KR20010025055A - Anti-Viral Compounds - Google Patents

Abstract

The present invention relates to compounds of formula (I) which inhibit the growth of picornavirus, hepatitis virus, enterovirus, cardiovirus, polio virus, coxsackievirus of the A and B groups, echo virus and mengo virus. In the above formula or pharmaceutically acceptable salts thereof, A is hydrogen, halo, CN, C ₁ -C ₄ alkyl, -C≡CH, CO (C ₁ -C ₄ alkyl), CO ₂ (C ₁ -C ₄ alkyl) ), Or CONR ² R ³ , R ² and R ³ are independently hydrogen or C ₁ -C ₄ alkyl, A ′ is hydrogen, halo, C ₁ -C ₆ alkyl, benzyl, naphthyl, thienyl, furyl , Pyridyl, pyrrolyl, COR ⁴ , S (O) _n R ⁴ , or a group of formula (II), R ⁴ is C ₁ -C ₆ alkyl, phenyl or substituted phenyl, n is 0, 1 Or 2, R ⁵ is independently hydrogen or halo at each position, m is 1, 2, 3 or 4, R ⁶ is hydrogen, halo, CF ₃ , OH, CO ₂ H, NH ₂ , NO ₂ , CONHOCH ₃ , C ₁ -C ₄ alkyl or CO ₂ (C ₁ -C ₄ alkyl), C ₁ -C ₄ alkoxy.

<Formula I>

<Formula II>

Description

Anti-Viral Compounds

The development of viral upper respiratory disease, common cold, is widespread. Nearly one million cases a year in the United States alone. Rhinovirus, a member of the picornaviridae family, is a major cause of the common cold in humans. Since more than 110 strains of rhinoviruses have been identified, the development of comprehensive rhinovirus vaccines is not practical. Thus, chemotherapy may be a more desirable approach. The other member of the picornavirus family is an enterovirus, comprising approximately 80 human pathogens. Many of these enteroviruses cause cold-like symptoms, while others cause more serious diseases such as poliomyelitis, conjunctivitis, aseptic meningitis and myocarditis.

Diseases associated with rhinovirus infection are identified by nasal discharges and obstructions. Moreover, it is associated with otitis media, exacerbates sinusitis, and is associated with the sedimentation response of asthma disease. Although it may not be a nuisance to the majority, nevertheless, frequent outbreaks and the resulting economic importance in healthy individuals have made rhinovirus infection a comprehensive research topic.

The ability of compounds to suppress the growth of viruses in vitro can be readily demonstrated using viral plaque inhibition test or cytopathic effects test (CPE) [Siminoff, Applied Microbiology, 9 (1), 66 (1961)]. Although a number of compounds that inhibit picornaviruses have been identified, most are unacceptable because of 1) limited spectrum of activity, 2) unwanted side effects, or 3) lack of preventing infection or illness in animals or humans. Textbook of Human Virology, edited by Robert B. Belshe, chapter 16, "Rhinoviruses," Roland A. Levandowski, 391-405 (1985). Thus, despite the perceived therapeutic potential associated with rhinovirus inhibitors, the research effect of consuming somewhat viable therapeutics has not yet been shown. For example, antiviral benzimidazole compounds are disclosed in US Pat. Nos. 4,008,243, 4,018,790, 4,118,573, 4,118,742 and 4,174,454.

Accordingly, the present invention relates to picornaviruses such as rhinoviruses (bovine and human), coxsackieviruses of groups A and B, or echoviruses, encephalomycarditis Novel pyridimidazole compounds that inhibit the growth of hepatitis viruses such as cardioviruses such as viruses (EMC), apthoviruses such as foot and mouth disease viruses, and Hepatitis C virus, etc. To provide.

The present invention relates to antiviral compounds and their use in the field of pharmaceutical and medicinal chemistry.

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

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 is hydrogen, halo, CN, C ₁ -C ₄ alkyl, —C≡CH, CO (C ₁ -C ₄ alkyl), CO ₂ (C ₁ -C ₄ alkyl), or CONR ² R ³ ,

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

A ′ is hydrogen, halo, C ₁ -C ₆ alkyl, benzyl, naphthyl, thienyl, furyl, pyridyl, pyrrolyl, COR ⁴ , S (O) _n R ⁴ , or formula Is the flag of,

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

n is 0, 1 or 2,

R ⁵ in each occurrence is independently hydrogen or halo,

m is 1, 2, 3 or 4,

R ⁶ is hydrogen, halo, CF ₃ , OH, CO ₂ H, NH ₂ , NO ₂ , CONHOCH ₃ , C ₁ -C ₄ alkyl, CO ₂ (C ₁ -C ₄ alkyl) or C ₁ -C ₄ alkoxy .

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

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

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

The present invention also provides the use of a compound of formula (I) to inhibit picornavirus, rhinovirus or hepatitis virus.

<Detailed description of the invention>

The present invention relates to compounds of formula (I) which are useful as antiviral agents as described above.

All temperatures described above are in degrees Celsius (° C.). All units of measurement used herein are weight units except liquid in volume units.

As used herein, the term “C ₁ -C ₆ alkyl” refers to straight or branched chain alkyl having 1 to 6 carbon atoms. Typical C ₁ -C ₆ alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, neo-pentyl, hexyl, and the like. The term "C ₁ -C ₆ alkyl" includes the term "C ₁ -C ₄ alkyl" within its definition and includes cycloalkyl groups in which the alkyl group forms a ring.

The term "halo" refers to chloro, fluoro, bromo, or iodo.

As used herein, the term “substituted phenyl” is each substituted with 1, 2 or 3 substituents selected from the group consisting of halo, C ₁ -C ₄ alkyl, C ₁ -C ₆ alkoxy, or trifluoromethyl, respectively Phenyl ring.

As used herein, the term "substituted pyridyl" is each substituted with 1, 2 or 3 substituents selected from the group consisting of halo, C ₁ -C ₄ alkyl, C ₁ -C ₆ alkoxy or trifluoromethyl Pyridyl ring.

As mentioned above, the present invention includes pharmaceutically acceptable salts of compounds as defined by formula (I). Although generally neutral, the compounds of the present invention may be sufficiently acidic, sufficiently basic, or both functional groups, and thus react with any inorganic base and inorganic and organic acids to produce pharmaceutically acceptable salts.

As used herein, the term “pharmaceutically acceptable salts” relates to salts of compounds of formula (I) which are substantially nontoxic to biological organisms. Typically pharmaceutically acceptable salts are those salts prepared by reacting a compound of the present invention with a mineral or organic acid or inorganic base. Such salts are known as acid addition salts and base addition salts.

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

Examples of such pharmaceutically acceptable salts include sulfates, pyrosulfonates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromide, iodides, acetates, propionic acids Salts, decanoates, caprylates, acrylates, formates, isobutyrates, caprolates, heptates, propionates, oxalates, malonates, succinates, suverates, sebacates, fumarates, maleates , Butyne-1,4-dioate, hexyn-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, Xylenesulfonate, phenylacetate, phenylpropionate, phenylbutylate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, methanesulfonate, Propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like, but are not limited thereto. Preferred pharmaceutically acceptable acid addition salts are those formed from mineral acids such as hydrochloric acid and hydrobromic acid and from organic acids such as maleic acid and methanesulfonic acid.

Base addition salts are derived from inorganic bases such as, but not limited to, ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates and the like. Bases useful for preparing the salts of the present invention are, but are not limited to, sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate and the like. Particular preference is given to potassium and sodium salt forms.

Certain counterions formed as part of any of the salts of the present invention are all pharmaceutically acceptable salts, unless they have important properties, and all are recognized as salts unless desired.

Pharmaceutically acceptable salts of the present invention are typically formed by reacting a compound of formula (I) with an equivalent or excess of acid or base. The reactants may generally be in acid base salts, in neutral bases such as diethyl ether, benzene, or the like, or in combination with water, alcohols and base addition salts. Salts precipitate normally from solvent for 1 hour to 10 days and can be isolated by filtration or other conventional methods.

The compounds of the present invention may be in cis or trans configuration, where cis denotes a compound that is cis in a ring represented by the substituent on the alkene moiety as "A", and trans denotes a substituent in the ring represented by "A" Phosphorus compounds). All isomers and mixtures thereof are included within the scope of the present invention.

While the paragraphs described below represent preferred embodiments of the invention, it is to be understood that the invention is not limited to such embodiments and that other embodiments may be contemplated. Preferred compounds of formula (I) are as follows.

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 -C ₄ alkyl), or CN,

j) R ¹ is CONR ² R ³ ,

k) R ¹ is CO ₂ (C ₁ -C ₄ alkyl),

l) R ² and R ³ are independently methyl or hydrogen,

m) A 'is C ₁ -C ₆ alkyl, naphthyl, thienyl, COR ^4, S (O) _n R ^4, or the general formula Is the flag of,

n) A 'is C ₁ -C ₆ alkyl, COR ⁴ , S (O) _n R ⁴ , or Is the flag of,

o) A 'is Is the flag of,

p) A 'is C ₁ -C 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 fluoro, m is 5,

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

t) R ⁶ is CF ₃ , OH, CO ₂ H, NH ₂ , NO ₂ , CONHOCH ₃ , C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy,

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

v) R ⁶ is CF ₃ , OH, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy.

<Scheme>

Compounds of formula (I) may be prepared by synthetic methods known in the art and by the methods disclosed herein. A compound of formula (I), wherein A 'is hydrogen, C ₁ -C ₆ alkyl, naphthyl, thienyl, furyl, pyridyl, pyrrolyl or formula Can be prepared according to Scheme I shown below.

L represents a leaving group selected from the group consisting of halo, O-triplate, O-mesylate, O-tosylate and the like.

Z is hydrogen, C ₁ -C ₆ alkyl naphthyl, thienyl, furyl, pyridyl, pyrrolyl or formula Represents a group.

Compounds of formula (A) can be prepared by synthetic methods known in the art and by the methods disclosed herein. For example, the compound of formula (A) can be prepared according to Scheme II shown below.

Suitably substituted aryl groups can be acylated with suitably substituted acid anhydrides, carboxylic acids, or acid chlorides in the presence of Lewis acid under Friedel-Craft conditions to form compounds of Formula (H) Friedel-Crafts and Related Reactions, Ed. GA, Olah, J. Wiley and sons, N.Y., chapters 31, 32 (1964)]. Suitable Lewis acid catalysts include, but are not limited to, trifluoroacetic anhydride / phosphate, trifluoromethanesulfonic acid, iron (III) chloride, zinc chloride, copper triflate (CuOTf), phosphorus oxychloride, trifluoroacetic acid, aluminum trichloride, and the like. Do not. Aluminum trichloride is the preferred Lewis acid. Suitable 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" using a substituted aryl group as the preferred solvent. Substituted aryl groups are generally used in substantially molar excess. For example, approximately 3 to 10 excess moles are generally used relative to 6-chloronicotinoyl chloride. An excess of about 3.8 moles is typically preferred. The reaction is preferably carried out at about 80 ° C.

Alternatively, compounds of formula (H) may be prepared by reacting compounds of formula (G) with aryl anions by methods known in the art. Weinreb amides of formula (G) can be prepared from the corresponding 1-chloro-5-nicotinic acid by methods known in the art. In addition, acyl anions used to prepare formula (H) are known in the art and can be prepared by the methods described in the art. For example, suitably substituted bromo or iodo aryl groups can be brought into the metal-halogen exchange state by the methods disclosed in the art and herein to obtain metal aryl anions. A general discussion of metal-halogen exchange states is given in Organic Reactions, vol. 6, pg. 339, (1951). Suitable solvents include, but are not limited to toluene, dimethylformamide, methylene chloride, diethyl ether, acetonitrile, tetrahydrofuran and the like. Tetrahydrofuran is a preferred solvent. Suitable sources of metal are, but are not limited to, alkyl lithium, including lithium molecules, in particular t-butyl lithium. N-butyl lithium is a preferred source of metal. Metals are generally used in slightly excess moles. For example, molar amounts of approximately 1 to 1.1 excess are generally used. A molar excess of 1.03 is typically preferred. The reaction is preferably carried out at about -78 ° C for approximately 15 minutes.

Compounds of formula (H) may be aminated with ammonia under high pressure to give compounds of formula (J). The compound of formula (H) was dissolved in a suitable solvent, liquid ammonia was added and the reaction was sealed in a container resistant to elevated pressure. Suitable solvents include, but are not limited to toluene, lower alcohols, acetonitrile, ethyl ether, tetrahydrofuran, dimethylformamide, chloroform, methylene chloride, and the like. Ethanol is the preferred solvent. The reaction is preferably carried out at about 145 ° C. for about 16 hours.

Compounds of formula (A) can be prepared by methods known in the art. For example, the compound of formula (J) can be tosylated in an inert solvent by the addition of a base and tosyl chloride. Suitable solvents include, but are not limited to, tetrahydrofuran, lower alcohols, ethyl acetate, methylene chloride, acetonitrile, chloroform and the like. Suitable bases are triethylamine, sodium bicarbonate, sodium hydroxide, imidazole and the like. Pyridine is the preferred base and solvent. Tosyl chloride is generally used in slightly excess moles. For example, approximately 1-2 molar excess is generally used for the compound of formula (J). 1: 1 molar excess is typically preferred. The reaction is preferably carried out at about 90 ° C. for about 16 hours.

Compounds of formula (B) may be prepared by synthetic methods in the art and by the methods disclosed herein. For example, a compound of formula (B), wherein L is bromine, can be prepared according to Scheme III shown below.

Properly substituted acetic acid of formula (K) is brominated in a suitable solvent in the presence of a radical initiator to give a compound of formula (L). Suitable brominating agents include, but are not limited to, bromine atoms, N-bromosuccinimides and the like. N-bromosuccinimide is the preferred brominating agent. Suitable solvents include, but are not limited to, diethyl ether, tetrahydrofuran, methylene chloride, chloroform, acetonitrile, benzene, dimethylsulfoxide, carbon tetrachloride, and the like. Carbon tetrachloride is a preferred solvent. Suitable radical initiators include, but are not limited to, phosphorus trichloride, phosphorus molecules, benzoylperoxides, UV irradiation, and the like. Preferred initiators are benzoylperoxide and UV radiation. Brominating agents are generally used in stoichiometric amounts. For example, 1 equivalent is generally used and typically preferred with respect to the compound of formula (K). Initiators are generally used in catalytic amounts. For example, about 0.1 to 1 mol% is generally used relative to the compound of formula (K). 0.4 mol% is typically preferred. The reaction is preferably carried out at about 77 ° C for about 5 hours.

Compounds of formula (M) can be prepared by amidation of compounds of formula (L) by methods known in the art. For example, the modification can be accomplished by dissolving or suspending the compound of formula (L) in a suitable solvent, followed by addition of a nucleophilic source of chlorine to obtain the corresponding acid chloride which can be amidated with gaseous ammonia in situ. Is performed. Suitable solvents include, but are not limited to, alkanes, dimethylformamides, lower alcohols, ethyl acetate, methylene chloride, tetrahydrofuran, diethyl ether, acetonitrile, chloroform and the like. Dimethylformamide, methylene chloride, hexane and toluene are preferred solvents. Suitable chlorinating agents are, but are not limited to, thionyl chloride, phosphorus pentachloride, bis (trichloromethyl) carbonate, aryl chloroformate, phosphorus trichloride, triphosgen, oxalyl chloride, and the like. Oxalyl chloride is the preferred chlorinating agent. Chlorinating agents are generally used in slight excess. For example, about 1-2 mol excess is generally used for the compound of formula (L). A 1.6 molar excess is typically preferred. Ammonia is generally used in substantially molar excess. For example, ammonia gas is preferably bubbled through the reaction mixture for about 1 hour to deliver an unspecified amount of ammonia. The reaction is preferably carried out at about 0 ° C. when the chlorinating agent is added, followed by 3 hours at about 22 ° C. and then gaseous ammonia at about 22 ° C. for about 1 hour.

In addition, compounds of formula (B), wherein L is O-tosylate, can be prepared according to Scheme IV shown below.

Compounds of formula (O) can be prepared from aldehydes which are suitably substituted by methods known in the art. For example, the compound of formula (N) is hydrolyzed by mixing with an acyl anion equivalent of carboxylate, such as trimethylsilylcyanide, to obtain a compound of formula (O). Suitable solvents include, but are not limited to, lower alcohols, ethyl acetate, methylene chloride, acetonitrile, chloroform and the like. The reaction is preferably carried out "neat" when the aldehyde or acyl anion equivalent is a liquid. Acyl anion equivalents are generally used in stoichiometric ratios. For example, one equivalent of acyl anion equivalent to benzaldehyde is generally used and is typically preferred. The reaction is preferably carried out at about 25 ° C. for about 72 hours and at about 100 ° C. for about 18 hours after the addition of the acyl anion equivalent to give the compound of formula (O).

Compounds of formula (P) can be prepared from compounds of formula (O) by methods known in the art. Acetylation of hydroxy acids is disclosed in all parts of the art. See, eg, Greene T.W., Protective Groups in Organic Synthesis, John Wiley & Sons (1981).

Compounds of formula (Q) can be prepared by amidation of compounds of formula (P) by methods known in the art and by the methods described herein. Amidation is substantially similar to the method used to prepare compounds of formula (M) from compounds of formula (L).

Compounds of formula (Q) may be prepared by removing acetyl protecting groups from compounds of formula (P) by methods known in the art. See, eg, Greene T.W., Protective Groups in Organic Synthesis, John Wiley & Sond (1981).

Compounds of formula (R) having alcohol moieties that are converted to leaving groups are prepared by methods known in the art. See, eg, S tan g, et al., Synthesis, pp. 85-1266 (1982).

Compounds of formula (C) may be prepared by methods known in the art and by the methods disclosed herein. For example, a compound of formula (A) is combined with a compound of formula (B) to obtain a compound of formula (C). Suitable solvents include but are not limited to toluene, tetrahydrofuran, methylene chloride, diethyl ether, acetonitrile and the like. Dimethylformamide is typically a preferred solvent. Suitable bases are cesium fluoride, cesium carbonate, sterically hindered alkylamines and the like, in particular but not limited to diisopropylethylamine. Sodium hydride is typically the preferred base. Bases are generally used in slightly excess moles. For example, about 1 to 1.25 molar excess is generally used for the compound of formula (A). A 1.1 molar excess is typically preferred. Compounds of formula (B) are generally used in slightly excess moles. For example, about 1 to 1.1 molar excess is generally used for the compound of formula (A). A 1.05 molar excess is typically preferred. Deprotonation is performed at room temperature for about 1.5 hours. After addition of the compound of formula (B), the reaction is typically carried out at room temperature, preferably for about 7 days.

Compounds of formula (D) can be prepared by methods known in the art and by the methods disclosed herein. For example, the compound of formula (C) can be cyclized by dissolving the compound of formula (C) in a suitable solvent and adding trifluoroacetic anhydride to obtain the compound of formula (D). Suitable solvents include, but are not limited to toluene, dimethylformamide, tetrahydrofuran, diethyl ether, acetonitrile and the like. Methylene chloride is typically the preferred solvent. Trifluoroacetic anhydride is generally used in some molar excess. For example, about 5-20 molar excess is generally used for the compound of formula (C). 12.4 molar excess is typically preferred. The reaction is typically performed at about reflux temperature (40 ° C.) of methylene chloride for about 3 hours.

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

Compounds of formula (E) wherein X is CHR ¹ and R ¹ is CONH ₂ , CO (C ₁ -C ₄ alkyl), CONR ² R ³ or CO ₂ (C ₁ -C ₄ alkyl) It can be prepared from the compound of formula (D) by the methods disclosed herein as well as methods known in the art. For example, a suitably substituted Horner-Emmons reagent (see Organic Reactions, 1977 Volume 25, pg. 73.) is deprotonated with a strong base in an aprotic solvent and formula (D) Was added to give a compound of formula (E). Suitable strong bases are, but are not limited to, alkyllithium, lithium diisopropylamine, lithium bistrimethylsilylamide, and the like. Potassium t-butoxide is the preferred base. Suitable solvents include, but are not limited to, diethyl ether, tetrahydrofuran, methylene chloride, chloroform, dimethyl sulfoxide, and the like. Dimethylformamide and tetrahydrofuran are preferred solvents. Horner-Emmons reagent is commonly used in slightly excess moles. For example, about 1-2 molar excess is common with respect to the compound of formula (D). A 1.1 molar excess is typically preferred. The reaction is preferably carried out at about 0 ° C. when the compound of formula (A) is added and then at about 25 ° C. for about 1 hour.

Compounds of formula (E), wherein X is NOH, can be prepared from compounds of formula (D) by methods known in the art as well as the methods disclosed herein. For example, the compound of formula (D) can be dissolved or suspended in a suitable solvent and hydroxyamine can be added to obtain the compound of formula (E). Suitable solvents include, but are not limited to, low alcohol, ethyl acetate, methylene chloride, chloroform and the like. Methanol or pyridine is the preferred solvent. Hydroxyamines are generally used in significant molar excesses. For example, about 3 to 10 molar excess is common for compounds of formula (E). A 5.0 molar excess is typically preferred. The reaction was carried out at about 25 ° C for about 24 hours.

Compounds of formula (E), wherein X is CHR ¹ and R ¹ is H or CN, can be prepared from compounds of formula (D) by methods known in the art as well as the methods disclosed herein. For example, suitably substituted Peterson olefination reagents (see Organic Reactions, 1990, volume 38, pg. 1.) can be dissolved in a suitable solvent and deprotonated with strong bases. Compounds of formula (D) may be added to the product. Suitable strong bases include but are not limited to potassium t-butoxide, alkyllithium, lithium diisopropylamine, lithium bistrimethylsilylamide, and the like. N-butyllithium is the preferred base. Suitable solvents include, but are not limited to, diethyl ether, methylene chloride, chloroform, dimethylformamide, dimethyl sulfoxide, and the like. Tetrahydrofuran is the preferred solvent. Peterson's reagent is commonly used in significant molar excesses. For example, about 3 to 10 molar excess is common for the compound of formula (D). A 5.0 molar excess is usually preferred. The reaction is preferably carried out at about −78 ° C. and then at about 25 ° C. for 24 hours when deprotonating the Peterson reagent and adding the compound of formula (D).

The compounds of formula (E) (wherein, X is CHR ^1, R ¹ is halo-Im), a compound of formula (E) by the method disclosed herein as well as methods known in the art (wherein, X is CH ₂ Im It can be prepared from). For example, a compound of formula (E), wherein X is CH ₂ , can be dissolved in a suitable solvent and a suitable halogenating agent can be added to form the product. Suitable solvents include but are not limited to methylene chloride, tetrahydrofuran, chloroform, acetonitrile, acetic acid and the like. Tetrahydrofuran and carbon tetrachloride are preferred solvents. Suitable halogenating agents are, but are not limited to, benzene seleninyl chloride / aluminum chloride, thionyl chloride, bromine molecules, CsSO ₄ F, NFTh, and the like. Halogenation reagents are generally used in slightly molar excess. For example, about 1 to 2 molar excess relative to the starting material. A 1.1 molar excess is typically preferred. The reaction is preferably carried out at −10 ° C. when the halogenating agent is added and then at about 22 ° C. for about 1 hour.

Those skilled in the art will appreciate that the ratio of cis / trans products isolated by the schemes disclosed herein may be completely cis or trans, or both may be in the same proportions or vary widely, depending on the starting materials used and the reaction conditions used.

Compounds of formula (I), wherein A ′ is COR ^5, can be prepared according to the methods shown in Scheme V set forth below.

Compounds of formula (S) may be prepared according to methods known in the art and the methods disclosed herein. For example, a compound of formula (H) can be converted to a compound of formula (S) in a manner substantially similar to that of converting a compound of formula (D) to a compound of formula (E) disclosed herein.

Compounds of formula (T) may be prepared according to methods known in the art and the methods disclosed herein. For example, the compound of formula (S) and the compound of formula BrCH ₂ COR ⁵ may be dissolved in a suitable solvent in the presence of an iodine anion to obtain a compound of formula (T). Suitable solvents include but are not limited to toluene, dimethylformamide, methylene chloride, tetrahydrofuran, diethyl ether, acetonitrile and the like. Acetonitrile is a preferred solvent. Suitable sources of iodine anions are, but are not limited to, iodine salts such as sodium iodide, potassium iodide and ammonium iodide and the like. Sodium iodide is the preferred source of iodine anions. Compounds of formula BrCH ₂ COR ⁵ are generally used in significant molar excesses. For example, an excess of about 2 to 10 moles of the compound of formula (S) is generally used. 3.7 molar excess is typically preferred. Iodine anions are commonly used in significant molar excesses. For example, an excess of about 2 to 10 moles of the compound of formula (S) is generally used. A 3.8 molar excess is typically preferred. The reaction is preferably carried out for about 40 hours at the reflux temperature of the solvent.

Compounds of formula (U) can be prepared by methods known in the art and by the methods disclosed herein. For example, the compound of formula (T), aminonitrile and base can be mixed and dissolved in a suitable solvent to obtain a compound of formula (U). Suitable solvents include but are not limited to toluene, dimethylformamide, methylene chloride, tetrahydrofuran, diethyl ether, acetonitrile and the like. Acetonitrile is the preferred solvent. Suitable bases include, but are not limited to, carbonates, hydroxides, and the like. Potassium carbonate is the preferred base. Aminonitrile is generally used in some molar excess. For example, it is generally used in about 1 to 1.05 molar excess relative to the compound of formula (T). A 1.02 molar excess is typically preferred. Bases are generally used in significant molar excess. For example, about 2 to 5 molar excess is generally used for the compound of formula (T). A 3.05 molar excess is typically preferred. The reaction is typically carried out preferably for about 14 hours at the reflux temperature of the solvent.

Compounds of formula (I) wherein A ′ is S (O) _n R ⁵ can be prepared according to the methods shown in Scheme VI shown below.

Compounds of formula (W) can be prepared by methods known in the art and by the methods disclosed herein. For example, a compound of formula (V) may be converted to a compound of formula (W) in a manner substantially similar to that of converting a compound of formula (D) to a compound of formula (E) described in the above range.

Compounds of formula (X) may be prepared by methods known in the art and by the methods disclosed herein. For example, the compound of formula (W) may be dissolved in a suitable solvent and the iodide may be added to obtain the compound of formula (X). Suitable solvents include but are not limited to toluene, dimethylformamide, methylene chloride, tetrahydrofuran, diethyl ether, acetonitrile and the like. Acetonitrile is the preferred solvent. Suitable iodide agents are, but are not limited to, iodine molecules, N-iodosuccinimides, and the like. N-iodosuccinimide is the preferred iodide agent. Iodide agents are generally and preferably used in stoichiometric or equimolar amounts relative to the compound of formula (W). The reaction is preferably carried out at about 0 ° C for about 15 minutes.

Compounds of formula (Y) can be prepared by methods known in the art and by the methods disclosed herein. For example, suitably substituted sulfides may be reacted with imidazopyridyl anions or anion equivalents by methods known in the art. Suitable sulfides include, but are not limited to, symmetric sulfides, asymmetric disulfides and thiol-sulfonates. Thiol sulfonates are known in the art and described in J. Am. Chem. Soc. 1977, 4405, which may be prepared from generally commercially available disulfides.

Compounds of formula (Y) can be prepared from compounds of formula (X) by methods known in the art and by the methods disclosed herein. For example, metal-halogen exchange reactions with compounds of formula (X) are performed substantially similarly to those described above in the preparation of compounds of formula (H), followed by addition of suitably substituted sulfides. The skilled practitioners, in contrast to the preparation of phenyl anions used to produce compounds of formula (H) (without acid protons), have analogous compounds of formula (X) having 1 acid proton and therefore must be deprotonated with a base only Halogen exchange reactions can be carried out. Suitable bases include, but are not limited to, lithium molecules, alkyllithium, lithium amines such as lithium diisopropylamine, lithium hydride and the like. Phenyllithium is the preferred base. t-butyllithium is a preferred preferred source of metal. Suitable solvents include, but are not limited to toluene, dimethylformamide, methylene chloride, acetonitrile, diethyl ether, tetrahydrofuran and the like. Tetrahydrofuran is the preferred solvent. Bases are generally used in slight to significant molar excess. For example, about 1.5 to 3 molar excess is generally used for the compound of formula (X). A 2.2 molar excess is typically preferred. Metals are used in slight to significant molar excesses. For example, about 1.5 to 3 molar excess is generally used for the compound of formula (X). A 2.5 molar excess is typically preferred. The reaction is preferably carried out at about −78 ° C. for about 3 minutes after the addition of the base, for about 10 minutes after the addition of the metal source, and for about 30 minutes after the addition of the sulfide.

Alternatively, compounds of formula (Y) can be prepared from compounds of formula (X), imidazopyridyl anion equivalents, under Ullmann-like binding conditions. See Synthesis, 9-21 (1974), published on the Ulman reaction. For example, the compound of formula (X) can be dissolved in a suitable solvent, and a suitably substituted sulfide can be added to which a copper source can be 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 sources of copper are, but are not limited to, copper molecules, copper oxide (I), and the like. Bronze copper or copper powder is a preferred source. Copper is generally used in a slight to significant molar excess. For example, about 1.2 to 3 molar excess is generally used for the compound of formula (X). A 1.5 molar excess is typically preferred. Sulphides are generally used with slightly molar differences. For example, about 50 to 95 mol% is generally used for the compound of formula (X). 78 mol% is typically preferred. The reaction is preferably carried out at about 100 ° C for about 80 hours.

Alternatively, the compound of formula (Y) may be prepared using the palladium catalyzed crosslinking reaction between the compound of formula (X) and substituted trimethyl-thio-tin (ie, R ⁴ S-Sn (alkyl) ₃ ). It can be prepared from the compound of X). Synth. Commun, 22, (5), p. 683, (1992).

Compounds of formula (Z) may be prepared by the oxidation of compounds of formula (Y) by methods known in the art and by methods disclosed herein. A general view of sulfide to sulfone oxidation is described in Comprehensive Organic Synthesis, Volume 7, Ch. 6.2, pg. 762, Pergamon Press, Inc. New York, (1991).

Those skilled in the art will understand that, although not required, there may be advantages in removing the trifluoroacetyl protecting groups found in the above schemes from various aspects in the synthesis of the compounds of the present invention. Removal of such protecting groups can be accomplished by methods known in the art and by the methods disclosed herein. For example, the trifluoroacetyl group may be dissolved by dissolving the compound of formula (D), (E), (V), (W), (X), (Y) or (Z) in a suitable solvent to add a base. It can be removed by obtaining the corresponding deprotected product. Suitable bases include, but are not limited to, hydroxides, carbonates, amines, and the like. Preferred base is diisopropylethylamine. Alternatively, the protecting group may be hydrolyzed on the silica gel support. See Greene T.W., Protective Groups in Organic Synthesis, John Wiley & Sons (1981).

In general, the reactions of Schemes I-VI terminate substantially within about 15 minutes to 72 hours when carried out at -78 ° C to the reflux temperature of the reaction mixture. The skilled person will generally understand that the reaction rate increases with increasing temperature. This is not necessary, but it is advantageous to carry out the reaction at a low rate in order to better control the number and amount of by-products produced. The choice of reaction solvent is not critical if the solvent used is inert to the reaction to be carried out in the future and the reactants are sufficiently dissolved to carry out the desired reaction. Once the reaction is complete, the intermediate compound can be isolated according to methods known in the art, if necessary. For example, the compound may be crystallized and then collected by filtration, or the reaction solvent may be removed by extraction, evaporation or decantation. The intermediate may be further purified by conventional techniques such as recrystallization or chromatography on a solid support such as silica gel or alumina, if desired. The compounds of the formulas A to Z are preferably isolated and then used in the next reaction.

Preparation Examples and Examples

The following preparations and examples further illustrate certain aspects of the invention. However, it will be understood that these embodiments are merely illustrative and are not intended to limit the scope of the invention in any aspect.

Compounds used as starting starting materials in the synthesis of compounds of the invention are known in the art and are readily synthesized by standard methods commonly used in the art, in amounts not commercially available.

Those skilled in the art will understand that in carrying out the methods described above, it is desirable to introduce chemical protecting groups into the reactants to prevent the occurrence of secondary reactions. For example, amines, alcohols, alkylamines or carboxyl groups that may be present in the reactants may be protected using any standard protecting group that does not adversely affect the residues of the molecule that can react in the desired manner. Various protecting groups can be removed simultaneously or sequentially using methods known in the art.

Cis and trans forms of the compounds of the invention can be separated using column chromatography, for example reverse phase HPLC. The compound can be eluted from a column with a suitable ratio of acetonitrile and water or methanol and water.

In the following Preparation Examples and Examples, the term melting point, nuclear magnetic resonance spectrum, electron collision mass spectrometer, magnetic field emission mass spectrum, high-speed atomic impact mass spectrum, high resolution mass spectrum, infrared spectrum, ultraviolet spectrum, elemental analyzer, high performance liquid chromatography Chromatography, thin layer chromatography, nitrogen, water, ethyl acetate, ethyl ether, dichloromethane, dimethylformamide, chloroform, methanol, ethanol, acetonitrile, tetrahydrofuran, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sulfuric acid, hydrobromic acid, Hydrochloric acid, ammonium hydroxide, sodium sulfite, sodium bisulfite, sodium nitrite, sodium sulfate, saturated sodium chloride, sodium bromide, ammonium chloride, magnesium sulfate, sodium acetate and room temperature are "mp", "NMR", "EIMS", "MS" (FD) "," MS (FAB) "," MS (HR) "," IR "," UV "," Analysis "," HPLC "and" TLC "," N ₂ "," Water "," EtOAc ", "E ₂ 0", "CH ₂ Cl ₂ ", "DMF", "CHCl ₃ ", "MeOH", "EtOH", "CH ₃ CN", "THF", "NaOH", "KOH", "NaHCO ₃ "," H ₂ SO ₄ "," HBr "," HCl "," NH ₄ OH "," Na ₂ SO ₃ "," NaHSO ₃ "," NaNO ₂ "," Na ₂ SO ₄ "," Bromium "," NaBr "," NH ₄ Cl "," MgSO ₄ "," NaOAc "and" RT ". Unless indicated otherwise, values reported in MS (FD) correspond to mass numbers. Thus, the maximum absorption listed for the IR spectrum is for those of interest, not for all observed maximums.

NMR spectra were purchased from Bruker. 300 MHz machine on 270 MHz machine or General Electric QE-300. Chemical shifts are expressed as delta (δ) values (parts per million downfield from tetramethylsilane). MS (FD) spectra were obtained with a dispersion-MAT 731 spectrometer using carbon dendrite emitters. EIMS spectra were obtained on a CEC 21-110 machine from Consolidated Electrodynamics Corporation. IR spectra were obtained on a Perkin-Elmer 281 machine. UV spectra were obtained on a Cary 118 machine. TLS this. Performed on E. Merck silica gel plates. Melting point was not accurate.

In combining by NMR spectrum, the following abbreviations were used. "s" is singlet, "d" is doublet, "dd" is doublet of doublet, "t" is triplet, "q" is quartet, "m" is multiline, "dm" is doublet of multiline "br.s", "br.d" and "br.m" are broad singlet, doublet, triplet and multiline, respectively, "J" represents the coupling constant in hertz (Hz). Unless otherwise noted, NMR data refer to the free base of the compound of interest.

The terms "MS", "analytical", "IR", "UV" and "NMR" used in the preparation examples indicate that the corresponding mass spectrum, elemental analysis, infrared spectrum, ultraviolet spectrum and nuclear magnetic resonance spectrum consist of the desired product. Indicates.

Preparation Example 1

2-chloro-5-benzoylpyridine

Ammonium chloride (100 g, 0.730 mol) was suspended in 200 mL of benzene under N ₂ . A solution of 6-chloronicotinoyl chloride in 100 mL of benzene (53 g, 0.30 mol) was added and the suspension was stirred rapidly and then refluxed overnight. The reaction was cooled to RT, 1 L EtOAc was added and the pH was adjusted to 8.5 with 5 N NaOH. Aluminum was precipitated and filtered off. The filtrate was washed with water, dried over Na ₂ SO ₄ and concentrated in vacuo. The resulting tan solid was recrystallized from 3: 2 Et ₂ O: hexane to give 54.6 g (83%) of the product as tan crystals. EA, MS (FD).

Preparation Example 2

2-chloro-5- (4-fluorobenzoyl) pyridine

Fluorobenzene (150 mL, 1.60 mmol) and 6-chloronicotinoyl chloride (17.7 g, 100 mmol) were converted to the product in a manner substantially similar to Preparation Example 1 to give 15.2 g (66.1%). EA, MS (FD), NMR.

Preparation Example 3

2-amino-5-benzoylpyridine

2-chloro-5-benzoylpyridine (100 g, 0.460 mol) was dissolved in 500 mL of 3A EtOH and 400 mL of anhydrous ammonia, left in a spray bomb and heated at 145 ° C. for 16 hours. The solvent was removed in vacuo and the residual tan solid was recrystallized from EtOH / water to give 77.4 g (85%) of the product as a tan solid. EA, MS (FD).

Preparation Example 4

2-amino-5- (4-fluorobenzoyl) pyridine

2-chloro-5- (4-fluorobenzoyl) pyridine (59.1 g, 251 mmol) was converted to the product in a manner substantially similar to Preparation Example 3 to give 35.4 g (65.3%). EA, MS (FD).

Preparation Example 5

1,2-dihydro-2-toluenesulfonimido-5-benzoylpyridine

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

Preparation Example 6

1,2-dihydro-2-toluenesulfonimido-5- (4-fluorobenzoyl) pyridine

2-amino-5- (4-fluorobenzoyl) pyridine (35.0 g, 162 mmol) was converted in a substantially similar manner to Preparation 5 to give 47.7 g (79.6%). MA (FD), NMR.

Preparation Example 7

α-bromo- (4-fluorophenyl) acetic acid

4-fluorophenylacetic acid (20 g, 0.13 mol), benzoyl peroxide (130 mg, 0.540 mmol) and N-bromosuccinimide (23.1 g, 0.130 mol) were mixed in 500 mL of carbon tetrachloride under nitrogen and UV Reflux under irradiation (GE solar lamp) for 5 hours. The reaction was cooled to RT and the succinimide was removed by filtration. Carbon tetrachloride was removed under vacuum to recrystallize the residual oil from hexanes to give 26.2 g (87%) of the product as a light yellow solid. EA, MS (FD).

Preparation Example 8

α-bromo- (4-methoxyphenyl) acetic acid

4-methoxyphenylacetic acid (25.0 g, 150 mmol) was converted to the product in a manner substantially similar to Preparation Example 7 to give 36.6 g (100%). MS (FD), NMR.

Preparation Example 9

α-bromo- (naphth-2-yl) -acetic acid

(Naf-2-yl) acetic acid (37.2 g, 200 mmol) was converted to the product in a manner substantially similar to Preparation 7 to give 34.5 g (65%). MS (FD), NMR.

Preparation Example 10

α-bromo-naphthyl acetic acid

Naphthylacetic acid (37.2 g, 200 mmol) was converted to the product in a manner substantially similar to Preparation 7 to give 32.4 g (60.8%). MS (FD), NMR.

Preparation Example 11

α-bromo- (2-fluorophenyl) acetic acid

(2-fluorophenyl) acetic acid (19.9 g, 129 mmol) was converted to the product in a manner substantially similar to Preparation 7 to give 24.0 g (79.9%).

Preparation Example 12

α-bromo- (3-fluorophenyl) acetic acid

(3-fluorophenyl) acetic acid (20.0 g, 130 mmol) was converted to the product in a manner substantially similar to Preparation 7 to give 24.3 g (80.0%).

Preparation Example 13

α-bromo- (2,4-difluorophenyl) acetic acid

2,4-difluorophenylacetic acid (21.3 g, 124 mmol) was converted to the product in a manner substantially similar to Preparation 7 to give 24.8 g (79.5%). NMR.

Preparation Example 14

α-bromo- (3,5-difluorophenyl) acetic acid

(3,5-difluorophenyl) acetic acid (20.4 g, 118 mmol) was converted to the product in a manner substantially similar to Preparation 7 to give 21.0 g (70.9%). NMR.

Preparation Example 15

α-bromo- (2,5-difluorophenyl) acetic acid

(2,5-difluorophenyl) acetic acid (20.5 g, 119 mmol) was converted to the product in a manner substantially similar to Preparation Example 7 to give 27.3 g (91.0%). NMR.

Preparation Example 16

α-bromo- (3-trifluoromethylphenyl) acetic acid

(3-trifluoromethylphenyl) acetic acid (20 g, 90 mmol) was converted to the product in a manner substantially similar to Preparation 7 to give 27.7 g (100%). NMR.

Preparation Example 17

α-bromo- (4-bromophenyl) acetic acid

(4-Bromophenyl) acetic acid (25.8 g, 120 mmol) was converted to the product in substantially the same manner as in Preparation 7 to give 30.2 g (85.7%). NMR.

Preparation Example 18

α-bromo- (2,3,4-trifluorophenyl) acetic acid

(2,3,4-trifluorophenyl) acetic acid (9.55 g, 50.3 mmol) was converted to the product in a manner substantially similar to that of Preparation 7 to give 13.5 g (100%). NMR

Preparation Example 19

α-bromo- (3,4-difluorophenyl) acetic acid

(3,4-difluorophenyl) acetic acid (15.2 g, 88.2 mmol) was converted to the product in a manner substantially similar to Preparation 7 to give 22.2 g (100%). NMR

Preparation Example 20

α-bromo- (3,4-difluorophenyl) acetic acid

(3,4-difluorophenyl) acetic acid (25.0 g, 122 mmol) was converted to the product in a manner substantially similar to Preparation 7 to give 34.6 g (100%). NMR

Preparation Example 21

α-bromo- (2,4,5-trifluorophenyl) acetic acid

(2,4,5-trifluorophenyl) acetic acid (9.56 g, 50.3 mmol) was converted to the product in a manner substantially similar to that of Preparation Example 1 to give 13.6 g (100%). NMR

Preparation Example 22

α-bromo- (2-chlorophenyl) acetic acid

(2-Chlorophenyl) acetic acid (25.3 g, 148 mmol) was converted to the product in substantially the same manner as in Preparation 7 to give 22.8 g (62.0%). NMR

Preparation Example 23

α-bromo- (3-chlorophenyl) acetic acid

(3-chlorophenyl) acetic acid (20.9 g, 123 mmol) was converted to the product in a manner substantially similar to that of Preparation 7 to give 30.5 g (100%). NMR

Preparation Example 24

α-bromo- (4-chlorophenyl) acetic acid

(4-chlorophenyl) acetic acid (25.0 g, 147 mmol) was converted to the product in a manner substantially similar to Preparation 7 to give 21.7 g (60.0%). NMR

Preparation Example 25

α-bromo- (4-trifluoromethoxyphenyl) acetic acid

(4-Trifluoromethoxyphenyl) acetic acid (9.91 g, 45.1 mmol) was converted to the product in a manner substantially similar to Preparation 7 to give 13.5 g (100%). NMR

Preparation Example 26

α-bromo- (3-trifluoromethoxyphenyl) acetic acid

(3-Trifluoromethoxyphenyl) acetic acid (9.75 g, 44.3 mmol) was converted to the product in a manner substantially similar to Preparation Example 7, giving 13.3 g (100%). NMR

Preparation Example 27

α-bromo- (2-fluoro-4-trifluoromethylphenyl) acetic acid

(2-Fluoro-4-trifluoromethylphenyl) acetic acid (9.56 g, 43.1 mmol) was converted to the product in a manner substantially similar to Preparation 7 to give 13.0 g (100%). NMR

Preparation Example 28

α-bromo- (2-methoxyphenyl) acetic acid

(2-methoxyphenyl) acetic acid (25.0 g, 150 mmol) was converted to the product in a manner substantially similar to Preparation 7 to give 26.5 g (72%). MS (FD), NMR

Preparation Example 29

α-bromo- (4-nitrophenyl) acetic acid

(4-nitrophenyl) acetic acid (25.5 g, 141 mmol) was converted to the product in a manner substantially similar to Preparation 7 to give 36.6 g (100%). NMR

Preparation Example 30

α-bromo- (3-thienyl) acetic acid

(Thiophen-3-yl) mandelic acid (8.60 g, 54.4 mmol) was dissolved in 30% HBr in 100 mL of acetic acid. The solution was stirred for 18 h at RT. The clear black solution was poured into 2.5 L of ice water and immediately extracted with Et ₂ O (4 × 400 mL). The ether was dried over Na ₂ S0 ₄ and treated with bleached carbon. Et ₂ O was evaporated and the residue was azeotropic with toluene to remove residual acetic acid. The crude solid product was recrystallized from hexanes to give 9.07 g (75%). EA, MS (FD).

Preparation Example 31

α-bromo-benzylacetic acid

NaNO _{2 in} a solution of L-phenylalanine (55.0 g, 330 mmol) and NaBr (130 g, 1.09 mol) dissolved in 550 mL of 3N H ₂ SO ₄ cooled at 0 ° C. was maintained at a reaction temperature of 0-5 ° C. (32.0 g, 469 mmol) was added slowly. Stirring was continued at about 0 ° C. for 1 hour and then at RT for 1.5 hours. The mixture was extracted with Et ₂ O (4 × 300 mL). Et ₂ O was washed with brine (2 × 500 mL), dried over MgSO ₄ and removed in vacuo. The residue was recrystallized from 50 mL of cyclohexane to give phenylalanine starting material as crystals. The solid was filtered off and the filtrate was concentrated in vacuo to yield 64 g of crude product which was used without further purification (84.7%).

Preparation Example 32

α-bromo- (4-fluorophenyl) acetamide

Α-bromo- (4-fluorobenzyl) acetic acid (26.1 g, 112 mmol) and 3 drops of DMF in 175 mL of anhydrous CH ₂ Cl ₂ were cooled in an ice bath under nitrogen. Oxalyl chloride (25.0 g, 224 mmol) in 25 mL of anhydrous CH ₂ Cl ₂ was added dropwise for 25 minutes. The ice bath was removed and the reaction stirred for 3 hours. The solvent was removed in vacuo and then azeotropic with toluene (3 × 25 mL). The residual oil was dissolved in 300 mL of toluene and 300 mL of hexane and stirred vigorously with a mechanical stirrer. Thereafter, ammonia gas was introduced into the upper layer of this solution through the gas dispersion tube for 1 hour. The resulting solid was filtered off and the solvent was removed in vacuo. The solid was dissolved in EtOAc / water and the organic layer was washed with 1N HCl, saturated with NaHCO ₃ , brine and dried over Na ₂ SO ₄ . Na ₂ S0 ₄ was filtered and EtOAc was removed in vacuo. The residual solid was recrystallized from EtOAc / hexanes to give 19.6 g (75%) of the desired product. MS (FD), NMR.

Preparation Example 33

α-bromo- (4-methoxyphenyl) acetamide

α-bromo- (4-methoxyphenyl) acetic acid (36.6 g, 150 mmol) was converted to the product in a manner substantially similar to Preparation 32 to give 13.5 g (37%). MS (FD), NMR.

Preparation Example 34

α-bromo- (naphth-2-yl) phenylacetamide

α-bromo- (naphth-2-yl) acetic acid (34.5 g, 130 mmol) was converted to the product in a manner substantially similar to Preparation 32 to give 11.5 g (33.5%). EA, MS (FD).

Preparation 35

α-bromo-naphthylacetamide

α-bromo-naphthylacetic acid (32.4 g, 122 mmol) was converted to the product in a substantially similar manner as Preparation Example 32 to give 14.6 g (46%). MS (FD), NMR.

Preparation Example 36

α-bromo- (2-fluorophenyl) acetamide

α-bromo- (2-fluorophenyl) acetic acid (24.0 g, 103 mmol) was converted to the product in a manner substantially similar to Preparation Example 32 to give 14.0 g (60%). MS (FD), NMR.

Preparation Example 37

α-bromo- (3-fluorophenyl) acetamide

α-bromo- (3-fluorophenyl) acetic acid (24.3 g, 104 mmol) was converted to the product in a manner substantially similar to Preparation Example 32 to give 16.3 g (67.0%). MS (FD), NMR.

Preparation Example 38

α-bromo- (2,4-difluorophenyl) acetamide

α-bromo- (2,4-difluorophenyl) acetic acid (23.3 g, 93.0 mmol) was converted to the product in a manner substantially similar to Preparation Example 32 to yield 7.88 g (34.3%). NMR.

Preparation Example 39

α-bromo- (3,5-difluorophenyl) acetamide

α-bromo- (3,5-difluorophenyl) acetic acid (21.0 g, 83.8 mmol) was converted to the product in a manner substantially similar to Preparation 32 to give 14.4 g (68.7%). NMR.

Preparation Example 40

α-bromo- (2,5-difluorophenyl) acetamide

α-bromo- (2,5-difluorophenyl) acetic acid (27.3 g, 109 mmol) was converted to the product in a manner substantially similar to Preparation 32 to give 18.5 g (68.0%). MS (FD), NMR.

Preparation Example 41

α-bromo- (3-trifluoromethylphenyl) acetamide

α-bromo- (3-trifluoromethylphenyl) acetic acid (27.7 g, 98.0 mmol) was converted to the product in a manner substantially similar to Preparation Example 32 to give 14.2 g (51.4%). MS (FD), NMR.

Preparation Example 42

α-bromo- (4-bromophenyl) acetamide

α-bromo- (4-bromophenyl) acetic acid (30.2 g, 103 mmol) was converted to the product in a manner substantially similar to Preparation Example 32 to give 23.5 g (78.1%). MS (FD), NMR.

Preparation Example 43

α-bromo- (2,3,4-trifluorophenyl) acetamide

α-bromo- (2,3,4-trifluorophenyl) acetic acid (13.5 g, 50.3 mmol) was converted to the product in a manner substantially similar to Preparation 32 to give 10.2 g (75.7%). MS (FD), NMR.

Preparation Example 44

α-bromo- (3,4-difluorophenyl) acetamide

α-bromo- (3,4-difluorophenyl) acetic acid (22.2 g, 88.0 mmol) was converted to the product in a manner substantially similar to Preparation Example 32 to yield 7.88 g (35.7%). MS (FD), NMR.

Preparation Example 45

α-bromo- (3,4-dichlorophenyl) acetamide

α-bromo- (3,4-dichlorophenyl) acetic acid (34.6 g, 122 mmol) was converted to the product in a manner substantially similar to Preparation Example 32 to give 11.8 g (34.2%). MS (FD), NMR.

Preparation Example 46

α-bromo- (2,4,5-trifluorophenyl) acetamide

α-bromo- (2,4,5-trifluorophenyl) acetic acid (13.6 g, 50.3 mmol) was converted to the product in a manner substantially similar to Preparation 32 to yield 7.34 g (54.4%). NMR.

Preparation 47

α-bromo- (2-chlorophenyl) acetamide

α-bromo- (2-chlorophenyl) acetic acid (22.8 g, 91.7 mmol) was converted to the product in a manner substantially similar to Preparation 32 to give 17.5 g (77%). MS (FD), NMR.

Preparation Example 48

α-bromo- (3-chlorophenyl) acetamide

α-bromo- (2-chlorophenyl) acetic acid (30.5 g, 123 mmol) was converted to the product in a manner substantially similar to Preparation Example 32 to obtain 17.8 g (59%). MS (FD), NMR.

Preparation 49

α-bromo- (4-chlorophenyl) acetamide

α-bromo- (4-chlorophenyl) acetic acid (21.7 g, 86.9 mmol) was converted to the product in a manner substantially similar to Preparation 32 to give 15.7 g (73%). MS (FD), NMR.

Preparation 50

α-bromo- (4-trifluoromethoxyphenyl) acetamide

α-bromo- (4-trifluoromethoxyphenyl) acetic acid (13.5 g, 45.1 mmol) was converted to the product in a manner substantially similar to Preparation 32 to give 11.1 g (83%). MS (FD), NMR.

Preparation Example 51

α-bromo- (3-trifluoromethoxyphenyl) acetamide

α-bromo- (3-trifluoromethoxyphenyl) acetic acid (13.3 g, 44.3 mmol) was converted to the product in a manner substantially similar to Preparation Example 32 to yield 9.43 g (71%). MS (FD), NMR.

Preparation Example 52

α-bromo- (2-fluoro-4-trifluoromethylphenyl) acetamide

α-bromo- (2-fluoro-4-trifluoromethylphenyl) acetic acid (13.0 g, 43.1 mmol) was converted to the product in a manner substantially similar to Preparation 32 to give 11.1 g (86%). MS (FD), NMR.

Preparation Example 53

α-bromo-phenylacetamide

α-bromo-phenylacetic acid (21.5 g, 100 mmol) was converted to the product in a manner substantially similar to Preparation Example 32 to give 16.8 g (78%). NMR.

Preparation Example 54

α-bromo- (thiophen-3-yl) acetamide

α-bromo- (thiophen-3-yl) acetic acid (9.07 g, 41.0 mmol) was converted to the product in substantially the same manner as in Preparation 32 to give 6.50 g (72.0%). MS, MP.

Preparation Example 55

α-bromo- (2-methoxyphenyl) acetamide

α-bromo- (2-methoxyphenyl) acetic acid (26.5 g, 108 mmol) was converted to the product in a manner substantially similar to Preparation 32 to give 21.6 g (82.0%). NMR.

Preparation Example 56

α-bromo-isobutylacetamide

α-bromo- (4-methyl) pentanoic acid (35.0 g, 179 mmol) was converted to the product in a manner substantially similar to that of Preparation 32 to give 20.9 g (60.1%). EA, MS (EI).

Preparation Example 57

α-bromo-benzylacetamide

α-bromo-benzylacetic acid (64.0 g, 279 mmol) was converted to the product in a manner substantially similar to Preparation Example 32 to give 22.5 g (35.4%). EA, MS (FD).

Preparation 58

α-bromo- (4-nitrophenyl) acetamide

α-bromo- (4-nitrophenyl) acetic acid (36.6 g, 141 mmol) was converted to the product in a manner substantially similar to Preparation 32 to give 19.3 g (52.9%). NMR.

Preparation Example 59

2,6-difluoromandelic acid

2,6-difluorobenzaldehyde (25.0 g, 176 mmol) and zinc iodide (5.0 mg, 0.02 mmol) were placed in a 250 mL cedar round bottom flask, which was dried by flame under nitrogen. Trimethylsilyl cyanide (17.45 g, 176.0 mmol) was added dropwise for 20 minutes and the reaction stirred for 72 hours. 9N HCl (200 mL) was added and the solution was refluxed overnight. The reaction was cooled to RT and extracted with Et ₂ O. Et ₂ O was extracted with saturated NaHCO ₃ and then oxidized to pH 1 with 5N HCl. The oxidation solution was extracted with Et ₂ O and the organic layer was dried over Na ₂ SO ₄ . Na ₂ SO ₄ was filtered off and Et ₂ O was removed under vacuum to recrystallize the remaining white solid with CHCl ₃ to give 23.6 g (71%) of the product as a white solid. NMR, MS, IR, EA.

Preparation Example 60

2,3,4,5,6-pentafluoromandelic acid

2,3,4,5,6-pentafluorobenzaldehyde (49.4 g, 252 mmol) was converted to the product in a substantially similar manner to Preparation 59 to give 52.3 g (86.0%). EA, MS (FD).

Preparation Example 61

2-trifluoromethylmandelic acid

2-Trifluoromethylbenzaldehyde (43.9 g, 252 mmol) was converted to the product in a substantially similar manner as Preparation Example 59 to obtain 39.1 g (70.5%). EA, MS (FD).

Preparation Example 62

Thiophen-3-ylmandelic acid

Thiophen-3-ylcarboxaldehyde (28.3 g, 252 mmol) was converted to the product in a manner substantially similar to Preparation 59 to give 13.4 g (33.8%). EA, MS (FD).

Preparation Example 63

2-trifluoromethyl-4-fluoromandelic acid

2-trifluoromethyl-4-fluorobenzaldehyde (48.4 g, 252 mmol) was converted to the product in a substantially similar manner as Preparation Example 59 to give 50.1 g (84%). EA, MS (FD).

Preparation Example 64

2-fluoro-6-trifluoromethylmandelic acid

2-Fluoro-6-trifluoromethylbenzaldehyde (48.4 g, 252 mmol) was obtained in 49.7 g (84%) of the product in a manner substantially similar to that of Preparation Example 59. EA, MS (FD).

Preparation 65

4-carboxymandelic acid

4-cyanobenzaldehyde (33.0 g, 252 mmol) was converted to the product in a substantially similar manner as Preparation Example 59 to obtain 27.0 g (54.6%). MS (FD), NMR.

Preparation 66

α-O-acetyl- (2,6-difluorophenyl) acetic acid

30% HBr in acetic acid (150 mL) was added to 2,6-difluoromandelic acid (16.9 g, 89.9 mmol) in 50 mL of acetic acid and stirred overnight. The reaction was poured into 1.5 L of ice water and stirred for 1 hour. The aqueous solution was extracted with Et ₂ O, and the organic layer was dried over Na ₂ SO ₄ . Na ₂ SO ₄ was filtered off, and Et ₂ O was removed in vacuo and the remaining white solid was recrystallized from Et ₂ O / hexanes to give 18.54 g (90%) of the product as a white solid. EA, MS (FD).

Preparation Example 67

α-O-acetyl- (2,3,4,5,6-pentafluorophenyl) acetic acid

2,3,4,5,6-pentafluoromandelic acid (70.5 g, 291 mmol) was converted to the product in substantially the same manner as in Preparation 66 to give 82.8 g (100%) of the product. EA, MS (FD).

Preparation Example 68

α-O-acetyl- (2-trifluoromethylphenyl) acetic acid

2-Trifluoromethylmandelic acid (19.8 g, 90.0 mmol) was converted to the product in a manner substantially similar to Preparation 66 to give 20.8 g (88.0%) of the product. EA, MS (FD).

Preparation Example 69

α-O-acetyl- (2-trifluoromethyl-4-fluorophenyl) acetic acid

2-Trifluoromethyl-4-fluoromandelic acid (49.4 g, 208 mmol) was converted to the product in a manner substantially similar to Preparation 66 to give 58.1 g (100%) of the product. EA, MS (FD).

Preparation 70

α-O-acetyl- (2-fluoro-6-trifluoromethylphenyl) acetic acid

2-fluoro-6-trifluoromethylmandelic acid (48.4 g, 252 mmol) was converted to the product in a manner substantially similar to Preparation 66 to give 82.8 g (84%) of the product. EA, MS (FD).

Preparation Example 71

α-O-acetyl- (4-trifluoromethylphenyl) acetic acid

4-trifluoromethylmandelic acid (19.8 g, 89.9 mmol) was converted in a manner substantially similar to Preparation 66 to give 20.3 g (86%) of the product. MS (FD), NMR.

Preparation Example 72

α-O-acetyl- (4-carboxyphenyl) acetic acid

4-carboxymandelic acid (27.0 g, 138 mmol) was converted to the product in substantially the same manner as in Preparation 66 to give 27.5 g (83.9%) of product. MS (FD), NMR.

Preparation Example 73

α-O-acetyl- (2,6-difluorophenyl) acetamide

Α-O-acetyl- (2,6-difluorophenyl) acetic acid (18.5 g, 80.4 mmol) and 3 drops of DMF in 200 mL of anhydrous CH ₂ Cl ₂ were cooled in an ice bath under nitrogen. Oxalyl chloride (50.0 g, 448 mmol) in 50 mL of anhydrous CH ₂ Cl ₂ was added dropwise for 25 minutes. The ice bath was removed and the reaction stirred for 3 hours. The solvent was removed in vacuo and then azeotropic with toluene (3 × 25 mL). The residual oil was dissolved in 100 mL of toluene and 700 mL of hexane and stirred vigorously with a mechanical stirrer. Thereafter, ammonia gas was blown into the upper layer of this solution through a gas dispersion tube for 1 hour. The resulting solid was filtered off and the solvent was removed in vacuo. The solid was dissolved in EtOAc / water and the organic layer was washed with 1N HCl, saturated NaHCO ₃ , brine and then dried over Na ₂ SO ₄ . Na ₂ S0 ₄ was filtered and EtOAc was removed in vacuo. The remaining solid was recrystallized from EtOAc / hexanes to give 16.7 g (90%) of the desired product.

Preparation Example 74

α-O-acetyl- (2,3,4,5,6-pentafluorophenyl) acetamide

94.0 g (89%) of α-O-acetyl- (2,3,4,5,6-pentafluorophenyl) acetic acid (106 g, 373 mmol) was converted to the product in a substantially similar manner as in Preparation 73 The product of was obtained. EA, MS (FD).

Preparation 75

α-O-acetyl- (2-trifluoromethylphenyl) acetamide

α-O-acetyl- (2-trifluoromethylphenyl) acetic acid (20.8 g, 79.4 mmol) was converted to the product in substantially the same manner as in Preparation 73 to give 18.8 g (90.7%) of product. EA, MS (FD).

Preparation Example 76

α-O-acetyl- (2-trifluoromethyl-4-fluorophenyl) acetamide

52.4 g (90.0%) of the product was converted to α-O-acetyl- (2-trifluoromethyl-4-fluorophenyl) acetic acid (58.1 g, 208 mmol) into a product in substantially the same manner as in Preparation 73 Got. EA, MS (FD).

Preparation Example 77

α-O-acetyl- (2-fluoro-6-trifluoromethylphenyl) acetamide

α-O-acetyl- (2-fluoro-4-trifluoromethylphenyl) acetic acid (53.4 g, 191 mmol) was converted to the product in substantially the same manner as in Preparation 73 to obtain 47.9 g (90%) of the product. Got it. EA, MS (FD).

Preparation Example 78

α-O-acetyl- (4-trifluoromethylphenyl) acetamide

α-O-acetyl- (4-trifluoromethylphenyl) acetic acid (20.3 g, 77.3 mmol) was converted to the product in substantially the same manner as in Preparation 73 to give 18.8 g (93%) of the product.

Preparation Example 79

Methyl- (α-hydroxy-4-carbomethoxybenzyl) acetate

α-O-acetyl- (4-carboxyphenyl) acetic acid (23.2 g, 97.3 mmol) was suspended in 300 mL of CH ₂ Cl ₂ and 3 drops of DMF were added while stirring the reaction under nitrogen in an ice bath. Oxalyl chloride (50.0 g, 448 mmol) in 50 mL of anhydrous CH ₂ Cl ₂ was added dropwise for 20 minutes. The ice bath was removed and the reaction stirred at RT for about 5 hours (until the solution was all solid). The solvent was removed and the residue and 200 mL of MeOH were added to the addition funnel and stirred overnight. The solvent is then removed and the residue is dissolved in EtOAc. EtOAc was washed with NaHCO ₃ (3 × 100 mL), brine and then dried over NaSO ₄ . EtOAc was removed in vacuo to give 22 g of oil (100%). EA, MS (FD).

Preparation Example 80

α-hydroxy- (2,6-difluorophenyl) acetamide

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

Preparation Example 81

α-hydroxy- (2,3,4,5,6-pentafluorophenyl) acetamide

66.6 g (94%) of α-O-acetyl- (2,3,4,5,6-pentafluorophenyl) acetamide (83.0 g, 293 mmol) was converted to the product in a manner substantially similar to that of Preparation Example 80. ) Product. EA, MS (FD).

Preparation Example 82

α-hydroxy- (2-trifluoromethylphenyl) acetamide

α-O-acetyl- (2-trifluoromethylphenyl) acetamide (18.4 g, 70.6 mmol) was converted to the product in substantially the same manner as in Preparation 80 to give 14.3 g (92.4%) of product. MS (FD), NMR.

Preparation Example 83

α-hydroxy- (2-trifluoromethyl-4-fluorophenyl) acetamide

40.9 g (95%) of α-O-acetyl- (2-trifluoromethyl-4-fluorophenyl) acetamide (50.4 g, 181 mmol) was converted to the product in a manner substantially similar to that of Preparation Example 80. The product was obtained. EA, MS (FD).

Preparation Example 84

α-hydroxy- (2-fluoro-6-trifluoromethylphenyl) acetamide

32.1 g (85%) of α-O-acetyl- (2-fluoromethyl-6-trifluoromethylphenyl) acetamide (44.6 g, 160 mmol) was converted to the product in a manner substantially similar to that of Preparation Example 80. The product was obtained. EA, MS (FD).

Preparation Example 85

α-hydroxy- (4-trifluoromethylphenyl) acetamide

α-O-acetyl- (4-trifluoromethylphenyl) acetamide (18.8 g, 65.3 mmol) was converted to the product in substantially the same manner as in Preparation 80 to give 13.8 g (96.1%) of product. EA, MS (FD).

Preparation 86

α-hydroxy- (4-carbomethoxyphenyl) acetamide

Ammonia (300 mL) in freshly prepared methanol was added to methyl- (α-hydroxy-4-carbomethoxybenzyl) acetate (21.8 g, 97.3 mmol) and stirred overnight. The solvent was removed in vacuo and the residue was recrystallized from CH ₂ Cl ₂ to give 17.5 g of product (85.7%). EA, MS (FD).

Preparation 87

α-O-toluenesulfonylimido- (2,6-difluorophenyl) acetamide

α-hydroxy- (2,6-difluorophenyl) acetamide (9.80 g, 52.4 mmol), 4-dimethylaminopyridine (500 mg, 4.10 mmol) and diisopropylethylamine (10.04 ml, 57.6 mmol) Was mixed with 300 mL of anhydrous CH ₂ Cl ₂ under nitrogen. p-toluenesulfonyl chloride (11.0 g, 57.6 mmol) was added and the reaction stirred overnight. The solvent was removed in vacuo and the residual solid was dissolved in EtOAc. EtOAc was washed with 1N HCl, saturated NaHCO ₃ , brine and dried over Na ₂ SO ₄ . Na ₂ S0 ₄ was filtered and EtOAc was removed in vacuo to give a white solid. The solid was recrystallized from EtOAc / hexanes to give 15.8 g (88%) of the desired product as a white powder. EA, MS (FD).

Preparation Example 88

α-O-toluenesulfonylimido- (2,3,4,5,6-pentafluorophenyl) acetamide

18.3 g (92%) of α-hydroxy- (2,3,4,5,6-pentafluorophenyl) acetamide (12.1 g, 50.0 mmol) was converted to the product in a manner substantially similar to that of Preparation Example 87. Got as. EA, MS (FD).

Preparation Example 89

α-O-toluenesulfonylimido- (2-trifluoromethylphenyl) acetamide

α-hydroxy- (2-trifluoromethylphenyl) acetamide (14.3 g, 65.2 mmol) was converted to the product in substantially the same manner as in Preparation 87 to give 21.0 g (86%). EA, MS (FD).

Preparation 90

α-O-toluenesulfonylimido- (2-trifluoromethyl-4-fluorophenyl) acetamide

α-hydroxy- (2-trifluoromethyl-4-fluorophenyl) acetamide (11.9 g, 50.0 mmol) was converted to the product in substantially the same manner as in Preparation 87 to give 17.0 g (87%). . EA, MS (FD).

Preparation 91

α-O-toluenesulfonylimido- (2-fluoro-6-trifluoromethylphenyl) acetamide

α-hydroxy- (2-fluoro-4-trifluoromethylphenyl) acetamide (11.9 g, 50.0 mmol) was converted to the product in substantially the same manner as in Preparation 87 to give 17.8 g (91%). EA, MS (FD).

Preparation Example 92

α-O-toluenesulfonylimido- (4-trifluoromethylphenyl) acetamide

α-hydroxy- (4-trifluoromethylphenyl) acetamide (9.35 g, 42.7 mmol) was converted to the product in a substantially similar manner as Preparation Example 87 to give 12.7 g (80%). EA, MS (FD).

Preparation Example 93

α-O-toluenesulfonylimido- (4-carbomethoxyphenyl) acetamide

α-hydroxy- (4-carbomethoxyphenyl) acetamide (10.5 g, 50.0 mmol) was converted to the product in a manner substantially similar to Preparation Example 87 to give 14.6 g (80.2%). EA, MS (FD).

Preparation Example 94

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [2,4-difluorophenyl] -carbamoylmethyl) -pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) was dissolved in 75 mL of DMF and stirred in a flask dried with flame under nitrogen. Sodium hydride (1.32 g, 33.0 mmol) was added and the solution stirred for 1.5 h. Then α-bromo- (2,4-difluorophenyl) acetamide (7.88 g, 31.5 mmol) was added and the solution was stirred for 7 days at RT. The solution was poured into 2.5 L of water to terminate the reaction and stirred for 1 hour. The resulting precipitate was collected by filtration. The filter cake was recrystallized from EtOAc / hexanes to give 13.2 g (84%). EA, MS (FD).

Preparation Example 95

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [4-fluorophenyl] -carbamoylmethyl) -pyridine

Prepare 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (27.1 g, 77.0 mmol) and α-bromo- (4-fluorophenyl) acetamide (19.6 g, 84.5 mmol) 35.0 g (90.4%) were obtained by conversion to the product in substantially the same manner as in Example 94. EA, MS (FD).

Preparation Example 96

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [4-methoxyphenyl] -carbamoylmethyl) -pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and α-bromo- (4-methoxyphenyl) acetamide (8.05 g, 33.0 mmol) are fluorinated 6.32 g (41.0%) were obtained by conversion to the product in substantially the same manner as in Preparation 94 except that cesium was used instead of sodium hydride and sodium iodide (4.50 g, 30.0 mmol). EA, MS (FD).

Preparation Example 97

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [naphth-2-yl] -carbamoylmethyl) -pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (18.5 g, 52.7 mmol) and α-bromo- (naphth-2-yl) acetamide (14.6 g, 55.3 mmol) Conversion to the product in a manner substantially similar to Preparation 94 gave 15.0 g (53.3%). EA, MS (FD).

Preparation Example 98

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1-naphthyl-carbamoylmethyl) -pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (14.6 g, 41.5 mmol) and α-bromo- (naphth-1-yl) acetamide (11.5 g, 43.6 mmol) 14.3 g (64%) were obtained by conversion to the product in substantially the same manner as in Preparation 94. EA, MS (FD).

Preparation Example 99

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [2-fluorophenyl] -carbamoylmethyl) -pyridine

Prepare 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (12.3 g, 35.1 mmol) and α-bromo- (2-fluorophenyl) acetamide (8.54 g, 36.8 mmol) Conversion to the product in a manner substantially similar to Example 94 gave 16.5 g (93.6%). EA, MS (FD).

Preparation Example 100

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [3-fluorophenyl] -carbamoylmethyl) -pyridine

Prepare 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (23.6 g, 66.9 mmol) and α-bromo- (3-fluorophenyl) acetamide (16.3 g, 70.3 mmol) Conversion to the product in a manner substantially similar to Example 94 gave 29.8 g (88.5%). EA, MS (FD).

Preparation Example 101

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [3,5-difluorophenyl] -carbamoylmethyl) -pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and α-bromo- (3,5-difluorophenyl) acetamide (7.88 g, 31.5 mmol ) Was converted to the product in substantially the same manner as in Preparation 94 to give 14.2 g (91.0%). EA, MS (FD).

Preparation Example 102

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [2,5-difluorophenyl] -carbamoylmethyl) -pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and α-bromo- (2,5-difluorophenyl) acetamide (7.88 g, 31.5 mmol ) Was converted to the product in substantially the same manner as in Preparation 94 to give 15.3 g (98%). EA, MS (FD).

Preparation Example 103

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [3-trifluoromethylphenyl] -carbamoylmethyl) -pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and α-bromo- (3-trifluoromethylphenyl) acetamide (8.88 g, 31.5 mmol) Conversion to the product in a manner substantially similar to Preparation 94 gave 12.7 g (76%). EA, MS (FD).

Preparation Example 104

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [4-bromophenyl] -carbamoylmethyl) -pyridine

Prepare 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and α-bromo- (4-bromophenyl) acetamide (9.23 g, 31.5 mmol) Conversion to the product in substantially the same manner as in Example 94 gave 13.7 g (81%). EA, MS (FD).

Preparation Example 105

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [2,3,4-trifluorophenyl] -carbamoylmethyl) -pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and α-bromo- (2,3,4-trifluorophenyl) acetamide (8.44 g, 31.5 mmol) was converted to the product in a manner substantially similar to Preparation 94 to give 11.3 g (70%).

Preparation Example 106

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [3,4-difluorophenyl] -carbamoylmethyl) -pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and α-bromo- (3,4-difluorophenyl) acetamide (7.88 g, 31.5 mmol ) Was converted to the product in substantially the same manner as in Preparation 94 to give 9.53 g (61%). EA, MS (FD).

Preparation Example 107

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [3,4-dichlorophenyl] -carbamoylmethyl) -pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and α-bromo- (3,4-dichlorophenyl) acetamide (9.00 g, 31.5 mmol) Conversion to the product in a manner substantially similar to Preparation 94 gave 13.8 g (83%). EA, MS (FD).

Preparation Example 108

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [2,4,5-trifluorophenyl] -carbamoylmethyl) -pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (9.18 g, 26.1 mmol) and α-bromo- (2,4,5-trifluorophenyl) acetamide (7.34 g, 27.4 mmol) was converted to the product in a substantially similar manner as in Preparation 94 to give 11.6 g (83%). MS (FAB), NMR.

Preparation Example 109

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [2-chlorophenyl] -carbamoylmethyl) -pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and α-bromo-chlorophenylacetamide (7.83 g, 31.5 mmol) were substantially prepared in Preparation 94. Conversion to the product in a similar manner yielded 10.4 g (69%). EA, MS (FD).

Preparation 110

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [3-chlorophenyl] -carbamoylmethyl) -pyridine

Preparation of 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and α-bromo- (3-chlorophenyl) acetamide (7.83 g, 31.5 mmol) Conversion to the product in a manner substantially similar to 94 yielded 13.4 g (77%). EA, MS (FD).

Preparation Example 111

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [4-chlorophenyl] -carbamoylmethyl) -pyridine

Preparation of 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and α-bromo- (4-chlorophenyl) acetamide (7.81 g, 31.5 mmol) Conversion to the product in a manner substantially similar to 94 yielded 13.8 g (88%). EA, MS (FD).

Preparation Example 112

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [4-trifluoromethoxyphenyl] -carbamoylmethyl) -pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and α-bromo- (4-trifluoromethoxyphenyl) acetamide (9.83 g, 33.0 mmol) Was converted to the product in substantially the same manner as in Preparation 94 to give 13.2 g (77%). EA, MS (FD).

Preparation Example 113

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [3-trifluoromethoxyphenyl] -carbamoylmethyl) -pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and α-bromo- (3-trifluoromethoxyphenyl) acetamide (9.43 g, 31.6 mmol) Was converted to product in a manner substantially similar to Preparation Example 94 to give 12.5 g (73%). EA, MS (FD).

Preparation Example 114

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [2-fluoro-4-trifluoromethylphenyl] -carbamoylmethyl) -pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (7.04 g, 20.0 mmol) and α-bromo- (2-fluoro-4-trifluoromethylphenyl) acetamide (6.50 g , 21.7 mmol) was converted to the product in a substantially similar manner as in Preparation 94 to give 10.1 g (88%). EA, MS (FD).

Preparation Example 115

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1-phenyl-carbamoylmethyl) -pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and α-bromo-phenylacetamide (6.74 g, 31.5 mmol) were replaced with cesium fluoride instead of sodium hydride. Except for the use, conversion to the product was carried out in substantially the same manner as in Preparation Example 94 to give 13.3 g (91%). EA, MS (FD).

Preparation Example 116

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [4-trifluoromethylphenyl] -carbamoylmethyl) -pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.0 g, 28.5 mmol) and α-O-toluenesulfonylimido- (4-trifluoromethylphenyl) acetamide (11.1 g , 29.9 mmol) was converted to the product in a substantially similar manner as in Preparation 94 to give 13.9 g (88%). EA, MS (FD).

Preparation Example 117

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [2-fluoro-6-trifluoromethylphenyl] -carbamoylmethyl) -pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and α-O-toluenesulfonylimido- (2-trifluoromethyl-6-fluorophenyl Acetamide (12.9 g, 33.0 mmol) was converted to the product substantially similar to that of Preparation Example 94, except that diisopropylethylamine was used instead of sodium hydride and the reaction was carried out at 90 to 100 ° C. 2.90 g (16.9%) was obtained. MS (FD), NMR.

Preparation Example 118

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [2,3,4,5,6-pentafluorophenyl] -carbamoylmethyl) -pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (5.28 g, 15.0 mmol) and α-O-toluenesulfonylimido- (2,3,4,5,6-pentafluoro Rophenyl) acetamide (5.93 g, 15.0 mmol) was converted to product in substantially the same manner as in Preparation Example 94, except that cesium carbonate was used in place of sodium hydride and the reaction was carried out at 60 ° C. to 5.07 g ( 59%). EA, MS (FD).

Preparation Example 119

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [2,6-difluorophenyl] -carbamoylmethyl) -pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and α-O-toluenesulfonylimido- (2,6-difluorophenyl) acetamide ( 10.7 g, 31.5 mmol) was converted to the product in a manner substantially similar to Preparation Example 94 except that the reaction was carried out at 60 ° C, yielding 7.44 g (48%). EA, MS (FD).

Preparation Example 120

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [2-trifluoromethylphenyl] -carbamoylmethyl) -pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and α-O-toluenesulfonylimido- (2-trifluoromethylphenyl) acetamide (11.8 g , 31.5 mmol) was converted to the product in a manner substantially similar to Preparation Example 94 except that the reaction was carried out at 70 ° C., to obtain 7.37 g (44.4%). EA, MS (FD).

Preparation Example 121

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [thiophen-3-yl] -carbamoylmethyl) -pyridine]

1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (9.90 g, 28.1 mmol) and α-O-toluenesulfonylimido- (thiophen-3-yl) acetamide (6.50 g , 29.6 mmol) were converted to the product in a manner substantially similar to Preparation 94 to give 11.3 g (81.7%). EA, MS (FD).

Preparation Example 122

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [2-trifluoromethyl-4-fluorophenyl] -carbamoylmethyl) -pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and α-O-toluenesulfonylimido- (2-trifluoromethyl-6-fluorophenyl Acetamide (12.9 g, 33.0 mmol) was converted to the product in a manner substantially similar to Preparation Example 1, except that diisopropylethylamine was used instead of sodium hydride and the reaction was carried out at 50 to 60 ° C. g (84%) was obtained. EA, MS (FD).

Preparation Example 123

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1-benzyl-carbamoylmethyl) -pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and α-bromo-benzylacetamide (7.52 g, 33.0 mmol) were substantially similar to Preparation 94 Conversion to the product yielded 802 mg (5.36%). MS (FD), NMR.

Preparation Example 124

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1-isobutyl-carbamoylmethyl) -pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (7.04 g, 20.0 mmol) and α-bromo-isobutylacetamide (8.54 g, 44.0 mmol) were replaced with cesium carbonate instead of sodium hydride 3.35 g (36%) were obtained by conversion to the product in a manner substantially similar to Preparation Example 94 except for use in. EA, MS (FD).

Preparation Example 125

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [2-methoxyphenyl] -carbamoylmethyl) -pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and α-O-toluenesulfonylimido- (2-methoxyphenyl) acetamide (7.69 g, 31.5 mmol) was converted to the product in a substantially similar manner as in Preparation 94 to give 10.4 g (68%). EA, MS (FD).

Preparation Example 126

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [4-carbomethoxyphenyl) -carbamoylmethyl) -pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (12.0 g, 34.2 mmol) and α-O-toluenesulfonylimido- (4-carbomethoxyphenyl) acetamide (13.0 g , 35.9 mmol) was converted to the product in a substantially similar manner as in Preparation 94 to give 15.5 g (83%). EA, MS (FD).

Preparation Example 127

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [4-nitrophenyl) -carbamoylmethyl) -pyridine

Preparation of 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and α-bromo- (4-nitrophenyl) acetamide (8.55 g, 33.0 mmol) Conversion to the product in a manner substantially similar to 94 yielded 15.3 g (96.2%). MS (FD), NMR.

Preparation Example 128

1,2-dihydro-2-toluenesulfonylimido-5- (4-fluorobenzoyl) -N- (1- [4-fluorophenyl] -carbamoylmethyl) -pyridine

1,2-dihydro-2-toluenesulfonylimido-5- (4-fluorobenzoyl) pyridine (7.40 g, 20.0 mmol) and α-bromo- (4-fluorophenyl) acetamide (5.10 g , 22.0 mmol) were converted to the product in a manner substantially similar to Preparation 94 to give 9.15 g (88%). EA, MS (FD).

Preparation 129

1,2-dihydro-2-toluenesulfonylimido-5- (4-fluorobenzoyl) -N- (1- [2-fluoro-4-trifluoromethylphenyl] -carbamoylmethyl)- Pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (7.40 g, 20.0 mmol) and α-bromo- (2-fluoro-4-trifluoromethylphenyl) acetamide (8.60 g , 22.0 mmol) was converted to the product in substantially the same manner as in Preparation 94, except that diisopropylethylamine was used instead of sodium hydride to obtain 8.95 g (76%). EA, MS (FD).

Preparation Example 130

2-amino-5-carbomethoxy-pyridine

6-aminonicotinic acid (50.0 g, 0.362 mol) was dissolved in 3.5 L of MeOH under nitrogen and cooled to 0 ° C. Hydrogen chloride gas was bubbled into the solution for 45 minutes while maintaining the temperature of the solution at 0-15 ° C. The reaction was then heated at 65 ° C. for 4 hours. MeOH was removed under vacuum and the residue was dissolved in 400 mL of water. The pH was adjusted to about 6.3 with saturated NaHCO ₃ to produce a precipitate. The precipitate was filtered off and washed with water. The filter cake was dried in vacuo at 80 ° C. to give 48.9 g of product (88.7%). EA, MS (FD).

Preparation Example 131

2-toluenesulfonylimido-5-carbomethoxy pyridine

2-amino-5-carbomethoxy-pyridine (48.9 g, 0.321 mol) was dissolved in 400 mL of pyridine under nitrogen. p-Pluenesulfonic acid (73.5 g, 0.386 mol) was added and the solution was heated at about 77.5 ° C for 16 h. The volume was reduced to 3/4 in vacuo and 3.5 L of water were added. The resulting precipitate was filtered, washed with water and air dried to give 78.4 g (79.7%) of product. MS (FD), NMR.

Preparation Example 132

1,2-dihydro-2-toluenesulfonylimido-5-carbomethoxy- (1-phenyl-carbamoylmethyl) pyridine

2-Toluenesulfonylimido-5-methoxycarbonylpyridine (73.4 g, 0.240 mol) was suspended in 465 mL of DMF under nitrogen. Sodium hydride (60%, 10.1 g, 0.253 mol) was added in two portions. When the reaction was all in solution (about 45 minutes), α-bromophenylacetamide (53.8 g, 0.252 mol) was added and the solution stirred for 64 hours. The volume was reduced to 2/3 under vacuum, the mixture was poured into 3 L of water and the mixture was stirred for 2 hours. The precipitate was filtered off and washed with water. The filter cake was dried under vacuum at 60 ° C. to give 103.4 g of product (98.2%). MS (FD), NMR.

Preparation Example 133

2-trifluoroacetamido-3-phenyl-6- (carbomethoxy) imidazo [1,2-a] pyridine

1,2-dihydro-2-toluenesulfonylimido-5-carbomethoxy-N- (1-phenyl-carbamoylmethyl) pyridine (103.3 g, 0.235 mol), trifluoroacetic anhydride (286 mL , 2.03 mol) and 573 mL of CH ₂ Cl ₂ were mixed under nitrogen and heated to reflux. The solution was refluxed for 6 hours and then concentrated in vacuo. The residue was dissolved in 1.5 L of CH ₂ Cl ₂ , washed with saturated NaHCO ₃ (3 × 500 mL), brine (2 × 500 mL), dried over Na ₂ SO ₄ and filtered. The mother liquor was concentrated in vacuo, the residue was dissolved in 250 mL of hot EtOAc and the product precipitated with 700 mL of hexane. The precipitated mixture was placed in a freezer for 18 hours, then filtered, washed with hexane and dried under vacuum at 40 ° C. to give 75.3 g of product. (Quantitative, yield). NMR.

Preparation Example 134

2-amino-3-phenyl-6- (carbomethoxy) imidazo [1,2-a] pyridine

2-trifluoroacetamido-3-phenyl-6- (carbomethoxy) imidazo- [1,2-a] -pyridine (136 g, 0.440 mol) was dissolved in 845 mL of MeOH. Diisopropylethylamine (280 mL, 1.61 mol) was added for 15 minutes. The reaction was slowly heated to reflux and stirred for 68 hours. The reaction was cooled at 0 ° C and the precipitate was filtered off. The filter cake was air washed with cold MeOH and dried to give 84.0 g of product (71.4%). EA, MS (FD).

Preparation Example 135

2-amino-3-phenyl-6- (carboxy) imidazo [1,2-a] pyridine

2-amino-3-phenyl-6- (carbomethoxy) imidazo- [1,2-a] -pyridine (83.9 g, 0.314 mol), lithium hydroxide monohydrate (65.9 g, 1.57 mol), 1113 mL of THF and 371 mL of water were mixed and stirred for 18 h at RT. The reaction was concentrated in vacuo to dissolve the residue in at least 5 L of water. The pH was adjusted to 5 with 5N HCl. The resulting precipitate was filtered and air dried for 72 hours to yield 80.5 g of product. (Quantitative, yield). NMR, MS (FD).

Preparation Example 136

2-amino-3-phenyl-6- (N-methyl-N-methoxycarbamoyl) imidazo [1,2-a] pyridine

2-amino-3-phenyl-6- (carboxy) imidazo- [1,2-a] -pyridine (80.4 g, 0.317 mol) and N, O-dimethylhydroxyamine hydrochloride (92.8 g, 0.951 mol) Was dissolved in 500 mL of DMF under nitrogen. Diisopropylethylamine (123 g, 0.951 mol) was added and the mixture was stirred at RT for 30 minutes. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (122 g, 0.634 mol) was added and stirred for 19 h at RT. The DMF was removed under vacuum and the residue was poured into 4 L of water. The aqueous layer was extracted with CH ₂ Cl ₂ (3 × 500 mL) and the organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was dissolved in 400 mL of EtOAc and stirred for 1 h at RT to form a precipitate. The precipitate was filtered off and washed with cold EtOAc. The filter cake was dried under vacuum at 40 ° C. to give 55.5 g of product (59.2%). MS (FD), NMR.

Preparation Example 137

2-iodopyridine

A mixture of 2-bromopyridine (48.0 g, 303 mmol) and 240 mL of 47% hydroiodic acid was refluxed for 8 hours and then stirred at RT for 3.5 days. The reaction mixture was poured into aqueous NaOH solution (240 mL of 40% NaOH and 250 g ice). The mixture was extracted with Et ₂ O (3 × 200 mL), the ether was washed with 100 mL of brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was distilled twice in vacuo to collect fractions at 83-88 ° C. to give 18.6 g of product (30%). EA, MS (FD).

Preparation Example 138

4-iodopyridine

4-Bromopyridinehydrochloride (50.0 g, 257 mmol) was converted to the product in a substantially similar manner as Preparation Example 137 to give 32.9 g (62.4%). MS (FD), NMR.

Preparation Example 139

N- (3-phenyl-6- [N-methyl-N-carbamoyl] imidazo [1,2-a] pyridin-2-yl) -2,2,5,5-tetramethyl-1-aza -2,5-disilacyclopentane

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

Preparation 140

1-carbamoylmethyl-1,2-dihydro-2-toluenesulfonimido-6-benzoylpyridine

To a stirred suspension of 1,2-dihydro-2-toluenesulfonimido-5-benzoylpyridine (11.65 g, 32.10 mmol) in 100 mL of anhydrous DMF was added diisopropylethylamine (6.34 ml, 34.2 mmol). It was. After 15 minutes, the solution turned transparent. Iodoacetamide (6.74 g, 34.2 mmol) was added. The mixture was stirred for 24 hours, then water (2 L) was poured and stirred for a further 1 hour. The solids were combined and air dried to give 13.15 g (97%) of a white solid. EIMS, NMR.

Preparation Example 141

Diethyl- (N-methylcarbamoylmethyl) phosphonate

A solution of 4.12 mL of 40% methylamine (aqueous solution, 47 mmol) in 8.3 mL of MeOH was cooled at -78 ° C. Triethylphosphonic acetate (8.85 mL, 44.2 mmol) was added dropwise over 10 minutes. The reaction mixture was warmed at RT and then 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 mmHg / 130 ° C.) (87%). NMR.

Preparation Example 142

Isopropyl isopropanethiol-sulfonate iPr-S (O) ₂ -S- (iPr)

To a solution of diisopropylpropanethiol sulfonate (10.0 g, 66.5 mmol) in 55 mL acetic acid was added 33% hydrogen peroxide (14.4 g, 140 mmol) dropwise at 0 ° C. over 30 minutes. After stirring at room temperature for 24 hours, the solvent was evaporated to dryness and the crude oil was purified by column chromatography (EtOAc / hexanes) to give 8.5 g of a colorless oil product (70%). ¹ H-NMR, ¹³ C-NMR.

Preparation Example 143

1-carbamoylmethyl-1,2-dihydro-2-toluenesulfonimido-6- (carbomethoxy) pyridine

1,2-dihydro-2-toluenesulfonimido-5-methoxycarbonylpyridine (20 g, 65.3 mmol) was suspended in anhydrous DMF (120 mL) and stirred under argon. Diisopropylethylamine (125.2 mL, 71.82 mmol) and 2-iodoacetamide (13.28 g, 71.82 mmol) were added and the reaction mixture was stirred at RT for 24 h. The reaction was poured into water (60 mL) and stirred for 90 minutes. The solid was collected by filtration, washed with water (1 L), Et ₂ O (200 mL) and dried under vacuum to afford 21.8 g (91.7%) of the desired product as a white solid. MS (FAB), NMR.

Preparation Example 144

2-trifluoroacetamido-6-carbomethoxy-imidazo [1,2-a] pyridine

Argon in a suspension of 1-carbamoylmethyl-1,2-dihydro-2-toluenesulfonimido-6- (carbomethoxy) pyridine (5.00 g, 13.8 mmol) in anhydrous CH ₂ Cl ₂ (75 mL). Trifluoroacetic anhydride (60 mL, 425 mmol) was added to the atmosphere. The resulting solution was refluxed for 3 hours. The solvent was removed in vacuo. The residue was dissolved in EtOAc (150 mL) and the suspension was stirred for 30 minutes. The solids were combined, poured into water (50 mL) and stirred for 30 minutes. The solids were combined and dried in vacuo to give 1.92 g (49%) of the product as a white solid. MS (FAB), NMR.

Preparation Example 145

2-trifluoroacetamido-6- (N-methoxy-N-methylamido) -imidazo [1,2-a] pyridine

2-trifluoroacetamido-6-carbomethoxy-imidazo [1,2-a] pyridine (1.50 g, 5.23 mmol) and NO-dimethylaminohydrochloride (893 mg, 9.15 mmol in 30 mL of THF To the cooled solution of) isopropyl magnesium chloride (12.0 mLm 24.1 mmol) was added dropwise for 20 minutes. The reaction mixture was stirred at -20 ° C for 1 hour. The solvent was removed and the residue was dissolved in EtOAc and washed with saturated NH ₄ Cl. The combined organic extracts were dried (Na ₂ SO ₄ ) and the solvent removed in vacuo to yield 1.23 g of a white solid (75%). HRMS calcd C ₁₂ H ₁₁ N ₄ O ₃ F ₃ : 316.0783. Found: 316.0782, NMR.

Preparation Example 146

2-trifluoroacetamido-3-phenyl-6- (N-methyl-N-methoxycarbamoyl) -imidazo [1, -a] pyridine

2-Trifluoroacetamido-3-phenyl-6-carbomethoxy-imidazo [1,2-a] pyridine (12.0 g, 33 mol) was converted to the product in a manner substantially similar to Preparation Example 189 8.0 g (68%) was obtained. MS (FAB), NMR.

Preparation Example 147

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

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

Preparation Example 148

2-chloro-5- (1-phenyl-2-N-methylcarbamoylvinyl) pyridine

To a solution of potassium hexamethyldisilazide (9.2 g, 46 mmol) in 25 mL anhydrous DMF in diethyl (N-methylcarbamoylmethyl) phosphonate (4.81 in 50 mL anhydrous DMF at 0 ° C. under an argon atmosphere. g, 23.0 mmol) was added. The reaction mixture was stirred at 0 ° C for 2 h. A solution of 2-chloro-5-benzoylpyridine (2.5 g, 11.5 mmol) in 25 mL of anhydrous DMF was added via cannula. The ice bath was removed and the resulting brown solution was warmed at RT and stirred for 16 h. The mixture was quenched with saturated NH ₄ Cl (30 mL) and extracted with EtOAc. The organic layers were combined and washed with saturated NH ₄ Cl and brine. After drying over NaSO ₄ , the solvent is removed in vacuo and the resulting residue is passed through a chromatography column (Hex / AcOEt 1: 1) to 1.5 g (50%) of a 1: 1.5 ratio of E: Z isomer mixture. Got. Isomers were isolated by crystallization. Z-isomer, IR, NMR and E-isomer, IR, NMR.

Preparation Example 149

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

To a solution of 1-bromo-2,3-difluorobenzene (0.114 g, 0.746 mmol) in 3 mL of anhydrous THF was added n-butyllithium (1.6 M in hexane, 0.47 mL, 0.749 mmol) at −78 ° C. Added. The reaction mixture was stirred at this temperature for 1 hour. A solution of a solution of 6-chloro-N-methoxy-N-methyl-nicotinamide (0.13 g, 0.68 mmol) in 5 mL of THF was added and the reaction mixture was allowed to warm to RT and stirred for 6 h. Saturated NH ₄ Cl was added and the mixture was extracted with CH ₂ Cl ₂ (3 × 100 mL). The organic layers were mixed, washed with brine and dried over NaSO ₄ . The solvent was removed in vacuo and the residue was purified by column chromatography (Hex / AcOEt 9: 1) to give 130 mg (77%) of oil product. IR, NMR.

Preparation 150

2-chloro-5- (1- (2,3-difluorophenyl) -2-N-methylcarbamoylvinyl) pyridine

2-Chloro-5- (2,3-difluorobenzoyl) pyridine was converted to the product in a manner substantially similar to Preparation Example 203 to give two isomeric mixtures. After recrystallization from EtOAc, the Z isomer was isolated in 35% yield (IR, NMR) and the E isomer was recovered from the filtrate in 17% yield (IR, NMR).

Preparation Example 151

1- (2-oxo-2-phenylethyl) -2-chloro-5-[(E) -1-phenyl-2-methylcarbamoylvinyl] pyridinium iodide

2-chloro-5-[(E) -1-phenyl-2-N-methylcarbamoylvinyl] pyridine (100 mg, 0.367 mmol) and bromoacetophenone (0.270 g, 1.35 in 5 mL of CH ₃ CN) NaI (0.21 g, 1.45 mmol) was added to the mixture. The reaction mixture was refluxed for 40 hours. CH ₃ CN was removed under vacuum to dissolve the resulting residue with hot EtOH (40-45 ° C.). After rapid filtration, the filtrate was removed in vacuo, the resulting solid was washed with 100 mL of Et ₂ O and then with cold EtOAc to give the product as 85% yield of solid. IR, NMR.

Preparation Example 152

1- [2-oxo-2- (4-fluorophenyl) ethyl] -2-chloro-5-[(E) -1-phenyl-2-methylcarbamoylvinyl] pyridinium iodide

2-Chloro-5-[(E) -1-phenyl-2-N-methylcarbamoylvinyl] pyridine (300 mg, 1.10 mmol) and 4-fluorobromoacetophenone were substantially similar to Preparation Example 151 Conversion to the product gave 395 mg (67%). IR, NMR.

Preparation Example 153

1- [2-oxopropyl] -2-chloro-5-[(E) -1-phenyl-2-methylcarbamoylvinyl] pyridinium iodide

2-chloro-5-[(E) -1-phenyl-2-N-methylcarbamoylvinyl] pyridine (300 mg, 1.10 mmol) and chloropropanone were converted to a method substantially similar to Preparation Example 151 to give 297 mg (60%) was obtained. NMR.

Preparation Example 154

1- [2-oxo-3,3-dimethylbutyl] -2-chloro-5-[(E) -1-phenyl-2-methylcarbamoylvinyl] pyridinium iodide

2-chloro-5-[(E) -1-phenyl-2-N-methylcarbamoylvinyl] pyridine (300 mg, 1.10 mmol) and chloropinacolone were converted to the product in a manner substantially similar to Preparation Example 151 To give 141 mg (26%). IR.

Preparation Example 155

1- (N, N-diethylacetamyl) -2-chloro-5-[(E) -1-phenyl-2-methylcarbamoylvinyl] pyridinium iodide

2-Chloro-5-[(E) -1-phenyl-2-N-methylcarbamoylvinyl] pyridine (140 mg, 0.514 mmol) and 2-chloro-N, N-diethylacetamide were prepared as Preparation Example 151 Conversion to the product in a manner substantially similar to yielded 75.9 mg (29%). NMR.

Preparation Example 156

1- [2-oxo-3,3-dimethylbutyl] -2-chloro-5-[(E) -1- (2,3-difluorophenyl) -2-methylcarbamoylvinyl] pyridinium Odoid

2-Chloro-5-[(E) -1-2,3-difluorophenyl) -2-N-methylcarbamoylvinyl] pyridine (250 mg, 0.810 mmol) and chloropinacolone were prepared in Preparation Example 151. Conversion to the product in a substantially similar manner yielded 199 mg (46%). IR.

Example

Example 1

2-trifluoroacetamido-3- (2,5-difluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine

1,2-dihydro-2-toluenesulfonylimido-5-bezoyl-N- (1- [2,5-difluorophenyl] -carbamoylmethyl) -pyridine (14.9 g, 28.6 mmol) Was dissolved in 400 mL of CH ₂ Cl ₂ and trifluoroacetic anhydride (50 mL, 354 mmol) was added. The solution was heated to reflux (using an anhydrous cooling condenser to reflux the volatiles) and stirred for 3 hours. The solvent was removed in vacuo and the residue was dissolved in 700 mL of EtOAc. The solution was washed with saturated NaHCO ₃ (3 × 100 mL), brine (3 × 100 mL), dried over NaSO ₄ , filtered and concentrated in vacuo. The crude product was recrystallized from EtOAc / hexanes to give 12.1 g (94.6%). EA, MS (FD).

Example 2

2-trifluoroacetamido-3- (4-methoxyphenyl) -6-benzoyl-imidazo [1,2-a] pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [4-methoxyphenyl] -carbamoylmethyl) -pyridine (13.2 g, 23.3 mmol) Conversion to the product was carried out in a substantially similar manner to 10.6 g (92%). EA.

Example 3

2-trifluoroacetamido-3- (naphth-2-yl) -6-benzoyl-imidazo [1,2-a] pyridine

Example 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [naphth-2-yl] -carbamoylmethyl) -pyridine (14.7 g, 27.4 mmol) Conversion to the product in a manner substantially similar to 1 yielded 10.4 g (82.4%). EA, MS (FD).

Example 4

2-trifluoroacetamido-3-naphthyl-6-benzoyl-imidazo [1,2-a] pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1-naphthyl-carbamoylmethyl) -pyridine (11.3 g, 22.0 mmol) was substantially similar to Example 1 Conversion to the product yielded 8.25 g (82%). EA, MS (FD).

Example 5

2-trifluoroacetamido-3- (2-fluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [2-fluorophenyl] -carbamoylmethyl) -pyridine (12.3 g, 24.5 mmol) Conversion to the product in a substantially similar manner to yielded 10.2 g (97%). EA, MS (FD).

Example 6

2-trifluoroacetamido-3- (3-fluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [3-fluorophenyl] -carbamoylmethyl) -pyridine (26.6 g, 52.8 mmol) in Example 1 Conversion to the product was carried out in a substantially similar manner to 21.6 g (95.8%). EA, MS (FD).

Example 7

2-trifluoroacetamido-3- (2,4-difluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [2,4-difluorophenyl] -carbamoylmethyl) -pyridine (11.0 g, 21.1 mmol) Conversion to the product in substantially the same manner as in Example 1 yielded 9.24 g (98.5%). EA, MS (FD).

Example 8

2-trifluoroacetamido-3- (3,5-difluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [3,5-difluorophenyl] -carbamoylmethyl) -pyridine (13.3 g, 25.6 mmol) Conversion to the product in substantially the same manner as in Example 1 yielded 10.2 g (90.1%). EA, MS (FD).

Example 9

2-trifluoroacetamido-3- (4-fluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [4-fluorophenyl] -carbamoylmethyl) -pyridine (35.0 g, 69.6 mmol) 18.6 g (62.7%) was obtained by conversion to the product in a manner substantially similar to. EA, MS (FD).

Example 10

2-trifluoroacetamido-3- (3-trifluoromethylphenyl) -6-benzoyl-imidazo [1,2-a] pyridine

Example of 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [3-trifluoromethylphenyl] -carbamoylmethyl) -pyridine (13.3 g, 24.1 mmol) Conversion to the product in a manner substantially similar to 1 yielded 9.08 g (80%). EA, MS (FD).

Example 11

2-trifluoroacetamido-3- (4-bromophenyl) -6-benzoyl-imidazo [1,2-a] pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [4-bromophenyl] -carbamoylmethyl) -pyridine (12.7 g, 22.5 mmol) Conversion to the product in a manner substantially similar to yielded 10.5 g (95.4%). EA, MS (FD).

Example 12

2-trifluoroacetamido-3- (2,3,4-trifluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [2,3,4-trifluorophenyl] -carbamoylmethyl) -pyridine (11.3 g, 20.9 mmol ) Was converted to the product in substantially the same manner as in Example 1 to give 8.43 g (87%). EA, MS (FD).

Example 13

2-trifluoroacetamido-3- (3,4-difluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [3,4-fluorophenyl] -carbamoylmethyl) -pyridine (9.53 g, 18.3 mmol) was carried out. Conversion to the product in substantially the same manner as in Example 1 yielded 7.44 g (91%). EA, MS (FD).

Example 14

2-trifluoroacetamido-3- (3,4-dichlorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [3,4-difluorophenyl] -carbamoylmethyl) -pyridine (13.8 g, 24.9 mmol) Conversion to the product in a manner substantially similar to that of Example 1 yielded 9.91 g (83%). EA, MS (FAB).

Example 15

2-trifluoroacetamido-3- (2,4,5-trifluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [2,4,5-trifluorophenyl] -carbamoylmethyl) -pyridine (11.6 g, 21.5 mmol ) Was converted to the product in a manner substantially similar to that of Example 1 to yield 9.28 g (93%). EA, MS (FD).

Example 16

2-trifluoroacetamido-3- (2-chlorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [2-chlorophenyl] -carbamoylmethyl) -pyridine (14.2 g, 27.3 mmol) was prepared in accordance with Example 1 Conversion to the product in a substantially similar manner yielded 10.8 g (88%). EA, MS (FD).

Example 17

2-trifluoroacetamido-3- (3-chlorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [3-chlorophenyl] -carbamoylmethyl) -pyridine (12.0 g, 23.1 mmol) was prepared in accordance with Example 1 Conversion to the product in a substantially similar manner yielded 8.97 g (88%). EA, MS (FD).

Example 18

2-trifluoroacetamido-3- (4-chlorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [4-chlorophenyl] -carbamoylmethyl) -pyridine (13.8 g, 26.5 mmol) was prepared in accordance with Example 1 Conversion to the product in a substantially similar manner yielded 10.7 g (91%). EA, MS (FD).

Example 19

2-trifluoroacetamido-3- (4-trifluoromethoxyphenyl) -6-benzoyl-imidazo [1,2-a] pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [4-trifluoromethoxyphenyl] -carbamoylmethyl) -pyridine (13.2 g, 23.3 mmol) was carried out. Conversion to the product in a manner substantially similar to that of Example 1 yielded 10.6 g (92%). EA, MS (FD).

Example 20

2-trifluoroacetamido-3- (3-trifluoromethoxyphenyl) -6-benzoyl-imidazo [1,2-a] pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [3-trifluoromethoxyphenyl] -carbamoylmethyl) -pyridine (12.5 g, 22.0 mmol) was carried out. Conversion to the product in a manner substantially similar to that of Example 1 yielded 10.4 g (96%). EA, MS (FD).

Example 21

2-trifluoroacetamido-3- (2-fluoro-4-trifluoromethylphenyl) -6-benzoyl-imidazo [1,2-a] pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [2-fluoro-4-trifluoromethylphenyl] -carbamoylmethyl) -pyridine (10.1 g, 17.7 mmol) was converted to the product in a substantially similar manner as in Example 1 to give 8.03 g (92%). EA, MS (FD).

Example 22

2-trifluoroacetamido-3-phenyl-6-benzoyl-imidazo [1,2-a] pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1-phenyl-carbamoylmethyl) -pyridine (13.3 g, 27.3 mmol) in substantially the same manner as in Example 1 Conversion to the product gave 10.0 g (90%). EA, MS (FD).

Example 23

2-trifluoroacetamido-3- (2,6-difluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [2,6-difluorophenyl] -carbamoylmethyl) -pyridine (7.44 g, 14.3 mmol) Conversion to the product in a manner substantially similar to that of Example 1 yielded 5.26 g (82.8%). EA, MS (FD).

Example 24

2-trifluoroacetamido-3- (2,3,4,5,6-pentafluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [2,3,4,5,6-pentafluorophenyl] -carbamoylmethyl) -pyridine (3.00 g, 5.22 mmol) was converted to the product in a manner substantially similar to that of Example 1 to obtain 1.58 g (60.8%). EA, MS (FD).

Example 25

2-trifluoroacetamido-3- (2-trifluoromethylphenyl) -6-benzoyl-imidazo [1,2-a] pyridine

Example of 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [2-trifluoromethylphenyl] -carbamoylmethyl) -pyridine (7.37 g, 13.3 mmol) Conversion to the product in a manner substantially similar to 1 yielded 6.22 g (98%). EA, MS (FD).

Example 26

2-trifluoroacetamido-3- (thiophen-3-yl) -6-benzoyl-imidazo [1,2-a] pyridine

Example of 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [thiophen-3-yl] -carbamoylmethyl) -pyridine (11.4 g, 23.1 mmol) Conversion to the product in a manner substantially similar to 1 yielded 8.88 g (92.6%). EA, MS (FD).

Example 27

2-trifluoroacetamido-3- (2-trifluoromethyl-4-fluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [2-trifluoromethyl-4-fluoropetyl] -carbamoylmethyl) -pyridine (14.5 g, 25.3 mmol) was converted to the product in a manner substantially similar to that of Example 1 to give 11.0 g (88%). EA, MS (FD).

Example 28

2-trifluoroacetamido-3- (2-fluoro-6-trifluoromethylphenyl) -6-benzoyl-imidazo [1,2-a] pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [2-fluoro-6-trifluoromethylphenyl] -carbamoylmethyl) -pyridine (2.90 g, 5.08 mmol) was converted to the product in a manner substantially similar to that of Example 1 to give 2.37 g (94%). EA, MS (FD).

Example 29

2-trifluoroacetamido-3- (4-trifluoromethylphenyl) -6-benzoyl-imidazo [1,2-a] pyridine

Example of 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [4-trifluoromethylphenyl] -carbamoylmethyl) -pyridine (13.3 g, 24.1 mmol) Conversion to the product in a manner substantially similar to 1 yielded 10.1 g (88.1%). EA, MS (FD).

Example 30

2-trifluoroacetamido-3- (2-methoxyphenyl) -6-benzoyl-imidazo [1,2-a] pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [2-methoxyphenyl] -carbamoylmethyl) -pyridine (10.4 g, 20.3 mmol) Conversion to the product in a substantially similar manner to yielded 7.40 g (83%). EA, MS (FD).

Example 31

2-trifluoroacetamido-3- (4-carbomethoxyphenyl) -6-benzoyl-imidazo [1,2-a] pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [2-methoxyphenyl] -carbamoylmethyl) -pyridine (15.5 g, 28.5 mmol) Conversion to the product in a manner substantially similar to yielded 12.6 g (94.5%). EA, MS (FD).

Example 32

2-trifluoroacetamido-3- (4-nitrophenyl) -6-benzoyl-imidazo [1,2-a] pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1- [2-methoxyphenyl] -carbamoylmethyl) -pyridine (15.3 g, 28.9 mmol) Conversion to the product in a manner substantially similar to yielding 11.2 g (85.1%). EA, MS (FD).

Example 33

2-trifluoroacetamido-3-benzyl-6-imidazo [1,2-a] pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1-benzyl-carbamoylmethyl) -pyridine (3.44 g, 6.89 mmol) in substantially the same manner as in Example 1 Conversion to the product gave 2.19 g (74.0%). EA, MS (FD).

Example 34

2-trifluoroacetamido-3-isobutyl-6-benzoyl-imidazo [1,2-a] pyridine

1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1-isobutyl-carbamoylmethyl) -pyridine (3.30 g, 7.09 mmol) was substantially similar to Example 1 Conversion to the product yielded 2.37 g (85.9%). EA, MS (FD).

Example 35

2-trifluoroacetamido-3- (4-fluorophenyl) -6- (4-fluorobenzoyl) -imidazo [1,2-a] pyridine

1,2-dihydro-2-toluenesulfonylimido-5- (4-fluorobenzoyl) -N- (1- [4-fluorophenyl] -carbamoylmethyl) -pyridine (9.15 g, 17.6 mmol) was converted to the product in a manner substantially similar to that of Example 1 to yield 7.11 g (91%). EA, MS (FD).

Example 36

2-trifluoroacetamido-3- (2-fluoro-4-trifluoromethylphenyl) -6- (4-fluorobenzoyl) -imidazo [1,2-a] pyridine

1,2-dihydro-2-toluenesulfonylimido-5- (4-fluorobenzoyl) -N- (1- [2-fluoro-4-trifluoromethylphenyl] -carbamoylmethyl)- Pyridine (8.95 g, 15.2 mmol) was converted to the product in a substantially similar manner as in Example 1 to give 6.75 g (87%). EA, MS (FD).

Example 37

2-trifluoroacetamido-6-benzoyl-imidazo [1,2-a] pyridine

1-Carbamoylmethyl-1,2-dihydro-2-toluenesulfonylimido-6-benzoylpyridine (7.15 g, 17.46 mmol) in 85 mL of anhydrous CH ₂ Cl ₂ was diluted with trifluoroacetic anhydride (62 mL, 439 mmol) was added. The mixture was stirred for 2.5 h at 30 ° C. under argon atmosphere. The solvent was removed in vacuo and the foam dissolved with EtOAc (600 mL) and washed with NaHCO ₃ (2 × 250 mL) and brine (1 × 250 mL). The organic layer was dried (Na ₂ SO ₄ ) and the solvent removed in vacuo to give 5.5 g (92%) of the product as a white solid. EIMS, NMR.

Example 38

2-trifluoroacetamido-3-iodo-6-benzoyl-imidazo [1,2-a] pyridine

N-iodosuccinimide (1.35) in a solution of 2-trifluoroacetamido-6-benzoyl-imidazo [1,2-a] pyridine (2.0 g, 6.0 mmol) in 50 mL of anhydrous CH ₃ CN. g, 6.0 mmol) was added in portions. The mixture was stirred for 10 minutes. Acetonitrile was removed in vacuo and the residue was dissolved in EtOAc (250 mL) and washed with NaHCO ₃ (40% p / v, 2 × 100 mL) and NaHCO ₃ (2 × 200 mL). The organic layer was dried (Na ₂ SO ₄ ) and EtOAc was removed in vacuo to give 2.60 g (95%) of the product as a yellow solid. EIMS, NMR.

Example 39

2-trifluoroacetamido-3-methylthio-6-benzoyl-imidazo [1,2-a] pyridine

2-Trifluoroacetamido-3-iodo-6-benzoyl-imidazo [1,2-a] pyridine (1.00 g, 2.17 mmol) was added to 20 mL of pyridine (KOH and molecular sieve 3A under argon atmosphere). Predryed, 0.04% water). Bronze copper (207 mg, 3.25 mmol) was added. To the golden suspension in brown solution methyldisulfide (160 μl, 2.17 mmol) was added via syringe. The reaction mixture was heated at 104 ° C. for 1 hour and then at 100 ° C. for 68 hours. The development of the reaction was followed by NMR (in each case, samples were taken, hydrolyzed, washed with ammonia / NH ₄ Cl (1: 9) and checked by NMR). At the end of the reaction, the reaction mixture was diluted in 3 L of EtOAc and stirred for 15 minutes. 2 L of NH ₄ OH / NH ₄ Cl 1: 9 was added and the mixture was stirred for 30 min in a 10 L funnel. The layers were separated and 2 L of NH ₄ OH / NH ₄ Cl (1: 9) was added to the organic layer. The mixture was stirred again for 30 minutes and then left without stirring for 5-10 minutes. The layers were separated and the organic layer was washed with brine. The organic layer was removed in vacuo and the resulting brown solid was subjected to ultrafast column chromatography (MeOH / CH ₂ Cl ₂ , 2:98) to give 670 mg (81%) of a yellow solid. NMR.

Example 40

2-trifluoroacetamido-3-methylsulfonyl-6-benzoyl-imidazo [1,2-a] pyridine

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

Example 41

2-trifluoroacetamido-3-isopropylthio-6-benzoyl-imidazo [1,2-a] pyridine

2-trifluoroacetamido-3-iodo-6-benzoyl-imidazo [1,2-a] pyridine (100 mg, 0.22 mmol) was dissolved in anhydrous pyridine (10 mL) at RT under argon atmosphere. . Bronze copper (21 mg, 0.33 mmol) was added according to diisopropyl disulfide (35 μl, 0.22 mmol). The mixture was stirred and stirred at 100-102 ° C. for 83 hours. The reaction was cooled to rt, poured into 1 L EtOAc and stirred for 1 h. 9: 1 NH ₄ Cl / NH ₄ OH (750 mL) solution was added and the mixture was stirred with a mechanical stirrer for 15 minutes. The aqueous layer turned light blue and the organic layer was washed with 750 mL of 9: 1 NH ₄ Cl / NH ₄ OH solution (15 minutes) and then again with brine (750 mL). EtOAc was removed in vacuo and the residue was quickly purified by chromatography (EtOAc: hexanes 1: 1). The product gave a brown oil in 20% yield (18 mg). ¹ H-NMR, ¹³ C-NMR.

Example 42

2-trifluoroacetamido-6-[(E) -1-phenyl-2-N-methylcarbamoylvinyl] -imidazo [1,2-a] pyridine

Diethyl- (N-methylcarbamoylmethyl) phosphonate (1.88 g, 9.00 mmol) and 250 mL of dry THF were placed in a flame dried flask under an argon atmosphere. The solution was cooled to -78 ° C and then hexamethyldisilazide (30 mL, 22.5 mmol; 0.5 M in toluene) was added dropwise. The mixture was stirred for 2 h at -78 ° C. 2-trifluoroacetamido-6-benzoyl-imidazo [1,2-a] pyridine (2.00 g, 6.00 mmol) in 100 mL of dry THF was added dropwise. The reaction mixture was stirred at -78 ° C for 2 hours and then warmed to room temperature. The resulting brown solution was stirred for 60 h at RT. THF was stirred in vacuo, the residue was dissolved in 400 mL of EtOAc, washed with saturated NH ₄ Cl (2 × 100 mL) and then once with brine. After drying with MgSO ₄ , the solvent was removed in vacuo to give a brown solid. Formulations of NMR analysis appeared only as "E" isomers with any other byproducts not identified. The crude was purified by column chromatography CH ₃ CN: CH ₂ Cl ₂ (2: 1) to give 920 mg (40%) of product. EIMS, NMR.

Example 43

2-trifluoroacetamido-3-iodo-6-[(E) -1-phenyl-2-N-methylcarbamoylvinyl] -imidazo [1,2-a] pyridine

2-trifluoroacetamido-6-[(E) -2-N-methylcarbamoyl-1-phenylvinyl] -imidazo [1,2 in 20 mL of anhydrous CH ₃ CN cooled at 0 ° C. To a solution of -a] pyridine (423 mg, 1.22 mmol) was added a portion of N-iodosuccinimide (1.34 mmol, 302 mg) and the mixture was stirred for 10 minutes. The desired product was precipitated into a filtered white solid and air dried to give 375 mg of crude product. CH ₃ CN was removed in vacuo and the residue was dissolved in EtOAc (50 mL). EtOAc was washed with NaHSO ₃ (40% p / v) (2 × 50 mL) and NaHCO ₃ (2 × 50 mL). The organic layer was dried (NaSO ₄ ) and EtOAc was removed in vacuo to give 240 mg (98% total yield) of the product as a white solid. EIMS, NMR.

Example 44

2-trifluoroacetamido-3-isopropylsulfonyl-6-[(E) -1-phenyl-2-N-methylcarbamoylvinyl] -imidazo [1,2-a] pyridine

2-trifluoroacetamido-3-iodo-6-[(E) -2-N-methylcarbamoyl-1-phenylvinyl] -imidazo [in 5 mL of THF cooled at −78 ° C. To a solution of 1,2-a] pyridine (70 mg, 0.15 mmol) was added phenyllithium (230 μl, 0.33 mmol) under argon atmosphere. The reaction mixture was stirred for 3 minutes and then t-butyllithium (310 μl, 0.38 mmol) was added. After stirring for 10 minutes, a solution of isopropyl isopropanethiol-sulfonate (109 mg, 0.60 mmol) in 5 mL of THF was added. The reaction mixture was stirred at −78 ° C. for 30 minutes and then quenched with 2 drops of water and 10 mL of THF. Ethyl acetate (15 mL) was added and the mixture was warmed at RT. The solution was filtered through celite and the solvent was removed in vacuo. The residue was then dissolved in anhydrous CH ₂ Cl ₂ (10 mL) and cooled to 0 ° C. Pre-dried mCPBA (208 mg, sulfide binding to 100% theoretical yield of product calculated in excess of 5 equivalents) is dissolved in CH ₂ Cl ₂ (40 mL) and the starting material is then completely monitored by sulfone (TLC) Dropwise until conversion to). The solution was then washed with Na ₂ SO ₃ (50 mL) and NaHCO ₃ (2 × 50 mL). The organic layer was dried (Na ₂ SO ₄ ) and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel (CH ₃ CN: CH ₂ Cl ₂ 1: 1) to give 47 mg of the product as a white solid (63%). NMR.

Example 45

2-trifluoroacetamido-6- (2,3-difluorobenzoyl) -imidazo [1,2-a] pyridine

To a solution of 1-bromo-2,3-difluorobenzene (480 mL, 4.32 mmol) in THF is added n-butyllithium (2.05 mL, 4.42 mmol) in THF in 10 mL at -78 ° C under argon gas. It was. After stirring for 10 minutes, 2-trifluoroacetamido-6- (N-methoxy-N-methylamido) -imidazo [1,2-a] pyridine (513 mg, in THF (15 ml) 1.88 mmol) was added dropwise. The reaction mixture was stirred at -78 ° C for 1 hour. NH ₄ Cl was then added and the reaction was extracted with EtOAc (25 mL) and washed with NH ₄ Cl (2 × 20 mL). The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (CH ₂ Cl ₂ : CH ₃ CN 2.5: 1) to give 395 g of product as a white solid (57%). EIMS, NMR.

Example 46

2-trifluoroacetamido-6-[(E) -1- (2,3-difluorophenyl) -2-N-methylcarbamoylvinyl] -imidazo [1,2-a] pyridine

2-Trifluoroacetamido-6- (2,3-difluorobenzoyl) -imidazo [1,2-a] pyridine (0.454 g, 1.27 mmol) was obtained in substantially the same manner as in Production Example 183. Converted to yield 120 mg (23%). ¹ H-NMR, ¹³ C-NMR.

Example 47

2-trifluoroacetamido-3-iodo-6-[(E) -1- (2,3-difluorophenyl) -2-N-methylcarbamoylvinyl] -imidazo [1, 2-a] pyridine

2-trifluoroacetamido-6-[(E) -1- (2,3-difluorophenyl) -2-N-methylcarbamoyl in 10 mL of anhydrous CH ₃ CN cooled at 0 ° C. N-iodosuccinimide (67 mg, 0.30 mmol) was added in portions to a solution of vinyl] -imidazo [1,2-a] pyridine (116 mg, 0.27 mmol). The solvent was removed in vacuo and the residue was dissolved in EtOAc (25 mL) and washed with NaHSO ₃ (40% p / v, 2 × 25 mL) followed by NaHCO ₃ (2 × 25 mL). The organic layer was dried (Na ₂ SO ₄ ) and EtOAc was removed in vacuo to give 130 mg (86%) of product. ¹ H-NMR, ¹³ C-NMR.

Example 48

2-trifluoroacetamido-3-phenyl-6- (2,3-difluorobenzoyl) -imidazo [1,2-a] pyridine

To a solution of 2,3-difluorobromobenzene (471 mL, 4.206 mmol) was added a solution of n-butyllithium (1.6 M in hexanes, 2.63 mL) at -78 ° C. The resulting yellow solution was stirred at the same temperature for 70 minutes and then 2-trifluoroacetamido-3-phenyl-6- (N-methyl-N-methoxycarbamoyl) in anhydrous THF (20 mL). A solution of imidazo [1,2-a] pyridine (0.500 g, 1.28 mmol) was added via cannula. The red orange solution was allowed to warm for 60 minutes. Saturated NH ₄ Cl was added and the mixture was stirred for 25 minutes and then extracted with EtOAc. The organic layer was washed with brine, dried (Na ₂ CO ₄ ) and concentrated in vacuo to purify by column chromatography (CH ₂ Cl ₂ / CH ₃ CN 4/1) to give 390 mg of an orange solid (69%). . MS (FAB), NMR.

Example 49

2-trifluoroacetamido-3-phenyl-6-[(E) -1- (2,3-difluorophenyl) -2-methylcarbamoylvinyl] -imidazo [1,2-a ] Pyridine

Diethyl- (N-methylcarbamoylmethyl) phosphonate (217 mg, 1.04 mmol) in 250 mL of anhydrous THF was placed in a flame dried flask under an argon atmosphere. The solution was cooled to -78 ° C and then potassium hexamethyldisilazide (5.13 mL, 2.56 mmol; 0.5 M in toluene) was added. The mixture was stirred at -78 ° C for 2 h. Of 2-trifluoroacetamido-3-phenyl-6- (2,3-difluorobenzoyl) -imidazo [1,2-a] pyridine (300 mg, 0.693 mmol) in 100 mL of dry THF. The solution was added dropwise. The reaction mixture was stirred at -78 ° C for 2 h and warmed to RT. The resulting brown solution was stirred at RT for 48 hours (note that once excess mixed solvent was needed to avoid treating the mixed reaction with a heterogeneous medium). THF was removed in vacuo and the mixture was diluted with 400 mL of EtOAc and washed once with saturated NH ₄ Cl (2 × 100 mL) and brine. After drying with MgSO ₄ , the solvent was removed in vacuo to give a brown solid. The residue was purified by column chromatography (CH ₃ CN: CH ₂ Cl ₂ , 2: 1) to give 57.6 mg of product (22%). ¹ H-NMR, ¹³ C-NMR.

Example 50

2-trifluoroacetamido-3-phenyl-6-[(E) -1-phenyl-2-N-methylcarbamoylvinyl] -imidazo [1,2-a] pyridine

526 mg of 2-trifluoroacetamido-3-phenyl-6-benzoyl-imidazo [1,2-a] pyridine (618 mg, 1.27 mmol) was converted to the product in a manner substantially similar to that of Example 49. (75%) was obtained. EIMS, NMR.

Example 51

2-trifluoroacetamido-3- (2,5-difluorophenyl) -6-[(E) -1-phenyl-2-N-methylcarbamoylvinyl] -imidazo [1,2 -a] pyridine

2-Trifluoroacetamido-3- (2,5-difluorophenyl) -6-benzoylimadizo [1,2-a] pyridine (500 mg, 1.15 mmol) was substantially similar to Example 49 Conversion to the product yielded 483 mg (86%). EIMS, NMR.

Example 52

2-trifluoroacetamido-3- (2-trifluoromethyl-4-fluorophenyl) -6-[(E) -1-phenyl-2-N-methylcarbamoylvinyl] -imidazo [1,2-a] pyridine

2-Trifluoroacetamido-3- (2-trifluoromethyl-4-fluoro-phenyl) -6-benzoylimidazo [1,2-a] pyridine (500 mg, 1.04 mmol) was carried out. Conversion to the product in substantially the same manner as in Example 49 gave 439 mg (79%). EIMS, NMR.

Example 53

2-trifluoroacetamido-3- (2,3,4-trifluorophenyl) -6-[(E) -1-phenyl-2-N-methylcarbamoylvinyl] -imidazo [1 , 2-a] pyridine

2-Trifluoroacetamido-3- (2,3,4-trifluorophenyl) -6-benzoylimidazo [1,2-a] pyridine (303 mg, 0.672 mmol) was prepared in accordance with Example 49 Conversion to the product in a substantially similar manner yielded 168 mg (50%). NMR.

Example 54

2-trifluoroacetamido-3- (3,5-difluorophenyl) -6-[(E) -1-phenyl-2-methylcarbamoylvinyl] -imidazo [1,2-a ] Pyridine

2-Trifluoroacetamido-3- (3,5-difluorophenyl) -6-benzoylimidazo [1,2-a] pyridine (240 mg, 0.554 mmol) was substantially prepared with Example 49. Conversion to the product in a similar manner yielded 161 mg of two isomers (E: Z 1: 1 ratio). Yield 60%. EIMS, NMR.

Example 55

2-trifluoroacetamido-3- (3-trifluoromethylphenyl) -6-[(E) -1-phenyl-2-N-methylcarbamoylvinyl] -imidazo [1,2-a ] Pyridine

2-Trifluoroacetamido-3- (3-trifluoromethylphenyl) -6-benzoylimidazo [1,2-a] pyridine (228 mg, 0.491 mmol) was substantially similar to Example 49 Conversion to the product yielded 228 mg (57%). EIMS, NMR.

Example 56

2-amino-3- (2,4-difluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine

2-Trifluoroacetamido-3- (2,4-difluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine (9.24 g, 20.8 mmol) was charged with 250 mL of MeOH and 170 dissolved in mL of 1N NaOH. The solution was stirred for 2 weeks at RT under nitrogen. The precipitate was filtered off and the filter cake was dissolved in 900 mL of EtOAc. The solution was washed with brine (3 × 50 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was recrystallized from EtOAc / hexanes to give 5.57 g (76.8%) of 2 products. EA, MS (FD).

Example 57

2-amino-3- (3,5-difluorophenyl) -6-benzoyl-imizazo [1,2-a] pyridine

2-Trifluoroacetamido-3- (3,5-difluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine (10.2 g, 22.9 mmol) was substantially equivalent to Example 56. Conversion to the product in a similar manner yielded 4.93 g (61.1%). Ea, MS (FD).

Example 58

2-amino-3- (naphth-2-yl) -6-benzoyl-imidazo [1,2-a] pyridine

2-Trifluoroacetamido-3- (naphth-2-yl) -6-benzoyl-imidazo [1,2-a] pyridine (6.05 g, 13.7 mmol) was substantially similar to Example 56. Conversion to the product yielded 3.50 g (70.4%). MS (FD), NMR.

Example 59

2-amino-3-naphthyl-6-benzoyl-imidazo [1,2-a] pyridine

2-Trifluoroacetamido-3-naphthyl-6-benzoyl-imidazo [1,2-a] pyridine (8.25 g, 18.0 mmol) was converted to the product in a manner substantially similar to Example 56 to 4.73. g (73%) was obtained. EA, MS (FD).

Example 60

2-amino-3- (2,5-difluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine

2-Trifluoroacetamido-3- (2,5-difluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine (12.1 g, 27.1 mmol) was substantially equivalent to Example 56. Conversion to the product in a similar manner yielded 6.10 g (64.6%). EA, MS (FD).

Example 61

2-amino-3- (2,6-difluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine

2-Trifluoroacetamido-3- (2,6-difluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine (6.01 g, 13.5 mmol) was substantially equivalent to Example 56. The product was converted in a similar manner to yield 3.42 g (72.6%). EA, MS (FD).

Example 62

2-amino-3- (4-trifluoromethylphenyl) -6-benzoyl-imidazo [1,2-a] pyridine

2-Trifluoroacetamido-3- (4-trifluoromethylphenyl) -6-benzoyl-imidazo [1,2-a] pyridine (10.1 g, 21.2 mmol) was substantially similar to Example 56. The product was converted to yield 4.43 g (54.8%). EA, MS (FD).

Example 63

2-amino-3- (2-fluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine

2-Trifluoroacetamido-3- (2-fluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine (9.46 g, 22.2 mmol) was prepared in a substantially similar manner to Example 56. The product was converted to give 6.70 g (91.4%). EA, MS (FD).

Example 64

2-amino-3- (3-fluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine

2-Trifluoroacetamido-3- (3-fluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine (14.3 g, 33.6 mmol) was prepared in a substantially similar manner to Example 56. The product was converted to yield 8.30 g (74.7%). EA, MS (FD).

Example 65

2-amino-3- (4-fluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine

2-Trifluoroacetamido-3- (4-trifluoromethylphenyl) -6-benzoyl-imidazo [1,2-a] pyridine (18.6 g, 43.7 mmol) was substantially similar to Example 56. The product was converted to give 11.2 g (77.2%). EA, MS (FD).

Example 66

2-amino-3-benzyl-6-benzoyl-imidazo [1,2-a] pyridine

1.29 g of 2-trifluoroacetamido-3-benzyl-6-benzoyl-imidazo [1,2-a] pyridine (2.14 g, 5.06 mmol) was converted to product in a manner substantially similar to that of Example 56. (78.2%) was obtained. EA, MS (FD).

Example 67

2-amino-3- (3-trifluoromethylphenyl) -6-benzoyl-imidazo [1,2-a] pyridine

2-trifluoroacetamido-3- (3-trifluoromethylphenyl) -6-benzoyl-imidazo [1,2-a] pyridine (9.39 g, 19.7 mmol) is dissolved in 200 mL of MOH, Diisopropylethylamine (100 mL, 574 mmol) was added. The solution was heated to reflux and stirred under reflux for 2 days under nitrogen. The solution was concentrated in vacuo and the residue was recrystallized from EtOAc / hexanes to give 6.59 g (87.9%) of product. EA, MS (FD).

Example 68

2-amino-3- (4-methoxyphenyl) -6-benzoyl-imidazo [1,2-a] pyridine

2-Trifluoroacetamido-3- (4-methoxyphenyl) -6-benzoyl-imidazo [1,2-a] pyridine (4.89 g, 11.1 mmol) was prepared in a substantially similar manner to Example 67. Conversion to the product gave 3.08 g (80%). EA, MS (FD).

Example 69

2-amino-3- (4-bromophenyl) -6-benzoyl-imidazo [1,2-a] pyridine

2-Trifluoroacetamido-3- (4-bromophenyl) -6-benzoyl-imidazo [1,2-a] pyridine (3.00 g, 6.15 mmol) in a substantially similar manner as in Example 67 Conversion to the product gave 1.80 g (75%). EA, MS (FD).

Example 70

2-amino-3- (2,3,4-trifluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine

2-Trifluoroacetamido-3- (2,3,4-trifluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine (8.43 g, 18.2 mmol) was prepared in Example 67. Conversion to the product in a substantially similar manner yielded 5.82 g (87%). EA, MS (FD).

Example 71

2-amino-3- (3,4-difluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine

2-Trifluoroacetamido-3- (3,4-difluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine (7.44 g, 16.7 mmol) was substantially prepared in Example 67. Conversion to the product in a similar manner yielded 5.09 g (87.2%). EA, MS (FD).

Example 72

2-amino-3- (3,4-dichlorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine

2-Trifluoroacetamido-3- (3,4-dichlorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine (9.91 g, 20.8 mmol) was substantially similar to Example 67. Conversion to the product yielded 7.17 g (90.4%). EA, MS (FD).

Example 73

2-amino-3- (2,4,5-trifluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine

2-Trifluoroacetamido-3- (2,4,5-trifluorophenyl) -6-benzoyl-imidazo [1,2-apyridine (9.28 g, 20.0 mmol) was substantially the same as Example 67. Was converted to the product in a similar manner to yield 7.28 g (98.9%). EA, MS (FD).

Example 74

2-amino-3- (2-chlorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine

2-Trifluoroacetamido-3- (2-chlorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine (10.8 g, 24.2 mmol) was obtained in substantially the same manner as in Example 67. Conversion to yield 7.45 g (88.5%). EA, MS (FD).

Example 75

2-amino-3- (3-chlorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine

2-Trifluoroacetamido-3- (3-chlorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine (8.97 g, 20.2 mmol) was obtained in substantially the same manner as in Example 67. Switched to yield 6.05 g (86.1%). EA, MS (FD).

Example 76

2-amino-3- (4-chlorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine

2-Trifluoroacetamido-3- (4-chlorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine (10.8 g, 24.2 mmol) was obtained in substantially the same manner as in Example 67. Conversion to yield 7.17 g (85.2%). EA, MS (FD).

Example 77

2-amino-3- (4-trifluoromethoxyphenyl) -6-benzoyl-imidazo [1,2-a] pyridine

2-Trifluoroacetamido-3- (4-trifluoromethoxyphenyl) -6-benzoyl-imidazo [1,2-a] pyridine (10.6 g, 21.5 mmol) was substantially similar to Example 67. Conversion to the product yielded 8.24 g (96.7%). EA, MS (FD).

Example 78

2-amino-3- (3-trifluoromethoxyphenyl) -6-benzoyl-imidazo [1,2-a] pyridine

2-Trifluoroacetamido-3- (3-trifluoromethoxyphenyl) -6-benzoyl-imidazo [1,2-a] pyridine (10.4 g, 21.2 mmol) was substantially similar to Example 67. Conversion to the product yielded 7.89 g (94.4%). MS (FD), NMR.

Example 79

2-amino-3- (2-fluoro-4-trifluoromethylphenyl) -6-benzoyl-imidazo [1,2-a] pyridine

Example 67 Example 2-Trifluoroacetamido-3- (2-fluoro-4-trifluoromethylphenyl) -6-benzoyl-imidazo [1,2-a] pyridine (8.03 g, 16.2 mmol) 6.00 g (92.8%) were obtained by conversion to the product in a manner substantially similar to. EA, MS (FD).

Example 80

2-amino-3- (2,3,4,5,6-pentafluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine

2-trifluoroacetamido-3- (2,3,4,5,6-pentafluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine (5.03 g, 10.1 mmol) Conversion to the product in a manner substantially similar to that of Example 67 yielded 3.79 g (93.3%). EA, MS (FD).

Example 81

2-amino-3- (2-trifluoromethylphenyl) -6-benzoyl-imidazo [1,2-a] pyridine

2-Trifluoroacetamido-3- (2-trifluoromethylphenyl) -6-benzoyl-imidazo [1,2-a] pyridine (6.22 g, 13.0 mmol) was substantially similar to Example 67. Conversion to the product yielded 4.25 g (85.5%). EA, MS (FD).

Example 82

2-amino-3- (thiophen-3-yl) -6-benzoyl-imidazo [1,2-a] pyridine

2-Trifluoroacetamido-3- (thiophen-3-yl) -6-benzoyl-imidazo [1,2-a] pyridine (8.88 g, 21.4 mmol) was substantially similar to Example 67. Conversion to the product yielded 5.51 g (80.7%). EA, MS (FD).

Example 83

2-amino-3- (2-trifluoromethyl-4-fluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine

Example of 2-trifluoroacetamido-3- (2-trifluoromethyl-4-fluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine (11.0 g, 22.2 mmol) Conversion to the product in a manner substantially similar to 67 yielded 8.60 g (97.2%). MS (FD).

Example 84

2-amino-3- (2-fluoro-6-trifluoromethylphenyl) -6-benzoyl-imidazo [1,2-a] pyridine

2-Trifluoroacetamido-3- (2-fluoro-6-trifluoromethylphenyl) -6-benzoyl-imidazo [1,2-a] pyridine (1.80 g, 3.64 mmol) was prepared in Example 76. Conversion to the product in a manner substantially similar to yielded 1.28 g (88.3%). EA, MS (FD).

Example 85

2-amino-3- (2-methoxyphenyl) -6-benzoyl-imidazo [1,2-a] pyridine

2-Trifluoroacetamido-3- (2-methoxyphenyl) -6-benzoyl-imidazo [1,2-a] pyridine (7.40 g, 16.8 mmol) was prepared in a substantially similar manner as in Example 67. Conversion to the product gave 5.0 g (87%). EA, MS (FD).

Example 86

2-amino-3- (4-carbomethoxyphenyl) -6-benzoyl-imidazo [1,2-a] pyridine

2-Trifluoroacetamido-3- (4-carbomethoxyphenyl) -6-benzoyl-imidazo [1,2-a] pyridine (2.13 g, 16.8 mmol) was substantially similar to Example 67. Conversion to the product yielded 1,44 g (85%). EA, MS (FD).

Example 87

2-amino-3- (4-nitrophenyl) -6-benzoyl-imidazo [1,2-a] pyridine

2-Trifluoroacetamido-3- (4-nitrophenyl) -6-benzoyl-imidazo [1,2-a] pyridine (8.59 g, 18.9 mmol) was obtained in substantially the same manner as in Example 67. Conversion to yield 5.04 g (74.4%). EA, MS (FD).

Example 88

2-amino-3-isobutyl-6-benzoyl-imidazo [1,2-a] pyridine

2-trifluoroacetamido-3-isobutyl-6-benzoyl-imidazo [1,2-a] pyridine (2.37 g, 6.09 mmol) was converted to the product in a manner substantially similar to Example 67 to 1.49. g (83.5%) was obtained. EA, MS (FD).

Example 89

2-amino-3- (4-carboxyphenyl) -6-benzoyl-imidazo [1,2-a] pyridine

2-amino-3- (4-carbomethoxyphenyl) -6-benzoyl-imidazo [1,2-a] pyridine (3.00 g, 8.09 mmol) is dissolved in 25 mL of THF and 8 mL of water, Stir at RT. Lithium hydroxide (968 mg, 40.4 mmol) was added and the reaction stirred overnight. The solvent was removed, water was added to the solid, filtered and washed with water. The solid was recrystallized from MeOH to give 2.62 g of product (91%). EA, MS (FD).

Example 90

2-amino-3- (4-N-methoxyamido) -6-benzoyl-imidazo [1,2-a] pyridine

2-amino-3- (4-carboxyphenyl) -6-benzoyl-imidazo [1,2-a] pyridine (714 mg, 2.00 mmol), methoxyamine hydrochloride (1.34 g, 16.0 mmol) and diiso Propylethylamine (2.93 mL, 16.0 mmol) was suspended in nitrogen in 20 mL of anhydrous DMF. Within 20 minutes the solution became clear to yellow-orange. The reaction was stirred at rt overnight. The DMF was removed under vacuum and the residue was poured into water and stirred for 1 hour. The solid was then filtered and air dried. The crude product was recrystallized from EtOAc to give 317 mg of product (41.0%). EA, MS (FD).

Example 91

2-amino-3- (4-fluorophenyl) -6- (4-fluorobenzoyl) -imidazo [1,2-a] pyridine

Example 67 2-Trifluoroacetamido-3- (4-fluorophenyl) -6- (4-fluorobenzoyl) -imidazo [1,2-a] pyridine (7.11 g, 16.0 mmol) Conversion to the product in a manner substantially similar to yielded 4.80 g (86.2%). MS (FD), NMR.

Example 92

2-amino-3- (2-fluoro-4-trifluoromethylphenyl) -6- (4-fluorobenzoyl) -imidazo [1,2-a] pyridine

2-trifluoroacetamido-3- (2-fluoro-4-trifluoromethylphenyl) -6- (4-fluorobenzoyl) -imidazo [1,2-a] pyridine (6.75 g, 13.2 mmol) was converted to the product in a manner substantially similar to that of Example 67 to yield 4.66 g (85%). EA, MS (FD).

Example 93

2-amino-3-phenyl-6- (α-phenylacetyl) -imidazo [1,2-a] pyridine

N- (3-phenyl-6- [N-methyl-N-methoxycarbamoyl] imidazo [1,2-a] pyridin-2-yl) -2,2,5,5-tetramethyl-1 Aza-2,5-disilacyclopentane (812 mg, 4 mmol) was dissolved in 30 mL of THF under nitrogen and benzylmagnesium chloride (2M in THF, 6 mL, 12.0 mmol) was added. The mixture was stirred for 18 h at RT before 15 mL of MeOH and 3 mL of acetic acid were added. The mixture was stirred at RT for 1 h. The solvent was removed in vacuo and the residue was dissolved in 400 mL EtOAc and 60 mL NaHCO ₃ . EtOAc was separated, washed with brine (2 × 75 mL), dried over NaSO ₄ and concentrated in vacuo. The residue was purified by normal flash chromatography (EtOAc). The product fractions were recrystallized from EtOAc to give 398 mg of product (31.6%). MS (FD), NMR.

Example 94

2-amino-3-phenyl-6- (picolinoyl) -imidazo [1,2-a] pyridine

2-iodopyridine (1.23 g, 6.00 mmol) was dissolved in 40 mL of THF under nitrogen and ethylmagnesium bromide (2 mL, 3 M, 6 mmol) was added. The mixture was stirred for 30 min at RT and then N- (3-phenyl-6- [carboxyl] imidazo [1,2-a] pyridin-2-yl) -2,2,5, in 25 mL of THF. 5-tetramethyl-1-aza-2,5-disilacyclopentane (820 mg, 2 mmol) was added via cannula. The resulting mixture was stirred for 18 h at RT. Methanol (4 mL) and 2 mL of acetic acid were added and the mixture was stirred at RT for 1 h. The solvent was removed in vacuo and the residue was purified by normal chromatography. The product fractions were recrystallized from EtOAc to give 205 mg of product (10.9%). MS (FD), NMR.

Example 95

2-amino-3-phenyl-6- (nicotinoyl) -imidazo [1,2-a] pyridine

N- (3-phenyl-6- [carboxyl] imidazo [1,2-a] pyridin-2-yl) -2,2,5,5-tetramethyl-1-aza-2,5-disila Cyclopentane (820 mg, 2.00 mmol) was converted to the product using 3-iodopyridine in a substantially similar manner as in Example 94 to give 271 mg (14.4%). EA, MS (FD).

Example 96

2-amino-3-phenyl-6- (isonicotinoyl) -imidazo [1,2-a] pyridine

N- (3-phenyl-6- [carboxyl] imidazo [1,2-a] pyridin-2-yl) -2,2,5,5-tetramethyl-1-aza-2,5-disila Cyclopentane (3.28 g, 8.00 mmol) was converted to the product in a manner substantially similar to Example 94 using 4-iodopyridine to give 1.74 g (69.3%). EA, MS (FD).

Example 97

2-amino-3- (2,4-difluorophenyl) -6-[(E) -benzyloxime-α-yl] -imidazo [1,2-a] pyridine

2-amino-3- (2,4-difluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine (1.00 g, 2.87 mmol) was dissolved in 40 mL of 80% EtOAc / water. . Hydroxyamine hydrochloride (2.39 g, 34.4 mmol) and NaOAc (2.82 g, 34.4 mmol) were added and the mixture was refluxed for 4 hours and heated to monitor the progress of the reaction by HPLC. The reaction was terminated by removing the solvent under vacuum and the residue was dissolved in 900 mL of EtOAc. The solution was washed with saturated NaHCO ₃ (3 × 100 mL), brine (3 × 100 mL), 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-α-yl) -imidazo [1,2-a] pyridine

2-amino-3- (4-methoxyphenyl) -6-benzoyl-imidazo [1,2-a] pyridine (2.00 g, 5.83 mmol) was converted to the product in a manner substantially similar to that of Example 97 to give 490 mg of E-product (24.0%) was obtained (EA, MS (FD)) and a small but unspecific amount of Z-product was obtained. EA, MS (FD).

Example 99

2-amino-3- (naphth-2-yl) -6-[(E) -benzyloxime-α-yl] -imidazo [1,2-a] pyridine

2-amino-3- (naphth-2-yl) -6-benzoyl-imidazo [1,2-a] pyridine (2.00 g, 5.51 mmol) was converted to the product in a manner substantially similar to that of Example 97 115 mg of E-product was obtained (5.52%). EA, MS (FD).

Example 100

2-amino-3-naphthyl-6- (benzyloxime-α-yl) -imidazo [1,2-a] pyridine

470 mg of E-product was converted to 2-amino-3-naphthyl-6-benzoyl-imidazo [1,2-a] pyridine (2.00 g, 5.51 mmol) into the product in a manner substantially similar to that in Example 97. (22.6%, EA, MS (FD)) and 810 mg of Z-product were obtained (38.9%, NMR).

Example 101

2-amino-3- (2-fluorophenyl) -6-[(E) -benzyloxime-α-yl] -imidazo [1,2-a] pyridine

2-amino-3- (2-fluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine (2.62 g, 7.92 mmol) was converted to the product in a manner substantially similar to Example 97 to 1.08. g of E-product was obtained (39.3%). MS (FD), NMR.

Example 102

2-amino-3- (3-fluorophenyl) -6-[(E) -1-benzyloxime-α-yl] -imidazo [1,2-a] pyridine

2-amino-3- (3-fluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine (2.00 g, 6.04 mmol) was converted to the product in a manner substantially similar to that of Example 97 to give 463 Converted to mg E-product (22.2%). EA, MS (FD).

Example 103

2-amino-3- (4-fluorophenyl) -6-[(E) -benzyloxime-α-yl] -imidazo [1,2-a] pyridine

2-amino-3- (4-fluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine (3.00 g, 9.06 mmol) was converted to the product in a manner substantially similar to that of Example 97; , 78 g of E-product were obtained (88.8%). EA, MS (FD).

Example 104

2-amino-3- (3,5-difluorophenyl) -6-[(E) -benzyloxime-α-yl] -imidazo [1,2-a] pyridine

2-amino-3- (3,5-difluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine (1.00 g, 2.87 mmol) was converted into the product in a manner substantially similar to that of Example 97. Conversion resulted in 65 mg of E-product (6.22%). EA, MS (FD).

Example 105

2-amino-3- (2,5-difluorophenyl) -6-[(E) -benzyloxime-α-yl] -imidazo [1,2-a] pyridine

2-amino-3- (2,5-difluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine (1.00 g, 2.87 mmol) was converted into the product in a manner substantially similar to that of Example 97. Conversion resulted in 315 mg of E-product (30.2%). EA, MS (FD).

Example 106

2-amino-3- (3-trifluoromethylphenyl) -6-[(E) -benzyloxime-α-yl] -imidazo [1,2-a] pyridine

2-amino-3- (3-trifluoromethylphenyl) -6-benzoyl-imidazo [1,2-a] pyridine (2.00 g, 5.24 mmol) was converted to product in a manner substantially similar to that of Example 97. 579 mg of E-product was obtained (27.9%). EA, MS (FD).

Example 107

2-amino-3- (4-bromophenyl) -6- (benzyloxime-α-yl) -imidazo [1,2-a] pyridine

2-amino-3- (4-bromophenyl) -6-benzoyl-imidazo [1,2-a] pyridine (1.80 g, 4.59 mmol) was converted to 1.20 by conversion of the product in a manner substantially similar to that of Example 97. A mixture of g 1: 1 E: Z isomer product was obtained (64.2%). EA, MS (FD).

Example 108

2-amino-3- (2,3,4-trifluorophenyl) -6-[(E) -benzyloxime-α-yl] -imidazo [1,2-a] pyridine

2-amino-3- (2,3,4-trifluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine (2.00 g, 5.45 mmol) in a substantially similar manner as in Example 97 Conversion to the product yielded 508 g of E-product (24.1%). EA, MS (FD).

Example 109

2-amino-3- (3,4-difluorophenyl) -6-[(E) -benzyloxime-α-yl] -imidazo [1,2-a] pyridine

2-amino-3- (3,4-difluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine (2.00 g, 5.73 mmol) was converted into the product in a manner substantially similar to that of Example 97. Conversion resulted in 507 mg of E-product (24.2%). EA, MS (FD).

Example 110

2-amino-3- (3,4-dichlorophenyl) -6-[(E) -benzyloxime-α-yl] -imidazo [1,2-a] pyridine

2-amino-3- (3,4-dichlorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine (2.00 g, 5.25 mmol) was converted to the product in a manner substantially similar to that of Example 97 Obtained as 643 mg of E-product (31.1%). EA, MS (FD).

Example 111

2-amino-3- (2,4,5-trifluorophenyl) -6-[(E) -benzyloxime-α-yl] -imidazo [1,2-a] pyridine

2-amino-3- (2,4,5-trifluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine (2.00 g, 5.45 mmol) in substantially the same manner as in Example 97 Conversion to the product yielded 344 mg of E-product (16.6%). EA, MS (FD).

Example 112

2-amino-3- (2-chlorophenyl) -6-[(E) -benzyloxime-α-yl] -imidazo [1,2-a] pyridine

180 mg of 2-amino-3- (2-chlorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine (2.00 g, 5.76 mmol) was converted to the product in a manner substantially similar to that of Example 97 E-products were obtained (8.61%). EA, MS (FD).

Example 113

2-amino-3- (3-chlorophenyl) -6-[(E) -benzyloxime-α-yl] -imidazo [1,2-a] pyridine

551 mg of 2-amino-3- (3-chlorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine (2.00 g, 5.75 mmol) was converted to the product in a manner substantially similar to that of Example 97. E-products were obtained (26.4%). EA, MS (FD).

Example 114

2-amino-3- (4-chlorophenyl) -6-[(E) -benzyloxime-α-yl] -imidazo [1,2-a] pyridine

180 mg of 2-amino-3- (4-chlorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine (2.00 g, 5.75 mmol) was converted to the product in a manner substantially similar to that of Example 97 E-products were obtained (8.61%). EA, MS (FD).

Example 115

2-amino-3- (4-trifluoromethoxyphenyl) -6-[(E) -benzyloxime-α-yl] -imidazo [1,2-a] pyridine

2-amino-3- (4-trifluoromethoxyphenyl) -6-benzoyl-imidazo [1,2-a] pyridine (2.00 g, 5.04 mmol) was converted to the product in a manner substantially similar to that of Example 97 To give 383 mg of E-product (18.4%). EA, MS (FD).

Example 116

2-amino-3- (3-trifluoromethoxyphenyl) -6-[(E) -benzyloxime-α-yl] -imidazo [1,2-a] pyridine

2-amino-3- (3-trifluoromethoxyphenyl) -6-benzoyl-imidazo [1,2-a] pyridine (2.00 g, 5.04 mmol) was converted to the product in a manner substantially similar to that of Example 97 To give 224 mg of E-product (10.8%). EA, MS (FD).

Example 117

2-amino-3- (2-fluoro-4-trifluoromethylphenyl) -6- (benzyloxime-α-yl) -imidazo [1,2-a] pyridine

2-amino-3- (2-fluoro-4-trifluoromethylphenyl) -6-benzoyl-imidazo [1,2-a] pyridine (2.00 g, 5.01 mmol) was substantially similar to Example 97. Conversion to the product yielded 742 mg of E-product (35.7%). EA, MS (FD).

Example 118

2-amino-3-phenyl-6-[(E) -benzyloxime-α-yl] -imidazo [1,2-a] pyridine

2-amino-3-phenyl-6-benzoyl-imidazo [1,2-a] pyridine (133 mg, 0.426 mmol) was added hydroxylamine hydrochloride (500 mg, 7.20 mmol), 2.5 mL pyridine and 7.5 mL Treated with anhydrous EtOH. After refluxing for 2.5 hours, 200 mL of EtOAc was added and the solution was washed twice with saturated NaHCO ₃ . The organic layer was dried over MgSO ₄ and the solvent was removed in vacuo. The product was crystallized with EtOAc to give 64 mg of E-product (45.7%), MS (FD), and 68 mg of Z product (48.6%). MS (FD).

Example 119

2-amino-3- (2,6-difluorophenyl) -6-[(E) -benzyloxime-α-yl] -imidazo [1,2-a] pyridine

2-amino-3- (2,6-difluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine (2.00 g, 5.73 mmol) was converted into the product in a manner substantially similar to that of Example 97. Conversion resulted in 383 mg of E-product (18.4%). EA, MS (FD).

Example 120

2-amino-3- (2,3,4,5,6-pentafluorophenyl) -6-[(E) -benzyloxime-α-yl] -imidazo [1,2-a] pyridine

2-amino-3- (2,6-difluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine (4.52 g, 11.2 mmol) was converted into the product in a manner substantially similar to that of Example 97. Conversion resulted in 940 mg of E-product (20%). EA, MS (FD).

Example 121

2-amino-3- (2-trifluoromethylphenyl) -6-[(E) -benzyloxime-α-yl] -imidazo [1,2-a] pyridine

2-amino-3- (2-trifluoromethylphenyl) -6-benzoyl-imidazo [1,2-a] pyridine (2.00 g, 5.25 mmol) was converted to the product in a manner substantially similar to that of Example 97 146 mg of E-product was obtained (7.02%). EA, MS (FD).

Example 122

2-amino-3- (thiophen-3-yl) -6-[(E) -benzyloxime-α-yl] -imidazo [1,2-a] pyridine

2-amino-3- (thiophen-3-yl) -6-benzoyl-imidazo [1,2-a] pyridine (2.00 g, 6.27 mmol) was converted to the product in a manner substantially similar to that of Example 97 497 mg of E-product was obtained (23.8%). EA, MS (FD).

Example 123

2-amino-3- (2-trifluoromethyl-4-fluorophenyl) -6-[(E) -benzyloxime-α-yl] -imidazo [1,2-a] pyridine

2-Amino-3- (2-trifluoromethyl-4-fluorophenyl) -6-benzoyl-imidazo [1,2-a] pyridine (2.00 g, 5.01 mmol) was substantially similar to Example 97. Conversion to the product yielded 288 mg of E-product (13.8%). EA, MS (FD).

Example 124

2-amino-3- (2-fluoro-6-trifluoromethylphenyl) -6-[(E) -benzyloxime-α-yl] -imidazo [1,2-a] pyridine

2-Amino-3- (2-fluoro-6-trifluoromethylphenyl) -6-benzoyl-imidazo [1,2-a] pyridine (1.28 g, 3.21 mmol) was substantially similar to Example 97. Conversion to the product yielded 75.0 mg of E-product (5.64%, EA, MS (FD)) and 395 mg of E-product (29.7%). MA (FD), NMR.

Example 125

2-amino-3- (4-trifluoromethylphenyl) -6-[(E) -benzyloxime-α-yl] -imidazo [1,2-a] pyridine

2-amino-3- (4-trifluoromethylphenyl) -6-benzoyl-imidazo [1,2-a] pyridine (2.00 g, 5.25 mmol) was converted to the product in a manner substantially similar to that of Example 97 512 mg of E-product were obtained (24.6%). EA, MS (FD).

Example 126

2-amino-3- (4-carbomethoxyphenyl) -6-[(E) -benzyloxime-α-yl] -imidazo [1,2-a] pyridine

2-amino-3- (4-trifluoromethylphenyl) -6-benzoyl-imidazo [1,2-a] pyridine (1.00 g, 2.70 mmol) was converted to the product in a manner substantially similar to that of Example 97 437 mg of E-product were obtained (43.5%). EA, MS (FD).

Example 127

2-amino-3- (4-carboxyphenyl) -6-benzyloxime-α-yl] -imidazo [1,2-a] pyridine

990 mg of 2-amino-3- (4-carboxyphenyl) -6-benzoyl-imidazo [1,2-a] pyridine (2.00 g, 5.60 mmol) was converted to the product in a manner substantially similar to that of Example 97. A mixture of E and Z isomers was obtained (46.6% total yield). NMR.

Example 128

2-amino-3-benzyl-6- [benzyloxime-α-yl] -imidazo [1,2-a] pyridine

2-amino-3-benzyl-6-benzoyl-imidazo [1,2-a] pyridine (2.00 g, 5.60 mmol) was converted to the product in a manner substantially similar to that of Example 97 to give 210 mg of E-isomer product. Was obtained (16.5%). EA, MS (FAB).

Example 129

2-amino-3-isobutyl-6- [benzyloxime-α-yl] -imidazo [1,2-a] pyridine

120 mg of E-product was converted to 2-amino-3-isobutyl-6-benzoyl-imidazo [1,2-a] pyridine (820 mg, 2.80 mmol) into the product in a manner substantially similar to that of Example 97. Was obtained (13.9%). EA, MS (AB).

Example 130

2-amino-3- (4-fluorophenyl) -6-[(E) -1- (4-fluorobenzyl) oxime-α-yl] -imidazo [1,2-a] pyridine

2-amino-3- (4-fluorophenyl) -6- (4-fluorobenzoyl) -imidazo [1,2-a] pyridine (2.00 g, 5.73 mmol 0 in a substantially similar manner as in Example 97 Conversion to the product yielded 572 mg of E-product (9.47%) EA, MS (FD).

Example 131

2-amino-3- (2-fluoro-4-trifluoromethylphenyl) -6-[(E) -1- (4-fluorobenzyl) oxime-α-yl] -imidazo [1,2- a] pyridine

Example of 2-amino-3- (2-fluoro-4-trifluoromethylphenyl) -6- (4-fluorobenzoyl) -imidazo [1,2-a] pyridine (2.00 g, 4.80 mmol) Conversion to the product in a manner substantially similar to 97 yielded 310 mg of E-product (15%). EA, MS (FD).

Example 132

2-amino-3-phenyl-6-[(E) -phenylacetoxime-α-yl] -imidazo [1,2-a] pyridine

485 mg of 2-amino-3-phenyl-6- (α-phenylacetyl) -imidazo [1,2-a] pyridine (732 mg, 2.24 mmol) was converted to the product in a manner substantially similar to that of Example 97. E-products were obtained (63.3%). EA, MS (FD).

Example 133

2-amino-3-phenyl-6- (picolinyloxime-α-yl) -imidazo [1,2-a] pyridine

2-amino-3-phenyl-6- (picolinoyl) -imidazo [1,2-a] pyridine (1.57 g, 5.00 mmol) in 100 mL of 80% aqueous solution of EtOH was dissolved in hydroxyamine hydrochloride (4.17 g , 60.0 mmol) and NaOAc (4.92 g, 60.0 mmol). The mixture was refluxed for 6 hours and then the solvent was removed in vacuo. The residue was partitioned between 900 mL of EtOAc and 100 mL of saturated NaHCO ₃ . EtOAc was separated, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was recrystallized from EtOAc to give a mixture of both isomer products. The mixture was triturated with CH ₂ Cl ₂ to filter the solids. The filtrate was chromatographed (normal) to give 75.8 mg of cis product (4.6%). EA, MS (FD). The solid was recrystallized twice from MeOH to give 134 mg of trans product (8.1%). EA, MS (FD).

Example 134

2-amino-3-phenyl-6- (nicotinyloxime-α-yl) -imidazo [1,2-a] pyridine

2-amino-3-phenyl-6- (nicotinoyl) -imidazo [1,2-a] pyridine (1.18 g, 3.75 mmol) was converted to the product in a manner substantially similar to that of Example 78 to 127 mg of Cis product (10.3%, MS (FD), NMR) and 20.5 mg of 80% trans product were obtained (1.3% correct). MS (FD), NMR.

Example 135

2-amino-3-phenyl-6- (cis-isonicotinyloxime-α-yl) -imidazo [1,2-a] pyridine

466 mg of 2-amino-3-phenyl-6- (isonicotinoyl) -imidazo [1,2-a] pyridine (1.57 g, 5.00 mmol) was converted to the product in a manner substantially similar to that of Example 78 Cis (28.3%, EA, MS (FD), NMR) and 230 mg of trans (14%, EA, MS (FD)) were obtained.

Example 136

2-amino-3-phenyl-6- (1-phenyl-2-cyanovinyl) -imidazo [1,2-a] pyridine

2-amino-3-phenyl-6-benzoyl-imidazo [1,2-a] pyridine (1.57 g, 5.00 mmol) is dissolved in 30 mL of THF and diethylcyanophosphonate (1.63 g, 10.0 mmol ), Then potassium bistrimethylsilylamide (0.5 M in toluene, 5 mL, 10 mmol) was added. The reaction was stirred for 5 days. THF was removed under vacuum and the residue was dissolved in 500 mL of EtOAc. EtOAc was washed with 50 mL of water, brine (2 × 50 mL), dried over NaSO ₄ and concentrated in vacuo. The residue was purified by normal flash chromatography (EtOAc) to give 250 mg of product and recrystallized from EtOAc to give 98 mg of Z-product (5.82%, EA, MS (FD)) and 128 mg of E-product. (7.60%, EA, MS (FD)).

Example 137

2-amino-3-isobutyl-6- (1-phenyl-2-cyanovinyl) -imidazo [1,2-a] pyridine

200 mg of Z-product was converted to 2-amino-3-isobutyl-6-benzoyl-imidazo [1,2-a] pyridine (1.46 g, 5.00 mmol) into the product in a manner substantially similar to that of Example 136. (12.7%, MS (FD), NMR) and 130 mg of E-product were obtained (8.23%, EA, MS (FD)).

Example 138

2-amino-3-methylthio-6-benzoyl-imidazo [1,2-a] pyridine

2-Trifluoroacetamido-3-methylthio-6-benzoyl-imidazo [1,2-a] pyridine (100 mg, 263 mmol) was dissolved in 20 mL of MeOH / CH ₂ Cl ₂ 1: 1. And 5 g of silica gel were added. The mixture was stirred at RT for 2 days. The residue was filtered and washed with CH ₂ Cl ₂ to concentrate the solution in vacuo to give 63 mg (85%) of a yellow solid.

Example 139

2-amino-3-methylsulfonyl-6-benzoyl-imidazo [1,2-a] pyridine

2-Trifluoroacetamido-3-methylsulfonyl-6-benzoyl-imidazo [1,2-a] pyridine (160 mg, 0.438 mmol) was converted to the product in a manner substantially similar to that of Example 138. 92 mg were obtained (78%).

Example 140

2-amino-3-isopropylthio-6-benzoyl-imidazo [1,2-a] pyridine

2-Trifluoroacetamido-3-isopropylsulfonyl-6-benzoyl-imidazo [1,2-a] pyridine (16 mg, 0.0393 mmol) was converted to the product in a manner substantially similar to that of Example 138 11 mg (88%).

Example 141

2-amino-3-phenyl-6- (2-fluorobenzoyl) -imidazo [1,2-a] pyridine

T-butyllithium was added dropwise to a solution of 1-bromo-2-fluorobenzene (191 mL, 1.75 mmol) in dry THF (2 mL) under argon atmosphere. After stirring at −78 ° C. for 50 minutes, 2-amino-3-phenyl-6- (N-methyl-N-methoxycarbamoyl) imidazo [1,2-a] pyridine in anhydrous THF (3 mL) (148 mg, 0.5 mmol) was added. The resulting reddish orange solution was stirred at the same temperature for the remaining 50 minutes and then warmed to RT. The solution was poured into water (20 mL) and extracted with EtOAc (2 × 20 mL). The organic layer was washed with water, dried (Na ₂ SO ₄ ) and removed in vacuo to give a brown solid. The crude solid was purified by column chromatography (CH ₂ Cl ₂ / CH ₃ CN 2.5: 1) to give 84.0 mg (50.6%) of the product as a yellow solid.

Example 142

2-amino-3-phenyl-6- (3-fluorobenzoyl) -imidazo [1,2-a] pyridine

2-amino-3-phenyl-6- (N-methyl-N-methoxycarbamoyl) imidazo [1,2-a] pyridine (148 mg, 0.500 mmol) and 1-bromo-3-fluoro Benzene was converted to the product in a substantially similar manner as in Example 141 to give 37 mg (37%).

Example 143

2-amino-3-phenyl-6- (4-fluorobenzoyl) -imidazo [1,2-a] pyridine

2-amino-3-phenyl-6- (N-methyl-N-methoxycarbamoyl) imidazo [1,2-a] pyridine (584 mg, 1.97 mmol) and 1-bromo-4-fluoro Benzene was converted to the product in a substantially similar manner as in Example 141 to give 205 mg (52%).

Example 144

2-amino-3-phenyl-6- (2,3-difluorobenzoyl) -imidazo [1,2-a] pyridine

To a solution of 2,3-difluorobromobenzene (0.945 g, 8.44 mmol) in anhydrous THF (20 mL) was added n-butyllithium (1.6 M in hexanes, 5.27 mL) at -78 ° C. The resulting yellow solution was stirred at the same temperature for 70 minutes and then 2-amino-3-phenyl-6- (N-methyl-N-methoxycarbamoyl) imidazo [1, in anhydrous THF (20 mL). A solution of 2-a] pyridine (500 mg, 1.69 mmol) was added dropwise via cannula under argon. The resulting orange solution was warmed to RT very slowly for 2.5 hours. Saturated NH ₄ Cl was added and the mixture was stirred for 25 minutes and then extracted with EtOAc. The organic layer was washed with brine and dried (NaSO ₄ ). The solvent was evaporated and the residue was purified by column chromatography (CH ₂ Cl ₂ / CH ₃ CN, 4/1) to give 440 mg (74.7%) of the product as a yellow solid.

Example 145

2-amino-3-methylthio-6- (1-phenyl-2-cyanovinyl) -imidazo [1,2-a] pyridine

Diethyl phosphononitrile (265 mg, 1.5 mmol) in a solution of 2-amino-3-methylthio-6-benzoyl-imidazo [1,2-a] pyridine (40 mg, 0.14 mmol) in 4 mL of dry THF. ) Was added dropwise at -78 ° C. An orange solid formed. 2 mL of THF was added and the reaction mixture was stirred for 2 h at -78 ° C. The reaction mixture was warmed up to RT for 3 h. The solution turned green. The mixture was hydrolyzed with a few drops of water and the solvent was removed in vacuo to give 23 mg (51%) of E-isomer by column chromatography (EtOAc).

Example 146

2-amino-3-methylsulfonyl-6- (1-phenyl-2-cyanovinyl) imidazo [1,2-a] pyridine

2-amino-6-benzoyl-3- (methylsulfonyl) imidazo [1,2-a] pyridine was converted to the product in a manner substantially similar to that of Example 145, yielding two isomer E: Z ratios of 1: 2. Vinyl nitrile was obtained with a mixture of 77% total yield of phosphorus. Z-isomers were isolated by column chromatography (isopropanol: EtOAc / 3: 7).

Example 147

2-amino-6-[(E) -1-phenyl-2-N-methylcarbamoylvinyl] -imidazo [1,2-a] pyridine

2-trifluoroacetamido-6-[(E) -1-phenyl-2-N-methylcarbamoylvinyl] -imidazo [1,2-a] pyridine (300 mg, 0.77 mmol) in 0.5 Stir for 5 h at RT in the presence of N NaOH (17 mL). The solution was neutralized with HCl (5% aqueous solution) to pH = 7 and extracted with CHCl ₃ (3 × 50 mL). The combined organic extracts were dried (Na ₂ SO ₄ ) and the solvent removed in vacuo to give 130 mg (58%) of the product as a light brown solid.

Example 148

2-amino-3-isopropylthio-6-[(E) -1-phenyl-2-N-methylcarbamoylvinyl] -imidazo [1,2-a] pyridine

2-trifluoroacetamido-3-iodo-6-[(E) -1-phenyl-2-N-methylcarbamoylvinyl] -imidazo [in 5 mL of THF cooled at −78 ° C. To a solution of 1,2-a] pyridine (72 mg, 0.15 mmol) phenyllithium (230 μl, 0.33 mmol) was added under argon atmosphere. The reaction mixture was stirred for 3 minutes and then t-butyllithium (310 μl, 0.38 mmol) was injected. After stirring for 10 minutes, a solution of isopropyl isopropanethiol-sulfonate (109 mg, 0.600 mmol) in 5 mL of THF was added. The reaction mixture was stirred at −78 ° C. for 30 minutes and then quenched with 2 drops of water and 10 mL of THF. Ethyl acetate (15 mL) was added and the mixture was warmed to RT. The solution was filtered through celite and the solvent was removed in vacuo. Circular chromatography was performed on isopropyl sulfide with degraded trifluoroacetyl group to give the intermediate in pure form. The ratio of intermediates / products was dependent on the speed of circular chromatography. Trifluoroacetyl material was mixed with silica gel in MeOH / CH ₂ Cl ₂ and the cake was stirred for 2 days. After filtration, the product was obtained in 73% total yield.

Example 149

2-amino-3-isopropylsulfonyl-6-[(E) -1-phenyl-2-N-methylcarbamoylvinyl] -imidazo [1,2-a] pyridine

2-trifluoroacetamido-3-isopropylsulfonyl-6-[(E) -1-phenyl-2-N-methylcarbamoylvinyl] -imidazo [1,2-a] pyridine (45 mg, 0.09 mmol) was dissolved in a MeOH: CH ₂ Cl ₂ 1: 1 mixture and silica gel was added to give a cake. The cake was stirred vigorously for 2 days. After filtration through celite, the product was obtained as a white solid.

Example 150

2-amino-3-phenyl-6- (1- (2,3-difluorophenyl) oxime) -imidazo [1,2-a] pyridine

2-amino-3-phenyl-6- (2,3-difluorobenzoyl) -imidazo [1,2-a] pyridine (0.15 g, 0.43 mmol) in 80% solution of EtOH (9 mL) Mixed with hydroxyamine hydrochloride (0.357 g, 5.16 mmol) and NaOAc (0.424 g, 5.16 mmol). The reaction mixture was stirred under argon for 20 hours. The solvent was stirred in vacuo and the residue was dissolved in EtOAc-water. The organic layer was washed with saturated NaHCO ₃ (2 × 20 mL) and brine (2 × 25 mL), dried (NaSO ₄ ) and evaporated to afford the product as a yellow solid. The E: Z ratio measured by NMR was 2/1.

Example 151

2-amino-3-phenyl-6- (1- (2,3-difluorophenyl) -2-N-methylcarbamoylvinyl) -imidazo [1,2-a] pyridine

2-trifluoroacetamido-3-phenyl-6-[(E) -1- (2,3-difluorophenyl) -2-methylcarbamoylvinyl] -imidazo [1,2-a ] Pyridine (0.13 g, 0.26 mmol) was dissolved in MeOH / diisopropylethylamine (4 mL 1/1 v / v) and refluxed under argon for 4 days. The solvent was removed under vacuo and the mixture was purified by column chromatography (CH ₂ Cl ₂ / CH ₃ CN / MeOH 55/40/5) to recover 27 mg (32.5%) of the product.

Example 152

2-amino-3-phenyl-6-[(E) -1-phenyl-2-N-methylcarbamoylvinyl] -imidazo [1,2-a] pyridine

2-trifluoroacetamido-3-phenyl-6-[(E) -1-phenyl-2-N-methylcarbamoylvinyl] -imidazo [1,2-a] pyridine (190 mg, 0.420 mmol) was converted to the product in a manner substantially similar to that of Example 151 to give 127 to 135 mg (85 to 90%).

Example 153

2-amino-3- (2,5-difluorophenyl) -6-[(E) -1-phenyl-2-N-methylcarbamoylvinyl] -imidazo [1,2-a] pyridine

2-trifluoroacetamido-3- (2,5-difluorophenyl) -6-[(E) -1-phenyl-2-N-methylcarbamoylvinyl] -imidazo [1,2 -a] pyridine (333 mg, 0.682 mmol) was converted to the product in a manner substantially similar to that of Example 151 to give 227 to 241 mg (85 to 90%).

Example 154

2-amino-3- (2-trifluoromethyl-4-fluorophenyl) -6-[(E) -1-phenyl-2-N-methylcarbamoylvinyl] -imidazo [1,2- a] pyridine

2-trifluoroacetamido-3- (2-trifluoromethyl-4-fluorophenyl) -6-[(E) -1-phenyl-2-N-methylcarbamoylvinyl] -imidazo [1,2-a] pyridine (310 mg, 0.576 mmol) was converted to the product in a manner substantially similar to that of Example 151 to yield 216 to 229 mg.

Example 155

2-amino-3- (2,3,4-trifluorophenyl) -6-[(E) -1-phenyl-2-N-methylcarbamoylvinyl] -imidazo [1,2-a] Pyridine

2-trifluoroacetamido-3- (2,3,4-trifluorophenyl) -6-[(E) -1-phenyl-2N-methylcarbamoylvinyl] -imidazo [1,2 -a] pyridine (134 mg, 0.265 mmol) was converted to the product in a manner substantially similar to that of Example 151 to give 92.3 to 97.7 g (85 to 90%).

Example 156

2-amino-3- (3,5-difluorophenyl) -6- (1-phenyl-2-N-methylcarbamoylvinyl) -imidazo [1,2-a] pyridine

2-trifluoroacetamido-3- (3,5-difluorophenyl) -6- (1-phenyl-2-N-methylcarbamoylvinyl) -imidazo [1,2-a] pyridine (113 mg, 0.232 mmol) was converted to the product in a manner substantially similar to that of 151 to give 77.3 to 81.8 g (85 to 90%).

Example 157

2-amino-3- (3-trifluoromethylphenyl) -6-[(E) -1-phenyl-2-N-methylcarbamoylvinyl] -imidazo [1,2-a] pyridine

2-trifluoroacetamido-3- (3-trifluoromethylphenyl) -6-[(E) -1-phenyl-2-N-methylcarbamoylvinyl] -imidazo [1,2-a ] Pyridine (142 mg, 0.273 mmol) was converted to the product in a substantially similar manner as in Example 151 to give 98.4 to 104 mg (85 to 90%).

Example 158

2-amino-3-benzoyl-6-[(E) -1-phenyl-2-N-methylcarbamoylvinyl] -imidazo [1,2-a] pyridine

1- (2-oxo-2-phenylethyl) -2-chloro-5-[(E) -1-phenyl-2-methylcarbamoylvinyl] pyridinium iodide (0.250 g, 0.482 mmol) was added to 10 Mix with aminonitrile (220 mg, 0.49 mmol) and K ₂ CO ₃ (200 mg, 1.47 mmol) in mL of CH ₃ CN. The reaction mixture was refluxed for 14 hours. After cooling to RT, the mixture was filtered and 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 product as a light colored solid in 39% yield. MS (HR), NMR.

Example 159

2-amino-3- (4-fluorobenzoyl) -6-[(E) -1-phenyl-2-N-methylcarbamoylvinyl] -imidazo [1,2-a] pyridine

1- [2-oxo-2- (4-fluorophenyl) ethyl] -2-chloro-5-[(E) -1-phenyl-2-methylcarbamoylvinyl] pyridinium iodide (400 mg , 0.740 mmol) was converted to the product in a manner substantially similar to that of Example 158 to give 118 mg (38%).

Example 160

2-amino-3-acetyl-6-[(E) -1-phenyl-2-N-methylcarbamoylvinyl] -imidazo [1,2-a] pyridine

1- [2-oxopropyl] -2-chloro-5-[(E) -1-phenyl-2-methylcarbamoylvinyl] pyridinium iodide (400 mg, 0.870 mmol) was substantially treated with Example 158. Was converted to the product in a similar manner to give 118 mg (40%).

Example 161

2-amino-3-t-butylacetyl-6-[(E) -1-phenyl-2-N-methylcarbamoylvinyl] -imidazo [1,2-a] pyridine

1- [2-oxo-3,3-dimethylbutyl] -2-chloro-5-[(E) -1-phenyl-2-methylcarbamoylvinyl] pyridinium iodide (140 mg, 0.280 mmol) Was converted to the product in a manner substantially similar to that of 158 to give 31.9 mg (30%).

Example 162

2-amino-3-t-butylacetyl-6-[(E) -1- (2,3-difluorophenyl) -2-N-methylcarbamoylvinyl] -imidazo [1,2-a ] Pyridine

1- [2-oxo-3,3-dimethylbutyl] -2-chloro-5-[(E) -1- (2,3-difluorophenyl) -2-methylcarbamoylvinyl] pyridinium Odide (120 mg, 0.220 mmol) was converted to the product in a manner substantially similar to that of Example 158 to give 11.2 mg (12%).

As described above, the compounds of the present invention are useful as antiviral agents. It exhibits inhibitory activity against various types of enteroviruses and rhinoviruses. An embodiment of the invention is a method of treating or preventing a pinaconnavirus infection comprising administering to a host in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

As used herein, the term "effective amount" means the amount of a compound of formula (I) capable of inhibiting viral replication. Pinacornavirus inhibition contemplated by this method suitably includes therapeutic or prophylactic treatment. The specific dosage of the compound administered so as to obtain a therapeutic or prophylactic effect according to the invention, as well as by certain environmental peripheral factors, including, for example, the compound administered, the route of administration, the disease being treated and the patient being treated. do. Typical daily dosages will include the active compounds of the present invention at dosage levels of from about 0.01 mg / kg to about 50 mg / kg per body weight. Preferred daily dosages will generally be from about 0.05 mg / kg to about 20 mg / kg and ideally from about 0.1 mg / kg to about 10 mg / kg.

The compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal. The compounds of the present invention are preferably formulated before administration. Therefore, another embodiment of the present invention is a pharmaceutical formulation comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient thereof.

In such formulations the active ingredient comprises from 0.1% to 99.9% by weight of the formulation. "Pharmaceutically acceptable" means that the carrier, diluent or excipient is compatible with the other ingredients of the formulation and is not harmful to the recipient thereof.

Pharmaceutical formulations of the invention are prepared by known methods using known and readily available ingredients. In preparing the compositions of the present invention, the active ingredient is typically mixed with the carrier, diluted with the carrier, or sealed in a carrier which may be in the form of a capsule, sachet, paper or other container. When the carrier is supplied as a diluent, it may be a solid, semisolid or liquid substance which acts as a vehicle, excipient or medium for the active ingredient. Thus, the compositions can be used in tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or liquid medium), for example at least 10% by weight. Ointments comprising the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, sterile packaged powders and the like.

The following preparations are for illustrative purposes only and are not intended to limit the scope of the invention in any way.

Formulation 1

Hard gelatin capsules were prepared using the following ingredients.

Volume (mg / capsule)

Active ingredient 250

Starch anhydrous 200

Magnesium Stearate 10

460 mg in total

Test Methods

African green monkey kidney cells (BSC-1) or hela cells (5-3) in a Falcon flask at 5 ° C with 5% inactive calf fetal serum (FBS), penicillin (1 mL 150 units) and streptomycin (150 micrograms per milliliter) Cultured in medium 199 gram (μg / mL)). Once a confluent monolayer was formed, the floating growth medium was removed and 0.3 mL of appropriately diluted virus (ie Echo, Mengo, Coxsackie, Polio or Linervirus) was added to each flask. After uptake for 1 hour at room temperature, the virus infected cell sheets were subjected to 1% Ionagar 2 and FBS, penicillin and It was placed on a medium containing a double concentration of medium 199 with streptomycin. The flask without drug was used as a control for the test. The stock solution of the compound was diluted with dimethyl sulfoxide at a concentration of 104 μg / mL. The flask was then incubated with polio, coxsackie, echo and mengo virus at 37 ° C. for 72 hours and with liner virus at 32 ° C. for 120 hours. Virus plaques seen in such areas are infected viruses and have been regenerated intracellularly. 10% formalin and 2% sodium acetate solution were placed in each flask to inactivate the virus and fix the cell sheet on the surface of the flask. After ignoring the size of the virus plaques, the surrounding cells were contaminated with purple crystals. Plaque numbers were compared to control numbers at each drug concentration. The activity of the test compound can be expressed as percentage plaque reduction or percentage inhibition. Alternatively, drug concentrations that inhibit the plaque formulation by 50% can be used to measure activity. 50% inhibition value is expressed as "IC ₅₀ ". The compounds of the present invention exhibited at least 30%, preferably 50%, most preferably 85% inhibitory plaque formulation at a single dose of 50 μmol. Dose response titrations on the compounds of the present invention exhibit IC ₅₀ values of less than 10 μM.

Claims (9)

A compound of formula (I) or a pharmaceutically acceptable salt thereof. <Formula I> Where 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 is hydrogen, halo, CN, C ₁ -C ₄ alkyl, —C≡CH, CO (C ₁ -C ₄ alkyl), CO ₂ (C ₁ -C ₄ alkyl), or CONR ² R ³ , R ² and R ³ are independently hydrogen or C ₁ -C ₄ alkyl, A ′ is hydrogen, halo, C ₁ -C ₆ alkyl, benzyl, naphthyl, thienyl, furyl, pyridyl, pyrrolyl, COR ⁴ , S (O) _n R ⁴ , or formula Is the flag of, R ⁴ is C ₁ -C ₆ alkyl, phenyl or substituted phenyl, n is 0, 1 or 2, R ⁵ in each occurrence is independently hydrogen or halo, m is 1, 2, 3 or 4, R ⁶ is hydrogen, halo, CF ₃ , OH, CO ₂ H, NH ₂ , NO ₂ , CONHOCH ₃ , C ₁ -C ₄ alkyl, CO ₂ (C ₁ -C ₄ alkyl) or C ₁ -C ₄ alkoxy . The compound of claim 1, wherein R is hydrogen. The method of claim 2, A is phenyl or substituted phenyl, A ′ is C ₁ -C ₆ alkyl, COR ⁴ , S (O) _n R ^4, or The compound attributable to. The compound of claim 1, wherein X is NOH or CHR ¹ . The compound of claim 3, wherein X is NOH or CHR ¹ . The method of claim 5, X is CHR ¹ , R ¹ is CN, CO (C ₁ -C ₄ alkyl) or CONR ² R ³ , A is fluorophenyl or difluorophenyl, A 'is a chemical formula Is the flag of, R ⁵ is halo. A method of inhibiting hepatitis C virus, comprising administering an effective amount of a compound of any one of claims 1 to 6 to a host in need thereof. A method of inhibiting picornavirus comprising administering an effective amount of a compound of any one of claims 1 to 6 to a host in need thereof. A pharmaceutical formulation comprising as an active ingredient the compound of claim 1 together with one or more pharmaceutically acceptable carriers, excipients or diluents.