Process for synthesizing biaryl inhibitors of farnesyl-protein transferase

The present invention is directed to a process for synthesizing 1,5 disubstituted imidazoles with biaryl components of the formula (I): ##STR1## which are usefull as Farnesyl-Protein Transferase inhibitors.

BACKGROUND OF THE INVENTION
 The Ras proteins (Ha-Ras, Ki4a-Ras, Ki4b-Ras and N-Ras) are part of a
 signaling pathway that links cell surface growth factor receptors to
 nuclear signals initiating cellular proliferation. Mutated ras genes
 (Ha-ras, Ki4a-ras, Ki4b-ras and N-ras) are found in many human cancers,
 including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid
 leukemias.
 Ras must be localized to the plasma membrane for both normal and oncogenic
 functions. At least three post-translational modifications are involved
 with Ras membrane localization, and all three modifications occur at the
 C-terminus of Ras. The Ras C-terminus contains a sequence motif termed a
 "CAAX" or "Cys-Aaa.sup.1 -Aaa.sup.2 -Xaa" box (Cys is cysteine, Aaa is an
 aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature
 310:583-586 (1984)). Depending on the specific sequence, this motif serves
 as a signal sequence for the enzymes farnesyl-protein transferase or
 geranylgeranyl-protein transferase, which catalyze the alkylation of the
 cysteine residue of the CAAX motif with a C.sub.15 or C.sub.20 isoprenoid,
 respectively. (S. Clarke., Ann. Rev. Biochem. 61:355-386 (1992); W. R.
 Schafer and J. Rine, Ann. Rev. Genetics 30:209-237 (1992)).
 The peptide derived inhibitors of farnesyl-protein transferase (FPTase)
 that have been described are generally cysteine containing molecules that
 are related to the CAAX motif that is the signal for protein prenylation.
 (Schaber et al., J. Biol. Chem., 265:14701-14704 (1990); Reiss et. al.,
 Cell, 62:81-88 (1990); Reiss et al., PNAS, 88:732-736 (1991)). Such
 inhibitors may inhibit protein prenylation while serving as alternate
 substrates for the farnesyl-protein transferase enzyme, or may be purely
 competitive inhibitors (U.S. Pat. No. 5,141,851, University of Texas; N.
 E. Kohl et al., Science, 260:1934-1937 (1993); Graham, et al., J. Med.
 Chem., 37, 725 (1994)). In general, while deletion of the thiol from a
 CAAX derivative has been shown to reduce the inhibitory potency of the
 compound, the thiol group can adversely affect the pharmacokinetics,
 pharmacodynamics and toxicity of FPTase inhibitors. Consequently,
 functional replacements for the thiol group have been achieved.
 Thiol replacements that incorporate a 1,5 disubstituted imidazole with a
 biaryl component have been observed to be FPTase inhibitors. The synthesis
 of 1,5 disubstituted imidazoles from primary amines, dihydroxyacetone and
 potassium thiocyanate via thioimidazoles has been reported in the
 classical literature (Marckwald, Chem Ber. 1892, 25, 2354; Duncia, J. M.
 et al, J. Med Chem. 1990, 33, 1312-1330; Jones, R. G., J. Am. Chem. Soc.
 1949, 71, 383 and 644; Pyman, J. Chem. Soc. 1911, 99, 668). Literature
 protocols for the dethionation of 2-mercaptoimidazoles describe treatment
 with concentrated nitric acid, with or without a nitrite; such procedures
 give variable results and often result in the sudden violent release of
 nitrogen oxide gases.
 Therefore, the need exists for a process for synthesizing 1,5 disubstituted
 imidazoles with biaryl components which has a predictably higher yield
 than known methods and which utilizes reaction conditions that are free
 from the drawbacks described above.
 SUMMARY OF THE INVENTION
 The present invention provides a novel process for the preparation of
 compounds with the formula (I), which are useful as FPTase inhibitors:
 ##STR2##
 wherein:
 R.sup.1, R.sup.2 and R.sup.3 are independently selected from:
 a) hydrogen,
 b) aryl, substituted aryl, heterocycle, substituted heterocycle, C.sub.3
 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl,
 perfluoroalkyl, F, Cl, Br, R.sup.11 O--, R.sup.12 S(O).sub.m --, R.sup.11
 C(O)NR.sup.11 --, (R.sup.11).sub.2 NC(O)--, R.sup.12 S(O).sub.2 NR.sup.11
 --, (R.sup.11).sub.2 NS(O).sub.2 --, R.sup.11.sub.2 N--C(NR.sup.11)--, CN,
 NO.sub.2, R.sup.11 C(O)--, N.sub.3, --N(R.sup.11).sub.2, or R.sup.12
 OC(O)NR.sup.11 --, and
 c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by aryl,
 cyanophenyl, heterocycle, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6
 alkenyl, C.sub.2 -C.sub.6 alkynyl, perfluoroalkyl, F, Cl, Br, R.sup.11
 O--, R.sup.12 S(O).sub.m--, R.sup.11 C(O)NR.sup.11 --, (R.sup.11).sub.2
 NC(O)--, R.sup.12 S(O).sub.2 NR.sup.11 --, (R.sup.11).sub.2 NS(O).sub.2
 --, R.sup.11.sub.2 N--C(NR.sup.11)--, CN, R.sup.11 C(O)--, N.sub.3,
 --N(R.sup.11).sub.2, or R.sup.11 OC(O)NH--;
 R.sup.5, R.sup.6 and R.sup.7 are independently selected from:
 a) hydrogen,
 b) unsubstituted or substituted aryl, unsubstituted or substituted
 heterocycle, C.sub.3 -C.sub.10 cycloalkyl, halogen, C.sub.1 -C.sub.6
 perfluoroalkyl, R.sup.13 O--, R.sup.12 S(O).sub.m --, R.sup.11
 C(O)NR.sup.11 --, (R.sup.11).sub.2 NC(O)--, R.sup.12 C(O)O--,
 R.sup.11.sub.2 N--C(NR.sup.11)--, R.sup.11 C(O)--, --N(R.sup.11).sub.2, or
 R.sup.12 OC(O)NR.sup.11 --,
 c) unsubstituted C.sub.1 -C.sub.6 alkyl,
 d) substituted C.sub.1 -C.sub.6 alkyl wherein the substituent on the
 substituted C.sub.1 -C.sub.6 alkyl is selected from unsubstituted or
 substituted aryl, unsubstituted or substituted heterocyclic, C.sub.3
 -C.sub.10 cycloalkyl, R.sup.13 O--, R.sup.12 S(O).sub.m --, R.sup.11
 C(O)NR.sup.11 --, (R.sup.11).sub.2 NC(O)--, R.sup.11.sub.2
 N--C(NR.sup.11)--, R.sup.11 C(O)--, --N(R.sup.11).sub.2, and R.sup.12
 OC(O)--NR.sup.11 --;
 R.sup.8, R.sup.9 and R.sup.10 are independently selected from:
 a) hydrogen,
 b) unsubstituted or substituted aryl, unsubstituted or substituted
 heterocycle, C.sub.3 -C.sub.10 cycloalkyl, halogen, C.sub.1 -C.sub.6
 perfluoroalkyl, R.sup.13 O--, R.sup.12 S(O).sub.m --, R.sup.11
 C(O)NR.sup.11 --, (R.sup.11).sub.2 NC(O)--, R.sup.12 S(O).sub.2 NR.sup.11
 --, (R.sup.11).sub.2 NS(O).sub.2 --, R.sup.12 C(O)O--, R.sup.11.sub.2
 N--C(NR.sup.11)--, R.sup.11 C(O)--, --N(R.sup.11).sub.2, or R.sup.12
 OC(O)NR.sup.11 --,
 c) unsubstituted C.sub.1 -C.sub.6 alkyl,
 d) substituted C.sub.1 -C.sub.6 alkyl wherein the substituent on the
 substituted C.sub.1 -C.sub.6 alkyl is selected from unsubstituted or
 substituted aryl, unsubstituted or substituted heterocyclic, C.sub.3
 -C.sub.10 cycloalkyl, R.sup.13 O--, R.sup.12 S(O).sub.m --, R.sup.11
 C(O)NR.sup.11 --, (R.sup.11).sub.2 NC(O)--, R.sup.12 S(O).sub.2 NR.sup.11
 --, (R.sup.11).sub.2 NS(O).sub.2 --, R.sup.11.sub.2 N--C(NR.sup.11)--,
 R.sup.11 C(O)--, --N(R.sup.11).sub.2, and R.sup.12 OC(O)--NR.sup.11 --; or
 any two of R.sup.8, R.sup.9 and R.sup.10 on adjacent carbon atoms are
 combined to form a diradical selected from --CH.dbd.CH--CH.dbd.CH--,
 --CH.dbd.CH--CH.sub.2 --, --(CH.sub.2).sub.4 -- and --(CH.sub.2).sub.3 --;
 A is:
 a 5, 6 or 7 membered carbocyclic ring wherein from 0 to 3 carbon atoms are
 replaced by a heteroatom selected from N, S and O, and wherein A is
 attached to B through a carbon atom;
 B is:
 a 4, 5, 6 or 7 membered heterocyclic ring which comprises a nitrogen atom
 through which B is attached to A and 0-2 additional heteroatoms selected
 from N, S and O, and which also comprises a carbonyl, thiocarbonyl,
 --C(.dbd.NR.sup.14)-- or sulfonyl moiety adjacent to the nitrogen atom
 attached to A;
 R.sup.11 is independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl,
 amino-C.sub.1 -C.sub.6 alkyl, N-(unsubstituted or substituted
 benzoyl)-amino-C.sub.1 -C.sub.6 alkyl, (C.sub.1 -C.sub.6 alkyl).sub.2
 -amino-C.sub.1 -C.sub.6 alkyl, acetylamino-C.sub.1 -C.sub.6 alkyl,
 phenyl-C.sub.1 -C.sub.6 alkyl, 2,2,2-trifluoroethyl, aryl and substituted
 aryl;
 R.sup.12 is independently selected from C.sub.1 -C.sub.6 alkyl and aryl;
 R.sup.13 is independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl,
 C.sub.1 -C.sub.6 aralkyl, C.sub.1 -C.sub.6 substituted aralkyl, C.sub.1
 -C.sub.6 heteroaralkyl, C.sub.1 -C.sub.6 substituted heteroaralkyl, aryl,
 substituted aryl, heteroaryl, substituted heteraryl, C.sub.1 -C.sub.6
 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
 R.sup.14 is selected from hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.1
 -C.sub.6 alkylsulfonyl and C.sub.1 -C.sub.6 acyl;
 m is 0, 1 or 2.
 Compounds of the formula (I) are synthesized by dethionating a
 thioimidazole of the formula (II):
 ##STR3##
 The thioimidazole of formula (II) is prepared by coupling a hydroxyketone
 of formula (III):
 ##STR4##
 with a benzylic amine of formula (IV):
 ##STR5##
 The instant invention also involves the synthesis of the novel
 hydroxyketone of formula (III) and the novel benzylic amine of formula
 (IV).
 DETAILED DESCRIPTION OF THE INVENTION
 The present invention is directed to a novel process for the separation of
 compounds of the formula (I):
 ##STR6##
 (wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, R.sup.7, R.sup.8,
 R.sup.9, R.sup.10, A and B are defined as set forth above)
 which comprises dethionating a thioimidazole of formula (II):
 ##STR7##
 (wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, R.sup.7, R.sup.8,
 R.sup.9, R.sup.10, A and B are defined as set forth above)
 with an oxidizing agent in the presence of a first acid. The thioimidazole
 of formula (II) is prepared by condensing a hydroxyketone of the formula
 (III):
 ##STR8##
 wherein R.sup.1, R.sup.2 and R.sup.3 are defined as set forth above)
 with a benzylic amine of the formula (IV):
 ##STR9##
 (wherein R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10 and A and B
 are defined as set forth above)
 in the presence of a thiocyanate and a second acid.
 Oxidizing agents suitable for the dethionation of the thioimidazole of
 formula (II) include: hydrogen peroxide, nitric acid, nitrous acid,
 nitrite salts and nitrite esters. Preferred oxidizing agents for this step
 include: hydrogen peroxide and nitrous acid. The most preferred oxidizing
 agents for this step include aqueous NaNO.sub.2 or aqueous KNO.sub.2,
 which are added to an acidic solution of the thioimidazole.
 First acids suitable for the dethionation of the thioimidazole of formula
 (II) include: anhydrous or aqueous HF, HCl, HBr, HI, sulfuric, phosphoric,
 MsOH, TsOH, carboxylic acids and TFA. Preferred first acids for this step
 include: MsOH and carboxylic acids such as HOAc and TFA. The most
 preferred first acid for this step is HOAc.
 A suitable temperature range for the dethionation of the thioimidazole of
 formula (II) is about -50 to about 250.degree. C., with a preferred
 temperature range being about -20 to about 100.degree. C. and the most
 preferred temperature range being about -10 to about 40.degree. C.
 Dethionation of the thioimidazole of formula (II) may be run neat. However,
 solvents suitable for the dethionation include: water; alcohols such as
 MeOH, EtOH, n-PrOH, i-PrOH, butanols and alkoxyethanols; hydrocarbons such
 as toluene or xylenes; chlorinated hydrocarbons such as dichloromethane,
 chloroform, chlorobenzene and ODCB; nitriles such as acetonitrile,
 propionitrile, benzolitrile and tolunitrile; ketones such as acetone, MEK,
 MIBK and cyclohexanone; ethers such as diethyl ether, MTBE, THF, DME and
 DEM; other polar aprotic solvents such as formamide, DMF, DMA, NMP, DMPU,
 DMSO, and sulfolane; acids such as anhydrous or aqueous HF, HCl, HBr, HI,
 sulfuric, phosphoric, MsOH, TsOH, carboxylic acids such as HOAc and TFA.
 Preferred solvents for this step include: water or acids such as anhydrous
 or aqueous, MsOH, carboxylic acids such as HOAc and TFA. The most
 preferred solvents for this step include: water HOAc and TFA.
 Thiocyanates suitable for the condensation of the hydroxyketone of formula
 (III) and the benzylic amine of formula (IV) include: LiSCN, NaSCN, KSCN,
 CsSCN, MgSCN, CaSCN, guanidine thiocyanate, HSCN and TMS-SCN. Preferred
 thiocyanates for this step include: NaSCN and KSCN. The most preferred
 thiocyanate for this step is KSCN.
 Second acids suitable for the condensation of the hydroxyketone of formula
 (III) and the benzylic amine of formula (IV) include: anhydrous or aqueous
 HF, HCl, HBr, HI, sulfuric, phosphoric, MsOH, TsOH, ammonium halides,
 phosphate salts, carboxylic acids such as HOAc and TFA. Preferred second
 acids for this step include: anhydrous or aqueous HF, HCl, HBr, HI,
 ammonium halides, carboxylic acids such as HOAc and TFA. The most
 preferred second acid for this step is HOAc.
 A suitable temperature range for the condensation of the hydroxyketone of
 formula (III) and the benzylic amine of formula (IV) is about -50 to about
 250.degree. C., with a preferred temperature range being about 0 to about
 100.degree. C. and the most preferred temperature range being about 50 to
 about 75.degree. C.
 Condensation of the hydroxyketone of formula (III) and the benzylic amine
 of formula (IV) may be run neat. However, solvents suitable for the
 condensation include: water; alcohols such as MeOH, EtOH, n-PrOH, i-PrOH,
 butanols and alkoxyethanols; hydrocarbons such as toluene or xylenes;
 chlorinated hydrocarbons such as dichloromethane, chloroform,
 chlorobenzene and ODCB; esters such as EtOAc, I and BuOAc; nitrites
 such as acetonitrile, propionitrile, benzonitrile and tolunitrile; ketones
 such as acetone, MEK, MIBK and cyclohexanone; ethers such as diethyl
 ether, MTBE, THO, DME and DEM; other polar aprotic solvents such as
 formamide, DMF, DMA, NMP, DMPU, DMSO, and sulfolane or mixtures thereof.
 Preferred solvents for this step include: water; alcohols such as MeOH,
 EtOH, n-PrOH, i-PrOH and butanols; nitriles such as acetonitrile,
 propionitrile, benzonitrile and tolunitrile; mixtures of nitriles with
 toluene and mixtures of nitriles with water. The most preferred solvents
 for this step include: water, butanol, acetonitrile, a mixture of
 acetonitrile and water or a mixture of acetonitrile and toluene.
 One embodiment of the instant invention involves the preparation of a
 compound of formula (IV), which is useful as an intermediate in the
 preparation of compounds of formula (I):
 ##STR10##
 (wherein R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, A and B are
 defined as set forth above)
 which comprises reducing a biaryl nitrile of formula (V)
 ##STR11##
 (wherein R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, A and B are
 defined as set forth above)
 by hydrogenation in the presence of a first catalyst, with or without an
 additive.
 The biaryl nitrile of formula (V) is prepared by alkylating a nitrile of
 the formula (VI):
 ##STR12##
 (wherein R.sup.5, R.sup.6, R.sup.7 and A are defined as set forth above; X
 is selected from halogen, sulfonate or phosphate)
 with a compound of the formula (VII):
 ##STR13##
 (wherein R.sup.8, R.sup.9, R.sup.10 and B are defined as set forth above)
 in the presence of a base, with or without a Lewis acid.
 The nitrile of formula (VI) can be prepared by one of three methods:
 (1) dehydrating an amide of the formula (VIII):
 ##STR14##
 (wherein R.sup.5, R.sup.6, R.sup.7 and A are defined as set forth above; X
 is selected from halogen, sulfonate or phosphate)
 by treating the amide with an inorganic acid halide, organic acid halide,
 or other active halogenating agent; or
 (2) diazotizing an amine of the formula IX:
 ##STR15##
 (wherein R.sup.5, R.sup.6, R.sup.7 and A are defined as set forth above; X
 is selected from halogen, sulfonate or phosphate)
 with a nitrite in the presence of an acid followed by treatment with a
 first metallic cyanide; or
 (3) treating a compound of the formula (Xa):
 ##STR16##
 wherein R.sup.5, R.sup.6, R.sup.7 and A are defined as set forth above; X
 is selected from halogen, sulfonate or phosphate; Y is selected from
 halogen, sulfonate or phosphate and Y is more reactive than X tow rds a
 second metallic cyanide, with or without a second catalyst)
 with a second metallic cyanide, with or without a second catalyst.
 First catalysts suitable for the reduction of the biaryl nitrile of formula
 (V) include: noble metals such as Pd, Rh, Ru, Pt, Mo, Ir and various
 salts, oxides, hydroxides and organometallic derivatives thereof;
 transition metals such as Ni, Co, Fe, Cu, Cr, Mn, B and various salts,
 hydroxides, oxides and organometallic derivatives thereof as well as other
 complex oxides such as copper chromite. Preferred first catalysts for this
 step include: Ni, Pd, Pt, Rh, Co and Mo. The most preferred first
 catalysts for this step include: Ni, Pd and Co.
 Additives suitable for the reduction of the biaryl nitrile of formula (V)
 include: ammonia, ammonium hydroxide, NaOH, KOH, HCl or other additives
 commonly used in the hydrogenation of nitrites.
 The source of hydrogen suitable for the hydrogenation of biaryl nitrile of
 formula (V) includes: H.sub.2 or a suitable hydrogen transfer agent such
 as 1,4 cyclohexadiene or a formate salt.
 A suitable temperature range for the reduction of the biaryl nitrile of
 formula (V) is about -80 to about 350.degree. C., with a preferred
 temperature range being about 0 to about 140.degree. C. and the most
 preferred temperature range being about 20 to about 90.degree. C.
 Reduction of the biaryl nitrile of formula (V) may be run neat. However,
 suitable solvents for the reduction include: water; alcohols such as MeOH,
 EtOH, n-PrOH, i-PrOH, butanols and alkoxyethanols; esters such as EtOAc,
 I and BuOAc; hydrocarbons such as toluene or xylenes; chlorinated
 hydrocarbons such as dichloromethane, dichloroethane, chloroform,
 chlorobenzene and ODCB; ketones such as acetone, MEK, MIBK and
 cyclohexanone; ethers such as diethyl ether, MTE, THF, DME and DEM; other
 polar aprotic solvents such as formamide, DMF, DMA, NMP, DMPU, DMSO, and
 sulfolane or mixtures thereof. Preferred solvents for this step include:
 alcohols such as MeOH, EtOH, n-PrOH, i-PrOH, butanols and alkoxyethanols;
 ethers such as diethyl ether, MTBE, THF, DME and DEM; esters such as
 EtOAc, I and BuOAc; other pollar aprotic solvents such as formamide,
 DMF, DMA, NMP, DMPU, DMSO, and sulfolane. The most preferred solvents for
 this step include: alcohols such as MeOH, EtOH, n-PrOH, i-PrOH; and THF.
 Bases suitable for the alkylation of the nitrile of formula (VI) include:
 Et.sub.3 N, DIEA, n-Bu.sub.3 N, Imidazole, N-Me-imidazole, Pyridine,
 2,6-Lutidine, 2,4,6-Collidine, 2,6-tBu.sub.2 -pyridine, 2,6-tBu.sub.2
 -4-Me-pyridine, DMAP, DBU, DBN, DABCO, N-Me-morpholine, N-Et-morpholine,
 1,2,2,6,6-Me.sub.5 -piperidine, Me.sub.4 -guanidine, Proton Sponge,
 N,N-Me.sub.2 -aniline, N,N-Et.sub.2 -aniline, Quinoline, i-Pr.sub.2 NH,
 Cyclohex.sub.2 NH, (Cyclohex)iPrNH, Pyrrolidine, Piperidine,
 2,2,6,6-Me.sub.4 -piperidine, TMS.sub.2 NH (HMDS), LiNH.sub.2, NaNH.sub.2,
 H.sub.2, LHMDS, NaHMDS, KHMDS, BnNMe.sub.3 OMe, NaOEt, TlOEt, LiOt-Bu,
 NaOt-Bu, KOt-Bu, LiOt-Am, NaOt-Am, KOt-Am, KH, KOTMS, NaH, KOH, n-Bu.sub.4
 NOH, Triton-B, Ca(OH).sub.2, CaO, BaO, Li.sub.2 CO.sub.3, Na.sub.2
 CO.sub.3, K.sub.2 CO.sub.3, Cs.sub.2 CO.sub.3, (NH.sub.4).sub.2 CO.sub.3,
 Guanidine carbonate, CaCO.sub.3, NaHCO.sub.3, KHCO.sub.3, and K.sub.3
 PO.sub.4. Preferred bases for this step include: Li.sub.2 CO.sub.3,
 Na.sub.2 CO.sub.3, K.sub.2 CO.sub.3, Cs.sub.2 CO.sub.3, DBU, DBN and
 Me.sub.4 -guanidine. The most preferred bases for this step include
 Cs.sub.2 CO.sub.3 and Me.sub.4 -guanidine.
 Lewis acid additives suitable for alkylation of the nitrile of formula (VI)
 include: metal halides, metal triflates, metal tetrafluoroborates, metal
 hexafluorophosphates, metal hexafluoroantimonates, or metal sulfates. The
 most preferred Lewis acid additive for this step is Cu(OTf).sub.2 with
 metallic Cu.
 A suitable temperature range for alkylation of the nitrile of formula (VI)
 is about -80 to about 350.degree. C., with a preferred temperature range
 being about 0 to about 140.degree. C. and the most preferred temperature
 range being about 50 to about 90.degree. C.
 Alkylation of the nitrile of formula (VI) may be run neat. However,
 suitable solvents for the alkylation include: water; alcohols such as
 MeOH, EtOH, n-PrOH, i-PrOH, butanols and alkoxyethanols; esters such as
 EtOAc, I and BuOAc; hydrocarbons such as toluene or xylenes;
 chlorinated hydrocarbons such as dichloromethane, dichloroethane,
 chloroform, chlorobenzene and ODCB; nitriles such as acetonitrile,
 propionitrile, benzonitrile and tolunitrile; ketones such as acetone, MEK,
 MIBK and cyclohexanone; ethers such as diethyl ether, MTBE, THF, DME and
 DEM; other polar aprotic solvents such as formamide, DMF, DMA, NMP, DMPU,
 DMSO, and sulfolane or mixtures thereof. Preferred solvents for this step
 include: alcohols such as MeOH, EtOH, n-PrOH, i-PrOH, butanols and
 alkoxyethanols; nitrites such as acetonitrile, propionitrile, benzonitrile
 and tolunitrile; ethers such as diethyl ether, MIBE, THF, DME and DEM;
 other polar aprotic solvents such as formamide, DMF, DMA, NMP, DMPU, DMSO,
 and sulfolane. The most preferred solvents for this step include:
 Acetonitrile, THF and DMF.
 Inorganic acid halides suitable for dehydrating the amide of formula (VIII)
 include: SOCl.sub.2, SO.sub.2 Cl.sub.2, S.sub.2 Cl.sub.2, PCl.sub.3,
 PCl.sub.5, POCl.sub.3, PSCl.sub.3, other mono or dihalophosphites
 [(RO).sub.2 PCl or ROPCl.sub.2 ], other mono or dihalophosphates
 [(RO).sub.2 POCl or ROPOCl.sub.2 ], other mono or dihalophosphines
 [R.sub.2 PCl or RPCl.sub.2 ], other mono or dihalophosphine oxides
 [R.sub.2 POCl or RPOCl.sub.2 ], SiCl.sub.4, SnCl.sub.4, and other metl or
 non-metal halides. The most preferred inorganic acid halides for this step
 include SOCl.sub.2 and POCl.sub.3.
 Organic acid halides suitable for dehydrating the amide of formula (VIII)
 include: oxalyl chloride, acetyl chloride, phosgene, di and tri-phosgene,
 the chloroformates, the carbamoyl chlorides and the sulfonyl chlorides
 such as mesyl chloride or tosyl chloride. Preferred organic acid halides
 for this step are oxalyl chloride and mesyl chloride The most preferred
 organic acid halide for this step is oxlyl chloride.
 Other active halogenating agents suitable four dehydrating the amide of
 formula (VIII) include: cyanouric chloride, Vilsmeier areagent,
 Phosgenimine, Gold's reagent, chlorinated heterocycles and combinations of
 halogenating agents, such as halogens, CCl.sub.4, C.sub.2 Cl.sub.6, or
 other alkyl halides, with reducing agents, such as triaryl or tialkyl
 phosphines or phosphites and a hydrogen halide, in the presence of a
 dehydrating agent. Preferred other active halogenating agents for this
 step include cyanouric chloride and Vilsmeier reagent. The most preferred
 other active halogenating agent for this step is Vilsmeier reagent.
 A suitable temperature range for dehydration of the amide of formula (VIII)
 is about -50 to about 250.degree. C., with a preferred temperature range
 being about -20 to about 100.degree. C. and the most preferred temperature
 range being about 10 to about 90.degree. C.
 Dehydration of the amide of formula (VIII) may be run neat. However,
 suitable solvents for the dehydration include: hydrocarbons such as
 toluene or xylenes; chlorinated hydrocarbons such as dichloromethane,
 dichloroethane, chloroform, chlorobenzene and ODCB; nitriles such as
 acetonitrile, propionitrile, benzonitrile and tolunitrile; esters such as
 EtOAc, I and BuOAc; ketones such as acetone, MEK, MIBK and
 cyclohexanone; ethers such as diethyl ether, MTBE, THF, DME and DEM; other
 polar aprotic solvents such as formamide, DMF, DMA, NMP, DMPU, DMSO, and
 sulfolane or mixtures thereof. Preferred solvents for this step include:
 hydrocarbons such as toluene or xylenes; chlorinated hydrocarbons such as
 dichloromethane, chloroform, chlorobenzene and ODCB; nitriles such as
 acetonitrile, propionitrile, benzonitrile and tolunitrile; esters such as
 EtOAc, I and BuOAc; other polar aprotic solvents such as formamide,
 DMF, DMA, NMP, DMPU, DMSO, and sulfolane or mixtures thereof. The most
 preferred solvents for this step include: toluene, acetonitrile or DMF or
 mixtures thereof.
 Nitrites suitable for the diazotization of the ainine of formula (IX)
 include: NaNO.sub.2, KNO.sub.2 and alkyl nitrites (RONO).
 Acids suitable for the diazotization of the amine of formula (IX) include:
 HCl, HBr, HI, sulfuric, phosphoric, MsOH, TsOH, ammonium halides,
 phosphate salts and carboxylic acids such as HOAc and TFA. Preferred acids
 for this step include: HCl, HOAc, MsOH and sulfuric.
 First metallic cyanides suitable for diazotization of the amine of formula
 (IX) include: CuCN, Zn(CN).sub.2, NaCN and KCN. Preferred first metallic
 cyanides for this step include: CuCN and Zn(CN).sub.2.
 A suitable temperature range for the diazotization of the amine of formula
 (IX) is about -20 to about 100.degree. C., with a preferred temperature
 range being about -15 to about 50.degree. C. and the most preferred
 temperature range being about -10 to about 30.degree. C.
 Diazotization of the amine of formula (IX) may be run neat. However,
 suitable solvents for this step include: water; alcohols such as MeOH,
 EtOH, n-PrOH, i-PrOH, butanols and alkoxyethanols; esters such as EtOAc,
 I and BuOAc; hydrocarbons such as toluene or xylenes; chlorinated
 hydrocarbons such as dichloromethane, dichloroethane, chloroform,
 chlorobenzene and ODCB; nitriles such as acetonitrile, propionitrile,
 benzonitrile and tolunitrile; ketones such as acetone, MEK, MIBK and
 cyclohexanone; ethers such as diethyl ether, MTBE, THF, DME and DEM; other
 polar aprotic solvents such as formamide, DMF, DMA, NMP, DMPU, DMSO, and
 sulfolane or mixtures thereof. Preferred solvents for this step include:
 H.sub.2 O and HOAc.
 Second metallic cyanides suitable for reaction with the compound of formula
 (Xa) include: CuCN, Zn(CN).sub.2, NaCN and KCN. Preferred second metallic
 cyanides for this step include: GuCN and Zn(CN).sub.2.
 Second catalysts suitable for reaction with the compound of formula (Xa)
 include: Ni, Pd. Pt and the salts or complexes thereof such as halides,
 carboxylates, sulfonates and sigma donor complexes of the salts or metals.
 Preferred second catalysts for this step include: PdCl.sub.2,
 Pd(OAc).sub.2, Pd(PPh.sub.3).sub.4, Pd(Ph.sub.3).sub.2 Cl.sub.2, Pd.sub.2
 (dba).sub.3, Ni(PPh.sub.3).sub.2 Cl.sub.2 and Ni(Ph.sub.3).sub.4.
 A suitable temperature range for the reaction with the compound of formula
 (Xa) is about -20 to about 250.degree. C., with a preferred temperature
 range being about 0 to about 200.degree. C. and the most preferred
 temperature range being about 20 to about 180.degree. C.
 The reaction of the compound (Xa) may be run neat. However, suitable
 solvents for this step include: water; alcohols such as MeOH, EtOH,
 n-PrOH, i-PrOH, butanols and alkoxyethanols; esters such as EtOAc, I
 and BuOAc; hydrocarbons such as toluene or xylenes; chlorinated
 hydrocarbons such as dichloromethane, dichloroethane, chloroform,
 chlorobenzene and ODCB; nitriles such as acetonitrile, propionitrile,
 benzonitrile and tolunitrile; ketones such as acetone, MEK, MIBK and
 cyclohexanone; ethers such as diethyl ether, MTBE, THF, DME and DEM; other
 polar aprotic solvents such as formamide, DMF, DMA, NMP, DMPU, DMSO, and
 sulfolane or mixtures thereof Preferred solvents for this step include:
 NMP, DMF and DMPU.
 Another embodiment of the instant invention involves the preparation of a
 compound of the formula (III) which is useful as an intermediate in the
 preparation of compounds of formula (I):
 ##STR17##
 (wherein R.sup.1, R.sup.2 and R.sup.3 are defined as set forth above)
 which comprises hydrolyzing a vinyl sulfide of formula (XI):
 ##STR18##
 (wherein R.sup.1, R.sup.2 and R.sup.3 are defined as set forth above; R4 is
 selected from substituted or unsubstituted alkyl and substituted or
 unsubstituted aryl)
 in the presence of an acid or a first transition metal or combination
 thereof The vinyl sulfide of formula (XI) is prepared by treating an
 alkyne of the formula (XII).
 ##STR19##
 (wherein R.sup.1, R.sup.2 and R.sup.3 are defined as set forth above)
 with a thiol in the presence of a first base. The alkyne of formula (XII)
 is prepared by treating a compound of the formula (XIII):
 ##STR20##
 (wherein R.sup.1, R.sup.2 and R.sup.3 are defined as set forth above; X is
 independently selected from: halogen, sulfonate and phosphate)
 with propargyl alcohol in the presence of a second transition metal
 catalyst and a second base.
 Acids suitable for hydrolyzing the vinyl sulfide of the formula (XI)
 include: HCl, HBr, HI, sulfuric, phosphoric, MsOH, TsOH, ammonium halides,
 phosphate salts and carboxylic acids such as HOAc and TFA. The most
 preferred acids for this step include: sulfuric, phosphoric, MsOH, TsOH
 and HCl.
 First transition metals suitable for hydrolyzing the vinyl sulfide of
 formula (XI) include: Cu, Ni, Co, Fe, Mn, Cr, V, Ti, Sc, Y, Zr, Nb, Mo,
 Ru, Rh, Pd, Ag, Cd, La, Hf, Ta, W, Re, Os, Ir, Pt, Au, Zn, Hg and donor
 complexes thereof such as the phosphine complexes and various salts,
 hydroxides, oxides, and organometallic derivatives thereof such as the
 halides, carboxylates, triflates, tetrafluoroborates,
 hexafluorophosphates, hexafluoroantimonates, or sulfates and phosphine
 derivatives thereof and other Lewis Acids.
 Combinations of the above transition metals and their derivatives with the
 above acids or various bases such as alkali or alkaline earth metal
 hydroxides, oxides, and carbonates are also suitable for hydrolyzing the
 vinyl sulfide of formula (XI).
 A suitable temperature range for hydrolyzing the vinyl sulfide of formula
 (XI) is about -75 to about 200.degree. C., with a preferred temperature
 range being about 0 to about 100.degree. C. and the most preferred
 temperature range being about 40 to about 80.degree. C.
 Hydrolysis of the vinyl sulfide of formula (XI) may be run neat. However,
 solvents suitable for the hydrolysis include: water;
 alcohols such as MeOH, EtOH, n-PrOH, i-PrOH, butanols and alkoxyethanols;
 esters such as EtOAc, I and BuOAc; hydrocarbons such as toluene or
 xylenes; chlorinated hydrocarbons such as dichloromethane, dichloroethane,
 chloroform, chlorobenzene and ODCB; nitrites such as acetonitrile,
 propionitrile, benzonitrile and tolunitrile; ketones such as acetone, MEK,
 MIBK and cyclohexanone; ethers such as diethyl ether, AMBE, THF and DME;
 other polar aprotic solvents such as formamide, DMF, DMA, NMP, DMPU, DMSO,
 and sulfolane or mixtures thereof. Preferred solvents for this step
 include: water; alcohols such as MeOH, EtOH, n-PrOH and i-PrOH; THF, DME,
 acetonitrile, formamide, DMF, DMA, NMP, DMPU, DNMSO, and sulfolane. The
 most preferred solvents for this step include: water; alcohols such as
 MeOH, EtOH, n-PrOH and i-PrOH; THE, DME and acetonitrile.
 Thiols suitable for reaction with the alkyne of formula (XII) include:
 alkyl and aryl thiols such as: MeSH, EtSH, t-BuSH, n-BuSH, BnSH, PhSH,
 p-Thiocresol, HSCH.sub.2 COOH, HSCH.sub.2 COOMe and HSCH.sub.2 COOEt. The
 most preferred thiols for this step include: EtSH, t-BuSH, BnSH, PhSH,
 n-BuSH and p-Thiocresol.
 First bases suitable for reaction with the alkyne of formula (XII) include:
 Et.sub.3 N, DIEA, n-Bu.sub.3 N, Imidazole, N-Me-imidazole, Pyridine,
 2,6-Lutidine, 2,4,6-Collidine, 2,6-tBu.sub.2 -pyridine, 2,6-tBu.sub.2
 -4-Me-pyridine, DMAP, DBU, DBN, DABCO, N-Me-morpholine, N-Et-morpholine,
 1,2,2,6,6-Me.sub.5 -piperidine, Me.sub.4 -guanidine, Proton Sponge,
 N,N-Me.sub.2 -aniline, N,N-Et.sub.2 -aniline, Quinoline, i-Pr.sub.2 NH,
 CYclohex.sub.2 NH, (Cyclohex)iPrNH, Pyrrolidine, Piperidine,
 2,2,6,6-Me.sub.4 -piperidine, TMS.sub.2 NH (HMDS), LiNH.sub.2, NaNH.sub.2,
 KNH.sub.2, LHMDS, NaHMDS, KHMDS, BnNMe.sub.3 OMe, NaOEt, TlOEt, LiOt-Bu,
 NaOt-Bu, KOt-Bu, LiOt-Am, NaOt-Am, KOt-Am, KH, KOTMS, NaH, LiOH, NaOH,
 KOH, n-Bu.sub.4 NOH, Triton-B, Ca(OH).sub.2, CaO, BaO, Li.sub.2 CO.sub.3,
 Na.sub.2 CO.sub.3, K.sub.2 CO.sub.3, Cs.sub.2 CO.sub.3, (NH.sub.4).sub.2
 CO.sub.3, Guanidine carbonate, CaCO.sub.3, NaHCO.sub.3, KHCO.sub.3,
 K.sub.3 PO.sub.4, EtNH.sub.2, n-PrNH.sub.2, n-BuNH.sub.2, t-BuNH.sub.2 and
 CyclohexylNH.sub.2. Preferred first bases for this step include: Et.sub.3
 N, DIEA, NaH, LiOH, NaOH and KOH. The most preferred first bases for this
 step include: LiOH, NaOH and KOH.
 A suitable temperature range for the reaction with alkyne of formula (XII)
 is about -80 to about 350.degree. C., with a preferred temperature range
 being about 0 to about 140.degree. C. and the most preferred temperature
 range being about 0 to about 70.degree. C.
 The reaction of the alkyne of formula (XII) may be run neat. However,
 solvents suitable for this step include: water; alcohols such as MeOH,
 EtOH, n-PrOH, i-PrOH, butanols and alkoxyethanols; esters such as EtOAc,
 I and BuOAc; hydrocarbons such as toluene or xylenes; chlorinated
 hydrocarbons such as dichloromethane, dichloroethane, chloroform,
 chlorobenzene and ODCB; nitriles such as acetonitrile, propionitrile,
 benzonitrile and tolunitrile; ketones such as acetone, MEK, MIBK and
 cyclohexanone; ethers such as diethyl ether, MTBE, THF, DME and DEM; other
 polar aprotic solvents such as formamide, DMF, DMA, NMP, DMPU, DMSO, and
 sulfolane or mixtures thereof. Preferred solvents for this step include:
 hydrocarbons such as toluene or xylenes; nitriles such as acetonitrile,
 piropionitrile, benzonitrile and tolunitrile; ethers such as diethyl
 ether, MTBE, THF, DME and DEM; other polar aprotic solvents such as
 formamide, DMF, DMA, NMP, DMPU, DMSO, and sulfolane. The most pre,erred
 solvents for this step include: ethers such as diethyl ether, MTBE, THF,
 DME and DEM; nitriles such as acetonitrile, propionitrile, benzonitrile
 and tolunitrile.
 Second transition metal catalysts suitable for reaction with compounds of
 formula (XIII) include: Cu, Ni, Co, Fe, Mn, Cr, V, Ti, Sc, Y, Zr, Nb, Mo,
 Ru, Rh, Pd, Ag, Cd, La, Hf, Ta, W, Re, Os, Ir, Pt, Au, Hg and donor
 complexes thereof such as the phosphine complexes and various salts,
 hydroxides, oxides, and organometallic derivatives thereof such as the
 halides, carboxylates, triflates, tetrafluoroborates,
 hexafluorophosphates, hexafluoroantimonates, or sulfates and phosphine
 derivatives thereof. Combinations of the above second transition metal
 catalysts are also suitable for reaction with compounds of the formula
 (XIII).
 Second bases suitable for reaction with compounds of formula (XIII)
 include: Et.sub.3 N, DIEA, n-Bu.sub.3 N, Imidazole, N-Me-imidazole,
 Pyridine, 2,6-Lutidine, 2,4,6-Collidine, 2,6-tBu.sub.2 -pyridine,
 2,6-tBu.sub.2 -4-Me-pyridine, DMAP, DBU, DBN, DABCO, N-Me-morpholine,
 N-Et-morpholine, 1,2,2,6,6-Me.sub.5 -piperidine, Me.sub.4 -guanidine,
 Proton Sponge, N,N-Me.sub.2 -aniline, N,N-Et.sub.2 -aniline, Quinoline,
 i-Pr.sub.2 NH, Cyclohex.sub.2 NH, (Cyclohex)iPrNH, Pyrrolidine,
 Piperidine, 2,2,6,6-Me.sub.4 -piperidine, TMS.sub.2 NH (HMDS), LiNH.sub.2,
 NaNH.sub.2, KNH.sub.2, LHMDS, NaHMDS, KHMDS, BnNMe.sub.3 OMe, NaOEt,
 TlOEt, LiOt-Bu, NaOt-Bu, KOt-Bu, LiOt-Am, NaOt-Am, KOt-Am, KH, KOTMS, NaH,
 KOH, n-Bu.sub.4 NOH, Triton-B, Ca(OH).sub.2, CaO, BaO, Li.sub.2 CO.sub.3,
 Na.sub.2 CO.sub.3, K.sub.2 CO.sub.3, Cs.sub.2 CO.sub.3, (NH.sub.4).sub.2
 CO.sub.3, Guanidine carbonate, CaCO.sub.3, NaHCO.sub.3, KHCO.sub.3,
 K.sub.3 PO.sub.4, EtNH.sub.2, n-PrNH.sub.2, n-BuNH.sub.2, t-BuNH.sub.2 and
 CyclohexylNH.sub.2. Preferred second bases for this step include: Et.sub.3
 N, DIEA, n-Bu.sub.3 N, Imidazole, N-Me-imidazole, Pyridine, 2,6-Lutidine,
 i-Pr.sub.2 NH, Cyclohex.sub.2 NH, (Cyclohex)iPrNH, Pyrrolidine,
 Piperidine, Me.sub.4 -guanidine, EtNH.sub.2, n-PrN.sub.2, n-BuNH.sub.2,
 t-BuNH.sub.2 and CyclohexylNH.sub.2. The most preferred second bases for
 this step include n-PrNH.sub.2, n-BuNH.sub.2 and t-BuNH.sub.2.
 A suitable temperature range for the reaction with compound (XIII) is about
 -80 to about 350.degree. C., with a preferred temperature range being
 about 0 to about 140.degree. C. and the most preferred temperature range
 being about 0 to about 70.degree. C.
 The reaction with compound (XIII) may be run neat. However, solvents
 suitable for this step include water; alcohols such as MeOH, EtOH, n-PrOH,
 i-PrOH, butanols and alkoxyethanols; esters such as EtOAc, I and BuOAc;
 hydrocarbons such as toluene or xylenes; chlorinated hydrocarbons such as
 dichloromethane, dichloroethane, chloroform, chlorobenzene and ODCB;
 nitriles such as acetonitrile, propionitrile, benzonitrile and
 tolunitrile; ketones such as acetone, MEK, MIBK and cyclohexanone; ethers
 such as diethyl ether, MTBE, TEHF, DME and DEM; other polar aprotic
 solvents such as formamide, DMF, DMA, NMP, DMPU, DMSO, and sulfolane or
 mixtures thereof. Preferred solvents for this step include: hydrocarbons
 such as toluene or xylenes; nitriles such as acetonitrile, propionitrile,
 benzonitrile and tolunitrile; ethers such as diethyl ether, MTBE, THF, DME
 and DEM; other polar aprotic solvents such as formamide, DMF, DMA, NMP,
 DMPU, DMSO, and sulfolane. The most preferred solvents for this step
 include ethers such as diethyl ether, MTBE, THF, DME and DEM.
 As used herein, "alkyl" and the alkyl portion of aralkyl and similar terms,
 is intended to include both branched and straight-chain saturated
 aliphatic hydrocarbon groups having the specified number of carbon atoms;
 "alkoxy" represents an alkyl group of indicated number of carbon atoms
 attached through an oxygen bridge.
 As used herein, "cycloalkyl" is intended to include non-aromatic cyclic
 hydrocarbon groups having the specified number of carbon atoms. Examples
 of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,
 cyclohexyl and the like.
 "Alkenyl" groups include those groups having the specified number of carbon
 atoms and having one or several double bonds. Examples of alkenyl groups
 include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl,
 cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1-propenyl,
 2-butenyl, 2-methyl-2-butenyl, isoprenyl, farnesyl, geranyl,
 geranylgeranyl and the like.
 "Alkynyl" groups include those groups having the specified number of carbon
 atoms and having one triple bond. Examples of alkynyl groups include
 acetylene, 2-butynyl, 2-pentynyl, 3-pentynyl and the like.
 "Halogen" or "halo" as used herein means fluoro, chloro, bromo and iodo.
 As used herein, "aryl," and the aryl portion of aroyl and aralkyl, is
 intended to mean any stable monocyclic or bicyclic carbon ring of up to 7
 members in each ring, wherein at least one ring is aromatic. Examples of
 such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl,
 biphenyl, phenanthryl, althryl or acenaphthyl.
 The term heterocycle or heterocyclic, as used herein, represents a stable
 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclic
 heterocyclic ring which is either saturated or unsaturated, and which
 consists of carbon atoms and from one to four heteroatoms selected from
 the group consisting of N, O, and S, and including any bicyclic group in
 which any of the above-defined heterocyclic rings is fused to a benzene
 ring. The heterocyclic ring may be attached at any heteroatom or carbon
 atom which results in the creation of a stable structure. Examples of such
 heterocyclic elements include, but are not limited to, azepinyl,
 benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl,
 benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl,
 chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl,
 dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl,
 imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl,
 isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl,
 isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl,
 oxazolyl, 2-oxopiperazinyl, 2-oxopiperdinyl, 2-oxopyrrolidinyl, piperidyl,
 piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl,
 pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl,
 quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl,
 tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide,
 thiazolyl, thiazolinyl, thienofuryl, thienothienyl, thienyl, and
 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-4-yl.
 As used herein, "heteroaryl" is intended to mean any stable monocyclic or
 bicyclic carbon ring of up to 7 members in each ring, wherein at least one
 ring is aromatic and wherein from one to four carbon atoms are replaced by
 heteroatoms selected from the group consisting of N, O, and S. Examples of
 such heterocyclic elements include, but are not limited to,
 benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl,
 benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl,
 chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl,
 dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl,
 imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl,
 isothiazolyl, naphthyridinyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl,
 pyridazinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl,
 quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl,
 thienofuryl, thienothienyl, and thienyl.
 As used herein in the definition of R.sup.5, R.sup.6, R.sup.7, R.sup.8,
 R.sup.9 and R.sup.10 the term "the substituted group" is intended to mean
 a substituted C.sub.1-8 alkyl, substituted aryl or substituted heterocycle
 from which the substituent(s) R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9
 and R.sup.10 are selected.
 As used herein, when no specific substituents are set forth, the terms
 "substituted aryl", "substituted heterocycle" and "substituted cycloalkyl"
 are intended to include the cyclic group which is substituted on a
 substitutable ring carbon atom with 1 or 2 substituents selected from the
 group which includes but is not limited to F, Cl, Br, CF.sub.3, NH.sub.2,
 N(C.sub.1 -C.sub.6 alkyl).sub.2, (C.sub.1 -C.sub.6 alkyl)O--, --OH,
 NO.sub.2, CN, N.sub.3, (C.sub.1 -C.sub.6 alkyl)S(O).sub.m --, (C.sub.1
 -C.sub.6 alkyl)C(O)NH--, H.sub.2 N--C(NH)--, (C.sub.1 -C.sub.6
 alkyl)C(O)--, (C.sub.1 -C.sub.6 alkyl)OC(O)--, (C.sub.1 -C.sub.6
 alkyl)OC(O)NH--, phenyl, pyridyl, imidazolyl, oxazolyl, isoxazolyl,
 thiazolyl, thienyl, furyl, isothiazolyl and C.sub.1 -C.sub.20 alkyl.
 Preferably, the structure
 ##STR21##
 is selected from:
 ##STR22##
 Most preferably, B is
 ##STR23##
 It is understood that such rings may be substituted by R.sup.8, R.sup.9
 and/or R.sup.10 as defined hereinabove.
 Preferably A is the moiety designated by the following structure
 ##STR24##
 wherein f is independently selected from CH and N; which represents an
 aromatic 6-membered ring and includes the following ring systems:
 ##STR25##
 wherein it is understood that one of the ring carbon atoms is substituted
 with B. Preferably, A is selected from phenyl and pyridyl.
 More preferably A is the moiety designated by the following structure
 ##STR26##
 wherein f is independently selected from CH and N; which represents an
 aromatic 6-membered ring and includes the following ring systems:
 ##STR27##
 Preferably, A is selected from phenyl, pyrazine and pyridyl. Most
 preferably A is pyridyl.
 Preferably, R.sup.1 and R.sup.2 are independently selected from:
 a) hydrogen, and
 b) aryl, substituted aryl, heterocycle, substituted heterocycle, C.sub.1
 -C.sub.6 perfluoroalkyl, R.sup.11 O-- or CN.
 More preferably R.sup.1 is 4. CN and R.sup.2 is hydrogen.
 Preferably R.sup.3 is hydrogen
 Preferably, R.sup.5 is selected from:
 a) hydrogen,
 b) C.sub.3 -C.sub.10 cycloalkyl, halogen, C.sub.1 -C.sub.6 perfluoroalkyl,
 R.sup.13 O--, R.sup.11 C(O)-- or --N(R.sup.11).sub.2,
 c) unsubstituted C.sub.1 -C.sub.6 alkyl,
 d) substituted C.sub.1 -C.sub.6 alkyl wherein the substituent on the
 substituted C.sub.1 -C.sub.6 alkyl is selected from unslibstituted or
 substituted aryl, unsubstituted or substituted heterocyclic, C.sub.3
 -C.sub.10 cycloalkyl, R.sup.13 O--, R.sup.12 S(O).sub.m --, R.sup.11
 C(O)NR.sup.11 --, (R.sup.11).sub.2 NC(O)--, R.sup.11.sub.2
 N--C(NR.sup.11)--, R.sup.11 C(O)--, --N(R.sup.11).sub.2, and R.sup.12
 OC(O)--NR.sup.11 --.
 More preferably R.sup.5 is hydrogen.
 Preferably, R.sup.6 is selected from: hydrogen, halogen, trifluoromethyl,
 trifluoromethoxy and C.sub.1 -C.sub.6 alkyl. More preferably R.sup.6 is
 hydrogen.
 Preferably, R.sup.7 is hydrogen.
 Preferably, R.sup.8, R.sup.9 and R.sup.10 are independently selected from:
 a) hydrogen,
 b) C.sub.3 -C.sub.10 cycloalkyl, halogen, C.sub.1 -C.sub.6 perfluoroalkyl,
 R.sup.13 O--, R.sup.12 S(O).sub.m --, R.sup.11 C(O)-- or
 --N(R.sup.11).sub.2,
 c) unsubstituted C.sub.1 -C.sub.6 alkyl;
 d) substituted C.sub.1 -C.sub.6 alkyl wherein the substituent on the
 substituted C.sub.1 -C.sub.6 alkyl is selected from unsubstituted or
 substituted aryl, C.sub.3 -C.sub.10 cycloalkyl, R.sup.13 O--, R.sup.12
 S(O).sub.m --, R.sup.11 C(O)-- or --N(R.sup.11).sub.2.
 More preferably R.sup.8 is 5-Cl, R.sup.9 is hydrogen and R.sup.10 is
 hydrogen.
 Preferably, R.sup.11 is independently selected from hydrogen, C.sub.1
 -C.sub.6 alkyl, benzyl, 2,2,2-trifluoroethyl, aryl and substituted aryl.
 More preferably, R.sup.11 is selected from H, C.sub.1 -C.sub.6 alkyl and
 benzyl.
 Abbreviations used throughout the specification include:

ACN Acetonitrile;
 Bn benzyl;
 Bu butyl;
 Bu.sub.3 N tributylamine;
 BuOAc butyl acetate;
 Cu(OTf).sub.2 copper (II) triflate;
 cyclohex cyclohexane;
 DABCO diazabicyclo[2.2.2]octane;
 dba trans, trans-dibenzylideneacteone;
 DBU 1,8-diazabicyclo[5.4.0]undec-7-ene;
 DBN 1,5-diazabicyclo[4.3.0]non-5-ene;
 DEM diethoxymethane;
 DIEA diisopropylethylamine;
 DMA N,N-dimethylacetamide;
 DMAP 4-Dimethylaminopyridine;
 DME 1,2-Dimethoxyethane;
 DMF dimethylformamide;
 DMPU 1,3-Dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone;
 DMSO dimethyl sulfoxide;
 Et ethyl;
 Et.sub.3 N triethylamine;
 EtOAc ethyl acetate;
 HOAc acetic acid;
 I isopropyl acetate;
 KHMDS potassium bis(trimethylsilyl)amide;
 KOt-Am potassium tert-pentoxide;
 KOTMS potassium trimethylsilanolate;
 LHMDS lithium bis(trimethylsilyl)amide;
 LiOt-Am lithium tert-pentoxide;
 Me methyl;
 MEK methyl ethyl ketone;
 MIBK methyl isobutyl ketone;
 MsOH methanesulfonic acid;
 MTBE methyl-t-butyl-ether;
 NaHMDS sodium bis(trimethylsilyl)amide;
 NaOt-Am sodium tert-pentoxide;
 NMP N-Methyl pyrrolidinone;
 ODCB ortho Dichlorobenzene, or 1,2-dichlorobenzene;
 Ph phenyl;
 Pr propyl;
 TFA trifluoroacetic acid;
 THF tetrahydrofuran;
 TMS.sub.2 NH 1,1,1,3,3,3 -hexamethyldisilazine;
 HMDS 1,1,1,3,3,3 -hexamethyldisilazine;
 TMS-SCN trimethylsilyl cyanide;
 TsOH P-Toluenesulfonic acid.
 Scheme I provides further illustration of the reaction sequence of the
 instant invention.
 ##STR28##
 ##STR29##
 Wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, R.sup.7, R.sup.8,
 R.sup.9, R.sup.10, A, B, X and Y are defined as set forth above and
 R.sup.4 is selected from substituted or unsubstituted alkyl and
 substituted or unsubstituted aryl.
 A preferred embodiment of the present invention involves preparation of a
 compound of formula (10):
 ##STR30##
 by the process set forth in Schemes II, III and IV:
 ##STR31##
 Treatment of chloronicotinamide 1 with a slight excess of oxalylchloride in
 DMF leads rapidly and cleanly to nitrile 2. Na.sub.2 CO.sub.3 is added to
 the crude nitrile solution to scavenge the HCl. The insoluble salts are
 then filtered off. Alternatively, nitrile 2 can be synthesized from the
 corresponding amine, halide, sulfonate or phosphate. For example, nitrile
 2 can be prepared by diazotization of the corresponding amine followed by
 treatment with a metallic cyanide such as CuCN, Zn(CN).sub.2, NaCN or KCN.
 Nitrile 2 can also be synthesized from the corresponding halide, sulfonate
 or phosphate by treatment with a metallic cyanide such as CuCN,
 Zn(CN).sub.2, NaCN or KCN, with or without a catalyst such as Ni, Pd or
 Pt.
 Numerous reaction conditions were explored to convert nitrile 2 into 3.
 After overnight stirring with K.sub.2 CO.sub.3 at 70.degree. C. in DMF, an
 85:15 mixture of the N- and O-alkylated pyridones is produced. Upon
 further examination of this reaction, it was found that the reactivity and
 the N/O-alkylation ratio increased as one proceeded down the Group IA
 metals. Based upon these discoveries, an optimized procedure was developed
 in which the nitrile 2 is dissolved in DMF and the pyridone and Cs.sub.2
 CO.sub.3 are added. After aging at 75.degree. C., followed by
 crystallization with H.sub.2 O, cyanopyridone 3 is isolated.
 The cyanopyridone 3 was reduced to benzylic amine 4, by hydrogenation at 40
 psi, 50.degree. C., Raney Ni, using 2 M NH.sub.3 in 2-propanol. Reduction
 of the cyanopyridone 3 can also be achieved by hydrogenation at 40 psi,
 25.degree. C., Raney Ni, using aqueous ammonium hydroxide in MeOH and THF.
 ##STR32##
 Coupling of 4, bromobenzonitrile 5 with propargyl alcohol in the presence
 of Pd(OAc).sub.2 and n-BuNH.sub.2 gives alkyne 6.
 Hydration of alkyne 6 to hydroxyketone 8 is achieved by a two step
 procedure. Thiols (EtSH, PhSH and n-BuSH for example) in the presence of
 K.sub.2 CO.sub.3, LiOH, KOH or NaOH add smoothly and regioselectively in a
 [1,8] sense to alkyne 6, giving the corresponding vinyl sulfide 7.
 Hydrolysis of vinyl sulfide 7 to hydroxyketone 8 is realized with 0.1 M
 H.sub.2 SO.sub.4 at 70-75.degree. C.
 ##STR33##
 Treatment of hydroxyketone 8 and benzylic amine 4 with KSCN and acetic acid
 in n-BuOH or an ACN/water mixture provides thioimidazole 9. Dethionation
 to imidazole 10 was achieved by adding an aqueous solution of NaNO.sub.2
 to an acetic acid solution of thioimidazole 9. Dethionation under these
 mild conditions gives a controlled exotherm and a controlled release of
 nitroger oxide gas.

EXAMPLES
 The instant invention is further illustrated by the following examples:
 Example 1
 Preparation of Chloronitrile 2
 ##STR34##
 A 1L 4 neck flask equipped with a mechanical stirrer was charged with
 6-chloronicotinamide 1 (105 g, 672 mmol). POCl.sub.3 (4 mL/g, 413 mL) was
 added and the solution was heated to 75.degree. C. for 30 min then heated
 at 85.degree. C. for 1 h. The excess POCl.sub.3 was removed via vacuum
 distillation. The POCl.sub.3 distilled at 45-55.degree. C./20-25 torr.
 After most of the POCl.sub.3 was removed, 100 mL of toluene was added and
 then removed by distillation. MeOH was added to the crude solid that
 remained in the flask. The mixture was stirred overnight yielding a white
 powdery suspension. NaOH (5N, 250 mL) was added until the pH was adjusted
 to 12. The reaction mixture was filtered. The product was dried under
 vacuum with a low flow of nitrogen yielding 91.4 g (98%) of a
 6-chloronicotinonitrile 2.
 Example 2
 Preparation of Chloronitrile 2
 ##STR35##
 6-Chloronicotinamide 1 (4.7 g, 30 mmol) was dissolved in 38 mL of DMF.
 Oxalyl chloride (2.7 mL, 30.3 mmol) was added dropwise over 10 min. There
 was a rapid evolution of CO and CO.sub.2 and the temperature increased to
 38.degree. C. The solution was cooled to 0.degree. C. and NaOH (5N, 15.5
 mL) was added slowly. Water (125 mL) was added keeping the temperature
 below 10.degree. C. The mixture was aged 2 h at 0.degree. C. then
 filtered. The solid was washed with water (slurry (30 mL), displacement
 (20 mL)). The isolated yield was 3.33 g (80%) of 6-chloronicotinonitrile 2
 (100% pure by HPLC).
 Example 3
 Preparation of Biaryl Nitrile 3
 ##STR36##
 A mixture of chloronitrile 2 (20.1 g, 142 mmol), 5-chloro-2-pyridinol (20.6
 g, 156 mmol), cesium carbonate (56.3 g, 170 mmol) and DMF (300 mL) was
 heated to 75.degree. C. for 19 h. The mixture was cooled to 25.degree. C.
 and diluted with water (300 mL). The precipitated product was filtered
 off, washed with water (1.5 L) and dried to provide biaryl nitrile 3 (29.3
 g, 89%).
 .sup.13 C NMR (75.5 MHz, CDCl.sub.3) .delta. 160.4, 152.9, 151.7, 141.7,
 141.1, 131.9, 123.4, 120.7, 115.8, 114.3, 109.1. Anal. Calcd for C.sub.11
 H.sub.6 N.sub.3 OCl: C, 57.04; H, 2.61; N, 18.14. Found: C, 56.87; H,
 2.59; N, 18.08.
 Example 4
 Preparation of Benzylic Amine 4
 ##STR37##
 A mixture of biaryl nitrile 3 (0.51 g, 2.2 mmol), Raney nickel (0.16 g,
 EtOH washed wet), concentrated aqueous ammonium hydroxide (7 mL), MeOH (7
 mL) and THF (7 mL) was hydrogenated at 25.degree. C. with 40 psi hydrogen
 for 18 h. The mixture was filtered through, a pad of Celite and the pad
 was washed with THF (25 mL). Quantitative HPLC analysis indicated 0.53 g,
 84% of benzylic amine 4.
 .sup.13 C NMR (75.5 MHz, CDCl.sub.3) .delta. 160.6, 149.7, 147.7, 141.1,
 138.4, 136.9, 133.5, 122.8, 120.7, 113.2, 43.2. Anal. Calcd for C.sub.11
 H.sub.10 N.sub.3 OCl: C, 56.06; H, 4.28; N, 17.83. Found: C, 55.86; H,
 4.16; N, 17.67.
 Example 5
 Preparation of Benzylic Amine 4
 ##STR38##
 Raney nickel (1.00 g) was charge to a hydrogenation vessel and washed three
 times with IPA. To this same vessel was added 2.0 M NH.sub.3 in IPA (80
 mL) and the biaryl nitrile 3 (2.0 g, 8.6 mmol). The mixture was
 pressurized with H.sub.2 (40 psi) and shaken while heating at 50.degree.
 C. for 15 h. To the mixture was added CH.sub.2 Cl.sub.2 until the organic
 solids dissolved. The solution was filtered through Celite, washing with
 CH.sub.2 Cl.sub.2 and MeOH. The crude material was concentrated, then
 chromatographed on SiO.sub.2 (1:1 CH.sub.2 Cl.sub.2 /MeOH), yielding 1.45
 g (71%) of the desired benzylic amine 4.
 .sup.13 C NMR (75.5 MHz, CDCl.sub.3) .delta. 160.6, 149.7, 147.7, 141.1,
 138.4, 136.9, 133.5, 122.8, 120.7, 113.2, 43.2.
 Example 6
 Preparation of Propargylic Alcohol 6
 ##STR39##
 A 100 mL three-neck oven-dried flask with magnetic stir bar was purged with
 nitrogen, then charged with triphenyl phosphine (1.9994 g, 7.6 mmol),
 bromobenzonitrile 5 (9.2235 g, 50.7 mmol), copper iodide (0.624 g, 3.3
 mmol), and palladium acetate (0.556 g, 2.5 mmol). THF (30 mL) was added
 and the solution purged with nitrogen. Butylamine (20 ml, 202.4 mmol) was
 added to form a clear, blue solution. To the room temperature solution,
 propargyl alcohol (3.554 g, 50.7 mmol) was slowly added by addition funnel
 over 15 minutes. After 4 hours, the reaction was complete by HPLC. The THF
 was removed under reduced pressure and the black oil purified on silica
 gel (50 g, hexane/ethyl acetate eluant). A pale yellow solid (4.01 g,
 50.3%) was obtained.
 Example 7
 Preparation of Propargylic Alcohol 6
 ##STR40##
 A 250 mL three-neck oven-dried flask with magnetic stir bar was purged with
 nitrogen, then charged with triphenyl phosphine (5.2230 g, 19.9 mmol),
 bromobenzonitrile 5 (18.51 g, 101.7 mmol), copper iodide (2.1843 g, 11.5
 mmol), and palladium acetate (0.9114 g, 40 mmol). MTBE (100 mL) was added
 and the solution purged with nitrogen. Butylamine (20 ml, 202.4 mmol) was
 added to form a clear solution. The solution was warmed to 50.degree. C.,
 and propargyl alcohol (7.0 mL, 130.0 mmol) was slowly added by addition
 funnel over 30 minutes. The reaction was aged for 72 hours. HPLC showed
 complete conversion. The reaction was concentrated under reduced pressure
 and the residue passed through 100 g silica with MTBE. The filtrate was
 concentrated to dryness under reduced pressure to give a yellow solid.
 Toluene (100 mL) was added and the mixture heated to 60.degree. C. to
 dissolve the solid. The solution was hot filtered through solkaflok and
 cooled to 10.degree. C. Hexanes (50 mL) was added dropwise to form a
 yellow precipitate. The slurry aged for 1.5 hours at 10.degree. C. The
 solid was collected by vacuum filtration, washed with cold 1:1
 toluene/hexanes (2.times.40 mL) and hexanes (60 mL). The yellow solid was
 dried overnight under vacuum to provide the desired alkynol 6 (12.08 g,
 76.9% yield).
 Example 8
 Preparation of Vinyl Sulfide 7
 ##STR41##
 The alcohol 6 (1.02 g, 6.51 mmol) was dissolved in MeCN (3.5 mL) at
 25.degree. C. Ethanethiol (0.65 mL, 8.8 mmol) and LiOH monohydrate (0.23
 g, 6.7 mmol) were added and the mixture was heate, to 60.degree. C. for 1
 h. The mixture was cooled to 25.degree. C. and diluted with MeCN to a
 total volume of 10 mL and used in the next step without isolation. The
 HPLC assay yield was 84%.
 Example 9
 Preparation of Phenyl Vinyl Sulfide 7a
 ##STR42##
 The alcohol 6 (10.5 g, 66.7 mmol) was dissolved in MTBE (67 mL) at
 25.degree. C. Thiophenol (8.81 g, 80.0 mmol) and LiOH monohydrate (0.28 g,
 6.7 mmol) were added and the mixture was heated to 50.degree. C. for 3 h.
 The mixture was diluted with MTBE (50 mL), washed with brine (100 mL) and
 dried (MgSO.sub.4). The organic extract was evaporated down to 50 mL
 volume and hexane (120 mL) was added gradually over 1 h at 20.degree. C.
 The crystalline solid was filtered off, washed with hexane (60 mL) and
 dried to provide 2-thiophenyl-3-(4-cyanophenyl)-2-propene-1-ol (16.9 g,
 95%).
 Anal. Calcd for C.sub.16 H.sub.13 NOS: C, 71.88; H, 4.90; N, 5.24. Found:
 C, 71.88; H, 4.76; N, 5.20.
 Example 10
 Preparation of Butyl Vinyl Sulfide 7b
 ##STR43##
 The alcohol 6 (7.86 g, 50.0 mmol) and KOH (45%, 1.28 g, 10.2 mmol) were
 slurried in MeCN (50 mL) at 25.degree. C. Butanethiol (7.0 mL, 65.4 mmol)
 was added by syringe over 30 minutes. A slight exotherm was noticed. After
 1 hour, the mixture was concentrated under reduced pressure and the crude
 oil was adsorbed onto silica gel. The silica was washed with 50 mL
 hexanes, then 200 mL MTBE. The MTBE wash was concentrated under reduced
 pressure to afford the butyl vinyl sulfide (11.69 g, 94.5% yield) as a
 dark yellow oil.
 Example 11
 Preparation of Butyl Vinyl Sulfide 7b
 ##STR44##
 The alcohol 6 (1.57 g, 10.0 mmol) and powdered NaOH (0.44 g, 11.0 mmol)
 were slurried in MeCN (10 mL) at 25.degree. C. Butanethiol (1.2 mL, 11.2
 mmol) was added by syringe over 10 minutes. A slight exotherm was noticed,
 with the temperature maintaines between 30-35.degree. C. After 15 minutes,
 the mixture was concentrated under reduced pressure and the crude oil was
 purified on silica gel with 0.5 g of DARCO as the top layer using MTBE as
 the eluant. The MTBE filtrate was concentrated under reduced pressure to
 afford the vinyl sulfide (2.24 g, 90.7% yield) as an orange oil.
 .sup.1 H NMR (300 MHz, CDCl.sub.3): .delta. 7.67 (d, 2H), 7.68 (d, 2H),
 6.78 (s, 1H), 4.37 (d, 2H), 2.80 (t, 2H), 2.13 (t, 1H), 1.53 (m, 2H), 1.36
 (m, 2H), 0.87 (t, 3H).
 The following additional compounds were prepared by the methods set forth
 in Example 11 by starting with the appropriate alcohol: