AU7583098A - Anti-viral compounds - Google Patents

Description

WO 99/59587 PCTIUS98/10299 -1 ANTI-VIRAL COMPOUNDS Field of the Invention The present invention relates to anti-viral 5 compounds and their use in the fields of pharmaceutical and medicinal chemistry. Background of the Invention The incidence of viral upper respiratory disease, 10 the common cold, is immense. It has been estimated that nearly a billion cases annually appear in the United States alone. Rhinovirus, a member of the picornaviridae family, is the major cause of the common cold in humans. Since more than 110 strains of rhinovirus have been 15 identified, the development of a comprehensive rhinovirus vaccine is not practical. Accordingly, chemotherapy appears to be a more desirable approach. Another member of the picornavirus family is the enterovirus, which includes approximately eighty human pathogens. Many of 20 these enteroviruses cause cold-like symptoms; others can cause more serious diseases such as polio, conjunctivitis, aseptic meningitis and myocarditis. Illness related to rhinovirus infection is evidenced by nasal discharge and obstruction. Furthermore, it has 25 been implicated in otitis media, predisposes the development of bronchitis, exacerbates sinusitis, and has been implicated in the precipitation of asthmatic disease. Although it is considered by many to be a mere nuisance, its frequent occurrence in otherwise healthy 30 individuals and the resulting economic importance has made rhinovirus infection the subject of extensive investigation. The ability of chemical compounds to suppress the growth of viruses in vitro may be readily demonstrated 35 using a virus plaque suppression test or a cytopathic effect test (CPE). Cf Siminoff, Applied Microbiology, 9(1), 66 (1961). Although a number of chemical compounds that inhibit picornaviruses have been identified, many WO99/59587 PCTIUS98/10299 -2 are unacceptable due to 1) limited spectrum of activity, 2) undesirable side effects or 3) inability to prevent infection or illness in animals or humans. See Textbook of Human Virology, edited by Robert B. Belshe, chapter 5 16, "Rhinoviruses," Roland A. Levandowski, 391-405 (1985). Thus, despite the recognized therapeutic potential associated with a rhinovirus inhibitor and the research efforts expended thus far, a viable therapeutic agent has not yet emerged. For example, antiviral 10 benzimidazole compounds have been disclosed in U.S. Pat. Ser. Nos. 4,008,243, 4,018,790, 4,118,573, 4,118,742 and 4,174,454. Accordingly, the present invention provides novel pyridoimidazole compounds which inhibit the growth of 15 picornaviruses, such as rhinoviruses (bovine and human) and the like; enteroviruses, such as polioviruses and the like; coxsackieviruses of the A and B groups, or echo virus; cardioviruses, such as encephalomyocarditis virus (EMC) and the like; apthoviruses, such as foot and mouth 20 disease virus and the like; and Hepatitis viruses, such as Hepatitis C virus, and the like. Summary of the Invention The present invention provides compounds of 25 Formula (I): ~N / NHR A N.1 N / X A' (I) wherein: A is phenyl, pyridyl, substituted phenyl, 30 substituted pyridyl, or benzyl; R is hydrogen, COR 4 , or COCF3; X is N-OH, O, or CHR 1

;

WO 99/59587 PCT/US98/10299 -3

R

1 is hydrogen, halo, CN, C 1

-C

4 alkyl, C CH

CO(CI-C

4 alkyl), C02(Cl-C4 alkyl), or CONR 2

R

3 ;

R

2 and R 3 are independently hydrogen or Cl-C4 alkyl; A' is hydrogen, halo, C 1

-C

6 alkyl, benzyl, naphthyl, 5 thienyl, furyl, pyridyl, pyrollyl, COR 4 , S(O)nR 4 , or a group of the formula (R5)m

R

6

R

4 is C1-C6 alkyl, phenyl, or substituted phenyl; n is 0, 1, or 2; 10 R 5 is independently at each occurance hydrogen or halo; m is 1, 2, 3, or 4; and

R

6 is hydrogen, halo, CF3, OH, CO2H, NH2, NO2, CONHOCH3, C1-C4 alkyl, or C02(Cl-C4 alkyl), C1-C4 alkoxy; 15 or pharmaceutically acceptable salts thereof. The present invention also provides pharmaceutical formulations comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, 20 in combination with a pharmaceutically acceptable carrier, diluent or excipient thereof. The present invention also provides a method for inhibiting a picornavirus comprising administering to a host in need thereof, an effective amount of a compound 25 of Formula I, or a pharmaceutically acceptable salt thereof. The present invention also provides a method for inhibiting a Hepatitis C virus comprising administering to a host in need thereof, an effective amount of a 30 compound of Formula I, or a pharmaceutically acceptable salt thereof. The present invention also provides for the use of compounds of Formula (I) for inhibiting a picornavirus, a rhinovirus, or a Hepatitis virus.

WO99/59587 PCT/US98/10299 -4 Detailed Description of the Invention The present invention relates to compounds of formula (I), as described above, that are useful as 5 antiviral agents. All temperatures stated herein are in degrees Celsius (oC). All units of measurement employed herein are in weight units except for liquids which are in volume units. 10 The term "Cl-C 6 alkyl", as used herein, represents a straight or branched alkyl chain having from one to six carbon atoms. Typical Cl-C 6 alkyl groups include, but are not intended to be limited to; methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, 15 neo-pentyl, hexyl, and the like. The term "C 1

-C

6 alkyl" includes within its definition the term "Cl-C 4 alkyl", and includes within its definition cycloalkyl groups wherein the alkylgroup is formed into a ring. The term "halo" represents chloro, fluoro, bromo, or 20 iodo. The term "substituted phenyl", when used herein, represents a phenyl ring substituted with 1, 2 or 3 substituents independently selected from the group consisting of; halo, Cl-C 4 alkyl, Cl-C 6 alkoxy, or 25 trifluoromethyl. The term "substituted pyridyl", when used herein, represents a pyridyl ring substituted with 1, 2 or 3 substituents independently selected from the group consisting of; halo, C 1

-C

4 alkyl, C 1

-C

6 alkoxy, or 30 trifluoromethyl. As mentioned above, the invention includes the pharmaceutically acceptable salts of the compounds defined by Formula (I). Although generally neutral, a compound of this invention can possess a sufficiently 35 acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic bases, and inorganic acids and organic acids, to form a pharmaceutically acceptable salt.

WO 99/59587 PCT/US98/10299 -5 The term "pharmaceutically acceptable salt" as used herein, refers to salts of the compounds of formula I which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those 5 salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base. Such salts are known as acid addition and base addition salts. Acids commonly employed to form acid addition salts 10 include, but are not intended to be limited to, inorganic acids such as; hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like; and organic acids such as; p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic 15 acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts include, but are not intended to be limited to; sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, 20 monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, 25 fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, y 30 hydroxybutyrate, glycollate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, napththalene 2-sulfonate, mandelate, and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and 35 hydrobromic acid, and those formed with organic acids such as maleic acid and methanesulfonic acid. Base addition salts include, but are not intended to be limited to, those derived from inorganic bases, such WO99/59587 PCT/US98/10299 -6 as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium 5 hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like. The potassium and sodium salt forms are particularly preferred. It should be recognized that the particular 10 counterion forming a part of any salt of this invention is not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole. 15 The pharmaceutically acceptable salts of the invention are typically formed by reacting a compound of Formula (I) with an equimolar or excess amount of acid or base. The reactants are generally combined in a neutral solvent such as diethyl ether, benzene, and the like, for 20 acid addition salts, or water, alcohols, and the like for base addition salts. The salts normally precipitate out of solution within about one hour to about ten days, and can be isolated by filtration or other conventional methods. 25 The compounds of the present invention can occur in either the cis or trans configuration, wherein, cis refers to those compounds where the substituent on the alkene moiety is cis to the ring designated "A" and trans refers to those compounds where the substituent on the 30 alkene moiety is trans to the ring designated "A". Both isomers and mixtures thereof are included within the scope of the present invention. The following lettered paragraphs represent preferred embodiments of the present invention, however, 35 it is to be understood that the present invention is not limited to such embodiments and that other embodiments are contemplated. Preferred compounds of Formula (I) are those wherein: WO 99/59587 PCT/US98/10299 -7 a) A is phenyl, pyridyl, substituted phenyl, or substituted pyridyl; b) A is phenyl or substituted phenyl; c) A is difluorophenyl or fluorophenyl; 5 d) A is pyridyl, substituted phenyl, or substituted pyridyl; e) R is hydrogen f) R is COCF3; g) X is NOH; 10 h) X is CHR 1 ; i) R 1 is CONR 2

R

3 , C0 2

(C

1

-C

4 alkyl), or CN; j) R 1 is CONR 2

R

3 ; k) R 1 is C02(Cl-C4 alkyl); 1) R 2 and R 3 are independently methyl or hydrogen; 15 m) A' is Cl-C6 alkyl, naphthyl, thienyl, COR 4 , S(O)nR 4 , or a group of the formula

(R

5 )m R6 n) A' is C1-C6 alkyl, COR 4 , S(O)nR 4 , or a group of the formula

(R

5 )m 20 R o) A' is a group of the formula

(R

5 )m R6 p) A' is C1-C6 alkyl, COR 4 , or S(O)nR 4 ; q) A' is COR 4 , or S(O)nR 4 ; 25 r) R 5 is fluoro and m is 5; s) m is 1, 2, 3, or 5. t) R6 is CF3, OH, CO2H, NH2, N02, CONHOCH3, Cl-C4 alkyl, C 1

-C

4 alkoxy; WO 99/59587 PCT/US98/10299 -8 u) R6 is CF3, OH, CONHOCH3, C 1

-C

4 alkyl, C1-C4 alkoxy; and v) R6 is CF3, OH, Cl-C4 alkyl, C 1

-C

4 alkoxy. 5 SCHEMES The compounds of formula (I) can be prepared by synthetic methods known in the art and by methods disclosed herein. The compounds of formula (I) wherein A' is; hydrogen, Cl-C6 alkyl, napthyl, thienyl, furyl,

(R

5 )m 10 pyridyl, pyrollyl, or a group of the formula R , can be prepared according to Scheme I shown below. Scheme I N-Tos N-Tos 0 A ,NH2 A HO NC o (A) ( L +(C) z L N z NH 2 NHOF CNHCOCF3 O (B) z X (E) 15 L represents a leaving group selected from the group consisting of: halo, O-triflate, O-mesylate, O-tosylate, and the like. Z represents hydrogen, Cl-C6 alkyl, napthyl, 20 thienyl, furyl, pyridyl, pyrollyl, or a group of the fo(R5)m form-ul 6 formula

R

WO99/59587 PCTIUS98/10299 -9 Compounds of Formula (A) can be prepared by synthetic methods known in the art and by methods disclosed herein. For example, compounds of Formula (A) can be prepared according to Scheme II shown below. 5 Scheme II -C Cl Cl NN Cl A NH 2 - C o (H) o () /NN CN-Tos o (G) A 0 (A) An appropriately substituted aryl group can be acylated under Friedel-Crafts conditions, in the presence of a Lewis Acid, with an appropriately substituted acid 10 anhydride, carboxylic acid, or acid chloride to form the compounds of Formula (H). (See e.g.; Friedel-Crafts and Related Reactions, Ed. G.A., Olah, J. Wiley and Sons, N.Y., chapters 31,32 (1964)) Suitable Lewis acid catalysts include, but are not limited to, 15 trifluoroacetic anhydride/phosphoric acid, trifluoromethanesulfonic acid, iron(III) chloride, zinc chloride, copper triflate (CuOTf), phosphorous oxychloride, trifluoroacetic acid, aluminum trichloride, and the like. Aluminum trichloride is the preferred 20 Lewis acid. Suitable solvents include, but are not limited to, methylene chloride, acetonitrile, 1,2 dichloroethane, nitromethane, lower alcohols, acetonitrile, dimethylsulfoxide, and the like. The reaction is preferably run "neat" using the substituted 25 aryl group as the preferred solvent. The substituted aryl group is generally employed in a substantial molar excess. For example, an approximately 3 to 10 molar excess, relative to the 6-chloronicotinoylchloride, is WO99/59587 PCT/US98/10299 -10 generally employed. A molar excess of about 3.8 is typically preferred. The reaction is preferably carried out at about 80 0 C. Alternatively, compounds of formula (H) can be 5 prepared by reacting a compound of formula (G) with an aryl anion by methods well known in the art. The Weinreb amide of formula (G) can be prepared from the corresponding 1-chloro-5-nicotinic acid by methods well known in the art. Likewise, the acyl anions utilized to 10 prepare the compounds of formula (H) are well known in the art and can be prepared by methods described in the art. For example, an appropriately substituted bromo or iodo aryl group can be subjected to metal-halogen exchange conditions to afford the metal aryl anion by 15 methods well known in the art and disclosed herein. See Organic Reactions, vol. 6, pg. 339, (1951) for a general discussion of metal-halogen exchange conditions. Suitable solvents include, but are not limited to, toluene, dimethylformamide, methylene chloride, diethyl 20 ether, acetonitrile, tetrahydrofuran, and the like. Tetrahydrofuran is the preferred solvent. Suitable sources of metal include, but are not limited to, molecular lithium, alkyl lithiums, and the like including especially t-butyl lithium. N-Butyl lithium is a 25 preferred source of metal. The metal is generally employed in a slight molar excess. For example, approximately a 1 to 1.1 molar excess is generally employed. A 1.03 molar excess is typically preferred. The reaction is preferably carried out at about -78 0 C for 30 approximately 15 minutes. Compounds of formula (H) can be aminated with ammonia under high pressures to yield compounds of formula (J). A compound of Formula (H) is dissolved in a suitable solvent, liquid ammonia added, and the reaction 35 sealed in a vessel resistant to elevated pressures. Suitable solvents include, but are not limited to, toluene, lower alcohols, acetontrile, ethyl ether, tetrahydrofuran, dimethylformamide, chloroform, WO 99/59587 PCT/US98/10299 -11 methylenechloride, and the like. Ethanol is the preferred solvent. The reaction is preferably carried out at about 145 0 C for approximately 16 hours. The compounds of formula (A) can be prepared by 5 procedures well known in the art. For example, a compound of formula (J) can be tosylated in an inert solvent by addition of a base and tosyl chloride. Suitable solvents include, but are not limited to, tetrahydrofuran, lower alcohols, ethyl acetate, methylene 10 chloride, acetonitrile, chloroform, and the like. Suitable bases include triethylamine, sodium bicarbonate, sodium hydroxide, imidazole, and the like. Pyridine is the preferred base and solvent. The tosyl chloride is generally employed in a slight molar excess. For 15 example, approximantely a 1 to 2 molar excess, relative to the compound of formula (J), is generally employed. A 1.1 molar excess is typically preferred. The reaction is preferably carried out at about 90 0 C for approximately 16 hours. 20 Compounds of formula (B) can be prepared by synthetic methods known in the art and by methods disclosed herein. For example, compounds of formula (B), wherein L is bromide, can be prepared according to Scheme III shown below. 25 Scheme III Br Br Z OH Z OH

NH

2 0 (K) 0 (L) 0 (M) An appropriately substituted acetic acid of formula (K) is brominated in an appropriate solvent in the presence of a radical initiator to afford compounds of 30 formula (L). Suitable brominating agents include, but are not limited to, molecular bromine, N Bromosuccinimide, and the like. N-Bromosuccinimide is the preferred brominating agent. Suitable solvents include, but are not limited to, diethyl ether, 35 tetrahydrofuran, methylene chloride, chloroform, WO 99/59587 PCT/US98/10299 -12 acetonitrile, benzene, dimethylsulfoxide, carbon tetrachloride, and the like. Carbon tetrachloride is the preferred solvent. Suitable radical initiators include, but are not limited to, phosphorous trichloride, 5 molecular phosphorous, benzoylperoxide, UV radiation, and the like. Preferred initators are benzoylperoxide and UV radiation. The brominating reagent is generally employed in a stoichiometric amount. For example, 1 equivalent, relative to the compound of formula (K), is generally 10 employed and is typically preferred. The initiator is generally employed in a catalytic amount. For example, an approximately 0.1 to 1 mole percent, relative to the compound of formula (K), is generally employed. A 0.4 mole percentage is typically preferred. The reaction is 15 preferably carried out at about 77 0 C for approximately 5 hours. Compounds of formula (M) can be prepared by amidation of compounds of formula (L) by procedures known in the art. For example, the transformation can be 20 carried out by dissolving or suspending the compound of formula (L) in an appropriate solvent and then adding a nucleophilic source of chlorine to afford the corresponding acid chlorides, which can then be amidated in situ with gaseous ammonia. Suitable solvents include, 25 but are not limited to, alkanes, dimethylformamide, lower alcohols, ethyl acetate, methylene chloride, tetrahydrofuran, diethyl ether, acetonitrile, chloroform, and the like. Dimethylformamide, methylene chloride, hexanes and toluene are the preferred solvents. Suitable 30 chlorinating agents include, but are not limited to, thionyl chloride, phosphorous pentachloride, bis(trichloromethyl)carbonate, allyl chloroformate, phosphorous trichloride, triphosgene, oxalyl chloride, and the like. Oxalyl chloride is the preferred 35 chlorinating agent. The chlorinating agent is generally employed in a slight molar excess. For example, approximately a 1 to 2 molar excess, relative to the compound of formula (L), is generally employed. A 1.6 WO99/59587 PCTIUS98/10299 -13 molar excess is typically preferred. The ammonia is generally employed in a substantial molar excess. For example, ammonia gas is preferably bubbled through the reaction mixture for approximately one hour delivering an 5 unspecified amount of ammonia. The reaction is preferably carried out at about 0OC when adding the chlorinating agent and then for approximately 3 hours at about 22 0 C before adding the gaseous ammonia over approximately 1 hour at about 22 0 C. 10 Additionally, compounds of Formula (B), wherein L is O-tosylate, can be prepared according to Scheme IV shown below. Scheme IV OH OAc zCHO I Z - OH Z

NH

2 (N) 0 (0) 0 (P) L OH z NH 2 2NH 2 0 (R) 0 (Q) 15 The compounds of formula (0) can be prepared from appropriately substituted aldehydes by methods known in the art. For example, a compound of formula (N) is mixed with the acyl anion equivalent of a carboxylate, such as 20 trimethylsilylcyanide, to afford, upon hydrolysis, the compounds of formula (0). Suitable solvents include, but are not limited to, lower alcohols, ethyl acetate, methylene chloride, acetonitrile, chloroform, and the like. The reaction is preferably run "neat" when either 25 the aldehyde or acyl anion equivalent is a liquid. The acyl anion equivalent is generally employed in a stoichiometric ratio. For example, 1 equivalent of acyl anion, relative to the benzaldehyde, is generally employed and is typically preferred. The reaction is 30 preferably carried out at about 25 0 C for approximately 72 WO 99/59587 PCTIUS98/10299 -14 hours after addition of the acylanion equivalent and then at about 100 0 C for approximantely 18 hours to yield compounds of formula (0). The compounds of Formula (P) can be prepared from 5 compounds of Formula (0) by methods well known in the art. Acetylation of hydroxyacids is described throughout the art. For example, see Greene T.W., Protective Groups in Organic Synthesis, John Wiley & Sons (1981). Compounds of formula (Q) can be prepared by 10 amidation of compounds of Formula (P) by procedures well known in the art and disclosed herein. The amidation is substantially analogous to the method utilized to prepare compounds of formula (M) from compounds of formula (L). The compounds of Formula (Q) can be prepared by 15 removal of the acetyl protecting group in compounds of Formula (P) by methods well known in the art. For example, see Greene T.W., Protective Groups in Organic Synthesis, John Wiley & Sons (1981). The compounds of Formula (R) which have an alcohol 20 moiety converted to a leaving group are prepared by procedures well known in the art. For example, see Stang, et. al., Synthesis, pp. 85-1266 (1982). Compounds of Formula (C) can be prepared by methods known in the art and by methods disclosed herein. For 25 example, a compound of Formula (A) is combined with a compound of Formula (B) to afford the compounds of Formula (C). Suitable solvents include, but are not limited to, toluene, tetrahydrofuran, methylene chloride, diethyl ether, acetonitrile, and the like. 30 Dimethylformamide is typically the preferred solvent. Suitable bases include, but are not limited to, cesium fluoride, cesium carbonate, hindered alkyl amines, and the like, including especially diisopropylethyl amine. Sodium hydride is typically the preferred base. The base 35 is generally employed in a slight molar excess. For example, approximately a 1 to 1.25 molar excess, relative to the compound of Formula (A), is generally employed. A 1.1 molar excess is typically preferred. The compound of WO 99/59587 PCT/US98/10299 -15 Formula (B) is generally employed in a slight molar excess. For example, approximately a 1 to 1.1 molar excess, relative to the compound of Formula (A), is generally employed. A 1.05 molar excess is typically 5 preferred. The deprotanation is preferably carried out at room temperature for approximately 1.5 hours. After addition of the compound of Formula (B), the reaction is typically preferably carried out at room temperature for about 7 days. 10 Compounds of Formula (D) can be prepared by methods known in the art and by methods disclosed herein. For example, a compound of formula (C) can be cyclized by dissolving a compound of formula (C) in a suitable solvent and adding trifluoroacetic anyhdride to afford 15 the compounds of Formula (D). Suitable solvents include, but are not limited to, toluene, dimethylformamide, tetrahydrofuran, diethyl ether, acetonitrile, and the like. Methylenechloride is typically the preferred solvent. The trifluoroacetic anhydride is generally 20 employed in a substantial molar excess. For example, approximately a 5 to 20 molar excess, relative to the compound of Formula (C), is generally employed. A 12.4 molar excess is typically preferred. The reaction is typically preferably carried out at about the reflux 25 temperature of methylene chloride (40 0 C) for approximately 3 hours. . Compounds of Formula (E) can be prepared by methods known in the art and by methods disclosed herein. The compounds of Formula (E), wherein X is CHR 1 and 30 R 1 is CONH2, CO(Cl-C4 alkyl), CONR 2

R

3 , or C02(C1-C4 alkyl) can be prepared from compounds of formula (D) by procedures known in the art as well as procedures disclosed herein. For example, an appropriately substituted Horner-Emmons reagent (see Organic Reactions, 35 1977 Volume 25, pg. 73.) is deprotonated with a strong base in an aprotic solvent and a compound of Formula (D) added to afford compounds of Formula (E). Suitable strong bases include, but are not limited to, alkyl WO99/59587 PCT/US98/10299 -16 lithiums, lithium diisopropylamine, lithium bistrimethylsilylamide, and the like. Potassium t butoxide is the preferred base. Suitable solvents include, but are not limited to, diethyl ether, 5 tetrahydrofuran, methylene chloride, chloroform, dimethylsulfoxide, and the like. Dimethylformamide and tetrahydrofuran are the preferred solvents. The Horner Emmons reagent is generally employed in a slight molar excess. For example, from about a 1 to 2 molar excess, 10 relative to the compound of formula (D), is common. A 1.1 molar excess is typically preferred. The reaction is preferably carried out at about 0 0 C when adding the compound of Formula (A), and then at about 25 0 C for approximately 1 hour. 15 The compounds of Formula (E), wherein X is NOH, can be prepared from compounds of Formula (D) by procedures known in the art as well as procedures disclosed herein. For example, compounds of Formula (D) can be dissolved or suspended in an appropriate solvent and hydroxylamine 20 added to afford the compounds of Formula (E). Suitable solvents include, but are not limited to, lower alcohols, ethyl acetate, methylene chloride, chloroform, and the like. Methanol or pyridine is the preferred solvent. The hydroxylamine is generally employed in a substantial 25 molar excess. For example, from about a 3 to 10 molar excess, relative to the compound of Formula (E), is common. A 5.0 molar excess is typically preferred. The reaction is preferably carried out at about 25 0 C for approximately 24 hours. 30 The 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 procedures known in the art as well as procedures disclosed herein. For example, an appropriately substituted Peterson Olefination Reagent 35 (see Organic Reactions, 1990, volume 38, pg. 1.) can be dissolved in a suitable solvent and deprotonated with a strong base. A compound of Formula (D) can then added to the product. Suitable strong bases include, but are not WO 99/59587 PCTIUS98/10299 -17 limited to, potassium t-butoxide, alkyl lithiums, lithium diisopropylamine, lithium bistrimethylsilylamide, and the like. N-Butyl lithium is the preferred base. Suitable solvents include, but are not limited to, diethyl ether, 5 methylene chloride, chloroform, dimethylformamide, dimethylsulfoxide, and the like. Tetrahydrofuran is the preferred solvent. The Peterson Reagent is generally employed in a substantial molar excess. For example, from about a 3 to 10 molar excess, relative to the 10 compound of Formula (D), is common. A 5.0 molar excess is typically preferred. The reaction is preferably carried out at about -78 0 C when deprotonating the Peterson Reagent and when adding the compound of Formula (D), and then at about 25 0 C for approximately 24 hours. 15 The compounds of Formula (E), wherein X is CHR 1 and

R

1 is halo, can be prepared from compounds of Formula (E), wherein X is CH2, by procedures known in the art as well as procedures disclosed herein. For example, a compound of Formula (E), wherein X is CH2, can be 20 dissolved in a suitable solvent and an appropriate halogenating agent 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 25 tetrachloride are the preferred solvents. Suitable halogenating agents include, but are not limited to, benzene seleninyl chloride/aluminum chloride, thionyl chloride, molecular bromine, CsSO4F, NFTh, and the like. The halogenating reagent is generally employed in a 30 slight molar excess. For example, from about a 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 about -10 0 C when adding the halogenating agent and then at about 22 0 C for 35 approximately 1 hour. A skilled artisan would appreciate that the ratio of cis/trans products isolated by the schemes disclosed herein can vary widely, from completely cis or trans to WO 99/59587 PCT/US98/10299 -18 equally proportions of both, depending upon the starting materials employed and the reaction conditions utilized. Compounds of formula (I) wherein A' is COR 5 can be prepared according procedures shown in Scheme V outlined 5 below. Scheme V ClCl Cl A N C1 01 A C1 A 0 (H) X (S) X (T) COR N A N NH2 I

COR

5 X (U) Compounds of Formula (S) can be prepared by methods 10 known in the art and disclosed herein. For example, compounds of Formula (H) can be converted to compounds of Formula (S) in a manner substantially analogous to the conversion of compounds of Formla (D) to those of Formula (E) described herein. 15 Compounds of Formula (T) can be prepared by methods known in the art and disclosed herein. For example, a compound of Formula (S) and a compound of the formula BrCH2COR 5 can be dissolved in an appropriate solvent in the presence of iodide anion to afford the compounds of 20 formula (T). 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 sources of iodide anion include, but are not 25 limited to, iodide salts such as sodium, potassium, and ammonium iodide, and the like. Sodium iodide is the preferred source of iodide anion. The compound of the formula BrCH2COR 5 is generally employed in a substantial molar excess. For example, approximately a 2 to 10 molar WO 99/59587 PCTIUS98/10299 -19 excess, relative to the compound of Formula (S), is generally employed. A 3.7 molar excess is typically preferred. The iodide anion is generally employed in a substantial molar excess. For example, approximately 2 5 to 10 molar excess, relative to the compound of Formula (S), is generally employed. A 3.8 molar excess is typically preferred. The reaction is preferably carried out at about the reflux temperature of the solvent for approximately 40 hours. 10 Compounds of Formula (U) can be prepared by methods known in the art and disclosed herein. For example, a compound of Formula (T), aminonitrile, and a base can be combined and dissolved in an appropriate solvent to afford the compounds of formula (U). Suitable solvents 15 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. 20 Potasium carbonate is the preferred base. The aminonitrile is generally employed in a slight molar excess. For example, approximately a 1 to 1.05 molar excess, relative to the compound of Formula (T), is generally employed. A 1.02 molar excess is typically 25 preferred. The base is generally employed in a substantial molar excess. For example, approximately a 2 to 5 molar excess, relative to the compound of Formula (T), is generally employed. A 3.05 molar excess is typically preferred. The reaction is typically 30 preferably carried out at about the reflux temperature of the solvent for approximately 14 hours. Compounds of formula (I) wherein A' is S(O)nR 5 can be prepared according procedures shown in Scheme VI outlined below. 35 Scheme VI WO 99/59587 PCT/US98/10299 -20 N A

--NHCOCF

3 t A-

NHCOCF

3 o (V) (W) N N A NHCOCF 3 NHCOCF3 X (Y) SR x (X) 1 - N A -.. N / _.NHCOCF 3 A7J S (0) &R4 X (Z) s(o) Compounds of Formula (W) can be prepared by methods known in the art and disclosed herein. For example, compounds of Formula (V) can be converted to compounds of 5 Formula (W) in a manner substantially analogous to the conversion of compounds of Formla (D) to those of Formula (E) described previously within. Compounds of Formula (X) can be prepared by methods known in the art and disclosed herein. For example, 10 compounds of Formula (W) can be dissolved in a suitable solvent and an iodinating reagent added to form the compounds of Formula (X). Suitable solvents include, but are not limited to, toluene, dimethylformamide, methylene chloride, tetrahydrofuran, diethyl ether, acetonitrile, 15 and the like. Acetonitrile is the preferred solvent. Suitable iodinating reagents include, but are not limited to, molecular iodine, N-iodosuccinimide, and the like. N-iodosuccinimide is the preferred iodinating reagent. The iodinating reagent is generally and preferably 20 employed in a stoichiometric or equimolar amount relative to the compound of Formula (W). The reaction is preferably carried out at about 0 0 C for approximately 15 minutes. Compounds of Formula (Y) can be prepared by methods 25 known in the art and disclosed within. For example, appropriately substituted sulfides can be reacted with an WO99/59587 PCT/US98/10299 -21 imidazopyridyl anion or anion equivalent by methods well known in the art. Suitable sulfides include but are not limited to, symetrical sulfides, unsymetrical disulfides, and thiol-sulfonates. The thiol sulfonates can be 5 prepared from the generally commercially available disulfides by methods well known in the art and taught in J. Am. Chem. Soc. 1977, 4405. Compounds of Formula (Y) can be prepared from compounds of Formula (X) by methods well known in the art 10 and methods disclosed herein. For example, a metal halogen exchange reaction with a compound of Formula (X), substantially analogous to that described previously in the preparation of compounds of Formula (H), followed by the addition of an appropriately substituted sulfide. 15 The skilled artisan will recognize that in contrast to the preparation of the phenyl anion, which is used to form compounds of Formula (H), where there are no acidic protons, the analogous compounds of Formula (X) have one acidic proton and therefore should be deprotonated with a 20 base before attempting the metal-halogen exchange reaction. Suitable bases include, but are not limited to, molecular lithium, alkyl lithiums, lithium amines such as lithium diisopropyl amine, lithium hydride and the like. Phenyl lithium is the preferred base. T 25 Butyl lithium is the preferred metal source. Suitable solvents include, but are not limited to, toluene, dimethylformamide, methylene chloride, acetonitrile, diethyl ether, tetrahydrofuran, and the like. Tetrahydrofuran is the preferred solvent. The base is 30 generally employed in a slight to substantial molar excess. For example, approximately 1.5 to 3 molar excess relative to the compound of Formula (X) is generally employed. A 2.2 molar excess is typically preferred. The metal is generally employed in a slight to 35 substantial molar excess. For example, approximately 1.5 to 3 molar excess relative to the compound of Formula (X) is generally employed. A 2.5 molar excess is typically preferred. The reaction is preferably carried out at WO99/59587 PCT/US98/10299 -22 about -78 0 C for approximately 3 minutes after the addition of the base, for approximately 10 minutes after the addition of the metal source, and for approximately 30 minutes after addition of the sulfide. 5 Alternatively, compounds of Formula (Y), can be prepared from an imidazopyridyl anion equivalent, prepared from compounds of Formula (X) under Ullmann like coupling conditions. See Synthesis, 9-21, (1974) for a review of the Ullmann reaction. For example, a compound 10 of the Formula (X) can be dissolved in a suitable solvent, a copper source is added, followed by an appropriately substituted sulfide. Suitable solvents include, but are not limited to, toluene, dimethylformamide, methylene chloride, acetonitrile, 15 diethyl ether, tetrahydrofuran, pyridine, and the like. Pyridine is the preferred solvent. Suitable sources of copper include, but are not limited to, molecular copper, copper(I)oxide, and the like. Copper bronze or powdered copper is the preferred source. The copper is generally 20 employed in a slight to substantial molar excess. For example, approximately 1.2 to 3 molar excess relative to the compound of Formula (X) is generally employed. A 1.5 molar excess is typically preferred. The sulfide is generally employed in a slight molar deficiency. For 25 example, approximately a 50 to 95 molar percent, relative to the compound of Formula (X), is generally employed. A 78 molar percent is typically preferred. The reaction is preferably carried out at about 100 0 C for approximately 80 hours. 30 As another alternative, compounds of formula (Y) can be prepared from compounds of formula (X) by the use of a palladium catalyzed cross coupling reaction between a compound of the Formula (X) and an appropriately substituted trimethyl-thio-tin, i.e. R 4 S-Sn(Alkyl)3. See 35 for example Synth.Commun, 22, (5), p. 683, (1992). Compounds of Formula (Z) can be prepared by oxidation of compounds of Formula (Y) by procedures well WO99/59587 PCT/US98/10299 -23 known in the art and disclosed herein. For a general review of the oxidation of sulfides to sulfones, see Comprehenive Organic Synthesis, Volume 7, Ch. 6.2, pg. 762, Pergamon Press, Inc. New York, (1991). 5 The skilled artisan will recognize that it may become advantageous, although not necessary, to remove the trifluoroacetyl protecting group, found in the above schemes, at various points in the syntheses of the compounds of the present invention. The removal of this 10 protecting group can be accomplished by methods well known in the art and disclosed herein. For example, the trifluoroacetylgroup can be removed by dissolving compounds of Formula (D), (E), (V), (W), (X), (Y), or (Z) in an appropriate solvent then adding a base to afford 15 the corresponding deprotected products. Appropriate bases include, but are not limited to, hydroxides, carbonates, amines, and the like. The preferred base is diisopropylethylamine. Alternatively, the protecting group can be hydrolyzed on a silica gel support. See 20 also Greene T.W., Protective Groups in Organic Synthesis, John Wiley & Sons (1981). In general, the reactions of Schemes I-VI are substantially complete in about 15 minutes to 72 hours when conducted at a temperature range of from about -78 0 C 25 to the reflux temperature of the reaction mixture. A skilled artisan would appreciate that the rate of a reaction generally increases with an increase in temperature. It is often advantageous, although not necessary, however, to conduct reactions at a slower rate 30 to better control the number and quantity of side products generated. The choice of reaction solvent is not critical so long as the solvent employed is inert to the ongoing reaction and the reactants are sufficiently solubilized to effect the desired reaction. Once a 35 reaction is complete, the intermediate compound may be isolated, if desired, by procedures known in the art. For example, the compound may be crystallized and then collected by filtration, or the reaction solvent may be WO99/59587 PCT/US98/10299 -24 removed by extraction, evaporation, or decantation. The intermediate may be further purified, if desired by common techniques such as recrystallization or chromatography over solid supports such as silica gel or 5 alumina. The compounds of Formula A-Z are preferably isolated before use in subsequent reactions. Preparations and Examples The following Preparations and Examples further 10 illustrate specific aspects of the present invention. It is to be understood, however, that these examples are included for illustrative purposes only and are not intended to limit the scope of the invention in any respect and should not be so construed. 15 The compounds employed as initial starting materials in the synthesis of the compounds of this invention are known in the art, and, to the extent not commercially available are readily synthesized by standard procedures commonly employed in the art. 20 It will be understood by those skilled in the art that in performing the processes described above it may be desirable to introduce chemical protecting groups into the reactants in order to prevent secondary reactions from taking place. For example, any amine, alcohol, 25 alkylamine or carboxy groups which may be present on the reactants may be protected using any standard protecting group which does not adversely affect the remainder of the molecule's ability to react in the manner desired. The various protective groups may then be removed 30 simultaneously or successively using methods known in the art. The cis and trans forms of the compounds of the present invention can be separated using column chromatography, for example reverse phase HPLC. The 35 compounds may be eluted from the column using an appropriate ratio of acetonitrile and water or methanol and water.

WO99/59587 PCTIUS98/10299 -25 In the following Preparations and Examples, the terms melting point, nuclear magnetic resonance spectra, electron impact mass spectra, field desorption mass spectra, fast atom bombardment mass spectra, high 5 resolution mass spectra, infrared spectra, ultraviolet spectra, elemental analysis, high performance liquid chromatography, thin layer chromatography, nitrogen, water, ethyl acetate, ethyl ether, dichloromethane, dimethylformamide, chloroform, methanol, ethanol, 10 acetonitrile, tetrahydrofuran, sodium hydroxide, potasium hydroxide, sodium bicarbonate, sulfuric acid, hydrobromic acid, hydrochloric acid, ammonium hydroxide, sodium sulfite, sodium hydrosulfite, sodium nitrite, sodium sulfate, saturated sodium chloride, sodium bromide, 15 ammonium chloride, magnesium sulfate, sodium acetate, and room temperature are abbreviated "m.p.", "NMR", "EIMS", "MS (FD) "II, "MS (FAB) ", "MS (HR), "IR", "UJV", "Analysis", "HPLC", and "TLC", "N2", "H20", "EtOAc", "E20", "CH2C12", "DMF", "CHCL3", "MeOH", "EtOH", "CH3CN", "THF", "NaOH", 20 "KOH", "NaHCO3", "H2SO4", "HBr", "HC1", "NH4OH", "Na2SO3", "NaHSO3", "NaNO2", "Na2SO4", "brine", "NaBr", "NH4Cl", "MgSO4", "NaOAc", and "RT" respectively. The values reported for MS(FD) correspond to mass numbers unless otherwise indicated. In addition, the absorption 25 maxima listed for the IR spectra are only those of interest and not all of the maxima observed. The NMR spectra were obtained on a Braker Corp. 270 MHz instrument or on a General Electric QE-300 300 MHz instrument. The chemical shifts are expressed in delta 30 (6) values (parts per million downfield from tetramethyl silane). The MS(FD) spectra were taken on a Varian-MAT 731 Spectrometer using carbon dendrite emitters. EIMS spectra were obtained on a CEC 21-110 instrument from Consolidated Electrodynamics Corporation. IR spectra 35 were obtained on a Perkin-Elmer 281 instrument. UV spectra were obtained on a Cary 118 instrument. TLC was carried out on E. Merck silica gel plates. Melting points are uncorrected.

WO99/59587 PCT/US98/10299 -26 In conjunction with the NMR spectra, the following abbreviations are used: "s" is singlet, "d" is doublet, "dd" is doublet of doublets, "t" is triplet, "q" is quartet, "m" is multiplet, "dm" is a doublet of 5 multiplets and "br.s", "br.d", "br.t", and "br.m" are broad singlet, doublet, triplet, and multiplet respectively. "J" indicates the coupling constant in Hertz (Hz). Unless otherwise noted, NMR data refers to the free base of the subject compound. 10 When used within the preparations, the terms "MS", "Analysis", "IR", "UV", and "NMR" indicate that the corresponding mass spectrum, elemental analysis, infrared spectrum, ultraviolet spectrum, and nuclear magnetic resonance spectrum were consistent with the desired 15 product. Preparation 1 2-Chloro-5-benzoylpyridine Aluminum chloride (100 g, 0.730 mol) was suspended in 200 ml benzene under N2. A solution of 6 20 chloronicotinoyl chloride (53 g, 0.30 mol) in 100 ml benzene was added to the rapidly stirring suspension then refluxed overnight. The reaction was cooled to RT, 1 L EtOAc was added, and the pH was adjusted to 8.5 with 5N NaOH. Aluminum salts precipitated and were filtered 25 away. The filtrate was washed with H20, dried over Na2SO4, and concentrated in vacuo. The resulting tan solid was recrystallized from 3:2 Et20:hexanes yielding 54.6 g (83%) of product as tan crystals. EA, MS(FD). Preparation 2 30 2-Chloro-5-(4-fluorobenzoyl)pyridine The fluorobenzene (150 ml, 1.60 mmol) and 6 chloronicotinoyl chloride (17.7 g, 100 mmol) were converted to product in a manner substantially analogous to Preparation 1 to yield 15.2 g. (66.1%). EA, MS(FD), 35 NMR. Preparation 3 2-amino-5-benzoylpyridine WO99/59587 PCT/US98/10299 -27 The 2-chloro-5-benzoylpyridine (100 g, 0.460 mol) was dissolved in 500 ml of 3A EtOH and 400 ml of anhydrous ammonia, placed in a bomb, then heated at 145 0 C for 16 hours. The solvents were removed in vacuo and the 5 remaining tan solid was recrystallized from EtOH/H20 yielding 77.4 g (85%) of product as a tan solid. EA, MS(FD). Preparation 4 2-amino-5-(4-fluorobenzoyl)pyridine 10 The 2-chloro-5-(4-fluorobenzoyl)pyridine (59.1 g, 251 mmol) was converted to product in a manner substantially analogous to Preparation 3 to yield 35.4 g. (65.3%). EA, MS(FD). Preparation 5 15 1,2-Dihydro-2-toluenesulfonimido-5-benzoylpyridine N Tos ,/ N OyO 0 The 2-amino-5-benzoylpyridine (77.44 g, 0.390 mol) and p-toluenesulfonyl chloride (82.03 g, 0.43 mol) were combined in 300 ml of pyridine and heated to 90 0 C under 20 N2 for 16 hours. The pyridine was removed in vacuo and the solids stirred in 1.5 L of H20 for 1 hour. The solids were filtered away and recrystallized from EtOAc yielding 118.7 g (86%) of product as off-white crystals. EA, MS(FD). 25 Preparation 6 1,2-Dihydro-2-toluenesulfonimido-5-(4 fluorobenzoyl)pyridine The 2-amino-5-(4-fluorobenzoyl)pyridine (35.0 g, 162 mmol) was converted to product in a manner substantially 30 analogous to Preparation 5 to yield 47.7 g. (79.6%). MS(FD), NMR. Preparation 7 a-Bromo-(4-fluorophenyl)acetic acid WO99/59587 PCT/US98/10299 -28 Br OH F The 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 combined in 500 5 ml carbon tetrachloride under N2 and refluxed under UV irradiation (GE sunlamp) for 5 hours. The reaction was cooled to RT and the succinimide filtered away. The carbon tetrachloride was removed in vacuo and the remaining oil recrystallized from hexanes yielding 26.2 g 10 (87%) of product as a light yellow solid. EA, MS(FD). Preparation 8 a-Bromo-(4-methoxyphenyl)acetic acid The 4-methoxyphenylacetic acid (25.0 g, 150 mmol) was converted to product in a manner substantially 15 analogous to Preparation 7 to yield 36.6 g. (100%). MS(FD), NMR. Preparation 9 a-Bromo-(napth-2-yl)acetic acid The (napth-2-yl)acetic acid (37.2 g, 200 mmol) was 20 converted to product in a manner substantially analogous to Preparation 7 to yield 34.5 g. (65%). MS(FD), NMR. Preparation 10 a-Bromo-napthylacetic acid The napthylacetic acid (37.2 g, 200 mmol) was 25 converted to product in a manner substantially analogous to Preparation 7 to yield 32.4 g. (60.8%). MS(FD), NMR. Preparation 11 x-Bromo-(2-fluorophenyl)acetic acid 30 The (2-fluorophenyl)acetic acid (19.9 g, 129 mmol) was converted to product in a manner substantially analogous to Preparation 7 to yield 24.0 g. (79.9%). Preparation 12 WO99/59587 PCT/US98/10299 -29 a-Bromo-(3-fluorophenyl)acetic acid The (3-fluorophenyl)acetic acid (20.0 g, 130 mmol) was converted to product in a manner substantially analogous to Preparation 7 to yield 24.3 g. (80.0%). 5 Preparation 13 a-Bromo-(2,4-difluorophenyl)acetic acid The 2,4-difluorophenylacetic acid (21.3 g, 124 mmol) was converted to product in a manner substantially analogous to Preparation 7 to yield 24.8 g. (79.5%). 10 NMR. Preparation 14 a-Bromo-(3,5-difluorophenyl)acetic acid The (3,5-difluorophenyl)acetic acid (20.4 g, 118 mmol) was converted to product in a manner substantially 15 analogous to Preparation 7 to yield 21.0 g. (70.9%). NMR. Preparation 15 a-Bromo-(2,5-difluorophenyl)acetic acid The (2,5-difluorophenyl)acetic acid (20.5 g, 119 20 mmol) was converted to product in a manner substantially analogous to Preparation 7 to yield 27.3 g. (91.0%). NMR. Preparation 16 a-Bromo-(3-trifluoromethylphenyl)acetic acid 25 The (3-trifluoromethylphenyl)acetic acid (20 g, 90 mmol) was converted to product in a manner substantially analogous to Preparation 7 to yield 27.7 g. (100%). NMR. Preparation 17 30 a-Bromo-(4-bromophenyl)acetic acid The (4-bromophenyl)acetic acid (25.8 g, 120 mmol) was converted to product in a manner substantially analogous to Preparation 7 to yield 30.2 g. (85.7%). NMR. 35 Preparation 18 x-Bromo-(2,3,4-trifluorophenyl)acetic acid WO99/59587 PCTIUS98/10299 -30 The (2,3,4-trifluorophenyl)acetic acid (9.55 g, 50.3 mmol) was converted to product in a manner substantially analogous to Preparation 7 to yield 13.5 g. (100%). NMR. 5 Preparation 19 x-Bromo-(3,4-difluorophenyl)acetic acid The (3,4-difluorophenyl)acetic acid (15.2 g, 88.2 mmol) was converted to product in a manner substantially analogous to Preparation 7 to yield 22.2 g. (100%). 10 NMR. Preparation 20 a-Bromo-(3,4-dichlorophenyl)acetic acid The (3,4-dichlorophenyl)acetic acid (25.0 g, 122 15 mmol) was converted to product in a manner substantially analogous to Preparation 7 to yield 34.6 g. (100%). NMR. Preparation 21 c-Bromo-(2,4,5-trifluorophenyl)acetic acid 20 The (2,4,5-trifluorophenyl)acetic acid (9.56 g, 50.3 mmol) was converted to product in a manner substantially analogous to Preparation 7 to yield 13.6 g. (100%). NMR. Preparation 22 25 x-Bromo-(2-chlorophenyl)acetic acid The (2-chlorophenyl)acetic acid (25.3 g, 148 mmol) was converted to product in a manner substantially analogous to Preparation 7 to yield 22.8 g. (62.0%). MS(FD), NMR. 30 Preparation 23 c-Bromo-(3-chlorophenyl)acetic acid The (3-chlorophenyl)acetic acid (20.9 g, 123 mmol) was converted to product in a manner substantially analogous to Preparation 7 to yield 30.5 g. (100%). 35 NMR. Preparation 24 a-Bromo-(4-chlorophenyl)acetic acid WO99/59587 PCT/US98/10299 -31 The (4-chlorophenyl)acetic acid (25.0 g, 147 mmol) was converted to product in a manner substantially analogous to Preparation 7 to yield 21.7 g. (60.0%). NMR. 5 Preparation 25 x-Bromo-(4-trifluoromethoxyphenyl)acetic acid The (4-trifluoromethoxyphenyl)acetic acid (9.91 g, 45.1 mmol) was converted to product in a manner substantially analogous to Preparation 7 to yield 13.5 g. 10 (100%). NMR. Preparation 26 x-Bromo-(3-trifluoromethoxyphenyl)acetic acid The (3-trifluoromethoxyphenyl)acetic acid (9.75 g, 44.3 mmol) was converted to product in a manner 15 substantially analogous to Preparation 7 to yield 13.3 g. (100%). NMR. Preparation 27 x-Bromo-(2-fluoro-4-trifluoromethylphenyl)acetic acid The (2-fluoro-4-trifluoromethylphenyl)acetic acid 20 (9.56 g, 43.1 mmol) was converted to product in a manner substantially analogous to Preparation 7 to yield 13.0 g. (100%). NMR. Preparation 28 a-Bromo-(2-methoxyphenyl)acetic acid 25 The (2-methoxyphenyl)acetic acid (25.0 g, 150 mmol) was converted to product in a manner substantially analogous to Preparation 7 to yield 26.5 g. (72%). MS(FD), NMR. Preparation 29 30 x-Bromo-(4-nitrophenyl)acetic acid The (4-nitrophenyl)acetic acid (25.5 g, 141 mmol) was converted to product in a manner substantially analogous to Preparation 7 to yield 36.6 g. (100%). NMR. 35 Preparation 30 c-Bromo-(3-thienyl)acetic acid The (thiophen-3-yl)mandelic acid (8.60 g, 54.4 mmol) was dissolved in 100 ml of 30% HBr in acetic acid. The WO99/59587 PCTIUS98/10299 -32 solution was stirred for 18 hours at RT. The clear black solution was poured onto 2.5 L of ice water and immediately extracted with Et20 (4 x 400 ml). The ether was dried over Na2SO4 and treated with decolorizing 5 carbon. The Et20 was evaporated and the residue was azeotroped with toluene to remove residual acetic acid. The crude solid product was recrystalized from hexanes to yield 9.07 g. (75.%). EA, MS(FD). Preparation 31 10 a-Bromo-benzylacetic acid To a solution of L-phenylalanine (55.0 g, 330 mmol) and NaBr (130 g, 1.09 mol) dissolved in 550 ml of 3N H2S04 cooled to 0 0 C, was added slowly NaNO2 (32.0 g, 469 mmol) keeping the temperature of the reaction between 0 15 and 5 0 C. The stirring was continued at about 0 0 C for 1 hour and then for 1.5 hours at RT. The mixture was extracted with Et20 (4 x 300 ml). The Et20 was washed with brine (2 x 500 ml), dried over MgSO4, and then removed in vacuo. The residue was recrystalized from 50 20 ml of cyclohexane to give the phenylalanine starting material as crystals. The solids were filtered and the filtrate was concentrated in vacuo to yield 64 g of crude product to be used without further purification. (84.7%). 25 Preparation 32 a-Bromo-(4-fluorophenyl)acetamide Br NH2 F The a-bromo-(4-fluorophenyl)acetic acid (26.1 g, 112 mmol), in 175 ml of dry CH2C12, and 3 drops of DMF were 30 cooled in an ice bath under N2. Oxalyl chloride (25.0 g, 224 mmol) in 25 ml of dry CH2Cl2 was added dropwise over 25 minutes. The ice bath was removed and the reaction stirred for 3 hours. The solvent was removed in vacuo then azeotroped with toluene (3 x 25 ml). The remaining WO99/59587 PCT/US98/10299 -33 oil was dissolved in 300 ml of toluene and 300 ml hexanes and stirred vigorously with a mechanical stirrer. Ammonia gas was then blown through a gas dispersion tube over the top of this solution for 1 hour. The resulting 5 solid was filtered and the solvents removed in vacuo. The solid was dissolved in EtOAc/H20 and the organic layer washed with 1N HC1, saturated NaHC03, brine, then dried over Na2SO4. The Na2SO4 was filtered and the EtOAc was removed in vacuo. The remaining solid was 10 recrystallized from EtOAc/hexanes yielding 19.6 g (75%) of the desired product. MS(FD), NMR. Preparation 33 a-Bromo-(4-methoxyphenyl)acetamide The a-bromo-(4-methoxyphenyl)acetic acid (36.6 g, 15 150 mmol) was converted to product in a manner substantially analogous to Preparation 32 to yield 13.5 g. (37%). MS(FD), NMR. Preparation 34 a-Bromo-(napth-2-yl)phenylacetamide 20 The a-bromo-(napth-2-yl)acetic acid (34.5 g, 130 mmol) was converted to product in a manner substantially analogous to Preparation 32 to yield 11.5 g. (33.5%). EA, MS(FD). Preparation 35 25 a-Bromo-napthylacetamide The a-bromo-napthylacetic acid (32.4 g, 122 mmol) was converted to product in a manner substantially analogous to Preparation 32 to yield 14.6 g. (46%). MS(FD), NMR. 30 Preparation 36 a-Bromo-(2-fluorophenyl)acetamide The a-bromo-(2-fluorophenyl)acetic acid (24.0 g, 103 mmol) was converted to product in a manner substantially analogous to Preparation 32 to yield 14.0 g. (60%). 35 MS(FD), NMR. Preparation 37 a-Bromo-(3-fluorophenyl)acetamide WO99/59587 PCTIUS98/10299 -34 The c-bromo-(3-fluorophenyl)acetic acid (24.3 g, 104 mmol) was converted to product in a manner substantially analogous to Preparation 32 to yield 16.3 g. (67.0%). MS(FD), NMR. 5 Preparation 38 a-Bromo-(2,4-difluorophenyl)acetamide The a-bromo-(2,4-difluorophenyl)acetic acid (23.3 g, 93.0 mmol) was converted to product in a manner substantially analogous to Preparation 32 to yield 7.88 10 g. (34.3%). NMR. Preparation 39 c-Bromo-(3,5-difluorophenyl)acetamide The a-bromo-(3,5-difluorophenyl)acetic acid (21.0 g, 83.8 mmol) was converted to product in a manner 15 substantially analogous to Preparation 32 to yield 14.4 g. (68.7%). NMR. Preparation 40 c-Bromo-(2,5-difluorophenyl)acetamide The a-bromo-(2,5-difluorophenyl)acetic acid (27.3 g, 20 109 mmol) was converted to product in a manner substantially analogous to Preparation 32 to yield 18.5 g. (68.0%). MS(FD), NMR. Preparation 41 a-Bromo-(3-trifluoromethylphenyl)acetamide 25 The a-bromo-(3-trifluoromethylphenyl)acetic acid (27.7 g, 98.0 mmol) was converted to product in a manner substantially analogous to Preparation 32 to yield 14.2 g. (51.4%). MS(FD), NMR. Preparation 42 30 x-Bromo-(4-bromophenyl)acetamide The a-bromo-(4-bromophenyl)acetic acid (30.2 g, 103 mmol) was converted to product in a manner substantially analogous to Preparation 32 to yield 23.5 g. (78.1%). MS(FD), NMR. 35 Preparation 43 a-Bromo-(2,3,4-trifluorophenyl)acetamide WO 99/59587 PCT/US98/10299 -35 The a-bromo-(2,3,4-trifluorophenyl)acetic acid (13.5 g, 50.3 mmol) was converted to product in a manner substantially analogous to Preparation 32 to yield 10.2 g. (75.7%). MS(FD), NMR. 5 Preparation 44 a-Bromo-(3,4-difluorophenyl)acetamide The a-bromo-(3,4-difluorophenyl)acetic acid (22.2 g, 88.0 mmol) was converted to product in a manner substantially analogous to Preparation 32 to yield 7.88 10 g. (35.7%). MS(FD), NMR. Preparation 45 a-Bromo-(3,4-dichlorophenyl)acetamide The a-bromo-(3,4-dichlorophenyl)acetic acid (34.6 g, 122 mmol) was converted to product in a manner 15 substantially analogous to Preparation 32 to yield 11.8 g. (34.2%). MS(FD), NMR. Preparation 46 a-Bromo-(2,4,5-trifluorophenyl)acetamide The (x-bromo-(2,4,5-trifluorophenyl)acetic acid (13.6 20 g, 50.3 mmol) was converted to product in a manner substantially analogous to Preparation 32 to yield 7.34 g. (54.4%). NMR. Preparation 47 a-Bromo-(2-chlorophenyl)acetamide 25 The -bromo-(2-chlororophenyl)acetic acid (22.8 g, 91.7 mmol) was converted to product in a manner substantially analogous to Preparation 32 to yield 17.5 g. (77%). MS(FD), NMR. Preparation 48 30 c-Bromo-(3-chlorophenyl)acetamide The a-bromo-(2-chlororophenyl)acetic acid (30.5 g, 123 mmol) was converted to product in a manner substantially analogous to Preparation 32 to yield 17.8 g. (59%). MS(FD), NMR. 35 Preparation 49 c-Bromo-(4-chlorophenyl)acetamide WO99/59587 PCT/US98/10299 -36 The a-bromo-(4-chlororophenyl)acetic acid (21.7 g, 86.9 mmol) was converted to product in a manner substantially analogous to Preparation 32 to yield 15.7 g. (73%). MS(FD), NMR. 5 Preparation 50 x-Bromo-(4-trifluoromethoxyphenyl)acetamide The a-bromo-(4-trifluoromethoxyphenyl)acetic acid (13.5 g, 45.1 mmol) was converted to product in a manner substantially analogous to Preparation 32 to yield 11.1 10 g. (83%). MS(FD), NMR. Preparation 51 x-Bromo-(3-trifluoromethoxyphenyl)acetamide The (x-bromo-(3-trifluoromethoxyphenyl)acetic acid (13.3 g, 44.3 mmol) was converted to product in a manner 15 substantially analogous to Preparation 32 to yield 9.43 g. (71%). MS(FD), NMR. Preparation 52 a-Bromo-(2-fluoro-4-trifluoromethylphenyl)acetamide The a-bromo-(2-fluoro-4-trifluoromethylphenyl)acetic 20 acid (13.0 g, 43.1 mmol) was converted to product in a manner substantially analogous to Preparation 32 to yield 11.1 g. (86%). MS(FD), NMR. Preparation 53 x-Bromo-phenylacetamide 25 The a-bromo-phenylacetic acid (21.5 g, 100 mmol) was converted to product in a manner substantially analogous to Preparation 32 to yield 16.8 g. (78%). NMR. Preparation 54 a-Bromo-(thiophen-3-yl)acetamide 30 The a-bromo(thiophen-3-yl)acetic acid (9.07 g, 41.0 mmol) was converted to product in a manner substantially analogous to Preparation 32 to yield 6.50 g. (72.0%). MS, MP. Preparation 55 35 a-Bromo-(2-methoxyphenyl)acetamide The a-bromo-(2-methoxyphenyl)acetic acid (26.5 g, 108 mmol) was converted to product in a manner WO 99/59587 PCT/US98/10299 -37 substantially analogous to Preparation 32 to yield 21.6 g. (82.0%). NMR. Preparation 56 a-Bromo-isobutylacetamide Br

NH

2 0 5 The a-bromo-(4-methyl)pentanoic acid (35.0 g, 179 mmol) was converted to product in a manner substantially analogous to Preparation 32 to yield 20.9 g. (60.1%). EA, MS(EI). 10 Preparation 57 a-Bromo-benzylacetamide The a-bromo-benzylacetic acid (64.0 g, 279 mmol) was converted to product in a manner substantially analogous to Preparation 32 to yield 22.5 g. (35.4%). EA, MS(FD). 15 Preparation 58 a-Bromo-(4-nitrophenyl)acetamide The a-bromo-(4-nitrophenyl)acetic acid (36.6 g, 141 mmol) was converted to product in a manner substantially analogous to Preparation 32 to yield 19.3 g. (52.9%). 20 NMR. Preparation 59 2,6-Difluoromandelic acid F OHOH 0 F The 2,6-difluorobenzaldehyde (25.0 g, 176 mmol) 25 and zinc iodide (5.0 mg, 0.02 mmol) were placed in a flame-dried 250 ml 3-necked round bottom flask under N2. Trimethylsilyl cyanide (17.45 g, 176.0 mmol) was added dropwise over 20 minutes and the reaction was allowed to stir for 72 hours. 9N HC1 (200 ml) was added and the 30 solution was refluxed overnight. The reaction was cooled WO99/59587 PCT/US98/10299 -38 to RT and extracted with Et20. The Et20 was extracted with saturated NaHCO3 then acidified to pH 1 with 5N HC1. The acidic solution was extracted with Et20 and the organic layer dried over Na2SO4. The Na2SO4 was filtered 5 and the Et20 removed in vacuo leaving a white solid which was recrystallized from CHC13 yielding 23.6 g (71%) of product as a white solid. NMR, MS, IR, EA. Preparation 60 2,3,4,5,6-Pentafluoromandelic acid 10 The 2,3,4,5,6-pentafluorobenzaldehyde (49.4 g, 252 mmol) was converted to product in a manner substantially analogous to Preparation 59 to yield 52.3 g. (86.0%). EA, MS(FD). Preparation 61 15 2-Trifluoromethylmandelic acid The 2-trifluoromethylbenzaldehyde (43.9 g, 252 mmol) was converted to product in a manner substantially analogous to Preparation 59 to yield 39.1 g. (70.5%). EA, MS(FD). 20 Preparation 62 Thiophen-3-ylmandelic acid The thiophen-3-ylcarboxaldehyde (28.3 g, 252 mmol) was converted to product in a manner substantially analogous to Preparation 59 to yield 13.4 g. (33.8%). 25 EA, MS(FD). Preparation 63 2-Trifluoromethyl-4-fluoromandelic acid The 2-trifluoromethyl-4-fluorobenzaldehyde (48.4 g, 252 mmol) was converted to product in a manner 30 substantially analogous to Preparation 59 to yield 50.1 g. (84%). EA, MS(FD). Preparation 64 2-Fluoro-6-trifluoromethylmandelic acid The 2-fluoro-6-trifluoromethylbenzaldehyde (48.4 g, 35 252 mmol) was converted to product in a manner substantially analogous to Preparation 59 to yield 49.7 g. (84%). EA, MS(FD).

WO99/59587 PCT/US98/10299 -39 Preparation 65 4-Carboxymandelic acid The 4-cyanobenzaldehyde (33.0 g, 252 mmol) was converted to product in a manner substantially analogous 5 to Preparation 59 to yield 27.0 g. (54.6%). MS(FD), NMR. Preparation 66 x-O-acetyl-(2,6-difluorophenyl)acetic acid F OAc OH F 10 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 onto 1.5 L of ice water and stirred for 1 hour. The aqueous solution was extracted with Et20 and the 15 organic layer dried over Na2SO4. The Na2SO4 was filtered and the Et20 removed in vacuo leaving a white solid which was recrystallized from Et20/hexanes yielding 18.54 (90%) of product as a white solid. EA, MS(FD). Preparation 67 20 a-O-acetyl-(2,3,4,5,6-pentafluorophenyl)acetic acid The 2,3,4,5,6-pentafluoromandelic acid (70.5 g, 291 mmol) was converted to product in a manner substantially analogous to Preparation 66 to yield 82.8 g. (100%). EA, MS(FD). 25 Preparation 68 a-O-acetyl-(2-trifluoromethylphenyl)acetic acid The 2-trifluoromethylmandelic acid (19.8 g, 90.0 mmol) was converted to product in a manner substantially analogous to Preparation 66 to yield 20.8 g. (88.0%). 30 EA, MS(FD). Preparation 69 X-O-acetyl-(2-trifluoromethyl-4-fluorophenyl)acetic acid The 2-trifluoromethyl-4-fluoromandelic acid (49.4 g, 208 mmol) was converted to product in a manner WO99/59587 PCT/US98/10299 -40 substantially analogous to Preparation 66 to yield 58.1 g. (100%). EA, MS(FD). Preparation 70 a-O-acetyl-(2-fluoro-6-trifluoromethylphenyl)acetic acid 5 The 2-fluoro-6-trifluoromethylmandelic acid (48.4 g, 252 mmol) was converted to product in a manner substantially analogous to Preparation 66 to yield 50.1 g. (84%). EA, MS(FD). Preparation 71 10 a-O-acetyl-(4-trifluoromethylphenyl)acetic acid The 4-trifluoromethylmandelic acid (19.8 g, 89.9 mmol) was converted to product in a manner substantially analogous to Preparation 66 to yield 20.3 g. (86%). MS(FD), NMR. 15 Preparation 72 a-O-acetyl-(4-carboxyphenyl)acetic acid The 4-carboxymandelic acid (27.0 g, 138 mmol) was converted to product in a manner substantially analogous to Preparation 66 to yield 27.5 g. (83.9%). MS(FD), 20 NMR. Preparation 73 x-0-acetyl-(2,6-difluorophenyl)acetamide The a-o-acetyl-(2,6-difluorophenyl)acetic acid (18.5 g, 80.4 mmol), in 200 ml of dry CH2C12, and 3 drops DMF 25 were cooled in an ice bath under N2. Oxalyl chloride (50.0 g, 448 mmol) in 50 ml dry CH2C12 was added dropwise over 25 minutes. The ice bath was removed and the reaction was allowed to stir for 3 hours. The solvent was removed in vacuo then azeotroped with toluene (3 x 25 30 ml). The remaining oil was dissolved in 100 ml of toluene and 700 ml of hexanes and stirred vigorously with a mechanical stirrer. Ammonia gas was then blown through a gas dispersion tube over the top of this solution for 1 hour. The resulting solid was filtered and solvents 35 removed in vacuo. The solid was dissolved in EtOAc/H20 and the organic layer washed with 1N HC1, saturated NaHCO3, brine, then dried over Na2SO4. The Na2SO4 was filtered and the EtOAc removed in vacuo. The remaining WO99/59587 PCT/US98/10299 -41 solid was recrystallized from EtOAc/hexanes yielding 16.7 g (90%) of the desired product. Preparation 74 5 a-O-acetyl-(2,3,4,5,6-pentafluorophenyl)acetamide The a-o-acetyl-(2,3,4,5,6-pentafluorophenyl)acetic acid (106 g, 373 mmol) was converted to product in a manner substantially analogous to Preparation 73 to yield 94.0 g. (89%). EA, MS(FD). 10 Preparation 75 a-O-acetyl-(2-trifluoromethylphenyl)acetamide The a-o-acetyl-(2-trifluoromethylphenyl)acetic acid (20.8 g, 79.4 mmol) was converted to product in a manner substantially analogous to Preparation 73 to yield 18.8 15 g. (90.7%). EA, MS(FD). Preparation 76 a-O-acetyl-(2-trifluoromethyl-4-fluorophenyl)acetamide The a-o-acetyl-(2-trifluoromethyl-4 fluorophenyl)acetic acid (58.1 g, 208 mmol) was converted 20 to product in a manner substantially analogous to Preparation 73 to yield 52.4 g. (90.0%). EA, MS(FD). Preparation 77 x-0-acetyl-(2-fluoro-6-trifluoromethylphenyl)acetamide The a-o-acetyl-(2-fluoro-4 25 trifluoromethylphenyl)acetic acid (53.4 g, 191 mmol) was converted to product in a manner substantially analogous to Preparation 73 to yield 47.9 g. (90%). EA, MS(FD). Preparation 78 a-O-acetyl-(4-trifluoromethylphenyl)acetamide 30 The a-o-acetyl-(4-trifluoromethylphenyl)acetic acid (20.3 g, 77.3 mmol) was converted to product in a manner substantially analogous to Preparation 73 to yield 18.8 g. (93%). Preparation 79 35 Methyl-(a-hydroxy-4-carbomethoxybenzyl)acetate The a-0-acetyl-(4-carboxyphenyl)acetic acid (23.2 g, 97.3 mmol) was suspended in 300 ml of CH2Cl2 and 3 drops of DMF was added while the reaction stirred under N2 in WO99/59587 PCTIUS98/10299 -42 an ice bath. Oxalyl chloride (50.0 g, 448 mmol) in 50 ml of dry CH2C12 was added dropwise over 20 minutes. The ice bath was removed and the reaction stirred at RT for about 5 hours (until all solids in solution). The 5 solvents were removed and the residue and 200 ml of MeOH were placed in an addition funnel and stirred overnight. The solvents were then removed and the residue taken up in EtOAc. The EtOAc was washed with NaHCO3 (3 x 100 ml), brine, and then dried over NaSO4. The EtOAc was removed 10 in vacuo to give 22 g of an oil. (100%). EA, MS(FD). Preparation 80 x-Hydroxy-(2,6-difluorophenyl)acetamide The (x-O-acetyl-(2,6-difluorophenyl)acetamide (16.7 g, 73.0 mmol) was dissolved in 125 ml of methanol and 35 15 ml of diisopropylethylamine then refluxed for 3 hours. The solvents were removed in vacuo and the remaining solid was recrystallized from EtOAc/hexanes yielding 11.42 g (84%) of product as a white solid. EA, MS(FD). Preparation 81 20 a-Hydroxy-(2,3,4,5,6-pentafluorophenyl)acetamide The a-O-acetyl-(2,3,4,5,6 pentafluorophenyl)acetamide (83.0 g, 293 mmol) was converted to product in a manner substantially analogous to Preparation 80 to yield 66.6 g. (94%). EA, MS(FD). 25 Preparation 82 a-Hydroxy-(2-trifluoromethylphenyl)acetamide The a-O-acetyl-(2-trifluoromethylphenyl)acetamide (18.4 g, 70.6 mmol) was converted to product in a manner substantially analogous to Preparation 80 to yield 14.3 30 g. (92.4%). MS(FD), NMR. Preparation 83 x-Hydroxy-(2-trifluoromethyl-4-fluorophenyl)acetamide The a-O-acetyl-(2-trifluoromethyl-4 fluorophenyl)acetamide (50.4 g, 181 mmol) was converted 35 to product in a manner substantially analogous to Preparation 80 to yield 40.9 g. (95%). EA, MS(FD). Preparation 84 c-Hydroxy-(2-fluoro-6-trifluoromethylphenyl)acetamide WO99/59587 PCT/US98/10299 -43 The (x-O-acetyl-(2-fluoromethyl-6 trifluoromethylphenyl)acetamide (44.6 g, 160 mmol) was converted to product in a manner substantially analogous to Preparation 80 to yield 32.1 g. (85%). EA, MS(FD). 5 Preparation 85 a-Hydroxy-(4-trifluoromethylphenyl)acetamide The c-O-acetyl-(4-trifluoromethylphenyl)acetamide (18.8 g, 65.3 mmol) was converted to product in a manner substantially analogous to Preparation 80 to yield 13.8 10 g. (96.1%). EA, MS(FD). Preparation 86 a-Hydroxy-(4-carbomethoxyphenyl)acetamide Freshly prepared ammonia in methanol (300 ml) was added to methyl-(a-hydroxy-4-carbomethoxybenzyl)acetate 15 (21.8 g, 97.3 mmol) and stirred overnight. The solvents were removed in vacuo and the residue recrystalized from CH2C12 to give 17.5 g of product. (85.7%). EA, MS(FD). Preparation 87 a-O-toluenesulfonylimido-(2,6-difluorophenyl)acetamide F F O-Tos NH2 0 20 F The a-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) were combined in 300 ml of dry CH2C12 under N2. The p 25 toluenesulfonyl chloride (11.0 g, 57.6 mmol) was added and the reaction was stirred overnight. The solvents were removed in vacuo and the remaining solids dissolved in EtOAc. The EtOAc was washed with 1N HC1, saturated NaHCO3, brine, then dried over Na2SO4. The Na2SO4 was 30 filtered and the EtOAc removed in vacuo leaving a white solid. The solids were recrystallized from EtOAc/hexanes yielding 15.8 g (88%) of the desired product as a white powder. EA, MS(FD).

WO99/59587 PCTIUS98/10299 -44 Preparation 88 a-O-toluenesulfonylimido-(2,3,4,5,6 pentafluorophenyl)acetamide The a-hydroxy-(2,3,4,5,6-pentafluorophenyl)acetamide 5 (12.1 g, 50.0 mmol) was converted to product in a manner substantially analogous to Preparation 87 to yield 18.3 g. (92%). EA, MS(FD). Preparation 89 a-O-toluenesulfonylimido-(2 10 trifluoromethylphenyl)acetamide The (x-hydroxy-(2-trifluoromethylphenyl)acetamide (14.3 g, 65.2 mmol) was converted to product in a manner substantially analogous to Preparation 87 to yield 21.0 g. (86%). EA, MS(FD). 15 Preparation 90 x-O-toluenesulfonylimido-(2-trifluoromethyl-4 fluorophenyl)acetamide The a-hydroxy-(2-trifluoromethyl-4 fluorophenyl)acetamide (11.9 g, 50.0 mmol) was converted 20 to product in a manner substantially analogous to Preparation 87 to yield 17.0 g. (87%). EA, MS(FD). Preparation 91 a-O-toluenesulfonylimido-(2-fluoro-6 trifluoromethylphenyl)acetamide 25 The x-hydroxy-(2-fluoro-4 trifluoromethylphenyl)acetamide (11.9 g, 50.0 mmol) was converted to product in a manner substantially analogous to Preparation 87 to yield 17.8 g. (91%). EA, MS(FD). Preparation 92 30 a-O-toluenesulfonylimido-(4 trifluoromethylphenyl)acetamide The a-hydroxy-(4-trifluoromethylphenyl)acetamide (9.35 g, 42.7 mmol) was converted to product in a manner substantially analogous to Preparation 87 to yield 12.7 35 g. (80%). EA, MS(FD). Preparation 93 X-O-toluenesulfonylimido-(4-carbomethoxyphenyl)acetamide WO 99/59587 PCTIUS98/10299 -45 The x-hydroxy-(4-carbomethoxyphenyl)acetamide (10.5 g, 50.0 mmol) was converted to product in a manner substantially analogous to Preparation 87 to yield 14.6 g. (80.2%). EA, MS(FD). 5 Preparation 94 1,2-Dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[2,4 difluorophenyl]-carbamoylmethyl)-pyridine NTos N NH 2 O F F The 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine 10 (10.6 g, 30.0 mmol) was dissolved in 75 ml of DMF and stirred in a flame dried flask under N2. Sodium hydride (1.32 g, 33.0 mmol) was added and the solution stirred for 1.5 hours. The a-bromo-(2,4-difluorophenyl)acetamide (7.88 g, 31.5 mmol) was then added and the solution was 15 allowed to stir at RT for 7 days. The reaction was worked up by pouring the solution onto 2.5 L of H20 and stirring for 1 hour. The resulting precipitate was collected by filtration. The filter cake was recrystalized from EtOAc/hexane to yield 13.2 g. (84%). 20 EA, MS(FD). Preparation 95 1,2-Dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[4 fluorophenyl]-carbamoylmethyl)-pyridine The 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine 25 (27.1 g, 77.0 mmol) and a-bromo-(4-fluorophenyl)acetamide (19.6 g, 84.5 mmol) were converted to product in a manner substantially analogous to Preparation 94 to yield 35.0 g. (90.4%). EA, MS(FD). Preparation 96 30 1,2-Dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[4 methoxyphenyl]-carbamoylmethyl)-pyridine The 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and x-bromo-(4- WO99/59587 PCT/US98/10299 -46 methoxyphenyl)acetamide (8.05 g, 33.0 mmol) were converted to product in a manner substantially analogous to Preparation 94, except cesium fluoride was employed instead of sodium hydride and sodium iodide (4.50 g, 30.0 5 mmol) was added, to yield 6.32 g. (41.0%). EA, MS(FD). Preparation 97 1,2-Dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[napth 2-yll-carbamoylmethyl)-pyridine The 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine 10 (18.5 g, 52.7 mmol) and a-bromo-(napth-2-yl)acetamide (14.6 g, 55.3 mmol) were converted to product in a manner substantially analogous to Preparation 94 to yield 15.0 g. (53.3%). EA, MS(FD). Preparation 98 15 1,2-Dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1 napthyl-carbamoylmethyl)-pyridine The 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (14.6 g, 41.5 mmol) and a-bromo-(napth-1-yl)acetamide (11.5 g, 43.6 mmol) were converted to product in a manner 20 substantially analogous to Preparation 94 to yield 14.3 g. (64%). EA, MS(FD). Preparation 99 1,2-Dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[2 fluorophenyl]-carbamoylmethyl)-pyridine 25 The 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (12.3 g, 35.1 mmol) and a-bromo-(2-fluorophenyl)acetamide (8.54 g, 36.8 mmol) were converted to product in a manner substantially analogous to Preparation 94 to yield 16.5 g. (93.6%). EA, MS(FD). 30 Preparation 100 1,2-Dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[3 fluorophenyl]-carbamoylmethyl)-pyridine The 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (23.6 g, 66.9 mmol) and a-bromo-(3-fluorophenyl)acetamide 35 (16.3 g, 70.3 mmol) were converted to product in a manner substantially analogous to Preparation 94 to yield 29.8 g. (88.5%). EA, MS(FD). Preparation 101 WO 99/59587 PCT/US98/10299 -47 1,2-Dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[3,5 difluorophenyl]-carbamoylmethyl)-pyridine The 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and a-bromo-(3,5 5 difluorophenyl)acetamide (7.88 g, 31.5 mmol) were converted to product in a manner substantially analogous to Preparation 94 to yield 14.2 g. (91.0%). EA, MS(FD). Preparation 102 10 1,2-Dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[2,5 difluorophenyl]-carbamoylmethyl)-pyridine The 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and a-bromo-(2,5 difluorophenyl)acetamide (7.88 g, 31.5 mmol) were 15 converted to product in a manner substantially analogous to Preparation 94 to yield 15.3 g. (98%). EA, MS(FD). Preparation 103 1,2-Dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[3 trfluoromethylphenyl]-carbamoylmethyl)-pyridine 20 The 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0) and x-bromo-(3 trifluoromethylphenyl)acetamide (8.88 g, 31.5 mmol) were converted to product in a manner substantially analogous to Preparation 94 to yield 12.7 g. (76%). EA, MS(FD). 25 Preparation 104 1,2-Dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[4 bromophenyl]-carbamoylmethyl)-pyridine The 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0) and a-bromo-(4-bromophenyl)acetamide (9.23 30 g, 31.5 mmol) were converted to product in a manner substantially analogous to Preparation 94 to yield 13.7 g. (81%). EA, MS(FD). Preparation 105 1,2-Dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[2,3,4 35 trifluorophenyl]-carbamoylmethyl)-pyridine The 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and c-bromo-(2,3,4 trifluorophenyl)acetamide (8.44 g, 31.5 mmol) were WO99/59587 PCT/US98/10299 -48 converted to product in a manner substantially analogous to Preparation 94 to yield 11.3 g. (70%). Preparation 106 1,2-Dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[3,4 5 difluorophenyl]-carbamoylmethyl)-pyridine The 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and a-bromo-(3,4 difluorophenyl)acetamide (7.88 g, 31.5 mmol) were converted to product in a manner substantially analogous 10 to Preparation 94 to yield 9.53 g. (61%). EA, MS(FD). Preparation 107 1,2-Dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[3,4 dichlorophenyl]-carbamoylmethyl)-pyridine The 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine 15 (10.6 g, 30.0 mmol) and a-bromo-(3,4 dichlorophenyl)acetamide (9.00 g, 31.5 mmol) were converted to product in a manner substantially analogous to Preparation 94 to yield 13.8 g. (83%). EA, MS(FD). Preparation 108 20 1,2-Dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[2,4,5 trifluorophenyl]-carbamoylmethyl)-pyridine The 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (9.18 g, 26.1 mmol) and a-bromo-(2,4,5 trifluorophenyl)acetamide (7.34 g, 27.4 mmol) were 25 converted to product in a manner substantially analogous to Preparation 94 to yield 11.6 g. (83%). MS(FAB), NMR. Preparation 109 1,2-Dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[2 chlorophenyll-carbamoylmethyl)-pyridine 30 The 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and x-bromo-2-chlorophenylacetamide (7.83 g, 31.5 mmol) were converted to product in a manner substantially analogous to Preparation 94 to yield 10.4 g. (69%). EA, MS(FD). 35 Preparation 110 1,2-Dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[3 chlorophenyl]-carbamoylmethyl)-pyridine WO 99/59587 PCT/US98/10299 -49 The 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and a-bromo-(3-chlorophenyl)acetamide (7.83 g, 31.5 mmol) were converted to product in a manner substantially analogous to Preparation 94 to yield 13.4 5 g. (77%). EA, MS(FD). Preparation 111 1,2-Dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[4 chlorophenyll-carbamoylmethyl)-pyridine The 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine 10 (10.6 g, 30.0 mmol) and a-bromo-(4-chlorophenyl)acetamide (7.81 g, 31.5 mmol) were converted to product in a manner substantially analogous to Preparation 94 to yield 13.8 g. (88%). EA, MS(FD). Preparation 112 15 1,2-Dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[4 trifluoromethoxyphenyl]-carbamoylmethyl)-pyridine The 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and x-bromo-(4 trifluoromethoxyphenyl)acetamide (9.83 g, 33.0 mmol) were 20 converted to product in a manner substantially analogous to Preparation 94, except cesium fluoride was employed instead of sodium hydride, to yield 13.2 g. (77%). EA, MS(FD). Preparation 113 25 1,2-Dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[3 trifluoromethoxyphenyl]-carbamoylmethyl)-pyridine The 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and a-bromo-(3 trifluoromethoxyphenyl)acetamide (9.43 g, 31.6 mmol) were 30 converted to product in a manner substantially analogous to Preparation 94 to yield 12.5 g. (73%). EA, MS(FD). Preparation 114 1,2-Dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[2 fluoro-4-trifluoromethylphenyl]-carbamoylmethyl)-pyridine 35 The 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (7.04 g, 20.0 mmol) and a-bromo-(2-fluoro-4 trifluoromethylphenyl)acetamide (6.50 g, 21.7 mmol) were WO99/59587 PCT/US98/10299 -50 converted to product in a manner substantially analogous to Preparation 94 to yield 10.1 g. (88%). EA, MS(FD). Preparation 115 1,2-Dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-phenyl 5 carbamoylmethyl)-pyridine The 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and x-bromo-phenylacetamide (6.74 g, 31.5 mmol) were converted to product in a manner substantially analogous to Preparation 94, except cesium 10 fluoride was employed instead of sodium hydride, to yield 13.3 g. (91%). EA, MS(FD). Preparation 116 1,2-Dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[4 trifluoromethylphenyll-carbamoylmethyl)-pyridine 15 The 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.0 g, 28.5 mmol) and c-O-toluenesulfonylimido-(4 trifluoromethylphenyl)acetamide (11.1 g, 29.9 mmol) were converted to product in a manner substantially analogous to Preparation 94 to yield 13.9 g. (88%). EA, MS(FD). 20 Preparation 117 1,2-Dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[2 fluoro-6-trifluoromethylphenyl]l-carbamoylmethyl)-pyridine The 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and a-O-toluenesulfonylimido-(2 25 trifluoromethyl-6-fluorophenyl)acetamide (12.9 g, 33.0 mmol) were converted to product in a manner substantially analogous to Preparation 94, except that diisopropylethylamine was employed instead of sodium hydride and the reaction was conducted between 90 and 30 100 0 C, to yield 2.90 g. (16.9%). MS(FD), NMR. Preparation 118 1,2-Dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1 [2,3,4,5,6-pentafluorophenyl]-carbamoylmethyl)-pyridine The 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine 35 (5.28 g, 15.0 mmol) and x-O-toluenesulfonylimido (2,3,4,5,6-pentafluorophenyl)acetamide (5.93 g, 15.0 mmol) were converted to product in a manner substantially analogous to Preparation 94, except that cesium carbonate WO99/59587 PCT/US98/10299 -51 was employed instead of sodium hydride and the reaction was conducted at 60 0 C, to yield 5.07 g. (59%). EA, MS(FD). Preparation 119 5 1,2-Dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[2,6 difluorophenyl]-carbamoylmethyl)-pyridine The 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and a-O-toluenesulfonylimido-(2,6 difluorophenyl)acetamide (10.7 g, 31.5 mmol) were 10 converted to product in a manner substantially analogous to Preparation 94 except that the reaction was run at 60 0 C to yield 7.44 g. (48%). EA, MS(FD). Preparation 120 1,2-Dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[2 15 trifluoromethylphenyl]-carbamoylmethyl)-pyridine The 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and -O-toluenesulfonylimido-(2 trifluoromethylphenyl)acetamide (11.8 g, 31.5 mmol) were converted to product in a manner substantially analogous 20 to Preparation 94 except that the reaction was run at 70 0 C to yield 7.37 g. (44.4%). EA, MS(FD). Preparation 121 1,2-Dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1 [thiophen-3-yl]-carbamoylmethyl)-pyridine 25 The 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (9.90 g, 28.1 mmol) and a-O-toluenesulfonylimido (thiophen-3-yl)acetamide (6.50 g, 29.6 mmol) were converted to product in a manner substantially analogous to Preparation 94 to yield 11.3 g. (81.7%). EA, MS(FD). 30 Preparation 122 1,2-Dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[2 trifluoromethyl-4-fluorophenyll-carbamoylmethyl)-pyridine The 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and a-O-toluenesulfonylimido-(2 35 trifluoromethyl-6-fluorophenyl)acetamide (12.9 g, 33.0 mmol) were converted to product in a manner substantially analogous to Preparation 94, except that diisopropylethylamine was employed instead of sodium WO99/59587 PCT/US98/10299 -52 hydride and the reaction was conducted between 50 and 60 0 C, to yield 14.5 g. (84%). EA, MS(FD). Preparation 123 1,2-Dihydro-2-toluenesulfonylimido-5-benzoyl-N-(l-benzyl 5 carbamoylmethyl)-pyridine The 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and a-bromo-benzylacetamide (7.52 g, 33.0 mmol) were converted to product in a manner substantially analogous to Preparation 94 to yield 802 10 mg. (5.36%). MS(FD), NMR. Preparation 124 1,2-Dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1 isobutyl-carbamoylmethyl)-pyridine The 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine 15 (7.04 g, 20.0 mmol) and a-bromo-isobutylacetamide (8.54 g, 44.0 mmol) were converted to product in a manner substantially analogous to Preparation 94, except that cesium carbonate was employed instead of sodium hydride, to yield 3.35 g. (36.0%). EA, MS(FD). 20 Preparation 125 1,2-Dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[2 methoxyphenyl]-carbamoylmethyl)-pyridine The 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and c-O-toluenesulfonylimido-(2 25 methoxyphenyl)acetamide (7.69 g, 31.5 mmol) were converted to product in a manner substantially analogous to Preparation 94 to yield 10.4 g. (68%). EA, MS(FD). Preparation 126 1,2-Dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[4 30 carbomethoxyphenyl]-carbamoylmethyl)-pyridine The 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (12.0 g, 34.2 mmol) and a-O-toluenesulfonylimido-(4 carbomethoxyphenyl)acetamide (13.0 g, 35.9 mmol) were converted to product in a manner substantially analogous 35 to Preparation 94 to yield 15.5 g. (83%). EA, MS(FD). Preparation 127 1,2-Dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[4 nitrophenyl]-carbamoylmethyl)-pyridine WO 99/59587 PCT/US98/10299 -53 The 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (10.6 g, 30.0 mmol) and a-bromo-(4-nitrophenyl)acetamide (8.55 g, 33.0 mmol) were converted to product in a manner substantially analogous to Preparation 94 to yield 15.3 5 g. (96.2%). MS(FD), NMR. Preparation 128 1,2-Dihydro-2-toluenesulfonylimido-5-(4-fluorobenzoyl)-N (1-[4-fluorophenyl]-carbamoylmethyl)-pyridine The 1,2-dihydro-2-toluenesulfonylimido-5-(4 10 fluorobenzoyl)pyridine (7.40 g, 20.0 mmol) and x-bromo (4-fluorophenyl)acetamide (5.10 g, 22.0 mmol) were converted to product in a manner substantially analogous to Preparation 94 to yield 9.15 g. (88%). EA, MS(FD). Preparation 129 15 1,2-Dihydro-2-toluenesulfonylimido-5-(4-fluorobenzoyl)-N (1-[2-fluoro-4-trifluoromethylphenyl]-carbamoylmethyl) pyridine The 1,2-dihydro-2-toluenesulfonylimido-5-benzoylpyridine (7.40 g, 20.0 mmol) and a-bromo-(2-fluoro-4 20 trifluoromethylphenyl)acetamide (8.60 g, 22.0 mmol) were converted to product in a manner substantially analogous to Preparation 94, except diisopropylethylamine was employed instead of sodium hydride, to yield 8.95 g. (76%). EA, MS(FD). 25 Preparation 130 2-Amino-5-carbomethoxy-pyridine The 6-aminonicotinic acid (50.0 g, 0.362 mol) was dissolved in 3.5 L of MeOH under N2 and chilled to OoC. Hydrogen chloride gas was bubbled through the solution 30 for 45 minutes with the temperature of the solution maintained between 0-15 0 C. The reaction was then heated to 65 0 C for 4 hours. The MeOH was removed in vacuo and the residue taken up in 400 ml of H20. The pH was adjusted to about 6.3 with saturated NaHCO3 to produce a 35 precipitate. The precipitate was filtered and washed with H20. The filter cake was dried in vacuo at 80 0 C to give 48.9 g of product. (88.7%). EA, MS(FD). Preparation 131 WO 99/59587 PCT/US98/10299 -54 2-toluenesulfonylimido-5-carbomethoxy pyridine MeO 2 CN N NHTos The 2-amino-5-carbomethoxy-pyridine (48.9 g, 0.321 mol) 5 was dissolved in 400 ml of pyridine under N2. p Toluenesulfonic acid (73.5 g, 0.386 mol) was added and the solution heated to about 77.5 0 C for 16 hours. The volume was reduced by 3/4 in vacuo and 3.5 L of H20 was added. The resulting precipitate was filtered, washed 10 with H20, and air dried to give 78.4 g of product. (79.7%). MS(FD), NMR. Preparation 132 1,2-Dihydro-2-toluenesulfonylimido-5-carbomethoxy-(1 phenyl-carbamoylmethyl)pyridine MeO 2 C N NTos

SCONH

2 15 The 2-toluenesulfonylimido-5-methoxycarbonylpyridine (73.4 g, 0.240 mol) was suspended in 465 ml of DMF under N2. Sodium hydride (60%, 10.1 g, 0.253 mol) was added in two portions. When the reactants were all in solution, 20 (about 45 minutes) x-bromophenylacetamide (53.8 g, 0.252 mol) was added and the solution was allowed to stir for 64 hours. The volume was reduced by 2/3 in vacuo and the mixture was poured into 3 L of H20 and the mixure stirred for 2 hours. The precipitate was filtered and washed 25 with H20. The filter cake was dried in vacuo at 600C to give 103.4 g of product. (98.2%). MS(FD), NMR. Preparation 133 2-Trifluoroacetamido-3-phenyl-6 (carbomethoxy)imidazo[1,2-a]pyridine WO 99/59587 PCT/US98/10299 -55 ~N MeO2 NHCOCF 3 MeO2C N The 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 5 of CH2C12 were combined under N2 and heated to reflux. The solution was refluxed for 6 hours before concentrating in vacuo. The residue was dissolved in 1.5 L of CH2C12 and washed with saturated NaHCO3 (3 x 500 ml), brine (2 x 500 ml), dried over Na2SO4, and filtered. 10 The mother liquor was concentrated in vacuo, the residue taken up in 250 ml of hot EtOAc, and the product precipitated with 700 ml of hexanes. The precipatating mixture was placed in the freezer for 18 hours, then filtered, washed with hexane, and dried in vacuo at 40 0 C 15 to give 75.3 g of product. (quant. yeild). NMR. Preparation 134 2-Amino-3-phenyl-6-(carbomethoxy)imidazo[1,2-a] pyridine N

NH

2 MeO2C N The 2-trifluoroacetamido-3-phenyl-6 20 (carbomethoxy)imidazo-[1,2-a]-pyridine (136 g, 0.440 mol) was dissolved in 845 ml of MeOH. The diisopropylethylamine (280 ml, 1.61 mol) was added over 15 minutes. The reaction was heated slowly to reflux and stirred for 68 hours. The reaction was cooled to OoC and 25 the precipitate filtered. The filter cake was washed with cold MeOH and air dried to give 84.0 g of product. (71.4%). EA, MS(FD). Preparation 135 WO99/59587 PCTIUS98/10299 -56 2-Amino-3-phenyl-6-(carboxy)imidazo[1,2-a]pyridine The 2-amino-3-phenyl-6-(carbomethoxy)imidazo-[1,2-a] pyridine (83.9 g, 0.314 mol), lithium hyroxide monohydrate (65.9 g, 1.57 mol), 1113 ml of THF, and 371 5 ml of H20 were combined and stirred for 18 hours at RT. The reaction was concentrated in vacuo and the residue taken up in 5 L of H20. The pH was adjusted to 5 with 5N HC1. The resulting precipitate was filtered and air dried for 72 hours to give 80.5 g of product. (quant. 10 yeild). NNR, MS(FD). Preparation 136 2-Amino-3-phenyl-6-(N-methyl-N methoxycarbamoyl)imidazo[1,2-a] pyridine ~N

NH

2 MeON N N 15 The 2-amino-3-phenyl-6-(carboxy)imidazo-[1,2-a]-pyridine (80.4 g, 0.317 mol) and N,O-dimethylhydroxylamine hydrochloride (92.8 g, 0.951 mol) were dissolved in 500 ml DMF under N2. The diisopropylethylamine (123 g, 0.951 mol) was added and the mixture stirred for 30 minutes at 20 RT. The 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (122 g, 0.634 mol) was added and allowed to stir for 19 hours at RT. The DMF was removed in vacuo and the residue was poured onto 4 L of H20. The aqueous layer was extracted with CH2C12 (3 x 500 ml) and the 25 organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was taken up in 400 ml of EtOAc and stirred for 1 hour at RT to form the precipitate. The precipitate was filtered and washed with cold EtOAc. The filter cake was dried in 30 vacuo at 40 0 C to yield 55.5 g of product. (59.2%s). MS(FD), NMR. Preparation 137 2-Ilodopyridine WO 99/59587 PCT/US98/10299 -57 A mixture of 2-bromopyridine (48.0 g, 303 mmol) and 240 ml of a 47% hydroiodic acid solution were refluxed for 8 hours and then stirred at RT for 3.5 days. The reaction mixture was poured onto aqueous NaOH (240 ml of 5 40% NaOH and 250 g of ice). The mixture was extracted with Et20 (3 x 200 ml) and the ether was washed with 100 ml of brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was distilled in vacuo twice collecting fractions between 83 and 88 0 C to 10 yield 18.6 g of product. (30%). EA, MS(FD). Preparation 138 4-Ilodopyridine The 4-bromopyridinehydrochloride (50.0 g, 257 mmol) was converted to product in a manner substantially 15 analogous to Preparation 137 to yield 32.9 g. (62.4%). MS(FD), NMR. Preparation 139 N-(3-phenyl-6-[N-methyl-N-carbamoyl]imidazo[1,2 a]pyridin-2-yl)-2,2,5,5-tetramethyl-l-aza-2,5 20 disilacyclopentane N Si N \ N N Si MeO- N N / 0 O \/ The 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. The 25 1,1'ethylenebis(N,N,1,1,-tetramethylsilanamine) (1.227 g, 5.28 mmol) and zinc iodide (10 mg, 0.031 mmol) were added and the mixture heated to reflux for 4 hours. The solvent was removed in vacuo and the crude product was used in subsequent reactions without further 30 purification. Preparation 140 WO 99/59587 PCT/US98/10299 -58 1-Carbamoylmethyl-1,2-dihydro-2-toluenesulfonimido-6 benzoylpyridine 01 * N-Tos k, CONH 2 0 To a stirred suspension of 1,2-dihydro-2 5 toluenesulfonimido-5-benzoylpyridine (11.65 g, 32.10 mmol) in 100 ml of dry DMF was added diisopropylethylamine (6.34 ml, 34.2 mmol). After 15 minutes, the solution turned clear. Iodoacetamide (6.74g, 34.2 mmol) was then added. The mixture was stirred for 10 24 hours and then poured onto H20 (2 L) and stirred for an additional hour. The solids were collected and air dried yielding 13.15 g (97%) of a white solid. EIMS, NMR. Preparation 141 15 Diethyl-(N-methylcarbamoylmethyl)phosphonate 0 EtO II EtO P CONHMe A solution of 4.12 mL of 40% methylamine (aqueous, 47 mmol) in 8.3 mL of MeOH was cooled to -78 0 C. Triethyl phosphonoacetate (8.85 mL, 44.2 mmol) was added dropwise 20 over 10 minutes. The reaction mixture was allowed to warm to RT then stirred at this temperature for 29 hours (TLC: MeOH/CH2CL2: 1/9). The solvents were removed in vacuo at 35 0 C and the resulting colorless liquid was purified by distillation (0.5 mmHg/130 0 C). (87%). NMR. 25 Preparation 142 Isopropyl isopropanethiol-sulfonate iPr-S(0)2-S-(iPr) To a solution of diisopropylpropanethiol sulfonate (10.0 g, 66.5 mmol) in 55 ml of acetic acid was added dropwise 30 33% hydrogen peroxide (14.4 g, 140 mmol) over a 30 minute period at 0 0 C. After stirring for 24 hours at room temperature, the solvents were evaporated to dryness and WO99/59587 PCTIUS98/10299 -59 the crude oil was purified by column chromatography (EtOAc/hexane) to give 8.5 g of a colorless oil product. (70%). 1 H-NMR, 13 C-NMR. Preparation 143 5 1-Carbamoylmethyl-1,2-dihydro-2-toluenesulfonimido-6 (carbomethoxy)pyridine Z rN-Tos Ns

CONH

2 MeO 2 C The 1,2-dihydro-2-toluenesulfonimido-5 methoxycarbonylpyridine (20 g, 65.3 mmol) was suspended 10 in dry 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 hours. The reaction was poured onto H20 (60 mL) and stirred for 90 15 minutes. The solid was collected by filtration, washed with H20 (1 L), Et20 (200 mL), and dried in vacuo to give 21.8 g (91.7%) of desired product as a white solid. MS(FAB), NIMR. Preparation 144 20 2-Trifluoracetamido-6-carbomethoxy-imidazo[1,2-a ]pyridine r NHCOCF3 Me02C To a suspension of 1-carbamoylmethyl-1,2-dihydro-2 toluenesulfonimido-6-(carbomethoxy)pyridine (5.00 g, 13.8 25 mmol) in dry CH2C12 (75 mL), under an argon atmosphere, was added trifluoracetic anhydride (60 ml, 425 mmol). The resulting solution was refluxed for 3 hours. The solvents were removed in vacuo. The residue was taken up in EtOAc (150 mL) and the suspension was stirred for 30 30 minutes. The solids were collected, poured onto H20 (50 mL) and stirred for 30 minutes. The solids were collected and dried in vacuo to give 1.92 g (49%) of product as a white solid. MS(FAB), NMR.

WO 99/59587 PCT/US98/10299 -60 Preparation 145 2-Trifluoroacetamido-6-(N-methoxy-N-methylamido) imidazo[1,2-a] pyridine N N N NHCOCF 3 MeON N 0 5 To a cooled solution (-20 0 C) of 2-trifluoracetamido 6-carbomethoxy-imidazo[1,2-a ]pyridine (1.50 g, 5.23 mmol) and N-0-dimethylaminohydrochloride (893 mg, 9.15 mmol) in 30 ml of THF was added dropwise isopropyl magnesiun chloride (12.0 ml, 24.1 mmol) over 20 minutes. 10 The reaction mixture was stirred at -20 0 C for 1 hour. The solvent was removed and the residue was dissolved in EtOAc and washed with saturated NH4Cl. The combined organic extracts were dried (Na2SO4) and the solvent was removed in vacuo to give 1.23 g of a white solid. (75%). 15 HRMS calcd. for C12H1N403F3: 316.0783. Found: 316.0782, NMR. Preparation 146 2-Trifluoroacetamido-3-phenyl-6-(N-methyl-N methoxycarbamoyl)-imidazo[1,2-a]pyridine OMe ' N N NNHCOCF 3 ,N0, N / o\ 20 The 2-trifluoroacetamido-3-phenyl-6-carbomethoxy imidazo[1,2-a]pyridine (12.0 g, 33 mol) was converted to product in a manner substantially analogous to Preparation 189 to yield 8.0 g. (68%). MS(FAB), NMR. 25 Preparation 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 was added N-methoxy-N methylamino hydrochloride (500 mg, 5.13 mmol) and 30 diisopropylethylamine (1.33 g, 10.2 mmol). The reaction mixture was stirred for 10 minutes. The solvent was WO99/59587 PCT/US98/10299 -61 removed in vacuo and the resulting residue was purified by column chromatography to give 950 mg of product as an oil. (95%). Preparation 148 5 2-Chloro-5-(l-phenyl-2-N-methylcarbamoylvinyl)pyridine -rCl MeNHOC To a solution of potasium hexamethyldisilazide (9.2 g, 46 mmol) in 25 mL of dry DMF under an argon atmosphere at 0 0 C was added a solution of diethyl(N 10 methylcarbamoylmethyl)phosphonate (4.81 g, 23.0 mmol) in 50 mL of dry DMF. The reaction mixture was stirred at 0 0 C for about 2 hours. A solution of 2-chloro-5 benzoylpyridine (2,5 g, 11,5 mmol) in 25 mL of dry DMF was added via cannula. The ice bath was removed and the 15 resulting brown solution was allowed to warm to RT and stir for 16 hours. The mixture was quenched with saturated NH4Cl (30 mL) and extracted with EtOAc. The organic layers were combined and washed with saturated NH4Cl and then with brine. After drying over NaSO4, the 20 solvent was removed in vacuo and the resulting residue was passed through a chromatography column (Hex/AcOEt 1:1) to give 1.5 g (50%) of a mixture of isomers E:Z in 1:1.5 ratio. The isomers were separated by crystallization. Z-isomer, IR, NMR and the E-isomer, IR, 25 NMR. Preparation 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 dry THF was added, at -78 0 C, n 30 butyl lithium (1.6 M in hexane, 0.47 ml, 0.749 mmol). The reaction mixture was stirred at this temperature for 1 hour. A solution of 6-chloro-N-methoxy-N-methyl nicotinamide (0.13 g, 0.68 mmol) in 5ml of THF was added and the reaction mixture was allowed to warm to RT and WO99/59587 PCTIUS98/10299 -62 stir for 6 hours. Saturated NH4Cl was added and the mixture was extracted with CH2C12 (3 x 10 ml). The organic layers were combined, washed with brine, and dried over NaSO4. The solvents were removed in vacuo and 5 the residue was purified by column chromatography (Hex/AcOEt 9:1) to give 130 mg (77%) of an oily produt. IR, NMR. Preparation 150 2-Chloro-5-(1-(2,3-difluorophenyl)-2-N 10 methylcarbamoylvinyl)pyridine ,r ,-Cl F N F MeNHOC The 2-chloro-5-(2,3-difluorobenzoyl)pyridine was converted to product in a manner substantially analogous to preparation 203 to obtain a mixture of two isomers. 15 After crystallization from EtOAc, the Z isomer was isolated in 35% yield, IR, NMR, while the E isomer was recovered from the filtrate in 17% yield, IR, NMR. Preparation 151 1-(2-Oxo-2-phenylethyl)-2-chloro-5-[(E)-l-phenyl-2 20 methylcarbamoylvinyl]pyridinium iodide Cl N + I Ph O MeNHOC To a mixture of 2-chloro-5-[(E)-l-phenyl-2-N methylcarbamoylvinyl]pyridine (100 mg, 0.367 mmol) and bromoacetophenone (0.270 g, 1.35 mmol) in 5 ml of CH3CN 25 was added Nal (0.21 g, 1.4 mmol). The reaction mixture was refluxed for 40 hours. The CH3CN was removed in vacuo and the resulting residue was dissolved in hot EtOH (40-45 0 C). After a rapid filtration, the filtrate was removed in vacuo and the resulting solid was washed with WO99/59587 PCT/US98/10299 -63 100 mL of Et20 then with cold EtOAc to yield product as a solid in 85% yield. IR, NMR. Preparation 152 1-[2-Oxo-2-(4-fluorophenyl)ethyl]-2-chloro-5-[(E)-1 5 phenyl-2-methylcarbamoylvinyl]pyridinium iodide -Cl /N +

F

0 MeNHOC F The 2-chloro-5-[(E)-1-phenyl-2-N methylcarbamoylvinyl]pyridine (300 mg, 1.10 mmol) and 4 fluorobromoacetophenone were converted to product in a 10 manner substantially analogous to Preparation 151 to yield 395 mg. (67%) IR, NMR. Preparation 153 1-[2-Oxopropyl]-2-chloro-5-[(E)-l-phenyl-2 methylcarbamoylvinyl]pyridinium iodide 15 + 15 MeNHOC The 2-chloro-5-[(E)-1-phenyl-2-N methylcarbamoylvinyl]pyridine (300 mg, 1.10 mmol) and chloropropanone were converted to product in a manner substantially analogous to Preparation 151 to yield 297 20 mg. (60%). NMR. Preparation 154 1-[2-Oxo-3,3-dimethylbutyl]-2-chloro-5-[(E)-l-phenyl-2 methylcarbamoylvinyl]pyridinium iodide The 2-chloro-5-[(E)-l-phenyl-2-N 25 methylcarbamoylvinyl]pyridine (300 mg, 1.10 mmol) and chloropinacolone were converted to product in a manner substantially analogous to Preparation 151 to give 141 mg. (26%). IR. Preparation 155 WO99/59587 PCT/US98/10299 -64 1-(N,N-diethylacetamidyl)-2-chloro-5-[(E)-1-phenyl-2 methylcarbamoylvinyl]pyridinium iodide -Cl EtN O MeNHOC I Et The 2-chloro-5-[(E)-1-phenyl-2-N 5 methylcarbamoylvinyl]pyridine (140 mg, 0.514 mmol) and 2 chloro-N,N-diethylacetamide were converted to product in a manner substantially analogous to Preparation 151 to give 75.9 mg. (29%). NMR. Preparation 156 10 l-[2-Oxo-3,3-dimethylbutyl]-2-chloro-5-[(E)-l-(2,3 difluorophenyl)-2-methylcarbamoylvinyl]pyridinium iodide ,/ ,-Cl

/

+ F F \ 1N F t- Bu) O MeNHOC The 2-chloro-5-[(E)-1-(2,3-difluorophenyl)-2-N methylcarbamoylvinyl]pyridine (250 mg, 0.810 mmol) and 15 chloropinacolone were converted to product in a manner substantially analogous to Preparation 151 to give 199 mg. (46%). IR. Examples Example 1 20 2-Trifluoroacetamido-3-(2,5-difluorophenyl)-6-benzoyl imidazo[1,2-a]pyridine $ NCOCF 3 o / F The 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1 [2,5-difluorophenyl]-carbamoylmethyl)-pyridine (14.9 g, 25 28.6 mmol) was dissolved in 400 ml of CH2C12 and WO99/59587 PCT/US98/10299 -65 trifluoroacetic anhydride (50 ml, 354 mmol) was added. The solution was heated to reflux (a dry ice condensor was used to keep volatiles refluxing) and allowed to stir for 3 hours. The solvents were removed in vacuo and the 5 residue taken up in 700 ml of EtOAc. The solution was washed with saturated NaHCO3 (3 x 100 ml), brine (3 x 100 ml), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was recrystalized from EtOAc/hexanes to yield 12.1 g. (94.6%). EA, MS(FD). 10 Example 2 2-Trifluoroacetamido-3-(4-methoxyphenyl)-6-benzoyl imidazo[1,2-a] pyridine N N

NCOCF

3 OMe The 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[4 15 methoxyphenyl]-carbamoylmethyl)-pyridine (13.2 g, 23.3 mmol) was converted to product in a manner substantially analogous to Example 1 to yield 10.6 g. (92%). EA, MS(FD). Example 3 20 2-Trifluoroacetamido-3-(napth-2-yl)-6-benzoyl imidazo[1,2-a]lpyridine - N

NCOCF

3 O : N The 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1 [napth-2-yl]-carbamoylmethyl)-pyridine (14.7 g, 27.4 25 mmol) was converted to product in a manner substantially analogous to Example 1 to yield 10.4 g. (82.4%). EA, MS(FD). Example 4 WO 99/59587 PCT/US98/10299 -66 2-Trifluoroacetamido-3-napthyl-6-benzoyl-imidazo[1,2 a]pyridine N NCOCF3 O ' / F The 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1 5 napthyl-carbamoylmethyl)-pyridine (11.3 g, 22.0 mmol) was converted to product in a manner substantially analogous to Example 1 to yield 8.25 g. (82%). EA, MS(FD). Example 5 2-Trifluoroacetamido-3-(2-fluorophenyl)-6-benzoyl 10 imidazo[1,2-a]pyridine -N N COCF 3 o F The 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[2 fluorophenyl]-carbamoylmethyl)-pyridine (12.3 g, 24.5 mmol) was converted to product in a manner substantially 15 analogous to Example 1 to yield 10.2 g. (97%). EA, MS(FD). Example 6 2-Trifluoroacetamido-3-(3-fluorophenyl)-6-benzoyl imidazo[1,2-a]pyridine

NCOCF

3 20 F The 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[3 fluorophenyl]-carbamoylmethyl)-pyridine (26.6 g, 52.8 mmol) was converted to product in a manner substantially analogous to Example 1 to yield 21.6 g. (95.8%). EA, 25 MS(FD). Example 7 WO 99/59587 PCT/US98/10299 -67 2-Trifluoroacetamido-3-(2,4-difluorophenyl)-6-benzoyl imidazo[1,2-a] pyridine N SN/ ~ NCOCF 3 o F F The 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1 5 [2,4-difluorophenyl]-carbamoylmethyl)-pyridine (11.0 g, 21.1 mmol) was converted to product in a manner substantially analogous to Example 1 to yield 9.24 g. (98.5%). EA, MS(FD). Example 8 10 2-Trifluoroacetamido-3-(3,5-difluorophenyl)-6-benzoyl imidazo[1,2-a]pyridine

NCOCF

3 o F F The 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1 [3,5-difluorophenyl]-carbamoylmethyl)-pyridine (13.3 g, 15 25.6 mmol) was converted to product in a manner substantially analogous to Example 1 to yield 10.2 g. (90.1%). EA, MS(FD). Example 9 2-Trifluoroacetamido-3-(4-fluorophenyl)-6-benzoyl 20 imidazo[1,2-a] pyridine -N N NCOCF 3 F The 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[4 fluorophenyl]-carbamoylmethyl)-pyridine (35.0 g, 69.6 mmol) was converted to product in a manner substantially 25 analogous to Example 1 to yield 18.6 g. (62.7%). EA,

MS(FD).

WO 99/59587 PCT/US98/10299 -68 Example 10 2-Trifluoroacetamido-3-(3-trifluoromethylphenyl)-6 benzoyl-imidazo[1,2-a]pyridine

$NCOCF

3 0 /

F

3 C 5 The 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[3 trifluoromethylphenyl]-carbamoylmethyl)-pyridine (13.3 g, 24.1 mmol) was converted to product in a manner substantially analogous to Example 1 to yield 9.08 g. (80%). EA, MS(FD). 10 Example 11 2-Trifluoroacetamido-3-(4-bromophenyl)-6-benzoyl imidazo[1,2-a]pyridine -N

NCOCF

3 O / o Br The 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[4 15 bromophenyl]-carbamoylmethyl)-pyridine (12.7 g, 22.5 mmol) was converted to product in a manner substantially analogous to Example 1 to yield 10.5 g. (95.4%). EA, MS(FD). Example 12 20 2-Trifluoroacetamido-3-(2,3,4-trifluorophenyl)-6-benzoyl imidazo[1,2-a]pyridine

SNCOCF

3 0 F F F The 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1 [2,3,4-trifluorophenyl]-carbamoylmethyl)-pyridine (11.3 25 g, 20.9 mmol) was converted to product in a manner WO 99/59587 PCTIUS98/10299 -69 substantially analogous to Example 1 to yield 8.43 g. (87%). EA, MS(FD). Example 13 2-Trifluoroacetamido-3-(3,4-difluorophenyl)-6-benzoyl 5 imidazo[1,2-a] pyridine

NCOCF

3 o F F The 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1 [3,4-fluorophenyl]-carbamoylmethyl)-pyridine (9.53 g, 18.3 mmol) was converted to product in a manner 10 substantially analogous to Example 1 to yield 7.44 g. (91%). EA, MS(FD). Example 14 2-Trifluoroacetamido-3-(3,4-dichlorophenyl)-6-benzoyl imidazo [1,2-a] pyridine S!01'N

NCOCF

3 o Cl 15 Cl The 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1 [3,4-dichlorophenyl]-carbamoylmethyl)-pyridine (13.8 g, 24.9 mmol) was converted to product in a manner substantially analogous to Example 1 to yield 9.91 g. 20 (83%). EA, MS(FAB). Example 15 2-Trifluoroacetamido-3-(2,4,5-trifluorophenyl)-6-benzoyl imidazo[1,2-a] pyridine NCOCF3 N- F F F

F

WO 99/59587 PCTIUS98/10299 -70 The 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N- (1 [2,4,5-trifluorophenyl]-carbamoylmethyl)-pyridine (11.6 g, 21.5 mmol) was converted to product in a manner substantially analogous to Example 1 to yield 9.28 g. 5 (93%). EA, MS(FD). Example 16 2-Trifluoroacetamido-3-(2-chlorophenyl)-6-benzoyl imidazo[1,2-a]pyridine NCOCF3 ~c1 0 10 The 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[2 chlorophenyl]-carbamoylmethyl)-pyridine (14.2 g, 27.3 mmol) was converted to product in a manner substantially analogous to Example 1 to yield 10.8 g. (88%). EA, MS(FD). 15 Example 17 2-Trifluoroacetamido-3-(3-chlorophenyl)-6-benzoyl imidazo[1,2-a]pyridine - N N NCOCF3 -% Cl The 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[3 20 chlorophenyl]-carbamoylmethyl)-pyridine (12.0 g, 23.1 mmol) was converted to product in a manner substantially analogous to Example 1 to yield 8.97 g. (88%). EA, MS(FD). Example 18 25 2-Trifluoroacetamido-3-(4-chlorophenyl)-6-benzoyl imidazo[1,2-a]pyridine WO 99/59587 PCT/US98/10299 -71 toN

NCOCF

3 O / Cl The 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[4 chlorophenyl]-carbamoylmethyl)-pyridine (13.8 g, 26.5 mmol) was converted to product in a manner substantially 5 analogous to Example 1 to yield 10.7 g. (91%). EA, MS(FD). Example 19 2-Trifluoroacetamido-3-(4-trifluoromethoxyphenyl)-6 benzoyl-imidazo[1,2-a]pyridine O@ N-/NCOCF 3 o 10 OCF 3 The 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[4 trifluoromethoxyphenyl]-carbamoylmethyl)-pyridine (13.2 g, 23.3 mmol) was converted to product in a manner substantially analogous to Example 1 to yield 10.6 g. 15 (92%). EA, MS(FD). Example 20 2-Trifluoroacetamido-3-(3-trifluoromethoxyphenyl)-6 benzoyl-imidazo[1,2-a]pyridine O N /NCOCF 3

OCF

3 20 The 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[3 trifluoromethoxyphenyl]-carbamoylmethyl)-pyridine (12.5 g, 22.0 mmol) was converted to product in a manner substantially analogous to Example 1 to yield 10.4 g. (96%). EA, MS (FD). 25 Example 21 WO 99/59587 PCTIUS98/10299 -72 2-Trifluoroacetamido-3-(2-fluoro-4 trifluoromethylphenyl)-6-benzoyl-imidazo[1,2-a]pyridine 0 NN/NCOCF3 ~F

CF

3 The 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[2 5 fluoro-4-trifluoromethylphenyl]-carbamoylmethyl)-pyridine (10.1 g, 17.7 mmol) was converted to product in a manner substantially analogous to Example 1 to yield 8.03 g. (92%). EA, MS(FD). Example 22 10 2-Trifluoroacetamido-3-phenyl-6-benzoyl-imidazo[1,2 a] pyridine NNCOCF3 The 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1 phenyl-carbamoylmethyl)-pyridine (13.3 g, 27.3 mmol) was 15 converted to product in a manner substantially analogous to Example 1 to yield 10.0 g. (90%). EA, MS(FD). Example 23 2-Trifluoroacetamido-3-(2,6-difluorophenyl)-6-benzoyl imidazo[1,2-a] pyridine

-NCOCF

3 N 20 The 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1 [2,6-difluorophenyl]-carbamoylmethyl)-pyridine (7.44 g, 14.3 mmol) was converted to product in a manner substantially analogous to Example 1 to yield 5.26 g. 25 (82.8%). EA, MS(FD). Example 24 WO 99/59587 PCT/US98/10299 -73 2-Trifluoroacetamido-3-(2,3,4,5,6-pentafluorophenyl)-6 benzoyl-imidazo[1,2-a]pyridine NN

NCOCF

3 F F 0 F - F F F The 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1 5 [2,3,4,5,6-pentafluorophenyl]-carbamoylmethyl)-pyridine (3.00 g, 5.22 mmol) was converted to product in a manner substantially analogous to Example 1 to yield 1.58 g. (60.8%). EA, MS(FD). Example 25 10 2-Trifluoroacetamido-3-(2-trifluoromethylphenyl)-6 benzoyl-imidazo[1,2-a]pyridine N

ONCOCF

3 0CF 3 The 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[2 trifluoromethylphenyl]-carbamoylmethyl)-pyridine (7.37 g, 15 13.3 mmol) was converted to product in a manner substantially analogous to Example 1 to yield 6.22 g. (98%). EA, MS(FD). Example 26 2-Trifluoroacetamido-3-(thiophen-3-yl)-6-benzoyl 20 imidazo[1,2-alpyridine N

NCOCF

3 0 S The 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1 [thiophen-3-yl]-carbamoylmethyl)-pyridine (11.4 g, 23.1 mmol) was converted to product in a manner substantially 25 analogous to Example 1 to yield 8.88 g. (92.6%). EA, MS(FD). Example 27 WO 99/59587 PCTIUS98/10299 -74 2-Trifluoroacetamido-3-(2-trifluoromethyl-4 fluorophenyl)-6-benzoyl-imidazo[1,2-a]pyridine NCOCF3 N-

CF

3 F The 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[2 5 trifluoromethyl-4-fluorophenyl]-carbamoylmethyl)-pyridine (14.5 g, 25.3 mmol) was converted to product in a manner substantially analogous to Example 1 to yield 11.0 g. (88%). EA, MS(FD). Example 28 10 2-Trifluoroacetamido-3-(2-fluoro-6 trifluoromethylphenyl)-6-benzoyl-imidazo[1,2-a]pyridine - N N N...>NCOCF 3 0 F3CO The 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[2 fluoro-6-trifluoromethylphenyl]-carbamoylmethyl)-pyridine 15 (2.90 g, 5.08 mmol) was converted to product in a manner substantially analogous to Example 1 to yield 2.37 g. (94%). EA, MS(FD). Example 29 2-Trifluoroacetamido-3-(4-trifluoromethylphenyl)-6 20 benzoyl -imidazo[1,2-a]pyridine -NCOCF3 N

CF

3 The 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[4 trifluoromethylphenyl]-carbamoylmethyl)-pyridine (13.3 g, 24.1 mmol) was converted to product in a manner 25 substantially analogous to Example 1 to yield 10.1 g. (88.1%). EA, MS(FD).

WO 99/59587 PCTIUS98/10299 -75 Example 30 2-Trifluoroacetamido-3-(2-methoxyphenyl)-6-benzoyl imidazo[1,2-a] pyridine N -/NCOCF3 O MeOO 5 The 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[2 methoxyphenyl]-carbamoylmethyl)-pyridine (10.4 g, 20.3 mmol) was converted to product in a manner substantially analogous to Example 1 to yield 7.40 g. (83%). EA, MS(FD). 10 Example 31 2-Trifluoroacetamido-3-(4-carbomethoxyphenyl)-6-benzoyl imidazo[1,2-a]pyridine -NCOCF3 N 0 CO2Me The 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[2 15 methoxyphenyl]-carbamoylmethyl)-pyridine (15.5 g, 28.5 mmol) was converted to product in a manner substantially analogous to Example 1 to yield 12.6 g. (94.5%). EA, MS(FD). Example 32 20 2-Trifluoroacetamido-3-(4-nitrophenyl)-6-benzoyl imidazo [1,2-a]pyridine N N NCOCF3 O \ NO2 The 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1-[2 methoxyphenyl]-carbamoylmethyl)-pyridine (15.3 g, 28.9 25 mmol) was converted to product in a manner substantially WO 99/59587 PCTIUS98/10299 -76 analogous to Example 1 to yield 11.2 g. (85.1%). EA, MS(FD). Example 33 2-Trifluoroacetamido-3-benzyl-6-benzoyl-imidazo[1,2 5 a] pyridine NCOCF3 O Bn The 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1 benzyl-carbamoylmethyl)-pyridine (3.44 g, 6.89 mmol) was converted to product in a manner substantially analogous 10 to Example 1 to yield 2.19 g. (74.0%). EA, MS(FD). Example 34 2-Trifluoroacetamido-3-isobutyl-6-benzoyl-imidazo[1,2 a] pyridine NCOCF3

--

r 0 iPr 15 The 1,2-dihydro-2-toluenesulfonylimido-5-benzoyl-N-(1 isobutyl-carbamoylmethyl)-pyridine (3.30 g, 7.09 mmol) was converted to product in a manner substantially analogous to Example 1 to yield 2.37 g. (85.9%). EA, MS(FD). 20 Example 35 2-Trifluoroacetamido-3-(4-fluorophenyl)-6-(4 fluorobenzoyl) -imidazo[1,2-a] pyridine F 4 N- NCOCF3 o F The 1,2-dihydro-2-toluenesulfonylimido-5-(4 25 fluorobenzoyl)-N-(1-[4-fluorophenyl]-carbamoylmethyl) pyridine (9.15 g, 17.6 mmol) was converted to product in a manner substantially analogous to Example 1 to yield 7.11 g. (91%). EA, MS(FD). Example 36 WO 99/59587 PCTIUS98/10299 -77 2-Trifluoroacetamido-3-(2-fluoro-4 trifluoromethylphenyl)-6-(4-fluorobenzoyl)-imidazo[1,2 a] pyridine F -~N F N NCOCF3 O F/\ CF3 5 The 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 product in a manner substantially analogous to Example 1 to yield 6.75 g. (87%). EA, MS(FD). 10 Example 37 2-Trifluoroacetamido-6-benzoyl-imidazo[1,2-a]pyridine N 0 To a suspension of 1-carbamoylmethyl-1,2-dihydro-2 toluenesulfonimido-6-benzoylpyridine (7.15 g, 17.46 mmol) 15 in 85 ml of dry CH2C12 was added trifluoroacetic anhydride (62 ml, 439 mmol). The mixture was stirred for 2.5 hours at 30 0 C under an argon atmosphere. The solvents were removed in vacuo and the foam was taken-up in EtOAc (600 ml), then washed with NaHCO3 (2 x 250 ml) 20 and brine (1 x 250 ml). The organic layer was dried (Na2SO4) and the solvents were removed in vacuo to afford 5.5 g (92%) of product as a white solid. EIMS, NNR. Example 38 2-Trifluoroacetamido-3-iodo-6-benzoyl-imidazo[1,2 25 a]pyridine EL NHCOCF3 I 0 WO 99/59587 PCT/US98/10299 -78 To a solution of 2-trifluoroacetamido-6-benzoyl imidazo[1,2-a]pyridine (2.0 g, 6.0 mmol) in 50 ml of dry CH3CN cooled at 0 0 C, was added N-iodosuccinimide (1.35 g, 6.0 mmol) portionwise. The mixture was stirred for 10 5 minutes. Acetonitrile was removed in vacuo and the residue was dissolved in EtOAc (250 ml), washed with NaHSO3 (40% p/v, 2 x 200 ml) and NaHCO3 (2 x 200 ml). The organic layer was dried (Na2SO4) and EtOAc was removed in vacuo to afford 2.60 g (95%) of product as a 10 yellow solid. EIMS, NMR. Example 39 2-Trifluoroacetamido-3-methylthio-6-benzoyl-imidazo[1,2 a]pyridine I, NHCOCF 3 N/ SMe 0 15 The 2-trifluoroacetamido-3-iodo-6-benzoyl imidazo[l,2-a]pyridine (1.00 g, 2.17 mmol) was dissolved in 20 ml of pyridine (predried over KOH and then molecular sieve 3A , 0.04% H20) under argon atmosphere. Copper bronze (207 mg, 3.25 mmol) was added. To the 20 golden suspension in brown solution was added methyldisulfide (160 41, 2.17 mmol) via syringe. The reaction mixture was heated for 1 hour at 104 0 C then 68 hours at 1000C. The evolution of the reaction was followed by NMR (in each case, a sample was taken, 25 hydrolized and washed with ammonia/NH4Cl (1:9) before checking by NMR). When the reaction was complete, the reaction mixture was diluted in 3 L of EtOAc and stirred for 15 minutes. Two liters of NH4OH/NH4Cl 1:9 were added and the mixture was strongly stirred for 30 minutes in a 30 10 L funnel. The layers were separated and 2 L of NH4OH/NH 4 C1 (1:9) were added to the organic layer. The mixture was again stirred for 30 minutes and then left without stirring for 5 to 10 minutes. The layers were separated and the organic layer was washed with brine.

WO99/59587 PCT/US98/10299 -79 The organic layers were removed in vacuo and the resulting brown solid was subjected to a vary rapid column chromatography (MeOH/CH2Cl2, 2:98) to give 670 mg (81%) of a yellow solid. NMR. 5 Example 40 2-Trifluoroacetamido-3-methylsulfonyl-6-benzoyl imidazo[1,2-a]pyridine N /-NHCOCF 3 O SO2Me 0 The 2-trifluoroacetamido-3-methylthio-6-benzoyl 10 imidazo[1,2-a]pyridine (500 mg, 1.37 mmol) was mixed with mCPBA (563 mg, 2.62 mmol) in 20 ml of dry CH2C12. The reaction mixture was stirred for 3 hours at 0oC and then washed with 1 ml of saturated NaHCO3. The mixture was filtered through celite and washed with EtOAc. The 15 filtrate was removed in vacuo and the residue was purified by column chromatography to yield 385 mg (67%) of a white yellow solid. NMR. Example 41 2-Trifluoroacetamido-3-isopropylthio-6-benzoyl 20 imidazo[1,2-a]pyridine NHCOCF3 N O S o The 2-trifluoroacetamido-3-iodo-6-benzoyl imidazo[1,2-a]pyridine (100 mg, 0.22 mmol) was dissolved in dry pyridine (10 ml) at RT under an argon atmosphere. 25 Copper bronze (21 mg, 0.33 mmol) was added followed by diisopropyl disulfide (35 A1, 0.22 mmol). The mixture was stirred and heated at 100-102 0 C for 83 hours. The reaction was cooled to RT, poured onto 1 L of EtOAc and stirred for 1 hour. A 9:1 solution of NH4Cl/NH40H (750 30 ml) was then added and the mixture stirred for 15 minutes with a mechnical stirrer. The aqueous layer turned WO99/59587 PCT/US98/10299 -80 light-blue and the organic extract was washed again with 750 ml of the 9:1 NH4Cl/NH40H solution (15 minutes) followed by brine (750 ml). The EtOAc was removed in vacuo and the residue was purified by flash 5 chromatography (EtOAc:Hexane 1:1). The product was obtained as a brown oil in 20% yield (18 mg). 1 H-NMR, 1 3 C-NMR. Example 42 2-Trifluoroacetamido-6-[(E)-l-phenyl-2-N 10 methylcarbamoylvinyll -imidazo [1,2-a]pyridine ELJENHCOCF3 MeHN 0 The 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 15 solution was cooled to -78 0 C before the dropwise addition of potasium hexamethyldisilazide (30 mL, 22.5 mmol; 0.5M in toluene). The mixture was stirred for 2 hours at 78 0 C. A solution of 2-trifluoroacetamido-6-benzoyl imidazo[1,2-a]pyridine (2.00 g, 6.00 mmol) in 100 mL of 20 dry THF was added dropwise. The reaction mixture was stirred at -78 0 C for 2 hours and then allowed to warm to room temperature. The resulting brown solution was stirred at RT for 60 hours. The THF was removed in vacuo and the residue was taken up in 400 mL of EtOAc and 25 washed with saturated NH4Cl (2 x 100 mL) and once with brine. After drying over MgSO4, the solvents were removed in vacuo to give a brown solid. NMR analysis of the crude showed only the "E" isomer along with some other side products that were not identified. The crude 30 was purified by column chromatography CH3CN:CH2Cl2 (2:1) to give 920 mg (40%) of product. EIMS, NMR. Example 43 WO99/59587 PCT/US98/10299 -81 2-Trifluoroacetamido-3-iodo-6-[(E)-l1-phenyl-2-N methylcarbamoylvinyl]-imidazo[1,2-a]pyridine N

NHCOCF

3 '. N MeHN I 0 To a solution of 2-trifluoroacetamido-6-[(E)-2-N 5 methylcarbamoyl-1-phenylvinyl]-imidazo[1,2-a]pyridine (423 mg, 1.22 mmol) in 20 ml of dry CH3CN cooled at 0oC, was added N-iodosuccinimide (1,34 mmol, 302 mg) portionwise and the mixture was stirred for 10 minutes. The desired product precipitates as a white solid which 10 is filtered and air-dried affording 375 mg of crude product. The CH3CN was removed in vacuo and the residue dissolved in EtOAc (50 ml). The EtOAc was washed with NaHSO3 (40% p/v) (2 x 50 ml) and NaHCO3 (2 x 50 ml). The organic layer was dried (Na2SO4) and the EtOAc removed in 15 vacuo, affording 240 mg (98% overall yield) of 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

NHCOCF

3 MeHN SO 2 iPr 20 0 To a solution of 2-trifluoroacetamido-3-iodo-6-[(E) 2-N-methylcarbamoyl-l-phenylvinyl]-imidazo[1,2-a]pyridine (70 mg, 0.15 mmol) in 5 ml of THF cooled to -78 0 C was added phenyl lithium (230 A1, 0.33 mmol) under an argon 25 atmosphere. The reaction mixture was stirred for 3 minutes before injecting t-butyl lithium (310 p1l, 0.38 mmol). After stirring for a 10 minute period, a solution WO 99/59587 PCT/US98/10299 -82 of isopropyl isopropanethiol-sulfonate (109 mg, 0.60 mmol) in 5 ml of THF was added. The reaction mixture was stirred for 30 minutes at -78 0 C and then quenched with 2 drops of H20 and 10 ml of THF. Ethyl acetate (15 ml) was 5 added and the mixture was allowed to warm to RT. The solution was filtered through celite and the solvents were removed in vacuo. The residue was then dissolved in dry CH2C12 (10 ml) and cooled to 0oC. Previously dried mCPBA (208 mg, 5 equiv. excess calculated over 100% 10 theoretical yield of sulfide coupling product) dissolved in CH2C12 (40 ml) was then added dropwise until the starting material was completely converted to the sulfone (monitor by TLC). The solution was then washed with Na2SO3 (50 ml) and NaHCO3 (2 x 50 ml). The organics were 15 dried (Na2SO4) and the solvent removed in vacuo. The residue was purified by flash chromatography in silica gel (CH3CN:CH2Cl2 1:1) to give 47 mg of product as a white solid. (63%). NMR Example 45 20 2-Trifluoroacetamido-6-(2,3-difluorobenzoyl)-imidazo[1,2 a]pyridine F N/ > NHCOCF 3 F F 0 To a solution of 1-bromo-2,3-difluorobenzene (480 ml, 4.32 mmol) in THF was added n-butyl lithium (2.05 ml, 25 4.42 mmol) in 10 ml of dry THF at -78 0 C under an argon atmosphere. After 10 minutes stirring, a solution of 2 trifluoroacetamido-6-(N-methoxy-N-methylamido) imidazo[1,2-a]pyridine (513 mg, 1.88 mmol) in THF (15 ml) was added dropwise. The reaction mixture was stirred at 30 -78 0 C for 1 hour. NH4Cl was then added and the reaction was extracted with EtOAc (25 ml) and washed with NH4Cl (2 x 20 ml). The solvents were removed in vacuo and the residue was purified by flash chromatography on silica WO 99/59587 PCT/US98/10299 -83 gel (CH2Cl2:CH3CN 2.5:1) affording 395 mg of product as a white solid. (57%). EIMS, NMR. Example 46 2-Trifluoroacetamido-6-[(E)-1-(2,3-difluorophenyl)-2-N 5 methylcarbamoylvinyll -imidazo [1,2-a] pyridine NHCOCF3

N

N F MeNHOC The 2-trifluoroacetamido-6-(2,3-difluorobenzoyl) imidazo[1,2-a]pyridine (0.454 g, 1.27 mmol) was converted to product in a manner substantially analogous to 10 Preparation 183 to yield 120 mg. (23%). 1 H-NNR, 13

C

NMR. Example 47 2-Trifluoroacetamido-3-iodo-6-[(E)-1-(2,3 difluorophenyl)-2-N-methylcarbamoylvinyl]-imidazo[1,2 15 a] pyridine NHCOCF3 F I MeNHOC To a solution of 2-trifluoroacetamido-6-[(E)-l-(2,3 difluorophenyl)-2-N-methylcarbamoylvinyl]-imidazo [1,2 a]pyridine (116 mg, 0.27 mmol) in 10 ml of dry CH3CN 20 cooled at OOC, was added N-iodosuccinimide (67 mg, 0.30 mmol) portionwise. The reaction mixture was stirred for 15 minutes. The solvent was removed in vacuo, the residue was dissolved in EtOAc (25 ml), washed with NaHSO 3 (40%p/v, 2 x 25 ml), and then with NaHCO3 (2 x 25 25 ml). The organic layer was dried (Na2SO4) and the EtOAc removed in vacuo, affording 130 mg (86%) of product. 1

H

NMR, 13C-NMR. Example 48 2-Trifluoroacetamido-3-phenyl-6-(2,3-difluorobenzoyl) 30 imidazo[1 , 2-a] pyridine WO 99/59587 PCTIUS98/10299 -84 F 77 F , N

NHCOCF

3 aN %0 To a solution of 2,3-difluorobromobenzene (471 ml, 4.206 mmol) in dry THF (20 mL) was added a solution of n butyl lithium (1.6M in hexanes, 2.63 mL) at -78 0 C. The 5 resulting yellow solution was stirred at the same temperature for 70 minutes, then a solution of 2 trifluoroacetamido-3-phenyl-6-(N-methyl-N methoxycarbamoyl)imidazo[1,2-alpyridine (0.500 g, 1.28 mmol) in dry THF (20 mL), was added dropwise via a 10 cannula. The red-orange solution was allowed to warm over 60 minutes. Saturated NH4Cl was added and the mixture was stirred for 25 minutes before extracting with EtOAc. The organic layer was washed with brine, dried (Na2SO4), concentrated in vacuo and purified by column 15 chromatography (CH2Cl2/CH3CN 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 20 a]pyridine F , F / N NHCOCF3 MeNHOC The diethyl-(N-methylcarbamoylmethyl)phosphonate (217 mg, 1.04 mmol) in 250 mL of dry THF was placed in a flame dried flask under an argon atmosphere. The 25 solution was cooled to -78 0 C before the dropwise addition of potasium hexamethyldisilazide (5.13 mL, 2.56 mmol; 0.5 M in toluene). The mixture was stirred for 2 hours at 78 0 C. A solution of the 2-trifluoroacetamido-3-phenyl-6- WO 99/59587 PCTIUS98/10299 -85 (2,3-difluorobenzoyl)-imidazo[l,2-a]pyridine (300 mg, 0.693 mmol) in 100 mL of dry THF was added dropwise. The reaction mixture was stirred at -78 0 C for 2 hours and then allowed to warm to RT. The resulting brown solution 5 was stirred at RT for 48 hours (as it is noted a high amount of sovent was required in order to avoid dealing with heterogenous medium once the reagents were mixed). The THF was removed in vacuo and the mixture was diluted in 400 mL of EtOAc and washed with saturated NH4Cl (2 x 10 100 mL) and once with brine. After drying over MgSO4, the solvents were removed in vacuo to give a brown solid. The residue was purified by column chromatography (CH3CN:CH2Cl2, 2:1) to give 57.6 mg of product. (22%). 1 H NMR, 13 C NMR. 15 Example 50 2-Trifluoroacetamido-3-phenyl-6-[(E)-l-phenyl-2-N methylcarbamoylvinyl] - imidazo[1,2-a]pyridine NHCOCF3 I N /i MeNHOC The 2-trifluoroacetamido-3-phenyl-6-benzoyl 20 imidazo[1,2-a]pyridine (618 mg, 1.27 mmol) was converted to product in a manner substantially analogous to Example 49 to yield 526 mg. (75%). EIMS, NMR. Example 51 2-Trifluoroacetamido-3-(2,5-difluorophenyl)-6-[(E)-1 25 phenyl-2-N-methylcarbamoylvinyl]-imidazo[1,2-a]pyridine NH NHCOCF3 FF MeNHOC The 2-trifluoroacetamido-3-(2,5-difluorophenyl)-6 benzoylimidazo[l,2-a]pyridine (500 mg, 1.15 mmol) was converted to product in a manner substantially analgous 30 to Example 49 to give 483 mg. (86%). EIMS, NMR.

WO 99/59587 PCT/US98/10299 -86 Example 52 2-Trifluoroacetamido-3-(2-trifluoromethyl-4 fluorophenyl)-6-[(E) -1-phenyl-2-N-methylcarbamoylvinyll] imidazo[1,2-a]pyridine NHCOCF3 F3C/ MeNHOC 5 F The 2-trifluoroacetamido-3-(2-trifluoromethyl-4 fluoro-phenyl)-6-benzoylimidazo[l,2-a]pyridine (500 mg, 1.04 mmol) was converted to product in a manner substantially analogous to Example 49 to give 439 mg. 10 (79%). EIMS, NMR. Example 53 2-Trifluoroacetamido-3-(2,3,4-trifluorophenyl)-6-[(E) -1 phenyl-2-N-methylcarbamoylvinyl] -imidazo[1,2-a] pyridine NHCOCF3 MeNHOCF F F 15 The 2-trifluoroacetamido-3-(2,3,4-trifluorophenyl) 6-benzoylimidazo[1,2-a]pyridine (303 mg, 0.672 mmol) was converted to product in a manner substantially analogous to Example 49 to give 168 mg. (50%). NMR. Example 54 20 2-Trifluoroacetamido-3-(3,5-difluorophenyl)-6-[(E)-l phenyl-2-N-methylcarbamoylvinyl] - imidazo[1,2-a] pyridine NHCOCF3 -. F MeNHOC F F The 2-trifluoroacetamido-3-(3,5-difluorophenyl)-6 benzoylimidazo[1,2-a]pyridine (240 mg, 0.554 mmol) was WO 99/59587 PCT/US98/10299 -87 converted to product in a manner substantially analogous to Example 49 to give 161 mg of two isomers E:Z in 1:1 ratio. Yield: 60%. EIMS, NMR. Example 55 5 2-Trifluoroacetamido-3-(3-trifluoromethylphenyl)-6-[(E) 1-phenyl-2-N-methylcarbamoylvinyl] -imidazo [1,2-a] pyridine NHCOCF3 '1 N/ ~CF3 MeNHOC The 2-trifluoroacetamido-3-(3 trifluoromethylphenyl)-6-benzoylimidazo[1,2-a]pyridine 10 (228 mg, 0.491 mmol) was converted to product in a manner substantially analogous to Example 49 to give 228 mg. (57%). EIMS, NMR. Example 56 2-Amino-3-(2,4-difluorophenyl)-6-benzoyl-imidazo[l,2 15 a] pyridine N o F F The 2-trifluoroacetamido-3-(2,4-difluorophenyl)-6 benzoyl-imidazo[1,2-a]pyridine (9.24 g, 20.8 mmol) was dissolved in 250 ml of MeOH and 170 ml of 1N NaOH. The 20 solution was stirred at RT under N2 for 2 weeks. The precipitant was filtered and the filter cake was dissolved in 900 ml of EtOAc. The solution was washed with brine (3 x 50 ml), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was recrystalized 25 from EtOAc/hexane to give 2 crops yielding 5.57 g. (76.8%). EA, MS(FD). Example 57 2-Amino-3-(3,5-difluorophenyl)-6-benzoyl-imidazo[1,2 a]pyridine WO 99/59587 PCT/US98/10299 -88 ON/ 0 F F The 2-trifluoroacetamido-3-(3,5-difluorophenyl)-6 benzoyl-imidazo[1,2-a]pyridine (10.2 g, 22.9 mmol) was converted to product in a manner substantially analogous 5 to Example 56 to yield 4.93 g. (61.6%). EA, MS(FD). Example 58 2-Amino-3-(napth-2-yl)-6-benzoyl-imidazo[1,2-a]pyridine N NH2 The 2-trifluoroacetamido-3-(napth-2-yl)-6-benzoyl 10 imidazo[l,2-a]pyridine (6.05 g, 13.7 mmol) was converted to product in a manner substantially analogous to Example 56 to yield 3.50 g. (70.4%). MS(FD), NMR. Example 59 2-Amino-3-napthyl-6-benzoyl-imidazo[1,2-a]pyridine N NH 15 The 2-trifluoroacetamido-3-napthyl-6-benzoyl-imidazo[1,2 a]pyridine (8.25 g, 18.0 mmol) was converted to product in a manner substantially analogous to Example 56 to yield 4.73 g. (73%). EA, MS(FD). 20 Example 60 2-Amino-3-(2,5-difluorophenyl)-6-benzoyl-imidazo[1,2 a] pyridine WO 99/59587 PCT/US98/10299 -89 KN 2 F The 2-trifluoroacetamido-3-(2,5-difluorophenyl)-6 benzoyl-imidazo[1,2-a]pyridine (12.1 g, 27.1 mmol) was converted to product in a manner substantially analogous 5 to Example 56 to yield 6.10 g. (64.6%). EA, MS(FD). Example 61 2-Amino-3-(2,6-difluorophenyl)-6-benzoyl-imidazo[1,2 a] pyridine N2 OFF 0 F 10 The 2-trifluoroacetamido-3-(2,6-difluorophenyl)-6 benzoyl-imidazo[1,2-a]pyridine (6.01 g, 13.5 mmol) was converted to product in a manner substantially analogous to Example 56 to yield 3.42 g. (72.6%). EA, MS(FD). Example 62 15 2-Amino-3-(4-trifluoromethylphenyl)-6-benzoyl imidazo[1,2-a] pyridine

N

oNH 2

CF

3 The 2-trifluoroacetamido-3-(4-trifluoromethylphenyl)-6 benzoyl-imidazo[1,2-a]pyridine (10.1 g, 21.2 mmol) was 20 converted to product in a manner substantially analogous to Example 56 to yield 4.43 g. (54.8%). EA, MS(FD). Example 63 2-Amino-3-(2-fluorophenyl)-6-benzoyl-imidazo[1,2 a] pyridine WO 99/59587 PCT/US98/10299 -90 N NH2 o / F The 2-trifluoroacetamido-3-(2-fluorophenyl)-6-benzoyl imidazo[1,2-a]pyridine (9.46 g, 22.2 mmol) was converted to product in a manner substantially analogous to Example 5 56 to yield 6.70 g. (91.4%). EA, MS(FD). Example 64 2-Amino-3-(3-fluorophenyl)-6-benzoyl-imidazo[l,2 a] pyridine N NH2 o F 10 The 2-trifluoroacetamido-3-(3-fluorophenyl)-6-benzoyl imidazo[1,2-a]pyridine (14.3 g, 33.6 mmol) was converted to product in a manner substantially analogous to Example 56 to yield 8.30 g. (74.7%). EA, MS(FD). Example 65 15 2-Amino-3-(4-fluorophenyl)-6-benzoyl-imidazo[1,2 a]pyridine

NH

2 O- N o F The 2-trifluoroacetamido-3-(4-fluorophenyl)-6-benzoyl imidazo[1,2-a]pyridine (18.6 g, 43.7 mmol) was converted 20 to product in a manner substantially analogous to Example 56 to yield 11.2 g. (77.2%). EA, MS(FD). Example 66 2-Amino-3-benzyl-6-benzoyl-imidazo[1,2-a]pyridine WO 99/59587 PCT/US98/10299 -91 NH2 N o Bn The 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 analogous to Example 56 to 5 yield 1.29 g. (78.2%). EA, MS(FD). Example 67 2-Amino-3-(3-trifluoromethylphenyl)-6-benzoyl imidazo [1,2-a] pyridine

NH

2 o

F

3 C 10 The 2-trifluoroacetamido-3-(3-trifluoromethylphenyl)-6 benzoyl-imidazo[1,2-a]pyridine (9.39 g, 19.7 mmol) was dissolved in 200 ml of MeOH and diisopropylethylamine (100 ml, 574 mmol) was added. The solution was heated to reflux and then stirred at reflux under N2 for 2 days. 15 The solution was concentrated in vacuo and the residue recrystalized from EtOAc/hexane to yield 6.59 g of product. (87.9%). EA, MS(FD). Example 68 2-Amino-3-(4-methoxyphenyl)-6-benzoyl-imidazo[1,2 20 a] pyridine N

NH

2 O -8 OMe The 2-trifluoroacetamido-3-(4-methoxyphenyl)-6-benzoyl imidazo[1,2-a]pyridine (4.89 g, 11.1 mmol) was converted to product in a manner substantially analogous to Example 25 67 to yield 3.08 g. (80%). EA, MS(FD). Example 69 WO 99/59587 PCT/US98/10299 -92 2-Amino-3-(4-bromophenyl)-6-benzoyl-imidazo[1,2 a] pyridine

NH

2 Br The 2-trifluoroacetamido-3-(4-bromophenyl)-6-benzoyl 5 imidazo[1,2-a]pyridine (3.00 g, 6.15 mmol) was converted to product in a manner substantially analogous to Example 67 to yield 1.80 g. (75%). EA, MS(FD). Example 70 2-Amino-3-(2,3,4-trifluorophenyl)-6-benzoyl-imidazo[1,2 10 a] pyridine -~ NH o F F F The 2-trifluoroacetamido-3-(2,3,4-trifluorophenyl)-6 benzoyl-imidazo[1,2-a]pyridine (8.43 g, 18.2 mmol) was converted to product in a manner substantially analogous 15 to Example 67 to yield 5.82 g. (87%). EA, MS(FD). Example 71 2-Amino-3-(3,4-difluorophenyl)-6-benzoyl-imidazo[1,2 a] pyridine q 2 F F F 20 The 2-trifluoroacetamido-3-(3,4-difluorophenyl)-6 benzoyl-imidazo[1,2-a]pyridine (7.44 g, 16.7 mmol) was converted to product in a manner substantially analogous to Example 67 to yield 5.09 g. (87.2%). EA, MS(FD). Example 72 WO 99/59587 PCT/US98/10299 -93 2-Amino-3-(3,4-dichlorophenyl)-6-benzoyl-imidazo[1,2 a] pyridine N2 S N/ o Cl Cl The 2-trifluoroacetamido-3-(3,4-dichlorophenyl)-6 5 benzoyl-imidazo[1,2-a]pyridine (9.91 g, 20.8 mmol) was converted to product in a manner substantially analogous to Example 67 to yield 7.17 g. (90.4%). EA, MS(FD). Example 73 2-Amino-3-(2,4,5-trifluorophenyl)-6-benzoyl-imidazo[1,2 10 a] pyridine ONH2 F 0 F The 2-trifluoroacetamido-3-(2,4,5-triifluorophenyl)-6 benzoyl-imidazo[1,2-a]pyridine (9.28 g, 20.0 mmol) was converted to product in a manner substantially analogous 15 to Example 67 to yield 7.28 g. (98.9%). EA, MS(FD). Example 74 2-Amino-3-(2-chlorophenyl)-6-benzoyl-imidazo[1,2 a] pyridine K N, O /2 20 The 2-trifluoroacetamido-3-(2-chlorophenyl)-6-benzoyl imidazo[1,2-a]pyridine (10.8 g, 24.2 mmol) was converted to product in a manner substantially analogous to Example 67 to yield 7.45 g. (88.5%). EA, MS(FD). Example 75 WO 99/59587 PCT/US98/10299 -94 2-Amino-3-(3-chlorophenyl)-6-benzoyl-imidazo[I,2 a] pyridine N

NH

2 SCl The 2-trifluoroacetamido-3-(3-chlorophenyl)-6-benzoyl 5 imidazo[1,2-a]pyridine (8.97 g, 20.2 mmol) was converted to product in a manner substantially analogous to Example 67 to yield 6.05 g. (86.1%). EA, MS(FD). Example 76 2-Amino-3-(4-chlorophenyl)-6-benzoyl-imidazo[1,2 10 a] pyridine N NH2 N1 o Cl The 2-trifluoroacetamido-3-(4-chlorophenyl)-6-benzoyl imidazo[1,2-a]pyridine (10.8 g, 24.2 mmol) was converted to product in a manner substantially analogous to Example 15 67 to yield 7.17 g. (85.2%). EA, MS(FD). Example 77 2-Amino-3-(4-trifluoromethoxyphenyl)-6-benzoyl imidazo [1,2-a]pyridine A: y~L:,,NH2

OCF

3 20 The 2-trifluoroacetamido-3-(4-trifluoromethoxyphenyl)-6 benzoyl-imidazo[1,2-a]pyridine (10.6 g, 21.5 mmol) was converted to product in a manner substantially analogous to Example 67 to yield 8.24 g. (96.7%). EA, MS(FD). Example 78 WO 99/59587 PCT/US98/10299 -95 2-Amino-3-(3-trifluoromethoxyphenyl)-6-benzoyl imidazo[1,2-a] pyridine NH2 O /N 0 -- OCF 3 The 2-trifluoroacetamido-3-(3-trifluoromethoxyphenyl)-6 5 benzoyl-imidazo[1,2-a]pyridine (10.4 g, 21.1 mmol) was converted to product in a manner substantially analogous to Example 67 to yield 7.89 g. (94.4%). MS(FD), NMR. Example 79 2-Amino-3-(2-fluoro-4-trifluoromethylphenyl)-6-benzoyl 10 imidazo[1,2-a] pyridine N NF2 0

CF

3 The 2-trifluoroacetamido-3-(2-fluoro-4 trifluoromethylphenyl)-6-benzoyl-imidazo[l,2-a]pyridine (8.03 g, 16.2 mmol) was converted to product in a manner 15 substantially analogous to Example 67 to yield 6.00 g. (92.8%). EA, MS(FD). Example 80 2-Amino-3-(2,3,4,5,6-pentafluorophenyl)-6-benzoyl imidazo [1,2-a] pyridine

NH

2 F 0 F F F 20 F The 2-trifluoroacetamido-3-(2,3,4,5,6-pentafluorophenyl) 6-benzoyl-imidazo[l,2-a]pyridine (5.03 g, 10.1 mmol) was converted to product in a manner substantially analogous to Example 67 to yield 3.79 g. (93.3%). EA, MS(FD).

WO 99/59587 PCTIUS98/10299 -96 Example 81 2-Amino-3-(2-trifluoromethylphenyl)-6-benzoyl imidazo[1,2-a] pyridine N2 0 5 The 2-trifluoroacetamido-3-(2-trifluoromethylphenyl)-6 benzoyl-imidazo[1,2-a]pyridine (6.22 g, 13.0 mmol) was converted to product in a manner substantially analogous to Example 67 to yield 4.25 g. (85.5%). EA, MS(FD). Example 82 10 2-Amino-3-(thiophen-3-yl)-6-benzoyl-imidazo[1,2 a] pyridine I N yN NH N NH2 NN 0 S The 2-trifluoroacetamido-3-(thiophen-3-yl)-6-benzoyl imidazo[1,2-a]pyridine (8.88 g, 21.4 mmol) was converted 15 to product in a manner substantially analogous to Example 67 to yield 5.51 g. (80.7%). EA, MS(FD). Example 83 2-Amino-3-(2-trifluoromethyl-4-fluorophenyl)-6-benzoyl imidazo[1,2-a]pyridine N 0 20 F The 2-trifluoroacetamido-3-(2-trifluoromethyl-4 fluorophenyl)-6-benzoyl-imidazo[l,2-a]pyridine (11.0 g, 22.2 mmol) was converted to product in a manner substantially analogous to Example 67 to yield 8.60 g. 25 (97.2%). MS(FD). Example 84 WO 99/59587 PCTIUS98/10299 -97 2-Amino-3-(2-fluoro-6-trifluoromethylphenyl)-6-benzoyl imidazo[1,2-a] pyridine NN I NH 2 y N 'i-' F 0

F

3 C The 2-trifluoroacetamido-3-(2-fluoro-6 5 trifluoromethylphenyl) -6-benzoyl - imidazo[1,2-a] pyridine 2-trifluoroacetamido-3-(2,3,4,5,6-pentafluorophenyl)-6 benzoyl-imidazo[1,2-a]pyridine (1.80 g, 3.64 mmol) was converted to product in a manner substantially analogous to Example 67 to yield 1.28 g. (88.3%). EA, MS(FD). 10 Example 85 2-Amino-3-(2-methoxyphenyl)-6-benzoyl-imidazo[1,2 a] pyridine N N NH 0 MeO The 2-trifluoroacetamido-3-(2-methoxyphenyl)-6--benzoyl 15 imidazo[1,2-a]pyridine (7.40 g, 16.8 mmol) was converted to product in a manner substantially analogous to Example 67 to yield 5.0 g. (87%). EA, MS(FD). Example 86 2-Amino-3-(4-carbomethoxyphenyl)-6-benzoyl-imidazo[1,2 20 a] pyridine -N I NH2 N N CO2M The 2-trifluoroacetamido-3-(4-carbomethoxyphenyl)-6 benzoyl-imidazo[l,2-a]pyridine (2.13 g, 16.8 mmol) was converted to product in a manner substantially analogous 25 to Example 67 to yield 1.44 g. (85%). EA, MS(FD). Example 87 WO 99/59587 PCT/US98/10299 -98 2-Amino-3-(4-nitrophenyl)-6-benzoyl-imidazo[l,2 a]lpyridine

NO

2 The 2-trifluoroacetamido-3-(4-nitrophenyl)-6-benzoyl 5 imidazo[1,2-a]pyridine (8.59 g, 18.9 mmol) was converted to product in a manner substantially analogous to Example 67 to yield 5.04 g. (74.4%). EA, MS(FD). Example 88 2-Amino-3-isobutyl-6-benzoyl-imidazo[1,2-a]pyridine N iPr 10 0 The 2-trifluoroacetamido-3-isobutyl-6-benzoyl imidazo[l,2-a]pyridine (2.37 g, 6.09 mmol) was converted to product in a manner substantially analogous to Example 67 to yield 1.49 g. (83.5%). EA, MS(FD). 15 Example 89 2-Amino-3-(4-carboxyphenyl)-6-benzoyl-imidazo[1,2 a]lpyridine N NH2 CO2H The 2-amino-3-(4-carbomethoxyphenyl)-6-benzoyl 20 imidazo[1,2-a]pyridine (3.00 g, 8.09 mmol) was dissolved in 25 ml of THF and 8 ml of H20 and stirred at RT. Lithium hydroxide (968 mg, 40.4 nmmol) was added and the reaction stirred overnight. The solvents were removed, and H20 added to solids which were then filtered and 25 washed with H20. The solids were recrystalized from MeOH to yield 2.62 g of product. (91%). EA, MS(FD). Example 90 WO99/59587 PCT/US98/10299 -99 2-Amino-3-(4-N-methoxyamido)-6-benzoyl-imidazo[1,2 a] pyridine N N2 N_ NOMe 0 The 2-amino-3-(4-carboxyphenyl)-6-benzoyl-imidazo[1,2 5 a]pyridine (714 mg, 2.00 mmol), methoxyamine hydrochloride (1.34 g, 16.0 mmol), and diisopropylethylamine (2.93 ml, 16.0 mmol) were suspended in 20 ml of dry DMF under N2. Within 20 minutes the solution was clear to yellow-orange. The reaction was 10 stirred overnight at RT. The DMF was removed in vacuo and the residue poured onto H20 and stirred for 1 hour. The solids were then filtered and air dried. The crude product was recrystalized from EtOAc to give 317 mg of product. (41.0%). EA, MS(FD). 15 Example 91 2-Amino-3-(4-fluorophenyl)-6-(4-fluorobenzoyl) imidazo[1,2-a]pyridine F N 2 Nj 0 F The 2-trifluoroacetamido-3-(4-fluorophenyl)-6-(4 20 fluorobenzoyl)-imidazo[1,2-a]pyridine (7.11 g, 16.0 mmol) was converted to product in a manner substantially analogous to Example 67 to yield 4.80 g. (86.2%). MS(FD), NMR. Example 92 25 2-Amino-3-(2-fluoro-4-trifluoromethylphenyl)-6-(4 fluorobenzoyl)-imidazo[1,2-a]pyridine WO 99/59587 PCTIUS98/10299 -100 F Ng FF

CF

3 The 2-trifluoroacetamido-3-(2-fluoro-4 trifluoromethylphenyl)-6-(4-fluorobenzoyl)-imidazo[1,2 a]pyridine (6.75 g, 13.2 mmol) was converted to product 5 in a manner substantially analogous to Example 67 to yield 4.66 g. (85%). EA, MS(FD). Example 93 2-amino-3-phenyl-6-(a-phenylacetyl)-imidazo[l,2 a]pyridine .N

NH

2 Bn N i00 10 The N-(3-phenyl-6-[N-methyl-N methoxycarbamoyl]imidazo[l,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 N2 and 15 benzylmagnesiumchloride (2 M in THF, 6 ml, 12.0 mmol) was added. The mixture was allowed to stir for 18 hours at RT before adding 15 ml of MeOH and 3 ml of acetic acid. The mixture was allowed to stir for 1 hour at RT. The solvents were removed in vacuo and the residue taken up 20 in 400 ml of Et0Ac and 60 ml of NaHCO3. The EtOAc was separated and washed with with brine (2 x 75 ml), dried over NaSO 4 , and then concentrated in vacuo. The residue was purified by normal phase flash chromatography (EtOAc). The product fractions were recrystalized from 25 EtOAc to yield 398 mg of product. (31.6%). MS(FD), NMR. Example 94 2-Amino-3-phenyl-6-(picolinoyl)-imidazo[1,2-a] pyridine WO 99/59587 PCT/US98/10299 -101 N2 N 0 The 2-iodopyridine (1.23 g, 6.00 mmol) was dissolved in 40 ml of THF under N2 and ethylmagnesiumbromide (2 ml, 3 M, 6 mmol) was added. The mixture was allowed to stir 5 for 30 minutes at RT before adding N-(3-phenyl-6 [carboxyl]imidazo[l,2-a]pyridin-2-yl)-2,2,5,5 tetramethyl-1-aza-2,5-disilacyclopentane (820 mg, 2 mmol) in 25 ml THF via cannula. The resulting mixture was allowed to stir for 18 hours at RT. Methanol (4 ml) and 10 2 ml of acetic acid were added and the mixture was allowed to stir for 1 hour at RT. The solvents were removed in vacuo and the residue purified by normal phase chromatography. The product fractions were recrystalized from EtOAc to yield 205 mg of product. (10.9%). MS(FD), 15 NMR. Example 95 2-Amino-3-phenyl-6-(nicotinoyl)-imidazo[1,2-a]pyridine NH2 N, The N-(3-phenyl-6-[carboxyl]imidazo[1,2-a]pyridin-2-yl) 20 2,2,5,5-tetramethyl-l-aza-2,5-disilacyclopentane (820 mg, 2.00 mmol) was converted to product using 3-iodopyridine in a manner substantially analogous to Example 94 to yield 271 mg. (14.4%). EA, MS(FD). Example 96 25 2-Amino-3-phenyl-6-(isonicotinoyl)-imidazo[1,2-a]pyridine WO 99/59587 PCT/US98/10299 -102 N Na / NH2 The N-(3-phenyl-6-[carboxyl]imidazo[1,2-a]pyridin-2-yl) 2,2,5,5-tetramethyl-l-aza-2,5-disilacyclopentane (3.28 g, 8.00 mmol) was converted to product using 4-iodopyridine 5 in a manner substantially analogous to Example 94 to yield 1.74 g. (69.3%). EA, MS(FD). Example 97 2-Amino-3-(2,4-difluorophenyl)-6-[(E)-benzyloxim-a-yl] imidazo[1,2-a] pyridine N

NH

2 N N HON F 10 F The 2-amino-3-(2,4-difluorophenyl)-6-benzoyl-imidazol[,2 a]pyridine (1.00 g, 2.87 mmol) was dissolved in 40 ml of 80% EtOH/H20. Hydroxylamine hydrochloride (2.39 g, 34.4 mmol) and NaOAc (2.82 g, 34.4 mmol) were added and this 15 mixture was heated to reflux for 4 hours, monitoring the progress of the reaction by HPLC. The reaction was worked up by removing the solvents in vacuo and taking the residue up in 900 ml of EtOAc. The solution was washed with saturated NaHCO3 (3 x 100 ml), brine (3 x 100 20 ml), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was recrystalized with EtOAc and further purified by HPLC to yield 130 mg of the E-isomer. (17.2%) . MS(FD), UV. Example 98 25 2-Amino-3-(4-methoxyphenyl)-6-(benzyloxim-a-yl) imidazo[1,2-a] pyridine WO 99/59587 PCT/US98/10299 -103 N

NH

2 N / HO OMe The 2-amino-3-(4-methoxyphenyl)-6-benzoyl-imidazo[1,2 a]pyridine (2.00 g, 5.83 mmol) was converted to product in a manner substantially analogous to Example 97 to 5 yield 490 mg of E-product, (24.0%), EA, MS(FD), and a small but unspecified amount of Z-product. EA, MS(FD). Example 99 2-Amino-3-(napth-2-yl)-6-[(E) -benzyloxim-a-yl] imidazo[1,2-a] pyridine NH2 oN HO 10 The 2-amino-3-(napth-2-yl)-6-benzoyl-imidazo[1,2 a]pyridine (2.00 g, 5.51 mmol) was converted to product in a manner substantially analogous to Example 97 to yield 115 mg of E-product. (5.52%). EA, MS(FD). 15 Example 100 2-Amino-3-napthyl-6-(benzyloxim-a-yl)-imidazo [1,2 a] pyridine N NH N

HO

The 2-amino-3-napthyl-6-benzoyl-imidazo [1,2-a] pyridine 20 (2.00 g, 5.51 mmol) was converted to product in a manner substantially analogous to Example 97 to yield 470 mg of E-product, (22.6%), EA, MS(FD), and 810 mg of Z-product. (38.9%). NMR. Example 101 WO 99/59587 PCTIUS98/10299 -104 2-Amino-3-(2-fluorophenyl)-6- [(E)-benzyloxim-a-yl] imidazo[1,2-a] pyridine NH2 N HO

F

The 2-amino-3-(2-fluorophenyl)-6-benzoyl-imidazo[1,2 5 a]pyridine (2.62 g, 7.92 mmol) was converted to product in a manner substantially analogous to Example 97 to yield 1.08 g of E-product. (39.3%). MS(FD), NMR. Example 102 2-Amino-3-(3-fluorophenyl)-6- [(E) -1-benzyloxim-a-yl] 10 imidazo[1,2-a]pyridine -N

NH

2 N HO F The 2-amino-3-(3-fluorophenyl)-6-benzoyl-imidazo[1,2 a]pyridine (2.00 g, 6.04 mmol) was converted to product in a manner substantially analogous to Example 97 to 15 yield 463 mg of E-product. (22.2%), EA, MS(FD). Example 103 2-Amino-3-(4-fluorophenyl)-6- [(E)-benzyloxim-a-yl] imidazo[1,2-a]pyridine N

NH

2 N

HO

F 20 The 2-amino-3-(4-fluorophenyl)-6-benzoyl-imidazo[1,2 a]pyridine (3.00 g, 9.06 mmol) was converted to product in a manner substantially analogous to Example 97 to yield 2.78 g of E-product. (88.8%). EA, MS(FD). Example 104 25 2-Amino-3-(3,5-difluorophenyl)-6- [(E)-benzyloxim-a-yl] imidazo[1,2-a]pyridine WO 99/59587 PCT/US98/10299 -105 NH2 HO N F F The 2-amino-3-(3,5-difluorophenyl)-6-benzoyl-imidazo[1,2 a]pyridine (1.00 g, 2.87 mmol) was converted to product in a manner substantially analogous to Example 97 to 5 yield 65 mg of E-product. (6.22%). EA, MS(FD). Example 105 2-Amino-3-(2,5-difluorophenyl)-6-[(E)-benzyloxim-a-yl] imidazo[1,2-a] pyridine NF a I 'NH2 N/ HO F 10 The 2-amino-3-(2,5-difluorophenyl)-6-benzoyl-imidazo[1,2 alpyridine (1.00 g, 2.87 mmol) was converted to product in a manner substantially analogous to Example 97 to yield 315 mg of E-product. (30.2%). EA, MS(FD). Example 106 15 2-Amino-3-(3-trifluoromethylphenyl)-6-[(E)-benzyloxim-a yl] -imidazo [1,2-a] pyridine NH2

N

NO HO

F

3 C The 2-amino-3-(3-trifluoromethylphenyl)-6-benzoyl imidazo[l,2-a]pyridine (2.00 g, 5.24 mmol) was converted 20 to product in a manner substantially analogous to Example 97 to yield 579 mg of E-product. (27.9%). EA, MS(FD). Example 107 2-Amino-3 - (4-bromophenyl)-6-(benzyloxim-a-yl) imidazo[1,2-a]pyridine WO 99/59587 PCT/US98/10299 -106 $H2 N N HO Br The 2-amino-3-(4-bromophenyl)-6-benzoyl-imidazo[1,2 a]pyridine (1.80 g, 4.59 mmol) was converted to product in a manner substantially analogous to Example 97 to 5 yield 1.20 g of a 1:1 mixture of E and Z isomer products. (64.2%). EA, MS(FD). Example 108 2-Amino-3-(2,3,4-trifluorophenyl)-6-[(E)-benzyloxim-a yl]-imidazo[1,2-a] pyridine N NH2 N0' F / HO 10 F F The 2-amino-3-(2,3,4-trifluorophenyl)-6-benzoyl imidazo[l,2-a]pyridine (2.00 g, 5.45 mmol) was converted to product in a manner substantially analogous to Example 97 to yield 508 mg of E-product. (24.1%). EA, MS(FD). 15 Example 109 2-Amino-3-(3,4-difluorophenyl)-6-[(E)-benzyloxim-a-yl] imidazo[1,2-a] pyridine

NH

2 HO / F F F The 2-amino-3-(3,4-difluorophenyl)-6-benzoyl-imidazo[1,2 20 a]pyridine (2.00 g, 5.73 mmol) was converted to product in a manner substantially analogous to Example 97 to yield 507 mg of E-product. (24.2%). EA, MS(FD). Example 110 WO 99/59587 PCT/US98/10299 -107 2-Amino-3-(3,4-dichlorophenyl)-6-[(E)-benzyloxim-a-yl] imidazo[1,2-a] pyridine NH2

O

/

N / HO Cl C1 Cl The 2-amino-3-(3,4-dichlorophenyl)-6-benzoyl-imidazo[1,2 5 a]pyridine (2.00 g, 5.25 mmol) was converted to product in a manner substantially analogous to Example 97 to yield 643 mg of E-product. (31.1%). EA, MS(FD). Example 111 2-Amino-3-(2,4,5-trifluorophenyl)-6-[(E)-benzyloxim-a 10 yl] -imidazo[1,2-a] pyridine y N NH2 HO F

HO

/ N . F F The 2-amino-3-(2,4,5-trifluorophenyl)-6-benzoyl imidazo[1,2-a]pyridine (2.00 g, 5.45 mmol) was converted to product in a manner substantially analogous to Example 15 97 to yield 344 mg of E-product. (16.6%). EA, MS(FD). Example 112 2-Amino-3-(2-chlororphenyl)-6-[(E)-benzyloxim-a-yl] imidazo[1,2-a]pyridine HO 20 The 2-amino-3-(2-chlorophenyl)-6-benzoyl-imidazo[l,2 a]pyridine (2.00 g, 5.76 mmol) was converted to product in a manner substantially analogous to Example 97 to yield 180 mg of E-product. (8.61%). EA, MS(FD). Example 113 WO 99/59587 PCT/US98/10299 -108 2-Amino-3-(3-chlorophenyl)-6-[(E)-benzyloxim-(-yl] imidazo[1,2-a] pyridine NN

N

HO - Cl The 2-amino-3-(3-chlorophenyl)-6-benzoyl-imidazo[1,2 5 a]pyridine (2.00 g, 5.75 mmol) was converted to product in a manner substantially analogous to Example 97 to yield 551 mg of E-product. (26.4%). EA, MS(FD). Example 114 2-Amino-3-(4-chlorophenyl)-6-[(E)-benzyloxim-a-yl] 10 imidazo[1,2-alpyridine

NH

2 N HO Cl The 2-amino-3-(4-chlorophenyl)-6-benzoyl-imidazo[1,2 a]pyridine (2.00 g, 5.75 mmol) was converted to product in a manner substantially analogous to Example 97 to 15 yield 180 mg of E-product. (8.61%). EA, MS(FD). Example 115 2-Amino-3-(4-trifluoromethoxyphenyl)-6-[(E)-benzyloxim-a yl] -imidazo [1,2-a] pyridine I NH2 NN HO /

OCF

3 20 The 2-amino-3-(4-trifluoromethoxyphenyl)-6-benzoyl imidazo[1,2-a]pyridine (2.00 g, 5.04 mmol) was converted to product in a manner substantially analogous to Example 97 to yield 383 mg of E-product. (18.4%). EA, MS(FD). Example 116 WO 99/59587 PCT/US98/10299 -109 2-Amino-3-(3-trfluoromethoxyphenyl)-6-[(E)-benzyloxim-a yl] -imidazo[1,2-a] pyridine N NH2 HO N OCF 3 The 2-amino-3-(3-trifluoromethoxyphenyl)-6-benzoyl 5 imidazo[1,2-a]pyridine (2.00 g, 5.04 mmol) was converted to product in a manner substantially analogous to Example 97 to yield 224 mg of E-product. (10.8%). EA, MS(FD). Example 117 2-Amino-3-(2-fluoro-4-trifluoromethylphenyl)-6 10 (benzyloxim-a-yl) - imidazo[1 , 2-a] pyridine N

NH

2 HO

CF

3 The 2-amino-3-(2-fluoro-4-trifluoromethylphenyl)-6 benzoyl-imidazo[l,2-a]pyridine (2.00 g, 5.01 mmol) was converted to product in a manner substantially analogous 15 to Example 97 to yield 742 mg of E-product. (35.7%). EA, MS(FD). Example 118 2-Amino-3-phenyl-6-[(E)-benzyloxim-a-yl] -imidazo[1,2 a] pyridine NH2 N/ HO 20 The 2-amino-3-phenyl - 6 -benzoyl - imidazo [1,2-a] pyridine (133 mg, 0.426 mmol) was treated with hydroxylamine hydrochloride (500 mg, 7.20 mmol), 2.5 ml of pyridine, and 7.5 ml of dry EtOH. After refluxing for 2.5 hours, 25 200 ml of EtOAc was added and the solution washed twice with saturated NaHSO3. THe organic layer was dried over WO 99/59587 PCT/US98/10299 -110 MgSO4 and the solvent removed in vacuo. The product crystalized out in EtOAc to yield 64 mg of E-product, (45.7%), MS(FD), and 68 mg of the Z isomer. (48.6%). MS(FD). 5 Example 119 2-Amino-3-(2,6-difluorophenyl)-6-[(E)-benzyloxim-a-yl] imidazo[1,2-a] pyridine HO N F HO The 2-amino-3-(2,6-difluorophenyl)-6-benzoyl-imidazo[1,2 10 a]pyridine (2.00 g, 5.73 mmol) was converted to product in a manner substantially analogous to Example 97 to yield 383 mg of E-product. (18.4%). EA, MS(FD). Example 120 2-Amino-3-(2,3,4,5,6-pentafluorophenyl)-6-[(E) 15 benzyloxim-o-yll] - imidazo[1,2-a] pyridine N NH2 N -' F HO F F F The 2-amino-3-(2,6-difluorophenyl)-6-benzoyl-imidazo[1,2 a]pyridine (4.52 g, 11.2 mmol) was converted to product in a manner substantially analogous to Example 97 to 20 yield 940 mg of E-product. (20%). EA, MS(FD). Example 121 2-Amino-3-(2-trifluoromethylphenyl)-6-[(E)-benzyloxim-a yl] -imidazo[1,2-a] pyridine N N N ..

NH

2 N CF 3 NO HO N 25 The 2-amino-3-(2-trifluoromethylphenyl)-6-benzoyl imidazo[1,2-a]pyridine (2.00 g, 5.25 mmol) was converted WO 99/59587 PCT/US98/10299 -111 to product in a manner substantially analogous to Example 97 to yield 146 mg of E-product. (7.02%). EA, MS(FD). Example 122 2-Amino-3-(thiophen-3-yl)-6-[(E)-benzyloxim-x-yl] 5 imidazo[1,2-a] pyridine N NH HO S The 2-amino-3-(thiophen-3-yl)-6-benzoyl-imidazo[1,2 a]pyridine (2.00 g, 6.27 mmol) was converted to product in a manner substantially analogous to Example 97 to 10 yield 497 mg of E-product. (23.8%). EA, MS(FD). Example 123 2-Amino-3-(2-trifluoromethyl-4-fluorophenyl)-6-[(E) benzyloxim-a-yl] -imidazo[1,2-a]pyridine N

CF

3 HON F 15 The 2-amino-3-(2-trifluoromethyl-4-fluorophenyl)-6 benzoyl-imidazo[l,2-a]pyridine (2.00 g, 5.01 mmol) was converted to product in a manner substantially analogous to Example 97 to yield 288 mg of E-product. (13.8%). EA, MS(FD). 20 Example 124 2-Amino-3-(2-fluoro-6-trifluoromethylphenyl)-6-[(E) benzyloxim-a-yl] -imidazo [1,2-a]pyridine N II F HO! N F 3 C The 2-amino-3-(2-fluoro-6-trifluoromethylphenyl)-6 25 benzoyl-imidazo[l,2-a]pyridine (1.28 g, 3.21 mmol) was converted to product in a manner substantially analogous WO 99/59587 PCT/US98/10299 -112 to Example 97 to yield 75.0 mg of E-product, (5.64%), EA, MS(FD), and 395 mg of Z-product. (29.7%). MS(FD), NMR. Example 125 2-Amino-3-(4-trifluoromethylphenyl)-6-[(E)-benzyloxim-a 5 yl] -imidazo[1,2-a] pyridine N NH2 HO

CF

3 The 2-amino-3-(4-trifluoromethylphenyl)-6-benzoyl imidazo[1,2-a]pyridine (2.00 g, 5.25 mmol) was converted to product in a manner substantially analogous to Example 10 97 to yield 512 mg of E-product. (24.6%). EA, MS(FD). Example 126 2-Amino-3-(4-carbomethoxyphenyl)-6-[(E)-benzyloxim-a-yl] imidazo[1,2-a] pyridine N NH2 I N 2 HO CO2M 15 The 2-amino-3-(4-carbomethoxyphenyl)-6-benzoyl imidazo[l,2-a]pyridine (1.00 g, 2.70 mmol) was converted to product in a manner substantially analogous to Example 97 to yield 437 mg of E-product. (43.5%). EA, MS(FD). Example 127 20 2-Amino-3-(4-carboxyphenyl)-6-[benzyloxim-a-yl] imidazo[1,2-a]pyridine N HO N

CO

2 H The 2-amino-3-(4-carboxyphenyl)-6-benzoyl-imidazo[1,2 a]pyridine (2.00 g, 5.60 mmol) was converted to product 25 in a manner substantially analogous to Example 97 to WO 99/59587 PCT/US98/10299 -113 yield 990 mg of an E and Z isomer mixture. (46.6% global yield). NMR. Example 128 2-Amino-3-benzyl-6- [benzyloxim-a-yl] -imidazo[1,2 5 a] pyridine N ) NH2 N Bn HO The 2-amino-3-benzyl-6-benzoyl-imidazoll[,2-a]pyridine (2.00 g, 5.60 mmol) was converted to product in a manner substantially analogous to Example 97 to yield 210 mg of 10 theE isomer product. (16.5%). EA, MS(FAB). Example 129 2-Amino-3-isobutyl-6-[benzyloxim-x-yll] -imidazo[1,2 a] pyridine HONH2 -. N> HOX-, iPr 15 The 2-amino-3-isobutyl-6-benzoyl-imidazo[1,2-a]pyridine (820 mg, 2.80 mmol) was converted to product in a manner substantially analogous to Example 97 to yield 120 mg of the E isomer product. (13.9%). EA, MS(FAB). Example 130 20 2-Amino-3-(4-fluorophenyl)-6-[(E)-- -(4-fluorobenzyl)oxim a-yl] -imidazo [1,2-a] pyridine F N I NH2 'Coo N HON F The 2-amino-3-(4-fluorophenyl)-6-(4-fluorobenzoyl) imidazo[1,2-a]pyridine (2.00 g, 5.73 mmol) was converted 25 to product in a manner substantially analogous to Example 97 to yield 572 mg of E-product, (27.4%), EA, MS(FD), and 198 mg of Z-product. (9.47%). EA, MS(FD).

WO 99/59587 PCT/US98/10299 -114 Example 131 2-Amino-3-(2-fluoro-4-trifluoromethylphenyl)-6-[(E) -1- (4 fluorobenzyl)oxim-a-yl] -imidazo[1,2-a]pyridine F'* N F NH2 HO N F

CF

3 5 The 2-amino-3-(2-fluoro-4-trifluoromethylphenyl)-6-(4 fluorobenzoyl)-imidazo[1,2-a]pyridine (2.00 g, 4.80 rmmol) was converted to product in a manner substantially analogous to Example 97 to yield 310 mg of E-product. (15%). EA, MS(FD). 10 Example 132 2-Amino-3-phenyl-6-[(E)-phenylacetoxim-a-yl] -imidazo[1,2 a] pyridine - N2 Bn -2. HO The 2-amino-3-phenyl-6-(a-phenylacetyl) -imidazo[1,2 15 a]pyridine (732 mg, 2.24 mmol) was converted to product in a manner substantially analogous to Example 97 to yield 485 mg of E-product. (63.3%). EA, MS(FD). Example 133 2-Amino-3-phenyl-6-(picolinyloxim-x-yl)-imidazo[1,2 20 a] pyridine / N

NH

2 NN HO To a suspension of 2-amino-3-phenyl-6-(picolinoyl) imidazo[1,2-a]pyridine (1.57 g, 5.00 mmol) in 100 ml of 80% aqueous EtOH was added hydroxylamine hydrochloride 25 (4.17 g, 60.0 mmol) and NaOAc (4.92 g, 60.0 mmol). The WO 99/59587 PCTUS98/10299 -115 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 NaHCO3. The EtOAc was separated and washed with brine, dried over 5 Na2SO4, filtered, and concentrated in vacuo. The residue was recrystalized from EtOAc to yield a mixture of both product isomers. The mixture was triturated with CH2C12 and the solids filtered. The filtrate was chromatographed (normal phase) to yield 75.8 mg of cis 10 product. (4.6%). EA, MS(FD). The solids were recrystalized twice from MeOH to yield 134 mg of trans product. (8.1%). EA, MS(FD). Example 134 2-Amino-3-phenyl-6-(nicotinyloxim-a-yl)-imidazo[1,2 15 a] pyridine ~N NH2 N_ N HO The 2-amino-3-phenyl-6-(nicotinoyl)-imidazo[1,2 a]pyridine (1.18 g, 3.75 mmol) was converted to product in a manner substantially analogous to Example 78 to 20 yield 127 mg of cis product, (10.3%), MS(FD), NNR, and 20.5 mg of 80% trans product. (1.3% corrected). MS(FD), NMR. Example 135 2-Amino-3-phenyl-6-(cis-isonicotinyloxim-a-yl) 25 imidazo [1,2-a] pyridine NN NH2 HO / The 2-amino-3-phenyl-6-(isonicotinoyl)-imidazo[1,2 a]pyridine (1.57 g, 5.00 mmol) was converted to product WO 99/59587 PCT/US98/10299 -116 in a manner substantially analogous to Example 78 to yield 466 mg of cis, (28.3%), EA, MS(FD), NMR, and 230 mg of trans. (14%). EA, MS(FD). Example 136 5 2-Amino-3-phenyl-6-(l-phenyl-2-cyanovinyl)-imidazo[l,2 a] pyridine N NNH2 NCN The 2-amino-3-phenyl-6-benzoyl-imidazo[1,2-a]pyridine (1.57 g, 5.00 mmol) was dissolved in 30 ml of THF and 10 diethylcyanophosphonate (1.63 g, 10.0 mmol) followed by potasium bistrimethylsilylamide (0.5 M in toluene, 5 ml, 10 mmol) were added. The reaction was allowed to stir for 5 days. The THF was removed in vacuo and the residue dissolved in 500 ml of EtOAc. The EtOAc was washed with 15 50 ml of H20, brine (2 x 50 ml), dried over NaSO4, and then concentrated in vacuo. The residue was purified by normal phase flash chromatography (EtOAc) to yield 250 mg of product which was recrystalized from EtOAc to yield 98 mg of Z-product, (5.82%), EA, MS(FD), and 128 mg of E 20 product. (7.60%). EA, MS(FD). Example 137 2-Amino-3-isobutyl-6-(l-phenyl-2-cyanovinyl)-imidazo[1,2 a] pyridine N

NH

2 iPr NC 25 The 2-amino-3-isobutyl-6-benzoyl-imidazo[l,2-a]pyridine (1.46 g, 5.00 mmol) was converted to product in a manner substantially analogous to Example 136 to yield 200 mg of Z-product, (12.7%), MS(FD), NMR, and 130 mg of E-product. (8.23%). EA, MS(FD).

WO 99/59587 PCT/US98/10299 -117 Example 138 2-Amino-3-methylthio-6-benzoyl-imidazo[1,2-a]pyridine ~N

NH

2 SMe 0 The 2-trifluoroacetamido-3-methylthio-6-benzoyl 5 imidazo[1,2-a]pyridine (100 mg, 263 mmol) was dissolved in 20 mL of a mixture of MeOH/CH2C12 1:1, and 5 g of silica gel was added. The mixture was stirred at RT for 2 days. The residue was filtered and washed with CH2C12 and the solution was concentrated in vacuo to give 63 mg 10 (85%) of a yellow solid. 1 H-NMR (200 MHz, CDC13) d 2.12 (s, 3H, SMe), 4.40 (bs, 2H, NH2), 7.46-7.80 (m, 7H, ArH + H7 +H8), 8.68 (d, J57= 1.7, H5). 13 C-NMR (50 MHz, CDC13) d 18.0 (SMe), 95.0, 122.7, 125.8, 127.7, 128.5, 129.6, 132.6, 137.4, 145.3, 156.1, 193.5. 15 Example 139 2-Amino- 3 -methylsulfonyl-6-benzoyl - imidazo[1,2-a] pyridine N N NH2

SO

2 Me 0 The 2-trifluoroacetamido-3-methylsulfonyl-6-benzoyl imidazo[1,2-a]pyridine (160 mg, 0.438 mmol) was converted 20 to product in a manner substantially analogous to Example 138 to give 92 mg. (78%). 1 H-NMR (200 MHz, CDC13) d 3.06 ( s, 3H, SO2Me), 4.82 (bs, 2H, NH2), 7.53-7.82 (m, 6H, ArH + H7 + H8), 8.78 (d, J57= 1.6, H5). Example 140 25 2-Amino-3-isopropylthio-6-benzoyl-imidazo[1,2-a]pyridine . N

NH

2 ON N / 0 The 2-trifluoroacetamido-3-isopropylsulfonyl-6 benzoyl-imidazo[1,2-a]pyridine (16 mg, 0.0393 mmol) was WO 99/59587 PCT/US98/10299 -118 converted to product in a manner substantially analogous to Example 138 to give 11 mg. (88%). EIMS m/z 311 M+(28), 268 (100), 224 (27), 105 (41), 77 (29), 1 H-NMR (CDC13) d 8.75 (s, 1H, H5), 7.79-7.47 (m, 7H, Ar), 4.62 5 (broad s, 2H, NH2), 3.09 (hept., 1H, J = 6.4 Hz, CH (CH3)2, 1.22 (d, 6H, J = 6.7 Hz, (CH3)2-CH), 13 C-NMR (CDC13) d 199.3, 157.1, 145.2, 137.3, 132.6, 129.5, 128.4, 127.9, 126.0, 122.8, 113.6, 40.8, 23.4. Example 141 10 2-Amino-3-phenyl-6-(2-fluorobenzoyl) -imidazo[1,2 a]pyridine F N N NH 2 Ph 0 To a solution of l-bromo-2-fluorobenzene (191 mL, 1.75mmol) in dry THF (2 mL) under an argon atmosphere was 15 added t-butyl lithium dropwise. After stirring for 50 minutes at -78 0 C, a solution of 2-amino-3-phenyl-6-(N methyl-N-methoxycarbamoyl)imidazo[1,2-a]pyridine (148 mg, 0.5 mmol) in dry THF (3 mL) was added. The resulting red-orange solution was stirred at the same temperature 20 for another 50 minutes and then allowed to warm to RT. The solution was poured into H20 (20 mL) and extracted with EtOAc (2 x 20 mL). The organic layer was washed with H20, dried (Na2SO4), and removed in vacuo to give a brown solid. The crude solid was purified by column 25 chromatography (CH2Cl2/CH3CN 2.5/1) to give 84.0 mg (50.6%) of product as a yellow solid. MS(FAB) m/z 332.2

(M

+ + 1, 51.99), NMR (200 MHz, CDC13) d 4.27 (bs, 2H, NH), 7.12 -7.58 (m, 11H, ArH + H7 + H8), 8.71 (s, H5). Example 142 30 2-Amino-3-phenyl-6-(3-fluorobenzoyl)-imidazo[1,2 a]pyridine WO 99/59587 PCT/US98/10299 -119 F N NH, F Ph 0 The 2-amino-3-phenyl-6-(N-methyl-N methoxycarbamoyl)imidazo[1,2-a]pyridine (148 mg, 0.500 mmol) and 1-bromo-3-fluorobenzene were converted to 5 product in a manner substantially analogous to Example 141 to give 37 mg. (37%). MS(FAB

+

) m/z 332.2 (M + + 1, 86.6), NMR (200 MHz, CDC13) d 4.22 (bs, 2H, NH), 7.21 7.55 (m, 11H, ArH + H7 + H8), 8.69 (d, J 5 7 = 1.1, H5). Example 143 10 2-Amino-3-phenyl-6-(4-fluorobenzoyl)-imidazo[1,2 a] pyridine N NH ~N Ph 0 The 2-amino-3-phenyl-6-(N-methyl-N 15 methoxycarbamoyl)imidazo[1,2-a]pyridine (584 mg, 1.97 mmol) and l-bromo-4-fluorobenzene were converted to product in a manner substantially analogous to Example 141 to yield 205 mg. (52%). NMR (200 MHz, CDC13) d 4.31 (bs, 2H, NH), 7.15 (m, 2H, F-ArH ), 7.25-7.56 (m, 20 7H, ArH +H7 + H8), 7.78 (m, 2H, F-ArH), 8.69 (s, H5). Example 144 2-Amino-3-phenyl-6-(2,3-difluorobenzoyl)-imidazo[1,2 a] pyridine F -F N Ph 0 25 To a solution of 2,3-difluorobromobenzene (0.945 g, 8.44 mmol) in dry THF (20 mL), was added n-butyl lithium (1.6M in hexanes, 5.27 mL) at -78 0 C. The resulting WO99/59587 PCT/US98/10299 -120 yellow solution was stirred at the same temperature for 70 minutes, then a solution of 2-amino-3-phenyl-6-(N methyl-N-methoxycarbamoyl)imidazo[1,2-a]pyridine (500 mg, 1.69 mmol) in dry THF (20 mL), under argon, was added 5 dropwise via a cannula. The resulting orange solution was allowed to warm very slowly to RT during a 2.5 hour period. Saturated NH4Cl was added, and the mixture was stirred for 25 minutes then extracted with EtOAc. The organic layer was washed with brine, and dried (Na2SO4). 10 The solvents were evaporated and the residue was purified by column chromatography (CH2Cl2/CH3CN, 4/1) to give 440 mg (74.7%) of product as a yellow solid. MS(FAB) m/z 350.1 (M + + 1,100.0 ), NMR (200 MHz, DMSO d6) d 5.71 (bs, 2H, NH), 7.27-7.70 (m, 11H, F-ArH + ArH + H7 + H8), 15 8.58 (dd, J 5 7 = 1.8, J 5 8 = 0.9, H5). Example 145 2-Amino-3-methylthio-6-(1-phenyl-2-cyanovinyl) imidazo[1,2-a]pyridine N N SMe NH2 NC 20 To a solution of 2-amino-3-methylthio-6-benzoyl imidazo[l,2-a]pyridine (40 mg, 0.14 mmol) in 4 mL of dry THF was added diethyl phospononitrile (265 mg, 1.5 mmol) dropwise at -78 0 C. An orange solid formed. Two ml of THF was added and the reaction mixture was stirred for 2 25 hours at -78 0 C. The reaction mixture was allowed to warm to RT over 3 hours. The solution turned green. The mixture was hydrolized with a drop of H20, the solvent was removed in vacuo, and the residue was subjected to column chromatography (EtOAc) to yield 23 mg, (51%), of 30 the E-isomer, 1 H-NMR (200 MHz, CDC13) d 2.22 ( s, 3H, SMe, 4.43 (bs, 2H, NH2), 5.75 (s, 1H, Hvinilic), 7.04 (dd, 1H, J57= 2.0, J78= 9.1, H7), 7.32-7.50 (m, 6H, ArH + H8), 8.54 (dd, J58= 0.9, J57= 2.0, H5), and 14mg, (32%) of the Z-isomer, 1 H-NMR (200 MHz, CDC13) d 2.10 ( s, 3H, WO 99/59587 PCT/US98/10299 -121 SMe, 4.40 (bs, 2H, NH2), 5.79 (s, 1H, Hvinilic), 7.13 (dd, 1H, J57= 1.9, J78= 9.2, H7), 7.32 (dd, J58= 0.8, J78= 9.2, H8),7.47-7.53 (mn, 5H, ArH), 8.07 (dd, J58= 0.8, J57= 1.9, H5). 5 Example 146 2-Amino-3-methylsulfonyl-6- (l-phenyl-2 cyanovinyl)imidazo[1,2-a] pyridine

NH

2

SO

2 Me NC The 2-amino-6-benzoyl-3-(methylsulfonyl)imidazo[1,2 10 a]pyridine was converted to product in a manner substantially analogous to Example 145 to give the vinyl nitrile as a mixture of 2 isomers E:Z in 1:2 ratio and 77% global yield. The Z-isomer was isolated by column chromatography (isopropanol:EtOAc/3:7). 1 H-NMR (200 MHz, 15 CDC13) d 3.17 (s, 3H, SO2Me), 4.66 (bs, 2H, NH2), 5.77 (s, 1H, vinylic), 7.10 (dd, 1H, J57= 1.8, J78= 9.3, H7), 7.30-7.46 (m, 6H, ArH + H8), 8.82 (dd, J58= 0.8, J57=1.8, H5). Example 147 20 2-Amino-6-[(E) -1-phenyl-2-N-methylcarbamoylvinyl] imidazo[1,2-a] pyridine NH2 MeNHOC The 2-trifluoroacetamido-6- [(E) -l-phenyl-2-N methylcarbamoylvinyl] -imidazo[1,2-a] pyridine (300 mg, 25 0.77 mmol) was stirred in the presence of 0.5 N NaOH (17 ml) at RT for 5 hours. The solution was neutralized to pH = 7 with HC1 (5% aqueous solution) and extracted with CHC1 3 (3 x 50 ml). The combined organic extracts were dried (Na2SO4) and the solvent was removed in vacuo to 30 yield 130 mg (58%) of product as a light-brown solid.

WO 99/59587 PCTIUS98/10299 -122 M.P. 97-99 0 C, NMR (CDC13) d 7.61 (d, 1H, J = 1.4 Hz, H5), 7.47-7.41 (m, 3H, Ar), 7.33-7.27 (m, 3H, Ar), 7.12 (dd, 1H, J = 9.3, 1.8 Hz, H7 6 H8), 6.77 (s, 1H, H3), 6.36 (s, 1H, H vinyl), 5.13 (broad d, 1H, J = 4.9 Hz, NHMe), 3.90 5 (broad s, 2H, NH2), 2.62 (d, 3H, J = 4.9 Hz, CH3NH), EIMS m/z 292 M + (1 00), 262(32), 234(20), 223(15), 215(13), 178(8), 160(10), 117(6), 105(9), 77(9). Example 148 2-Amino-3-ispropylthio-6-[(E)-1-phenyl-2-N 10 methylcarbamoylvinyl]-imidazo[1,2-a]pyridine NH2 MeNHOC To a solution of 2-trifluoroacetamido-3-iodo-6-[(E) l-phenyl-2-N-methylcarbamoylvinyl]-imidazo[1,2-a]pyridine (72 mg, 0.15 mmol) in 5 ml of THF cooled to -78 0 C was 15 added phenyl lithium (230 zl, 0.33 mmol) under an argon atmosphere. The reaction mixture was stirred for 3 minutes before injecting t-butyl lithium (310 p1l, 0.38 mmol). After stirring for a 10 minute period, a solution of isopropyl isopropanethiol-sulfonate (109 mg, 0.600 20 mmol) in 5 ml of THF was added. The reaction mixture was stirred for 30 minutes at -78 0 C and then quenched with 2 drops of H20 and 10 ml THF. Ethyl acetate (15 ml) was added and the mixture was allowed to warm to RT. The solution was filtered through celite and the solvents 25 were removed in vacuo. Radial chromatography affords the isopropyl sulfide with the trifluoroacetyl group cleaved and the intermediate in pure form. The ratio of intermediate/product depends on the speed of the radial chromatography. The trifluoroacetyl material was mixed 30 with silicagel in MeOH/CH2Cl2 and the cake was stirred for 2 days. After filtration the product was obtained in 73% global yield. EIMS m/z 366 M+(33), 323 (100), 293 (18), 237 (15), 196 (10), 178 (7), 102 (6), 1

H-NMR

WO 99/59587 PCT/US98/10299 -123 (CDC13) d 8.01 (d, 1H, J = 1.5 Hz, H5), 7.47-7.20 (m, 7H, Ar), 6.40 (s, 1H, Hvinyl), 5.20 (broad s, 1H, J = 4.9 Hz, NHMe), 4.26 (broad s, 2H, NH2), 2.97 (hept, 1H, J = 6.8 Hz, CH(CH3)2), 2.65 (d, 3H, J = 4.9 Hz, CH3NH), 1.13 (d, 5 6H, J = 6.8 Hz, (CH3)2CH). Example 149 2-Amino-3-isopropylsulfonyl-6- [(E)-1-phenyl-2-N methylcarbamoylvinyl] -imidazo [1,2-a] pyridine N NH2 N MeNHOC S02/ 10 The 2-trifluoroacetamido-3-isopropylsulfonyl-6 [(E) -1-phenyl-2-N-methylcarbamoylvinyl] -imidazo[1,2 a]pyridine (45 mg, 0.09 mmol) was disolved in a 1:1 mixture of MeOH:CH2Cl2 and silica gel was added until a cake is obtained. The cake was vigorously stirred for 2 15 days. After filtration through celite, the product is obtained as a white solid. (33 mg, 89%). EIMS m/z 398 M+(44), 292 (100), 262 (27), 233 (15), 215 (9), 205 (8), 178 (7), 77 (6), 58 (8), NMR (CDC13) d 8.46 (s, 1H, H5), 7.53-7.30 (m, 7H. Ar),. 6.41 (s, 1H, Hvinyl), 5.30 (d, 20 1H, J = 4.8 Hz, NHMe), 5.17 (broad s, 2H, NH2), 3.26 (hept, 1H, J = 7.0 Hz, CH(CH 3

)

2 ), 2.12 (d, 3H, J = 4.8 Hz, CH3NH), 1.34 (d, 6H, J = 7.0 Hz, (CH3)2CH). Example 150 2-Amino-3-phenyl-6- (1- (2,3-difluorophenyl)oxime) 25 imidazo[1,2-a] pyridine F NNH2 N Ph HO~r The 2-amino-3-phenyl-6-(2,3-difluorobenzoyl) imidazo[1,2-a]pyridine (0.15 g, 0.43 mmol) was mixed with hydroxylamine hydrochloride (0.357 g, 5.16 mmol) and WO 99/59587 PCT[US98/10299 -124 NaOAc (0.424 g, 5.16 mmol) in an 80% solution of EtOH (9 mL). The reaction mixture was refluxed under argon for 20 hours. The solvents were removed in vacuo and the residue was taken up in EtOAc-H20. The organic layer was 5 washed with saturated NaHCO3 (2 x 20 mL) and brine (2 x 25 mL) then dried (Na2SO4), and evaporated to give the product quantitavely as a yellow solid. The ratio E:Z determined by NMR was found to be (2/1). NMR (200 MHz, DMSO-d6) d 5.34 (bs, NH2 E), 5.38 (NH2 Z), 8.04 (s, H5 10 E), 8.91 (H5 Z), 11.77 (s, OH E), 12.14 (s, OH Z). Example 151 2-Amino-3-phenyl-6-(1-(2,3-difluorophenyl)-2-N methylcarbamoylvinyl)-imidazo[1,2-a]pyridine F F/ NH2 Ph MeNHOC 15 The 2-trifluoroacetamido-3-phenyl-6-[(E)-l-(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 solvents were removed in 20 vacuo and the mixture was purified by column chromatography (CH2Cl2/CH3CN/MeOH 55/40/5) to recover 27 mg (32.5%) of product. 1 H NMR (200 MHz, CDC13) d 3.86 (d, J= 9.0, 3H, CONHCH3), 4.15 (bs, 2H, NH), 6.64 (s, Hvinilic), 7.02-7.45 (m, 10H, F-ArH + ArH + H7 + H8), 25 8.14 (d, J57= 1.5, H5), 13 C NMR (50 MHz, CDC13) d 33.7, 114.6, 118.0, 118.4, 121.0, 121.6, 122.4, 122.6, 123.2, 124.2, 127.7, 127.7, 128.9, 129.7, 147.0, 148.7, 161.9. Example 152 2-Amino-3-phenyl-6-[(E)-l-phenyl-2-N 30 methylcarbamoylvinyl]-imidazo[1,2-a]pyridine WO 99/59587 PCT/US98/10299 -125 NH2 Ph MeNHOC The 2-trifluoroacetamido-3-phenyl-6- [(E)-1-phenyl-2 N-methylcarbamoylvinyl] -imidazo[1,2-a]pyridine (190 mg, 0.420 mmol) was converted to product in a manner 5 substantially analogous to Example 151 to give 127 - 135 mg. (85-90%). NMR (200 MHz, CD3OD): d 2.60 (s, 3H NHCH3), 6.44 ( s, 1H, H vinilic), 7.20-7.42 (m, 12H, ArH + H7 +H8), 7.91 (bs, 1H, H5). Example 153 10 2-Amino-3-(2,5-difluorophenyl)-6-[(E)-1-phenyl-2-N methylcarbamoylvinyl] - imidazo[1,2-a] pyridine NH2 N/ F / F MeNHOC The 2-trifluoroacetamido-3-(2,5-difluorophenyl)-6 [(E) -1-phenyl-2-N-methylcarbamoylvinyl] -imidazo[1,2 15 a]pyridine (333 mg, 0.682 mmol) was converted to product in a manner substantially analogous to Example 151 to give 227 - 241 mg. (85-90%). EIMS m/z 404 M+(100), 374(17), 345(12), 207(9), 152(7), 140(7), 105(7), 77(11), NMR (CDC13) d 7.62 (dd, 1H, J = 2.1, 1.2 Hz, H5), 7.45 20 6.99 (m, 10H, Ar). 6.35 (s, 1H, H vinyl), 5.19 (d, 1H, J = 4.9 Hz, NH), 4.18 (broad s, 2H, NH2), 2.63 (d, 3H, J = 5.0 Hz, CH3). Example 154 2-Amino-3-(2-trifluoromethyl-4-fluorophenyl)-6-[(E) -1 25 phenyl-2-N-methylcarbamoylvinyl] -imidazo[1,2-a] pyridine WO 99/59587 PCT/US98/10299 -126 ,/ ,N NH2 N/ F3C/ MeNHOC F The 2-trifluoroacetamido-3-(2-trifluoromethyl-4 fluorophenyl)-6-[(E) - 1-phenyl-2-N-methylcarbamoylvinyl] imidazo[l,2-a]pyridine (310 mg, 0.576 mmol) was converted 5 to product in a manner substantially analogous to Example 151 to give 216 - 229 mg. (85-90%). MS(FD) (EI

+

) m/z 454 M

+

(1 0 0), 424(19), 395(12), 356(7), 279(10), 209(11), 77(9), NMR (CDC13) d 7.52 (dd, 1H, J = 8.4 Hz, H7 6 H8), 7.47-7.16 (m, 9H, Ar), 6.94 (d, 1H, J = 8.9 Hz, H7 6 H8), 10 6.16 (s, 1H, Hvinyl), 5.39 (broad d, 1H, J = 4.6 Hz, NHMe), 3.92 (broad s, 2H, NH2), 2.55 (d, 3H, J = 4.7 Hz, CH3). Example 155 2-Amino-3-(2,3,4-trifluorophenyl)-6-[(E) -1-phenyl-2-N 15 methylcarbamoylvinyl l -imidazo[1,2-a] pyridine N NH2 N_/ F / MeNHOCF F The 2-trifluoroacetamido-3-(2,3,4-trifluorophenyl) 6-[(E) -1-phenyl-2-N-methylcarbamoylvinyll] -imidazo[1,2 a]pyridine (134 mg, 0.265 mmol) was converted to product 20 in a manner substantially analogous to Example 151 to give 92.3- 97.7 mg. (85-90%). EIMS m/z 423 M+(6), 422 (25), 392 (6), 353 (14), 259 (14), 105 (16), 84 (100), NMR (CDC13) d 7.70 (s, 1H, C7H3N2), 7.44-7.00 (m, 9H, Ar), 6.63 (s, 1H, CH=C), 5.20 (s broud, 1H, NH-CH3) 4.13 25 (s broud, 2H, NH2), 2.62 (d, J = 4.9 Hz, 3H, NH-CH3_. Example 156 2-Amino-3-(3,5-difluorophenyl)-6- (1-phenyl-2-N methylcarbamoylvinyl) -imidazo[1,2-a] pyridine WO 99/59587 PCT/US98/10299 -127 NH2 's N/ F MeNHOC F The 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 product 5 in a manner substantially analogous to Example 151 to give 77.3 - 81.8. (85-90%). EIMS m/z 405 M+(34), 404 (100), 374 (22), 345 (17), 84 (14), NMR (CDC13) d 8.28 and 7.92 (s, 1H, C 7 H3N2), 7.5-6.7 (m, 10H, Ar), 6.36 and 6.28 (s, 1H, CH=C), 5.71 y 5.24 (s broud, 1H, NH-CH3) 10 4.22 (s broud, 2H, NH2), 2.82 and 2.65 (d, J = 4.9 and 4.9 Hz, 3H, NH-CH3). Example 157 2-Amino-3-(3-trifluoromethylphenyl)-6-[(E) -1-phenyl-2-N methylcarbamoylvinyl] - imidazo [1,2-alpyridine NH2 NII 15MeNHOC - CF 3 The 2-trifluoroacetamido-3-(3 trifluoromethylphenyl)-6-[(E) -1-phenyl-2-N methylcarbamoylvinyll -imidazo[1,2-a]pyridine (142 mg, 0.273 mmol) was converted to product in a manner 20 substantially analogous to Example 151 to give 98.4 - 104 mg. (85-90%). EIMS m/z 437 M

+

(36), 436 (100), 406 (18), 377 (16), 279 (10), 77 (6), NMR (CDC13) d 7.83 (s, 1H, C7H3N2), 7.64 (m, 11H, Ar), 6.42 and 6.38 (s, 1H, CH=C), 5.13 (s broud, 1H, NH-CH3) 4.11 (s broud, 2H, 25 NH2), 2.62 (d, J = 4.9 Hz, 3H, NH-CH3) Example 158 2-Amino-3-benzoyl-6- [(E)-l-phenyl-2-N methylcarbamoylvinyl] - imidazo[1,2-a] pyridine WO 99/59587 PCTIUS98/10299 -128 N NH2 COPh MeNHOC The l-(2-oxo-2-phenylethyl)-2-chloro-5-[(E)-1 phenyl-2-methylcarbamoylvinyl]pyridinium iodide (0.250 g, 0.482 mmol) was mixed with aminonitrile (220 mg, 0.49 5 mmol) and K2CO3 (200 mg, 1,47 mmol) in 10 ml of CH3CN. The reaction mixture was refluxed for 14 hours. After cooling to RT the mixture was filtered and the filter cake was washed with CH3CN. The mother liquor was evaporated and the residue was purified by column 10 chromatography (acetone/EtOAc 1:1) to give 62.8 mg of product as slightly colored solid in 39% yield. MS(HR), NMR. Example 159 2-Amino-3-(4-fluorobenzoyl)-6-[(E)-1-phenyl-2-N 15 methylcarbamoylvinyl]-imidazo[1,2-a]pyridine NH2 N MeNHOC F The 1-[2-oxo-2-(4-fluorophenyl)ethyl]-2-chloro-5 [(E)-l1-phenyl-2-methylcarbamoylvinyl]pyridinium iodide (400 mg, 0.740 mmol) was converted to product in a manner 20 substantially analogous to Example 158 to give 118 mg. -i) (38%). IR (KBr) u (cm-1) 3676, 3457, 3283, 3102, 1735, 1640, 1640, 1448, 1352, 1154, 849, 700, NMR (300MHz, DMSO-d6) d 8,56(s,1H); 7,86(d,1H,J= 5,12); 7,56 7,49(m,2H); 7,36(d,1H,J= 8,79); 7,3-7,2(m,5H); 25 7,15(m,2H); 6,44(s,1H); 6(s,2H); 2,48(s,3H), MS(HR): calcd. for C24H19N402 414,1492, found 414,1498. Example 160 WO 99/59587 PCT/US98/10299 -129 2-Amino-3-acetyl-6-[(E)-1-phenyl-2-N methylcarbamoylvinyl] -imidazo[1,2-a] pyridine ,/ ,N NH2 N/ 0 MeNHOC The 1-[2-oxopropyl]-2-chloro-5-[(E)-1-phenyl-2 5 methylcarbamoylvinyl]pyridinium iodide (400 mg, 0.870 mmol) was converted to product in a manner substantially analogous to Example 158 to give 118 mg. (40%). MS(HR): m/z calcd. for C 1 9H18N402 334,1430. found.334,1430, IR (KBr) u (cm - 1) 3440, 1614, 1530, 1458, 1348, 820. 10 Example 161 2-Amino-3-t-butylacetyl-6-[(E)-1-phenyl-2-N methylcarbamoylvinyl] - imidazo[ ll, 2-al]pyridine NH2 N O t 0 ____t-Bu MeHNOC The 1-[2-oxo-3,3-dimethylbutyl]-2-chloro-5-[(E)-1 15 phenyl-2-methylcarbamoylvinyl]pyridinium iodide (140 mg, 0.280 mmol) was converted to product in a manner substantially analogous to Example 158 to give 31.9 mg. (30%). MS(HR): calcd. for C22H24N402 376,1899 found 376,1900, NMR (300MHz, DMSO-d6) d 9,22(s,1H); 7,8(d,1H,J= 20 4,4); 7,4-7,3(m,4H); 7,18(d,1H,J= 4); 7,16(d,1H,J=2,5); 6,43(s,1H); 6,35(sa,2H); 2,52(d,3H,J= 4,4); 1,17(s,9H). Example 162 2-Amino-3-t-butylacetyl-6-[(E)-- (2,3-difluorophenyl)-2 N-methylcarbamoylvinyl] - imidazo [1,2-a] pyridine F ,- F , N NH2 N/ O t -Bu 25 MeHNOC WO 99/59587 PCTIUS98/10299 -130 The 1-[2-oxo-3,3-dimethylbutyl]-2-chloro-5-[(E)-l-(2,3 diflurorphenyl)-2-methylcarbamoylvinyl]pyridinium iodide (120 mg, 0.220 mmol) was converted to product in a manner substantially analogous to Example 158 to give 11.2 mg. 5 (12%). MS(HR): calcd. for C22H22N402F2 412,1711, found. 412,1713, NMR (300MHz, CDC13) d 9,4(s,lH); 7,28(d,1H,J= 1,1); 7,21-7,14(m,3H); 6,98(m, 1H);6,49(s,1H); 5,62(sa,1H); 5,35(s,2H); 2,78((d,3H,J= 4,76); 1,32(s,9H). 10 As described above, the compounds of the present invention are useful as antiviral agents. They show inhibitory activity against various strains of enterovirus and rhinovirus. An embodiment of the present invention is a method of treating or preventing 15 picornaviridae infection comprising administering to a host in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. The term "effective amount" as used herein, means an 20 amount of a compound of Formula (I) which is capable of inhibiting viral replication. The picornaviridae inhibition contemplated by the present method includes either therapeutic or prophylactic treatment, as appropriate. The specific dose of compound administered 25 according to this invention to obtain therapeutic or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration, the condition being treated and the 30 individual being treated. A typical daily dose will contain a dosage level of from about 0.01 mg/kg to about 50 mg/kg of body weight of an active compound of this invention. Preferred daily doses generally will be from about 0.05 mg/kg to about 20 mg/kg and ideally from about 35 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 WO99/59587 PCTIUS98/10299 -131 of the present invention are preferably formulated prior to administration. Therefore, another embodiment of the present invention is a pharmaceutical formulation comprising an effective amount of a compound of Formula 5 (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient thereof. The active ingredient in such formulations comprises from 0.1% to 99.9% by weight of the formulation. By 10 "pharmaceutically acceptable" it is meant that the carrier, diluent or excipient is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The present pharmaceutical formulations are prepared 15 by known procedures using well-known and readily available ingredients. In making the compositions of the present invention, the active ingredient will usually be admixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, 20 sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, excipient or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, 25 cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, sterile 30 packaged powders and the like. The following formulation example is only illustrative and is not intended to limit the scope of the invention in any way. Formulation 1 35 Hard gelatin capsules are prepared using the following ingredients: Quantity (mg/capsule) WO99/59587 PCTIUS98/10299 -132 Active ingredient 250 Starch, dried 200 Magnesium stearate 10 Total 460 mg 5 Test Methods African green monkey kidney cells (BSC-1) or Hela cells (5-3) were grown in 25cc Falcon flasks at 37 0 C in 10 medium 199 with 5 percent inactivated fetal bovine serum (FBS), penicillin (150 units 1 ml) and streptomycin (150 micrograms per milliliter (pg/ml)). When confluent monolayers were formed, the supernatant growth medium was removed and 0.3 ml of an appropriate dilution of virus 15 (e.g. echo, Mengo, Coxsackie, polio or rhinovirus) were added to each flask. After absorption for one hour at room temperature, the virus infected cell sheet was overlaid with a medium comprising one part of 1 percent lonagar No. 2 and one part double strength medium 199 20 with FBS, penicillin and streptomycin which contains drug at concentrations of 100, 50, 25, 12, 6, 3 and 0 p g/ml. The flask containing no drug served as the control for the test. The stock solutions of compounds were diluted with dimethylsulfoxide to a concentration of 104 pig/ml. 25 The flasks were then incubated for 72 hours at 37 0 C for polio, Coxsackie, echo and Mengo virus and 120 hours at 32 0 C for rhinovirus. Virus plaques were seen in those areas were the virus infected and reproduced in the cells. A solution of 10 percent formalin and 2 percent 30 sodium acetate was added to each flask to inactivate the virus and fix the cell sheet to the surface of the flask. The virus plaques, irrespective of size, were counted after staining the surrounding cell areas with crystal violet. The plaque count was compared to the control 35 count at each drug concentration. The activity of the test compound can be expressed as percentage plaque reduction, or percent inhibition. Alternatively, the drug concentration which inhibits plaque formation by 50 WO99/59587 PCTIUS98/10299 -133 percent can be used as a measure of activity. The 50 percent inhibition value is denoted as the "IC 50 ". The compounds of the present invention displayed at least 30%, preferably 50% and most preferably over 85% 5 inhibition of plaque formation at a single dose of 50 pmol. Dose response titrations on the compounds of the present invention reveal IC 50 values of < 10 rIM.

Claims (9)

1. A compound of the Formula (I): N / NHR A -. N / X A' (I) 5 wherein: A is phenyl, pyridyl, substituted phenyl, substituted pyridyl, or benzyl; R is hydrogen, COR 4 , or COCF3; X is N-OH, O, or CHR 1 ; -C= CH 10 R 1 is hydrogen, halo, CN, Cl-C4 alkyl, , CO(C 1 -C 4 alkyl), CO2(C1-C4 alkyl), or CONR 2 R 3 ; R 2 and R 3 are independently hydrogen or Cl-C4 alkyl; A' is hydrogen, halo, Cl-C6 alkyl, benzyl, naphthyl, thienyl, furyl, pyridyl, pyrollyl, COR 4 , S(O)nR 4 , or a 15 group of the formula (R 5 )m R6 R 4 is C1-C6 alkyl, phenyl, or substituted phenyl; n is 0, 1, or 2; R 5 is independently at each occurance hydrogen or 20 halo; m is 1, 2, 3, or 4; and R 6 is hydrogen, halo, CF3, OH, CO2H, NH2, NO2, CONHOCH 3 , C1-C4 alkyl, or CO2(Cl-C4 alkyl), C1-C4 alkoxy; or pharmaceutically acceptable salts thereof. 25

2. A compound of claim 1 wherein R is hydrogen.

3. A compound of claim 2 wherein: A is phenyl or substituted phenyl; and WO 99/59587 PCT/US98/10299 -135 A' is Cl-C6 alkyl, COR

4 , S(O)nR 4 , or a group of the formula (R 5 )m R6 5 4. A compound of claim 1 wherein X is NOH or CHR 1 .

5. A compound of claim 3 wherein X is NOH or CHR'.

6. A compound of claim 5 wherein: 10 X is CHR. R 1 is CN, CO(Cl-C4 alkyl), or CONR 2 R 3 ; A is flourophenyl or diflourophenyl; A' is a group of the formula (R 5 )m R6 ; and 15 R 5 is halo.

7. A method for inhibiting a Hepatitus C virus comprising administering to a host in need thereof, an effective amount of a compound of any of claims 1 through 20 6.

8. A method for inhibiting a picornavirus comprising administering to a host in need thereof, an effective amount of a compound of any of claims 1 through 25 6.

9. A pharmaceutical formulation comprising as an active ingredient a compound of any of claims 1 through 6, associated with one or more pharmaceutically 30 acceptable carriers, excipients or diluents.