HUP0102117A2 - Imidazo[1,2-a]pyridine derivatives and medicinal preparations containing them - Google Patents

Description

P O 1 O 2 1 1 7

71.313/SZE

S.B.G. & K.

International Patent Office H-1062 Budapest, Andrássy út 113. Telephone: 34-24-950, Fax: 34-24-323

PUBLICATION COPY

Medicinal products containing volatile compounds

The invention relates to novel antiviral compounds and pharmaceutical compositions containing them.

The common cold, a viral upper respiratory tract infection, is very common. It is estimated that there are almost 1 billion cases of the common cold in the United States alone each year. In humans, the common cold is caused primarily by rhinoviruses, a member of the picornavirus family. Since more than 110 rhinovirus strains have been identified, the development of a rhinovirus vaccine that covers all of them is impractical. Chemotherapy is more effective. Another member of the picornavirus family is the enterovirus, which includes approximately 80 human pathogens. Many enteroviruses cause symptoms similar to the common cold; however, some cause more serious diseases, such as polio, conjunctivitis, aseptic meningitis, or myocarditis.

Rhinovirus infection is characterized by increased nasal discharge and nasal congestion. In addition, otitis media is common, bronchitis may develop, sinusitis may worsen, and asthma may develop. Although rhinovirus infection is often considered a nuisance, as it occurs very frequently in otherwise healthy individuals, rhinovirus infection has been the subject of extensive research.

The ability of chemical compounds to inhibit the growth of viruses in vitro can be easily demonstrated by the well-known viral plaque inhibition assay or cytopathogenicity assay (CPE) [Siminoff, Applied Microbiology, 9(1), 66 (1961)]. Although a number of chemical compounds have been found to inhibit the growth of picornaviruses, most of these compounds are not suitable for use because (1) they have a limited spectrum of activity, (2) they have undesirable side effects, or (3) they are unable to prevent infection or disease in animals or humans [see Textbook of Human Virology, edited by Belshe Robert B, Chapter 16, "Rhinoviruses", Levandowski Roland A, 391405 (1985)]. Thus, despite extensive research and the recognition of therapeutic potential for rhinovirus inhibitors, no useful therapeutic agent has been developed to date. For example, antiviral benzimidazole compounds are disclosed in U.S. Patents 4,008,243, 4,018,790, 4,118,573, 4,118,742, and 4,174,454.

The present invention relates to novel pyridoimidazole compounds that inhibit the proliferation of picornaviruses, including rhinoviruses (bovine and human, etc.), enteroviruses such as polioviruses and the like, coxsackieviruses of groups A and B, echoviruses, cardioviruses such as encephalomyocarditis virus (EMC) and the like, aptoviruses such as foot-and-mouth disease virus and the like, hepatitis viruses such as hepatitis C virus and the like.

Summary of the invention

The invention relates to compounds of general formula (I) and their pharmaceutically acceptable salts, wherein in the formula

A is phenyl, pyridyl, substituted phenyl, substituted pyridyl or benzyl;

R is hydrogen, -COR ⁴ or -COCF 3 ;

X is =N-OH, O= or -CHR ¹ ;

R ¹ represents a hydrogen atom, a halogen atom, -CN, C 1-4 alkyl-, -C=CH, -CO(C 1-4 alkyl), -CO ₂ (C 1-4 alkyl) or -CONR ² R ³ ;

R ² and R ³ are independently hydrogen or C 1-4 alkyl;

A' represents a hydrogen atom, a halogen atom, a C1-C6 alkyl, a benzyl, a naphthyl, a thienyl, a furyl, a pyridyl, a pyrrolyl, -COR ⁴ , -S(O) _n R ⁴ or a group of general formula (a);

R ⁴ is C 1-6 alkyl, phenyl or substituted phenyl;

n is 0, 1 or 2;

each R ⁵ independently represents a hydrogen atom or a halogen atom;

m is 1, 2, 3 or 4; and

R ⁶ represents a hydrogen atom, a halogen atom, -CF ₃ , -OH, -CO ₂ H, -NH ₂ , -NO ₂ , -CONHOCH 3 , a C 1-4 alkyl or -CO ₂ (C 1-4 alkyl) or a C 1-4 alkoxy group.

The invention also provides pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier, diluent or excipient.

The invention also provides a method for inhibiting picornavirus, comprising administering to a patient in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The invention also provides a method for inhibiting Hepatitis C virus, comprising administering to a patient in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The invention also relates to the use of compounds of general formula (I) for inhibiting picornavirus, rhinovirus or Hepatitis virus.

Detailed description of the invention

The subject of the invention is the compounds of general formula (I) as presented above, these compounds can be effectively used as antiviral agents.

All temperature values in this description are in degrees Celsius (°C). The units in this description are in mass units, with the exception of liquids, which are given in volume units.

The term "C1-6 alkyl" refers to a straight or branched chain alkyl group having 1-6 carbon atoms. Typical C1-6 alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, and the like. The term "C1-6 alkyl" also includes "C1-4 alkyl" groups and includes cycloalkyl groups in which the alkyl groups form a ring.

The term "halogen" or "halo" means a chlorine atom, a fluorine atom, a bromine atom, or an iodine atom.

The term "substituted phenyl" refers to a phenyl ring bearing 1, 2 or 3 substituents, in which the substituents may be independently halogen, C1-4 alkyl, C1-6 alkoxy or trifluoromethyl.

The term "substituted pyridyl" refers to a pyridyl group bearing 1, 2 or 3 substituents, where the substituents may be independently halogen, C1-4 alkyl, C1-6 alkoxy or trifluoromethyl.

As mentioned above, the invention also includes pharmaceutically acceptable salts of the compounds of formula (I). The compounds of the invention are generally neutral, but in some cases they may contain sufficiently acidic, sufficiently basic or both functional groups, and as a result the compounds can be reacted with inorganic bases, inorganic acids or organic acids to form a pharmaceutically acceptable salt.

The term "pharmaceutically acceptable salt" refers to salts of the compounds of formula (I) which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include salts of the compounds of the invention with inorganic or organic acids or inorganic bases. These salts are referred to as acid addition or base addition salts.

Acids commonly used to form acid addition salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like; organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.

Pharmaceutically acceptable salts include, but are not limited to: sulfate, pyrosulfate, hydrogen sulfate, sulfite, hydrogen sulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate salts, salts with mandelic acid and the like. Among the pharmaceutically acceptable acid addition salts, salts with inorganic acids such as hydrochloric acid salts and hydrobromic acid salts, and salts with organic acids such as maleic acid or methanesulfonic acid salts are preferred.

Base addition salts include, but are not limited to, salts formed with inorganic bases such as ammonium or alkali metal or alkaline earth metal hydroxides, carbonates, hydrogen carbonates, and the like. Bases useful in preparing the salts of the invention include sodium6 ·: ·:

• · · · · · « ·· Μ»

hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate and the like. The potassium and sodium salts are particularly preferred.

It is noted that for the salts of the invention, the counterion in the salt does not play a decisive role, provided that the salt as a whole is pharmaceutically acceptable and that the counterion does not impart undesirable properties to the salt.

The pharmaceutically acceptable salts of the invention are generally prepared by reacting the compounds of formula (I) with an equimolar or excess amount of an acid or base. The reactants are generally mixed in a neutral solvent, such as diethyl ether, benzene or the like for the preparation of acid addition salts, or water or alcohols and the like for the preparation of base addition salts. The salts generally precipitate from solution within about 1 hour to 10 days; the precipitate can be isolated by filtration or other conventional methods.

The compounds of the invention may have a cis or trans configuration, cis compounds being those in which the substituent on the alkene group is in the cis position relative to the ring designated A; trans compounds being those in which the substituent on the alkene group is in the trans position relative to the ring designated A. Isomers and mixtures thereof are also within the scope of the invention.

Preferred compounds of the invention are illustrated by the following lettered embodiments, without intending to limit the invention to these compounds. Preferred compounds of formula (I) are those in which: a) A is phenyl, pyridyl, substituted phenyl or substituted pyridyl;

b) A is phenyl or substituted phenyl;

c) A is difluorophenyl or fluorophenyl;

d) A is pyridyl, substituted phenyl or substituted pyridyl;

e) R is hydrogen;

f) R is -COCF ₃ ;

g) X is -NOH;

h) X is -CHR ¹ ;

i) R ¹ is -CONR ² R ³ , -CO ₂ -(C 1-4 alkyl)- or -CN;

j) R ¹ is -CONR ² R ³ ;

k) R ¹ is -CO ₂ (C 1 -C 4 alkyl)-group;

I) R ² and R ³ are independently methyl or hydrogen;

m) A' is a C1-C6 alkyl, naphthyl, thienyl, -COR ⁴ , -S(O) _n R ⁴ or a group of general formula (a);

n) A' is C1-6 alkyl, -COR ⁴ , -S(O) _n R ⁴ or a group of general formula (a);

o) A’ means a group of general formula (a);

p) A' is C1-6 alkyl, -COR ⁴ or -S(O) _n R ⁴ ;

q) A' is -COR ⁴ or -S(O) _n R ⁴ ;

r) R ⁵ is fluorine and m is 5;

s) m is 1, 2, 3 or 5;

t) R is -CF3, -OH, _-CO2H , _-NH2 , _-NO2 , _-CONHOCH3 , C1-4 alkyl, or C1-4 alkoxy;

u) R ⁶ is -CF ₃ , -OH, -CONHOCH 3 , C 1-4 alkyl, C 1-4 alkoxy; and

v) R is -CF ₃ , -OH, C 1-4 alkyl, C 1-4 alkoxy.

Reaction schemes

The compounds of formula (I) according to the invention can be prepared by known methods and by the methods described in this specification. The compounds of formula (I) in which A' is hydrogen, C1-C6 alkyl naphthyl, thienyl, furyl, pyridyl, pyrrolyl or a group of formula (a) can be prepared according to reaction scheme 1, where in the formulas

L is a leaving group selected from halogen, O-triflate, O-mesylate, O-tosylate and the like;

Z represents a hydrogen atom, a C1-C6 alkyl, naphthyl, thienyl, furyl, pyridyl, pyrrolyl or a group of general formula (a).

Compounds of formula (A) can be prepared by known methods and the processes described herein. For example, compounds of formula (A) can be prepared according to Scheme 2.

A suitably substituted aryl group can be acylated under Friedel-Crafts conditions in the presence of a Lewis acid using a suitably substituted acid anhydride, carboxylic acid or acid chloride to form a compound of formula (H) [see, e.g., Friedel-Crafts and Related Reactions, Olah G. A., ed. Wiley J. and Sons, N. Y. 31, chap. 32 (1964)]. Suitable Lewis acid catalysts include, but are not limited to, trifluoroacetic anhydride/phosphoric acid, trifluoromethanesulfonic acid, ferric chloride, zinc chloride, copper triflate (CuOTf), phosphorus trichloride oxide, trifluoroacetic acid, aluminum trichloride, and the like. Aluminum trichloride is preferred among Lewis acids. Preferred solvents include, but are not limited to, methylene chloride, acetonitrile, 1,2-dichloroethane, nitromethane, lower alcohols, acetonitrile, dimethyl sulfoxide, and the like. The reaction is preferably carried out neat, without solvent, preferably using the substituted aryl compound itself as the solvent. The substituted aryl compound is generally used in substantially a molar excess. Generally, the aryl compound is used in an excess of about 3 to 10 molars based on 6-chloronicotinic acid chloride. Generally, a molar excess of about 3.8 is preferred. The reaction is preferably carried out at a temperature of about 80°C.

Alternatively, the compounds of formula (H) can be prepared by reacting a compound of formula (G) with an aryl anion according to known methods. The Weinreb amide of formula (G) can be prepared by well-known methods starting from the corresponding 1-chloro-5-nicotinic acid. Similarly, the acyl anions used in the preparation of the compounds of formula (H) can be prepared by known methods, the acyl anions being well-known compounds. For example, a suitably substituted bromo- or iodo-aryl compound is subjected to a metal-halogen exchange reaction to give the corresponding metal aryl anion according to methods well known to those skilled in the art [see Organic Reactions, Vol. 6, 339 (1951), where the conditions for the metal-halogen exchange reaction are described in detail]. Suitable solvents for use in the process include, but are not limited to, toluene, dimethylformamide, methylene chloride, diethyl ether, acetonitrile, tetrahydrofuran, and the like. Tetrahydrofuran is preferred. Suitable metal sources include, but are not limited to, molecular lithium, alkyl lithiums, and the like, including tert-butyl lithium. n-Butyllithium is a particularly preferred metal source. The metal is generally used in a slight molar excess, such that about 1 to 1.1 molar excess is used; a 1.03 molar excess is preferred. The process is preferably carried out at -78°C, with the reaction taking about 15 minutes.

Compounds of formula (H) are amined with ammonia at elevated pressure to give compounds of formula (J). A compound of formula (H) is dissolved in a suitable solvent, liquid ammonia is added to the solution, and the reaction mixture is placed in a container resistant to elevated pressure and sealed. Suitable solvents include, for example, toluene, lower alcohols, acetonitrile, diethyl ether, tetrahydrofuran, dimethylformamide, chloroform, methylene chloride, and the like. Ethanol is preferred among the solvents. The operation is preferably carried out at a temperature of about 145°C, and the reaction is completed in approximately 16 hours.

The compounds of formula (A) can be prepared by known methods. For example, the compound of formula (J) can be tosylated by adding a base and tosyl chloride in an inert solvent. Suitable solvents for this operation include, for example, tetrahydrofuran, lower alcohols, ethyl acetate, methylene chloride, acetonitrile, chloroform and the like. Suitable bases include, for example, triethylamine, sodium bicarbonate, sodium hydroxide, imidazole and the like. Pyridine is preferably used as the base and solvent. Tosyl chloride is generally used in a slight molar excess. For example, about 1-2 molar excess of tosyl chloride is used based on the compound of formula (J), preferably about 1.1 molar excess. The reaction is preferably carried out at a temperature of about 90°C for about 16 hours.

Compounds of formula (B) can be prepared by known methods or by the methods described herein. For example, compounds of formula (B) containing a bromine atom in the position of L can be prepared according to reaction scheme 3.

The starting material is suitably substituted acetic acid of formula (K), which is brominated in a suitable solvent in the presence of a radical initiator to give the compound of formula (L). Suitable brominating agents include, but are not limited to, molecular bromine, N-bromosuccinimide and the like. Preferred brominating agents include, but are not limited to, N-bromosuccinimide. Suitable solvents include, but are not limited to, diethyl ether, tetrahydrofuran, methylene chloride, chloroform, acetonitrile, benzene, dimethyl sulfoxide, carbon tetrachloride and the like. Carbon tetrachloride is preferably used as the solvent. Suitable radical initiators include, for example, phosphorus trichloride, molecular phosphorus, benzoyl peroxide, UV radiation and the like. Preferred initiators include benzoyl peroxide and UV radiation. The bromination reagents are generally used in stoichiometric amounts. Generally, 1 equivalent of bromination agent is used based on the compound of formula (K), and the initiator is generally used in catalytic amounts. About 0.1 to 1 mol% of initiator is used based on the compound of formula (K), with 0.4 mol% being preferred. The operation is preferably carried out at a temperature of about 77°C for about 5 hours.

The compounds of formula (M) can be prepared from the compounds of formula (L) by known amidation methods. For example, the operation can be carried out by dissolving or suspending the compound of formula (L) in a suitable solvent, and then adding a nucleophilic chlorine source to the solution or suspension to obtain the corresponding acid chloride, which is then amidated with gaseous ammonia under in situ conditions. Suitable solvents for the process include, for example, alkanes, dimethylformamide, lower alcohols, ethyl acetate, methylene chloride, tetrahydrofuran, diethyl ether, acetonitrile, chloroform and the like. Preferred solvents include dimethylformamide, methylene chloride, hexane and toluene. Suitable chlorinating agents include, for example, thionyl chloride, phosphorus pentachloride, bis(trichloromethyl)carbonate, allyl chloroformate, phosphorus trichloride, triphosgene, oxalyl chloride and the like. Oxalyl chloride is preferred among the chlorinating agents. The chlorinating agent is generally used in a slight molar excess. Generally, the chlorinating agent is used in an approximately 1-2 molar excess based on the compound of formula (L); a 1.6 molar excess is preferred. Ammonia is generally used in a significant molar excess. For example, ammonia gas is passed through the reaction mixture for about 1 hour, introducing an unspecified amount of ammonia into the reaction mixture. The temperature of the reaction mixture is preferably about 0°C when the chlorinating agent is added, and the reaction mixture is then maintained at about 27°C for about 3 hours before gaseous ammonia is introduced into the mixture, the gas introduction being carried out at about 22°C for about 1 hour.

In addition, compounds of formula (B) containing an O-tosylate group in the L position can be prepared according to Scheme 4.

Compounds of formula (O) can be prepared from suitably substituted aldehydes by known methods. For example, a compound of formula (N) is mixed with an equivalent of a carboxylate acyl anion, for example trimethylsilyl cyanide can be used, and the reaction results in a compound of formula (O) after hydrolysis. Suitable solvents include, for example, lower alcohols, ethyl acetate, methylene chloride, acetonitrile, chloroform and the like. The reaction is preferably carried out without a solvent if the aldehyde or acyl anion equivalent is in a liquid state. The acyl anion equivalent is generally used in a stoichiometric ratio. For example, 1 equivalent of acyl anion is generally used for benzaldehyde, and this ratio is preferred. The reaction mixture is preferably maintained at about 25°C for approximately 72 hours after the addition of the equivalent of the acyl anion, and then the mixture is heated at 100°C for about 18 hours to obtain the compound of formula (O).

Compounds of formula (P) can be prepared by known methods starting from compounds of formula (O). Acetylation of hydroxy acid derivatives is known in the art [see Greene T. W., Protective Groups in Organic Synthesis John Wiley & Sons (1981)].

Compounds of formula (Q) can be prepared starting from compounds of formula (P) by amidation of the starting compound by methods well known in the art. The amidation is essentially similar to the process by which compounds of formula (L) are converted to compounds of formula (M).

Compounds of formula (Q) can be prepared from compounds of formula (P) by removing the acetyl protecting group present in these compounds, the transformation being carried out by known methods [see, for example, Greene T. W. Protective Groups in Organic Synthesis, John Wiley & Sons (1981)].

Compounds of formula (R) in which an alcohol group is converted into a leaving group can be prepared by well-known methods (see, for example, Stang et al., Synthesis, 85-1266 (1982)).

·;

Compounds of formula (C) can be prepared by known methods and the processes described herein. For example, a compound of formula (A) can be reacted with a compound of formula (B) to give compounds of formula (C). Suitable solvents include, but are not limited to, toluene, tetrahydrofuran, methylene chloride, diethyl ether, acetonitrile, and the like.

The preferred solvent is generally dimethylformamide. Examples of suitable bases include cesium fluoride, cesium carbonate, hindered alkylamines and the like, including in particular diisopropylethylamine. The preferred base is generally sodium hydride, the base being used in a slight molar excess. The base is used in about 1-1.25 molar excess based on the compound of formula (A), with a molar excess of 1.1 being preferred. The compound of formula (B) is used in a moderate molar excess, for example, a molar excess of about 1 to 1.1 relative to the compound of formula (A), with a molar excess of 1.05 being preferred. The deprotonation is preferably carried out at room temperature for about 1.5 hours. After addition of the compound of formula (B), the reaction generally proceeds at room temperature within about 7 days.

Compounds of formula (D) can be prepared by known procedures and methods described herein. For example, compound of formula (C) can be cyclized by dissolving compound of formula (C) in a suitable solvent and adding trifluoroacetic anhydride to the solution to obtain compound of formula (D). Suitable solvents include, for example, toluene, dimethylformamide, tetrahydrofuran, diethyl ether, acetonitrile and the like. Methylene chloride is generally preferred as the solvent. Trifluoroacetic anhydride is used in substantially molar excess. An excess of about 5 to 20 molars based on compound of formula (C) is preferred, generally a molar excess of about 12.4 is preferred. The reaction is carried out using a reflux condenser at the boiling point of methylene chloride (40°C) for approximately 3 hours.

Compounds of formula (E) can be prepared in known manner and by the methods described herein.

Compounds of formula (E) wherein X is -CHR ¹ and R ¹ is -CONH 2 , -CO(C 1-4 alkyl), -CONR ² R ³ or -CO2-(C 1-4 alkyl) can be prepared from compounds of formula (D) by known methods and by the processes described herein. For example, by deprotonating an appropriately substituted Homer-Emmons reagent [see Organic Reactions, Vol. 25, 73 (1977)] with a strong base in an aprotic solvent, followed by addition of a compound of formula (D) to give a derivative of formula (E). Suitable strong bases include, but are not limited to, alkyl lithiums, lithium diisopropylamine, lithium bis(trimethylsilyl)amide and the like. Potassium tert-butoxide is preferably selected as the strong base. Preferred solvents include diethyl ether, tetrahydrofuran, methylene chloride, chloroform, dimethyl sulfoxide and the like. Preferred solvents include dimethylformamide and tetrahydrofuran. The Horner-Emmons reagent is generally used in a slight molar excess, about 1-2 molar excess based on the compound of formula (D), preferably 1.1 molar excess. The reaction mixture is generally maintained at about 0°C when the compound of formula (A) is added to the mixture, and then the mixture is maintained at 25°C for 1 hour.

Compounds of formula (E) containing a -NOH group in the position of X can be prepared from compounds of formula (D) by known methods or by the processes described in the specification. For example, compounds of formula (D) can be dissolved or suspended in a suitable solvent, and hydroxylamine is added to the mixture to obtain derivatives of formula (E). Suitable solvents include, for example, lower alcohols, ethyl acetate, methylene chloride, chloroform and ha15 ’.· ·: :.. :.. :..

• · « · · · > similar. Methanol or pyridine are preferably selected as solvents. Hydroxylamine is generally used in a significant molar excess. A molar excess of 3-10 is preferred, generally 5.0 molar excess, based on the compound of formula (E). The reaction is carried out at a temperature of about 25°C for about 24 hours.

Compounds of formula (E) wherein X is -CHR ¹ and R is hydrogen or CN can be prepared from compounds of formula (D) by known methods or by the methods described herein. For example, a suitably substituted Peterson olefination reagent (see Organic Reactions, Vol. 38, p. 1 (1990)) is dissolved in a suitable solvent and deprotonated with a strong base. The product is then treated with compound of formula (D). Examples of strong bases include potassium tert-butoxide, alkyl lithiums, lithium diisopropylamine, lithium bis(trimethylsilyl)amide and the like. N-butyl lithium is preferably used as the base. Suitable solvents include diethyl ether, methylene chloride, chloroform, dimethylformamide, dimethyl sulfoxide and the like, with tetrahydrofuran being preferred. Peterson's reagent is generally used in a significant molar excess, with a molar excess of 3 to 10 based on the compound of formula (D) being acceptable. A molar excess of 5.0 is generally preferred. The reaction mixture is maintained at about -78°C while the Peterson's reagent is deprotonated and the compound of formula (D) is added, and the mixture is then maintained at about 25°C for about 24 hours.

Compounds of formula (E) wherein X is -CHR ¹ and R ¹ is halogen can be prepared from compounds of formula (E) wherein X is -CH ₂ by conversion by known methods or by the methods described herein. For example, a compound of formula (E) wherein X is -CH ₂ is dissolved in a suitable solvent and a suitable halogenating agent is added to the solution. Suitable solvents include, for example, methylene chloride, tetrahydrofuran, chloroform, acetonitrile, acetic acid and the like. Preferred solvents include tetrahydrofuran and carbon tetrachloride. Suitable halogenating agents include, for example, benzeneselenyl chloride/aluminum chloride, thionyl chloride, molecular bromine, CsSO ₄ F, NFTh and the like. The halogenating agent is generally used in a slight molar excess. A molar excess of 1-2 is generally used, preferably 1.1 molar excess, relative to the starting compound. The reaction mixture is preferably at a temperature of about -10°C when the halogenating agent is added, and then the mixture is maintained at a temperature of about 22°C for approximately 1 hour.

It is obvious to the skilled person that the ratio of isolated cis/trans products in the above processes can vary within wide limits; depending on the starting compounds used and the reaction conditions, the product can consist exclusively of cis or trans isomers, of mixtures thereof in different proportions, up to a mixture of the two isomers in equal proportions.

Compounds of formula (I) containing a -COR ⁵ group in the A' position can be prepared according to reaction scheme 5.

Compounds of formula (S) can be prepared by known methods and the processes described herein. For example, compounds of formula (H) can be converted to compounds of formula (S) as described for the conversion of compounds of formula (D) to compounds of formula (E).

The compounds of formula (T) can be prepared by known methods and the processes described herein. For example, starting with a compound of formula (S) and a compound of formula BrCH ₂ COR ⁵ in a suitable solvent, the compound of formula (T) is obtained in the presence of iodide anion. Suitable solvents include, for example, toluene, dimethylformamide, methylene chloride, tetrahydrofuran, diethyl ether, acetonitrile and the like. Acetonitrile is preferably selected as a solvent. Suitable sources of iodide anion include, for example, sodium or potassium iodide salts or ammonium iodide and the like. A preferred source of iodide anion is sodium ^iodide . The compound of the general formula BrCH ₂ COR ⁵ is generally used in a significant molar excess, it can be used in a molar excess of about 2-10, usually 3-7 molar excess is used, based on the starting compound of the general formula (S). The iodide anion is used in a significant molar excess, for example, about 2-10 molar excess is generally used, preferably 3.8 molar excess is used, based on the compound of the general formula (S). The reaction is preferably carried out at a temperature around the boiling point of the solvent for approximately 40 hours.

Compounds of formula (U) can be prepared by known methods and the processes described herein. For example, a compound of formula (T), an aminonitrile and a base are mixed and dissolved in a suitable solvent to obtain a compound of formula (U). Suitable solvents include, for example, toluene, dimethylformamide, methylene chloride, tetrahydrofuran, diethyl ether, acetonitrile and the like. Acetonitrile is preferred among the solvents. Suitable bases include, but are not limited to, carbonates, hydroxides and the like, with potassium carbonate being preferred. The aminonitrile is generally used in a slight molar excess, approximately 1-1.05 molar excess based on the compound of formula (T). Preferably, a 1.02 molar excess is used, with the base being present in a significant molar excess. For example, an approximately 2-5 molar excess of base, preferably a 3.05 molar excess, based on the compound of formula (T) is added to the reaction mixture. The operation is preferably carried out at the boiling point of the solvent using a reflux condenser for approximately 14 hours.

Compounds of formula (I) containing a group of the general formula -S(O) _n R ⁵ in the position of A' can be prepared according to reaction scheme 6.

Compounds of formula (W) can be prepared by known methods and the processes described herein. For example, compounds of formula (V) can be converted to compounds of formula (W) essentially as described for the conversion of compounds of formula (D) to compounds of formula (E).

Compounds of formula (X) can be prepared by known methods and the process described herein. For example, by dissolving compound of formula (W) in a suitable solvent and adding an iodinating agent to the solution, compound of formula (X) is obtained. Suitable solvents include, for example, toluene, dimethylformamide, methylene chloride, tetrahydrofuran, diethyl ether, acetonitrile, and the like, with acetonitrile being the preferred solvent. Suitable iodinating agents include, for example, molecular iodine, N-iodosuccinimide, and the like. N-iodosuccinimide is the preferred iodinating reagent. The iodinating reagent is generally and preferably used in a stoichiometric or equimolar amount based on compound of formula (W). The operation is preferably carried out at a temperature of about 0°C, and the reaction is completed in approximately 15 minutes.

Compounds of formula (Y) can be prepared by known methods and by the methods described herein. For example, suitably substituted sulfide derivatives can be reacted with an imidazopyridyl anion or anion equivalent according to methods known in the art. Suitable sulfide derivatives include, for example, symmetrical sulfides, unsymmetrical disulfides, and thiol sulfonates. Thiol sulfonates can be prepared from commercially available disulfide derivatives by well-known methods [J. Am. Chem. Soc. 4405 (1977)].

Compounds of formula (Y) can be prepared from compounds of formula (X) by methods well known in the art and as described herein. For example, a metal-halogen exchange reaction is carried out with a compound of formula (X) essentially as described herein above for compounds of formula (H), followed by the addition of an appropriately substituted sulfide derivative to the reaction mixture. It will be apparent to those skilled in the art that, in contrast to the preparation of the phenyl anion used to prepare compounds of formula (H), where no acidic protons are present, the

.........··..··..· In compounds of the general formula (X) an acidic proton is present, therefore the compounds must be deprotonated with a base before the metal-halogen exchange reaction is initiated. Suitable bases include, but are not limited to, molecular lithium, alkyl lithium, lithium amines such as lithium diisopropylamine, lithium hydride and the like. Among the bases, phenyl lithium is preferred. Tert-butyl lithium is a preferred metal source. Suitable solvents include, for example, toluene, dimethylformamide, methylene chloride, acetonitrile, diethyl ether, tetrahydrofuran and the like. Among the solvents, tetrahydrofuran is preferred. The base is generally used in a slight or significant molar excess. For example, the base is used in an approximately 1.5-3 molar excess relative to the compound of formula (X), preferably in an approximately 2.2 molar excess. The metal is used in a slight or significant molar excess, for example in an approximately 1.5-3 molar excess relative to the compound of formula (X). It is preferred to use a 2.5 molar excess of the metal. The reaction is preferably carried out at a temperature of -78°C within 3 minutes after the addition of the base; after the addition of the metal source, the reaction mixture is allowed to react for 10 minutes, and then after the addition of the sulfide derivative, the mixture is reacted for approximately 30 minutes.

Alternatively, compounds of formula (Y) can be prepared from one equivalent of imidazopyridyl anion, which can be prepared from compound of formula (X) under Ullmann coupling conditions [see Synhesis, 9-21 (1974), for a review of Ullmann reactions]. For example, the compound of formula (X) is dissolved in a suitable solvent, a source of copper is added, and then a suitably substituted sulfide derivative is added. Suitable solvents include, but are not limited to, toluene, dimethylformamide, methylene chloride, acetonitrile, diethyl ether, tetrahydrofuran, pyridine, and the like. Pyridine is a preferred solvent. Suitable copper sources include, for example, molecular copper, copper(I) oxide, and the like. Copper bronze or powdered copper are particularly preferred copper sources. Copper is generally used in a slight or significant molar excess, for example, a copper source can be used in an excess of approximately 1.2-3 molars based on the compound of general formula (X), preferably 1.5 molars. In contrast, slightly less than the molar ratio of sulfide is used. Generally, 50-95 mol% of sulfide compound is used based on the compound of general formula (X). Preferably, the sulfide compound is present in an amount of 78 mol%. The operation is carried out at a temperature of approximately 100°C, and the reaction takes approximately 80 hours.

Alternatively, compounds of formula (Y) can be prepared from compounds of formula (X) by a palladium-catalyzed cross-coupling reaction between compound of formula (X) and a suitably substituted trimethylthiotin compound, for example a compound of formula R ⁴ S-Sn(alkyl) ₃ [see, for example, Synth. Commun, (5) 683 (1992)].

Compounds of formula (Z) can be prepared starting from compounds of formula (Y) by oxidizing the starting compound by well-known methods or by the methods described herein. The oxidation of sulfide derivatives to sulfone derivatives is described in detail in the literature [Comprehensive Organic Synthesis, Volume 7, Chapter 6.2, 762, Pergamon Press, Inc. New York (1991)].

It will be apparent to those skilled in the art that it may be advantageous, although not necessary, to remove the trifluoroacetyl protecting group in the operations shown in the above reaction scheme. This reaction step may be carried out at various points in the preparation of the compounds of the invention. The removal of the protecting group may be carried out by methods well known in the art and by the methods shown in the specification. For example, the trifluoroacetyl group may be removed by dissolving the compound of formula (D), (E), (V), (W), (X), (Y) or (Z) in a suitable solvent and then removing the protecting group by adding a base. Suitable bases include, for example, hydroxides, carbonates, amines and the like. The base is preferably diisopropylethylamine. Alternatively, the hydrolysis of the protecting group may be carried out on a silica gel support [see, for example, Greene T. W., Protective Groups in Organic Synthesis John Wiley & Sons (1981)].

In general, the reaction steps illustrated in Schemes 1-6 are completed in about 15 minutes to 72 hours when the reaction is carried out at a temperature between about -78°C and the boiling point of the reaction mixture. It will be apparent to those skilled in the art that the reaction rate can be increased by increasing the temperature. However, it is often advantageous, although not necessary, to carry out the given operation at a lower reaction rate, in order to better control the number and amount of by-products formed. The choice of solvent is not critical as long as the solvent chosen is inert to the reaction and the reactants involved and is sufficiently solubilizing to allow the desired reaction to occur. After the reaction is complete, the intermediate product can be isolated, if desired, by known methods. For example, the resulting compound can be crystallized and then isolated by filtration, or the solvent can be removed by extraction, evaporation or decantation. The intermediate product can be further purified, if desired, by known methods, such as recrystallization or chromatography on a solid support such as silica gel or alumina. Preferably, the compounds of formula (A)-(Z) are isolated before being used in the next reaction step.

Production operations and examples

The invention is illustrated in detail by the following production operations and examples. It is emphasized, however, that these examples are for illustrative purposes only and are not intended to limit the invention in any way.

The starting compounds used in the preparation of the compounds of the invention are known and, if not commercially available, can be readily prepared by generally accepted standard procedures.

It will be apparent to those skilled in the art that in the operations described below it may often be desirable to apply chemical protecting groups to the reacting components in order to prevent the occurrence of secondary reactions. For example, if an amino, alcohol, alkylamino or carboxy group is present in the reacting compound, the reagent can be protected with a standard protecting group, using a protecting group that does not adversely affect the ability of the rest of the molecule to react in the desired manner. The various protecting groups can then be removed subsequently, either simultaneously or sequentially, by known methods.

The cis and trans forms of the compounds of the invention can be separated by column chromatography, such as reverse phase HPLC. The compounds can be eluted from the column with acetonitrile and water or methanol and water in appropriate proportions.

In the following preparation procedures and examples, several abbreviations are used, such as melting point, nuclear magnetic resonance spectrum, electron impact mass spectrum, field force desorption mass spectrum, fast atom bombardment mass spectrum, high-resolution mass spectrum, infrared spectrum, ultraviolet spectrum, elemental analysis, high-performance liquid chromatography, thin-layer chromatography, nitrogen, water, ethyl acetate, diethyl ether, dichloromethane, dimethylformamide, chloroform, methanol, ethanol, acetonitrile, tetrahydrofuran, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sulfuric acid, hydrogen bromide, hydrogen chloride, ammonium hydroxide, sodium sulfite, sodium bisulfite, sodium nitrite, sodium sulfate, saturated sodium chloride, sodium bromide, ammonium chloride, magnesium sulfate, and sodium acetate. EI-MS, MS — - (FD), MS (FAB), MS (HR), IR, UV, elemental analysis, HPLC, TLC, N ₂ , H ₂ 0, EtOAc, E ₂ O, CH ₂ CI ₂ ,DMF, CHCI ₃ , MeOH, EtOH, CH ₃ CN, THF, NaOH, KOH, NaHCO ₃ , H ₂ SO ₄ , HBr, HCI, NH4OH, Na ₂ SO ₃ , NaHSO ₃ , NaNO ₂ , Na ₂ SO ₄ , brine, NaBr, NH ₄ CI, MgSO ₄ and NaOAc. MS (FD) values correspond to mass numbers unless otherwise stated. In addition, for the IR spectrum, only the absorption maxima of interest are given and not all observed maxima.

For NMR spectra, a Brüker-Corp. 270 MHz instrument or a General Electric QE-300 300 MHz instrument is used. Chemical shifts are given in the form of delta (δ) values (parts per million, measured down from tetramethylsilane). MS (FD) spectra are recorded with a Varian-MAT 731 spectrometer using carbon dendrite emitters. For EI-MS spectra, a CEC 21-110 instrument (manufactured by Consolidated Electrodynamics Corporation) is used. For IR spectra, a Perkin-Elmer 281 instrument is used. For UV spectra, a Cary 118 instrument is used. TLC studies are performed on Merck E. silica gel plates. Melting point values are given without correction.

The following abbreviations are used in connection with NMR spectra: “s” means singlet, “d” means doublet, “dd” means doublet of doublets, “t” means triplet, “q” means quartet, “m” means multiplet, “dm” means doublet of multiplet; the abbreviations “br. s”, “br. d”, “br. t” and “br. m” mean broad singlet, doublet, triplet and multiplet, respectively. The notation “J” means coupling constant expressed in Hertz (Hz). Unless otherwise indicated, NMR data refer to the free base form of the compound under investigation.

The abbreviations “MS”, “elemental analysis”, “IR”, “UV” and “NMR” in the examples and preparations mean that the mass spectrum, elemental analysis, infrared spectrum, ultraviolet spectrum, and nuclear magnetic resonance spectrum data obtained when examining the compound in question are consistent with the structure of the product to be prepared.

1. Preparation of 2-Chloro-5-benzoylpyridine

100 g (0.730 mol) of aluminum chloride are suspended in 200 ml of benzene while introducing nitrogen gas. A solution of 53 g (0.30 mol) of 6-chloronicotinic acid chloride in 100 ml of benzene is added to the above suspension with rapid stirring, and the mixture is refluxed overnight. The reaction mixture is cooled to room temperature, 1 liter of EtOAc is added, and the pH is adjusted to 8.5 by adding 5 N NaOH. The aluminum salts precipitate and are removed by filtration. The filtrate is washed with H ₂ O, dried over Na ₂ SO ₄ , and concentrated in vacuo. The resulting brownish solid was recrystallized from _Et2O /hexane (3:2) to give 54.6 g (83%) of the title compound as brownish crystals. EA, MS (FD).

2. Preparation of 2-Chloro-5-(4-fluorobenzoyl)pyridine

Starting with 150 ml (1.60 mmol) of fluorobenzene and 17.7 g (100 mmol) of 6-chloronicotinoyl chloride, the title compound was obtained in 15.2 g (66.1%). EA, MS (FD), NMR.

3. Preparation of 2-Amino-5-benzoylpyridine

100 g (0.460 mol) of 2-chloro-5-benzoylpyridine was dissolved in 500 ml of 3A EtOH and 400 ml of anhydrous ammonia, the solution was charged into a reaction bomb and then heated at 145°C for 16 hours. The solvent was removed in vacuo and the remaining brownish solid was recrystallized from EtOH/H ₂ O to give 77.4 g of the title compound as a brownish solid (85%). EA, MS (FD).

4. Preparation of 2-Amino-5-(4-fluorobenzoyl)pyridine

Starting with 59.1 g (251 mmol) of 2-chloro-5-(4-fluorobenzoyl)pyridine and proceeding as described in Preparation 3, 35.4 g of the title compound were obtained (65.3%). EA, MS (FD).

5. Preparation of 1,2-Dihydro-2-toluenesulfonimido-5-benzoylpyridine: compound of formula (5E)

77.44 g (0.390 mol) of 2-amino-5-benzoylpyridine and 82.03 g (0.43 mol) of p-toluenesulfonyl chloride were mixed with 300 ml of pyridine and the mixture was heated at 90°C for 16 hours under nitrogen. The pyridine was removed in vacuo and the remaining solid was stirred with 1.5 L of water for 1 hour. The solid was collected by filtration and recrystallized from EtOAc to give 118.7 g of the title compound as off-white crystals (86%). EA, MS (FD).

6. Preparation of 1,2-Dihydro-2-toluenesulfonamido-5-(4-fluorobenzoyl)pyridine

Starting with 35.0 g (162 mmol) of 2-amino-5-(4-fluorobenzoyl)pyridine and proceeding as described in Preparation 5, 47.7 g of the title compound were obtained (79.6%). MS (FD), NMR.

7. Preparation of q-Bromo-(4-fluorophenyl)acetic acid; compound of formula (7E) g (0.13 mol) of 4-fluorophenylacetic acid, 130 mg (0.540 mmol) of benzoyl peroxide and 23.1 g (0.130 mol) of N-bromosuccinimide are mixed with 500 ml of carbon tetrachloride under a nitrogen atmosphere, then the mixture is refluxed for 5 hours under nitrogen gas introduction and UV irradiation (GE sun lamp). The re26 ·:.

The reaction mixture was cooled to room temperature and the resulting succinimide was isolated by filtration. The carbon tetrachloride was concentrated in vacuo and the residual oil was recrystallized from hexane to give 26.2 g (87%) of the title product as a pale yellow solid. EA, MS (FD).

8. Preparation of g-Bromo-(4-methoxyphenyl)acetic acid

Starting with 25.0 g (150 mmol) of 4-methoxyphenylacetic acid and proceeding as described in Preparation 7, 36.6 g of the title compound were obtained (100%). MS (FD), NMR.

9. Preparation of g-Bromo-(naphth-2-yl)acetic acid

Starting with 37.2 g (200 mmol) of naphth-2-ylacetic acid and proceeding as described in Preparation 7, 34.5 g of the title compound were obtained (65%). MS (FD), NMR.

10. Preparation of g-Bromonaphthylacetic acid

Starting from 37.2 g (200 mmol) of naphthylacetic acid and proceeding as described in Preparation 7, 32.4 g of the title compound were obtained (60.8%). MS (FD), NMR.

11. Preparation of g-Bromo-(2-fluorophenyl)acetic acid

Starting from 19.9 g (129 mmol) of (2-fluorophenyl)acetic acid and proceeding as described in Preparation 7, 24.0 g of the title compound were obtained (79.9%).

12. Preparation of g-Bromo-(3-fluorophenyl)acetic acid

Starting from 20.0 g (130 mmol) of (3-fluorophenyl)acetic acid and proceeding as described in Preparation 7, 24.3 g of the title compound were obtained (80.0%).

13. Preparation of g-Bromo-(2,4-difluorophenyl)acetic acid

Starting with 21.3 g (124 mmol) of 2,4-difluorophenylacetic acid and proceeding as described in Preparation 7, 24.8 g of the title compound were obtained (79.5%). NMR.

14. Preparation of g-Bromo-(3,5-difluorophenyl)acetic acid

Starting with 20.4 g (118 mmol) of (3,5-difluorophenyl)acetic acid and proceeding as described in Preparation 7, 21.0 g of the title compound were obtained (70.9%). NMR.

15. Preparation of g-Bromo-(2,5-difluorophenyl)acetic acid

Using 20.5 g (119 mmol) of (2,5-difluorophenyl)acetic acid as starting material and proceeding as described in Preparation 7, 27.3 g of the title compound were obtained (91.0%). NMR.

16. Preparation of a-Bromo-(3-trifluoromethylphenyl)acetic acid

Using 20 g (90 mmol) of (3-trifluoromethylphenyl)acetic acid as starting material and proceeding as described in Preparation 7, 27.7 g of the title compound were obtained (100%). NMR.

17. Preparation of g-Bromo-(4-bromophenyl)acetic acid

Using 25.8 g (120 mmol) of (4-bromophenyl)acetic acid as starting material and proceeding as described in Preparation 7, 30.2 g of the title compound were obtained (85.7%).

NMR.

18. Preparation of a-Bromo-(2,3,4-trifluorophenyl)acetic acid

Starting with 9.55 g (50.3 mmol) of (2,3,4-trifluorophenyl)acetic acid and proceeding as described in Preparation 7, 13.5 g of the title compound were obtained (100%). NMR.

19. Preparation of g-Bromo-(3,4-difluorophenyl)acetic acid

Starting with 15.2 g (88.2 mmol) of (3,4-difluorophenyl)acetic acid and proceeding as described in Preparation 7, 22.2 g of the title compound were obtained (100%). NMR.

20. Preparation of g-Bromo-(3,4-dichlorophenyl)acetic acid

Starting with 25.0 g (122 mmol) of (3,4-dichlorophenyl)acetic acid and proceeding as described in Preparation 7, 34.6 g of the title compound were obtained (100%). NMR.

21. Preparation of g-Bromo-(2,4,5-trifluoromethylphenyl)acetic acid

Starting with 9.56 g (50.3 mmol) of (2,4,5-trifluoromethylphenyl)acetic acid and proceeding as described in Preparation 7, 13.6 g of the title compound were obtained (100%). NMR.

22. Preparation of g-Bromo-(2-chlorophenyl)acetic acid

Starting with 25.3 g (148 mmol) of (2-chlorophenyl)acetic acid and proceeding as described in Preparation 7, 22.8 g of the title compound were obtained (62.0%). MS (FD), NMR.

........ -

23. Preparation of g-Bromo-(3-chlorophenyl)acetic acid

Starting with 20.9 g (123 mmol) of (3-chlorophenyl)acetic acid and proceeding as described in Preparation 7, 30.5 g of the title compound were obtained (100%). NMR.

24, Preparation of g-Bromo-(4-chlorophenyl)acetic acid

Using 25.0 g (147 mmol) of (4-chlorophenyl)acetic acid as starting material and proceeding as described in Preparation 7, 21.7 g of the title compound (60.0%) were obtained. NMR.

25. Preparation of g-Bromo-(4-trifluoromethoxyphenyl)acetic acid

Starting with 9.91 g (45.1 mmol) of (4-trifluoromethoxyphenyl)acetic acid and proceeding as described in Preparation 7, 13.5 g of the title compound were obtained (100%). NMR.

26. Preparation of g-Bromo-(3-trifluoromethoxyphenyl)acetic acid

Starting with 9.75 g (44.3 mmol) of (3-trifluoromethoxyphenyl)acetic acid and proceeding as described in Preparation 7, 13.3 g of the title compound were obtained (100%). NMR.

27. Preparation of g-Bromo-(2-fluoro-4-trifluoromethylphenyl)acetic acid

Starting with 9.56 g (43.1 mmol) of (2-fluoro-4-trifluoromethylphenyl)acetic acid and proceeding as described in Preparation 7, 13.0 g of the title compound were obtained (100%). NMR.

28. Preparation of a-Bromo-(2-methoxyphenyl)acetic acid

Starting with 25.0 g (150 mmol) of (2-methoxyphenyl)acetic acid and proceeding as described in Preparation 7, 26.5 g of the title compound were obtained (72%). MS (FD), NMR.

29. Preparation of g-Bromo-(4-nitrophenyl)acetic acid

Starting with 25.5 g (141 mmol) of (4-nitrophenyl)acetic acid and proceeding as described in Preparation 7, 36.6 g of the title compound were obtained (100%). NMR.

30. Preparation of g-Bromo-(3-thienyl)acetic acid

8.60 g (54.4 mmol) of (3-thiophen-3-yl)-mandelic acid were dissolved in 100 ml of a 30% HBr solution in acetic acid. The solution was stirred at room temperature for 18 hours. The black clear solution was poured into 2.5 liters of ice water and immediately extracted with 4x400 ml of diethyl ether. The ether extract was dried over sodium sulfate and decolorized with activated carbon. The diethyl ether was evaporated and the residual acetic acid was removed from the residue by azeotropic distillation with toluene to give a crude solid product, which was crystallized from hexane; yield: 9.07 g (75%). EA, MS (FD).

Example 31 g-Bromobenzylacetic acid

55.0 g (330 mmol) of L-phenylalanine and 130 g (1.09 mol) of NaBr are dissolved in 550 ml of 3N sulfuric acid, cooled to 0°C, and then 32.0 g (469 mmol) of NaNO ₂ are slowly added to the solution while maintaining the temperature of the reaction mixture between 0°C and 5°C. Stirring is continued at about 0°C for 1 hour and then at room temperature for 1.5 hours. The mixture is extracted with 4x300 ml of diethyl ether. The diethyl31

-ether extracts are washed with 2x500 ml saturated sodium chloride solution, dried over MgSO ₄ and concentrated in vacuo. The residue is recrystallized with 50 ml cyclohexane to give the starting material phenylalanine as a crystalline substance. The solid is removed by filtration and the filtrate is concentrated in vacuo to give 64 g of crude product, which is used without further purification (84.7 %) 32. Preparation of g-Bromo-(4-fluorophenyl)acetamide; Compound of formula (32E)

26.1 g (112 mmol) of a-bromo-(4-fluorophenyl)acetic acid were dissolved in 175 ml of anhydrous CH ₂ CI ₂ , 3 drops of DMF were added to the solution, then cooled in an ice bath while introducing nitrogen gas, then a solution of 25.0 g (224 mmol) of oxalyl chloride in 25 ml of anhydrous CH ₂ CI ₂ was added dropwise over 25 minutes. The ice bath was removed and the reaction mixture was stirred for 3 hours. The solvent was removed in vacuo and the residue was azeotropically distilled with 3x25 ml of toluene. The residual oil was dissolved in a mixture of 300 ml of toluene and 300 ml of hexane, then stirred vigorously with a mechanical stirrer. Ammonia gas was passed through a gas dispersion tube over the solution for 1 hour. The resulting solid was collected by filtration and the solvent was removed in vacuo. The remaining solid was dissolved in EtOAc/H ₂ O, the organic phase was washed with normal hydrochloric acid, saturated NaHCO ₃ , saturated sodium chloride, and finally dried over sodium sulfate. The sodium sulfate was removed by filtration and the EtOAc was distilled off in vacuo. The remaining solid was recrystallized from EtOAc/hexane to give 19.6 g of the desired product (75%). MS (FD), NMR.

33. Preparation of q-Bromo-(4-methoxyphenyl)acetic acid

ϊ.

Starting from 36.6 g (150 mmol) of α-bromo-(4-methoxyphenyl)acetic acid and proceeding as described in Preparation 32, 13.5 g of the title compound were obtained (37%). MS (FD), NMR.

34. Preparation of g-Bromo-(naphth-2-yl)phenylacetamide

Starting with 34.5 g (130 mmol) of α-bromo-(naphth-2-yl)acetic acid and proceeding as described in Preparation 32, 11.5 g of the title compound were obtained (33.5%). EA, MS (FD).

35. Preparation of g-Bromonaphthylacetamide

Starting with 32.4 g (122 mmol) of g-bromo-naphthylacetic acid and proceeding as described in Preparation 32, 14.6 g of the title compound were obtained (46%). MS(FD), NMR.

36. Preparation of g-Bromo-(2-fluoro)-acetamide

Starting with 24.0 g (103 mmol) of α-bromo-(2-fluorophenyl)acetic acid and proceeding as described in Preparation 32, 14.0 g of the title compound were obtained (60%). MS (FD), NMR.

37. Preparation of g-Bromo-(3-fluorophenyl)acetamide

Starting with 24.3 g (104 mmol) of g-bromo-(3-fluorophenyl)acetic acid and proceeding as described in Preparation 32, 16.3 g of the title compound were obtained (67.0%). MS (FD), NMR.

38. Preparation of g-Bromo-(2,4-difluorophenyl)acetamide

Starting with 23.3 g (93.0 mmol) of α-bromo-(2,4-difluorophenyl)acetic acid and proceeding as described in Preparation 32, 7.88 g of the title compound (34.3%) were obtained. NMR.

39. Preparation of g-Bromo-(3,5-difluorophenyl)acetamide

Starting with 21.0 g (83.3 mmol) of α-bromo-(3,5-difluorophenyl)acetic acid and proceeding as described in Preparation 32, 14.4 g of the title serine compound were obtained (68.7%). NMR.

40. Preparation of g-Bromo-(2,5-difluorophenyl)acetamide

Starting from 27.3 g (109 mmol) of g-bromo-2,5-difluorophenylacetic acid and proceeding as described in Preparation 32, 18.5 g of the title compound (68.0%) were obtained. MS (FD), NMR.

41. Preparation of a-Bromo-(3-trifluoromethylphenyl)acetamide

Starting with 27.7 g (98.0 mmol) of α-bromo-(3-trifluoromethylphenyl)acetic acid and proceeding as described in Preparation 32, 14.2 g of the title serine compound were obtained (51.4%). MS (FD), NMR.

42. Preparation of g-Bromo-(4-bromophenyl)acetamide

Starting with 30.2 g (103 mmol) of α-bromo-(4-bromophenyl)acetic acid and proceeding as described in Preparation 32, 23.5 g of the title compound were obtained (78.1%). MS (FD), NMR.

g-Bromo-(2,3,4-trifluorophenyl)acetamide

43, Production ί J ·*··.

··· «·*··· ·· ··

Starting from 13.5 g (50.3 mmol) of α-bromo-(2,3,4-trifluorophenyl)acetic acid and proceeding as described in Preparation 32, 10.2 g of the title compound were obtained (75.7%). MS (FD), NMR.

44. Preparation of a-Bromo-(3,4-difluorophenyl)acetamide

Starting with 22.2 g (88.0 mmol) of α-bromo-(3,4-difluorophenyl)acetic acid and proceeding as described in Preparation 32, 7.88 g of the title compound were obtained (35.7%). MS (FD), NMR.

45. Preparation of a-Bromo-(3,4-dichlorophenyl)acetamide

Starting with 34.6 g (122 mmol) of α-bromo-(3,4-dichlorophenyl)acetic acid and proceeding as described in Preparation 32, 11.8 g of the title compound were obtained (34.2%). MS (FD), NMR.

46. Preparation of a-Bromo-(2,4,5-trifluorophenyl)acetamide

Starting with 13.6 g (50.3 mmol) of α-bromo-(2,4,5-trifluorophenyl)acetic acid and proceeding as described in Preparation 32, 7.34 g of the title compound were obtained (54.4%). NMR.

47. Preparation of g-Bromo-(2-chlorophenyl)acetamide

Starting with 22.8 g (91.7 mmol) of α-bromo-(2-chlorophenyl)acetic acid and proceeding as described in Preparation 32, 17.5 g of the title compound were obtained (77%). MS (FD), NMR.

48. Preparation of q-Bromo-(3-chlorophenyl)acetamide

Starting with 30.5 g (123 mmol) of g-bromo-(2-chlorophenyl)acetic acid and proceeding as described in Preparation 32, 17.8 g of the title compound were obtained (59%). MS (FD), NMR.

49. Preparation of g-Bromo-(4-chlorophenyl)acetamide

Starting with 21.7 g (86.9 mmol) of α-bromo-(4-chlorophenyl)acetic acid and proceeding as described in Preparation 32, 15.7 g of the title compound were obtained (73%). MS (FD), NMR.

50. Preparation of g-Bromo-(4-trifluoromethoxyphenyl)acetamide

Starting with 13.5 g (45.1 mmol) of g-bromo-(4-trifluoromethoxyphenyl)acetic acid and proceeding as described in Preparation 32, 11.1 g of the title compound were obtained (83%). MS (FD), NMR.

51. Preparation of g-Bromo-(3-trifluoromethoxyphenyl)acetamide

Starting with 13.3 g (44.3 mmol) of g-bromo-(3-trifluoromethoxyphenyl)acetic acid and proceeding as described in Preparation 32, 9.43 g of the title compound were obtained (71%). MS (FD), NMR.

52. Preparation of g-Bromo-(2-fluoro-4-trifluoromethylphenyl)acetamide

Starting with 13.0 g (43.1 mmol) of g-bromo-(2-fluoro-4-trifluoromethylphenyl)acetic acid and proceeding as described in Preparation 32, 11.1 g of the title compound were obtained (86%). MS (FD), NMR.

53. Preparation of g-Bromophenylacetamide

Starting with 21.5 g (100 mmol) of α-bromophenylacetic acid and proceeding as described in Preparation 32, 16.8 g of the title compound were obtained (78%). MS(FD), NMR.

54. Preparation of g-Bromo-(thiophen-3-yl)acetamide

Starting with 9.07 g (41.0 mmol) of α-bromo-(triophene-3-yl)acetic acid and proceeding as described in Preparation 32, 6.50 g of the title compound were obtained (72%). MS, MP.

55. Preparation of g-Bromo-(2-methoxyphenyl)acetamide

Starting with 26.5 g (108 mmol) of α-bromo-(2-methoxyphenyl)acetic acid and proceeding as described in Preparation 32, 21.6 g of the title compound were obtained (82.0%). NMR.

56. Preparation of g-Bromoisobutylacetamide; compound of formula (56E)

Starting with 35.0 g (179 mmol) of g-bromo-(4-methyl)pentanoic acid and proceeding as described in Preparation 32, 20.9 g of the title compound were obtained (60.1%). EA, MS (EI).

57. Preparation of g-Bromobenzylacetamide

Starting with 64.0 g (279 mmol) of α-bromobenzylacetic acid and proceeding as described in Preparation 32, 22.5 g of the title compound were obtained (35.4%). EA, MS (FD).

58. Preparation of q-Bromo-(4-nitrophenyl)acetamide

Starting with 36.6 g (141 mmol) of α-bromo-(4-nitrophenyl)acetic acid and proceeding as described in Preparation 32, 19.3 g of the title compound were obtained (52.9%). NMR.

59. Preparation of 2,6-Difluoromandelic acid; compound of formula (59E)

25.0 g (176 mmol) of 2,6-difluorobenzaldehyde and 5.0 mg (0.02 mmol) of zinc iodide were placed in a flame-dried 250 ml three-necked round-bottomed flask under nitrogen. 17.45 g (176.0 mmol) of trimethylsilyl cyanide were added dropwise over 20 min and stirred for 72 h. After addition of 200 ml of 9N hydrochloric acid solution, the mixture was refluxed overnight. The reaction mixture was cooled to room temperature and extracted with diethyl ether. The diethyl ether solution was extracted with saturated NaHCO ₃ and acidified to pH 1 with 5N hydrochloric acid solution. The acidic solution was extracted with diethyl ether and the organic phase was dried over sodium sulfate. The Na ₂ SO ₄ was filtered off and the Et ₂ Ot was removed in vacuo to leave a white solid which was crystallized from CHCl ₃ to give 23.6 g of the title compound as a white solid (71%). NMR, MS, IR, EA.

60. Preparation of 2,3,4,5,6-Pentafluoromandelic acid

Starting from 49.4 g (252 mmol) of 2,3,4,5,6-pentafluorobenzaldehyde and proceeding as described in Preparation 59, 52.3 g of the title compound were obtained (86.0%). EA, MS (FD).

61. Preparation of 2-Trifluoromethylmandelic acid

Starting from 43.9 g (252 mmol) of 2-trifluoromethylbenzaldehyde and proceeding as described in Preparation 59, 39.1 g of the title compound were obtained (70.5%). EA, MS (FD).

62. Production

Thiophen-3-yl-mandelic acid

Starting with 28.3 g (252 mmol) of thiophen-3-ylcarboxaldehyde and proceeding as described in Preparation 59, 13.4 g of the title compound (33.8%) were obtained. EA, MS (FD).

63. Preparation of 2-Trifluoromethyl-4-fluoromandelic acid

Starting with 48.4 g (252 mmol) of 2-trifluoromethyl-4-fluorobenzaldehyde, the procedure described in Preparation 59 gave 50.1 g of the title compound (84%). EA, MS (FD).

64. Preparation of 2-fluoro-6-trifluoromethylmandelic acid

Starting with 48.4 g (252 mmol) of 2-fluoro-6-trifluoromethylbenzaldehyde and proceeding as described in Preparation 59, 49.7 g of the title compound were obtained (84%). EA, MS (FD).

65. Preparation of 4-Carboxymandelic acid

Starting with 33.0 g (252 mmol) of 4-cyanobenzaldehyde and proceeding as described in Preparation 59, 27.0 g of the title compound were obtained (54.6%). MS (FD), NMR.

66. Preparation of g-O-acetyl-(2,6-difluorophenyl)acetic acid; compound of formula (66E)

To a solution of 16.9 g (89.9 mmol) of 2,6-difluoromandelic acid in 50 ml of acetic acid was added 150 ml of 30% HBr in acetic acid with stirring, and the mixture was stirred overnight. The reaction mixture was poured into 1.5 l of ice water and stirred for 1 h. The aqueous solution was extracted with diethyl ether, and the organic phase was dried over Na ₂ SO ₄ - .:. .·. ^: ”· Ο. The sodium sulfate was filtered off and the diethyl ether was removed in vacuo to give a white solid, which was crystallized from Et ₂ O/hexane; 18.54 g of the title compound was obtained as a white solid (90%). EA, MS (FD).

67. Preparation of g-O-Acetyl-(2,3,4,5,6-pentafluorophenyl)acetic acid

Starting with 70.5 g (291 mmol) of 2,3,4,5,6-pentafluoromandelic acid and proceeding as described in Preparation 66, 82.8 g of the title compound were obtained (100%). EA, MS (FD).

68. Preparation of a-O-Acetyl-(2-trifluoromethylphenyl)acetic acid

Starting with 19.8 g (90.0 mmol) of 2-trifluoromethylmandelic acid, the procedure described in Preparation 66 gave 20.8 g of the title compound (88.0%). EA, MS (FD).

69. Preparation of g-O-Acetyl-(2-trifluoromethyl-4-fluorophenyl)acetic acid

Starting from 49.4 g (208 mmol) of (2-trifluoromethyl-4-fluorophenyl)-mandelic acid, the procedure described in Preparation 66 gave 58.1 g of the title compound (100%). EA, MS (FD).

70. Preparation of g-O-Acetyl-(2-fluoro-6-trifluoromethylphenyl)acetic acid

Starting with 48.4 g (252 mmol) of 2-fluoro-6-trifluoromethylmandelic acid and proceeding as described in Preparation 66, 50.1 g of the title compound were obtained (84%). EA, MS (FD).

71. Preparation of a-O-Acetyl-(4-trifluoromethylphenyl)acetic acid

Starting with 19.8 g (89.9 mmol) of 4-trifluoromethylmandelic acid and proceeding as described in Preparation 66, 20.3 g of the title compound were obtained (86%). MS (FD), NMR.

72. Preparation of a-O-Acetyl-(4-carboxyphenyl)acetic acid

Starting with 27.0 g (138 mmol) of 4-carboxymandelic acid and proceeding as described in Preparation 66, 27.5 g of the title compound were obtained (83.9%). MS (FD), NMR.

73. Preparation of g-O-Acetyl-(2,6-difluorophenyl)acetamide

To a solution of 18.5 g (80.4 mmol) of gO-acetyl-(2,6-difluorophenyl)acetic acid in 200 ml of anhydrous CH ₂ CI ₂ , 3 drops of DMF were added, and the mixture was cooled in an ice bath while nitrogen gas was introduced. Then, a solution of 50.0 g (448 mmol) of oxalyl chloride in 50 ml of anhydrous CH ₂ CI ₂ was added dropwise to the reaction mixture over a period of 25 minutes. The ice bath was removed and the reaction mixture was stirred for 3 hours. After removing the solvent in vacuo, the residue was azeotropically distilled with 3x25 ml of toluene. The residual oil was dissolved in a mixture of 100 ml of toluene and 700 ml of hexane and stirred vigorously with a mechanical stirrer. Ammonia gas was bubbled over the surface of the solution for 1 hour through a gas dispersion tube. The solid formed was collected by filtration and the solvent was removed in vacuo. The solid was dissolved in EtOAc/H ₂ O, the organic phase was washed with normal hydrochloric acid, saturated NaHCO ₃ , saturated sodium chloride and dried over Na ₂ SO ₄ . The sodium sulfate was removed by filtration and the EtOAc was distilled off in vacuo. The remaining solid was recrystallized from EtOAc/hexane to give 16.7 g of the desired compound (90%).

74. Production

a.-Q-Acetyl-(2,3,4,5,6-pentafluorophenyl)acetamide

Using 106 g (373 mmol) of α-O-acetyl-(2,3,4,5,6-pentafluorophenyl)acetic acid as starting material and proceeding as described in Preparation 73, 94.0 g of the title compound were obtained (89%). EA, MS (FD).

75. Preparation of g-O-Acetyl-(2-trifluoromethylphenyl)acetamide

Starting with 20.8 g (79.4 mmol) of α-O-acetyl(2-trifluoromethylphenyl)acetic acid, the procedure described in Preparation 73 gave 18.8 g of the title compound (90.7%). EA, MS (FD).

76. Preparation of g-O-Acetyl-(2-trifluoromethyl-4-fluorophenyl)-acetamide

Starting with 58.1 g (208 mmol) of α-O-acetyl-2-trifluoromethyl-2-acetic acid, the procedure described in Preparation 73 gave 52.4 g of the title compound (90.0%). EA, MS (FD).

77. Preparation of 2L-O-Acetyl-(2-fluoro-6-trifluoromethylphenyl)acetamide

Starting with 53.4 g (191 mmol) of n-O-acetyl-(2-fluoro-4-tris-acetic acid) and proceeding as described in Preparation 73, 47.9 g of the title compound were obtained (90%). EA, MS (FD).

78. Preparation of a-O-Acetyl-(4-trifluoromethylphenyl)acetamide

Using 20.3 g (77.3 mmol) of α-O-acetyl-(4-trifluoromethylphenyl)acetic acid as starting material and proceeding as described in Preparation 73, 18.8 g of the title compound were obtained (93%).

79. Production

Methyl-(g-hydroxy-4-carbonylmethoxybenzyl)acetate

23.2 g (97.3 mmol) of O-acetyl-(4-carboxyphenyl)acetic acid were suspended in 300 mL of CH ₂ Cl ₂ , 3 drops of DMF were added to the suspension, and the reaction mixture was stirred in an ice bath while nitrogen gas was introduced. A solution of 50.0 g (448 mmol) of oxalyl chloride in 50 mL of anhydrous CH ₂ Cl ₂ was added dropwise to the above mixture over about 20 min. The ice bath was removed, and the reaction mixture was stirred at room temperature for 5 h (until all solids had dissolved). The solvent was removed, the residue and 200 mL of MeOH were added to a separatory funnel, and the mixture was stirred overnight. The solvent was then removed, and the residue was taken up in EtOAc. The EtOAc solution was washed with 3x100 mL NaHCO ₃ solution, saturated sodium chloride solution, and dried over sodium sulfate. The EtOAc was removed in vacuo to give 22 g of oil (100%). EA, MS (FD).

80. Preparation of g-Hydroxy-(2,6-difluorophenyl)acetamide

Starting material, 16.7 g (73.0 mmol) of α-O-acetyl-(2,6-difluorophenyl)acetamide was dissolved in 125 mL of methanol and 35 mL of diisopropylethylamine and the solution was refluxed for 3 h. The solvent was removed in vacuo and the remaining solid was recrystallized from EtOAc/hexane to give 11.42 g of the title compound as a white solid (84%). EA, MS (FD).

81. Preparation of g-Hydroxy-(2,3,4,5,6-pentafluorophenyl)acetamide

Starting from 83.0 g (293 mmol) of α-O-acetyl-(2,3,4,5,6-pentafluorophenyl)acetamide and proceeding as described in Preparation 80, 66.6 g of the title compound were obtained (94%). EA, MS (FD).

82. Preparation of g-Hydroxy-(2-trifluoromethylphenyl)acetamide

Starting with 18.4 g (70.6 mmol) of g-O-acetyl-(2-trifluoromethylphenyl)acetamide and proceeding as described in Preparation 80, 14.3 g of the title compound were obtained (92.4%). MS (FD), NMR.

83. Preparation of a-Hydroxy-(2-trifluoromethyl-4-fluorophenyl)acetamide

Starting with 50.4 g (181 mmol) of g-O-acetyl-(2-trifluoromethyl-4-fluorophenyl)acetamide, the procedure described in Preparation 80 gave 40.9 g of the title compound (95%). EA, MS (FD).

84. Preparation of α-Hydroxy-(2-fluoro-6-trifluoromethylphenyl)acetamide

Starting with 44.6 g (160 mmol) of α-O-acetyl-(2-fluoromethyl-6-trifluoromethylphenyl)acetamide, the procedure described in Preparation 80 gave 32.1 g of the title compound (85%). EA, MS (FD).

85. Preparation of a-Hydroxy-(4-trifluoromethylphenyl)acetamide

Starting with 18.8 g (65.3 mmol) of g-O-acetyl-(4-trifluoromethylphenyl)acetamide, the procedure described in Preparation 80 gave 13.8 g of the title compound (96.1%). EA, MS (FD).

86. Preparation of g-Hydroxy-(4-carbonylmethoxyphenyl)acetamide

A freshly prepared solution of ammonia in 300 ml of methanol was added to 21.8 g (97.3 mmol) of (α-hydroxy-4-carbonylmethoxybenzyl)acetic acid methyl ester and the mixture was stirred overnight. The solvent was removed in vacuo and the residue was

Recrystallization _{from CH2Cl2} gave 17.5 g of the title compound (85.7%). EA, MS (FD).

87. Preparation of a-O-Toluenesulfonylimido-(2,6-difluorophenyl)acetamide: Compound of formula (87E)

9.80 g (52.4 mmol) of a-hydroxy-(2,6-difluorophenyl)acetamide, 500 mg (4.10 mmol) of 4-dimethylaminopyridine and 10.04 ml (57.6 mmol) of diisopropylethylamine were mixed with 300 ml of anhydrous CH ₂ Cl ₂ under nitrogen gas. 11.0 g (57.6 mmol) of p-toluenesulfonyl chloride were added to the mixture and the reaction mixture was stirred overnight. The solvent was removed in vacuo and the remaining solid was dissolved in EtOAc. The organic solution was washed with normal HCl solution, saturated NaHCO ₃ solution, saturated sodium chloride solution and dried over sodium sulfate. The Na ₂ SO ₄ was removed by filtration and the EtOAc was distilled off in vacuo to give a white solid. The resulting material was recrystallized from EtOAc/hexane to give 15.8 g of the title compound as a white powder (88%). EA, MS (FD).

88. Preparation of a_-O-Toluenesulfonylimido-(2,3,4,5,6-pentafluorophenyl)acetamide

Starting with 12.1 g (50.0 mmol) of α-hydroxy-(2,3,4,5,6-pentafluorophenyl)acetamide, the title compound was obtained in 18.3 g (92%) as described in Preparation 87. EA, MS (FD).

89. Preparation of a-O-Toluenesulfonylimido-(2-trifluoromethylphenyl)acetamide

Starting with 14.3 g (65.2 mmol) of α-hydroxy-(2-trifluoromethylphenyl)acetamide, the procedure described in Preparation 87 gave 21.0 g of the title compound (86%). EA, MS (FD).

90. Production ^=2^515212311121111421102^2412111014316^

Starting with 11.9 g (50.0 mmol) of α-hydroxy-(2-trifluoromethyl-4-fluorophenyl)acetamide, the procedure described in Preparation 87 afforded 17.0 g of the title compound (87%). EA, MS (FD).

91. Preparation of a-O-Toluenesulfonylamino-(2-fluoro-6-fluoromethylphenyl)-c _a ta _amide

Starting with 11.9 g (50.0 mmol) of α-hydroxy-(2-fluoro-4-trifluoromethylphenyl)-acetamide and proceeding as described in Preparation 87, 17.8 g of the title compound were obtained (91%). EA, MS (FD).

92. Preparation of a-O-Toluenesulfonylimido-(4-trifluoromethylphenyl)acetamide

Starting with 9.35 g (42.7 mmol) of α-hydroxy(4-trifluoromethylphenyl)acetamide, the procedure described in Preparation 87 gave 12.7 g of the title compound (80%). EA, MS (FD).

93. Production

Starting with 10.5 g (50.0 mmol) of α-hydroxy-(4-carbonylmethoxyphenyl)acetamide, the procedure described in Preparation 87 gave 14.6 g of the title compound (80.2%). EA, MS (FD).

Example 94

-methyl-pyridine (94E) compound

10.6 g (30.0 mmol) of 1,2-dihydro-2,4-trifluorophenylimido-5-benzoylpyridine were dissolved in 75 ml of DMF and stirred in a flame-dried flask under nitrogen. 1.32 g (33.0 mmol) of sodium hydride were added and the solution was stirred for 1.5 h. Then 7.88 g (31.5 mmol) of α-bromo-(2,4-difluorophenyl)acetamide were added and the solution was stirred at room temperature for 7 days. The reaction mixture was poured into 2.5 l of water and stirred for 1 h. The resulting precipitate was collected by filtration. The filter cake was recrystallized from EtOAc/hexane to give 13.2 g of the title compound (84%). EA, MS (FD).

95. Production

-pyridine

Starting from 27.1 g (77.0 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine and 19.6 g (84.5 mmol) of α-bromo-(4-fluorophenyl)acetamide, the title compound was obtained in 35.0 g (90.4%) of the title compound by the procedure described in Preparation 94. EA, MS (FD).

96. Preparation of 1,2-Dihydro-2-toluenesulfonyl-imido-5-benzoyl-N-tri-(4-methoxyphenyl) _{carbamoylmethylpyridine}

Starting from 10.6 g (30.0 mmol) of 1,2-dihydro-2-toluenesulfonyl-imido-5-benzoylpyridine and 8.05 g (33.0 mmol) of α-bromo-(4-methoxyphenyl)acetamide, the title compound was prepared as described in Preparation 94 except that 4.50 g (30.0 mmol) of cesium fluoride was used instead of the sodium hydride and sodium iodide mentioned in Preparation 94; yield: 6.32 g (40.0%). EA, MS (FD).

97. Production

-pyridine

Starting from 18.5 g (52.7 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine and 14.6 g (55.3 mmol) of α-bromo-(naphth-2-yl)acetamide, the title compound was obtained in the same manner as in Preparation 94 (15.0 g, 53.3%). EA, MS (FD).

98. Preparation of ^{;U:S!!!i£!£2:2:í2!!} ^^ -pyridine

Starting from 14.6 g (41.5 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine and 11.5 g (43.6 mmol) of α-bromo-(naphth-1-yl) _acetamide and proceeding as described in Preparation 94, 14.3 g of the title compound were obtained (64%). EA, MS (FD).

99. Production ^{12:Ηω£!!:2:2} * ^2!1!ί ^^

-pyridine

Starting from 12.3 g (35.1 mmol) of 1,2-dihydro-2-toluenesulfonyl-benzoylpyridine and 8.54 g (36.8 mmol) of α-bromo-(2- _fluorophenyl )acetamide, the title compound was obtained in the same manner as in Preparation 94 (16.5 g, 97.3%). EA, MS (FD).

100. Preparation of l^-Dihydro^-toluenesulfonimido.S-benzoyl-N-ri.tS.nuo^^

-pyridine

Starting from 23.6 g (66.9 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine and 16.3 g (70.3 mmol) of _abrom- (3- _fluorophenyl )acetamide, the title compound was obtained in 29.8 g (88.5%) of the title compound by the same procedure as described in Preparation 94. EA, MS (FD).

101. Preparation of l^-Dihydro-2-toluenesulfonyl.imido·^^^^^^

-methyl-pyridine

Starting from 10.6 g (30.0 mmol) of 1,^dihydro^-toluenesulfonylimido-S-benzoylpyridine and 7.88 g (31.5 mmol) of a-bromo-(3,5-difluorophenyl)acetamide, the title compound was obtained in 14.2 g (91.0%) of the title compound by the procedure described in Preparation 94. EA, MS (FD).

102. Production

L2 _: Dihydro-2-toluenesulfonyl-imido-5-benzoyl-N-ri-(2,5-difluoro-phenyl)-carbamoyl-methyl-pyridine

Starting from 10.6 g (30.0 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine and 7.88 g (31.5 mmol) of α-bromo-(2,5-difluorophenyl)acetamide, the title compound was obtained in 15.3 g (98%). EA, MS (FD).

103. Preparation of ^^^^S^oluolsulfoniHmido^e^

-carbamoylmethylpyridine

Starting from 10.6 g (30.0 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine and 8.88 g (31.5 mmol) of α-bromo-(3-trifluoromethylphenyl)acetamide and proceeding as described in Preparation 94, 12.7 g of the title compound were obtained (76%). EA, MS (FD).

104. Production

-pyridine

Starting from 10.6 g (30.0 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine and 9.23 g (31.5 mmol) of α-bromo-(4-bromophenyl)acetamide and proceeding as described in Preparation 94, 13.7 g of the title compound were obtained (81%). EA, MS (FD).

105. Production

-methyl-pyridine

Starting from 10.6 g (30.0 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine and 8.44 g (31.5 mmol) of α-bromo-(2,3,4-trifluorophenyl)acetamide as starting materials and proceeding as described in Preparation 94, 11.3 g of the title compound were obtained (70%).

106. Production

12.-Dihydro-2-toluenesulfonyl-imido-5-benzoyl-N-ri-(3,4-difluoro-phenin-carbamoyl.-methyl-pyridine

Starting from 10.6 g (30.0 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine and 7.88 g (31.5 mmol) of α-bromo-(3,4-difluorophenyl)acetamide, the title compound was obtained in 9.53 g (61%) as described in Preparation 94. EA, MS (FD).

107. Production

1,2-Dihydro-2-toluenesulfonyl-imido-5-benzoyl-N-ri-(3,4-dichlorophenine-carbamoyl-methyl-pyridine)

Starting from 10.6 g (30.0 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine and 9.00 g (31.5 mmol) of α-bromo-(3,4-dichlorophenyl)acetamide and proceeding as described in Preparation 94, 13.8 g of the title compound were obtained (83%). EA, MS (FD).

108. Production

-methyl-pyridine

Starting from 9.18 g (26.1 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine and 7.34 g (27.4 mmol) of α-bromo-(2,4,5-trifluorophenyl)acetamide, the title compound was obtained in 11.6 g (83%) as described in Preparation 94. MS(FAB), NMR.

109. Production

-pyridine

Starting from _10.6 g (30.0 mmol) of 1,2-dihydro-2-ol-1 _- olsulfonyl-benzenepyridine and 7.83 g (31.5 mmol) of a-bromo-( ₂ -chlorophenyl)acetamide, the _title compound was obtained in the same manner as in Preparation 94, yielding 10.4 g (69%). EA, MS (FD).

110. Production

1^Dlhydro-2-tol.mlsz _U |fonyl- _lmMo ^^

-pyridine

Starting from 10.6 g (30.0 mmol) of 1,2- _dihydro -2-toluenesulfonylimido-5-benzoicpyridine and 7.83 g (31.5 mmol) of α-bromo-4-chlorophenyl-acetamide, the title compound was obtained in 13.4 g (77%) of the title compound by the procedure described in Preparation 94. EA, MS (FD).

111. Production

1^p.hl<iro.2.tol _ibid | _S z _Ut fon _í |Hm.do. _S .henzoyl|.N41 ₄ 4-Chlorophenyl)4< _arbamnyl .m ₀ Hn· -pyridine

Starting from 10.6 g (30.0 mmol) of 1,2-dihydro-2-toluenesulfonimido-5-benzenepyridine and 7.81 g (31.5 mmol) of n-bromo-3-chlorophenylacetamide, the title compound was obtained in the same manner as in Preparation 94 (13.8 g, 88%). EA, MS (FD).

112. Preparation of 1-dihydro-toluenesulfonimido-s-benzoyl

-carbamoylmethylpyridine

Starting from 10.6 g (30.0 mmol) of 1-M-hydro-toluosulfonyl-benzoylpyridine and 9.83 g (33.0 mmol) of a-bromo-(4- _{trifluoromethoxy} )-propanol, _the title compound was obtained in the same manner as in Preparation 94, except that cesium fluoride was used instead of sodium hydride (77%). EA, MS (FD).

113, Production

1,2-Dihydro-2-toluenesulfonylimido-5-benzoyl-N-ri-(3-trifluoromethoxy-phenyne-carbamoyl-methyl-pyridine)

Starting from 10.6 g (30.0 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine and 9.43 g (31.6 mmol) of α-bromo-(3-trifluoromethoxyphenyl)acetamide and proceeding as described in Preparation 94, 12.5 g of the title compound were obtained (73%). EA, MS (FD).

114. Preparation ¹ _! ² - ^Dihydro -2-toluenesulfonylimido-5-benzoyl-N-ri-(2-fluoro-4-trifluoromethyl-phenylcarbamoylmethine-pyridine

Starting from 7.04 g (20.0 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine and 6.50 g (21.7 mmol) of α-bromo-(2-fluoro-4-trifluoromethylphenyl)acetamide, the title compound was obtained in 10.1 g (88%). EA, MS (FD).

115. Production

U-Dihydro^-toluenesulfonyl-imido-S-benzoyl-N-yl-phenyl-carbamoyl-methine-pyridine

Starting from 10.6 g (30.0 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine and 6.74 g (31.5 mmol) of α-bromophenylacetamide, the title compound was obtained in the same manner as in Preparation 94, except that cesium fluoride was used instead of sodium hydride, yield: 13.3 g (91%). EA, MS (FD).

116. Production

1,2-Dihydro-2-toluenesulfonylimido-5-benzoyl-N-F1-(4-trifluoromethylphenyl)carbamoylmethyl-pyridine

Starting materials were 10.0 g (28.5 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine and 11.1 g (29.8 mmol) of a-O-toluenesulfonylimido-(4-trifluoro52

Using (-methylphenyl)acetamide and proceeding as described in Preparation 94, 13.9 g of the title compound were obtained (88%). EA, MS (FD).

117. Preparation of fluoro-6-trifluoromethylphenyl

-carbamoylmethylpyridine

Starting from 10.6 g (30.0 mmol) of 1,2-dihydro-2-toluenesulfonyl-imido-5-benzoyl-pyridineb0l and 12.9 g (33.0 mmol) of «-O- _{toluenesulfonyl} -imino-(2-^^^) and proceeding as described in Preparation 94, the title compound was prepared with the difference that diisopropylethylamine was used instead of sodium chloride mentioned in the preparation and the reaction was carried out at a temperature between 90-100”C; yield: 2.90 g (16.9%). MS (FD), NMR.

118. Production

1,2-Hydro-2-toluenesulfone||-imido-5-benzoyl-N-ri-(2.3.4.5.6-oenthan..nr-phonine carbamoyl-methyl-pyridine

Starting from 5.28 g (15.0 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine and 5.93 g (15.0 mmol) of a-O-toluenesulfonylimido-(2,3,4,5,6-pentafluorophenyl)acetamide, the title compound was prepared as described in Preparation 94, except that cesium carbonate was used instead of sodium hydride and the operation was carried out at 60°C; yield: 5.07 g (59%). EA, MS (FD).

119. Production

-carbamoylmethylpyridine

Starting materials were 10.6 g (30.0 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine and 10.7 g (31.5 mmol) of α,O-toluenesulfonylimido-(2,6-difluorophenyl).

Using acetamide and proceeding as described in Preparation 94 except that the operation was carried out at 60°C, the title compound was prepared in yield 7.44 g (48%). EA, MS (FD).

120. Preparation of carbamoylmethylpyridine

Starting from 10.6 g (30.0 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine and 11.8 g _{(31.5 mmol} ) of (-O-toluenesulfonylimido-N-phenyl)acetamide, the title compound was prepared as described in Preparation 94 except that the reaction was carried out at 70°C; yield: 7.37 g (44.4%). EA, MS (FD).

121. Production

-methyl-pyridine

Starting from 9.90 g (28.1 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine and 6.50 g (29.6 mmol) of α-O-toluenesulfonylimido-(thiophen-3-yl)acetamide, the title compound was prepared as described in Preparation 94 in 11.3 g (81.7%). EA, MS (FD).

122. Production

1^Dihydro-2-toluene _U |fo _ní |.|mido.5-benzoyl-NH-(2^^^

-carbamoylmethylpyridine

Starting from 10.6 g (30.0 mmol) of 1,2-dihydro-2-toluenesulfonimido-5-benzoylpyridine and 12.9 g (33.0 mmol) of α-O-toluenesulfonimido-(2-trifluoromethyl-6-fluorophenyl)acetamide, the title compound was prepared as described in Preparation 94, except that diisopropylethylamine was used instead of sodium hydride and the reaction was carried out at 50-60°C; yield: 14.5 g (83%). EA, MS (FD).

123. Production

1^ _: Dihydro-2-toluenesulfonyl- _imido -5-benzoyl^

Starting from 10.6 g (30.0 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine and 7.52 g (33.0 mmol) of α-bromobenzylacetamide, the title compound was obtained in 802 mg (5.36%) as described in Preparation 94. MS (FD), NMR.

124. Production

L-2,:Dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-isobutylcarbamoH-methylyl-Diridin)

Starting from 7.04 g (20.0 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine and 8.54 g (44.0 mmol) of α-bromoisobutylacetamide, the title compound was prepared as described in Preparation 94, except that cesium carbonate was used instead of sodium hydride; yield: 3.35 g (36.0%). EA, MS (FD) 125. Preparation

-methyl-pyridine

Starting from 10.6 g (30.0 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine and 7.69 g (31.5 mmol) of α-O-toluenesulfonylimido-(2-methoxyphenyl)acetamide and proceeding as described in Preparation 94, 10.4 g of the title compound were obtained (68%). EA, MS (FD).

126. Production

12-Dihydro-2-toluenesulfoni[-imido-5-benzoyl-N-n-(4-carbonyl-methoxy-phenyl-carbamoyl-methyl-pyridine)

Starting from 12.0 g (34.2 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine and 13.0 g (35.9 mmol) of α-O-toluenesulfonylimido-(4-carbonylmethoxyphenyl)acetamide and proceeding as described in Preparation 94, 15.5 g of the title compound were obtained (83%). EA, MS (FD).

127, Preparation of ^-Dihydro^-toluenesulfonylimido-S-benzoyl-N-^nitro-phenyl-carbamoylmethine-pyridine

Starting from 10.6 g (30.0 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine and 8.55 g (33.0 mmol) of α-bromo-(4-nitrophenyl)acetamide, the procedure described in Preparation 94 afforded 15.3 g of the title compound (96.2%). MS(FD), NMR.

128. Production

-carbamoylmethyl]pyridine

Starting from 7.40 g (20.0 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-(4-fluorobenzoylpyridine) and 5.10 g (22.0 mmol) of n-bromo-(4-fluorophenyl)acetamide, the procedure described in Preparation 94 afforded 9.15 g of the title serine compound (88%). EA, MS (FD).

129. Production

Lg-Dihydro-2-toluenesulfonyl-imido-5-tetrafluorobenzoyl-N-fluoro-trifluoromethyl

-phenylcarbamoylmethyloridine

Starting from 7.40 g (20.0 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine and 8.60 g (22.0 mmol) of α-bromo-(2-fluoro-4-trifluoromethylphenyl)acetamide, the title compound was prepared as described in Preparation 94 except that diisopropylethylamine was used instead of sodium hydride; yield: 8.95 g (76%). EA, MS (FD).

130, Production

2-Amino-5-carbonylmethoxypyridine

50.0 g (0.362 mol) of 6-aminonicotinic acid were dissolved in 3.5 liters of MeOH while introducing nitrogen gas, and the solution was cooled to 0°C. Hydrogen gas was bubbled through the solution for 45 minutes while maintaining the temperature at 0-15°C. The reaction mixture was then heated at 65°C for 4 hours. The MeOH was removed in vacuo and the residue was taken up in 400 ml of H ₂ O. The pH of the solution was adjusted to 6.3 with saturated NaHCO 3 solution, at which point a precipitate formed. The precipitate formed was isolated by filtration and washed with water. The filter cake was dried in vacuo at 80°C to give 48.9 g of the title compound (88.7%). EA, MS (FD).

131. Production

48.9 g (0.321 mol) of 2-amino-5-carbonylmethoxypyridine are dissolved in 400 ml of pyridine while introducing nitrogen gas. After adding 73.5 g (0.386 mol) of p-toluenesulfonic acid, the solution is refluxed for 16 hours at a temperature of about 77.5°C. The volume of the solution is then reduced by 3/4 under vacuum, and 3.5 liters of water are added. The resulting precipitate is separated by filtration, washed with water, and air-dried, thus obtaining 78.4 g of product (79.7%). MS (FD), NMR.

132. Preparation of l^Dihydro^-toluenesulfonyl-imirto·^^

-pyridine; compound of formula (132E)

73.4 g (0.240 mol) of 2-toluenesulfonylimido-5-methoxycarbonylpyridine are suspended in 465 ml of DMF while introducing nitrogen gas. 10.1 g (0.253 mol) of 60% sodium hydride are added to the suspension in two portions. After about 45 minutes, all the components have gone into solution, at which time 53.8 g (0.252 mol) of a-bromophenylacetamide are added, and the mixture is stirred for 64 hours. The volume is reduced by 2/3 under vacuum, the mixture is poured into 3 liters of water, and then stirred for 2 hours. The precipitate formed is separated by filtration and washed with water. The filter cake was dried under vacuum at 60°C to give 103.4 g of the title product (98.2%). MS (FD)

NMR.

133. Preparation of ^{2zS:!í!!i2!::} 2S2íamMoááeniWd!a!Í2!!!!a!^^ compound

103.3 g (0.235 mol) of 1,2-dihydro-2-toluenesulfonylimido-5-carbonylmethoxy-N-(1-phenylcarbamoylmethyl)pyridine, 286 ml (2.03 mol) of trifluoroacetic anhydride and 573 ml of CH2Cl2 were mixed under nitrogen gas, the mixture was refluxed for 6 hours, then concentrated in vacuo. The residue was dissolved _in 1.5 liters of _CH2Cl2 , the organic solution was washed with 3x500 ml of saturated NaHCO3 _solution , 2x500 ml of saturated sodium chloride solution, dried with sodium sulfate and filtered. The mother liquor was concentrated in vacuo, the residue was taken up in 250 ml of hot EtOAc, and the product was precipitated with 700 ml of hexane. During the formation of the precipitate, the mixture was placed in a refrigerator for 18 hours, then filtered, the separated product was washed with hexane, and dried in vacuo at 40°C; thus, 75.3 g of product was obtained (quantitative yield). NMR. 134. Preparation

2-Amino-3-phenyl-6-(carbonylmethoxyimidazolium,2-allopyridine: (134E)-derived vehicle

136 g (0.440 mol) of 2-trifluoroacetamido-3-phenyl-6-(carbonylmethoxy)imidazo[1,2-a]pyridine were dissolved in 845 ml of MeOH. 280 ml (1.61 mol) of diisopropylethylamine were added to the solution over 15 min. The reaction mixture was carefully heated to boiling under reflux and stirred for 68 h. The reaction mixture was then cooled to 0°C and the precipitate was collected by filtration. The filter cake was washed with cold MeOH and air dried to give 84.0 g of product (71.4%). EA, MS(FD).

135. Production

2-Amino-3-phenyl-6-(carboxy)imidazol,2-alpyridine

83.9 g (0.314 mol) of 2-amino-3-phenyl-6-(carbonylmethoxy)-imidazo[1,2-a]pyridine, 65.9 g (1.57 mol) of lithium hydroxide monohydrate, 1113 ml of THF and 371 ml of H ₂ O are mixed and the mixture is stirred at room temperature for 18 hours. The reaction mixture is concentrated in vacuo and the residue is taken up in 5 liters of H ₂ O. The pH of the solution is adjusted to 5 with 5 normal hydrochloric acid. The precipitate formed is isolated by filtration and then air-dried for 72 hours to obtain 80.5 g of product (quantitative yield). NMR, MS (FD).

136. Production

g.- ^Amino -3-phenyl-6-(N-methyl-N-methoxycarbamoyl) _{-l ymidazolyl} (13Ke) compound of _formula

80.4 g (0.317 mol) of 2-amino-3-phenyl-6-(carboxy)-imidazo[1,2-a]pyridine and 92.8 g (0.951 mol) of Ν,Ο-dimethylhydroxylamine hydrochloride are dissolved in 500 ml of DMF while introducing nitrogen gas. After adding 123 g (0.951 mol) of diisopropylethylamine, the mixture is stirred for 30 minutes at room temperature. After adding 122 g (0.634 mol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, the mixture is stirred for 19 hours at room temperature. The DMF is removed in vacuo and the residue is poured into 4 liters of water. The aqueous phase was extracted with 3x500 ml CH^, the organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was taken up in 400 ml EtOAc, and the solution was stirred at room temperature for 1 hour, when a precipitate formed. The precipitate was collected by filtration and washed with cold EtOAc. The filter cake was dried at 40”C in vacuo to give 55.5 g of product (59.2%). MS (FD), NMR.

137. Production

2-Iodopyridine

48.0 g (303 mmol) of 2-bromopyridine and 240 ml of 47% hydrogen iodide solution were refluxed for 8 hours, then cooled to room temperature.

Stir for 3.5 days. Pour the reaction mixture into aqueous NaOH solution (240 ml of 40% NaOH and 250 ice). Extract with 3x200 ml of Et ₂ O, wash the ether with 100 ml of saturated sodium chloride solution, dry over sodium sulfate, filter, and concentrate in vacuo. The residue is distilled twice in vacuo to separate the fractions between 83°C and 88°C; 18.6 g of the title compound are obtained (30%). Ea, MS (FD):

138. Preparation of 4-Iodopyridine

Starting from 50.0 g (257 mmol) of 4-bromopyridine hydrochloride and proceeding as described in Preparation 137, 32.9 g of the title compound were obtained (62.4%). MS (FD), NMR. Preparation 139

N±3-Phenyl-6-(N-methyl-N-carbamoylHmidazol.2-alpyridine-24ll-^^

2aza-2,5-disilacyclopentane; compound with formula (139E)

0.592 g (2.00 mmol) of 2-amino-3-phenyl-6-(N-methyl-N-methoxycarbamoyl)-imidazo[1,2-a]pyridine was suspended in 20 ml of xylene. 1.227 g (5.28 mmol) of 1,1'-ethylenebis(N,N,1,1'-tetramethylsilanamine) and 10 mg (0.031 mmol) of zinc iodide were added and the mixture was refluxed for 4 h. The solvent was removed in vacuo and the resulting crude product was used in the next step without further purification.

140. Production of Í^ÖÍ^Sn’oildaetíM^áihjdroááSjuo!^^ compound

To a suspension of 11.65 g (32.10 mmol) of 1,2-dihydro-2-toluenesulfonimido-5-benzoylpyridine in 100 ml of anhydrous DMF was added 6.34 ml (34.2 mmol) of diisopropylethylamine. After 15 minutes the solution became clear. After adding 6.74 g (34.2 mmol) of iodoacetamide, the mixture was stirred for 24 hours, then poured into 2 liters of water and a further 1 εο .·. .·.

Stir for 1 hour. The solid was collected and air dried to give 13.15 g of white product (97%). EI-MS, NMR.

141, Production

Dimethyl-(N-methylcarbamoylmethylphosphonate: (141E1 _sulfuric acid ₎

A solution of 4.12 ml of 40% methylamine (aqueous, 47 mmol) in 8.3 ml of MeOH was cooled to -78°C. 8.85 ml (44.2 mmol) of triethylphosphonoacetate was added dropwise to the cooled solution over a period of about 10 min. The reaction mixture was allowed to warm to room temperature and stirred at this temperature for 29 h (TLC: MeOH/CH ₂ Cl ₂ 1:9). The solvent was removed in vacuo at 35°C and the resulting colorless liquid was purified by distillation (0.5 mm Hg/130°C) (87%). NMR.

142. Production

Isopropyl isopropane thiol sulfonate iPr-S(O) ₂ -S-(iPr)

A solution of 10.0 g (66.5 mmol) of diisopropylpropanethiol sulfonate in 55 mL of acetic acid was added dropwise to 14.4 g (140 mmol) of 33% hydrogen peroxide at 0°C over 30 min. The mixture was stirred at room temperature for 24 h, then the solvent was evaporated; the crude oil was purified by column chromatography (EtOAc/hexane) to give 8.5 g of a colorless oil (70%). 'H-NMR, ^,3 C-NMR

143. Preparation _of -6-(carbonylmethoxy) ^-methyl - ^1,2 -dihydro-2-toluenesulfonamide:

Compound (143E) g (65.3 mmol) of 1,2-dihydro-2-toluenesulfonimido-5-methoxycarbonylpyridine was suspended in 120 ml of anhydrous DMF and stirred under argon gas. After addition of 125.2 ml (71.82 mmol) of diisopropylethylamine and 13.28 g (71.82 mmol) of 2-iodoacetamide, the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was then poured into 60 ml of water and stirred for 90 minutes. The resulting solid was isolated by filtration, washed with 1 liter of water and 200 ml of diethyl ether, and dried over 100 °C.

dried in vacuo to give 21.8 g (91.7%) of the desired compound as a white product. MS (FAB), NMR.

144. Production ^{2:lQa!iSE:a£SÍ3!!!Íá2} ^lbo^^ assembly

To a suspension of 5.00 g (13.8 mmol) of 1-carbamoylmethyl-1,2-dihydro-2-toluenesulfonimido-6-(cartonylmethoxy)pyridine in 75 ml of anhydrous CHCl, 60 ml (425 mmol) of trifluoroacetic anhydride were added under argon gas. The resulting solution was refluxed for 3 h. The solvent was then removed in vacuo. The residue was taken up in 150 ml of EtOAc and the resulting suspension was stirred for 30 min. The solid was isolated by filtration, poured into 50 ml of water and stirred for 30 min. The solid was isolated and dried in vacuo to give 1.92 g (49%) of the title compound as a white solid. MS, (FAB), NMR.

145. Production

2: Trifluoroacetamido-64N-methoxy-N-methylamyclo)-lmM _a zofl.2-a1oridin·· _f14SEl

To a solution of 1.50 g (5.23 mmol) of 2-trifluoroacetamido-6-carbonylmethoxyimidazo[1,2-a]pyridine and 893 mg (9.15 mmol) of NO-dimethylamino hydrochloride in 30 ml of THF cooled to -20°C was added dropwise 12.0 ml (24.1 mmol) of isopropylmagnesium chloride over a period of about 20 minutes. The reaction mixture was stirred at -20°C for 1 hour. The solvent was removed, the residue was dissolved in EtOAc and washed with saturated NH ₄ Cl solution. The combined organic extracts were dried over sodium sulfate and the solvent was removed in vacuo to give 1.23 g of a white solid (75%). HRMS: calculated _{for C12H11N4O3F3} : _316.0783 , found _{: 316.0782} .

146. Preparation of ?-Trifluoroacetamido-3-phenyl-6-(N-methyl-N-methoxycarbamoylimidazole)- _a l· pyridine; compound of formula (146E)

Starting from 12.0 g (33 mol) of 2-trifluoroacetamido-3-phenyl-6-carbonylmethoxyimidazo[1,2-a]pyrimidine and proceeding as described in Preparation 189, 8.0 g of the title compound were obtained (68%). MS (FAB), NMR.

147. Production

2-Chloro-5-(N-methyl-N-methoxycarbamoyl)pyridine

To a solution of 880 mg (5 mmol) of 2,6-dichloronicotine in 20 ml of acetone was added 500 mg (5.13 mmol) of N-methoxy-N-methylamino hydrochloride and 1.33 g (10.2 mmol) of diisopropylethylamine. The reaction mixture was stirred for 10 minutes. The solvent was removed in vacuo and the residue was purified by column chromatography to give 950 mg of oil (95%).

148. Production

2-Chloro-5-(1-phenyl-2-N-methylcarbamoylvinyl)-pyridine: compound with formula (148E)

To a solution of 9.2 g (46 mmol) of potassium hexamethyldisilazide in 25 mL of anhydrous DMF at 0°C under argon gas was added a solution of 4.81 g (23.0 mmol) of diethyl-(N-methylcarbamoylmethyl)phosphonate in 50 mL of anhydrous DMF. The reaction mixture was stirred at 0°C for about 2 hours. A solution of 2.5 g (11.5 mmol) of 2-chloro-5-benzoylpyridine in 25 mL of anhydrous DMF was then added to the reaction mixture via cannula. The ice bath was removed, the brown solution was allowed to warm to room temperature, and then stirred for 16 hours. The mixture was diluted with 30 mL of saturated NH ₄ Cl solution and extracted with EtOAc. The organic phases are combined and washed with saturated NH ₄ CI solution and then with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and the solvent is removed in vacuo, and the resulting residue is passed through a chromatography column (hexane/AcOEt 1:1); 1.5 g of an isomeric mixture is obtained, in which the ratio of E:Z isomers is 1:1.5 (50% yield). The isomers are separated by crystallization. Z-isomer, IR, NMR and E-isomer, IR, NMR.

149. Production

2-Chloro-5-(2,3-difluorobenzoyl)pyridine

To a solution of 0.114 g (0.746 mmol) of 1-bromo-2,3-difluorobenzene in 3 ml of anhydrous THF at -78°C was added n-butyllithium solution (1.6 mol/l in hexane, 0.47 ml, 0.749 mmol). The reaction mixture was stirred at -78°C for 1 h. After addition of a solution of 0.13 g (0.68 mmol) of 6-chloro-N-methoxy-N-methylnicotinamide in 5 ml of THF, the reaction mixture was allowed to warm to room temperature and then stirred for 6 h. After addition of saturated NH.CI solution, the mixture was extracted with 3x10 ml of CH ₂ CI ₂ . The combined phases were washed with saturated sodium chloride solution and then dried over sodium sulfate. The solvent was removed in vacuo and the The residue was purified by column chromatography (hexane/AcOEt 9:1) to give 130 mg (77%) of oily product. IR, NMR.

150. Production

Z~Chloro-5-f1-(2,3-difluoro-phenyl)-2-N-methyl-carbamoyl-vinin-pyridine _{: (150E)} " _Αη ", _Μ group

Starting from 2-chloro-5-(2,3-difluorobenzoyl)pyridine and proceeding as described in Preparation 203, the title compound was prepared in two isomers. Recrystallization from EtOAc isolated the Z-isomer in 35% yield (IR, NMR), the E-isomer was obtained from the filtrate in 17% yield. IR, NMR.

151. Production

Compound of formula H2-Oxo-2-phenylethyl)-2-chloro-5-f(E)-1.phenyl^^ (151E)

To a mixture of 100 mg (0.367 mmol) of 2-chloro-5-[(E)-1-phenyl-2-N-methylcarbamylvinyl]pyridine and 0.270 g (1.35 mmol) of bromoacetophenone in 5 ml of CH ₃ CN was added 0.21 g (1.4

Λ-Γ 'Cmmol) Nal is added. The reaction mixture is refluxed for 40 hours. CH ₃ CN is removed in vacuo and the resulting residue is dissolved in hot (40-45°C) EtOH. After rapid filtration, the filtrate is concentrated in vacuo, the resulting solid is washed with 100 ml diethyl ether and then with cold EtOAc; a solid product is obtained in 85 % yield. IR, NMR.

152. Production ^UÍ^Sfi^líluoMeniü^tilladdj^

-pyridinium iodide; compound of formula (152E)

Starting from 300 mg (1.10 mmol) of 2-chloro-5-[(E)-1-phenyl-2-N-methylcarbamoylvinyl]pyridine and 4-fluorobromoacetophenone, and proceeding as described in Preparation 151, 395 mg of the title compound were obtained (67%). IR, NMR.

153. Preparation of compound of formula (153E)

Starting from 300 mg (1.10 mmol) of 2-chloro-5-[(E)-1-phenyl-2-N-methylcarbamoylvinyl]pyridine and chloropropanone, and proceeding as described in Preparation 151, 297 mg of the title compound were obtained (60%). NMR.

154. Production

1.((2-Xo-3,3-dimethylbutyl)-2-chloro-5-(E)-1-phenyl-2-methylcarbamoylvinylpyridinium iodide

Starting from 300 mg (1.10 mmol) of 2-chloro-5-[(E)-1-phenyl-2-N-methylcarbamoylvinyl]pyridine and chloropinacolone, and proceeding as described in Preparation 151, 141 mg of the title compound were obtained (26%). IR.

155. Production

HN,N-diethylacetamidyl)-2-chloro.5-f(E)-1-phenyl.2-methylcarbamoylvinyl- _P iridinium.

-iodide; compound of formula (155E)

Starting from 140 mg (0.514 mmol) of 2-chloro-5-[(E)-1-phenyl-2-N-methyl] and 2-chloro-N,N-diethylacetamide and proceeding as described in Preparation 151, 75.9 mg of the title compound were obtained (29%). NMR.

156. Production

H2-Oxo-3,3-dimethylbutyl)-2-chloro-5-[(E)-1-(2,3-difluorophenyl)-2-carbamoylvinyl ₁ ,

-pyridinium iodide; compound with formula (156E)

250 mg (0.810 mmol) 2-chloro-5-[(E)-1-(2,3-difl^^^^^^

Starting from -pinambol and chloropinacolone and proceeding as described in Preparation 151, 199 mg of the title compound are obtained (46%). IR.

Examples

Example 1

2-Trifluoroacetamido-3-(2,5-difluorophenyl)-6-benzoylimidazolyl,2-alpyridine; compound of formula (1)

14.9 g (28.6 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[2,5-difluorophenyl]carbamoylmethyl)pyridine were dissolved in 400 mL of CH2Cl2, and 50 mL (354 mmol) of trifluoroacetic anhydride were added to the solution. The solution was heated to reflux (a dry ice-filled condenser was used to ensure reflux of volatile components) and the mixture was stirred for 3 h. The solvents were removed in vacuo and the residue was taken up in 700 mL of EtOAc. The solution was washed with 3x100 mL saturated NaHCO3, 3x100 mL saturated sodium chloride solution, dried over Na ₂ SO 4 , filtered, and concentrated in vacuo. The crude product was recrystallized from EtOAc/hexane to give 12.1 g of the title compound (94.6%).

EA, MS (FD).

Example 2 ^rtfl _U or-acetamido-3-(4-methoxy-phenyl)-6-benzoyl-imidazo compound λ λ

13.2 g (23.3 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[4-methoxyphenyl]carbamoylmethyl)pyridine was converted to the title compound in the same manner as in Example 1, yield: 10.6 g (92%). EA, MS (FD).

Example 3 ^rjfluoroacetamido.3-(naphth.24^^ ₍₃ > sulfur _w .

gathering

Starting from 14.7 g (27.4 mmol) of 1,2-dihydro-toluenesulfonylimido-5-benzoyl-N-(1-[naphth-2-yl]carbamoylmethyl)pyridine, this compound was converted into the product dm as described in Example 1; yield: 10.4 g (82.4%). EA, MS (FD).

Example 4 2- _Trifluoro- acetamido-3-naphthyl-6.benzoyl4imidazo(1.2-alpyridin. (4) veovyl

11.3 g (22.0 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-naphthylcarbamoylmethyl)pyridine were converted to the title compound as described in Example 1. Yield: 8.25 g (82%). EA, MS (FD).

Example 5

2-Trifluoroacetamido-3-(2-fluorophenyl).6-benzoylimide^ .2-alpyridine: _{(5) k} » _p , _o ,·compound

12.3 g (24.5 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[2-fluorophenyl]carbamoylmethyl)pyridine was converted to the title compound essentially as described in Example 1. Yield: 10.2 g (97%). EA, MS (FD).

Example 6: Trifluoroacetamide- _3- (3-fluorophenyl)-6-benzoylimidazolyl,2-alpyridine: Compound (6)

26.6 g (52.8 mmol) 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[3-fluoro· _Λ — ·*-» ··*

Starting from ([(-phenyl]carbamoylmethyl)pyridine) and proceeding as described in Example 1, 21.6 g of the title compound (95.8%) were prepared. EA, MS (FD).

Example 7: Compound

Starting from 11.0 g (21.1 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[2,4-difluorophenyl]carbamoylmethyl)pyridine and proceeding as described in Example 1, 9.24 g of the title compound (98.5%) were prepared. EA, MS (FD).

Example 8. ?-Trifluoroacetamido-3-(3,5-difluorophenyl)-6-benzoylimidazole-1,2-alniridine: Compound of _interest

Starting from 13.3 g (25.6 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[3,5-difluorophenyl]carbamoylmethyl)pyridine and proceeding as described in Example 1, 10.2 g of the title compound (90.1%) were prepared. EA, MS (FD).

Example 9 Compound {Trifluoroacetamido-3-(4-fluorophenyl)} ₍₉₎

Starting from 35.0 g (69.6 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[4-fluorophenyl]carbamoylmethyl)pyridine and proceeding essentially as described in Example 1, 18.6 g of the title compound (62.7%) were prepared. EA, MS (FD). Example 10 Compound of formula

Starting from 13.3 g (24.1 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-(3-trifluoromethylphenyl]carbamoylmethyl)pyridine and proceeding essentially as described in Example 1, 9.08 g of the title compound (80%) were prepared. EA, MS (FD).

: :

Example 11

2-Trifluoroacetamido-3-(4-bromophenyl)-6.benzoylimidazolylpyridine: Hl) compound;

Starting from 12.7 g (22.5 mmol) of 1,2-dihydro-2-toluenesulfonyl-4-mido-5-benzoyl-N-(1-[4-bromophenyl]carbamoylmethyl)pyridine and proceeding as described in Example 1, 10.5 g of the title compound (95.4%) were prepared. EA, MS (FD).

Example 12: Compound with formula

Starting from 11.3 g (20.9 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[2,3,4-fluorophenyl]carbamoylmethyl)pyridine and proceeding as described in Example 1, 8.43 g of the title compound (87%) were prepared. EA, MS (FD).

Example 13

2-Trifluoroacetamido-3-(3,4-difluorophenyl)-6-benzoylimidazol,2-aldipyridine: _{(í31 k} z _r letű compound

Starting from 9.53 g (18.3 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-(3,4-fluorophenyl]carbamoylmethyl) _-pyridine and proceeding as described in Example 1, 7.44 g of the title compound (91%) were prepared. EA, MS (FD).

Example 14: Compound with

Starting from 13.8 g (24.9 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[3,4-dichlorophenyl]carbamoylmethyl)pyridine and proceeding as described in Example 1, 9.91 g of the title compound (83%) were prepared. EA, MS (FAB).

Example 15

2-Fluoroacetamido-3-(2,4,5- _{trifluorophenyl} )-6- _{benzoylimidazole} -1,2-chloropyridine: compound with formula

Starting from 11.6 g (21.5 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[2,4,5-trifluorophenyl]carbamoylmethyl)pyridine and proceeding as described in Example 1, 9.28 g of the title compound (93%) were prepared. EA, MS (FD).

Example 16

2^255^26131111(10^24(1(^^ compound

Starting from 14.2 g (27.3 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[2-chlorophenyl]carbamoylmethyl)pyridine and proceeding as described in Example 1, 10.8 g of the title compound (88%) were prepared. EA, MS (FD).

Example 17

2Jnfl _UO r-acetamido-343-chlorophenyl)-6- _b6 nzollimidazol.2.alniridine: compound (17)

Starting from 12.0 g (23.1 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[3-chlorophenyl]carbamoylmethyl)pyridine and proceeding as described in Example 1, 8.97 g of the title compound (88%) were prepared. EA, MS (FD).

Example 18

2-Aminofluoroacetamido-3-(4-chlorophenyl)-6-benzoylimidazol-2-ylpyridine: compound of formula (18)

Starting from 13.8 g (26.5 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[4-chlorophenyl]carbamoylmethyl]pyridine and proceeding as described in Example 1, 10.7 g of the title compound (91%) were prepared. EA, MS (FD).

Example 19

2-Trifluoroacetamido-3-(4-trifluoromethoxyphenyl)-6-benzoylimidazol-2-ylpyridine;

Compound of formula (19) *: ^: ;··.:··.

13.2 g (23.3 mmol) 1,2-dihydro-2-toluenesulfonyl-imido-5-benzoyl-N-(1-[4-trifluoro·

Starting from (-methoxyphenyl]carbamoylmethyl)pyridine and proceeding as described in Example 1, 10.6 g of the title compound (92%) were prepared. EA, MS (FD).

Example 2O

2-Trifluoroacetamido-3-(3-(trifluoromethoxyphenyl)-6-benzoylimidazoF1,2-alpyridine: compound of formula (20)

Starting from 12.5 g (22.0 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[3-trifluoromethoxyphenyl]carbamoylmethyl)pyridine and proceeding as described in Example 1, 10.4 g of the title compound (96%) were prepared. EA, MS (FD).

Example 21 ^ ^{Trifluoroacetamido} -3-(2-fluoro-4-trifluoromethylphenyl)-6-benzoylimidazo[1,2- ^a ]pyridine; compound of formula (21)

Starting from 10.1 g (17.7 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[2-fluoro-4-trifluoromethylphenyl]carbamoylmethyl)pyridine and proceeding as described in Example 1, 8.03 g of the title compound (92%) were prepared. EA, MS (FD) Example 22

2-Trifluoroacetamido-3-phenyl-6-benzoylimidazol,2-alpyridine: compound of formula (22)

13.3 g (27.3 mmol) 1,2-dihydro-2-toluenesulfonyl-imido-5-benzoyl-N-(1-phenyl

Starting from -carbamoylmethyl-pyridine and proceeding as described in Example 1, 10.0 g of the title compound (90%) were prepared. EA, MS (FD).

Example 23

2-Trifluoroacetamido-3-(2,6-trifluorophenyl-6-benzoylimidazol,2-aldipyridine: Compound of formula W

Starting from 7.44 g (14.3 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[2,6-difluorophenyl]carbamoylmethyl)pyridine and proceeding as described in Example 1, 5.26 g of the title compound (82.8%) were prepared. EA, MS (FD).

Example 24

2-Trifluoroacetamido-3-(2,3,4,5,6-pentafluorophenyl)-6-benzoylimidazolium,2-a)pyridine: compound of formula (24)

Starting from 3.00 g (5.22 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-(2,3,4,5 6-pentafluorophenyl]carbamoylmethyl)pyridine and proceeding as described in Example 1, 1.58 g of the title compound (60.8%) were prepared. EA, MS (FD). Example 25

2-Trifluoroacetamido-3-(2-trifluoromethylphenyl)-6-benzoH-imidazol.2-a1Pyridine: compound of formula (25)

Starting from 7.37 g (13.3 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[2-trifluoromethylphenyl]carbamoylmethyl)pyridine and proceeding as described in Example 1, 6.22 g of the title compound (98%) were prepared. EA, MS (FD).

Example 26: Trifluoroacetamido-3-(thiophen-3-yl)-6-benzoylimidazol-2-ylpyridine; compound of formula (26)

Starting from 11.4 g (23.1 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[thiophen-3-yl]carbamoylmethyl)pyridine and proceeding as described in Example 1, 8.88 g of the title compound (92.6%) were prepared. EA, MS (FD).

Example 27

Z:Trifluoroacetamido-3-(2-trifluoromethyl-4-fluorophenyl)-6-benzoylimidazol-2-ylpyridine; compound of formula (27)

Starting from 14.5 g (25.3 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[2-trifluoromethyl-4-fluorophenyl]carbamoylmethyl)pyridine and proceeding as described in Example 1, 11.0 g of the title compound (88%) were prepared. EA, MS (FD) Example 28

2 _: Trifluoroacetamido-3-(2-fluoro-6-trifluoromethylphenyl)-6-benzoylimidazol.2· apyridine; compound of formula (28)

Starting from 2.90 g (5.08 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[2-fluoro-6-trifluoromethylphenyl]carbamoylmethyl)pyridine and proceeding as described in Example 1, 2.37 g of the title compound (94%) were prepared. EA, MS (FD).

Example 29. formulaic compound

Starting from 13.3 g (24.1 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[4-trifluoromethylphenyl]carbamoylmethyl)pyridine and proceeding as described in Example 1, 10.1 g of the title compound (88%) were prepared. EA, MS (FD).

Example 30: Needle thread

Starting from 10.4 g (20.3 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[2-methoxyl· -phenyl]-carbamoylmethyl]-pyridine and proceeding as described in Example 1, 7.40 g of the title compound (83%) were prepared. EA, MS (FD).

Example 31 ^?;]ϊί£!22 ^ ^222ί2222 2 _; Compound of formula Η44<3 _Ι Ιχ^^ (31).

Starting from 15.5 g (28.5 mmol) of 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[2-methoxyphenyl]carbamoylmethyl)pyridine and proceeding as described in Example 1, 12.6 g of the title compound (94%) were prepared. EA, MS (FD).

Example 32: Compound

15.3 g (28.9 _mm6)) U-dibidro-^uo^

Starting from -carbamoyl-pyridine and _proceeding as described in Example 1, 11.2 g of the title compound (85.1%) were obtained. EA, MS (FD).

Example 33

2: ¹²²²²² ^^^^ qyület

Starting from 3.44 g (6.89 mmol) of 1,4-dihydro-toluoyl-carbamyl-methyl-pyridine and proceeding as described in Example 1, 2.19 g of the title compound (74.0%) were prepared. EA, MS (FD).

Example 34. qyület

Starting from 3.30 g (7.09 mmol) of (2-diNdr-toluene)carbamoylmethyl)pyridine and proceeding as described in Example 1,

2.37 g of the title compound (85.9%). EA, MS (FD).

Example 35. formula conclusion

9.15 Starting from 9 (17.6 mmol) of _1'2'bihydro -2-toluenesulfonylimido-5-(4-fluorobenzoyl)-N-(1-[4- _fluorophenyl ) _carbamoyl ] and proceeding as described in Example 1, 7.11 g of the title compound (91%) were prepared. EA, MS (FD).

Example 36

2:^ ^22212322122 ^^

11,2-alpyridine; compound of formula (36)

8.95 g (15.2 mmol) of 1.2-®dro-2^^

Starting from -N-(1-[2- _fluoro -4-trifluoromethyl)-4-[(2-fluoro-4- _{trifluoromethyl} )-4-[(2-fluoro-4-trifluoromethyl)-4-[(2-fluoro-4-trifluoro-4-methyl

Example 37 2-Trifluoroacetamido-6-benzoylimidazolylpyridine; compound of formula (37)

To a suspension of 7.15 g (17.46 mmol) of 1-carbamoylmethyl-1,2-dihydro-2-toluenesulfonimido-6-benzoylpyridine in 85 ml of anhydrous CH ₂ CI ₂ was added 62 ml (439 mmol) of trifluoroacetic anhydride. The mixture was stirred at 30°C under argon for 2.5 h. The solvent was then removed in vacuo, the remaining foam was taken up in 600 ml of EtOAc, the solution was washed with 2x250 ml of NaHCO ₃ and 1x250 ml of saturated sodium chloride solution. The organic phase was dried over Na ₂ SO ₄ and the solvent was removed in vacuo to give 5.5 g (92%) of the title compound as a white solid. EI-MS, NMR.

Example 38 (Trifluoroacetamido-3-iodo-6-benzoyl-4-imidazo[1,2-a]pyridine: Compound of formula (38)

A solution of 2.0 g (6.0 mmol) of 2-trifluoroacetamido-6-benzoylimidazo[1,2-a]pyridine in 50 ml of anhydrous CH ₃ CN was cooled to 0°C, and 1.35 g (6.0 mmol) of N-iodosuccinimide was added portionwise. The mixture was stirred for 10 min. The acetonitrile was removed in vacuo, the residue was dissolved in 250 ml of EtOAc, and the solution was washed with 2x200 ml of 40% w/v NaHSO ₃ solution, then with 2x200 ml of NaHCO ₃ solution. The organic phase was dried over Na ₂ SO ₄ and the EtOAc was removed in vacuo to give 2.60 g of product as a yellow solid (95%). EI-MS, NMR.

Example 39

2[(2,3-fluoroacetamido-3-methylthio-6-benzoylimidazol-2-yl]pyridine; compound of formula (39)

1.00 g (2.17 mmol) of 2-trifluoroacetamido-3-iodo-6-benzoylimidazo[1,2-a]pyridine is dissolved in 20 ml of pyridine (previously dried over KOH and filtered through a 3 Å molecular sieve, 0.04 % H ₂ O) under an argon atmosphere. 207 mg (3.25 mmol) of cuprous bronze is added to the solution. 160 μΙ (2.17 mmol) of methyl disulfide is added to the golden suspension in the brown solution using a syringe. The reaction mixture is heated at 104°C for 1 hour and then at 100°C for 68 hours. The progress of the reaction is monitored by NMR analysis (in each case, the sample is hydrolyzed and washed with a 1:9 ammonia/NH ₄ CI mixture before the NMR analysis). After the reaction is complete, the mixture is diluted with 3 liters of EtOAc and stirred for 15 minutes. After adding 2 liters of a 1:9 NH4OH/NH4Cl mixture, the mixture is stirred vigorously in a 10-liter separatory funnel for 30 minutes. The phases are separated, and 2 liters of a 1:9 NH4OH/NH4Cl mixture are added to the organic phase. The mixture is stirred again for 30 minutes and then left to stand without stirring for 5-10 minutes. The phases are separated, and the organic phase is washed with sodium chloride solution. The organic phase is separated and the remaining brown solid is purified by very fast column chromatography (MeOH/CH ₂ CI ₂ , 2:98) to give 670 mg of a yellow solid (81%). NMR. Example 40

2-Trifluoroacetamido-3-methylsulfonyl-6-benzoylimidazol-2-ylpyridine; compound (40)

500 mg (1.37 mmol) of 2-trifluoroacetamido-3-methylthio-6-benzoylimidazo[1,2-a]pyridine was combined with 563 mg (2.62 mmol) of mCPBA in 20 mL of anhydrous CH ₂ Cl ₂ . The reaction mixture was stirred at 0°C for 3 h and then washed with 1 mL of saturated NaHCO ₃ . The mixture was filtered through celite and washed with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by column chromatography to give 385 mg (67%) of a yellowish-white solid. NMR.

Example 41

Compound of formula 2-Trifluoroacetamido-3-isopropylthio-6-benzoylimidazo,2-alpyridine (41)

100 mg (0.22 mmol) of 2-trifluoroacetamido-3-iodo-6-benzoylimidazo[1,2-a]pyridine was dissolved in 10 ml of anhydrous pyridine at room temperature under an argon atmosphere. 21 mg (0.33 mmol) of copper bronze were added to the solution, followed by 35 μΙ (0.22 mmol) of diisopropyl disulfide. The mixture was heated to 100-120°C with stirring for 83 hours. The reaction mixture was cooled to room temperature, poured into 1 liter of EtOAc, and stirred for 1 hour. Then 750 ml of a 9:1 solution of NH ₄ CI/NH ₄ OH was added to the mixture, and the mixture was stirred for 15 minutes with a mechanical stirrer. The aqueous phase turned pale blue, the organic extract was washed with 750 ml of NH ₄ CI/NH ₄ OH 9:1 solution (15 min) and then with 750 ml of saturated sodium chloride solution. The EtOAc was removed in vacuo and the residue was purified by flash chromatography (EtOAc/hexane 1:1) to give 18 mg of a brownish oil (20% yield). ¹ H-NMR, ¹³ C-NMR.

Example 42

2-Trifluoroacetamido-6-[(E)-1-phenyl-2-N-methylcarbamoyl-vinimidazo[1,2-alpyridine; compound of formula (42)

1.88 g (9.00 mmol) of diethyl-(N-methylcarbamoylmethyl)phosphonate and 250 ml of anhydrous THF were charged into a flame-dried flask under argon. The solution was cooled to 78°C and 30 ml (22.5 mmol) of potassium hexamethyldisilazide solution (0.5 M in toluene) were added dropwise. The mixture was stirred at -78°C for 2 hours. Then a solution of 2.00 g (6.00 mmol) of 2-trifluoroacetamido-6-benzoylimidazo[1,2-a]pyridine in 100 ml of anhydrous THF was added dropwise. The reaction mixture was stirred at -78°C for 2 hours and then allowed to warm to room temperature. The resulting brown solution was stirred at room temperature for 60 h. The THF was removed in vacuo and the residue was taken up in 400 mL EtOAc, washed with 2x100 mL saturated NH ₄ CI solution and once with brine. After drying over magnesium sulfate, the solvent was removed in vacuo to give a brown solid. NMR analysis of the crude product showed only the “E” isomer with some unidentified by-products. The crude product was purified by column chromatography (CH ₃ CN:CH ₂ Cl2 2:1) to give 920 mg of the title compound (40%). EI-MS, NMR.

Example 43

2-Trifluoroacetamido-3-iodo-6-f(E)-1-phenyl-2-N-methylcarbamoylvinylimidazoF1,2-a1pyridine; compound of formula (43)

To a solution of 423 mg (1.22 mmol) of 2-trifluoroacetamido-6-[(E)-2-N-methylcarbamoyl-1-phenylvinyl]imidazo[1,2-a]pyridine in 20 mL of anhydrous CH ₃ CN at 0°C was added portionwise 302 mg (1.34 mmol) of N-iodosuccinimide and the mixture was stirred for 10 min. The desired compound precipitated as a white solid, which was collected by filtration and air dried to give 375 mg of crude product. The CH ₃ CN was removed in vacuo and the residue was dissolved in 50 mL of EtOAc. The EtOAc was washed with 2x50 mL of 40% w/v NaHSO ₃ and then with 2x50 mL of NaHCO ₃ . The organic phase was dried over Na ₂ SO ₄ and the EtOAc was removed in vacuo to give 240 mg of the title compound as a white solid (98% overall yield). EI-MS, NMR.

Example 44

2-Trifluoroacetamido-3-isopropylsulfonyl-6-[(E)-1-phenyl-2-N-methylcarbamoylvinylimidazolyl1,2-a]pyridine; Compound of formula (44) To a solution of 2-trifluoroacetamido-3-iodo-6-[(E)-2-N-methylcarbamoyl-1-phenylvinyl]imidazo[1,2-a]pyridine in 5 ml of THF cooled to -78°C, 230 μΙ (0.33 mmol) of phenyllithium was added under an argon atmosphere. After stirring for 3 minutes, 310 μΙ (0.38 mmol) of tert-butyllithium was injected. After stirring for 10 min, a solution of 109 mg (0.60 mmol) of isopropyl isopropanethiol sulfonate in 5 mL of THF was added to the mixture. The reaction mixture was stirred for 30 min at -78°C, then diluted with 2 drops of water and 10 mL of THF. After addition of 15 mL of ethyl acetate, the mixture was allowed to warm to room temperature. The solution was filtered through celite and the solvent was removed in vacuo. The residue was then dissolved in 10 mL of anhydrous CH ₂ Cl ₂ and cooled to 0°C. A solution of 208 mg (5 equivalents excess based on 100% theoretical yield of sulfide product) of previously dried mCPBA in 40 ml CH ₂ CI ₂ was then added to the above solution until the starting compound was completely converted to the sulfone derivative (the progress of the reaction was monitored by TLC). The solution was then washed with 50 ml Na ₂ SO ₃ solution and then 2x50 ml NaHCO ₃ solution. The organic phase was dried over Na ₂ SO 4 and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica gel, CH ₃ CN/CH ₂ CI ₂ 1:1) to give 47 mg of white solid (63%) NMR.

Example 45: Influoroacetamido-6-(2,3-difluorobenzoyl)imidazo[1,2-a]pyridine; compound of formula (45)

To a solution of 480 ml (4.32 mmol) of 1-bromo-2,3-difluorobenzene in THF was added 2.05 ml (4.42 mmol) of n-butyllithium solution (prepared in 10 ml of anhydrous THF), the addition was carried out under an argon atmosphere at -78°C. After stirring for 10 min, a solution of 513 mg (1.88 mmol) of 2-trifluoroacetamido-6-(N-methoxy-N-methylamido)-imidazo[1,2-a]pyridine in 15 ml of THF was added dropwise. The reaction mixture was stirred at -78°C for 1 h. After addition of NH ₄ CI, the mixture was extracted with 25 ml of EtOAc and then washed with 2x20 ml of NH ₄ CI. The solvent was removed in vacuo and the residue was purified by flash chromatography (silica gel, CH ₂ Cl ₂ /CH ₃ CN

2.5:1) 395 mg of the title compound was obtained as a white solid (57%). EI-MS, NMR.

Example 46

2-Trifluoroacetamido-6-[(E)-1-(2,3-difluorophenyl)-2-N-methylcarbamoylvinyl]imidazo[1,2-alpyridine; compound of formula (46)

Starting from 0.454 g (1.27 mmol) of 2-trifluoroacetamido-6-(2,3-difluorobenzoyl)imidazo[1,2-a]pyridine and proceeding essentially according to the method described in Preparation 183, 120 mg of the title compound (23%) were prepared. ¹ H-NMR, ¹³ C-NMR.

Example 47

2-Trifluoroacetamido-3-iodo-6-[(E)-1-(2,3-difluorophenyl)-2-N-methylcarbamoylvinylimidazo[1,2-a]pyridine; compound of formula (47)

To a solution of 116 mg (0.27 mmol) of 2-trifluoroacetamido-6-[(E)-1-(2,3-difluorophenyl)-2-N-methylcarbamoylvinyl]imidazo[1,2-a]pyridine in 10 mL of anhydrous CH ₃ CN and cooled to 0°C, 67 mg (0.30 mmol) of N-iodosuccinimide were added portionwise. The reaction mixture was stirred for 15 min. The solvent was removed in vacuo, the residue was dissolved in 25 mL of EtOAc, the solution was washed with 2x25 mL of NaHS0 ₃ (40% w/v) and then with 2x25 mL of NaHCO ₃ solution. The organic phase was dried over sodium sulfate and the EtOAc was removed in vacuo to give 130 mg of the title compound (86%). ¹ H-NMR, ¹³ C-NMR.

Example 48

2-Trifluoroacetamido-3-phenyl-6-(2,3-difluorobenzoyl)imidazol,2-alpyridine; compound of formula (48)

To a solution of 471 ml (4.206 mmol) of 2,3-difluorobromobenzene in 20 ml of anhydrous THF at -78°C was added n-butyllithium solution (2.63 ml, 1.6 mol/l in hexane). The resulting yellow solution was stirred at the same temperature for 70 min, then 0.500 g (1.28 mmol) of 2-trifluoro

-acetamido-3-phenyl-6-(N-methyl-N-methoxycarbamoyl)-imidazo[1,2-a]pyridine in 20 ml of anhydrous THF was added dropwise. The orange solution was allowed to warm to room temperature over about 60 min. After addition of saturated NH ₄ CI solution, the mixture was stirred for 25 min and then extracted with EtOAc. The organic phase was washed with brine, dried over Na ₂ SO ₄ , concentrated in vacuo and purified by column chromatography (CH ₂ CI ₂ /CH ₃ CN 4:1) to give 390 mg of orange solid (69%). MS (FAB), NMR.

Example 49

2 _: Trifluoroacetamido-3-phenyl-6-[(E)-1-(2,3-difluorophenyl)-2-methylcarbamoylvinylimidazo[1.2-a]pyridine; compound of formula (49)

A solution of 217 mg (1.04 mmol) of diethyl-(N-methylcarbamoylmethyl)phosphonate in 250 ml of anhydrous THF was charged into a flame-dried flask under argon. The solution was cooled to -78°C, and 5.13 ml (2.56 mmol) of potassium hexamethyldisilazide solution (0.5 mol/l in toluene) was added dropwise. The mixture was stirred at -78°C for 2 hours, and a solution of 300 mg (0.693 mmol) of 2-trifluoroacetamido-3-phenyl-6-(2,3-difluorobenzoyl)imidazo[1,2-a]pyridine in 100 ml of anhydrous THF was added dropwise. The reaction mixture was stirred at -78°C for 2 h and then allowed to warm to room temperature. The resulting brown solution was stirred at room temperature for 48 h (note that a large amount of solvent is required to avoid the formation of a heterogeneous medium when mixing the reagents). The THF was removed in vacuo, the residue was diluted with 400 mL of EtOAc, and washed with 2x100 mL of saturated _NH4CI and once with brine. After drying over magnesium sulfate, the solvent was removed in vacuo to give a brown solid. The residue was purified by column chromatography ( _CH3CN / _{CH2CI2 2} :1) to give 57.6 mg of the title compound (22%). ¹ H-NMR, ¹³ C-NMR.

> ♦ .:. 'i.

Example 50

2-Trifluoroacetamido-3-phenyl-6-r(E)-1-phenyl-2-N-methylcarbamoylvinylimidazol,2-a1-pyridine; compound of formula (50)

Starting from 618 mg (1.27 mmol) of 2-trifluoroacetamido-3-phenyl-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 49, 526 mg of the title compound were obtained (75%). EI-MS, NMR. Example 51

2-Trifluoroacetamido-3-(2,5-difluorophenyl-5-r(E)-1-phenyl)-2-N-methylcarbamoylvinyl-imidazol-2-al-pyridine; compound of formula (51)

Starting with 500 mg (1.15 mmol) of 2-trifluoroacetamido-3-(2,5-difluorophenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 49, 483 mg of the title compound were obtained (86%). EI-MS, NMR. Example 52

2-Trifluoroacetamido-3-(2-trifluoromethyl-4-fluorophenyl)-6-[(E)-1-phenyl-2-N-methylcarbamoylvinyl]imidazol,2-a]pyridine: compound of formula (52)

Starting with 500 mg (1.04 mmol) of 2-trifluoroacetamido-3-(2-trifluoromethyl-4-fluorophenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding essentially as described in Example 49, 439 mg of the title compound (79%) were obtained. EI-MS, NMR. Example 53

2-Trifluoroacetamido-3-(2,3,4-trifluorophenyl)-6-[(E)-1-phenyl-2-N-methylcarbamoylvinylimidazol,2-a]-pyridine; compound of formula (53)

Starting with 303 mg (0.672 mmol) of 2-trifluoroacetamido-3-(2,3,4-trifluorophenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding essentially as described in Example 49, 168 mg of the title compound were obtained (50%). NMR. Example 54

2-Trifluoroacetamido-3-(3,5-difluorophenyl)-6-ΠE)-1-phenyl)-2-N-methylcarbamoylvinylimidazol,2-al-pyridine; compound of formula (54)

Starting with 240 mg (0.554 mmol) of 2-trifluoroacetamido-3-(3,5-difluorophenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 49, 161 mg of the title compound were obtained in the form of two isomers, where the ratio of E:Z isomers was 1:1. Yield: 60%. EI-MS, NMR.

Example 55

2-Trifluoroacetamido-3-(3-trifluoromethylphenyl)-6-[(E)-1-phenyl]-2-N-methylcarbamoyl· -vinyl]-imidazo,2-a1-pyridine: compound of formula (55)

Starting with 228 mg (0.491 mmol) of 2-trifluoroacetamido-3-(3-trifluoromethylphenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 49, 228 mg of the title compound were obtained (57%). EI-MS, NMR.

Example 56 2-Amino-3-(2,4-difluorophenyl)-6-benzoylimidazoΓ1,2-alpyridine: compound of formula (56)

9.24 g (20.8 mmol) of 2-trifluoroacetamido-3-(2,4-difluorophenyl)-6-benzoylimidazo[1,2,a]pyridine were dissolved in 250 ml of MeOH and 170 ml of normal NaOH. The solution was stirred at room temperature under nitrogen for two weeks. The precipitate formed was collected by filtration and the filter cake was dissolved in 900 ml of EtOAc. The solution was washed with 3x50 ml of saturated sodium chloride solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was recrystallized from EtOAc/hexane to give 5.57 g of the title compound in two portions (76.8%). EA, MS (FD).

Example 57 2-Amino-3-(3,5-difluorophenyl)-6-benzoylimidazo[1,2-a]pyridine; compound of formula (57)

Starting with 10.2 g (22.9 mmol) of 2-trifluoroacetamido-3-(3,5-difluorophenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 56, 4.93 g of the title compound were obtained (61.6%). EA, MS (FD).

Example 58 2-Amino-3-(naphth-2-yl)-6-benzoyl-imidazo,2-alpyridine; compound of formula (58)

Starting from 6.05 g (13.7 mmol) of 2-trifluoroacetamido-3-(naphth-2-yl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 56, 3.50 g of the title compound were obtained (70.4%). MS (FD), NMR. Example 59

2-Amino-3-naphthyl-6-benzoyl-imidazo,2-alpyridine: compound of formula (59)

Starting from 8.25 g (18.0 mmol) of 2-trifluoroacetamido-3-naphthyl-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 56, 4.73 g of the title compound were obtained (73%). EA, MS (FD). Example 60

2-Amino-3-(2,5-difluorophenyl)-6-benzoylimidazol,2-alpyridine: compound of formula (60)

Starting with 12.1 g (27.1 mmol) of 2-trifluoroacetamido-3-(2,5-difluorophenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 56, 6.10 g of the title compound were obtained (64.6%). EA, MS (FD). Example 61

2-Amino-3-(2,6-difluorophenyl)-6-benzoylimidazo(1,2-alniridine: compound of formula (61)

Starting from 6.01 g (13.5 mmol) of 2-trifluoroacetamido-3-(2,6-difluorophenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 56, 3.42 g of the title compound were obtained (72.6%). EA, MS (FD). Example 62

2-Amino-3-(4-trifluoromethylphenyl)-6-benzoylimidazol,2-alpyridine: compound of formula (62)

Starting with 10.1 g (21.2 mmol) of 2-trifluoroacetamido-3-(4-trifluoromethylphenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 56, 4.43 g of the title compound were obtained (54.8%). EA, MS (FD).

Example 63 2-Amino-3-(2-fluorophenyl)-6-benzoylimidazolium,2-a]pyridine: Compound of formula (63)

Starting from 9.46 g (22.2 mmol) of 2-trifluoroacetamido-3-(2-fluorophenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 56, 6.70 g of the title compound were obtained (91.4%). EA, MS (FD). Example 64

2-Amino-3-(3-fluorophenyl)-6-benzoylimidazol,2-alpyridine; compound of formula (64)

Starting with 14.3 g (33.6 mmol) of 2-trifluoroacetamido-3-(3-fluorophenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 56, 8.30 g of the title compound were obtained (74.7%). EA, MS (FD). Example 65

2-Amino-3-(4-fluorophenyl)-6-benzoylimidazo[1,2-alpyridine]; compound of formula (65)

Starting with 18.6 g (43.7 mmol) of 2-trifluoroacetamido-3-(4-fluorophenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 56, 11.2 g of the title compound were obtained (77.2%). EA, MS (FD). Example 66

2-Amino-3-benzyl-6-benzoylimidazolium,2-a]pyridine; compound of formula (66)

Starting from 2.14 g (5.06 mmol) of 2-trifluoroacetamido-3-benzyl-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 56, 1.29 g of the title compound were obtained (78.2%). EA, MS (FD). Example 67

2-Amino-3-(3-trifluoromethylphenyl)-6-benzoylimidazo[1,2-alpyridine]; compound of formula (67)

9.39 g (19.7 mmol) of 2-trifluoroacetamido-3-(3-trifluoromethylphenyl)-6-benzoylimidazo[1,2-a]pyridine were dissolved in 200 ml of MeOH, and 100 ml (574 mmol) of diisopropylethylamine were added to the solution. The solution was heated to reflux at 85 °C.

• ·* ·* and then refluxed under nitrogen for two days with stirring. The solution was concentrated in vacuo and the residue was recrystallized from EtOAc/hexane to give 6.59 g of the title compound (87.9%). EA, MS (FD). Example 68

2-Amino-3-(4-methoxyphenyl)-6-benzoylimidazol,2-a1pyridine; compound of formula (68)

Starting from 4.89 g (11.1 mmol) of 2-trifluoroacetamido-3-(4-methoxyphenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 67, 3.08 g of the title compound were obtained (80%). EA, MS (FD). Example 69

2-Amino-3-(4-bromophenyl)-6-benzoylimidazol[2-a]pyridine; compound of formula (69)

Starting with 3.00 g (6.15 mmol) of 2-trifluoroacetamido-3-(4-bromophenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 67, 1.80 g of the title compound were obtained (75%). EA, MS (FD). Example 70

2-Amino-3-(2,3,4-trifluorophenyl)-6-benzoylimidazol,2-a1pyridine: compound of formula (70)

Starting from 8.43 g (18.2 mmol) of 2-trifluoroacetamido-3-(2,3,4-trifluorophenyl)-6-benzoylimidazo[1,2-a]pyridine, the procedure described in Example 67 gave 5.82 g of the title compound (87%). EA, MS (FD). Example 71

2-Amino-3-(3,4-difluorophenyl)-6-benzoylimidazoF1,2-a1pyridine; compound of formula (71)

Starting from 7.44 g (16.7 mmol) of 2-trifluoroacetamido-3-(3,4-difluorophenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 67, 5.09 g of the title compound were obtained (87.2%). EA, MS (FD). Example 72

2-Amino-3-(3,4-dichlorophenyl)-6-benzoylimidazo(1,2-alpyridine; compound of formula (72)

Starting from 9.91 g (20.8 mmol) of 2-trifluoroacetamido-3-(3,4-dichlorophenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 67, 7.17 g of the title compound were obtained (90.4%). EA, MS (FD). Example 73

2-Amino-3-(2,4,5-trifluorophenyl)-6-benzoyl-imidazo,2-a1pyridine; compound of formula (73)

Starting with 9.28 g (20.0 mmol) of 2-trifluoroacetamido-3-(2,4,5-trifluorophenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 67, 7.28 g of the title compound were obtained (98.9%). EA, MS (FD). Example 74

2-Amino-3-(2-chlorophenyl)-6-benzoylimidazol,2-alpyridine: compound of formula (74)

Starting with 10.8 g (24.2 mmol) of 2-trifluoroacetamido-3-(2-chlorophenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 67, 7.45 g of the title compound were obtained (88.5%). EA, MS (FD). Example 75

2-Amino-3-(3-chlorophenyl)-6-benzoylimidazolyl,2-ylpyridine; compound of formula (75)

Starting from 8.97 g (20.2 mmol) of 2-trifluoroacetamido-3-(3-chlorophenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 67, 6.05 g of the title compound were obtained (86.1%). EA, MS (FD). Example 76

2-Amino-3-(4-chlorophenyl)-6-benzoylimidazolium,2-a]pyridine; compound of formula (76)

Starting with 10.8 g (24.2 mmol) of 2-trifluoroacetamido-3-(4-chlorophenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 67, 7.17 g of the title compound were obtained (85.2%). EA, MS (FD). Example 77 .·.

2-Amino-3-(4-trifluoromethoxyphenyl)-6-benzoylimidazol-2-ylpyridine; compound of formula (77)

Starting with 10.6 g (21.5 mmol) of 2-trifluoroacetamido-3-(4-trifluoromethoxyphenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 67, 8.24 g of the title compound were obtained (96.7%). EA, MS (FD). Example 78

2-Amino-3-(3-trifluoromethoxyphenyl)-6-benzoylimidazol-2-ylpyridine; compound of formula (78)

Starting from 10.4 g (21.1 mmol) of 2-trifluoroacetamido-3-(3-trifluoromethoxyphenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 67, 7.89 g of the title compound were obtained (94.4%). EA, MS (FD). Example 79

2-Amino-3-(2-fluoro-4-trifluoromethylphenyl)-6-benzoylimidazol,2-alpyridine; compound of formula (79)

Starting with 8.03 g (16.2 mmol) of 2-trifluoroacetamido-3-(2-fluoro-4-trifluoromethylphenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 67, 6.00 g of the title compound were obtained (92.8%). EA, MS (FD). Example 80

2-Amino-3-(2,3,4,5,6-pentafluoro)-6-benzoylimidazol,2-alpyridine; compound of formula (80)

Starting with 5.03 g (10.1 mmol) of 2-trifluoroacetamido-3-(2,3,4,5,6-pentafluorophenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 67, 3.79 g of the title compound were obtained (93.3%). EA, MS (FD). Example 81

2-Amino-3-(2-trifluoromethylphenyl)-6-benzoylimidazol,2-alpyridine; compound of formula (81)

Starting with 6.22 g (13.0 mmol) of 2-trifluoroacetamido-3-(2-trifluoromethylphenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 67, 4.25 g of the title compound were obtained (85.5%). EA, MS (FD). Example 82

2-Amino-3-(2-thiophen-3-yl)-6-benzoylimidazolyl,2-apyridine; compound of formula (82)

Starting from 8.88 g (21.4 mmol) of 2-trifluoroacetamido-3-(thiophen-3-yl-)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 67, 5.51 g of the title compound were obtained (80.7%). EA, MS (FD). Example 83

2-Amino-3-(2-trifluoromethyl-4-fluorophenyl)-6-benzoylimidazol-2-ylpyridine; compound of formula (83)

Starting with 11.0 g (22.2 mmol) of 2-trifluoroacetamido-3-(2-trifluoromethyl-4-fluorophenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 67, 8.60 g of the title compound were obtained (97.2%). EA, MS (FD). Example 84

2-Amino-3-(2-fluoro-6-trifluoromethylphenyl)-6-benzoylimidazol-2-ylpyridine; compound of formula (84)

Starting from 1.80 g (3.64 mmol) of 2-trifluoroacetamido-3-(2-fluoro-6-trifluoromethylphenyl)-6-benzoylimidazo[1,2-a]pyridine, 2-trifluoroacetamido-3-(2,3,4,5,6-pentafluorophenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 67, 1.28 g of the title compound were obtained (88.3%). EA, MS (FD). Example 85

2-Amino-3-(2-methoxyphenyl)-6-benzoylimidazoH,2-alpyridine; compound of formula (85)

Starting from 7.40 g (16.8 mmol) of 2-trifluoroacetamido-3-(2-methoxyphenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 67, 5.0 g of the title compound were obtained (87%). EA, MS (FD).

Example 86

2-Amino-3-(4-carbonylmethoxyphenyl)-6-benzoylimidazolium,2-a]pyridine; compound of formula (86)

Starting from 2.13 g (16.8 mmol) of 2-trifluoroacetamido-3-(4-carbonylmethoxyphenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 67, 1.44 g of the title compound were obtained (85%). EA, MS (FD). Example 87

2-Amino-3-(4-nitrophenyl)-6-benzoylimidazol,2-alpyridine; compound of formula (87)

Starting from 8.59 g (18.9 mmol) of 2-trifluoroacetamido-3-(4-nitrophenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 67, 5.04 g of the title compound were obtained (74.4%). EA, MS (FD). Example 88

2-Amino-3-isobutyl-6-benzoyl-imidazo.2-alpyridine: compound of formula (88)

Starting with 2.37 g (6.09 mmol) of 2-trifluoroacetamido-3-isobutyl-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 67, 1.49 g of the title compound were obtained (83.5%). EA, MS (FD). Example 89

2-Amino-3-(4-carboxyphenyl)-6-benzoylimidazolium,2-a]pyridine: compound of formula (89)

3.00 g (8.09 mmol) of 2-amino-3-(4-carbonylmethoxyphenyl)-6-benzoylimidazo[1,2-a]pyridine was dissolved in 25 ml of THF and 8 ml of H ₂ O and the mixture was stirred at room temperature. After addition of 968 mg (40.4 mmol) of lithium hydroxide, the reaction mixture was stirred overnight. After removal of the solvent, water was added to the remaining solid, and the mixture was filtered, and the filter cake was washed with water. The solid was recrystallized from MeOH to give 2.62 g of the title compound (91%). EA, MS (FD):

Example 90

Compound of formula 2-Amino-3-(4-N-methoxyamido)-6-benzoylimidazolium,2-a)pyridine (90)

714 mg (2.00 mmol) of 2-amino-3-(4-carboxyphenyl)-6-benzoylimidazo[1,2-a]pyridine, 1.34 g (16.0 mmol) of methoxyamine hydrochloride and 2.93 mL (16.0 mmol) of diisopropylethylamine were suspended in 20 mL of anhydrous DMF under nitrogen. Within 20 min, the solution became clear and turned a yellowish orange color. The reaction mixture was stirred overnight at room temperature. The DMF was removed in vacuo, the residue was poured into water and the mixture was stirred for 1 h. The resulting solid was collected by filtration and air dried. The crude product was recrystallized from EtOAc to give 317 mg of the title compound (41.0%). EA, MS (FD).

91, example

2-Amino-3-(4-fluorophenyl)-6-(4-fluorobenzoyl)imidazo[1,2-a]pyridine; compound of formula (91)

Starting from 7.11 g (16.0 mmol) of 2-trifluoroacetamido-3-(4-fluorophenyl)-6-(4-fluorobenzoyl)imidazo[1,2-a]pyridine and proceeding as described in Example 67, 4.80 g of the title compound were obtained (86.2%). MS (FD), NMR.

Example 92

2-Amino-3-(2-fluoro-4-trifluoromethylphenyl)-6-(4-fluorobenzoyl)imidazol,2-alpyridine: compound of formula (92)

Starting from 6.75 g (13.2 mmol) of 2-trifluoroacetamido-3-(2-fluoro-4-trifluoromethylphenyl)-6-(4-fluorobenzoyl)imidazo[1,2-a]pyridine and proceeding as described in Example 67, 4.66 g of the title compound were obtained (85%). EA, MS (FD).

Example 93 2-Amino-3-phenyl-6-(α-phenylacetyl)imidazolium,2-a]pyridine; compound of formula (93)

812 mg (4 mmol) of N-(3-phenyl-6-[N-methyl-N-methoxycarbamoyl]-imidazo[1,2-a]pyridin2-yl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane were dissolved in 30 mL of THF under nitrogen gas, and a solution of benzyl magnesium chloride in THF (6 mL, 2 mol/L, 12.0 mmol) was added to the solution. The mixture was stirred at room temperature for 18 h, then 15 mL of MeOH and 3 mL of acetic acid were added. The mixture was stirred at room temperature for an additional 1 h. The solvent was removed in vacuo and the residue was taken up in a mixture of 400 mL of EtOAc and 60 mL of NaHCO ₃ . The EtOAc was separated, washed with brine (2x75 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by normal phase flash chromatography (EtOAc). The fraction containing the title compound was recrystallized from EtOAc to give 398 mg of product (31.6%). MS (FD), NMR.

Example 94 2-Amino-3-phenyl-6-(picolinoyl)imidazol,2-alpyridine: compound of formula (94)

1.23 g (6.00 mmol) of 2-iodopyridine was dissolved in 40 ml of THF under nitrogen gas, and then 2 ml of ethylmagnesium bromide solution (6 mmol, 3 mol/l concentration) was added. The mixture was stirred for 30 min at room temperature, then a solution of 820 mg (2 mmol) of N-(3-phenyl-6-[carboxyl]-imidazo[1,2-a]pyridin-2-yl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane in 25 ml of THF was added dropwise via a cannula. The resulting mixture was stirred at room temperature for 18 h. After addition of 4 ml of methanol and 2 ml of acetic acid, the mixture was stirred at room temperature for a further hour. The solvent was removed in vacuo and the residue was purified by normal phase chromatography. The product-containing fractions were recrystallized from EtOAc to give 205 mg of the title compound (10.9%). MS (FD), NMR.

Example 95 2-Amino-3-phenyl-6-(nicothionoyl)imidazo[1,2-alpyridine]: Compound of formula (95)

Starting from 820 mg (2.00 mmol) of N-(3-phenyl-6-[carboxyl]-imidazo[1,2-a]pyridin-2-yl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane as starting material, and

:. J. ^: J'· r \

Using 3-iodopyridine and proceeding as described in Example 94, 271 mg of the title compound were obtained (14.4%). EA, MS (FD).

Example 96 2-Amino-3-phenyl-6-(isonicotinoyl)imidazo-1,2-alpyridine; compound of formula (96)

Starting from 3.28 g (8.00 mmol) of N-(3-phenyl-6-[carboxyl]imidazo[1,2-a]pyridin-2-yl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane and 4-iodopyridine, the title compound was obtained in 1.74 g (69.3%). EA, MS (FD).

Example 97

2-Amino-3-(2,4-difluorophenyl)-6-[(E)-benzyloxime-a-ylimidazol,2-alpyridine; compound of formula (97)

1.00 g (2.87 mmol) of 2-amino-3-(2,4-difluorophenyl)-6-benzoylimidazo[1,2-a]pyridine was dissolved in 40 ml of 80 % EtOH/H ₂ O. After addition of 2.39 g (34.4 mmol) of hydroxylamine hydrochloride and 2.82 g (34.3 mmol) of NaOAc, the reaction mixture was refluxed for 4 h, and the reaction progress was monitored by HPLC. During the reaction mixture work-up, the solvent was removed in vacuo, and the residue was taken up in 900 ml of EtOAc. The solution was washed with 3x100 ml of saturated NaHCO ₃ solution, 3x100 ml of sodium chloride solution, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The residue was recrystallized from EtOAc and further purified by HPLC to give 130 mg of E-isomer (17.2%). MS (FD), UV.

Example 98

2-Amino-3-(4-methoxyphenyl)-6-(benzyloxime-a-yl)imidazolylpyridine; compound of formula (98)

Starting from 2.00 g (5.83 mmol) of 2-amino-3-(4-methoxyphenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 97, 490 mg of the title compound as the E-isomer (24.0%). EA, MS (FD). The compound is accompanied by a small, undetermined amount of the Z-isomer. EA, MS (FD).

Example 99

2-Amino-3-(naphth-2-yl)-6-[(E)-benzyl-oxim-a-yl]-imidazolium,2-alpyridine; compound of formula (99)

Starting from 2.00 g (5.51 mmol) of 2-amino-3-(naphth-2-yl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 97, 115 mg of the title compound were obtained as product E (5.52%). EA, MS (FD). Example 100

2-Amino-3-naphthyl·6-(benzyl-oxim-α-yl)-imidazoΓ1,2-aΊpyridine; compound of formula (100)

Starting from 2.00 g (5.51 mmol) of 2-amino-3-naphthyl-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 97, 470 mg of the title compound were obtained as E-product (22.6%), EA, MS (FD), accompanied by 810 mg of the Z-isomer (38.9%). NMR.

Example 101

2-Amino-3-(2-fluorophenyl)-6-r(E)-benzyloxime-a-yl-imidazol,2-alpyridine: compound of formula (101)

Starting from 2.62 g (7.92 mmol) of 2-amino-3-(2-fluorophenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 97, 1.08 g of the title compound as E-product (39.3%). MS (FD), NMR. Example 102

2-Amino-3-(3-fluorophenyl)-6-r(E)-1-benzyloxime-a-ynimidazol,2-a)pyridine; compound of formula (102)

Starting from 2.00 g (6.04 mmol) of 2-amino-3-(3-fluorophenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 97, 463 mg of the title compound were obtained as product E (22.2%). EA, MS (FD):

Example 103

2-Amino-3-(4-fluorophenyl)-6-nE)-benzyloxime-a-yl1-imidazone,2-a1pyridine; compound of formula (103)

Starting from 3.00 g (9.06 mmol) of 2-amino-3-(4-fluorophenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 97, 2.78 g of the title compound as the E-isomer (88.8%). EA, MS (FD). Example 104

2-Amino-3-(3,5-difluorophenyl)-6-r(E)-benzyloxime-g-yl-imidazol,2-alpyridine; compound of formula (104)

Starting from 1.00 g (2.87 mmol) of 2-amino-3-(3,5-difluorophenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 97, 65 mg of the title compound as the E-isomer (6.22%). EA, MS (FD). Example 105

2-Amino-3-(2,5-difluorophenyl)-6-[(E)-benzyloxim-g-yl]-imidazo[,2-alpyridine; compound of formula (105)

Starting from 1.00 g (2.87 mmol) of 2-amino-3-(2,5-difluorophenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 97, 315 mg of the title compound as the E-isomer (30.2%). EA, MS (FD). Example 106

2-Amino-3-(3-trifluoromethylphenyl)-6-Γ(E)-benzyloxime-g-yl-imidazoΓ1,2-a^pyridine.· Compound of formula (106)

Starting from 2.00 g (5.24 mmol) of 2-amino-3-(3-trifluoromethylphenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 97, 579 mg of the title compound as the E-isomer (27.9%). EA, MS (FD). Example 107

2-Amino-3-(4-bromophenyl)-6-(benzyloxime-a-yl)imidazo[1,2-alpyridine]; compound of formula (107)

Starting with 1.80 g (4.59 mmol) of 2-amino-3-(4-bromophenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 97, 1.20 g of product consisting of a 1:1 mixture of E and Z isomers (64.2%). EA, MS (FD).

Example 108

2-Amino-3-(2,3,4-trifluorophenyl)-6-[(E)-benzyl]Oxime-a-1H-imidazol,2-alpyridine; compound of formula (108)

Starting from 2.00 g (5.45 mmol) of 2-amino-3-(2,3,4-trifluorophenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 97, 508 mg of the title compound as the E-isomer (24.1%). EA, MS (FD). Example 109

2-Amino-3-(3,4-difluorophenyl)-6-r(E)-benzyloxime-a-yneimidazo(1.2a1pyridine: compound of formula (109)

Starting from 2.00 g (5.73 mmol) of 2-amino-3-(3,4-difluorophenyl)-6-benzoylimidazo[1,2-a]pyrine and proceeding as described in Example 97, 507 mg of the title compound as the E-isomer (24.2%). EA, MS (FD). Example 110

2-Amino-3-(3,4-dichlorophenyl)-6-[(E)-benzyloxime-a-yl-imidazo[1,2-a]pyridine; compound of formula (11Q)

Starting from 2.00 g (5.25 mmol) of 2-amino-3-(3,4-dichlorophenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 97, 643 mg of the title compound as the E-isomer (31.1%). EA, MS (FD). Example 111

2-Amino-3-(2,4,5-trifluorophenyl)-6-r(E)-benzyloxime-g-yl-imidazole 1,2-alpyridine; compound of formula (111)

Starting from 2.00 g (5.45 mmol) of 2-amino-3-(2,4,5-trifluorophenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 97, 344 mg of the title compound as the E-isomer (16.6%). EA, MS (FD). Example 112

2-Amino-3-(2-chlorophenyl)-6-r(E)-benzyloxime-g-yl-imidazolium,2-alpyridine; compound of formula (112)

Starting from 2.00 g (5.76 mmol) of 2-amino-3-(2-chlorophenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 97, 180 mg of the title compound as the E-isomer (8.61%). EA, MS (FD). Example 113

2-Amino-3-(3-chlorophenyl)-6-r(E)-benzyloxime-g-yl-imidazolium,2-alpyridine; compound of formula (113)

Starting from 2.00 g (5.75 mmol) of 2-amino-3-(3-chlorophenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 97, 551 mg of the title compound as the E-isomer (26.4%). EA, MS (FD). Example 114

2-Amino-3-(4-chlorophenyl)-6-r(E)-benzyloxime-g-yl-imidazol,2-alpyridine; compound of formula (114)

Starting from 2.00 g (5.75 mmol) of 2-amino-3-(4-chlorophenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 97, 180 mg of the title compound as the E-isomer (8.61%). EA, MS (FD). Example 115

2-Amino-3-(4-trifluoromethoxyphenyl)-6-r(E)-benzyloxime-g-yl-imidazoF1,2-a]pyridine;

Compound with formula (115)

Starting from 2.00 g (5.04 mmol) of 2-amino-3-(4-trifluoromethoxyphenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 97, 383 mg of the title compound as the E-isomer (18.4%) were obtained. EA, MS (FD).

Example 116 2-Amino-3-(3-trifluoromethoxyphenyl)-6-[(E)-benzyloxime-a-yl-imidazol-2-ylpyridine: Compound of formula (116)

Starting from 2.00 g (5.04 mmol) of 2-amino-3-(3-trifluoromethoxyphenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 97, 224 mg of the title compound as the E-isomer (10.8%) were obtained. EA, MS (FD).

Example 117

2-Amino-3-(2-fluoro-4-trifluoromethylphenyl)-6-benzyloxime-a-ynimidazol,2-a)pyridine: compound of formula (117)

Starting from 2.00 g (5.01 mmol) of 2-amino-3-(2-fluoro-4-trifluoromethylphenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 97, 742 mg of the title compound as the E-isomer (35.7%). EA, MS (FD). Example 118

2-Amino-3-phenyl-6-[(E)-benzyl-oxime-a-yl]-imidazoli,2-a1pyridine; compound of formula (118)

133 mg (0.426 mmol) of 2-amino-3-phenyl-6-benzoylimidazo[1,2-a]pyridine was treated with 500 mg (7.20 mmol) of hydroxylamine hydrochloride, 2.5 mL of pyridine, and 7.5 mL of anhydrous EtOH. The mixture was refluxed for 2.5 h, then 200 mL of EtOAc was added and the solution was washed twice with saturated NaHSO ₃ . The organic phase was dried over magnesium sulfate, and the solvent was removed in vacuo. The product was crystallized from EtOAc to give 64 mg of the E-isomer (45.7%), MS (FD), and 68 mg of the Z-isomer (48.6%). MS (FD).

Example 119

Compound with the formula 2^minq<^2J><iifluoro2phenyl}^>jiE)4jen2jl·^^

Starting from 2.00 g (5.73 mmol) of 2-amino-3-(2,6-difluorophenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 97, 383 mg of the E-isomer are obtained. (18.4%). EA, MS (FD). Example 120

2-Amino-3-(2,3,4,5,6-pentafluorophenyl)-6-yl(E)-benzyloxime-xyl-imidazol,2-a]pyridine; compound of formula (120)

Starting with 4.52 g (11.2 mmol) of 2-amino-3-(2,6-difluorophenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 97, 940 mg of E-isomer (20.%) EA, MS (FD) were obtained.

Example 121

2-Amino-3-(2-trifluoromethylphenyl)-6-Γ(E)-benzyloxime-α-yl-imidazoΓ1,2-alpyridine: compound of formula (121)

Starting from 2.00 g (5.25 mmol) of 2-amino-3-(2-trifluoromethylphenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 97, 146 mg of the E-isomer (7.02%) were obtained. EA, MS (FD). Example 122

2-Amino-3-(thiophen-3-yl)-6-r(E)-benzyl-oxime-a-yl-imidazo,2-alpyridine; compound of formula (122)

Starting from 2.00 g (6.27 mmol) of 2-amino-3-(thiophen-3-yl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 97, 497 mg of the E-isomer (23.8%) were obtained. EA, MS (FD). Example 123

2-Amino-3-(2-trifluoromethyl-4-fluorophenyl)-6-r(E)-benzyloxime-a-ynimidazol,2alpyridine; compound of formula (123)

Starting from 2.00 g (5.01 mmol) of 2-amino-3-(2-trifluoromethyl-4-fluorophenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 97, 288 mg of the E-isomer (13.8%) were obtained. EA, MS (FD). Example 124

2-Amino-3-(2-fluoro-6-trifluoromethylphenyl)-6-[(E)-benzyloxime-g-yl]imidazol,2-alpyridine; compound of formula (124)

Starting from 1.28 g (3.21 mmol) of 2-amino-3-(2-fluoro-6-trifluoromethylphenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 97, 75.0 mg of the E-isomer (5.64%) EA, MS (FD) and 395 mg of the Z-isomer (29.7%) MS (FD), NMR were obtained.

Example 125

2-Amino-3-(4-trifluoromethylphenyl)-6-[(E)-benzyloxime-a-yl-imidazol-2-ylpyridine: compound of formula (125)

Starting from 2.00 g (5.25 mmol) of 2-amino-3-(4-trifluoromethylphenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 97, 512 mg of the E-isomer (24.6%) were obtained. EA, MS (FD). Example 126

2-Amino-3-(4-carbonylmethoxyphenyl)-6-[(E)-benzyloxime-a-yl-imidazol-2-ylpyridine: compound of formula (126)

Starting from 1.00 g (2.70 mmol) of 2-amino-3-(4-carbonylmethoxyphenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 97, 437 mg of the E-isomer (43.5%) were obtained. EA, MS (FD). Example 127

Compound of formula 2-Amino-3-(4-carboxyphenyl)-6-Γbenzyl·oxime-α-yl-^imidazoΓ1,2-alpyridine,^ (127)

100

Starting from 2.00 g (5.60 mmol) of 2-amino-3-(4-carboxyphenyl)-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 97, 990 mg of product consisting of a mixture of E and Z isomers were obtained (overall yield: 46.6%). NMR. Example 128

2-Amino-3-benzyl-6-[benzyl-oxime-a-yl-imidazo[1,2-alpyridine; compound of formula (128)

Starting from 2.00 g (5.60 mmol) of 2-amino-3-benzyl-6-benzoyl)imidazo[1,2-a]pyridine and proceeding as described in Example 97, 210 mg of the E-isomer (16.5%) were obtained. EA, MS (FAB). Example 129

2-Amino-3-isobutyl-6-[benzyl-oxim-a-yl]-imidazolyl-1,2-alpyridine: compound of formula (129)

Starting with 820 mg (2.80 mmol) of 2-amino-3-isobutyl-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 97, 120 mg of the E-isomer (13.9%) were obtained. EA, MS (FAB).

Example 130

2-Amino-3-(4-fluorophenyl)-6-F(E)-1-(4-fluorobenzyl)-oxime-a-yl-imidazol,2-a]pyridine: compound of formula (130)

Using 2.00 g (5.73 mmol) of 2-amino-3-(4-fluorophenyl)-6-(4-fluorobenzoylimidazo[1,2-a]pyridine as starting material and proceeding as described in Example 97, 572 mg of the E-isomer (27.4%). EA, MS (FD) and 198 mg of the Z-isomer (9.47%). EA, MS (FD).

Example 131

2-Amino-3-(2-fluoro-4-trifluoromethylphenyl)-6-F(E)-1-(4-fluorobenzyl)oxime-a-yl-imidazoF1,2-a]pyridine; compound of formula (131)

101

Starting with 2.00 g (4.80 mmol) of 2-amino-3-(2-fluoro-4-trifluoromethylphenyl)-6-(4-fluorobenzoyl)imidazo[1,2-a]pyridine and proceeding as described in Example 97, 310 mg of the E-isomer were obtained (15%). EA, MS (FD).

Example 132

2^ηΊίηο _Σ 34βηϊΙ _Σ 6 ₂ [ίΕΗ6ηϊΙ _Σ 3θθΙοχϊτη _Σ α^Ι1 _: ϊπΊίΰ3^ group

Starting from 732 g (2.24 mmol) of 2-amino-3-phenyl-6-(α-phenylacetyl)imidazo[1,2-a]pyridine and proceeding as described in Example 97, 485 mg of the E-isomer were obtained (63.3%). EA, MS (FD). Example 133

2-Amino-3-phenyl)-6-(picolinyl-oxime-a-yl-imidazolium, 2-alpyridine: compound of formula (133)

Starting material 1.57 g (5.00 mmol) of 2-amino-3-phenyl-6-(picolinoyl)-imidazo[1,2-a]pyridine was suspended in 100 ml of 80% aqueous ethanol, and 4.17 g (60.0 mmol) of hydroxylamine hydrochloride and 4.92 g (60.0 mmol) of NaOAc were added. The mixture was refluxed for 6 hours, and the solvent was removed in vacuo. The residue was extracted with a mixture of 900 ml of EtOAc and 100 ml of saturated NaHCO ₃ . The organic phase was separated, washed with saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was recrystallized from EtOAc to give a mixture of both isomers. The mixture was triturated with CH ₂ Cl ₂ and the solid was collected by filtration. The filtrate was purified by normal phase chromatography to give 75.8 mg of the cis isomer (4.6%). EA, MS (FD). The solid was recrystallized twice from MeOH to give 134 mg of the trans isomer (8.1%). EA, MS (FD):

Example 134

102

2-Amino-3-phenyl-6-(nicotinoyloxim-a-yl)imidazo[1,2-a]pyridine; compound of formula (134)

Starting from 1.18 g (3.75 mmol) of 2-amino-3-phenyl-6-(nicothionoyl)imidazo[1,2-a]pyridine and proceeding as described in Example 78, 127 mg of the cis-isomer (10.3 %) (MS (FD), NMR) and 20.5 mg (80 %) of the trans-isomer (1.3 % correction) are obtained. MS (FD), NMR.

Example 135

2-Amino-3-phenyl-6-(cis-isonicotinyl-oxime-a-yl-imidazoli,2-a]pyridine; compound of formula (135)

Starting from 1.57 g (5.00 mmol) of 2-amino-3-phenyl-6-(isonicotinoyl)imidazo[1,2-a]pyridine and proceeding as described in Example 78, 466 mg of the cis isomer (28.3%), EA, MS (FD) and 230 mg of the trans isomer (14%) EA, MS (FD) were obtained. Example 136

2-Amino-3-phenyl-6-(1-phenyl-2-cyanovinyl)imidazo[2-a]pyridine: compound of formula (136)

To a solution of 1.57 g (5.00 mmol) of 2-amino-3-phenyl-6-benzoylimidazo[1,2-a]pyridine in 30 mL of THF was added 1.63 g (10.0 mmol) of diethyl cyanophosphonate, followed by potassium bistrimethylsilylamide (5 mL, 0.5 M solution in toluene, 10 mmol). The reaction mixture was stirred for 5 days. The THF was removed in vacuo and the residue was dissolved in 500 mL of EtOAc. The EtOAc was washed with 50 mL of H ₂ O and 2x50 mL of brine, dried over Na ₂ SO ₄ , and concentrated in vacuo. The residue was purified by normal phase flash chromatography (EtOAc) to give 250 mg of product which was recrystallized from EtOAc to give 98 mg of the Z-isomer (5.82%), EA, MS (FD) and 128 mg of the E-isomer (7.60%). EA, MS (FD).

Example 137

103 ’··, :··. ···.

2-Amino-3-isobutyl-6-(1-phenyl-2-cyanovinyl)-imidazo,2-a)pyridine; compound of formula (137)

Starting from 1.46 g (5.00 mmol) of 2-amino-3-isobutyl-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 136, 200 mg of Z-isomer (12.7%), MS (FD), NMR and 130 mg of E-isomer (8.23%), EA, MS (FD).

Example 138 2-Amino-3-methylthio-6-benzoylimidazolylpyridine; compound of formula (138)

100 mg (263 mmol) of 2-trifluoroacetamido-3-methylthio-6-benzoylimidazo[1,2-a]-pyridine was dissolved in 20 mL of a 1:1 mixture of MeOH/CH ₂ CI ₂ , and 5 g of silica gel was added to the solution. The reaction mixture was stirred at room temperature for 2 days. The residue was then filtered, washed with CH ₂ CI ₂ , and concentrated in vacuo to give 63 mg (85%) of a yellow solid.

^-NMR (200 MHz, CDCI ₃ ), δ: 2.12 (s, 3H, SME), 4.40 (broad s, 2H, NH ₂ ), 7.46-7.80 (m, 7H, ArH + H ₇ + H ₈ ), 8.68 (d, J ₅₇ = 1.7, H ₅ ).

¹³ C-NMR (50 MHz, CDCl ₃ ), δ: 18.0 (SMe), 95.0, 122.7, 125.8, 127.7, 128.5, 129.6, 132.6, 137.4, 145.3, 156.1, 193.5.

Example 139 2-Amino-3-methylsulfonyl-6-benzoylimidazolylpyridine; compound of formula (139)

Starting from 160 mg (0.438 mmol) of 2-trifluoroacetamido-3-methylsulfonyl-6-benzoylimidazo[1,2-a]pyridine and proceeding as described in Example 138, 92 mg of the title compound are obtained (78%).

¹ H-NMR (200 MHz, CDCI ₃ ), δ: 3.06 (s, 3H, SO ₂ Me), 4.82 (broad s, 2H, NH ₂ ), 7.53-7.82 (m, 6H, ArH + H ₇ + H ₈ ), 8.78 (d, J ₅₇ = 1.6, H ₅ ).

Example 140

2-Amino-3-isopropylthio-6-benzoylimidazo[1,2-alpyridine; compound of formula (140) > • * «··· ,» .»

104 :

*·♦ ··* ·« · · _>β * mg (0.0393 mmol) of 2-trifluoroacetamido-3-isopropylsulfonyl-6-benzoylimidazo[1,2-a]pyridine and the procedure described in Example 138 gave 11 mg of the title compound (88%). EI-MS (m/z): 311 M ⁺ (28), 268 (100), 224 (27), 105 (41), 77 (29).

¹ H-NMR (CDCI ₃ ), δ: 8.75 (s, 1H, H5), 7.79-7.47 (m, 7H, Ar), 4.62 (broad s, 2H, NH ₂ ), 3.09 (heptet, 1H, J = 6.4 Hz, CH(CH ₃ ) ₂ ), 1.22 (d, 6H, J = 6.7 Hz, (CH ₃ ) ₂ -CH).

¹³ C-NMR (CDCl ₃ ), δ: 199.3, 157.1, 145.2, 137.3, 132.6, 129.5, 128.4, 127.9, 126.0, 122.8, 113.6, 40.8, 23.4.

Example 141 2-Amino-3-phenyl-6-(2-fluorobenzoyl)imidazo[1,2-a]pyridine; compound of formula (141)

To a solution of 191 ml (1.75 mmol) of 1-bromo-2-fluorobenzene in 2 ml of anhydrous THF under argon, tert-butyllithium was added dropwise. The mixture was stirred at -78°C for 50 min, then a solution of 148 mg (0.5 mmol) of 2-amino-3-phenyl-6-(N-methyl-N-methoxycarbamoyl)imidazo[1,2-a]pyridine in 3 ml of anhydrous THF was added. The resulting red-orange solution was stirred at -78°C for a further 50 min, then allowed to warm to room temperature. The solution was poured into 20 ml of water and extracted with 2x20 ml of EtOAc. The organic phase was washed with water, dried over sodium sulfate, and the solvent was removed in vacuo to give a tan solid. The crude solid was purified by _column chromatography ( _CH2Cl2 / _CH3CN 2.5:1) to give 84.0 mg (50.6%) of yellow product. MS (FAB), (m/z): 332.2, (M ⁺⁺ 1; 51.99).

¹ H-NMR (200 MHz, CDCl ₃ ), δ: 4.27 (broad s, 2H, NH), 7.12-7.58 (m, 11H, ArH + H ₇ + H ₈ ), 8.71 (s, H ₅ ).

Example 142

2-Amino-3-phenyl-6-(3-fluorobenzoyl)imidazo[1,2-a]pyridine; compound of formula (142)

105

Starting from 148 mg (0.500 mmol) of 2-amino-3-phenyl-6-(N-methyl-N-methoxycarbamoyl)imidazo[1,2-a]pyridine and 1-bromo-3-fluorobenzene, the title compound was obtained in 37 mg (37%) as described in Example 141. MS (FAB ⁺ ), (m/z): 332.2 (M ⁺ + 1.86.6).

¹ H-NMR (200 MHz, CDCl ₃ ), δ: 4.22 (broad s, 2H, NH), 7.21-7.55 (m, 11H, ArH + H ₇ + H ₈ ), 8.69 (d, J ₅₇ =1.1, H ₅ ).

Example 143 2-Amino-3-phenyl-6-(4-fluorobenzoyl)imidazolyl,2-ylpyridine: Compound of formula (143)

Starting from 584 mg (1.97 mmol) of 2-amino-3-phenyl-6-(N-methyl-N-methoxycarbamoyl)imidazo[1,2-a]pyridine and 1-bromo-4-fluorobenzene and proceeding as described in Example 141, 205 mg of the title compound are obtained (52%).

¹ H-NMR (200 MHz, CDCl ₃ ), δ: 4.31 (broad s, 2H, NH), 7.15 (m, 2H, F-ArH), 7.25-7.56 (m, 7H, ArH + H ₇ + H ₈ ), 7.78 (m, 2H, F-ArH), 8.69 (s, H ₅ ).

Example 144

2-Amino-3-phenyl-6-(2,3-difluorobenzoyl)imidazol,2-a]pyridine; compound of formula (144)

To a solution of 0.945 g (8.44 mmol) of 2,3-difluorobromobenzene in 20 ml of anhydrous THF at -78°C was added 5.27 ml of n-butyllithium solution (1.6 mol/l in hexane). The resulting yellow solution was stirred at -78°C for 50 min, and then a solution of 500 mg (1.69 mmol) of 2-amino-3-phenyl-6-(N-methyl-N-methoxycarbamoyl)imidazo[1,2-a]pyridine in 20 ml of anhydrous THF was added dropwise via a cannula while argon gas was introduced. The resulting orange solution was allowed to warm very slowly to room temperature over about 2.5 h. After addition of saturated NH4Cl solution, the mixture was stirred for 25 min and then extracted with EtOAc. The organic phase was washed with saturated sodium chloride solution and dried over Na ₂ SO ₄ . After evaporation of the solvent, the residue was subjected to column chromatography.

106 ::

“* ··« _lt «Μ %·* purified (CH ₂ CI ₂ /CH ₃ CN 4:1) to give 440 mg (74.7%) of a yellow solid. (MS (FAB), (m/z): 350.1 (M ⁺ + 1,100.0).

¹ H-NMR (200 MHz, DMSO-d ₆ ), δ: 5.71 (broad s, 2H,NH), 7.27-7.70 (m, 11H, F-ArH + ArH + H ₇ + H ₈ ), 8.58 (dd, J ₅₇ = 1.8, J ₅₈ = 0.9, H ₅ ).

Example 145

2-Amino-3-methylthio-6-(1-phenyl-2-cyanovinyl)-imidazoΓ1,2-alpyridine; (145) To a solution of 2-amino-3-methylthio-6-benzoylimidazo[1,2-a]pyridine (145 mg, 0.14 mmol) in 4 ml of anhydrous THF at -78°C was added dropwise 265 mg (1.5 mmol) of diethylphosphonitrile, resulting in an orange solid. The reaction mixture was added with 2 ml of THF and stirred at -78°C for 2 h. The mixture was then allowed to warm to room temperature over 3 h. The solution then turned green. The mixture was hydrolyzed with a drop of water, the solvent was removed in vacuo, and the residue was purified by column chromatography (EtOAc) to give 23 mg of the title compound (51%) as the E-isomer.

¹ H-NMR (200 MHz, CDCl3), δ: 2.22 (s, 3H, SMe), 4.43 (broad s, 2H, NH2), 5.75 (s, 1H, vinylic H), 7.04 (dd, 1H, J57 = 2.0, J78 = 9.1, H7), 7.32-7.50 (m, 6H, ArH + H8), 8.54 (dd, J58 ⁼ 0>θ> J57 ⁼ 2.0, H5), 14 mg (32 %) of the Z-isomer are obtained.

¹ H-NMR 200 MHz, CDCl ₃ ), δ: 2.10 (s, 3H, SMe), 4.40 (broad s, 2H, NH ₂ ), 5.79 (s, 1H, vinylic H), 7.13 (dd, 1H, J ₅₇ = 1.9, J ₇₈ = 9.2, H ₇ ), 7.32 (dd, J ₅₈ = 0.8, J ₇₈ = 9.2, H ₈ ), 7.47-7.53 (m, 5H, ArH), 8.07 (dd, J ₅₈ = 0.8, J ₅₇ = 1.9, H ₅ ).

Example 146

2-Amino-3-methylsulfonyl-6-(1-phenyl-2-cyanovinyl)imidazol,2-alpyridine:______(146) compound

Starting from 2-amino-6-benzoyl-3-(methylsulfonyl)imidazo[1,2-a]pyridine and proceeding as described in Example 145, the title vinylnitrile derivative is prepared, the product contains the E:Z-isomers in a ratio of 1:2 (77% overall yield). The Z-isomer is isolated by column chromatography (isopropanol/EtOAc 3:7).

¹ H-NMR (200 MHz, CDCI ₃ ), δ: 3.17 (s, 3H, SO ₂ Me), 4.66 (broad s, 2H, NH ₂ ), 5.77 (s, 1H, vinylic), 7.10 (dd, 1H, J ₅₇ = 1.8, J ₇₈ = 9.3, H ₇ ). 7.30-7.46 (m, 6H, ArH + H ₈ ), 8.82 (dd, J ₅₈ = 0.8, J ₅ 7 = 1.8, H ₅ ).

Example 147

2-Amino-6-r(E)-1-phenyl-2-N-methylcarbamoylvininimidazoM,2-alpyridine; Compound of formula (147).

300 mg (0.77 mmol) of 2-trifluoroacetamido-6-[(E)-1-phenyl-2-N-methylcarbamoylvinyl]imidazo[1,2-a]pyridine were stirred in the presence of 17 ml of 0.5 N NaOH solution at room temperature for 5 h. The solution was neutralized to pH 7 with 5% aqueous HCl solution and extracted with 3x50 ml of CHCl ₃ . The combined organic extracts were dried over sodium sulfate; the solvent was removed in vacuo to give 130 mg of a light brown solid (58%). M.p.: 97-99°C.

¹ H-NMR (CDCI ₃ ), δ: 7.61 (d, 1H, J = 1.4 Hz, H ₅ ), 7.47-7.41 (m, 3H, Ar), 7.33-7.27 (m, 3H, Ar), 7.12 (dd, 1H, J = 9.3, 1.8 Hz, H ₇ , H ₈ ), 6.77 (s, 1H, H ₃ ), 6.36 (s, 1H, vinylic H), 5.13 (broad d, 1H, J = 4.9 Hz, NHMe), 3.90 (broad s, 2H, NH ₂ ), 2.62 (d, 3H, J = 4.9 Hz, CH ₃ NH). EI-MS (m/z): 292 M ⁺ (100), 262 (32), 234 (20), 223 (15), 215 (13), 178 (8), 160 (10), 117 (6), 105 (9), 77 (9).

Example 148

2-Amino-3-isopropyl-thio-6-r(E)-1-phenyl-2-N-methyl-carbamoyl-vinyl-imidazo-2-al-pyridine (148) mg (0.15 mmol) 2-trifluoroacetamido-3-iodo-6-[(E)-1-phenyl-2-N-methyl-carbamoyl-vinyl]-imidazo[1,2-a]pyridine prepared in 5 ml of THF and cooled to -78°C, 230 µl (0.33 mmol) of phenyllithium are added under an argon atmosphere. After stirring for 3 minutes, 310 µΙ (0.38 mmol) of tert-butyllithium are injected into the reaction mixture. 10

108 í ;

After stirring for 10 min, a solution of 109 mg (0.600 mmol) of isopropyl isopropanethiol sulfonate in 5 ml of THF was added to the mixture. The mixture was stirred at -78°C for 30 min and then quenched with 10 ml of THF containing 2 drops of water. After addition of 15 ml of ethyl acetate, the mixture was allowed to warm to room temperature. The solution was filtered through celite and the solvent was removed in vacuo. Radial chromatography was performed to obtain the isopropyl sulfide derivative (from which the trifluoroacetyl group had already been cleaved) and the intermediate in pure form. The ratio of intermediate to final product depended on the speed of radial chromatography. The trifluoroacetyl-containing compound was mixed with silica gel in MeOH/CH ₂ Cl ₂ , and the solid-containing mixture was stirred for 2 days. After filtration, the title compound was obtained in 73% overall yield. EI-MS (m/z): 366 m ⁺ (33), 323 (100), 293 (18), 237 (15), 196 (10), 178 (7), 102 (6).

¹ H-NMR (CDCI ₃ ), δ: 8.01 (d, 1H, J = 1.5 Hz, H ₅ ), 7.47-7.20 (m, 7H, Ar), 6.40 (s, 1H, vinyl H), 5.20 (broad s, 1H, J = 4.9 Hz, NHMe), 4.26 (broad s, 2H, NH ₂ ), 2.97 (heptet, 1H, J = 6.8 Hz, CH(CH ₃ ) ₂ ), 2.65 (d, 3H, J = 4.9 Hz, CH ₃ NH), 1.13 (d, 6H, J = 6.8 Hz, (CH ₃ ) ₂ CH).

Example 149

2-Amino-3-isopropylsulfonyl-6-[(E)-1-phenyl-2-N-methylcarbamoylvinyl]imidazo[1,2-a]pyridine (149) mg (0.09 mmol) of 2-trifluoroacetamido-3-isopropylsulfonyl-6-[(E)-1-phenyl-2-N-methylcarbamoylvinyl]imidazo[1,2-a]pyridine was dissolved in a 1:1 mixture of MeOH/CH ₂ Cl ₂ , and silica gel was added to the solution until a solid cake formed. The cake was stirred vigorously for 2 days. The mixture was filtered through celite to give the title compound as a white solid (33 mg, 89%). EI-MS (m/z): 398 M ⁺ (44), 292 (100), 262 (27), 233 (15), 215 (9), 205 (8), 178 (7), 77 (6), 58 (8).

109 ¹ H-NMR (CDCI ₃ ), δ: 8.46 (s, 1H, H ₅ ), 7.53-7.30 (m, 7H, Ar), 6.41 (s, 1H, vinylic H), 5.30 (d, 1H, J = 4.8 Hz, NHMe), 5.17 (broad s, 2H, NH ₂ ), 3.26 (heptet, 1H, J = 7.0 Hz, CH(CH ₃ ) ₂ ), 2.12 (d, 3H, J = 4.8 Hz, CH ₃ NH), 1.34 (d, 6H, J = 7.0 Hz, (CH ₃ ) ₂ CH).

Example 150

2-Amino-3-phenyl·6-Γ1-(2,3-difluorophenyl)-oximyl-imidazoΓ1,2-alpyridine; compound of formula (150)

0.15 g (0.43 mmol) of 2-amino-3-phenyl-6-(2,3-difluorobenzoyl)imidazo[1,2-a]pyridine was mixed with 0.357 g (5.16 mmol) of hydroxylamine hydrochloride and 0.424 g (516 mmol) of NaOAc in 9 ml of 80% EtOH. The reaction mixture was refluxed for 20 hours while argon gas was introduced. The solvent was removed in vacuo and the residue was taken up in EtOAc-H ₂ O. The organic phase was washed with 2x20 ml of saturated NaHCO ₃ solution and 2x25 ml of saturated sodium chloride solution, dried over sodium sulfate, and concentrated to give the title compound as a yellow solid in quantitative yield. The ratio of E- and Z-isomers is determined by NMR analysis (2:1).

¹ H-NMR (200 MHz, DMSO-d ₆ ), δ: 5.34 (broad s, NH ₂ E), 5.38 (NH ₂ Z), 8.04 (s, H ₅ E), 8.91 (H ₅ Z), 11.77 (s, OH E), 12.14 (s, OH Z).

Example 151

Compound of formula 2-Amino-3-phenyl-6-[(2,3-difluorophenyl)-2-N-methylcarbamoylvinyl]imidazo[1,2-a]pyridine (151)

0.13 g (0.26 mmol) of 2-trifluoroacetamido-3-phenyl-6-[(E)-1-[2,3-difluorophenyl)-2-methylcarbamoylvinyl]imidazo[1,2-a]pyridine was dissolved in a 1:1 mixture of MeOH/diisopropylethylamine (4 ml) and the solution was refluxed under argon for 4 days. The solvent was removed in vacuo and the residue was purified by column chromatography (CH ₂ CI ₂ /CH ₃ CN/MeOH 55:40:5) to give 27 mg (32.5%) of the title compound.

¹¹⁰ J. 1 ¹ H-NMR (200 MHz, CDCI ₃ ), δ: 3.86 (d, J = 9.0, 3H, CONHCH ₃ ), 4.15 (broad s, 2H, NH), 6.64 (s, vinyl H), 7.02-7.45 (m, 10H, F-ArH + ArH + H ₇ + H ₈ ), 8.14 (d, J ₅₇ = 1.5, H ₅ ).

¹³ C-NMR (50 MHz, CDCl ₃ ), δ: 33.7, 114.6, 118.0, 118.4, 121.0, 121.6, 122.4, 122.6, 123.2, 124.2, 127.7, 127.7, 128.9, 129.7, 147.0, 148.7, 161.9.

Example 152

2-Amino-3-phenyl-6-[(E)-1-phenyl-2-N-methylcarbamoylvinylimidazol,2-a]pyridine: compound of formula (152)

Starting from 190 mg (0.420 mmol) of 2-trifluoroacetamido-3-phenyl-6-[(E)-1-phenyl-2-N-methylcarbamoylvinyl]imidazo[1,2-a]pyridine and proceeding as described in Example 151, 127-135 mg of the title compound were obtained (85-90%).

¹ H-NMR (200 MHz, CD ₃ OD), δ: 2.60 (s, 3H, NHCH ₃ ), 6.44 (s, 1H, vinylic H), 7.20-7.42 (m, 12H, ArH + H ₇ + H ₈ ), 7.91 (broad s, 1H, H ₅ ).

Example 153 2-Amino-3-(2,5-difluorophenyl)-6-Γ(E)-1-phenyl-2-N-methylcarbamoylvinylimidazolyl,2-a]pyridine: compound of formula (153)

Starting from 333 mg (0.682 mmol) of 2-trifluoroacetamido-3-(2,5-difluorophenyl)-6-[(E)-1-phenyl-2-N-methylcarbamoylvinyl]imidazo[1,2-a]pyridine and proceeding as described in Example 151, 227-241 mg of the title compound were obtained (85-90%). EI-MS (m/z): 404 M ⁺ (100), 374 (17), 345 (12), 207 (9), 152 (7), 140 (7), 105 (7), 77 (11).

¹ H-NMR (CDCI ₃ ), δ: 7.62 (dd, 1H, J = 2.1, 1.2 Hz, H ₅ ), 7.45-6.99 (m, 10H, Ar), 6.35 (s, 1H, vinylic H), 5.19 (d, 1H, J = 4.9 Hz, NH), 4.18 (broad s, 2H, NH ₂ ), 2.63 (d, 3H, J = 5.0 Hz, CH ₃ ).

Example 154 2-Amino-3-(2-trifluoromethyl-4-fluorophenyl)-6-r(E)-1-phenyl-2-N-methylcarbamoylvinyl-

-imidazolium,2-alpyridine; compound of formula (154) *

¹¹¹ λ .1 !:>;··.:

Starting from 310 mg (0.576 mmol) of 2-trifluoroacetamido-3-(2-trifluoromethyl-4-fluorophenyl)-6-[(E)-1-phenyl-2-N-methylcarbamoylvinyl]imidazo[1,2-a]pyridine and proceeding as described in Example 151, 216-229 mg of the title compound were obtained (85-90%).

MS (FD) (ΕΓ (m/z): 454 (M ⁺ (100), 4.24 (19), 395 (12), 356 (7), 279 (10), 209 (11), 77 (9).

¹ H-NMR (CDCI ₃ ), δ: 7.52 (dd, 1H, J = 8.4 Hz, H ₇ + H ₈ ), 7.47-7.16 (m, 9H, Ar), 6.94 (d, 1H, J = 8.9 Hz, H ₇ + H ₈ ), 6.16 (s, 1H, vinyl H), 5.39 (broad d, 1H, J = 4.6 Hz, NHMe), 3.92 (broad s, 2H, NH ₂ ), 2.55 (d, 3H, J = 4.7 Hz, CH ₃ ).

Example 155

2-Amino-3-(2,3,4-trifluorophenyl)-6-[(E)-1-phenyl-2-N-methylcarbamoylvinyl]imidazol,2-apyridine: compound of formula (155)

Starting from 134 mg (0.265 mmol) of 2-trifluoroacetamido-3-(2,3,4-trifluorophenyl)-6-[(E)-1-phenyl-2-N-methylcarbamoylvinyl]imidazo[1,2-a]pyridine and proceeding as described in Example 151, 92.3-97.7 mg of the title compound were obtained (85-90%). EI-MS (M/z): 423 (M ⁺ (6), 422 (25), 392 (6), 353 (14), 259 (14), 105 (16), 84 (100).

¹ H-NMR (CDCl 3 ), δ: 7.70 (s, 1H, C ₇ H ₃ N ₂ ), 7.44-7.00 (m, 9H, Ar), 6.63 (s, 1H, CH=C), 5.20 (broad s, 1H, NH-CH^). 4.13 (broad s, 2H, NH ₂ ), 2.62 (d, J = 4.9 Hz, 3H, NH-CH^

Example 156

2-Amino-3-(3,5-difluorophenyl)-6-(1-phenyl-2-N-methylcarbamoylvinyl)imidazol,2-alpyridine; compound of formula (156)

Starting from 113 mg (0.232 mmol) of 2-trifluoroacetamido-3-(3,5-difluorophenyl)-6-(1-phenyl-2-N-methylcarbamoylvinyl)imidazo[1,2-a]pyridine and proceeding as described in Example 151, 77.3-81.8 mg of the title compound were obtained (85-90%). EI-MS (m/z): 405 M ⁺ (34), 404 (100), 374 (22), 345 (17), 84 (14).

< 4 ¹¹² Λ .1. :

¹ H-NMR (CDCl ₃ ), δ: 8.28 and 7.92 (s, 1H, C ₇ H ₃ N ₂ ), 7.5-6.7 (m, 10H, Ar), 6.36 and 6.28 (s, 1H, CH=C), 5.71 and 5.24 (broad s, 1H, NH-CHA 4.22 (broad s, 2H, NH ₂ ), 2.82 and 2.65 (d, J = 4.9 and 4.9 Hz, 3H, NH-CH ₃ ).

Example 157

2-Amino-3-(3-trifluoromethylphenyl)-6-F(E)-1-phenyl-2-N-methylcarbamoylvinylimidazo(1,2-a1pyridine; compound of formula (157)

Starting from 142 mg (0.273 mmol) of 2-trifluoroacetamido-3-(3-trifluoromethylphenyl)-6-[(E)-1-phenyl-2-N-methylcarbamoylvinyl]imidazo[1,2-a]pyridine and proceeding as described in Example 151, 98.4-104 mg of the title compound (85-90%) were obtained. EI-MS (m/z): 437 (M ⁺ (36), 436 (100), 406 (18), 377 (16), 279 (10), 77 (6).

¹ H-NMR (CDCl ₃ ), δ: 7.83 (s, 1H, C ₇ H ₃ N ₂ ), 7.64 (m, 11H, Ar), 6.42 and 6.38 (s, 1H, CH=C), 5.13 (broad s, 1H, NH-CH^). 4.11 (broad s, 2H, NH ₂ ), 2.62 (d, J = 4.9 Hz, 3H, NH-CH ₃ ).

Example 158

2-Amino-3-benzoyl-6-F(E)-1-phenyl-2-N-methylcarbamoylvinylimidazol,2-a1pyridine; compound of formula (158)

0.250 g (0.482 mmol) of 1-(2-oxo-2-phenylethyl)-2-chloro-5-[(E)-1-phenyl-2-methylcarbamoylvinyl]pyridinium iodide was mixed with 220 mg (0.49 mmol) of aminonitrile and 200 mg (1.47 mmol) of K ₂ CO ₃ in 10 ml of CH ₃ CN. The reaction mixture was refluxed for 14 h. The mixture was cooled to room temperature and filtered, the filter cake was washed with CH ₃ CN. The mother liquor was evaporated and the residue was purified by column chromatography (acetone/EtOAc 1:1) to give 62.8 mg of the title compound as a slightly colored product (39% yield). MS (HR), NMR. Example 159

2-Amino-3-(4-fluorobenzoyl)-6-F(E)-1-phenyl-2-N-methylcarbamoylvinyl]imidazoF1,2-a1-pyridine; compound of formula (159)

I ¹¹³ ·:.

Starting from 400 mg (0.740 mmol) of 1-[2-oxo-2-(4-fluorophenyl)ethyl]-2-chloro-5-[(E)-1-phenyl-2-methylcarbamoylvinyl]pyridinium iodide and proceeding as described in Example 158, 118 mg of the title compound are obtained (38%).

IR (KBr) μ, (cm' ¹ ): 3676, 3457, 3283, 3102, 1735, 1640, 1640, 1448, 1352, 1154, 849, 700.

¹ H-NMR (300 MHz, DMSO-d ₆ ), δ: 8.56 (s, 1H), 7.86 (d, 1H, J = 5.12), 7.56-7.49 (m, 2H), 7.36 (d, 1H, J = 8.79), 7.3-7.2 (m, 5H), 7.15 (m, 2H), 6.44 (s, 1H), 6 (s, 2H), 2.48 (s, 3H). MS (HR) based on the formula C ₂ 4H ₁₉ N ₄ O2:

calculated: 414.1492; found: 414.1498.

Example 160

2-Amino-3-acetyl-6-r(E)-1-phenyl-2-N-methylcarbamoylvinylimidazol,2-alpyridine: compound of formula (160)

Starting from 400 mg (0.870 mmol) of 1-[2-oxo-propyl]-2-chloro-5-[(E)-1-phenyl-2-methylcarbamoylvinyl]pyridinium iodide and proceeding as described in Example 158, 118 mg of the title compound were obtained (40%). MS (HR) (m/z) for C ₁₉ H ₁₈ N ₄ O ₂ : calcd.: 334.1430, found: 334.1430. IR (KBr) μ, (cm' ¹ ): 3440, 1614, 1530, 1458, 1348, 820.

Example 161

2-Amino-3-tert-butylacetyl-6-F(E)-1-phenyl-2-N-methylcarbamoylvinylimidazol,2-alpyridine; compound of formula (161)

Starting from 1-[2-oxo-3,3-dimethylbutyl]-2-chloro-5-[(E)-1-phenyl-2-methylcarbamoylvinyl]pyridinium iodide (140 mg, 0.280 mmol) and proceeding as described in Example 158, 31.9 mg of the title compound (30) were obtained. MS (HR) for C ₂₂ H ₂₄ N ₄ O ₂ : calcd. 376.1899, found 376.1900.

¹¹⁴ .:. 1 ^-NMR (300 MHz, DMSO-d ₆ ), δ: 9.22 (s, 1H), 7.8 (d, 1H, J = 4.4), 7.4-7.3 (m, 4H), 7.18 (d, 1H, J = 4), 7.16 (d, 1H, J = 2.5), 6.43 (s, 1H), 6.35 s, 2H), 2.52 (d, 3H, J = 4.4), 1.17 (s, 9H).

Example 162

2-Amino-3-tert-butylacetyl-6-nE)-1-(2,3-difluorophenyl)-2-N-methylcarbamoylvinylimidazol,2-a]pyridine; compound of formula (162)

Starting from 120 mg (0.220 mmol) of 1-[2-oxo-3,3-dimethylbutyl]-2-chloro-5-[(E)-1-(2,3-difluorophenyl)-2-methylcarbamoylvinyl]pyridinium iodide and proceeding as described in Example 158, 11.2 mg of the title compound (12%) were obtained. MS (HR): calculated for C22H22N4O2F2: 412.1711, found: 414.1713.

¹ H-NMR (300 MHz, CDCl ₃ ), δ: 9.4 (s, 1H), 7.28 (d, 1H, J = 1.1), 7.21-7.14 (m, 3H), 6.98 (m, 1H), 6.49 (s, 1H), 5.62 (s, 1H), 5.35 (s, 2H), 2.78 (d, 3H, J = 4.76), 1.32 (s, 9H).

As described above, the compounds of the invention are effective antiviral agents. They exhibit inhibitory activity against various enterovirus and rhinovirus strains. In the treatment or prophylaxis of picornavirus infections, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof.

The term "effective amount" as used herein refers to an amount of a compound of formula (I) that is capable of inhibiting viral replication. Picornavirus inhibition includes both therapeutic and prophylactic treatment. The dosage used for therapeutic or prophylactic treatment will be influenced by the circumstances of the disease, including, for example, the compound chosen, the route of administration, the condition being treated, and the patient being treated. In general, the daily dosage of a compound of the invention will be between about 0.01 mg/kg and about 50 mg/kg of body weight. The

K λ

_A preferred daily dose is between about 0.05 mg/kg and about 20 mg/kg, ideally between 0.1 mg/kg and 10 mg/kg.

The compounds of the invention can be administered by various routes, such as orally, rectally, transdermally, subcutaneously, intravenously, intramuscularly or intranasally. The compounds of the invention are preferably formulated prior to administration. The invention therefore also provides pharmaceutical compositions comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, diluent or excipient.

The active ingredient content of the compositions is between 0.1 and 99.9% by weight. The term "pharmaceutically acceptable" means that the carrier, diluent or excipient is compatible with the other components of the composition and does not have an adverse effect on the patient being treated.

The compositions of the invention are prepared by known methods from readily available components. In the preparation of pharmaceutical compositions, the active ingredient is generally mixed with the carrier or diluent or enclosed in the carrier, such as in a capsule, sachet, paper or other container. If the carrier also serves as a diluent, it may be solid, semi-solid or liquid and serves as a carrier, medium or medium for the active ingredient. The composition may be prepared in the form of tablets, dragees, powders, lozenges, sachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (the latter in solid or liquid media), ointments containing up to 10% active ingredient may also be prepared, as well as soft or gelatin capsules, suppositories, sterile injection solutions, sterilely packaged powders and the like.

An example of pharmaceutical compositions is presented below, which is intended to illustrate and not to limit the invention.

116

1. Preparation

We produce solid gelatin capsules from the following components:

components____________________________(mg/capsule) active ingredient250 starch, dried200 magnesium stearate10 total: 460mg.

Test methods

African green monkey kidney cells (BSC-1) or Hela cells (5-3) were cultured in 25 ml Falcon flasks at 37°C in medium 199 containing 5% inactivated fetal bovine serum (FBS), penicillin (150 units/ml) and streptomycin (150 pg/ml). When confluent monolayers were formed, the supernatant medium was removed and 0.3 ml of the appropriate dilution of virus (e.g. echo, Mengo, Coxsackie, polio or rhinovirus) was added to each flask. The viruses are allowed to absorb for 1 hour at room temperature, then a medium containing one part 1% Lonagar 2 and one part double strength 199 medium is layered onto the virus-infected cell layer, where the medium contains FBS, penicillin and streptomycin, and the active substance at concentrations of 100, 50, 25, 12, 6, 3 and 0 pg/mg. A flask without active substance serves as a control. The stock solution of the compounds is diluted with dimethyl sulfoxide to a concentration of 10 ⁴ pg/ml. The flasks are then incubated for 72 hours at 37°C for polio, Coxsackie, echo and Mengo viruses, and for 120 hours at 32°C for rhinoviruses. Viral plaques can be seen in the areas of the cells where viral infection and viral replication have occurred. 10% formalin and 2% sodium acetate solution are added to each flask to inactivate the virus and to fix the cell layer to the flask surface. Virus plaques are counted regardless of their size.

117 1 jJíjX:

surrounding cell surface stained with crystal violet. The plaque count results are compared with the control data for each active ingredient concentration. The effect of the test compound is expressed as a percentage of inhibition, i.e., as a percentage of the reduction in plaque number. Alternatively, the effect of the test compounds can be evaluated by using the concentration of active ingredient that inhibits plaque formation by 50%. The 50% inhibitory value is denoted by “IC ₅₀ ”. The compounds of the invention show at least a 30%, preferably 50%, more preferably 85% inhibitory effect on plaque formation after a single 50 gmol/dose administration. In titrating the dose response of the compounds of the invention, it was found that the IC ₅₀ values of the compounds were <10 pmol/l.

Claims (9)

X 118 PATENT CLAIMS 1. Compounds of general formula (I) or pharmaceutically acceptable salts thereof, wherein in the formula A is phenyl, pyridyl, substituted phenyl, substituted pyridyl or benzyl; R is hydrogen, -COR ⁴ or -COCF ₃ ; X is =N-OH, O= or =CHR ¹ ; R ¹ represents a hydrogen atom, a halogen atom, -CN, C 1-4 alkyl-, -C=CH, -CO(C 1-4 alkyl), -CO ₂ (C 1-4 alkyl) or -CONR ² R ³ ; R ² and R ³ are independently hydrogen or C 1-4 alkyl; A' represents a hydrogen atom, a halogen atom, a C1-C6 alkyl, a benzyl, a naphthyl, a thienyl, a furyl, a pyridyl, a pyrrolyl, -COR ⁴ , -S(O) _n R ⁴ or a group of general formula (a); R ⁴ is C 1-6 alkyl, phenyl or substituted phenyl; n is 0, 1 or 2; each R ⁵ independently represents a hydrogen atom or a halogen atom; m is 1,2,3 or 4; and R ⁶ represents a hydrogen atom, a halogen atom, -CF ₃ , -OH, -CO ₂ H, -NH ₂ , -NO ₂ , -CONHOCH ₃ , a C 1-4 alkyl or -CO ₂ (C 1-4 alkyl) or a C 1-4 alkoxy group. 2. Compounds according to claim 1, wherein R is hydrogen. 3. Compounds according to claim 2, wherein A is phenyl or substituted phenyl; and A is C1-6 alkyl, -COR ⁴ , S(O) _n R ⁴ , or a group of general formula (a). 119 4. Compounds according to claim 1, wherein X is =NOH or =CHR ¹ . 5. Compounds according to claim 3, wherein X is -NOH or =CHR ¹ . 6. Compounds according to claim 5, having the formula X is =CHR ¹ ; R ¹ is -CN, -CO(C 1-4 alkyl)- or -CONR ² R ³ ; A is a fluorophenyl or difluorophenyl group; A’ means a group of general formula (a), and R ⁵ represents a halogen atom. 7. A method for inhibiting Hepatitis C virus, comprising administering to a patient in need thereof an effective amount of a compound according to claims 1-6. 8. A method for inhibiting picornavirus, comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1-6. 9. Pharmaceutical compositions comprising as active ingredient a compound according to any of claims 1-6, and one or more pharmaceutically acceptable carriers, diluents and/or excipients. The authorized person: W| Szentpétei±4dám V ' η~106ηβΟ®^^ , Telephone: 34-24-323 1/26 .:.7,^13/^:: LIFE