title Compound]2H [ benzotriazol-1-ol])，7.64，7.72(2m_c2H [ the title Compound]1H [ benzotriazol-1-ol]) 7.98(d, 1H [ benzotriazol-1-ol)])，8.11(s，1H)。

xlv [ 8-hydroxy-2, 3-dimethyl-7- (3-oxo-3-phenyl-propyl) -imidazo [1, 2-a ] pyridin-6-yl ] -pyrrolidin-1-yl-methanone

A solution of (9-methoxy-2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridin-6-yl) -pyrrolidin-1-yl-methanone (1.80g, crude product from experiment xliv) in THF (25ml) was treated with 1N hydrochloric acid (10ml) and heated at 50 ℃ for 5H. The reaction mixture was allowed to cool to room temperature, poured into a mixture of ice water (25ml) and dichloromethane (30ml) and neutralized by the addition of 2N sodium hydroxide solution. The phases were separated and the aqueous phase was extracted with dichloromethane (2X 15 ml). The combined organic phases were washed with water (20ml), dried over sodium sulphate and concentrated in vacuo. The title compound (1.2g, HPLC purity: 98.42%) was further purified by flash chromatography [50g silica gel, eluent: ethyl acetate/methanol 10: 1(v/v) ]. A colorless solid was isolated, dried in vacuo and identified as pure title compound (1.03g, 46% overall yield), HPLC purity: 99.55% (RT ═ 10.9 min).

Melting point: 257 ℃ and 258 DEG C

¹H-NMR(dmso-d₆，200MHz)：δ＝1.84(m_c，4H)，2.32，2.36(2s，6H)，2.87(m_c，2H)，3.24(m_c，4H)，3.46(m_c，2H)，6.85(bs，1H)，7.52(t，2H)，7.64(t，1H)，7.77(s，1H)，7.96(d，2H).

xivi 9-methoxy-2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid methylamide

In an argon-filled flask, 9-methoxy-2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] was placed]Imidazo [1, 2-a ]]A suspension of pyridine-6-carboxylic acid (example xliii, 2.00g, 5.7mmol) in dry dichloromethane (35ml) was treated with TBTU (2.10g, 6.5 mmol). The reaction mixture was refluxed for 2 hours and then allowed to cool to room temperature. After gradual addition of methylamine (0.80ml of 8M solution in ethanol, 6.4mmol) a yellow solution was obtained which was stirred at room temperature for 1 hour. The reaction mixture was poured into a mixture of ice water (30ml) and dichloromethane (10ml) by addition of saturated sodium bicarbonateThe solution neutralizes the stirred biphasic mixture. Stirring was continued for a few minutes, the phases were separated and the aqueous phase was extracted with dichloromethane (2X 10 ml). The combined organic phases were washed with water (20ml), dried over sodium sulphate and concentrated under reduced pressure. The residue (5g solid) was purified by flash chromatography [100g silica gel, eluent: methylene chloride/methanol 100: 2(v/v)]. A colorless foamy solid (2.2g) was isolated which was a mixture of the title compound (53 mol-%), benzotriazol-1-ol (39 mol-%), and tetramethylurea (8 mol-%) [ by¹Determined by H-NMR spectroscopy]。

¹H-NMR(dmso-d₆，200MHz)：δ＝1.92(m_c，1H)，2.39，2.45(2s，m_c7H), 2.69 (tetramethylurea), 2.80(d, m)_c，4H)，3.03，3.05(s，m_c，4H)，7.48(m_c3H [ the title Compound]2H [ benzotriazol-1-ol])，7.67，7.72(2m_c2H [ the title Compound]1H [ benzotriazol-1-ol]) 7.99(d, 1H [ benzotriazol-1-ol)])，8.21(s，1H)，8.47(bq，1H)。

xlvii.8-hydroxy-2, 3-dimethyl-7- (3-oxo-3-phenyl-propyl) -imidazo [1, 2-a ] pyridine-6-carboxylic acid methylamide

A solution of 9-methoxy-2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid methylamide (2.10g, crude product from example xivi) in THF (25ml) was treated with 1N hydrochloric acid (10ml) and heated at 50 ℃ for 7H. The reaction mixture was stirred at room temperature for 18 hours and then neutralized by the addition of saturated sodium bicarbonate solution. A yellow suspension was obtained which was stirred at room temperature for 1 hour. The precipitate was isolated by filtration, washed with water (20ml) and dried in vacuo. The pure title compound (1.45g yellow solid) was isolated in 73% overall yield, HPLC purity: 99.57% (RT ═ 8.8 min).

Melting point: 284 + 286 deg.C (water)

¹H-NMR(dmso-d₆，200MHz)：δ＝2.32，2.38(2s，6H)，2.76(d，3H)，2.98(m_c，2H)，3.25(m_c，2H)，5.95(bs，1H)，7.52(t，2H)，7.64(t，1H)，7.82(s，1H)，7.98(d，2H)，8.34(bq，1H).

(9-methoxy-2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridin-6-yl) -methanol

In a flame-dried flask filled with argon, ethyl 9-methoxy-2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylate (example xlii, 3.80g, 10.0mmol) was suspended in anhydrous THF (70 ml). Lithium aluminum hydride (1.0g, 26mmol) was added in small portions over 30 minutes at room temperature. Stirring was continued at room temperature for 30 minutes and the reaction mixture was slowly poured into a mixture of saturated ammonium chloride solution (30ml) and dichloromethane (150 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (4X 15 ml). The combined organic phases were washed with water (2 × 20ml), dried over sodium sulphate and concentrated under reduced pressure. The residue, 2.9g, was dried in vacuo and was identified as the pure title compound (86% yield).

Melting point: 257 ℃ and 258 DEG C

¹H-NMR(dmso-d₆，200MHz)：δ＝1.91(m_c，1H)，2.31，2.35，2.37(s，m_c，s，7H)，2.70(m_c，1H)，2.86(m_c，1H)，2.98(s，3H)，4.53(s，2H)，5.19(bs，1H)，7.48(m_c，3H)，7.63(m_c，2H)，7.75(s，1H).

xlix.6-chloromethyl-9-methoxy-2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine

A suspension of (9-methoxy-2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridin-6-yl) -methanol (2.20g, 6.5mmol) in anhydrous dichloromethane (80ml) was cooled to 0 ℃ and thionyl chloride (0.59ml, 0.96g, 8.1mmol) was slowly added. A yellow solution was obtained which was stirred at 0 ℃ for 1 hour and then poured onto saturated sodium bicarbonate solution (20 ml). The aqueous mixture was stirred until gas evolution ceased and the phases separated. The aqueous phase was extracted with dichloromethane (2X 10 ml). The combined organic phases were washed with saturated ammonium chloride solution (20ml) and water (30ml), dried over sodium sulphate and the solvent was evaporated under reduced pressure. A colorless foamy solid was isolated and dried in vacuo. The title compound (2.3g, 99% yield) was used in the next step without further purification.

¹H-NMR(dmso-d₆，200MHz)：δ＝1.93(m_c，1H)，2.31，2.38，2.41(2s，m_c，7H)，2.82(m_c，1H)，2.99，3.02(s，m_c，4H)，4.89(dd，2H)，7.47(m_c，3H)，7.63(m_c，2H)，8.10(s，1H).

l.9-methoxy-6-methoxymethyl-2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine

6-chloromethyl-9-methoxy-2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine (crude from example xlix, 2.20g, 6.2mmol) is dissolved in dry methanol (20 ml). After addition of sodium methoxide (solution: 30 wt-% solution in methanol, 3.0ml, 17mmol) a yellow suspension is obtained, which is heated to 50 ℃. A yellow solution formed in 90 minutes, which was concentrated to a volume of 10ml and poured into a mixture of saturated ammonium chloride solution (15ml) and dichloromethane (20 ml). It is adjusted to pH 7 by addition of 2N hydrochloric acid and the phases are separated. The aqueous phase was extracted with dichloromethane (2X 8 ml). The combined organic phases were washed with water (20ml), dried over sodium sulphate and concentrated under reduced pressure. An oily residue was isolated and dried in vacuo. The title compound (2.1g foamy solid, 98% yield) was used in the next step without further purification.

¹H-NMR(dmso-d₆，400MHz)：δ＝1.92(m_c，1H)，2.30，2.37，2.37(2s，m_c，7H)，2.70(m_c，1H)，2.90(m_c，1H)，2.98(s，3H)，3.33(s)，4.43(s，2H)，7.46(m_c，3H)，7.62(m_c，2H)，7.82(s，1H).

3- (8-hydroxy-6-methoxymethyl-2, 3-dimethyl-imidazo [1, 2-a ] pyridin-7-yl) -1-phenyl-propan-1-one

A solution of 9-methoxy-6-methoxymethyl-2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine (crude from example l, 2.00g, 5.7mmol) in THF (40ml) is treated with 2N hydrochloric acid (15 ml). The yellow solution was stirred at room temperature for 19 hours, heated at 50 ℃ for 2 hours and poured onto a mixture of water (50ml) and dichloromethane (100 ml). The pH is adjusted to neutral by addition of 2N sodium hydroxide solution and the phases are separated. The aqueous phase was extracted with dichloromethane (2X 15 ml). The combined organic phases were washed with water (30ml), dried over sodium sulphate and evaporated to dryness. The solid residue (1.9g) was suspended in acetone (2 ml). After 30 minutes, the precipitate was isolated by filtration, washed with cold acetone (2ml) and diethyl ether (10ml) and dried in vacuo. The pure title compound was isolated in 63% yield (1.20g of light yellow solid), HPLC purity: 98.20% (RT ═ 12.1 min).

Melting point: 167 ℃ 168 ℃ (acetone/diethyl ether)

¹H-NMR(dmso-d₆，200MHz)：δ＝2.30，2.35(2s，6H)，2.97(t，2H)，3.25，3.28(m_c，s，5H)，4.47(s，2H)，7.11(bs)，7.58(m_c，3H)，7.71(s，1H)，7.98(m_c，2H).

Asymmetric reduction of prochiral ketones:

(3S) -8-hydroxy-7- (3-hydroxy-3-phenyl-propyl) -2, 3-dimethyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

In an argon-filled flame-dried flask, ketone 8-hydroxy-2, 3-dimethyl-7- (3-oxo-3-phenyl-propyl) -imidazo [1, 2-a ] is added]Pyridine-6-carboxylic acid dimethylamide (example xxxvi, 5.00g, 13.7mmol) is suspended in anhydrous isopropanol (400ml) which has been degassed with argon. Potassium tert-butoxide (1.85g,15.1mmol) of methanol, a yellow solution is obtained which is used with the hydrogenation catalyst RuCl₂[(R)-BINAP][(R)-DAIPEN](CAS 329735-86-6, catalyst from Strem Chemicals) (125mg, 0.11mmol, S/C125: 1). The reddish yellow solution was stirred at room temperature for 20 minutes and transferred under inert conditions to a 1L autoclave equipped with a glass inlay. The reaction mixture was pressurized with hydrogen (40 bar) and stirred at room temperature for 22 hours. The yellow-brown solution was concentrated to a volume of 80 ml. Ice water (80ml) and dichloromethane (130ml) were added and adjusted to neutral pH by addition of 2N hydrochloric acid. The phases were separated and the aqueous phase was extracted with dichloromethane (3X 15 ml). The combined organic phases were washed with water (30ml), dried over sodium sulphate and concentrated under reduced pressure. The residue green solid (8g) was purified by flash chromatography [80g silica gel, eluent: dichloromethane/methanol 20: 1(v/v)]. A suspension of the purified title compound in acetone (30ml) was stirred at room temperature for a few minutes. The precipitate was separated by filtration, washed with acetone (5ml) and diethyl ether (15ml) and dried in vacuo. A colorless solid was obtained (4.40g, 87% yield), which was identified as the title compound (optical purity: 95.5% ee).

Melting point: 185 deg.C and 187 deg.C (acetone).

Determination of optical purity by CE: RT [ (3S) -enantiomer ] ═ 18.5 min/97.7 area-%;

RT [ (3R) -enantiomer ] ═ 19.0 min/2.3 area-%; 95.5% ee (A).

¹H-NMR(dmso-d₆，200MHz)：δ＝1.81(m_c，2H)，2.30，2.33(2s，6H)，2.50(bm_c)，2.78，2.91(2s，6H)，4.49(t，1H)，5.43(bs)，7.25(m_c，5H)，7.59(s，1H).

(3R) -8-hydroxy-7- (3-hydroxy-3-phenyl-propyl) -2, 3-dimethyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

In an argon-filled flame-dried flask, ketone 8-hydroxy-2, 3-dimethyl-7- (3-oxo-3-phenyl-propyl) -imidazo [1, 2-a ] is added]Pyridine-6-carboxylic acid dimethyl acylThe amine (example xxxvi, 10.00g, 27.4mmol) was suspended in anhydrous isopropanol (400ml) which had been degassed with argon. After addition of potassium tert-butoxide (3.70g, 30.2mmol), stirring was continued until a yellow solution was obtained (about 30 min). Addition of hydrogenation catalyst RuCl₂[(S)-BINAP][(S)-DAIPEN](CAS212143-24-3, catalyst from Strem Chemicals) (240mg, 0.21mmol, S/C130: 1). The resulting reddish yellow solution was stirred at room temperature for 15 minutes and transferred under inert conditions to a 1L autoclave equipped with a glass inlay. The reaction mixture was pressurized with hydrogen (40 bar) and stirred at room temperature for 24 hours. The brown solution was concentrated to a volume of 50 ml. Poured into a cold mixture of saturated ammonium chloride solution (120ml) and dichloromethane (250 ml). It is adjusted to a neutral pH by addition of 6N hydrochloric acid. The phases were separated and the aqueous phase was extracted with dichloromethane (2X 40 ml). The combined organic phases were washed with water (30ml), dried over sodium sulphate and concentrated under reduced pressure. A pale green solid was obtained which was dried in vacuo and was identified as the title compound (9.30g, 92% yield, optical purity: 85.8% ee).

Melting point: 152 ℃ and 154 DEG C

Determination of optical purity by CE: RT [ (3S) -enantiomer ] ═ 20.2 min/7.1 area-%;

RT [ (3R) -enantiomer ] ═ 20.5 min/92.9 area-%; 85.8% ee (A).

(3R) - [ 8-hydroxy-7- (3-hydroxy-3-phenyl-propyl) -2, 3-dimethyl-imidazo [1, 2-a ] pyridin-6-yl ] -pyrrolidin-1-yl-methanone

In an argon-filled flame-dried flask, the ketone [ 8-hydroxy-2, 3-dimethyl-7- (3-oxo-3-phenyl-propyl) -imidazo [1, 2-a ] is added]Pyridin-6-yl]Pyrrolidin-1-yl-methanone (example xlv, 1.00g, 2.6mmol) was suspended in anhydrous isopropanol (120ml) which had been degassed with argon. After addition of potassium tert-butoxide (0.34g, 2.8mmol), a yellow solution is obtained with the hydrogenation catalyst RuCl₂[(S)-BINAP][(S)-DAIPEN](CAS212143-24-3, catalyst from Strem Chemicals) (130mg, 0.12mmol, S/C20: 1). The resulting mixture was stirred at room temperature for several minutes until catalyzedThe agent had completely dissolved and was transferred under inert conditions to a 1L autoclave equipped with a glass inlay. The reaction mixture was pressurized with hydrogen (40 bar) and stirred at room temperature for 22 hours. The green solution was concentrated to a volume of 30ml and poured onto a mixture of ice water (20ml) and dichloromethane (40 ml). It is adjusted to a neutral pH by addition of 6N hydrochloric acid. The phases were separated and the aqueous phase was extracted with dichloromethane (3X 10 ml). The combined organic phases were washed with water (20ml), dried over sodium sulphate and concentrated under reduced pressure. The green residue (1.8g) was purified by flash chromatography [80g silica gel, eluent: methylene chloride/methanol 100: 3(v/v)]. A suspension of the purified title compound in diethyl ether (10ml) was stirred at room temperature for a few minutes. The precipitate was isolated by filtration, washed with diethyl ether (5ml) and dried in vacuo. A pale green solid (780mg, 78% yield) was obtained, which was identified as the title compound (optical purity: 87.4% ee).

Melting point: 252 ℃ C (diethyl ether)

Determination of optical purity by CE: RT [ (3S) -enantiomer ] ═ 20.2 min/6.3 area-%;

RT [ (3R) -enantiomer ] ═ 20.4 min/93.7 area-%; 87.4% ee (A).

¹H-NMR(dmso-d₆，200MHz)：δ＝1.77(m_c，6H)，2.30，2.33(2s，6H)，2.55(m_c)，3.13，3.34(2t，4H)，4.49(t，1H)，5.93(bs)，7.25(m_c，5H)，7.65(s，1H).

Iv. (3R) -8-hydroxy-7- (3-hydroxy-3-phenyl-propyl) -2, 3-dimethyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid methylamide

In an argon-filled flame-dried flask, ketone 8-hydroxy-2, 3-dimethyl-7- (3-oxo-3-phenyl-propyl) -imidazo [1, 2-a ] is added]Pyridine-6-carboxylic acid methylamide (example xlvii, 1.30g, 3.7mmol) was suspended in anhydrous isopropanol (120ml) which had been degassed with argon. After addition of potassium tert-butoxide (0.50g, 4.1mmol), a thin yellow suspension is obtained, which is stirred at room temperature for 30 minutes. Further addition of degassed isopropanol30ml) the suspension was warmed slightly. Addition of RuCl as hydrogenation catalyst₂[(S)-BINAP][(S)-DAIPEN](CAS212143-24-3, catalyst from Strem Chemicals) (80mg, 0.07mmol, S/C50: 1). The resulting mixture was stirred at room temperature for 20 minutes until the catalyst had completely dissolved and transferred under inert conditions to a 1L autoclave equipped with a glass inlay. The reaction mixture was pressurized with hydrogen (40 bar) and stirred at room temperature for 22 hours. The green solution was concentrated to a volume of 20ml and poured into a stirred mixture of ice water (25ml) and dichloromethane (50 ml). It is adjusted to a neutral pH by addition of 6N hydrochloric acid. The phases were separated and the aqueous phase was extracted with dichloromethane (3X 15 ml). The combined organic phases (containing the precipitated title compound) were concentrated under reduced pressure. To remove the water, the green residue was co-evaporated in the presence of dichloromethane (3 ×). The crude product of the title compound (1.3g) was purified by crystallization from methanol (75 ml). The suspension was stirred at room temperature for 18 hours. The precipitate was isolated by filtration, washed with acetone (10ml) and diethyl ether (20ml) and dried in vacuo. A colorless solid was obtained (1.05g, 80% yield), which was identified as the title compound (optical purity: 92.0% ee).

Melting point: 250 + 252 deg.C (methanol)

Determination of optical purity by CE: RT [ (3S) -enantiomer ] ═ 19.2 min/4.0 area-%;

RT [ (3R) -enantiomer ] ═ 19.6 min/96.0 area-%; 92.0% ee (A).

Asymmetric hydrogenation of prochiral olefins:

ivi. (3R) -8-hydroxy-7- (3-hydroxy-3-phenyl-propyl) -2, 3-dimethyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

To an argon-filled flame-dried flask was added (R) -Alpine-boramine^TM(CAS 67826-92-0, 1.50g, 3.6 mmol). After addition of anhydrous THF (8ml) a colorless solution was obtained which was treated with boron trifluoride etherate (0.92ml, 1.03g, 7.3 mmol). The solution was stirred at room temperature for 2 hours. A colorless precipitate is obtained byThe precipitate was separated by filtration and washed with cold THF (6ml, argon atmosphere). The combined filtrate [ contains (-) -monoisopinocampheylborane]. (E) -8-hydroxy-2, 3-dimethyl-7- (3-phenyl-allyl) -imidazo [1, 2-a) is added slowly at room temperature]A suspension of pyridine-6-carboxylic acid dimethylamide (example xxiii, 0.42g, 1.2mmol) in dry THF (15ml) gave a yellow solution. After a reaction time of 5 hours, the solution was poured onto a cold mixture of aqueous potassium hydroxide solution (230mg solution in 1.6ml water), ethanol (4ml) and hydrogen peroxide (30 weight-% solution in water, 1.6 ml). After 30 minutes, the reaction mixture was poured onto a saturated ammonium chloride solution (20ml) and dichloromethane (40 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (1X 10 ml). The combined organic phases were washed with water, dried over sodium sulfate and concentrated under reduced pressure. The crude product (1.9g yellow oil) was purified by flash chromatography [40g silica gel, eluent: dichloromethane (to remove isopinocampheol) and then dichloromethane/methanol 20: 1(v/v)]. The corresponding fractions were evaporated to give a solid (320mg), which was washed with acetone (1ml), isolated by filtration and dried in vacuo. The title compound was isolated in 50% yield (0.22g of a colorless solid, optical purity: 27.8% ee).

Melting point: 178-

Determination of optical purity by CE: RT [ (3S) -enantiomer ] ═ 18.3 min/36.1 area-%;

RT [ (3R) -enantiomer ] ═ 18.6 min/63.9 area-%; 27.8% ee (A).

¹H-NMR(dmso-d₆，200MHz)：δ＝1.81(m_c，2H)，2.30，2.33(2s，6H)，2.50(bm_c)，2.78，2.91(2s，6H)，4.49(t，1H)，5.69(bs)，7.25(m_c，5H)，7.59(s，1H).

Analysis of configuration

The configurational assignments for the compounds of formulae 1 and 2 are based on the methods described in J.A.Dale and H.S.Mosher, J.Am.chem.Soc.1973, 95, 512-519. The following examples illustrate the process in more detail, but are not limited thereto. Other configurations of the compounds of formulas 1 and 2 can also be analyzed in a manner similar to that shown in scheme 8.

Reaction scheme 8:

it is well known that the Mitsunobu reaction proceeds with a conformational transition (see, e.g., O.Mit-sunobu Synthesis 1981, 1; D.L.Hughes org.Prep.Proc.int.1996, 28, 127). In particular, when a chiral secondary amine is employed, the reactant undergoes S_N2 displacement reactions with simultaneous conformational shifts (see, e.g., n.l. dirlam, b.s. moore, f.j.urban j.org.chem.1987, 52, 3587). Thus, the (9S) -enantiomer (compound of formula 1, example 2) was derived from (3R) -8-hydroxy-7- [ 3-hydroxy-3-phenyl-propyl]-2, 3-dimethyl-imidazo [1, 2-a [ ]]Pyridine-6-carboxylic acid dimethylamide. For 8-hydroxy-7- (3-hydroxy-3-phenyl-propyl) -2, 3-dimethyl-imidazo [1, 2-a]Configuration of the enantiomeric diol of pyridine-6-carboxylic acid dimethylamide to be imparted by the ketone 8-hydroxy-2, 3-dimethyl-7- (3-oxo-3-phenyl-propyl) -imidazo [1, 2-a]Hydrogenation of pyridine-6-carboxylic acid dimethylamide [1.2 equivalents of potassium tert-butoxide, 2 mol-% RuCl₂[(S)-BINAP][(S，S)-DPEN]82% yield at 45 bar hydrogen pressure, isopropanol, 80 ℃, 18 h]The enantiomerically enriched sample obtained was then treated with tert-butyldimethylsilyl chloride (reaction scheme 8). By reacting the resulting silyl ether (3S) -and (3R) -8- (tert-butyl-dimethylsilyloxy) -7- (3-hydroxy-3-phenyl-propyl) -2, 3-dimethyl-imidazo [1, 2-a ]]Pyridine-6-carboxylic acid dimethylamide, a compound of formula 24 (wherein R1, R2 ═ CH₃，R3＝(CH₃)₂HPLC separation of N-c (o), Arom ═ phenyl), (7: 3 enantiomer (3R): 3S ratio) confirmed the enantioselectivity of the catalytic hydrogenation reaction. Treatment of the reaction product of formula 24 with (S) - (+) -MTPACI affords the deacylated imidazopyridine of formula 25 (R1, R2 ═ CH)₃，R3＝(CH₃)₂N-c (o), Arom ═ phenyl). Cracking off phenolic ester group in 73 (R1, R2 ═ CH) gives diastereomeric Mosher esters of formula 26 (R1, R2 ═ CH)₃，R3＝(CH₃)₂N-c (o), Arom ═ phenyl), the ratio being determined as a result of the silyl ether enantiomer of formula 24.

FIG. 1 shows a schematic view of a

Shielding "

Mosher and coworkers have shown that for this class of compounds, the conformation shown in figure 1 is highly preferred. In the (3R) -diastereomer of the compound of formula 26, the methoxy function is located above the Arom group. The shielding effect of aromatic electrons can lead to the formation of methoxy groups in comparison with the (3S) -diastereomer¹The H-NMR signal is shifted to high fields. In a mixture of diastereomers¹In the H-NMR spectrum, signals of methoxy groups were observed at 3.43ppm (major)/3.52 ppm (minor), respectively. Thus, catalytic hydrogenation under the conditions reported above provides primarily the (3R) -diol of formula 23. After Mitsunobu etherification, an enantiomerically enriched sample of the (9S) -enantiomer of formula 1 was isolated.

Experimental details of configuration analysis

8-hydroxy-7- (3-hydroxy-3-phenyl-propyl) -2, 3-dimethyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide; produced by asymmetric catalytic hydrogenation

Reacting ketone 8-hydroxy-2, 3-dimethyl-7- (3-oxo-3-phenyl-propyl) -imidazo [1, 2-a]Pyridine-6-carboxylic acid dimethylamide (2.00g, 5.5mmol), potassium tert-butoxide (0.74g, 6.6mmol) and the hydrogenation catalyst RuCl₂[(S)-BINAP][(S，S)-DPEN](CAS 329736-05-2, a catalyst purchased from Strem Chemicals or obtainable according to the method described in R.Noyori and T.Ohkuma in Angew.chem.2001, 113, 40-75, 110mg, 0.11mmol, S/C60: 1) was dissolved in anhydrous isopropanol (150ml) which had been degassed with argon. The homogeneous brown solution was transferred to a 300ml autoclave and usedHydrogen was pressurized (45 bar) and heated to 80 ℃. The reaction mixture was kept at 80 ℃ for 18 hours, cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in water (50ml) and the pH of the solution was adjusted to 7.5 by the addition of 2N hydrochloric acid (2.4 ml). The aqueous phase was extracted with dichloromethane (3X 100 ml). The pH was again adjusted and the extraction repeated 2 more times. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography [100g silica gel, eluent: dichloromethane/methanol 15: 1(v/v)]. A grey solid was isolated (1.64g, 82% yield) and was identified as pure diol 8-hydroxy-7- (3-hydroxy-3-phenyl-propyl) -2, 3-dimethyl-imidazo [1, 2-a%]Pyridine-6-carboxylic acid dimethylamide. In the presence of a compound¹No trace chemical impurities were visible in the H-NMR spectrum. Due to the strong peak tail, direct determination of the optical purity and enantiomeric excess of the sample by chiral HPLC is not possible.

¹H-NMR(dmso-d₆，200MHz)：δ＝1.81(m_c，2H)，2.30，2.33(2s，6H)，2.50(bm_c，2.78，2.91(2s，6H)，4.49(t，1H)，7.25(m_c，5H)，7.59(s，1H).

b.8- (tert-butyl-dimethylsilyloxy) -7- (3-hydroxy-3-phenyl-propyl) -2, 3-dimethyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide; determination of the enantiomeric excess obtained by asymmetric reduction of ketones

For analysis, diol 8-hydroxy-7- (3-hydroxy-3-phenyl-propyl) -2, 3-dimethyl-imidazo [1, 2-a]Pyridine-6-carboxylic acid dimethylamide (200mg, 0.54mmol, asymmetric hydrogenation product described in example a) was dissolved in dichloromethane (10 ml). Triethylamine (110mg, 151. mu.l, 1.09mmol) and a solution of tert-butyldimethylsilyl chloride (179mg, 1.19mmol) in dichloromethane (5ml) were added. The reaction mixture was heated to reflux for 5.25 hours and then quenched by the addition of saturated ammonium chloride solution (10 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (2X 10 ml). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. A green oil was obtainedSubstance (296mg), which was purified by flash chromatography (20g silica gel, eluent: ethyl acetate). The title compound (190mg) was isolated in 73% yield. In a colourless oil¹No impurities were visible in the H-NMR spectrum. The enantiomeric excess was determined by chiral HPLC using the following conditions: column: 2CHIRALPAK^®AD-H column 250 × 4.6mm, 5 μm; eluent: isopropanol/hexane ═ 17: 83(v/v), flow rate: 1 ml/min; (ii) temperature; 35 ℃ is carried out. The (3R) -enantiomer (68.35 area-%) and the (3S) -enantiomer (31.65 area-%) of the title compound were eluted with a retention time of 9.97 min/10.60 min, respectively. Thus, the asymmetric catalytic hydrogenation was carried out at 36.7% ee.

¹H-NMR(CDCl₃，200MHz)：δ＝0.33，0.44(2s，6H)，1.02(s，9H)，2.00(m_c，2H)，2.33，2.37(2s，6H)，2.65(m_c，2H)，2.88，3.11(2s，6H)，4.58(dd，1H)，7.26m_c，5H)，7.38(s，1H).

(2R) -3, 3, 3-trifluoro-2-methoxy-2-phenyl-propionic acid [3- (6-dimethylcarbamoyl-8-hydroxy-2, 3-dimethyl-imidazo [1, 2-a ] pyridin-7-yl) - (1R, S) -1-phenyl-propyl ester; enantiomer configuration of 8-hydroxy-7- (3-hydroxy-3-phenyl-propyl) -2, 3-dimethyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide

(A) For the determination of 8-hydroxy-7- (3-hydroxy-3-phenyl-propyl) -2, 3-dimethyl-imidazo [1, 2-a]Absolute configuration of the (3S) -and (3R) -enantiomers of pyridine-6-carboxylic acid dimethylamide (example a) (S) - (+) -MTPACI (95mg, 0.38mmol) was dissolved in pyridine (810. mu.l) and carbon tetrachloride (810. mu.l). Addition of silyl ether 8- (tert-butyl-dimethylsilyloxy) -7- (3-hydroxy-3-phenylpropyl) -2, 3-dimethyl-imidazo [1, 2-a]A solution of the (3R) -and (3S) -enantiomers of pyridine-6-carboxylic acid dimethylamide (example b, 100mg, 0.21mmol, containing the two enantiomers in a ratio of 7: 3) in dichloromethane (500. mu.l). The reaction mixture was stirred at room temperature for 6 hours, then diluted with water (5ml) and chloroform (10 ml). The phases were separated and the aqueous phase was extracted with chloroform (2X 10 ml). The organic phase is saturatedAnd ammonium chloride solution (5ml), dried over sodium sulfate, and concentrated under reduced pressure. The crude product was dried thoroughly and then purified by flash chromatography (10g silica gel, eluent: ethyl acetate/petroleum ether 7: 3). A pale yellow oil was isolated (50mg, 30% yield) which was identified as a diastereomeric mixture of diesters of formula 25, where R1, R2 ═ CH₃，R3＝(CH₃)₂N-c (o), and Arom ═ phenyl.

¹H-NMR(CDCl₃，200MHz)：δ＝2.00-2.60(bs)，2.34，2.37(2s，∑10H)，2.73(s，3H)，2.87，2.97(2s，∑3H)，3.44，3.48(2s，∑3H)，3.79，3.85(2s，∑3H)，5.61(bt，1H)，7.30(m_c，10H)，7.54(m_c，3H)，7.63(s，1H)，8.06(m_c，2H).

(B) Wherein R1, R2 ═ CH₃，R3＝(CH₃)₂A solution of the diastereomeric mixture of N-c (o), and Arom ═ phenyl diester of formula 25 in deuterated chloroform at room temperature for 10 days. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography [2 × 6g silica gel, eluent: dichloromethane/methanol 15: 1(v/v)]Is isolated in 72% yield wherein R1, R2 ═ CH₃，R3＝(CH₃)₂N-c (o), and Arom ═ phenyl diastereomeric mixture of esters of formula 26 (22mg colorless foam). In the presence of the compound¹In the H-NMR spectrum, two different signals for the methoxy group of the acyl moiety were seen. The chemical shift value of the signal corresponding to the major/minor enantiomer was 3.43/3.52 ppm.

¹H-NMR(dmso-d₆，400MHz)：δ＝2.05(bs，1H)，2.17(bs，1H)，2.29，2.32(2s，6H)，2.48(bs)，2.71，2.75(2s，∑3H)，2.82，2.84(2s，∑3H)，3.43，3.52(2s，Σ3H)，5.98(m_c，1H)，7.41(m_c，10H)，7.61，7.62(2s，∑1H).

Based on the method proposed by Mosher et al (see above) for the configuration analysis, the main enantiomer of diol 8-hydroxy-7- (3-hydroxy-3-phenyl-propyl) -2, 3-dimethyl-imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide, prepared as described above, has the (3R) -configuration.

Commercial applicability

The compounds of formula 1 and their salts have useful pharmacological properties which make them commercially useful. In particular, they have a remarkable gastric secretion inhibitory effect and an excellent gastrointestinal protective function for warm-blooded animals, particularly humans. The compounds of the invention are distinguished by a high selectivity of action, a favorable duration of action, in particular good enteral activity, no significant side effects and a broad therapeutic spectrum.

"gastrointestinal protection" as used herein means the prevention and treatment of gastrointestinal diseases, especially gastrointestinal inflammatory diseases and lesions (e.g. gastric ulcers, peptic ulcers, including peptic ulcer bleeding, duodenal ulcers, gastritis, hyperacidity or drug-related functional gastric disorders) which may be caused by, for example, microorganisms (e.g. helicobacter pylori), bacterial toxins, drugs (e.g. certain anti-inflammatory and antirheumatic drugs, such as NSAIDs and COx-inhibitors), chemicals (e.g. ethanol), gastric acid or stress conditions. It is understood that according to general knowledge, "gastrointestinal protection" includes gastroesophageal reflux disease (GERD), symptoms of which include, but are not limited to, heartburn and/or acid regurgitation.

In various models for determining ulcer-inhibiting and secretion-inhibiting properties, the compounds of the present invention were demonstrated to be significantly superior to the compounds known in the prior art in terms of various excellent properties. Due to these properties, the compounds of formula 1 and their pharmaceutically acceptable salts are very suitable for use in human and animal medicine, especially when they are used for the treatment and/or prophylaxis of gastric and/or intestinal diseases.

Accordingly, another aspect of the present invention is a compound of formula 1 of the present invention for the treatment and/or prevention of the above-mentioned diseases.

Another aspect of the present invention is a compound of formula 1 of the present invention substantially free of a compound of formula 2 for use in the treatment and/or prevention of the above-mentioned diseases.

The invention likewise comprises the use of a compound of the formula 1 according to the invention which is substantially free of a compound of the formula 2 for the preparation of a medicament for the treatment and/or prophylaxis of the abovementioned diseases.

The invention also comprises the use of a compound of formula 1 according to the invention for the treatment and/or prophylaxis of the abovementioned diseases.

The invention also includes the use of a compound of formula 1 of the invention substantially free of a compound of formula 2 for the treatment and/or prophylaxis of the diseases mentioned above.

Another aspect of the present invention is a medicament comprising one or more compounds of formula 1 and/or pharmaceutically acceptable salts thereof.

Another aspect of the present invention is a medicament comprising one or more compounds of formula 1 and/or pharmaceutically acceptable salts thereof, said medicament being substantially free of a compound of formula 2.

These medicaments can be prepared by methods known per se and methods well known to the person skilled in the art. As medicaments, the pharmacologically active compounds according to the invention (═ active compounds) can be used as such or together with suitable pharmaceutical excipients or carriers in the form of tablets, coated tablets, capsules, suppositories, patches (e.g. as TTS), emulsions, suspensions or solutions, preferably in amounts of 0.1 to 95%, and pharmaceutical administration forms (e.g. sustained release forms or enteric forms) can be obtained which are well suited to the desired onset of the active compound and/or duration of action by appropriate selection of excipients and carriers.

The person skilled in the art is well known, based on his/her expert knowledge, as excipients or carriers suitable for the pharmaceutical formulation. In addition to solvents, gel-forming agents, suppository bases, tablet auxiliaries and other active compound excipients, it being possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavorings, preservatives, cosolvents, colorants or, in particular, permeation promoters and complexing agents (e.g. cyclodextrins).

The active compounds can be administered orally, parenterally or transdermally.

In general, it has proven advantageous to administer the active compounds orally in humans in the following doses: the daily dose is from about 0.01 to about 20, preferably from 0.05 to 5, in particular from 0.1 to 1.5, mg/kg of body weight, and, if appropriate, can be administered in a plurality of doses, preferably in 1 to 4 doses, in order to achieve the desired effect. When the treatment is carried out parenterally, similar dosages may be employed or, in particular in the case of intravenous administration of the active compounds, lower dosages are generally employed. Any person skilled in the art can easily determine on the basis of his/her expert knowledge the optimal dosage and mode of administration of the active compounds required in each case.

If the compounds of the invention and/or their salts are used for the treatment of the above-mentioned diseases, the pharmaceutical preparations may also contain one or more pharmacologically active ingredients of other pharmaceutical groups. Examples are neuroleptics (e.g. benzodiazepine  class drugs such as diazepam), antispasmodics (e.g. betaverine or camirofene), anticholinergics (e.g. oxybenzylamine or phencarbamide), local anaesthetics (e.g. tetracaine or procaine) and, if appropriate, enzymes, vitamins or amino acids.

Emphasis is placed in the present specification on the combination of the compounds of the invention with drugs having an acid secretion inhibiting effect such as H2 receptor blockers (e.g. cimetidine, ranitidine), H⁺/K⁺Combinations of ATPase inhibitors (e.g. omeprazole, pantoprazole) are either administered in combination with so-called peripheral anticholinergics (e.g. pirenzepine, telenzepine) and with gastrin antagonists in order to increase the main efficacy and/or to eliminate or reduce side effects in an additive or superadditive sense, or in combination with further antibacterial active substances (e.g. cephalosporins, tetracyclines, penicillins, macrolides, nitroimidazoles or bismuth salts) in order to control helicobacter pylori. Examples of suitable antimicrobial co-ingredients are mezlocillin, ampicillin,Amoxicillin, cephalothin (cefalothin), cefoxitin, cefotaxime, imipenem, gentamicin, amikacin, erythromycin, ciprofloxacin, metronidazole, clarithromycin, azithromycin, and combinations thereof (e.g., clarithromycin + metronidazole).

Due to their excellent gastric and intestinal protective action, the compounds of formula 1 are suitable for free or fixed combination with drugs known to have some ulcerogenic effects (e.g. some anti-inflammatory agents and antirheumatic drugs such as NSAIDs). Furthermore, the compounds of formula 1 are suitable for use in free or fixed combination with motility modulating drugs.

Pharmacology of

The excellent gastric protection and gastric acid secretion inhibition of the compounds of the present invention can be confirmed in the study of animal test models. The compounds of formula 1 and their optical antipodes of formula 2 according to the invention, which have been investigated in the following models, have been provided with numerical and letter numbers which correspond to the numerical and letter numbers of the examples of these compounds.

Testing the antisecretory Effect on perfused rat stomach

In the following table a, the effect of intraduodenal administration of the compounds of formula 1 and their optical antipodes of formula 2 according to the invention on pentagastrin-stimulated gastric acid secretion in perfused rat stomachs is shown.

TABLE A

Numerical sequence number	Dose (. mu. mol/kg) i.d.	Inhibition of gastric acid secretion (%)	Letter number	Dose (. mu. mol/kg) i.d.	Inhibition of gastric acid secretion (%)
Numerical sequence number	Dose (. mu. mol/kg) i.d.	Inhibition of gastric acid secretion (%)	Letter number	Dose (. mu. mol/kg) i.d.	Inhibition of gastric acid secretion (%)	1	1	100	A	3	＜40
2	1	100	B	3	＜40	1	1	100	A	3	＜40
2	1	100	B	3	＜40	3	6	＞50	C	6	＜30
4	3	＞60	D	3	＜40	3	6	＞50	C	6	＜30
4	3	＞60	D	3	＜40	5	3	＞70	E	3	＜30
6	3	100	F	3	＜40	5	3	＞70	E	3	＜30
6	3	100	F	3	＜40	7	1	100	G	3	＜40
8	2	100	H	3	＜40	7	1	100	G	3	＜40
8	2	100	H	3	＜40	9	1	100	I	1	＜50
10	1	100	J	3	＜50	9	1	100	I	1	＜50
10	1	100	J	3	＜50	11	1	100	K	1	＜40
12	3	100				11	1	100	K	1	＜40
12	3	100				13	3	100

Method

After tracheotomy, anesthetized rats (CD rats, female, 200-250 g; 1.5g/kg i.m. urethane) were opened ventrally through a median epigastric incision and one PVC catheter was fixed transorally in the esophagus and the other through the pylorus so that the end of the tube just protruded into the gastric cavity. The catheter led out from the pylorus is led out of the body through the side opening of the right abdominal wall.

After thorough rinsing (approximately 50-100ml), warm (37 ℃) physiological NaCl solution was passed continuously through the stomach (0.5 ml/min, pH 6.8-6.9; Braun-Unita I). The pH in the effluents collected at 15-minute intervals was determined in each case (pH meter 632, glass electrode EA 147; phi. about.5 mm, Metrohm) and the HCl secreted was determined by titration with freshly prepared 0.01N NaOH solution to pH 7(Dosimat 665 Metrohm).

Approximately 30 minutes after the end of the surgery (i.e. after the measurement of the 2 initial fractions), gastric secretion was stimulated by intravenous continuous infusion of 1 μ g/kg (═ 1.65ml/h) pentagastrin (left femoral vein). The test substance was intraduodenally administered at a liquid volume of 2.5ml/kg 60 minutes after the start of the pentapeptide gastrin infusion. The body temperature of the animals was kept constant at 37.8-38 ℃ by infrared irradiation and a heating pad (automatic, continuous (stepless) control by a rectal temperature sensor).

Claims

1. A compound of formula 1:

wherein

R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, and

r32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,

or therein

r6 is hydrogen, 1-4C-alkyl or halogen, and

r7 is hydrogen, 1-4C-alkyl or halogen,

wherein

Aryl is phenyl or substituted phenyl having 1, 2 or 3 identical or different substituents selected from the group consisting of: 1-4C-alkyl, 1-4C-alkoxy, carboxyl, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano.

2. A compound of formula 1 according to claim 1 and salts thereof, wherein

R1 is 1-4C-alkyl or 3-7C-cycloalkyl,

r2 is 1-4C-alkyl, halogen, hydroxy-1-4C-alkyl, 2-4C-alkenyl or 3-7C-cycloalkyl,

wherein

R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, and

r32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,

or therein

wherein

r6 is hydrogen, 1-4C-alkyl or halogen, and

r7 is hydrogen, 1-4C-alkyl or halogen,

wherein

3. A compound of formula 1 according to claim 1 and salts thereof, wherein

R1 is 1-4C-alkyl,

r2 is 1-4C-alkyl, halogen, hydroxy-1-4C-alkyl or 2-4C-alkenyl,

r3 is hydroxy-1-2C-alkyl, 1-4C-alkoxy-1-2C-alkyl or a radical-CO-NR 31R32,

wherein

R31 is hydrogen, 1-7C-alkyl,

r32 is hydrogen, 1-7C-alkyl,

or therein

arom is phenyl, furyl, thienyl, pyrrolyl or pyridyl substituted with R4 and R5,

wherein

r5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen or hydroxy.

4. A compound of formula 1 according to claim 1 and salts thereof, wherein

R1 is 1-4C-alkyl,

r2 is 1-4C-alkyl, halogen, hydroxy-1-4C-alkyl or 2-4C-alkenyl,

r3 is hydroxy-1-2C-alkyl, 1-4C-alkoxy-1-2C-alkyl or a radical-CO-NR 31R32,

wherein

R31 is hydrogen or 1-7C-alkyl,

r32 is hydrogen or 1-7C-alkyl,

or therein

arom is phenyl, furyl, thienyl, pyrrolyl or pyridyl substituted with R4 and R5,

wherein

r5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen or hydroxy.

5. A compound of formula 1 according to claim 1 and salts thereof, wherein

R1 is 1-4C-alkyl,

r2 is 1-4C-alkyl, halogen or hydroxy-1-4C-alkyl,

r3 is 1-4C-alkoxy-1-2C-alkyl or a radical-CO-NR 31R32, wherein

R31 is hydrogen or 1-7C-alkyl,

r32 is hydrogen or 1-7C-alkyl,

or therein

arom is phenyl or thienyl substituted with R4,

wherein

R4 is hydrogen, 1-4C-alkyl or halogen.

6. A compound of formula 1 according to claim 1 and salts thereof, wherein

R1 is 1-4C-alkyl,

r2 is 1-4C-alkyl,

r3 is a group-CO-NR 31R32,

wherein

R31 is hydrogen or 1-7C-alkyl,

r32 is hydrogen or 1-7C-alkyl,

arom is phenyl.

7. The compound (9S) -2, 3-dimethyl-9-phenyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide and salts thereof.

8. The compound (9S) -2, 3-dimethyl-9- (2-methylphenyl) -7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide and salts thereof.

9. The compound (9S) -9- (4-fluorophenyl) -2, 3-dimethyl-7H-8, 9-dihydro-pyrano [2, 3-c ] -imidazo [1, 2-a ] pyridine-6-carboxylic acid dimethylamide and salts thereof.

10. A process for the synthesis of a compound of formula 1 as defined in claim 1, said process comprising

Reacting a compound of formula 8

Wherein R1, R3 and Arom have the meanings given in claim 1, into a racemic mixture of a compound of formula 1 as claimed in claim 1 and its optical antipode of formula 2, wherein R1, R2, R3 and Arom have the meanings given in claim 1,

and

11. A process for the synthesis of a compound of formula 1 as defined in claim 1, said process comprising

Wherein R1, R2, R3 and Arom have the meanings given in claim 1,

12. A process for the synthesis of a compound of formula 1 as defined in claim 1, said process comprising

-converting the compound of formula 14 to the compound of formula 17

Wherein R1, R2, R3 and Arom have the meanings given in claim 1,

13. A process for the synthesis of a compound of formula 1 as defined in claim 1, said process comprising

-converting a compound of formula 13, wherein R1, R2 and R3 have the meanings given in claim 1, into a compound of formula 14, wherein R1, R2, R3 and Arom have the meanings given in claim 1

-and further conversion of the compound of formula 14 to a racemic mixture of the compound of formula 1 and its optical antipode of formula 2

And

14. A medicament comprising a compound according to claim 1 and/or a pharmaceutically acceptable salt thereof together with conventional pharmaceutical adjuvants and/or excipients.

15. Medicament comprising a compound according to claim 1 and/or a pharmaceutically acceptable salt thereof together with customary pharmaceutical auxiliaries and/or excipients, wherein the medicament is substantially free of compounds of the formula 2

Wherein R1, R2, R3 and Arom have the meanings given in claim 1.

16. The use of a compound of claim 1 and pharmaceutically acceptable salts thereof for the prevention and treatment of gastrointestinal disorders.