NZ238390A

NZ238390A - 4,4-bis(trifluoromethyl)imidazolidin-5-one derivatives and pharmaceutical compositions

Info

Publication number: NZ238390A
Application number: NZ238390A
Authority: NZ
Inventors: Jeffrey Thomas Billheimer; Lucca Indawati De; Peter John Gillies; George Albert Boswell; Spencer Drummond; James Michael Trzaskos
Original assignee: Du Pont Merck Pharma
Priority date: 1990-06-05
Filing date: 1991-06-04
Publication date: 1994-04-27
Also published as: EP0536316A1; IL98342A0; AU8194391A; KR930700453A; EP0536316A4; IE911909A1; AU650026B2; JPH05507496A; ZA914285B; WO1991019476A1; CA2084399A1

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £38390 238390 Priority Da I -A C(J . t w r!—r- con qs&ih^7So, u^, tfPfttfuoi lie) ^ /I. Cffiosvish33 n% .cp.lt&wJ&,.. tpiDs&h^ o|j<- .j NO 1. 19 j?!} ^ 5 L/i' sKsii'ir\i; N-Z-PATENT OFF1CB Patents Form No. 5 -4 SEP 1991 RECEfV" 1 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION ANTIHYPERCHOLESTEROLEMIC BIS-TRIFLUOROMETHYL-SUBSTITUTED IMIDAZOLINES AND DERIVATIVES THEREOF WE, THE DU PONT MERCK PHARMACEUTICAL COMPANY, (X ip» forrn&ci +e=» pVO'i'Saio'"& of a corporation under the lawG of tho State of -tKe. DeJo^osft- (-Wfoo-i F«j^v\avie^p Aci, \cccJUjd <pJr IOOT" Delaware, U.S.A. of 10th & Market Stroots/ Mo/Ui' feLUiU-^u«~gfe*—,/ D<r-lcu>J<5kre- SslcJea) «=>^ AW\C^CJ=\-, Wilmington, Delaware, U.S.A; hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: 1 (followed by page la) n O fi ') f; ( I ct o o cj J u » BP-6374-A 1 c\ Title Antihypercholesterolemic Bis-Trifluoromethvl-Substituted 5 Imidazolines and Derivatives Thereof Field of the Invention This invention relates to bis-trifluoromethvl-substituted imidazolines as inhibitors of Acyl-CoA:Cholesterol Acyltrans-ferase (ACAT), processes for their preparation and their use as 10 antihypercholesterolemic and antiatherosclerotic agents. Background of the Invention Hypercholesterolemia, elevated blood cholesterol, is an established risk factor in the development of atherosclerosis. Therapeutic agents which control the level of serum cholesterol 15 have proven to be effective in the treatment of coronary artery disease. While agents exist that can modulate circulating levels of cholesterol carrying lipoproteins, these agents have little or no effect on the intestinal absorption of cholesterol. Dietary cholesterol can increase the level of serum cholesterol to levels 20 which place an individual at increased risk for the development or exacerbation of atherosclerosis. Since much of the free or unesterified cholesterol that is absorbed by intestinal mucosal cells must first be esterified by ACAT prior to its incorporation and secretion into the bloodstream in large lipoprotein particles 25 called chylomicrons, inhibition of ACAT can reduce the absorption of dietary cholesterol. More important, the accumulation and storage of cholesteryl esters in the arterial wall is associated with increased activity of ACAT. Inhibition of the enzyme is expected to inhibit the formation or progression of 30 atherosclerotic lesions in mammals by promoting reverse cholesterol transport. There are a limited number of patents in the literature disclosing compounds that are useful as ACAT inhibitors in particular and antiatherosclerotic agents in general. For 35 example, U.S. Patent No. 4,623,662, issued to De Vries on (followed by page 2) N.2. PATENT OFFICE "4 SEP 1991 Received November 18, 1986, discloses ureas and thioureas as ACAT inhibitors useful for reducing the cholesterol ester content of an arterial wall, inhibiting atherosclerotic lesion development, and/or treatment of mammalian hyperlipidemia. U.S. Patent No. 4,722,927, issued to Holmes on February 2, 1988, discloses disubstituted pyrimidineamides of oleic and linoleic acids as ACAT inhibitors useful for inhibiting intestinal absorption of cholesterol. U.S. Patent No, 4,460,598, issued to Lautenschliiger et al. on July 17, 1984, discloses 2-substituted-l,4,5-triaryl imidazoles. The synthesis and the use of these compounds in the treatment of thromboembolic, inflammatory and/or atherosclerotic diseases is disclosed. U.S. Patent No. 4,654,358, issued to Lautenschliiger et al. on March 31, 1987, discloses 2-substituted-l,4,5-triaryl imidazoles. The synthesis and the use of these compounds in the treatment of inflammatory diseases, diseases of lipid metabolism, and/or hyperlipidemic diseases is disclosed. German Laid Open Applications No. DE 3,504,679, and German Laid Open Application No. DE 3,504,680, Lautenschliiger et al., published August 14, 1986, disclose 1,2,4,5-tetrasubstituted imidazoles. The synthesis and the use of these compounds in the treatment of thromboembolic, inflammatory, atherosclerotic, and lipid metabolism diseases in general is disclosed. K. Burger, et al., Synthesis. 1, 44 (1988) describe an alternative synthesis of the 5-imino-2-phenyl-4,4-bis(trifluoromethvl)-4H-imidazole system. This synthesis gives rise to compounds having a 1-mesityl substituent, which is not readily removed and therefore cannot be used to synthesize compounds of this invention, which have hydrogen or methyl at 1-position. No biological activity was disclosed. Co-assigned applications, U.S.S.N. 07/279,981 and 07/416, filed December 5, 1988 and October 10, 1989, respectively, r O 'if I tCuO uvIU 10 15 20 25 30 to diarylimidazoles as inhibitors of the -enzyme ACAT and their use to lower serum cholesterol in mammals. There are no known literature references disclosing the bis-trifluoromethyl-substituted imidazolines of this invention, their use as ACAT inhibitors, or their use in the treatment of atherosclerosis. The compounds of this invention are very potent ACAT inhibitors and/or inhibitors of cholesterol biosynthesis. As shown by the data presented below in Tables 6 and 7, the compounds of this invention inhibit the ACAT enzyme with a potency equal to or better than the potency of many of the ACAT inhibitors described in the current literature. The compounds of this invention also cause a reduction in the serum cholesterol level of normolipemic (non-cholesterol fed) hamsters, whereas in general known ACAT inhibitors fail to lower serum cholesterol levels in non-cholesterol fed animals. Compounds of the invention have also been shown to inhibit cholesterol synthesis in the liver. The compounds of this invention are systemically active and are therefore expected to be useful for the treatment of atherosclerosis. The compounds of this invention have been shown to lower serum cholesterol and to have systemic ACAT inhibitory activity following oral administration, and this invention should not be construed as limited to any particulaj antiatherosclerotic mechanism of action. Summary of the Invention The present invention provides novel compounds of Formula (I), processes for their preparation, pharmaceutical composition* containing bis-trifluoromethyl-substituted imidazolines and derivatives thereof, and therapeutic methods for their use as antihypercholesterolemic/antiatherosclerotic agents. 35 I 23 3 390 4 This invention provides compounds of'Formula (I) (i) CFj PFj /V3 • / Z N Af1' R1 10 wherein Ar* is phenyl, or mono-, di-, or tri-substituted phenyl, optionally substituted with -F, -CI, -Br, -I, -CF3, -C0NH2, -NO2, -CHO, -C02Et, -CN, -O2CR9, -SCH3, -SCF3, -SO2CF3, -SO2CH3, 5-tetrazolyl, -N(0)(CH3)2. OH, C1-C7 15 alkoxy, N-piperidyl, Cj-Cio alkyl, C3-C7 cycloalkyl, or C3-C10 substituted cycloalkyl, or Ar* may be C]_-Cio alkyl, C3-C7 cycloalkyl, or C4-C7 substituted cycloalkyl substituted as above, where R® is H or alkyl, alkenyl, or alkynyl of 1 to 20 carbon atoms; 20 Q is 0 or X-R^ wherein X is bonded to W, provided that when Q is 0, a is a double bond; X is N, NR6, CH, CHR6, or S and R6 is H, or alkyl, alkenyl, or alkynyl; W is C or CH provided that when a is a single bond, X is 25 NR**, S, or CHR^ and W is CH, and when a is a double 2 bond, W is C, and Q is O or XR and X is N or CH; Y is N or NR?, and is H or C1-C3 alkyl; Z is C or CH, provided that when b is a single bond, Y is HR^ and Z is CH, and when b is a double bond, Y is N and Z 30 is C; and, a and b are, independently, single or double bonds; R* is H or C1-C3 alkyl, alkenyl, or alkynyl; R^ is C4 to C15 alkyl, C4 to C15 alkynyl,'or C4 to C15 alkenyl, which may be straight or branched 35 (optionally with a terminal COCH or OH group) or cyclic^ or R2 is I - r- 'rrjIT Or-T',CE 2 3 DEC 1993 5 «j ft € 3 3 COR where R is to C15 alkyl; C2 to C15 alkynyl, or C2 to C^,. alkenyl, which may be straight or branched (optionally with a terminal COOH or OH group) or cyclic; R2 is COAr2, CI^Ar2, C02Ar2' CONR8Ar2^ where R8 is H or C]L-C3 alkyl, S02Ar2, S02NHAr2 or S02R3; 2 . Ar is N-morpholyl; 2- or 3-thienyl; 2- or 3-pyrrolyl; 3-furyl; or is ethyl, ethenyl, ethynyl, a carboaromatic moiety of up to 11 ring atoms or a saturated or unsaturated, straight, branched or nonaromatic cyclic Cj-C^ moiety, which may be substituted with 0-3 F, CI, Br, I, CF3, p-N02, CN, CHO, N3, C^-C^alkyl, C^-C^alkoxy, phenyl, or NR^R^, where R^ and R^ are independently H, C.-C, 45 ± o alkyl or R and R may be C^-C^ alkyl taken together to form a ring with N; provided that: when X is CH or CH0 and R2 is COAr2, Ar1 2 . and Ar are independently, phenyl or substituted phenyl and when X is CH2, R2 is COAr2, CH2Ar2 or COjAr2; or a resolved optical antipode of any chiral form thereof; of a pharmaceutically acceptable salt thereof. Preferred are compounds of Formula (I) above wherein: Ar1 is phenyl, or mono-, di-, or tri-substituted phenyl, optionally substituted with -F, -CI, -Br, -I, -CNf -CF3, -CONH2, -OH, -NO2, 5-tetrazolyl, C1-C7 alkoxy, N-piperidy1, -O2CR9, where R9 is C1-C20 alkyl, alkenyl, or alkynyl, C1-C10 alkyl, C3-C7 cycloalkyl, or C3-C10 substituted cycloalkyl, or Ar1 is cyclohexyl; Q is 0 or X-R2 wherein X is bonded to W, provided that when Q is 0, a is a double bond; is N, NR6, CH, CHR6, or S and R6 is H, or C1-C3 alkyl, alkenyl, or alkynyl; ^ is c or CH provided that when a is a single bond, X J. B, or CHR* and W is CH, and when S is «Rouble bond, W is C, and Q is O or XE and X is N or CB, 2 3 OEC m 23 6 Y is N or NR^, and R? is H or CH3; Z is C or CH, provided that when b is a single bond, Y is NR7 and Z is CH, and when b is a double bond, Y is N and Z is C; and a and b are, independently, single or double bonds; R* is H or Cj-C3 alkyl, alkenyl, or alkynyl; R2 is COAr2, CH2Ar2, C02Ar2, or C0NR®Ar2, wherein R® is H or C1-C3 alkyl; and 2 . Ar is N-morpholyl; 2- or 3-thienyl; 2- or 3-pyrrolyl; 3-furyl; or is ethyl, ethenyl, ethynyl, a carboaromatic moiety of up to 11 ring atoms or a saturated or unsaturated, straight, branched or nonaromatic cyclic moiety, which may be substituted with 0-3 F, CI, Br, I, CF3, p-N02, CN, CHO, N3, C,-C_alkyl, C1-C_alkoxy, phenyl, or NR^R^, 4 5 where R and R are independently H, C,-C_ 4 5 alkyl or R and R may be C3~C5 alkyl taken together to form a ring with N; 2 . 2 1 provided that: when X is CH or CH0 and R is COAr , Ar 2 . and Ar are independently, phenyl or substituted phenyl and when X is CH2, R^ is COAr^, CH2Ar^ or C02Ar^; or a resolved optical antipode of any chiral form thereof; of a pharmaceutically acceptable salt thereof. More preferred are compounds of Formula (I) above wherein: Ar* is phenyl, or monosubstituted phenyl, substituted with -F, -CI, -Br, -CN, -CF3, -OH, C1-C7 alkoxy, -NO2, -CONH2, N-piperidyl, CH3 or -O2CR9 where R9 is C1-C20 alkyl, alkenyl, or alkynyl or Ar1 is cyclohexyl; Q is X-R2 wherein X is bonded to W; X is NR5 or CH2, and R6 is H, or C1-C3 alkyl, alkenyl, or alkynyl; W is CH; Y is N; Z is C; R1 is H, CH3, or C2H5; and "- - R2 is COAr2 or C0NR8Ar2, wherein R8 is H or C1-C3 p— ——. alkyl; and j 2 3 DEC 1993, Ar2 is monosubstituted phenyl, optionally substituted with -F, -CI, -Br, -CN, -CF3, C1-C7 alkyl, C1-C4 alkoxy, E-NO2, phenyl, N-piperidyl, or dimethylamino, or Ar2 is saturated Cg-Cn, which may be straight or branched. Even more preferred are compounds of Formula (I) above wherein: Ar* is phenyl, or monosubstituted phenyl, {(-substituted with -F, -CI, -Br, -CN, -OH, -OCH3, N-piperidyl, -CONH2, or O2CR9 where R® is C1-C20 alkyl, alkenyl or alkynyl; Q is X-R2 wherein X is bonded to W; X is NR& or CH2, and R® is H or C1-C3 alkyl, alkenyl, or alkynyl; W is CH; Y is N; Z is C; R1 is CH3; R2 is COAr2 or C0NR®Ar2, wherein R® is H or C1-C3 alkyl; and Ar2 is monosubstituted phenyl, fi-substituted with -F, -CI, phenyl, C1-C4 alkyl, E-NO2. N-piperidyl, C1-C4 alkoxy, -CN, or Ar2 is saturated C5-C11, which may be straight or branched. 8 Specifically preferred are the compounds of the formula shown below wherein: o o r *) r > » U U <• J V 1 U 10 15 20 25 30 CF: !v°^ a \ H 1 >- -NR* ll "N m N \ I J CH, R'° R10 c F, R6 * ch3, R2 R10 = F, r6 = ch3, R2 R10 = F, r6 = ch3, R2 R10 . F, r6 « H, R2 Rio = F, R6 = ch3, R2 r1° = ^ R6 = H R2 R10 = F, r6 « ch3 R2 R10 = F, r6 = H R2 R10 = F, r6 = ch3 R2 RlO = F, R6 « ch3 R2 Rio = F, r6 = ch3 R2 {10 « ) R6 - ch3 R2 R2 -C0C6Hi3 R2 -C0C6Hi3 35 \ 9 o /'• ioovniu 9 n) (Ex. 34) R10 = CH30, R6 = CH3 ■ R2 =C0(CH2)3CH(CH3)2 n) (Ex. 27) R10 = F, R6 = CH3 R2 = -c-n-^^-ch(ch,), 0) (Ex. 18) R10 = F, R6 = CH3 R2 =C0(CH2)3CH(CH3)2 p) (Ex. 29) R10 = F, R6 = CH3 R2 =C0NH(CH2)7CH3 0 10 q) (Ex. Q) R10«CN R6 = CH3 R2 = -C~@-F 0 r) (Ex. R) R10=CN R6 = CH3 R2 = -C-(o)-CN 15 0 s) (Ex. S) R10=F R6 = CH3 R2 = -C-^^CN 20 t) R10=C00Ci7H33 R6=CH3 R2=C0CgHi3 u) R10-OOCH3 R6«CH3 R2-C0C6H13 25 30 35 v) R10=F R6«CH3 R2«C0C6Fs 0 OH R6«CH3 -C-@-0(CH2)3CH3 0 x) (Ex. 73) R10»CN R6=CH3 R2 = -C-@-CN R-isomer CO CO O- LU 0 > y) (Ex. 75) R10«CN R6-CH3 R2 - -C-©H2S04sal5t£RLis,ome ,L~ O. IX! z> ul a IU (C r 1 Also specifically preferred are the compounds: 1-(4-cyanophenyl)-2-[2-(4-f1uoropheny1)-4,5-di hydro-l-methy1 -4.4-bis(trifluoromethyl)-lH-imidazol-5-yll-ethanone; l-(4-fluorophenyl)-2-[2-(4-fluorophenyl)-4,5-dihydro-l-methyl-4l4-bis(trif1uoromethyl)-lH-imidazol-5-yl]-ethanone; and 1-(4-fluorophenyl)-2-[2-(4-f1uoropheny1)-4,5-di hydro-1-ethyl-4,4-bis(trifluoromethyl)-lH-imidazol-5-yl]-ethanone. Detailed Description of the Invention Synthesis The novel compounds of Formula (I) may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and suitable for the transformation being effected. It is understood by those skilled in the art of organic synthesis that the functionality present on the imidazoline and other portions of the molecule must be compatible with the reagents and reaction conditions proposed. Hot all compounds of Formula (I) falling into a given class may be compatible with some of the reaction conditions required in some of the methods described. Such restrictions to the substituents, which are compatible with the reaction conditions will be readil, apparent to one skilled in the art and alternative methods described must then be used. The compounds of Formula (I) wherein X is N, W is C, Z is C, Y is N, R2 is COAr2, Ar* is phenyl or substituted phenyl, and R* is H or CH3 can be prepared by the route shown in Scheme 1. The requisite 2-hexafluoroisopropylamino-4,5-diarylimidazoles (1) ar^ prepared as described in U.S. 4,348,404, the teaching of which is hereby incorporated by reference. Treatment of the 2-hexafluoroisopropylamino-4,5-diaryl-imidazole (1, R*«H or CH3) with excess peracid such as m-chloroperbenzoic acid (MCPBA), preferably 3 or more equivalents in 2 or more portions in refluxing chloroform for 2 hours, gives the corresponding N-T(4.4-bis(trifluoromethyl)-4.5-dihvdro- 2-aryl-l-methyl-lH-imidazol-5-ylidene)]-benzamide (2, R*=H or CH3). Alternatively, monoperoxyphthalic acid magnesium salt (MMPP) in glacial acetic acid may be used instead of MCPBA in ui o UL U. O H Z LLI !— <r a. N 2 o 8 3 J) u 10 11 chloroform in the conversion of the 2-hexafluoroisopropylamino-4,5-diarylimidazoles (1) to the bis-trifluoromethyl substituted imidazolines (2). Scheme 1 Ar' Ar' 1 V-N-C-Ar8 Ar1 R1 1 15 20 25 30 35 Alternatively, oxidation of 2-hexafluoroisopropylamino-4,5-diarylimidazoles (i) with singlet oxygen generated by irradiating oxygen with a Tungsten lamp (400 watt) in the presence of a catalytic amount of methylene blue in chloroform and methanol (1:1) followed by acid treatment gives the bis-trif luoromethyl substituted imidazolines (£), as shown in Scheme 1.1. Scheme 1.1 Ar^N Ar,#^N R1 AT»vNa^_C(CFJ2NH! *'1 cf>nPF. o=> n4 The compounds of Formula (I) wherein X is NH, Y is N, W is CH, Z is C, R2 is COAr2, and a is a single bond and b is a double bond can be prepared by the route shown in Scheme 2. The benzamides of Formula Q) can be prepared by reducing the requisite imines of Formula (2) with lithium aluminum hydride # 288300 12 (preferably, 2 equivalents) in tetrahydrofuran at room temperature for 1 to 24 hours or sodium borohydride (preferably 1.1 equivalents) in refluxing ethanol. Lithium aluminum hydride is the preferred reducing agent because reduction with sodium borohydride gives rise to a mixture of 2 and the ring reduction product of 4. Other hydride-type reducing reagents such as lithium aluminum tri-tertiarv-butoxvhvdride may also be used. Scheme 2 10 15 CF>SCF. Ij Vs^NC-Ar2 Ar1 \ , CFs CFj H O X m U NC-Ar2 Ar , 3 R + ^ 1 N-C-AJ* 20 NB» 25 Scheme 2.1 30 ArJ JKT n n 7=n-c- y-i. cf3 cf3 o o n n d <£ O O O J U 13 The ring reduction product 4, can be converted to the corresponding alkali metal salt by the addition of a base such as sodium hydride, and the salt is alkylated with methyl iodide in a polar solvent such as dimethyl formamide at room temperature to give compound 4^ (Scheme 2.1) The amides, carbamates and ureas of Formula Q) wherein R2 is as defined above can be prepared by the route shown in Scheme 3. The requisite benzamide of Formula Q) is converted to the corresponding alkali metal salt by the addition of a base such as sodium hydride, and the salt is alkylated with methyl iodide in a polar solvent such as dimethylformamide at room temperature. The N-methyl benzamides of Formula (5) can be cleaved to the N-methyl aminals of Formula (6) by the route shown in Scheme 3. Treatment of the requisite N-methyl benzamide with potassium tert-butoxide (6 equivalents) and water (2 equivalents) in ether at room temperature gives the corresponding N-methyl aminals of Formula (6), which can be converted into the hydrochloride salt with hydrochloric acid in ether. The amides, ureas and carbamates of Formula (7) are prepared by coupling the aminals of Formula (6) with an acyl chloride, isocyanate or chloroformate by the route shown in Scheme 3. Alternatively, other literature methods for forming amide bonds may be employed which involve reaction of carboxylic acids and amines. One method for amide bond formation is to use a coupling reagent which generates a reactive intermediate such as a mixed anhydride or active ester. Examples of such coupling agents are^ disubstituted carbodiimides, N.N'-carbonyldiimidazole, diphenylphosphoryl azide, and the like. For example, the coupling can be carried out with a disubstituted carbodiimide such as dicyclohexylcarbodiimide in an appropriate solvent such as methylene chloride, acetonitrile, toluene, or dimethyl-formamide. Nucleophilic hydroxy compounds such as 1-hydroxy-lH benzotriazole, which form highly active esters, may be added to catalyze the reaction. K —^ * an cn D-UJ CO "=3" I 10 9On<;rj0 OClu 14 Reaction of the requisite aminal (6) -with the appropriate acyl or aroyl chloride in pyridine and methylene chloride at room temperature gives the corresponding amides of Formula (7). Similarly, reaction of the aminal with alkyl or aryl isocyanates in methylene chloride at room temperature gives the corresponding ureas of Formula (7). The carbamates of Formula (2) are prepared by allowing the requisite N-methyl aminal of Formula {§) to react with alkyl or aryl chloroformates in methylene chloride at room temperature to the reflux temperature of the solvent. Scheme 3 15 CFjvCF3 Ho \ II 20 25 The benzamides of Formula (Z) having different oara-substituents on the benzamide group and the pendant phenyl group are prepared by the route shown in Scheme 4. By starting with g-30 fluoropheny1 analogs, which can be prepared according to Scheme 1 wherein Ar* = Ar2 ■ o-fluoro-phenyl, ortho substituted analogs can be prepared by aromatic nucleophilic substitution as shown in Scheme 4. Compounds wherein Ar2 may be ortho. meta. and/or oara j substituted may be prepared using Scheme 3 by reacting compound 35 (6) with the appropriate mono-, di-, or trisubstituted (any O n <) t ■ ."> O 0 tj v j 10 15 combinations at any positions) benzoyl chloride, to yield the desired compounds of Formula (7). Treatment of the requisite benzamide of Formula (£) with the appropriate nucleophile, e.g., cyanide, ethoxide, or piperidine, in a polar solvent such as dimethyl sulfoxide (DMSO) at a temperature from room temperature to the boiling point of the solvent gives the benzamides of Formulas (2), (10) and Ql), which may be separated by conventional means such as crystallization, high pressure liquid chromatography (HPLC), conventional column chromatography and other procedures known to those skilled in the art. Scheme 4 15 20 Nu S^CFg 10 25 30 As an alternative, the amides of Formula (12) wherein R2 COR-*, where is Ci to C15 alkyl, C2 to C15 alkenyl, or C2 t Cl5 alkynyl, with a terminal CO2H or OH group, may be prepar 35 according to the route shown in Scheme 5. Treatment of the fs u. U. O 1991 Q ( ! 1-7* LU f— i£j ■4 SEP "> LU O U Cu i * <ry rr\ A . : .. **•*■ KJf \J7 *w> 16 requisite amide of Formula (12) with the desired nucleophile, e.g., methoxide, piperidine, etc., gives the corresponding amide of Formula (13) wherein the para-fluorine of the pendant phenyl group has been replaced by the new group. 5 10 ♦ 15 20 25 USI! ■r; f SI. IL o or> cn a i > »-z OJ J- < CL Q. LU CO T V, ui O W 0: N I —*» «-r I 17 Scheme 5 CF 3 CF CF 3 CF3 5 Jf-R2 CHg F 10 The bis-trifluoromethyl substituted imidazolines of Formula (1§) are prepared by the route shown in Scheme 6. The requisite 2-hexafluoroisopropylamino-4,5-diarylpyrroles of Formula (14), are prepared according to the method of U.S. 4,335,136, the teaching of which is hereby incorporated by 15 reference. These compounds of Formula (14) are oxidized with singlet oxygen (see Scheme 6.1 below) as described above for Scheme 1.1. Alternatively, compounds of Formula (14) are allowed to react with excess MCPBA as described above for Scheme 1 to give the bis-trifluoromethyl substituted imidazoles of Formula 20 (i§) and the novel hydroxypyrrolinene of Formula (lji), which can be separated by chromatography or other means known to those skilled in the art. The alkylated derivatives of Formula (17) are made by converting the requisite imidazoline of Formula (1£) into the corresponding alkali metal salt by addition of a base 25 such as sodium hydride, and the salt is alkylated with methyl iodide in a polar solvent such as dimethylformamide at temperatures from room temperature to the reflux temperature of the solvent. 30 35 O O O 'Mi O 18 H Scheme 6 "\-C(CF 3)2NH2 Ar1--]! ^~"C(CF8^NH; "N _ ' N OH 15 10 15 CF CF 3 CF • i rv ^y 3 o VCF® o J^>"CH C-Ar2* ^ >-i Ar"> Ar.^N H R 17 1 CHC-Ar2 IB Scheme 6.1 20 25 30 35 Ar2 XV ArlX^N H C(CF3)2NH2 14 CF3v/CF3 Ar1 O CH-C—Ar2 I H 16 The imidazoles of Formula (17.1) can be prepared by reducing : the imidazoles of Formula (17) with zinc dust in refluxing acetit acid, as shown in Scheme 7.1. The imidazoles of Formula (12 or 17.1) having different para substituents on the phenyl ketone and the pendant phenyl group are prepared by the route shown in Scheme 7. Compounds having sii CO CT5 CL-l_U CO Q u.i Uj O LU IX n <-> 1} ') Q 0 o u ^ 19 10 15 20 ortho and/or meta substituted phenyl groups can be prepared by starting with compound (14) having appropriately substituted Ar* and Ar2 groups. Treatment of the requisite imidazole of Formula (18) with the appropriate nucleophile in a polar solvent such as dimethyl sulfoxide (DMSO) at a temperature from room temperature to the boiling of the solvent gives the imidazoles of Formulas (19). (20), and (21) which may be separated by conventional means such as crystallization, high pressure liquid chromatography (HPLC), conventional column chromatography and other procedures known to those skilled in the art. Scheme 7 C„X" 9_/~y ,JL>CHC V-/ N, CH ie cfV,cf, V tD " i rCHC—i /-Nu CH 19 25 30 35 Nu xA. to CFi..CFj H C —u Xy CH, cn cn CL. uu C/O -tf-i Q LU > UJ O LU az tl % O O O ') (i (\ 20 »iuooJU Scheme 7.1 10 9 CF. CFa f •O-JU* Ar R' Ar1 nr, 17 17.1 The carbamates of Formula (22) wherein the para-substituent of Ar2 is an electron-donating group such as alkoxide or alkyl 15 are prepared as shown in Scheme 8. Allowing the requisite 2-hexafluoroisopropylamino-4,5-diarylimidazole of Formula (!) to react with excess MCPBA as described in Scheme 1 gives either the corresponding carbamates of Formula (22) or a mixture of the carbamates of Formula (2£) and benzamides of Formula (2) 20 depending on the reaction time, degree of excess MCPBA, and the electron-donating ability of the para-substituents. 25 30 LU O LL O cn cn 9KS5 CI i t i— 2: u <r c£ Q_ UJ oo ■<? 1 UJ o LU tr N 35 i 21 Scheme 8 238300 ^-cccr^jNH, CFa CF• »A '9 , II >—N"C-Ar* a^n 10 CF 15 20 25 30 35 rCl9 « 1 /""N ~C ~0 A r Ar1 R1 It The carbamates of Formula (24, R^^Ar2), the benzamides of Formula (£4, R2=C0Ar2), and the ureas of Formula (24, R2=C0NHAr2) can also be prepared as shown in Scheme 9. Treatment of the requisite benzoyl imine of Formula (£) with ammonium hydroxide or ammonia in methanol at room temperature to the temperature of the refluxing solvent for 1 to 48 hours, or with a strong acid such as concentrated sulfuric acid at room temperature for 10-15 minutes, affords the amidine of Formula (£2). Other solvents known to those skilled in the art that are compatible with the reactants and products can be used in place of methanol. The benzamides, ureas, and carbamates of Formula (£4) wherein R2 is COAr2, CONHAr2, or C02Ar2 and Ar2 is different from the Ar* of the benzamide of Formula (2), are prepared by reacting the requisite amidine of Formula (24) with a compound of the formula CICOAr2, CICONHAr2, C1C0NHR3, C1C0R3, 0=C=N-Ar2, or 0=C=N-R3 in a polar solvent such as pyridine or benzene with dimethyl ami no pyridine. ( 1 '5 i i cC N i CO CT5 a i * CL *•— UJ UJ CO o V 1 I.U CC 22 Scheme 9 9 O o <) r; u O U\) cf* cf3 N-^C_ « || y .: n-c-af2 cfj. cfj JO" Ar1 \ 23 1 NH 10 15 cfj cfj X/~~" 24 20 An alternative synthesis of the benzoyl imines of Formula (2) of Scheme 1 wherein Ar* is different from Ar2 or Ar* is alkyl, cycloalkyl or substituted cycloalkyl, is shown in Scteme 10. Acylation of the requisite 2-hexafluoroisopropylamino-4,5-diarylimidazole of Formula (1), wherein R* is CH3 or H, in 25 refluxing benzene for 4 days, or neat for 4 hours at 150° or acid chloride and pyridine at 120°, with the appropriate acid chloride, R^COCl, wherein R^ can be Ar*, C3 to Cjo alkyl, C3 io^ C7 cycloalkyl, or C3 to C7 substituted cycloalkyl, gives the corresponding bicyclic derivatives of Formula (25). Compounds 30 wherein Ar* is ortho. meta. and/or para substituted phenyl can t prepared using Scheme 10, wherein compound (1) is reacted with i.r£j acid chloride, R^COCl, where R^ is a mono-, di-, and/or trisubstituted phenyl (any combinations at any positions). Or rH may be heteroaromatic, or aliphatic (straight chain, 35 branched, cycloalkyl), which may have additional substitutions, 7". I, J e< CL m or? cu LLi GO vr \ 23 23831)0 e.g., OH. Higher boiling solvents such as toluene, xylenes, or chlorobenzenes can be employed to accelerate the 5 reaction. The requisite bicyclic derivative of Formula (25) is uene, allowed to react with excess MCPBA in refluxing chloroform to give the bis-trifluoromethyl substituted imidazoline of Formula (26), which loses the Ar^CO substituent on nitrogen during the workup to afford (22). The N-substituted Ms-trifluoromethyl 10 substituted imidazolines of Formula (££) can be synthesized by converting the requisite benzamide of Formula (22) into the corresponding alkali metal salt by the addition of a base such as sodium hydride, and the resultant salt is alkylated with methyl iodide in a polar solvent such as dimethylformamide. 15 20 25 30 35 I 238300 10 15 20 25 30 JC ,r"N >-C(CFs)tNH, 24 Scheme 10 A Ar1 ,Xwf> Nx >-CF8 >=N I T/-N-C-Are t-^N 25 V* Cj-0 H 27 i L NFVF8 9 j( V"N ~C "A r2 26 Rf^N, 28 The imidazolinones of Formula (22) are prepared as shown in Scheme 11. Exposure of the requisite benzoyl imine of Formula (2) (Scheme 1) to chromatographic grade basic alumina (Activity II-IV) in ether at room temperature to the temperature of the refluxing solvent for 1 to 48 hours gives rise to the corresponding imidazoline-2-ones of Formula (22)• Other solvents such as tetrahydrofuran may be used. 35 9 'TO 'Hif) — imjuJU 25 Scheme 11 CFVCF3 O CF3, ,CF 1 N X "N"C-Ar2 N^C3 ^ \ Ar1^ R1 R1 10 29 Preparation of pharmaceutical^ suitable salts o" Formula (i) can be cone in accordance with well known techniques of forming 25 salts. Physiologically acceptable salts include but are not limited to acid addition salts, such as the hydrochloric, sulfuric, acetic, trifluoroacetic, succinic, citric, and benzenesulfonic acid salts. The compounds of this application that have a chiral center 2o may be resolved into the pure or partially pure optical isomers by any of the appropriate procedures known to those skilled in the art. The compounds of this invention and their preparation can be further understood by the following examples, which do not 25 constitute a limitation of the invention. In these examples, unless otherwise indicated, all temperatures are in degrees centigrade and parts and percentages are by weight. 30 35 Example 2 Preparation of N-T4.4-bis(trifluoromethyl)-2-(4-f1uoroohenvl)-4.5-dihvdro-l-methvl-lH-imidazol-5-v1idenel-4-f1uoro-benzamide Method A To a solution of a.a-bis(trif1uoromethvl)-4.5-bis(4-fluorophenyl)-l-methyl-lH-imidazole-2-methanamine (36.0 g, 0.0761 Li! g U_ • cn o . 2 T£ CU £ UJ CO £ "3- IM 1 n I.U O i.u CC O O O (CoO 26 mole) in chloroform (1.8 L) was added portionwise, inch loroperbenzoic acid (MCPBA, 26.1 g, 0.152 mole). The reaction mixture was refluxed under nitrogen for one hour. Then additional MCPBA (13.0 g, 0.076 mole) was added and the mixture 5 was refluxed for 1 hour. The solution was cooled to room temperature and poured into saturated sodium bicarbonate (1 L). The organic layer was washed successively with saturated sodium bicarbonate solution, 10% sodium sulfite solution, water, and saturated sodium chloride solution, dried over magnesium sulfate 10 and evaporated under vacuum. The residue was triturated with hexane to give the title compound (23.2 g, 68%) as an off-white solid. An analytical sample was prepared by recrystallization from methanol-hexane to give a white solid: mp 112-113°; HRMS m/e calcd for CigHnN30F8 (M+) 449.0774, found 449.0770; NMR 15 (CDCI3/THS) 6 3.13(sr3H,NCH3), 7.13-7.30(m,4H(Harorn), 7.73(q,2H,Harom), 8.06(q,2H,Haj»om) • Analysis Calcd for C19H11N3OFQ: C,50.79; H,2.47; N.9.35. Found: C,50.81; H.2.72; N,9.10. 20 Method B To a solution of a.a-bis(trifluoromethyl)-4.5-bis(4-fluorophenyl)-l-methyl-lH-imidazole-2-methanamine (17.6 g, 0.04 mole) in chloroform (1.25 L) was added portionwise, m-chloroperbenzoic acid (MCPBA, 17.2 g, 0.10 mole). The reaction 25 mixture was refluxed under nitrogen for one hour, coded to room temperature and poured into 10% sodium bicarbonate (1 L). The organic layer was washed successively with 10% sodium bicarbonate solution, 10% sodium sulfite solution, water, and saturated sodium chloride solution, dried over magnesium sulfate and 30 evaporated under vacuum. The residue was triturated with hexane'. to give the title compound (8.8 g, 50%) as a white solid: mp 109-114'; NMR (CDCI3/TMS) 6 3.13(s.3H,NCH3), 7.13-7.30(m,4H,Harom), 7.73(q,2H,Harom)» 8.06(q12H,• 35 Cj.. -sT 9 O O n n ( , (\ id o a u!)u 27 Method C To a solution of a.a-bis(trifluoromethyl)-4.5-bis(4-fluorophenyl)-l-methy1-lH-imidazole-2-methanamine (0.24 g, 0.5 tiimole) in acetic acid (10 mL) was added portionwise, 5 monoperoxyphthalic acid magnesium salt (MMPP, 0.30 g, 1.0 mmole). The reaction mixture was stirred under nitrogen overnight. Then additional MMPP (0.15 g, 0.5 mmole) was added and the mixture was heated at 112° for 4 hours. The solution was cooled to room temperature and poured into water. The organic layer was washed 10 successively with saturated sodium bicarbonate solution, 10% sodium sulfite solution, water, and saturated sodium chloride solution, dried over magnesium sulfate and evaporated under vacuum. The residue was triturated with hexane to give the title compound (0.60 g, 25%) as a yellow solid: *H NMR (CDCI3/TMS) 6 15 3.13 (s,3H,NCH3), 7.13-7.30(m,4H,Harom). 7.73(q,2H,Harom), 8.06(q,2H,Harom). Method D To a solution of a.a-bisftrifluoromethyl)-4.5-bis(4-20 fluorophenyl)-l-methyl-lH-imidazole-2-methanamine (0.5 g, 1.1 mole) in methanol (1.5 1) was added methylene blue (10 mg). Oxygen gas or air was bubbled through the solution while irradiating with a Tungsten lamp (400 watt) for 8 hours. 1M hydrochloric acid in ether (10 ml) was added to the reaction 25 mixture and stirred for 1 hour at room temperature. The mixture was treated with saturated sodium carbonate solution (15 ml) and then concentrated in vacuo. The concentrate was resuspended in ethyl acetate (200 ml) and water (50 ml). The organic layer was washed with saturated ammonium chloride and sodium chloride 30 solution, dried over sodium sulfate (anhyd.) and evaporated under vacuum. The residue was purified by column chromatography, i eluting with hexane-ethyl acetate (10:1) to give the title compound (312 mg, 61%). 35 I £ P o_ i UJ UJ ; OO O •sr ^ 1 a: O O O ( \ (.ou *..» * j u 28 Example 5 H-f4.4-bis(tri f luoromethyl )-2-(4-methvl phenyl)-4.5-di hvdro-lH-imi dazol-5-vli denel-4-methvlbenzami de To a solution of a.g-bis(trifluoromethyl)-4.5-bis(4-methylphenyl)-l-methyl-lH-imidazol-2-methanamine (1.0 g, 2.3 mmole) in chloroform (10 mL) was added portionwise, m-chloroperbenzoic acid (0.40 g, 2.3 mmole). The reaction mixture was refluxed under nitrogen for two hours. The solution was cooled to room temperature and poured into saturated sodium bicarbonate (100 mL). The organic layer was washed successively with saturated sodium bicarbonate solution, 10% sodium sulfite solution, water, and saturated sodium chloride solution, dried over magnesium sulfate and evaporated under vacuum. The residue (75% benzamide and 25% ester analyzed by HPLC with a (DL)-phenylglycine column eluted with 10% isopropanol-hexane) was purified by HPLC on a silica sorbax column which was eluted with dichloromethane to give the title compound (40 mg, 4%) as a semisolid: MS m/e 442 (M++H); *H NMR (CDCI3/TMS) 5 3.00(s,6H,CH3), 3.13(s,3H,NCH3), 7.27-7.37(m,4H,Harom), 7.57(d,J=7Hz,2H,Harom), 7.90(d,J=7Hz,2H,Haroni). The compounds of Examples 2 and 5, and other compounds of Formula (I) wherein a is a double bond which have been prepared or which could be prepared using the same or similar synthetic methods, are listed in Table 1. The additional compounds listed in Table 1 were prepared according to the procedure of Example 2, Method B. The yields may be improved by using the procedure of Example 2, Method A. Alternative peracids such as monoperoxyphthalic acid magnesium salt (MMPP) can be used as shown in Example 2, Method C. o ; ; C"3 cr> ex. LU CO i 29 2383130 Table 1 Ex. g' # R1 G G'' G' G' mp(°C) 10 1 ch3 h h H h 80-81 2 ch3 fi"F e-f h h 112-113 3 ch3 fi-cl e-cl h h 94-96 4 ch3 m-ch3 m-ch3 h h 113-114 5 ch3 fi-ch3 e-ch3 h h Semi-Sol id 15 6 h h h h h 134-135 7 h e-cl e-c1 h h 182-183 8 h m-ch3 rn-CH3 h h 118-120 9 h e-ch3 e-CH3 h h 136-137 9a CH3 e-f o(ch2)3ch3 h h 106-107 20 9b H fi-f e-f h h 161.9-163.9 9c CH2CH3 fi-f e-f h H oil 9d CH3 e-cn fi-f h h 9e CH3 £-CF3 0 e-CF3 0 m-n02 h 25 9f CH3 e-0cch3 e-occh3 h H 9g CH3 e-sch3 e-SCH3 H H 9h ch3 b-no2 e-no2 h h 91 ch3 e-no2 e-no2 m-CF3 m-CF3 9j ch3 e-cn e-cn h h - f 30 9k CH3 e-CH3SO2 fi-n3 m-f h - 91 h m-CN m-CN h h - 9*i ch3 fi-n3 e-n3 h H " ^ 9n CH3 e-CF3SO2 e-0c4hg-n h m-ch3 9o CH3 fi-CN e-C6Hi3-n h H 35 9p CH3 fi-n(0)(ch3)2 fi-(ch3)2cc6h4 h m- •f 9q CH3 e-(ch3)2n e-co2h h h i j CT> q j ' fx. 1 V , UJ LU CO 1 * , l<;i. i u UJ r.v.: 1 i- , .... , \ 30 Notes. Example 1: MS m/e 414; JH NMR (CDCI3) 6 3.10 (s,3H,NCH3), 7.43-7.66(m,8H,Haroro) < 8.00-8.03(m,2H, Harom) • Example 2: MS m/e 449; NMR (CDCI3) 6 3.13(st3HtNCH3), 7.13-7•30(m,4H,Harom)• 7.73(ro,2H,Haroni)» 8.06(m,2H,Harom)• Example 3: MS m/e 481; h NMR (CDCI3) 6 3.10(s.3H,NCH3), 7.43-7.66(m,6H,Hapom)> 7*90-7.97(m,2H,Harom)• Example 4: MS m/e 442; NMR (COCI3) 6 2.40(s,6H,2ArCH3), 3.07(s,3H,NCH3), 7.33-7.50(m,6HIHarOm). 7.77-7.83{m,2H,Haroni). Example 5: MS m/e 442; *H NMR (CDCI3) 6 3.00(s,6H,ArCH3), 3.13(s,3H,NCH3), 7.27-7.37(m,4H,Harom), 7.57(d,2H,J=7Hz,Harom). 7.90(d,2H,J=7Hz,Har0m)• Example 6; MS m/e 400; JH NMR (CDC13) 6 7.47- 7.70(m,6H,Hapom). 8.00-8.03(m,2H,Harom)» 8.33- 8.37(ml2H,Har0m). 11.73(s,1H.NH). Example 7: MS m/e 468; !H NMR (CDCI3) 6 7.43- 7.53(m,4H,Harom)> 7.93-8.00(m,2H,Harom)» 8.20-8.23(m,2H,Harom)* 11.73(s,lH,NH). Example 8: MS m/e 428; 2H NMR (CDC13) 6 2.50(2s.6H,2ArCH3), 7.43-7.57(m,4H,Harom). 7.77-7.90(m,2HfHarom). 8.17-8.23(m,2H,Har0in). 11.70(s,lH,NH). Example 9: MS m/e 428; *H NMR (CDCI3) 6 2.46(2s,6H,2ArCH3), 7.27-7.40(m,4H,Harom)1 7.87-7.90(m,2H,Harom)« 8.23-8.30(m,2H,Harom). 11.70(s,lH,NH). Preparation of N-r2.cvclohexvl-4.5-dihvdro-4.4-bis-(trifluoromethyl). lH-imidazo1-5-vlidenel-4-fluorobenzene carboxamide To a solution of a,a-bis(trifluoromethyl)-4,5-bis(4 fluorophenyl)-l-methyl-lH-imidazole-2-methanamine (3.38gr, ! 7.8 mmole) in pyridine (1.7gr) was added cyclohexane < carbonyl chloride (3.5gr, 23.9 mmole). The reaction mixture was heated at 130#C for 4 hours. The mixture was purifiedi Example 9R: Part A 31 by column chromatography, eluting with bexane, then mixture of hexane-ethylacetate (9:1) to give 5-cyclohexyl-2,3-bis(4-fluorophenyl)-7,7-bis(trifluoromethyl)-7H-imidazo[l,5-A]-imidazole (1.88gr,37%) as a white solid: mp 162.2-162.6. Anal. Calcd for C25Hi9FgN3:C,58.60;H,3.54;N,8.20. Found: C,58.43;H,3.79;N,8.16. To a solution of 5-cyclohexyl-2,3-bis(4-fluorophenyl)-7,7-bis(trifluoromethyl)-7H-imidazo[l,5-A]imidazole (3.88gr,7.6mmole) in chloroform (300ml) was added m-chloroperbenzoic acid (MCPBA, 2.6gr, 15.2 mmole). The mixture was refluxed under nitrogen for one hour. Then additional MCPBA (1.3gr, 7.6 mmole) was added and the mixture was refluxed for one hour. The mixture was worked up and columned as described in Example 2 Method A to give the title compound (0.56gr, 17%): mp 128-128.6 MS m/e 424 (M++H). Compounds listed in Table 1.1 were prepared according to the procedure of Example 9R. Part B Table 1.1 CH3 127.6-129.9 fii mp CO O H 128.0-128.6 O H NO n Oti'!'; > O CJ «.j v) U 10 15 20 25 30 32 Example 10 Preparation of N-r4.4-bis-(trifluoromethyl)-2-(4-fluorophenyl)--4.5-dihvdro-l-methvl-lH-imidazol-5-vll-4-fluorobenzan)ide Method A To a solution of N-[4,4-bij>(trifluoromethyl)-2-(4-fluorophenyl)-4,5-dihydro-l-methyl-lH-imidazol-5-ylidene]-4-fluoropheny1benzamide (8.8 g, 19.6 mmole) in anhydrous tetrahydrofuran (100 mL) at -78°C under nitrogen was added dropwise lithium aluminum hydride in tetrahydrofuran (40 mL of 1 M solution). The reaction mixture was stirred at room temperature for two hours, cooled to 0®C, quenched with water then extracted with methylene chloride. The organic layer was washed successively with saturated sodium bicarbonate solution, water and saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed under vacuum. The residue was triturated with hexane to give the title compound (5.65 g, 75%) as a white solid: mp 145-146°; MS m/e 452 (M++H); NMR (CDC13/TMS) 6 2.97(s,3H,NCH3), 6.43(d,lH,J= 7Hz,CH), 6.63(d,lH,J=7Hz,NH), 7.13-7.27(m,4H,Harom), 7.60-7.70(m,2H,Harom), 7.83-7.90(m,2H,Harom). Anal. Calcd for C19H13N3OF8: C,50.57; H,2.90; N,9.31. Found: C.50.79; H,3.05; N, 9.61. 35 Method B To a solution of N-[4,4-bis(trifluoromethyl)-2-(4-fluorophenyl)-4,5-dihydro-l-methyl-lH-imidazol-5-ylidene]-4-fluorobenzamide (1.8 g, 4 mmole) in ethanol (50 mL) at rooi temperature under nitrogen, was added portionwise sodium borohydride (170 mg, 4.5 mmole). The reaction mixture was hisf at reflux for three hours, and then stirred at room temperatlmei. overnight. The reaction mixture was cooled in an ice bath, quenched with water and hydrochloric acid (10 mL, 1 N solution), made basic using sodium hydroxide (1 N) and then extracted with ether. The organic layer was washed successively with sodium hydroxide (1 N), water and saturated sodium chloride solution, era era £L_ U_t GO vj-I 1 a : 1 > uj o LU a: 1 f, A ' ' ( • • \ O O <- J » i U 33 dried over anhydrous magnesium sulfate." The solvent was removed under vacuum and the residue was purified by column chromatography, eluted with hexane followed by hexane-ethyl acetate (20:1 to 50:50) to give two products. The major product 5 (0.8 g, 45%) is the same as the product of Example 10, Method A: mp 145-146°; MS m/e 452(M++H); !H NMR (CDCI3/TMS) 6 2.97(s,3H,NCH3), 6.43(d,1H,J=7Hz,CH), 6.63(d,1H,J=7Hz,NH), 7.13-7.27(m,4H, Harom)1 7.60-7.70(m, 2H,Harom), 7.83-7.90(m,2H,Hapom)• The minor product, N-[2-(4-fluorophenyl)-2,3,4,5-tetrahydro-l-10 methyl-4,4-b|s(trifluoromethyl)-lH-imidazol-5-ylidene]-4- fluorobenzamide, (0.5 g, 27%) was isolated as a solid: mp 132-133°; MS m/e 452 (M++H); *H NMR (CDCI3/TMS) 6 2.57(s,3H,CH3), 3.17(d, l.i, J=7Hz,NH), 5.63(d, 1H, J=7Hz,CH), 7.03-7.20(m,4H,Haroni), 7.40-7.EC(m,2H,Harom), 8.03-8.13(m,2H,Hapou]). Anal. Calcd for 15 CigH13N30F8: C,50.57; H.2.90; N,9.31. Found: C,50.34; H.2.68; N,9.15. Example 10A Preparation of N-r4.4-bis(trifluoromethvl)-2-(4-fluorophenyl)-4.5-dihvdro-l-methvl-lH-imidazol-5-vn-4-20 fluoropheny!-N-methvlbenzamide Sodium hydride (1.5 g, 3.75 mmole) 60% suspension in oil was washed with hexane and then it was suspended in enhydrous dimethylformamide (50 mL). To this suspension was added portionw-se N-[4,4-bis(trif1uoromethy 1)-2-(4-f1uoropheny1)-4,5-25 dihydro-l-methyl-lH-imidazol-5-yl]-4-fluorobenzamide (6.85 g, 15 mmole) and the mixture was allowed to stir at room temperature for one hour. Iodomethane (4.50 g, 30 mmole) was adoed dropwi»$ and the reaction mixture was allowed to stir at room temperatu overnight. The reaction mixture was poured into water and 1 30 extracted with ether. The organic layer was washed successively! with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated to give the title compound (6.46 g, 91%) as a crystalline solid: mp 112-113°; MS m/e 466(M++H); lH NMR (CDCI3/TMS) 6 2.93(s,3H,NCH3), 35 3.00(s,3H,NCH3), 6.79(s,lH,CH), 7.17(m,4H,Harom), 7.43-7.50(m,2H,Harom), 7.63-7«70(m,2H,Ha|rom) • rsj cn h- CO •sr ui C % 34 non'!!;:'! COOoJ V' Example 11 Preparation of N-r4.4-bis(trifluoromethvl)-2-(4-fluorophenyl)-4.5-dihvdro-l-methvl-lH-imidazol-5-vH-4-butoxv-N-methvlbenzamide 5 Part A To a solution of N-[4,4-bis(trifluoromethyl)-2-(4-f1uorophenyl)-4,5-di hydro-l-methyl-lH-imidazol-5-yl]-4-fluoro-N-methylbenzamide (6.46 g, 13.9 mmole) in ether (300 mL) was added potassium tert-butoxide (9.35 g, 6 equiv.) and water 10 (0.5 g, 2 equiv.). The reaction mixture was allowed to stir overnight at room temperature. The suspension was poured into water and the phases were separated. The organic layer was washed successively with water, then saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated 15 under vacuum to give a yellow oil (4.83 g, 100%). Treatment with hydrochloric acid (1M) in ether gave the 4,4-bis(trifluoromethyl )-2-(4-f 1 uorophenyl)-4,5-di hydro-5-amine-N,N-l, 5-dimethyl-lH-imidazole hydrochloride as a white solid: mp 206-207°; MS m/e 344 (M++H); *H NMR (CDCI3/TMS) 6 2.67(s,3H,NCH3), 20 2.93(s,3H,NCH3), 4.67(s,lH,CH), 7.10-7.20(m,2H,Harom), 7.53-7.63(m,2H,Harorn); Anal. Calcd for Ci3Hi2N3F7*HC1: C,41.12; H,3.45; N,11.07; Found: C.41.36; H,3.79; N,11.24. Part B 25 To a solution of 4,4-bii(trifluoromethyl)-2-(4- f1uorophenyl)-4,5-di hydro-5-ami ne-N,N-l,5-dimethyl-1H-imidazole (0.34 g, 1 mmole) in dichloromethane (10 mL) was added j>-butoxybenzoyl chloride (0.64 g, 3 mmole) and pyridine (0.24 g, 3 mmole). The reaction mixture was stirred overnight at room 30 temperature under nitrogen. The crude reaction mixture was quenched with water and extracted with ether. The organic layer was washed successively with water, sodium hydroxide (1 N) and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was 35 purified by flash chromatography eluting with hexane and hexane- til 0 iT O CD CT> 0 ft >- "kI UI 1- EX a. LU to UJ a L!J G.. N rtZ . . 35 ethyl acetate (20:1 to 50:50). The crude product (0.48 g, 92%) was recrystallized from dichloromethane-methanol-petroleum ether to give the title compound as a white solid: mp 84-85°; MS m/e 520 (M++H); lH NMR (CDCI3/TMS) 6 1.00(t,3H,J=7Hz,CH3), 1.43-5 1.60(m,2H,CH2), 1.73-1.87(m,2H,CH2), 2.97(s,3H,NCH3), 3.00(s,3H,NCH3), 4.00(t,2H,J=7Hz,0CH2), 6.73(s,1H,CH), 6.93t(d.2H(J-10Hz. Harom), 7.13-7.27(m.2H,Harom). 7.43(d,2H,J=7Hz,Harom), 7.63-7.70(m,2H,Harom). Anal. Calcd for C24H24N3O2F7: C,55.49; H(4.66; N.8.09. Found: C.55.27; H.4.56; 10 N,8.02. 15 20 25 30 Example 12 Preparation of N-r4.4-bis(trif1uoromethv1)-2-(4-fluorophenyl)-4.5-dihydro-1-methvl-lH-imidazol-5-vl1-4-methoxv-N-methvlbenzamide To a solution of 4.4-bis(trifluoromethyl)-2-(4-fluorophenyl)-4,5-dihydro-5-amine-N,N-l,5-dimethyl-1H-imidazole (0.34 g, 1 mmole) in dichloromethane (10 mL} was added p-anisoyl chloride (0.51 g, 3 mmole) and pyridine (0.24 g, 3 mmole). The reaction mixture was stirred overnight at room temperature under nitrogen. The crude reaction mixture was quenched with water and extracted with ether. The organic layer was washed successively with water, sodium hydroxide (1 N) and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography eluting with hexane and hexane-ethyl acetate (20:1 to 50:50). The crude product was recrystollized from dichloromethane-methanol-petroleum ether to give the title compound (0.25 g, 52%) as a white solid: mp 136-137°; MS m/e 478 (M++H). 2H NMR (CDCI3/TMS) 6 2.93(s,3H,HCH3), 2.97(s,3H,NCH3), 3.83(s,3H,0CH3), 6.73(s,lH,CH), 6.97(d,2H,J=7Hz,Har0m), 7.13-7.20(m,2H r , 7.43(d,2H,J-7Hz,Harom); 7.60-7.70(m,2H,Harom). lu •) Cl N CD CD CL. UJ CO V?* t L.1J Co XT I ii'] 1 XZ* u«i or! 35 r, o o O O kj 36 Example 13 Preparation of N-r4.4-bis(trif1uoromethv1)-2-(4-fluorophenyl)-4.5-dihvdro-1-methyl-lH-imidazol-5-vll-4-(l.l-dimethvlethvl)-N-methvlbenzamide 5 To a solution of 4.4-bis(trifluoromethyl)-2-(4- fluorophenyl)-4,5-dihydro-5-amine-N,N-l,5-dimethyl-lH-imidazole (0.34 g, 1 mmole) in dichloromethane (10 mL) was added E-(t-butyl)benzoyl chloride (0.59 g, 3 mmole) and pyridine (0.24 g, 3 mmole). The reaction mixture was stirred overnight at room 10 temperature under nitrogen. The crude reaction mixture was quenched with water and extracted with ether. The organic layer was washed successively with water, sodium hydroxide (1 N) and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was 15 purified by flash chromatography eluting with hexane and hexane-ethyl acetate (20:1 to 50:50). The crude product (0.40 g, 79%) was recrystallized from dichloromethane-methanol-petroleum ether to give the title compound (80 mg, 16%) as a white solid: mp 129-130°; MS m/e 504 (M++H); NMR (CDCI3/TMS) 6 1.33(s,9H,(CH3)3), 20 2.93(s,3H,NCH3), 3.00(s,3H,NCH3), 6.83(s,lH,CH), 7.17- 7.27(m,2H,Harom), 7.20-7.50(m,4H,HarOm)> 7.63-7.70(!if,2H,Harom)• Anal. Calcd for C24H24N30F/: C,57-26; H,4.81; N,8.35. Found: C,57.20; H,4.82; N,8.29. 25 Example 14 Preparation of N-r4.4-bis(trifluoromethv1)-2-(4-fluorophenyl)-4.5-dihvdro-l-methvl-lH-imidazol-5-vl1-N-methvl-4-nitrobenzami de To a solution of 4.4-bis(trifluoromethyl)-2-(4-30 fluorophenyl)-4,5-dihydro-5-amine-N,N-l,5-dimethyl-1H- imidazole (0.34 g, 1 mmole) in dichloromethane (10 mL) was fi-nitrobenzoyl chloride (0.56 g, 3 mmole) and pyridine (0.24 g, 3 mmole). The reaction mixture was stirred overnight at room temperature under nitrogen. The crude reaction mixture was 35 quenched with water and extracted with ether. The organic layer 9 n r; •; i . ^ l J 10 37 was washed successively with water, sodium hydroxide (1 N) and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography eluting with hexane and hexane-ethyl acetate (20:1 to 50:50). The crude product (0.40 g, 81%) was recrystallized from dichloromethane-methanol-petroleum ether to give the title compound (200 mg, 41%).as a white solid: mp 174-175°; MS m/e 493 (M++H); NMR (CDCI3/TMS) 6 2.90(s,3H,NCH3), 3.07(s,3H,NCH3), 6.77(s,lH,CH), 7.17-7.27(m,2H,Harom), 7.60-7-73(m,4H,, 8.37(d,2H,Js7Hz,Harom)• Anal. Calcd for C20H15N4O3F7: C,48.79; H,3.07; N.11.38. Found: C,48.76; H,2.81; N,11.27. Example 15 15 Preparation of N-r4.4-bis(trif1uoromethv1)-2-(4- fluorophenyl)-4.5-dihvdro-l-methvl-lH-imidazol-5-vl 1-N-methvl-n.1'-biDhenvll-4-carboxamide To a solution of 4.4-bis(trifluoromethyl)-2-(4-fluorophenyl)-4,5-dihydro-5-amine-N,N-l,5-dimethyl-1H-20 imidazole (0.34 g, 1 mmole) in dichloromethane (10 ml) was added fi-bipher.yl carbonyl chloride (0.65 g, 3 mmole) and pyridine (0.24 g, 3 mmcle). The reaction mixture was stirred overnight at room temperature under nitrogen. The crude reaction mixture was quenched with water and extracted with ether. The organic layer 25 was washed successively with water, sodium hydroxide (1 N) and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography eluting with hexane and hexane-ethyl acetate (20:1 to 50:50). The crude product was 30 recrystallized from dichloromethane-methanol-petroleum ether to give the title compound (0.09 g, 17%) as a white solid: mp 186-187°; MS m/e 524 (M++H); NMR (CDCI3/TMS) 6 3.00(s,3H,NCH3), 3.03(s,3H,NCH3), 6.87(s,1H,CH), 7.17-7.77(m,14H,Harom)• Anal. Calcd for C26H20N3F70: C,59.66; H,3.85; N,8.03. Found: C,59.41 35 H,3.72; N.7.89. n i ') <, ; > «.J U u J U 38 Example 16 Preparation of N-r4.4-bis(trifluoromethvl)-2-(4-fluorophenyl)-4.5-dihvdro-1-methvl-lH-imidazol-5-vll-N-methvlheptanamide hydrochloride 5 To a solution of 4.4-bis(trifluoromethyl)-2-(4- f 1 uorophenyl)-4,5-dihydro-5-amine-N,N-l,5-dimethyl-1H-imidazole (0.34 g, 1 mmole) in dichloromethane (10 mL) was added heptanoyl chloride (0.45 g, 3 mmole) and pyridine (0.24 g, 3 mmole). The reaction mixture was stirred overnight at room 10 temperature under nitrogen. The crude reaction mixture was quenched with water and extracted with ether. The organic layer was washed successively with water, sodium hydroxide (1 N) and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was 15 purified by flash chromatography eluting with hexane and hexane-ethyl acetate (20:1 to 50:50). The crude product (0.20 g, 41%) was treated with HC1 in ether and recrystallized from dichloromethane-methanol-petroleum ether to give the title compound as a white solid: mp 134-136°; MS m/e 456 (M++H); NMR 20 (CDCI3/TMS) 6 1.90(m,3H,CH3), 1.33(m,6H(CH2)3), 1.70(m,2H,CH2), 2.47(m,2H,CH2), 3.00(s,3H,NCH3), 3.23(s,3H,NCH3), 7.03(s,lH,CH), 7.20-7.40(m,2H,HarOm)1 7.93-8.17(m,2H,Harom)• Example 18 25 Preparation of N-r4.4-bis(trifluoromethv1)-2-(4- f luorophenyl)-4.5-dihvdro-1-methvl-lH-imidazol-5-vll-N.5-dimethvl-hexanamide hydrochloride To a solution of 5-methylhexanoic acid (0.53 g, 4 mmole) ip£ dichloromethane was added oxalyl chloride (0.77 g, 6 mmole). Tfje£ 30 reaction mixture was stirred at room temperature for 2 hours anc then evaporated under vacuum to give crude 5-methylhexanoyl chloride. To a solution of 4,4-bi^(trifluoromethyl)-2-(4-fluorophenyl)-4,5-dihydro-5-amine-N,N-l,5-dimethyl-lH-imidazole (0.60 g, 1.76 mmole) in dichloromethane (15 mL) was added 5-35 methylhexanoyl chloride and pyridine (0.42 g, 5 mmole). The IAJ O ijT l:. G fc! IM 00 CO <10 NT I a UI o LU CC 39 reaction mixture was stirred overnight at room temperature under nitrogen. The crude reaction mixture was quenched with water and extracted with ether. The organic layer was washed successively with water, sodium hydroxide (1 N) and saturated sodium chloride 5 solution, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography eluting with hexane and hexane-ethyl acetate (20:1 to 50:50). The crude product (0.42 g, 85%) was treated with HC1 in ether and recrystallized from dichloromethane-methanol-petroleum ether to 10 give the title compound as a white solid: mp 112-114°; MS m/e 456 (M++H); NMR (CDCI3/TMS) 6 0.90(s,3H,CH3), 0.93(s,3H,CH3), 1.27(m,2H,CH2), 1.67(m,3H,CH2,CH), 2.47(m,2H,CH2), 3.00(s,3H,NCH3), 3.23(s,3H,NCH3), 7.03(s,1H,CH), 7.33(m,2H,Harom), 8.00(m,2H,Harom). 15 Examples 25 and 26 Preparation of the diastereomers of N-T4.4-bi s(tri fluoromethyl)-2-(4-fluorophenyl)-4.5-dihvdro-l-methvl-lH-imidazol-5-vll-camphanvlamide 20 To a solution of 4.4-bis(trifluoromethyl)-2-(4- fluorophenyl)-4,5-dihydro-5-amine-N,N-l,5-dimethyl-lH-imidazole (0.34 g, 1 mmole) in dichloromethane (10 ml) was added camphanyl chloride (0.85 g, 3 mmole) and pyridine (0.24 g, 3 mmole). The reaction mixture was stirred overnight at room temperature under 25 nitroger. The crude reaction mixture was quenched with water and extracted with ether. The organic layer was washed successively with water, sodium hydroxide (1 N) and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentratedj under vacuum. The residue was purified by flash chromatography j 30 eluting with hexane and hexane-ethyl acetate (10:1) to give tne" i m diastereomers which were recrystallized from hexane- j >"•' r. dichloromethane mixture. The diastereomer that eluted first (joo ' mg, 19%) is a solid: mp 126-127°; [c]25d - -8.91° (c,0.606, "j ' MeOH); MS m/e 524(M++H); h NMR (CDC13/TMS) 6 1.03(s,3H,CH3) ,j 35 1.13(s,3HjCH3)# 1.23(s,3H,CH3), 1.63-2.43(m,4H, t 40 nor. \> t.f > •x O U u i) U 2.97(s,3H,NCH3), 3.13(s,3H,NCH3), 6.53(s,1H,C)H, 7.20(m,2H,Harom), 7.67(m,2H,Harom). Anal. Calcd for C23H24N3F703: C.52.78; H.4.62; N,8.03. Found: C,52.70; H,4.65; Nf7.97. The diastereomer that eluted last (80 mg, 15%) is a 5 solid: mp 87-88; [a] = + 7.04° (c,0.610, MeOH); MS m/e 524(M++H); lH NMR (CDCI3/TMS) 6 1.03(s,3H,CH3), 1.13(s,3H,CH3), 1.17(s,3H,CH3), 1.60-2.67(m,4H,(CH2)2), 2.97(s,3H,NCH3), 3.17(s,3H,NCH3), 6.60(s,1H.CH), 7.20(m,2H,Harom), 7.67(m,2H,Harom). Anal. Calcd for C23H24N3F703: C.52.78; 10 H.4.62; N.8.03. Found: C,52.82; H.4.39; N.8.03. Preparation of N-r4-4-bis(trifluoromethvl)-2-(4-f luorophenyl)-4.5-di hvdro-l-methvl-lH-imidazol-5-vn-N' -4-15 i sopropvlphenyl-N-methvl urea To a solution of 4,4-bis(trifluoromethyl)-2-(4-fluorophenyl)-4,5-di hydro-5-ami ne-N,N-l,5-dimethyl-1K-imidazole (0.34 g, 1 mmole) in dichloromethane (2 mL) and hexane (10 mL) was added 4-isopropylphenyl isocyanate (0.45 g, 3 mmole). 20 The reaction mixture was stirred overnight at room temperature under nitrogen. The crude reaction mixture was quenched with water and extracted with ether. The organic layer was washed successively with water, sodium hydroxide (1 N), and saturated sodium chloride solution, dried over anhydrous magnesium sulfate 25 and concentrated under vacuum. The residue was purified by flash chromatography eluting with hexane and hexane-ethyl acetate (10:1) to give the title compound (0.20 g, 40%) as a white solid: mp 203-204°; MS m/e 505 (M++H); lH NMR (CDCI3/TMS) 6 1.23(s,3H,CH3), 1.27(s,3H,CH3), 2.93(m,lH,CH), 3.00(s,6H,2 NCH3), 30 6.53(s,lH,NH), 6.67(s,lH,CH), 7.20-7.43(m,6H,Harom), 7.67- 7.77(m,2H,Harom). Anal. Calcd for C23H23N4F7O: C,54.76; H.4.60; N, 11.15. Found: C,54.85; H,4.62; N,11.02. Example 27 35 O O ( . <)(>;■' ., o i j «. j i j U 41 Example 28 Preparation of N-r4.4-bis(trifluoromethvl)-2-(4-fluorophenyl)-4.5-dihvdro-l-methv1-lK-imidazo1-5-v11-N'-2.4-difluorophenyl-N-methvlurea 5 To a solution of 4.4-bis(trifluoromethyl)-2- (4-fluorophenyl)-4,5-dihydro-5-amine-N,N-l,5-dimethyl-1H-imidazole (0.34 g, 1 mmole) in dichloromethane (2 mL) and hexane (10 mL) was added 2,4-difluorophenyl isocyanate (0.47 g, 3 mmole). The reaction mixture was stirred overnight at room 10 temperature under nitrogen. The crude reaction mixture was quenched with water and extracted with ether. The organic layer was washed successively with water, sodium hydroxide (1 N), and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue 15 (0.51 g, 100%) was purified by flash chromatography eluting with hexane and hexane-ethyl acetate (10:1) to give the title compound (100 mg, 20%) as a white solid: mp 176-177°; MS m/e 499 (M++H); !H NMR (CDCI3/TMS) 6 2.97(s,6H,2 NCH3), 6.57(s,lH,NH), 6.67(s,iH,CH), 6.85-6.93(m,2H,Har0m)1 7.17-7.27(m,2H,Hapom)> 20 7.63-7.73(m,2H,Harom), 8.00-8.13(m, lH,HapQp^). Anal. Calcd for C20H15F3N4°: C.48.20; H,3.03; N,11.24. Found: C,48.13; H,2.97; N,11.08 Example 29 25 Preparation of N-r4.4-bis(trifluoromethv1)-2-(4- fluoroplienvl)-4.5-dihydro-1-methvl-lH-imidazol-5-vll-N'-octvl-N-methvlurea hydrochloride To a solution of 4,4-bis(trifluoromethyl)-2-(4-f1uoropheny1)-4,5-di hydro-5-ami ne-N,N-l,5-dimethyl-1H-30 imidazole (0.34 g, 1 mmole) in dichloromethane (2 mL) and hexane (10 mL) was added n-octyl isocyanate (0.47 g, 3 mmole). The reaction mixture was stirred over 3 days at room temperature t refluxed for 4 hours under nitrogen. The crude reaction mixt was quenched with water and extracted with ether. The organi 35 layer was washed successively with water, sodium hydroxide (lj n O <■''V^O o O ^ 10 42 and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was treated with HCl in ether then purified by flash chromatography eluting with hexane and hexane-ethyl acetate (10:1) to give the title compound (50 mg, 9%) as a light brown solid: mp 45-47°; MS m/e 499 (M++H); lti NMR (CDCI3/TMS) 6 0.90(m,3H,CH3), 1.27(m,12H,(CH2)6), 2.60(d.3H,NCH3), 2.93(s,3H,NCH3), 3.13(iu,2H,CH2), 4.77(m, 1H,NH), 6.60(s,lH,CH), 7.17(m,2H,Harom), 7.63(m,2H,Harom). Example 30 Preparation of N-r4.4-bis(trifluoromethvl)-2-(4- f1uorophenyl)-4.5-di hvdro-l-methvl-lH-imidazol-5-vll-4- ethoxvbenzamide 15 To a solution of N-[4,4-bis(trifluoromethyl)-2-(4- fluorophenyl)-4,5-dihydro-lH-imidazol-5-yl]-4-fluorobenzamide (0.26 g, 0.6 mmole) in ethanol (10 nL) was added sodium hydroxide solution (1 mL, 50%). The reaction mixture was allowed to reflux overnight. The solution was cooled to room 20 temperature, poured into water and extracted with ether. The organic layer was washed successively with water, and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by HPLC with 85:15 hexane-ethyl acetate to give the title compound (20 25 mg, 7%) as a white solid: mp 115-116°; h NMR (CDC13/TMS) 6 1.43(t,J=7Hz,3H,CH3), 2.97(s,3H,NCH3), 4.07(q,J«7Hz,2H,CH2), 6.37(d,lH,J=14Hz,CH), 6.60(d,2H,J=14Hz,NH), 6.97(dl2HlJ=10HzlHarom)f 7.17(q,2H,J=7Hz,Harom), 7.57 (d, 2H, J=10Hz, Harom), 7.83 (m, 2H, Haroni). o o «, j >. J L j 10 15 20 25 30 43 Examples 31 and 32 Preparation of N-r4.4-bis(trif1uoroniethvl)-2-(4-f luorophenyl)-4.5-dihydro-l-methyl-lH-imidazol-5-vll-4-(1-piperidinvl) benzamide (Example 31) and N-T4.4-bis(trifluoromethyl)-4.5-dihvdro-l-methvl-2-l"4-(1-piperidinv1)phenv11-lH-imidazol-5-v11-4-f1uorobenzainide (Example 32) To a solution of N-[4,4-bis(trifluoromethyl)-2-(4-fluorophenyl)-4,5-dihydro-lH-imidazol-5-yl]-4-fluorobenzamide (0.9 g, 2 nwnole) in dimethyl sulfoxide (5 ml) was added potassium carbonate (0.83 g, 3 equiv.) and piperidine (0.51 g, 3 equiv.). The reaction mixture was heated at 145° overnight under nitrogen. The solution was cooled to room temperature, poured into water and extracted with dichloromethane. The organic layer was washed with water and saturated sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under vacuum. The residue was purified by MPLC with 9:1 hexane-ethyl acetate to give two product:.. N-[4,4-bis (trif 1 uoromethyl) -2- (4-f 1 uoropheny 1) -4,5-dihydro-l-methyl-lH-imidazol-5-yl]-4-(1-piperidinyl) benzamide (160 mg, 15%) was isolated as a white solid: mp 128-129°; MS m/e 517 (M+t-H); JH NMR (CDCI3/TMS) 6 1.67(m,6H, (^2)3), 2.93(s,3HfNCH2), 3.33(m,4H,CH2NCH2), 6.43-6.60(m,2H,NH.CH), 6.90(d,2H,J*7,Harom), 7.13-7.20(m,2H,Hapom)• 7.60-7.73(m,2H,Haf0m)• N-[4,4-bis(trifluoromethyl)-4,5-dihydro-l-methyl -2-[4-(1-pi peri dinyl)phenyl]-lH-imidazol-5-yl]-4-fluorobenzamide (80 mg, 8%) was isolated as a white solid: mp 123-124°; MS m/e 517 (M++H); lH NMR (CDC13/TMS) 6 1.67(m,6H,(CH2)3), 3.00(s.3H.NCH3), 3.30(m,4H(CH2NCH2). 6.37(d,lH,CH), e.eOOn.ZH.NH), 6.90(d,2H,J«7,Harom), 7.13-7.22(m,2H,Harom), 7.53(d,2H,Js7,Haroin), 7.80-7.90(m,2H,HarOm)• 35 ') '"> '■> q fi — u o u v/ u 44 Example 33 Preparation of N-r4.4-bis(trifluoromethvl)-4.5-dihvdro-l-methvl-2-f4-(1-piperidinvl)phenyl!-lH-imidazol -5-vll-N-methvlheptanamide. hydrochloride 5 To a solution of N-[4,4-bis(trifluoromethyl)-2-(4- fluorophenyl)-4,5-dihydro-lH-imidazol-5-yl]-N-methylheptanamide hydrochloride (0.20 g, 0.4 mmole) in dimethyl sulfoxide (5 mL) was added potassium carbonate (0.29 g, 1.2 mmole) and piperidine (0.10 g, 1.2 mmole). The reaction mixture 10 was heated at 145° overnight under nitrogen. The solution was cooled to room temperature, poured into water and extracted with ether. The ether layer was washed with 1 N HCl to give unreacted starting material. The aqueous layer was made basic and it was extracted with ether. The organic layer was washed with water 15 and saturated sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under vacuum. The residue was treated with HCl in ether to give the title compound (50 mg, 22%) as a semi solid: MS m/e 521 (M++H); lW NMR (CDCI3/TMS) 6 0.90(m,3H,CH3), 1.30(m,8H, (CH2)4), 1.67(m,6H, (CH2b), 20 2.40(t,2H,CH2), 2.90(s,3H,NCH3), 2.97(s,3H,NCH3), 3.30(m,4H,2CH2), 6.53(s,1H,CH), 6.90(d,2H,Harom), 7.53(d,2H,Har0m). Example 34 25 Preparation of N-F4.4-bis(trifluoromethv1)-2-(4- methoxvi)henvl)-4.5-dihvdro-l-methvl-lH-imidazo1-5-vll-N.5-dimethvlhexanamide hydrochloride . To N-T4.4-bis(trif1uoromethv1)-2-(4-f1uorophenyl)-4.5-dihydro-lH-imidazo1-5-yl]-N,5-dimethylhexanamide (0.05 g, 0.1 30 mmole) was added sodium methoxide solution (10 mL, 25%). The reaction mixture was allowed to reflux for 3 hours. The solution was coo'ied to room temperature, poured into water and extracted with ether. The organic layer was washed successively with water, and saturated sodium chloride solution, dried over 35 anhydroi.s magnesium sulfate and concentrated under vacuum. The l ' > '■> •' '} (i n & a o u J U 10 15 20 25 30 35 45 residue was treated with HCl in ether to "give the title compound (50 mg, 99%) as a white solid: mp 68-69°; MS m/e 468 (M++H); *H NMR (CDCI3/TMS) ^ 0.87(sf3H,CH3), 0.90(s,3H,CH3), 1.27(m(2H,CH2), 1.60(m,3H,CH2CH); 2.37(m,2H,CH2), 2.90(m,6H,2NCH3), 3.83(s,3H,0CH3), 6.60(s,lH,CH), 6.97(d,2H,Harom), 7.60(d,2H,Harom). Examples 0 and R Preparation of N-r4.4-bis(trif1uoromethvl)-2-(4-cvanophenvl)-4.5-dihvdro-l-methvl-lH-imidazo1-5-vll-N-methvl-4-fluorobenzamide (Example 0) and N-T4.4-bi s(tri f1uoromethvl)-4.5-di hvdro-l-methvl-2-U-cvanoohenvll -lH-imidazol-5-vll-N-methvl-4-cvanobenzamide (Example R) To a solution of N-[4,4-bis(trifluoromethyl)-2-(4-f1uorophenyl)-4,5-di hydro-lH-imi dazol-5-yl]-4-f1uoro-methylbenzamide (0.46 g, 1 mmole) in dimethyl sulfoxide (5 mL) was added potassium carbonate (0.41 g, 3 equiv.) and potassium cyanide (0.47 g, 3 equiv.). The reaction mixture was heated at 120° overnight under nitrogen. The solution was cooled to room temperature, poured into water and extracted with dichloromethane. The organic layer was washed with water and saturated sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under vacuum. The residue was purified on silica gel eluting with hexane, then a mixture of hexane-ethylacetate (20:1 to 50:50) to give two products. N-[4,4-bis(trif1uoromethyl)-2-(4-cyanophenyl)-4,5-di hydro-l-methyl-lH-imidazol-5-yl]-4-fluoromethylbenzamide (130 mg, 28%) was isolated as a white solid: mp 189-190°; MS m/e 473 (M++H); *H NMR (CDC13/7MS) 6 2.93 (s,3H,NCH3), 2.98(s,3H,NCH3), 6.80(bs,1H.CH), 7.18(m,2H,Harom), 7.45(m,2H,Harom)■ 7.80(m,4H,Harom)• Anal. Calcd for C21H15N4OF7: C,53.40; H,3.20; N,11.86. Found: C.53.12; H,3.16; N,11.69. N-T4.4-bis(trifluoromethvl)-4,5-dih> dro-l-methyl-2-[4-cyanopheny1]-lH-imidazol-5-yl]-4-cyanomet.hylbenzamide (40 mg, 8%) was isolated as a white solid: mp 128-129°; MS m/e 480 (M++H); XH NMR (CDC13/TMS) 6 2.90(s,3H,NCH3), 3.00(m,3H,NCH3), 6.80(bs.1H.CH), 7.55(m,2H,Harom), 7.80(m,6H,Haroni) • Recrystallization of N-[4,4-tns[trifluoromethyl)-4,5-di hydro-l-methyl-2-[4-cyanopheny1]-lH-imi dazol-5-yl]-N-methyl-4-cyanobenzamide from methylene chloride-hexane gave the polymorphic crystalline form that melts at 132 to 134°C. Recrystallization from ethyl acetate-hexane gave a polymorphic form melting at 181-183°C. X-ray powder diffraction showed that each polymorph has a distinct crystalline form. The polymorphs are interconvertible based on the solvent used for recrystallization. Differential scanning calorimetry of the compound of Example R resulted in three peaks at 131.7°C, 182.6°C, and 253.5°C, which correspond to polymorphic transitions from the 131°C form to the 182.6°C form, followed by decomposition at 253.5°C. The 132-134° melting polymorph is 3 fold more water soluble than the 181-183°C melting polymorph and has greater oral bioavailability leading to improved systemic ACAT inhibitory activity, compared to the higher melting form. Separation of [R] and [S] enautiomers of [4,4 bis-(tri f1uoromethyl)-4,5-di hydro-l-methyl-2-[4-cyanopheny1]-1H-imidazole-5-yl]-N-methyl-4-cyano-benzamide(example 73, 74) and their sulfate salts (Ex. 75, 76). The racemic mixture of the title compound was separated to the R and S enantioners using HPLC with a Chiracel-OJ column eluted with 50% ethanol-hexane. Upon concentration, the enantiomers are triturated with hexane to give amorphous solid. The sulfate salt can be obtained by dissolving the amorphous solid in ether and adding sulfuric acid (conc) to give white solid which can be recrystalized from methanol-ether to give the sulfate salt of the [S] enautiomer:mp 181.-183.7 Anal. Calcd for C22H15F6N5°*H2S04 '• j C,45.76; H,2.97; N.12.13: S5.55. Found: C.46,22; H,3.13; 11.6o/§ S.5.91. j The sulfate salt of the [R] enantiomer: mp 181.1-181.8 f^i Anal. Calcd for C22Hl5FgN50*H2S04: C,45.76; H,2.97; N.12.13; jg ! S5.55. Found C.46.32; H.3.13; N,11.63; $,5.99. ^oootlu 47 The compounds of Examples 10-18, 22-23, 25-34, Q, R, and S and other compounds of Formula (I) wherein a is a single bond which have been prepared or could be prepared using the same or similar synthetic methods, are listed in Table 2 and Table 2.1. 10 15 20 25 30 ■ Ex. # G £1 El £? mp(°C) 10 e-f H 0 ch3 h -c-0-f o 145-146 10a E-f H CH3 CH3 -C-^^-f fi 112-113 11 E-f H u CH3 CH3 -C-Q-0(CH2)3CH3 0 84-85 12 E-f H v CH3 CH3 -C-Q-0CH3 n 136-137 13 E-f H u CH3 CH3 -C-Q-C(CH3)3 n 129-130 14 E-f H CH3 CH3 -C-Q-N02 n 174-175 15 E-f H \J CH3 CH3 -C-^>C6H5 186-187 16 E-f H CH3 CH3 C0C6HI3 134-136 (HCl salt) 17 E-f H CH3 CH3 C0(CH2)I0CH3 72-74 (HCl salt) 18 E-f H CH3 CH3 C0(CH2)3CH(CH3)2 112-114 35 rcp(°P 22 fi-F H CH3 ch3 „ 111-112 0 23 E-F H CH3 CH3 12B-m 0 %lm3 25 fi-F H CH3 CH3 0 #*11, 0 ^ 81-88 f K CHj C«3 26 0 °^<j It 203-204 8 ^0 5 27 E-F H CH3 CH3 -c-NH-^~CH<CH3)2 28 E-F H CH3 CH3 -C-N 176-177 H 29 fi-F H CH3 CH3 CONHCgHn ,J5'47^ (HCl salt; 20 0 30 E-F H CH3 H -C-^-0CH2CH3 115-116 0 31 E-F H CH3 H 128-129 0 123-124 c«mi-sol1 25 30 35 ji * u 32 fi- o« ch3 h -c-o-f 33 t-lQ H CH3 CH3 C0C6Hi3 Semi-Sol id 34 P-OCH3 h CH3 ch3 C0(CH2)3ch(ch3)2 68-69 (HCl Silt) 0 Q p-CN H CH3 CH3 -C-^-F 189-190 0 R p-CN H CH3 CH3 -c-Q-CN 128-129 0 s e-f h ch3 ch3 -c«£)-cn 149.3-150.2 <) o ') f i f| O Cj "u j u 49 Table 2 (continued) ex. # g £1 b1 r6 b2 p 5 35 e-cn m-n02 ch3 ch3 -f-o-f 0 36 fi-cf3 h ch3 ch3 -c-o-f n 10 37 e-f h ch3 ch3 V -c-q-n02 38 e-cn h ch3 ch3 coc6h13 39 e-n02 m-cl ch3 ch3 coc6h13 n 40 e-f h ch3 ch3 u 15 0 II 41 e-c02et h ch3 ch3 *C-0"F 0 42 e-cn h ch3 ch3 v -c-^~^-0c4hg-n A 20 43 e-cn h ch3 ch3 0 -c-0-c(ch3)3 n 44 jhq 111-ch3 ch3 ch3 v -c-^t^-0c4hg-n 25 45 b-o h ch3 ch3 0 -c—^"^-0c4hg-n 0 46 e-0 h ch3 ch3 -c -Q-Q 0 47 e-o ci ch3 ch3 -c-o-f q 30 48 e-nqo h ch3 ch3 -c-q-f 0 49 e-oh h ch3 ch3 w -C-c6Hi3 0 50 e-och3 h ch3 ch3 v -c-c6h13 35 mp(°C) 183.3-184.8 141.2-143.4 189.5-191.5 o o f . ') (1 i'l ,r. O O o x t vy 10 15 Ex. # £ 51 fi-F 52 fi-F 53 fi-N02 54 fi-Cl 55 fi-fQ 56 fi-N02 50 Table 2 (continued) £1 £i £6 r2 H CH3 CH3 -(CH2)6CH3 0 h H CH3 CH3 -C-^-N(CH3)2 0 m-CF3 CH3 CH3 -C-^^-0C4Hg-n 0 D-Cl CH3 CH3 -C-Q-C(CH3)3 0 H CH3 CH3 -C-®-CN no2 0 m-CF3 CH3 CH3 -C-C6Hi3 fflpCC) 152.4(d) 128-129 20 25 30 35 57 fi-0CCH3 58 fi-0CH3 59 fi-0CH3 60 fi-F H CH3 CH3 C0C6HI3 0 H CH3 CH3 -C-^-F 0 H CH3 CH3 C-®-0CH3 H CH3 CH3 0 61 fi-Ci7H33C02 H CH3 CH3 -C-CgHi3-n 62 p-CN H • v CH3 CH3 -c-N-C-Q CH, 0 63 p-O H CH3 ch3 -c-Q-iT) o 64 p-OH H CH3 CH3 -c-o- CN oil 153.2-158.8 140.7-141.8 115-116 oil 51 Table 2 (continued! o o f; o (: fi iC Ul/UvIL' 5 Ex. # £ 65 p-CN 10 15 20 25 30 66 67 68 69 70 71 72 73 74 75 77 78 p-CN p-F p-F p-CN p-CN p-F p-F p-CN p-CN p-CN 76 p-CN p-F o P-c-och3 £1 R1 R6 H ch3 H r2 w»p(°Q) h h h h h h h h h h h h -c-o-en nd -i-o hd -i-ho-ch nd -I-O CH3 H ch3 n ch3 h ch3 h ch3 h -c-Q-f hd (S-isomer) o CH3 CH2CH=CH2 -C-Q-F 154.9(HClsalt) CH3 H -C-Q-f nd (R-isomer) 0 ND (S-isomer) ch3 ch3 ch3 ch3 ch3 ch3 -0-o-f ND (R-isomer) o ND (S-isomer) o -C-Q-GN 181.1-181.8 (R-isomer n H2SO4 salt) h ch3 ch3 -C-Q-CN 181.8-183.7 (S-isomer ch3 ch3 ch3 ch3 35 -chQ-b, -c-0"f h2so4 salt) 173.0-173.^ ! 162.4-163.7 co cn Q_ LU CO vy- q l'l > UJ o UJ a: o ° 0 '■ i fj o o <■; *•) v 52 Table 2 fcontinued) £*UL la £1 fil b6 r2 WIDCC) 79 p-CN h ch3 ch3 0 ND (R-isomer) 80 p-CN h ch3 ch3 0 —ND (S-isomer) 10 81 p-CN h ch3 ch3 0 -K> 201.0-201.9 82 p-CN N P-C-och3 h ch3 ch3 -C-Q-OH, 209.9-210.9 15 83 h ch3 ch3 J-O- F 142.7-143.2 84 p-F h ch3 ch3 -£-0 103-105 85 p-F h ch3 ch3 -C-^^-CN ND (R-isomer) 20 86 p-F h ch3 ch3 Q -C-Q-CN ND (S-isomer) 87 p-F h ch3 ch3 Xo 132-133.2 25 88 89 P-sch3 p-CN h ch3 h ch3 ch3 ch3 -C-^-SCH, -tO-CN 186.6-187.7 118 (d.HCl salt) 90 p-F h ch3 ch3 0 «*■ -C—N— 177.9 (isomer 1- 30 91 p-F h ch3 ch3 0 6h» -C—N— 101.0 (isomer 2- 92 P-F h ch3 ch3 0 -C—N— ND (isomer l-S)\ 35 ) LU <2 U.i CO n 1 "S) cr> I a« u" UJ UJ (k co a -R) I.* i "i 53 Table 2 (continued) Ex. # £ bl b6 b2 mpfC) o 93 p-F H ch3 ch3 -C—N~C-^ ND (isomer 2-S) Notes. Example 17: MS m/e 525; NMR (CDCI3) 6 0.87(s,3h,ch3)f 1.27(m,16H, (C^). 1.67(m,2HfCH2). 2.37(m,2H,ch2), 2.93(s,6H#2nch3), 6.63(s,lH,CH), 7.17(m,2H,Harom), 7.63(mf2H, Harom)• Example 22: MS m/e 454; NMR (cdci3) 6 3.00(s,3H,NCH3), 3.20(s,3HtNCH3), 6.70(s,lH,CH), 7.20(m(4H,Hapom) < 7.60(m(2H,HapOm)» 7.70(m,2H,Hainoni). Example 23: MS m/e 438; NMR (cdci3) 6 2.97(s,3H,NCH3), 3.20(s,3H,NCH3), 6.57(s,lH,CH), 6.73(s,lH,CH), 7.23(m,3HlHar0m)» 7.67(m,3H,Harom). Table 2.1 Ex. # Ar* bi b5 b* 95.1 -o ch3 h c-o- 95.2 -o ch3 ch3 t-o mp (°C) 125.9-126.9 q 'i (i 0 »_ g o u j ^ 54 Example 96 Preparation of 2-T4.4-bis(trifluoromethyl)-2-(4-f luorophenyl)-4.5-dihvdro-1-methvl-lH-imidazol-5-vlidenel-1-(4-fluorophenyl)-1-ethanone 5 Part A-l To a solution of a.a-bis(trifluoromethyl)-4.5-bis(4-fl uorophenyl)-lH-pyrrole-2-methanamine (4.0 g, 0.009 mole) in chloroform and methanol (1.5 1, 1:1) was added methylene blue (10 mg). Oxygen gas or air was bubbled through the solution while 10 irradiating with a Tungsten lamp (400 watt) for 1 hour. 1M hydrochloric acid in ether (10 ml) was added to the reaction mixture and stirred for 1 hour at room temperature. The mixture was treated with saturated sodium carbonate solution (15 ml) and the organic layer was separated, concentrated, resuspended in 15 ethyl acetate (200 ml), and washed with saturated ammonium chloride solution, saturated sodium chloride solution, dried over sodium sulfate (anhyd.) and evaporated under vacuum. The residue was purified by column chromatography, eluting with hexane-ethyl acetate (10:1) to give the 2-T4.4-bis(trifluoromethyl)-2-(4-20 f1uorophenyl)-4,5-dihydro-lH-imidazol-5-ylidine]-l-(4-fluorophenyl)-1-ethanone (2.03 g, 49%). Part A-2 To a solution of a.a-bis(tri-fluoromethyl)-4.5-bis(4-25 fluorophenyl)-lH-pyrrole-2-methanamine (5.0 g, 0.012 mole) in chloroform (100 mL) was added portionwise, m-chloroperbenzoic acid (MCPBA, 4.09 g, 0.024 mole). The reaction mixture was refluxed under nitrogen for one hour. Then additional MCPBA (2.05 g, 0.012 mole) was added and the mixture was refluxed for 1 30 hour. The solution was cooled to room temperature and poured into saturated sodium bicarbonate (200 mL). The organic layer f ] i.i i i1' was washed successively with saturated sodium bicarbonate solution, 10% sodium sulfite solution, water, and saturated sodium chloride solution, dried over magnesium sulfate and 35 evaporated under vacuum. The residue was columned in silica gel eluted with hexane-ethyl acetate 20:1 then 10:1 to give the 2-[4, 4-bis(trifluoromethyl)-2-(4-fluorophenyl)-4,5-dihydro-1H-imidazol-5-ylidene]-l-(4-fluorophenyl)-l-ethanone (1.02 g, 20%) as a yellow solid: rap 121-123°; MS m/e 435 (H^+H); *H NMR (cdci3/TMS) 6 6.73(sf1H,C=CH), 7.17-7.30(m,4H,Harom), 8.00-8.10(m,4H,Harom), 11.80(s,lH,NH). Another product, N[2-(4-f1uorophenyl)-4,5-di hydro-l-methyl-5.5-bis(trif1uoromethy1)-1H-imidazol-5-yl]-N-methylacetamide (2.09 g, 56%) was also isolated as a solid: mp 114-115°; MS m/e 437 (M++H); *H NMR (cdci3/TMS) 6 2.57(s,2H,NH2), 3.87(s,1H,NH), 6.77(s,1H.C-CH), 6.90-7.03(m,4H,Harom), 7.23-7.40(m,2H,Harom), 7.15-7.17(mI2H,Harom). Part B Sodium hydride (80 mg, 2.0 mmole) 60% suspension in oil was washed with hexane and then it was suspended in anhydrous dimethyl formamide (5 mL). To this suspension was added portionwise 2-[4,4-bis(trif1uoromethy1)-2-(4-f 1 uorophenyl)-4,5-dihydro-lH-imidazol-5-ylidene]-1-(4-fluorophenyl)-1-ethanone (0.43 g, 1 mmole) and the mixture was allowed to stir at room temperature for one hour. Iodomethane (0.28 g, 2 mmole) was added dropwise and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was poured into water and extracted with ether. The organic layer was washed successively with water and saturated sodium chloride solution, .... dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from dichloromethane-hexane to give : the title compound (0.20 g, 91%) as a crystalline solid: mp 128-129°; MS m/e 449(M++H); *H NMR (cdci3/TMS) 5 3.17(s,3H,NCH3), j -6.67(s, 1H,OCH), 7.13-7.30(m,4H,Hay»ojp), 7.77-7.87(m,2H,Hajrom) J 7.93-8.07(m,2H,Harom)' The compound of Example 96, and other compounds of Formula (I) wherein X is CH which have been prepared or could be prepared using the same or similar synthetic methods, are listed in Table 3 ft O n •} r s ] •-oouju 56 10 Ex. # G G' G" G''' R1 R6 mp(°C) 96 e-f h E-f h ch3 h 128-129 97 e-och3 h E-0CH3 h ch3 h nd 98 e-f h E-0CH3 h ch3 h nd 15 99 E-OC4H9 H E-OC4H9 h ch3 h nd 100 fi-cn h e-cn h ch3 h 101 e-cn h E-f h ch3 h 20 102 e-cf3 h E-CF3 h ch3ch2 h 103 e-ch3 h E-CH3 h CH3CH2 h 104 e-cl h fi-ci h h h 105 e-cl m-cl fi-ci m-cl ch2*chch2 h 25 106 E-f o-F E-f o-F ch3 h 107 e-n3 h E-N3 h CH3CH2 h 108 e-N3 h fi-f h ch2=chch2 h 109 E-O h E-O h ch3 h 30 110 e-o 0 h E-f 0 h ch3 h 111 e-coch3 h e-coch3 h CH3CH2 H j 112 e-n02 h e-n02 H CH3 h | 35 113 e-n02 ro-cl e-no2 nj-CI H H / o o o') (j r\ •w o o kj u 25 30 57 Table 3 (continued) • Ex. # G G' G" G''' R1 R6 114 fi-N02 m-CN fi-N02 m-CN CH3CH2 H 5 /~A >—s H 115 H fi-N 0 H ch3 • 116 E-N(CH3)2 H fi-f H CH2=CHCH2 H 117 E-f H £-N(CH3)2 H ch3 H 10 118 fi-S02CH3 h fi-S02CH3 h ch3 H mp(°C) 0 t 119 fi-n(ch3)2 h fi-f h ch2ch3 h 15 119*1 fi-f h fi-f h ch3 ch3 119.2 fi-f h fi-0ch3 h ch3 ch3 119.3 «-0 h e-o h ch3 h 20 119.4 2-0 h "•O h ch3 h 119.5 fi-f h «-o h ch3 h 209-211 (E-isomer) 138-139 (Z-isomer) 154.5-155.5 (Z-isomer) 35 Notes. Example 97: MS m/e 473; JH NMR (CDCI3) 6 3.17(s.3H,NCH3), 3.87(2s(6H,0CH3), 6.63(s,1H.CH), 7.00(m,4H,Harom), 7.73(d,2H,J=10Hz,Harom), 7.93(d,2H,J-lOHz,Harom). Example 98: MS m/e 461; lH NMR (CHCI3) 6 3.17(s,3H.HCH3), 3.90(s,3H,0CH3), 6.63(s,lH,CH), 7.00(d,2H,J*10Hz,Harom). 7.23(m,2H,Haroffl), 7.93(ml2H,Harom)1 8.00(d,2H,J=10Hz,Harom)• Example 99: MS m/e 557; *H NMR (CHCI3) 6 0.93(m,6H,2CH3), 1.50(m,4H,2CH2), 1.60(m,4H,2CH2), 3.17(s,3H.NCH3), 4.03(m,4H,20CH2) 6.60(s,1H.CH), 6.97(m,4HlHarom), 7.00(d,2H,J-lOHz,Harom), 7.93(d,2H,10Hz,Har0m)• i » O ( I i ^ «J (J <.'j l(J 58 Example 120 1-(4-fluorophenyl-2-T2-(4-fluorophenyl)-4.5-dihvdro-l-methvl-4.4-bis(trifluoromethy!)-lH-imidazol-5-vl1-ethanone To a refluxing solution of 2-f4.4-bis(trifluoromethyl)-2-(4» 5 fluorophenyl)-4,5-dihydro-l-methyl-lH-imidazol-5-ylidene]-1-(4-fluorophenyl)-1-ethanone (100 mg, 0.22 mmole) in acetic acid (15 ml) was added zinc dust (3.7 g, 56.6 mmole) over a period of 5 minutes. After 10 minutes, the mixture was filtered and washed with hot acetic acid. The filtrate was diluted with saturated 10 sodium bicarbonate solution (120 ml) and extracted with ether (4x50 ml). The combined organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate (anhyd.) and evaporated under vacuum to give the title compound (78 mg, 79%) as colorless needles, mp 145-146.6°C; NMR (CDCI3/TMS) 6 15 2.79(s,3H,CH3), 2.54-2.60(m,2H,CH2), 5.89-5.97(m, 1H,CH); 7.10-7.30(m,4H,Harom), 7.55-7.68(m,2H,Harom)» 8.02-8.09(m,2H,HarOm)• The compound of Example 120-120.2, and other compounds of formula (I) wherein X is CH2 which have been prepared or could be prepared using the same or similar synthetic 20 methods, are listed in Table 4. Table 4 r) ^ ' '}Cin u <j j u 10 15 20 25 30 35 59 Ex. # G G' R1 r6 R2 120 e-F H CH3 120.1 fi-F H CH2CH3 H jo- 0 120.2 fi-F H CH3 H 120.3 fi-F H ch3 CH3 120.4 fi-F H CH3 CH3 - 120.5 fi-0CH3 H CH3 CH3 120.6 fi-0CH3 H CH3 H 120.7 fi-0CH3 H CH3 H JOc" c-ry OCH, ;-Q-' o c-^^-ocha oh -c-Q-och, ch, oh -c-Q-och, ch, oh -c-Q-och, 120.8 fi-F H CH2CH=CH2 H 120.9 fi-0CH3 H CH3 120.10 fi-F H CH2CH3 H 120.11 fi-F H CH2CH3 H 120.12 fi-F H CH2CH3 H ch, o 11 s=\ -k> OH -k>' OH 120.13 fi-N H CH3 H -chQ-f OH n»p(°C) 145-146 NO ND ND (2S-isomer) ND (2R-isomer HCl salt) ND 151-152 (2S-isomer) ND (2R-isomer; HCl salt) ND 188.5 185-186 (S-isomer) 168-170 (R-isomer) ND ND % 23«3!)0 60 Example 121 Preparation of f4.4-bis(trifluoromethyl)-2-(4-methoxvphenv!)-4.5-dihvdro-lH-imidazol-5-vlidene!-carbamic acid-(4-methoxvphenv!)-ester 5 To a solution of a.a-bis(tri-f1uoromethy!)-4.5-bis(4- methoxyphenyl)-l-methyl-lH-imidazol-2-methanamine (0.40 g, 87 mmole) in chloroform (10 mL) was added portionwise, m-chloroperbenzoic acid (0.75 g, 4.30 mmole). The reaction mixture was refluxed under nitrogen for two hours. The solution was 10 cooled to room temperature and poured into saturated sodium bicarbonate (100 mL). The organic layer was washed successively with saturated sodium bicarbonate solution, 10% sodium sulfite solution, water, and saturated sodium chloride solution, dried over magnesium sulfate and evaporated under vacuum. The residue 15 was triturated with hexane to give the title compound (0.20 g, 40%) as a white solid: mp 141-142°; MS m/e 489 (M++H); NMR (CDCI3/TMS) 6 3.33(s,3H,NCH3), 3.83(s,3H,0CH3), 3.93(s,3H,0CH3), 6.85-7.20(m,6H,Harom), 7.67-7.73(m,2H,Harom); Anal. Calcd for C21H17N3°4F6: C.51.54; H,3.50; Found: C.50.92; H.3.68. 20 Example 122 Preparation of T4.4-bis(trifluoromethyl)-2-(4-methvlphenyl)-4.5-dihvdro-lH-imidazol-5-vlidene!-carbamic acid-(4-methvlphenvl)-ester 25 To a solution of a.a-bis(trifluoromethyl)-4.5-bis(4- methylphenyl)-l-methyl-lH-imidazol-2-methanamine (1.0 g, 2.3 mmole) in chloroform (10 mL) was added portionwise, m-chloroperbenzoic acid (1.20 g, 7 mmole). The reaction mixture was refluxed under nitrogen for two hours. The solution was 30 cooled to room temperature and poured into saturated sodium bicarbonate (100 mL). The organic layer was washed successively with saturated sodium bicarbonate solution, 10% sodium sulfite solution, water, and saturated sodium chloride solution, dried over magnesium sulfate and evaporated under vacuum. The residue 35 was triturated with petroleum ether to give the title compound o q ^ n lioouvlu 61 (0.15 g, 14%) as a solid: mp 161-163°; MS m/e 458 (M++H); NMR (CDC13/TMS) 5 2.43 (s,6H,CH3), 3.06(s,3H,NCH3), 7.23-7.40(m,4H,Haroni) i 7*50-7.63(m,2H,Ha^om)» 7.87—7.93(m,2H,• The compounds of Examples 120 and 121, and other compounds of Formula (I) wherein a is a double bond and Ar2 is C02Ar which could be prepared using the same or similar synthetic methods, are listed in Table 4. 10 15 Table 5 20 Ex. # 121 122 1 a»<2 d1 Ar1.Ar -0~°ch' ch3 -ch3 mp(°C) 141-142 161-163 25 30 35 Example 123 Preparation of 2-(4-fluorophenv1)-3.5-dihvdro-3-methvl-4.4-bis ftri f1uoromethvl)-4H-imi dazol-4-one A solution of N-[4,4-bis.(trif luoromethyl)-2-(4-fluorophenyl)-4,5-dihydro-l-methyl-lH-imidazol-5-yl idene]-4-f1uorophenylbenzamide (1.1 g, 2.3 mmole) in diethyl ether Wa^ eluted to the center of a basic alumina (III) column with ether; at room temperature. After two hours, the material was eluted*; from the column with ethyl acetate and the crude product was purified by column chromatography with hexane-ethyl acetate (10:1) to give the title compound in quantitative yield (0.80 g) as a white solid: mp 59-61°. MS m/e 329 (M++H). JH NMR cn ctj ex. LU CO v-r 1 n] q } ■ ! 'J 0 fi f) •v O O tj t f U 10 15 20 2 c 30 35 62 (CDC13/TMS) ^ 3.25(s.3HlNCH3), 7.25(m,2H,Harom), 7.80(m,2H,Hgrom)• Ex. # Ar1 Hi hip(°C) 123 -O CH3 59-61 Utility The compounds of the invention are effective antiatherosclerotic agents that act in a variety of ways. The compounds may be inhibitors of the enzyme acyl CoA:cholesterol acyl transferase (ACAT). Inhibition of ACAT has a variety of antiatherosclerotic effects, including inhibiting esterification and transport of cholesterol across the intestinal wall. In addition, by inhibiting cholesterol ester formation, the compounds may be useful in preventing the formation of cholesterol ester rich macrophages (foam cells) in the arterial wall. Foam cells are a source of the large quantity of cholesterol ester found in atheromatous lesions, as compared to the surrounding undiseased tissue. Other compounds of the invention may be inhibitors of cholesterol biosynthesis in th liver. Some compounds of the invention are both ACAT inhibitors' and inhibitors of cholesterol biosynthesis. A. Assay of the Inhibition of Acvl-CoA: Cholesterol Acvltransferase (ACAT) in j Hepatic Microsomes ; The ability of the compounds to inhibit ACAT, the enzyme 1 responsible for the intracellular synthesis of cholesteryl o '") m o o 63 esters, was tested as follows. Hale Sprague Dawley rats weighing 150-300 g were fed rat chow ad libitum. The animals were fasted for twenty-four hours prior to being sacrificed by decapitation. The livers were perfused jn situ with 50 ml of cold 0.25 M 5 sucrose, excised, and homogenized in three volumes of 0.1 M phosphate buffer, pH 7.4, that contained 0.5 mM EDTA (ethylenediaminetetraacetic acid), 1.0 mM. glutathione, 0.25 M sucrose and 20 mM leupeptin. Microsomes were obtained by differential centrifugation; the supernatant from an initial spin 10 at 15,000 x g for 15 minutes was centrifuged at 105,000 x g for 1 hour to pellet the microsomes. The microsomes were suspended in homogenization buffer, reisolated by centrifugation, and stored at -709C. Microsomes were used within one month of preparation. The control assay in a final volume of 200 /»1 consisted of 15 200 /jg of microsomal protein, 75 /»M ^C-oleoyl-CoA (10,000 dpm/nmol) in 0.1 M phosphate, pH 7.4, that contained 1 mM glutathione. Compounds were added in 5-10 /il of DMSO (dimethyl sulfoxide or ethanol) and additional controls were run with DMSO or ethanol only. All components, except the oleoyl-CoA, were 20 preincubated for 15 min. at 37°C prior to the initiation of the reaction by the addition of oleoyl CoA. The assay was terminated after 10 min by the addition of 4 ml of chloroform:methanol (2:1, v/v). 20,000 dpm of ^H-cholesteryl oleate and 10 /ig of unlabeled cholesteryl oleate and oleic acid were added as an internal 25 standard and carrier, respectively. After allowing 10 min. for lipid extraction, 0.8 ml of deionized water was added to separate the solution into two phases. The lower chloroform phase was collected, dried under nitrogen and resuspended in 100 pi of p~ chloroform. The sample containing the neutral lipids was spottjecL 30 onto a Gelman ITLC-SA polysilicic acid gel-impregnated sheet, which was developed using a hexane: diethyl ether: acetic acid (170:30:1 v/v/v) mobile phase. The lipids were visualized by their interaction with iodine vapor and the cholesteryl ester j ^ spot was scraped into a scintillation vial and counted. The 35 specific activity of ACAT in the control incubation averaged 2 ! crt l ' I ! '-J | UJ | co £ o o f . ') (• u u o v I u 64 pmol/min/mg microsomal protein. The inhibition of ACAT activity by the compounds is shown in Table 7; the data are expressed as the concentration at which ACAT activity is inhibited by 50% (IC50)• 5 B. Assay of the Inhibition of Cholesterol Esterification in Mammalian Cells The esterification of cholesterol was determined in the murine macrophage-like cell line J774.A1. Cells were seeded in 35 mm wells at a density of 300,000 cells per well in 2 mis of 10 Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum (FBS). Cells were incubated at 37°C in an atmosphere of 5% CO2 and 93% humidity. After 24 hours the media was changed to 0.68 mis 10% FBS-DMEM containing 34 pg of acetylated human low density lipoprotein (ac-LDL) to increase the 15 intracellular concentration of cholesterol and promote esterification. At 41 hours, various inhibitors were added to the cells in DMSO (10 /*1/ml maximum). At 43 hours, the cells were pulsed with 0.1 mM 14C oleic acid (10,000 dpm/nmol) complexed with BSA (bovine serum albumin) to follow cholesterol 20 ester formation. The experiment was terminated at 45 hours by washing the monolayers 3 times with 3 ml of Tris-buffered saline at 4°C. The lipids were extracted by incubating the monolayers with 1.5 ml of hexane: isopropanol (3:2, v/v) for 30 min. under gentle agitation. During this period, 10,000 dpm ^H-cholesteryl 25 linoleate and 10 fig of cholesteryl oleate were added as an internal standard and carrier respectively. The organic solvent was removed and the cells were washed with an additional 1.0 of hexane: isopropanol which was combined with the original extract. The cells were allowed to dry overnight, digested with 30 1.5 ml of 0.2 N sodium hydroxide for 1 hour and an aliquot of the solubi1ized protein used for protein determination using the Lowry method. The organic extract was taken to dryness, the residue resuspended in 100 ft1 of chloroform and the lipids separated on silica gel impregnated glass fiber plates using a 35 hexane: diethylether: acetic acid (170:30:1, v/v/v) solvent ( n o f ) <'> »c o o 65 system. Individual lipids were visualized with iodine and the cholesteryl ester spot cut out and transferred to scintillation vials to determine the amount of radioactivity. The conversion of oleic acid to cholesteryl ester in the control averaged 0.54 5 mmol/hr/mg protein and was increased upon the addition of ac-LDL to about 10.69 ± 0.69 mmol/hr/mg protein. The inhibition of esterification by the compounds is shown in Table 8; the data are expressed as the concentration at which ACAT activity is inhibited by 50% (ic50). 15 20 25 t 66 Table 7 Inhibition of In Vitro Hepatic ACAT Activity Bv Various Compounds Compound In Vitro ACAT IC50 of Example 2 5 10 10A 11 12 13 14 15 16 17 18 25 26 27 28 29 30 34 31 32 33 96B 121 20 pH 20 pM 41 pM 22 pM 2 pm 6 pm 4 pM 8 /|m 17 /iM 2 ph 6 pm 4 41 45 pM 3 pH 22 16 6 9 10 pH 2 /iM 10 /<M 19 pM 64 /»M 122 49 pM 123 >100 pm Q 1.91 jiM r 2.0 pm no o'lqn o ti *-j *' u 67 Table 8 Inhibition of Cholesterol Esterification in Macrophage bv Various Compounds 10 15 20 25 30 Cholesterol of Example 2 5 10A 11 13 14 15 16 25 26 27 31 32 33 R Q Compound Esterification :> 100 /iM 62 pM 105 /<M 14 pM 18 pM 18 p M 11 /<M 17 pM 98 fM 96 pM 16 /jm 13 pV\ 17 pH 13 pH 13 34 /*M (IC50) 35 Dosage Forms: The compounds of the present invention can be administered using a variety of pharmaceutically acceptable dosage forms known in the art. The active ingredient will normally be administered orally and can be supplied in solid dosage forms such as dry powders, granules, tablets, capsules, or bars, or in liquid dosage forms, such as syrups or aqueous suspensions. The active ingredient can be administered alone, but is generally administered with a pharmaceutical carrier. These compounds may be administered in combination with other active ingredients. In their therapeutic use as antihypercholesterolemic and/or antiatherosclerotic agents, the compounds of the invention are day. For a normal male adult human of approximately 70 kg of body weight, this translates into a dosage of 1 to 100 mg per kilogram body weight per day. The dosage administered will, c course, vary depending upon known factors such as the age, lil C } v— u. CT n ro CP ■r—•» 5K UJ cu UJ CO 5 0 < L'.J rr N 1 au. l 68 23831)0 health, and weight of the recipient nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired. The various classes of pharmaceutical preparations are 5 discussed in Remington's Pharmaceutical Sciences, a standard reference text in this field. See also, the USP/NF for solvents and other pharmaceutical necessities suitable for use in pharmaceutical dosage forms. The teaching of these references is hereby incorporated by reference. Useful pharmaceutical dosage 10 forms for administration of the compounds of this invention can be illustrated as follows: Tablets Tablets are prepared by conventional procedures so that the 15 dosage unit is 500 milligrams of active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose and 10 milligrams of magnesium stearate. Capsules Capsules are prepared by conventional procedures so that the 20 dosage unit is 500 milligrams of active ingredient, 100 milligrams of cellulose and 10 milligrams of magnesium stearate. Svrup Active Ingredient Liquid Sugar Sorbitol Glycerine 30 Flavor, Colorant and Preservative Water 35 Wt. % 10 50 20 5 as required as required 69 238300 The final volume is brought up to 100% by the addition of distilled water. Aoueous Suspension 10 15 20 25 30 Active Ingredient Sodium Saccharin Keltrol® (Food Grade Xanthan Gum) Liquid Sugar Flavor, Colorant and Preservative Water Wt. % 10 0.01 0.2 5 as required as required Xanthan gum is slowly added into distilled water before adding the active ingredient and the rest of the formulation ingredients. The final suspension is passed through a homogenizer to assure the elegance of the final products. Resuspendible Powder Active Ingredient Lactose Sugar Acacia Sodium Carboxylmethylcellulose Each ingredient is finely pulverized and then uniformly mixed together. Alternatively, the powder can be prepared as a suspension and then spray dried. Wt. % 50.0 35.0 10.0 J 1 ° 1$ / /- cn cn / P. 4.7 / 1 I 1 < 1 a. 4 SEP / UJ v UJ 1 1 0.3 I I —1 i | u. J 35 238300 Active Ingredient 10 5 Sodium Saccharin 0.02 Gelatin 2 Colorant, Flavor and as required Preservative n Water as required Gelatin is prepared in hot water. The finely pulverized active ingredient is suspended in the gelatin solution and then the rest of the ingredients are mixed in. The suspension is filled into a suitable packaging container and cooled down to form the gel. 70 Semi-Sol id Gel Wt. % Semi-Solid Paste 20 25 30 Active Ingredient Gelcarin® (Carrageenin gum) Sodium Saccharin Colorant, Flavor and Preservative Water Wt. % 10 1 0.01 as required as required Gelcarin® is dissolved in hot water (around 80*C) and then the fine-powder active ingredient is suspended in this solution, ' J I. V'. ■ ) \ ,! l rx u' t V 35 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 9 (? ') (\ ^ (.uouju Sodium saccharin and the rest of the formulation ingredients are added to the suspension while it is still warm. The suspension is homogenized and then filled into suitable containers. 5 Emulsifiable Paste Wt. % Active Ingredient 30 Tween® 80 and Span® 80 6 10 Keltrol® 0.5 Mineral Oil 63.5 All the ingredients are carefully mixed together to make a homogenous paste. 15 The term "consisting essentially of" in the present disclosure is intended to have its customary meaning; namely, that all specified materials and conditions are very important in practicing the invention but that unspecified materials and conditions are not excluded so long as they do not prevent the 20 benefits of the invention from being realized. 35 238390 WHAT X/Wfc ULAlM l.Si 72 WHAJ 15 CLAIM1ID.4-S-:

1. A compound of the formula: CFj CF, b\\ / ~ Z N Ar'' R1 wherein Ar* is phenyl, or mono-, di-, or tri-substituted phenyl, optionally substituted with -F, -CI, -Br, -I, -CF3, -C0NH2, -NO2, -CH0, -C02Et, -CN, -O2CR9, -SCH3, -SCF3, -S02CF3, -SO2CH3, 5-tetrazolyl, -N(0)(CH3)2, OH, C1-C7 alkoxy, N-piperidyl, Ci-Cjo alkyl, C3-C7 cycloalkyl, or C3-C10 substituted cycloalkyl, or Ar* may be C1-C10 alkyl, C3-C7 cycloalkyl, or C4-C7 substituted cycloalkyl substituted as above, where R9 is H or alkyl, alkenyl, or alkynyl of 1 to 20 carbon atoms; Q is 0 or X-R2 wherein X is bonded to W, provided that when Q is 0, a is a double bond; X is H, NR6, CH, CHR6, or S and R6 is H, or Cj-C3 alkyl, alkenyl, or alkynyl; W is C or CH provided that when a is a single bond, X is NR6, S, or CHR6 and W is CH, and when a is a double 2 bond, W is C, and Q is 0 or XR and X is N or CH; Y is N or NR7, and R^ is H or Ci-C3 alkyl; Z is C or CH, provided that when b is a single bond, Y is NR^ and Z is CH, and when b is a double bond, Y is N and Z is C; and, a and b are, independently, single or double bonds; R1 is H or C1-C3 alkyl, alkenyl, or alkynyl; R2 is C4 to C15 alkyl, C4 to. C15 alkynyl, or C4 to C15 alkenyl, which may be straight or branched _ - "-r,ce 2 3 dec 1993 n_'w_i v l.0 1 23 8 390 (optionally with a terminal COOH or OH group) or 2 3 3 cyclic; or R is COR where R is C^ to alkyl; C2 to C^g alkynyl, or C2 to C^ alkenyl, which may be straight or branched (optionally with a 2 2 terminal COOH or OH group) or cyclic; R is COAr , CH2Ar2, C02Ar2, C0NR8Ar2, where R8 is H or C1~C3 alkyl, S02Ar2, S02NHAr2 or S02R3? 2 . Ar is N-morpholy1; 2- or 3-thienyl; 2- or 3-pyrrolyl; 3-furyl; or is ethyl, ethenyl, ethynyl, a carboaromatic moiety of up to 11 ring atoms or a saturated or unsaturated, straight, branched or nonaromatic cyclic C3~C11 moiety, which may be substituted with 0-3 F, CI, Br, I, CF-,, p-N09, CN, CHO, 4 5 C.-C-alkyl, C,-C..alkoxy, phenyl, or NR R , 4 5 where R and R are independently H, alkyl or R^ and R^ may be C3-C5 alkyl taken together to form a ring with N; 2 2 1 provided that: when X is CH or CH0 and R is COAr , Ar 2 and Ar are independently, phenyl or substituted phenyl and when X is CH2, R2 is COAr2, CH2Ar2 or C02Ar2; or a resolved optical antipode of any chiral form thereof; of a pharmaceutically acceptable salt thereof.

2. A compound of Claim 1 wherein Ar1 is phenyl, or mono-, di-, or tri-substituted phenyl, optionally substituted with -F,'-C1, -Br, -I, -CN, -CF3, -C0NH2, -OH, -NO2, 5-tetrazolyl, C1-C7 alkoxy, N-piperidyl, -02CR9, where R9 is C1-C20 alkyl, alkenyl, or alkynyl, C1-C10 alkyl, C3-C7 cycloalkyl, or C3-C10 substituted cycloalkyl, or Ar* is cyclohexyl; Q is 0 or X-R2 wherein X is bonded to W, provided that when Q is 0, a is a double bond; 23 839Q 74 X is N, NR6, CH, CHR6, or S and R6 is H, or Cj-C^ alkyl, alkenyl, or alkynyl; W is C or CH provided that when a is a single bond, X is NR , S, or CHR and W is CH, and when a is a double bond, W is C, and Q is XR2 and X is N or CH; Y is N or NR7, and R7 is H or CH3; Z is C or CH, provided that when b is a single bond, Y is NR7 and Z is CH, and when b is a double bond, Y is N and Z is C; and a and b are, independently, single or double bonds; R* is H or C1-C3 alkyl, alkenyl, or alkynyl; R2 is COAr2, CH2Ar2, CC^Ar2, or CONR^Ar2, wherein R® is H or Cj-C3 alkyl; and Ar2 is N-morpholyl; 2- or 3-thienyl; 2- or 3-pyrrolyl; 3-furyl; or is ethyl, ethenyl, ethynyl, a carboaromatic moiety of up to 11 ring atoms or a saturated or unsaturated, straight, branched or nonaromatic cyclic moie-tyf which may be substituted with 0-3 F, CI, Br, I, CF,, p-N0o, CN, CHO, N,, 4 5 C1-C7alkyl, C^C^lkoxy, phenyl, or NR R , where R4 and R5 are independently H, Cj-C3 alkyl or R4 and R5 may be C3~C5 alkyl taken together to form a ring with N.

3. A compound of Claim 1 wherein: Ar* is phenyl, or monosubstituted phenyl, substituted with -F, -CI, -Br, -CN, -CF3, -OH, C1-C7 alkoxy, NO2-, -CONH2, N-piperidyl, CH3, or -O2CR9 where R9 is C1-C20 alkyl, alkenyl, or alkynyl, or Ar* is cyclohexyl; Q is X-R2 wherein X is bonded to W; _ . , f -'' ICE 2 3 dec 1993 ■ 75 23 8 3 9 0 X is Nr6 or CH2. and R is H, or C1-C3 alkyl, alkenyl, or alkynyl; W is CH; Y is N; Z is C; R1 is H, CH3, or C2H5; and R2 is COAr2 or C0NR®Ar2, wherein R® is H or C1-C3 alkyl; and 9 Ar is N-morpholyl; 2- or 3-thienyl; 2- or 3-pyrrolyl; 3-furyl; or is ethyl, ethenyl, ethynyl, a carboaromatic moiety of up to 11 ring atoms or a saturated or unsaturated, straight, branched or nonaromatic cyclic C^-C^ moiety, which may be substituted with 0-3 F, CI, Br, I, CF3, p-N02, CN, CHO, N3, C-.-C-alkyl, C1-C_alkoxy, phenyl, or NR^R5, 4 5 where R and R are independently H, C^-C3 alkyl or R4 and R^ may be C3~Cg alkyl taken together to form a ring with N.

4. A compound of Claim 1 wherein Ar* is phenyl, or monosubstituted phenyl, ^-substituted with -F, -CI, -Br, -CN, -OH, -OCH3, N-piperidyl, -CONH2 or 02CR^, where R9 is Ci^o^ alkyl, alkenyl, or alkynyl; Q is X-R2 wherein X is bonded to W; X is NR® or CH2, and R® is H or C1-C3 alkyl, alkenyl, or alkynyl; 2 « , 1 H is CH; \ UJANWK // y is n= Z is C; R1 is CH3; R2 is COAr2 or CONR^Ar2, wherein R® is H or c1-c3 alkyl; and 9 Ar is N-morpholyl; 2- or 3-thienyl; 2- or 3-pyrrolyl; 3-furyl; or is ethyl, ethenyl, ethynyl, a carboaromatic moiety of up to 11 ring atoms or a saturated or unsaturated, straight, branched or nonaromatic cyclic c3~cn moiety, which may be substituted with 0-3 F, CI, Br, I, CF,, p-N0o, CN, CHO, N,, 4 5 C.-C-alkyl, C.-C_alkoxy, phenyl, or NR R , 4 5 where R and R are independently H, C,-C, 4 5 alkyl or R and R may be Cg-Cg alkyl taken together to form a ring with N.

5. The compound of Claim 1 which is N-[4,4-bis(trifluoromethyl) -2- (4-fluorophenyl)-4,5-dihydro-l-methyl-lH-imidazol-5- I"*"*—wit * -J 76 O '"> 0 ') oou yl]-4-butoxy-N-methylbenzamide, or a pharmaceutical^ acceptable salt thereof.

6. The compound of Claim 1 which is N-[4,4-bis(trifluoromethyl )-2-(4-f1uorophenyl)-4,5-di hydro-l-methyl-lH-imi dazol -5-yl]-4-(l,l-dimethylethyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

7. The compound of Claim 1 which is. N-[4,4-bis(trifluoromethyl ) -2-(4-f1uorophenyl)-4,5-di hydro-l-methyl-lH-imi dazol -5-yl]-N-methyl-4-nitrobenzamide, or a pharmaceutically acceptable salt thereof.

8. The compound of Claim 1 which is N-[4,4-bis(trifluoromethyl ) -2- (4-f 1 uorophenyl)-4,5-di hydro-l-methyl-lH-imi dazol-5- y 1 ]-4-(1-piperidinyl) benzamide, or a pharmaceutically acceptable salt thereof.

9. The compound of Claim 1 which is N-[4,4-bis(trifluoromethyl ) -2-(4-f1uorophenyl)-4,5-di hydro-l-methyl-lH-imidazol-5-yl]-4-fluorophenyl-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

10. The compound of Claim 1 which is N-T4.4-bis(trifluoromethyl ) -4, 5-di hydro-l-methyl -2- [4- (1-pi peri di nyl) phenyl] -1H-imidazol-5-y1]-4-fluorobenzamide, or a pharmaceutically acceptable salt thereof.

11. The compound of Claim 1 which is N-T4.4-bis(trifluoro-methyl)-2-(4-f1uorophenyl)-4,5-di hydro-l-methyl-lH-imi dazol -5-yl]-N-methylheptanamide, or a pharmaceutically acceptable salt thereof.

12. The compound of Claim 1 which is N-[4,4-bji(trifluoromethyl )-2-(4-f1uorophenyl)-4,5-di hydro-l-methyl-lH-imi dazol-5-yl]-4-ethoxybenzamide, or a pharmaceutically acceptable salt thereof.

13. The compound of Claim 1 which is N-T4.4-bis(trifluoro-methyl)-2-(4-fluorophenyl)-4,5-di hydro-l-methyl-lH-imidazol-5-yl]-4-methoxy-N-methylbenzamide, or a pharmaceutically acceptabl salt thereof. 23831)0 77 10 15 20 25 30

14. The compound of Claim 1 which is N-[4,4-bis(trifluoromethyl ) -2- (4-f luorophenyl ) -4, 5-di hydro-l-methyl -lH-imi dazol -5-yl]-N-methyl-[l,r-biphenyl]-4-carboxamide, or a pharmaceutically acceptable salt thereof.

15. The compound of Claim 1 which is N-[4,4-bis(trifluoro-methyl)-2-(4-fluorophenyl)-4,5-dihydro-l-methyl-lH-imidazol-5-yl]-N'-2,4-difluorophenyl-N-methylurea, or a pharmaceutically acceptable salt thereof.

16. The compound of Claim 1 which is N-[4,4-Ms(trifluoromethyl )-4,5-d i hyd ro-1-methy 1-2-[4-(1-p i peri d i ny1)phenyl]-1H-imidazol-5-yl]-N-methylheptanamide, or a pharmaceutically acceptable salt thereof.

17. The compound of Claim 1 which is N-[4,4-bij>(trifluoromethyl) -2-(4-methoxyphenyl)-4,5-dihydro-l-methyl-lH-imi dazol-5-yl]-N,5-dimethylhexanamide, or a pharmaceutically acceptable salt thereof.

18. The compound of Claim 1 which is N-[4-4-bis(trifluoro-methyl)-2-(4-fluorophenyl)-4,5-dihydro-1-methyl-lH-imidazol-5-yl]-N'-4-isopropylphenyl-N-methylurea, or a pharmaceutically acceptable salt thereof.

19. The compound of Claim 1 which is N-[4,4-bis(trifluoromethyl )-2-(4-f1uorophenyl)-4,5-di hydro-l-methyl-lH-imidazol-5-yl]-N,5-dimethyl-hexanamide, or a pharmaceutically acceptable salt thereof.

20. The compound of Claim 1 which is N-[4,4-bis(trifluoromethyl ) -2-(4-f1uorophenyl)-4,5-di hydro-l-methyl-lH-imidazol-5-yl]-N'-octyl-N-methylurea, or a pharmaceutically acceptable salt thereof.

21. The compound of Claim 1 which is 1-(4-cyanopheny1)-2-[2-(4-f1uorophenyl)-4,5-di hydro-l-methyl-4.4-bis(trifluoromethy!)-lH-imidazol-5-vllethanone. or a pharmaceutically acceptable salt thereof. 35 cn cn Ol. LU CO vr i # 288390 78

22. The compound of Claim 1 which is'9-octadecenoic acid, [4-[4,5-di hydro-l-methyl -5-[methyl (1-oxoheptyl)ami no]-4.4-bis(trifluoromethyl)-lH-imidazol-2-vllphenyllester. or a pharmaceutically acceptable salt thereof. 5

23. The compound of Claim 1 which is benzamide, N- [2-(4-cyanopheny1)-4,5-dihydro-l-methyl-4,4-bis (trifluoromethy!)-lH-imidazol-5-vl1-4-cvano-N-methv1. or a pharmaceutically acceptable salt thereof.

24. The compound of Claim 1 which is benzamide, N-10 [2-(4-cyanopheny1)-4,5-dihydro-l-methyl-4,4-bi s(tri fluoro methyl)-lH-imidazol-5-yl]-4-cyano-N-methyl. R-isomer, or a pharmaceutically acceptable salt thereof.

25. The compound of Claim 1 which is phenol, 4-[4,5-dihydro-l-methyl-5-[methyl(l-oxoheptyl)amino]-4,4- 15 bis(trif1uoromethy!)-lH-imidazol-2-vll-. acetate (ester), or a pharmaceutically acceptable salt thereof.

26. The compound of Claim 1 which is benzamide, N-[2-(4-fluorophenyl)-4,5-dihydro-l-methyl-4,4- bis(trifluoromethyl)-lH-imidazol-5-yl]-4-cyano-N-methyl, or a 20 pharmaceutically acceptable salt thereof.

27. The compound of Claim 1 which is benzamide, N-[2-(4-cyanophenyl)-4,5-di hydro-l-methyl-4,4-bis(trifluoromethyl)-lH-imidazol-5-yl]-4-fluoro-N-methyl, or a pharmaceutically acceptable salt thereof. 25

28. The compound of Claim 1 which is benzamide, N-[2-(4- fluorophenyl)-4,5-dihydro-l-methyl-4.4-bis(trif1uoromethyl)-1H-imidazol-5-yl]-2,3,4,5,6-pentafluoro-N-methyl, or a pharmaceutically acceptable salt thereof.

29. The compound of Claim 1 which is l-(4-fluorophenyl)j 30 [2-(4-fluorophenyl)-4,5-dihydro-l-methyl)-4,4- bis(trifluoromethyl)-IH-imidazol-5-yll-ethanone. or a pharmaceutically acceptable salt thereof. 35 79

30. The compound of Claim 1 which is 1-(4-f luorophenyl)-2-[2-(4-fluorophenyl)-4,5-dihydro-1-ethyl)-4,4-lm(trifluoromethy1)-lH-imidazol-5-yl]-ethanone, or a pharmaceutically acceptable salt thereof.

31. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of a compound of Claim 1 and a pharmaceutically acceptable carrier.

32. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of a compound of Claim 2 and a pharmaceutically acceptable carrier.

33. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of a compound of Claim 3 and a pharmaceutically acceptable carrier.

34. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of a compound of Claim 4 and a pharmaceutically acceptable carrier.

35. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 5 and a pharmaceutically acceptable carrier.

36. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 6 and a pharmaceutically acceptable carrier.

37. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 7 and a pharmaceutically acceptable carrier.

38. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 8 and a pharmaceutically acceptable carrier.

39. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound bfj Claim 9 and a pharmaceutically acceptable carrier. / £

40. A pharmaceutical composition comprising an effective/£ ACAT inhibiting or antiatherosclerotic amount of the compound ^f j C. Claim 10 and a pharmaceutically acceptable carrier. |n/ 9 '")(>') r ■;. ^ OO oj (; 10 15 20 25 30 35 80

41. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 11 and a pharmaceutically acceptable carrier.

42. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 12 and a pharmaceutically acceptable carrier.

43. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 13 and a pharmaceutically acceptable carrier.

44. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 14 and a pharmaceutically acceptable carrier.

45. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 15 and a pharmaceutically acceptable carrier.

46. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 16 and a pharmaceutically acceptable carrier.

47. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 17 and a pharmaceutically acceptable carrier.

48. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 18 and a pharmaceutically acceptable carrier.

49. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 19 and a pharmaceutically acceptable carrier.

50. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 20 and a pharmaceutically acceptable carrier.

51. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound Claim 21 and a pharmaceutically acceptable carrier. /. ^ u / 0 81

52. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 22 and a pharmaceutically acceptable carrier.

53. A pharmaceutical composition comprising an effective 5 ACAT inhibiting or antiatherosclerotic'amount of the compound of Claim 23 and a pharmaceutically acceptable carrier.

54. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 24 and a pharmaceutically acceptable carrier. 10

55. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 25 and a pharmaceutically acceptable carrier.

56. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of 15 Claim 26 and a pharmaceutically acceptable carrier.

57. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 27 and a pharmaceutically acceptable carrier.

58. A pharmaceutical composition comprising an effective 20 ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 28 and a pharmaceutically acceptable carrier.

59. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 29 and a pharmaceutically acceptable carrier. 25

60. A method of treating hypercholesterolemia or /non-human atherosclerosis in s mammal comprising administering to the non-human mammal an effective ACAT inhibiting or antiatherosclerotic amount of a compound of Claim 1.

61. A method of treating hypercholesterolemia or athero- jion-human Jion-hurnan 30 sclerosis in a'mammal comprising administering to the/mammal an effective ACAT inhibiting or antiatherosclerotic amount of a compound of Claim 2. 35 * * CV /290ct1992"' «P p 1 ' j58590 82

62. A method of treating hypercholesterolemia or athero- /non-hpman . . , /ion-human sclerosis in a/mammal comprising administering to the/mammal an effective ACAT inhibiting or antiatherosclerotic amount of a compound of Claim 3. 5

63. A method of treating hypercholesterolemia or athero- ynon-hpiian . . , . . , . . /non-human sclerosis in a/mammal comprising administering to the/mammaT an effective ACAT inhibiting or antiatherosclerotic amount of a compound of Claim 4.

64. A method of treating hypercholesterolemia or athero- . Jion-hmian . . , . . A . . .. >non-hurian 10 sclerosis in a/mammal comprising administering to the/mammal an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 5.

65. A method of treating hypercholesterolemia or athero- , . . /ion-human . . ...... ^ /ion-human sclerosis in a/mammal comprising administering to the/mammal an 15 effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 6.

66. A method of treating hypercholesterolemia or athero- , . . non-human . . » t . . , .. /ion-human sclerosis in a/mammal comprising administering to the/mammal an effective ACAT inhibiting or antiatherosclerotic amount of the 20 compound of Claim 7.

67. A method of treating hypercholesterolemia or athero- non-hnman . . ...... , /ion-human sclerosis in a/mammai comprising administering to the/mammaT an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 8. 25

68. A method of treating hypercholesterolemia or athero- Jion-hpnan . , ... . , /ion-human sclerosis in a/mammal comprising administering to the/mammaT an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 9.

69. A method of treating hypercholesterolemia or athero-... .non-human . . , . . A .non-human 30 sclerosis in a/mammal comprising administering to the/mammaT an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 10. 35 ^ £N ^ v «<v (*2 9 oct 1992 " ^ <C\ + 5 10 15 20 25 \ 30 35 238590 83

70. A method of treating hypercholesterolemia or athero- /lon-human . . ... . ,. non-human sclerosis in a/mammaT comprising administering to the/mammal an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 11.

71. A method of treating hypercholesterolemia or athero- Jion-human ., , . . . • . ... /non-human sclerosis in a/mammal comprising administering to the/mammal an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 12.

72. A method of treating hypercholesterolemia or athero- . . ^on-human . . . . iion-human sclerosis in a/mammal comprising administering to the/mammal an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 13.

73. A method of treating hypercholesterolemia or atherosclerosis in a/fMmmat^^mprising administering to the/mammaT^ effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 14.

74. A method of treating hypercholesterolemia or athero- . . /non-human . . . . .. xion-human sclerosis in a/mammal comprising administering to the/mammal an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 15.

75. A method of treating hypercholesterolemia or athero- . . /ion-human . . .... . . Jion-human sclerosis in a/mammal comprising administering to the/mammaT an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 16.

76. A method of treating hypercholesterolemia or athero- . . /non-human . . . . -non-human sclerosis in a/mammal comprising administering to the/mammaT an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 17.

77. A method of treating hypercholesterolemia or athero- . . /non-human . . . . ... ,hon-human sclerosis in a/mammal comprising administering to the/mammaT an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 18. O * JC - c 2 9 OCT 1992 ■238390 84

78. A method of treating hypercholesterolemia or atherosclerosis in a/mammaT^mprising administering to the/mammaYman effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 19. 5

79. A method of treating hypercholesterolemia or athero- /lon-human .1 . ..." . , -non-human sclerosis in a/mammal comprising administering to the/mammaT an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 20.

80. A method of treating hypercholesterolemia or athero- , . /ion-human . . .... . . . Jion-human 10 sclerosis in a/mammai comprising administering to the/mammaT an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 21.

81. A method of treating hypercholesterolemia or athero- non-hixtian . . ... . -non-human sclerosis in a/mammal comprising administering to the/mammaT an 15 effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 22.

82. A method of treating hypercholesterolemia or athero- /lon-human . . ... . . non-human sclerosis in a/mammaT comprising administering to the/mammaT an effective ACAT inhibiting or antiatherosclerotic amount of the 20 compound of Claim 23.

83. A method of treating hypercholesterolemia or athero- jion-human . . ... . , /non-human sclerosis in a/mammai comprising administering to the/mammaT an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 24. 25

84. A method of treating hypercholesterolemia or athero- /non-human . . ... . , /ion-human sclerosis in a/mammal comprising administering to the/mammaT an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 25.

85. A method of treating hypercholesterolemia or athero- ... -non-human . . ... . . -non-human 30 sclerosis in a/mammal comprising administering to the/mammaT an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 26.

86. A method of treating hypercholesterolemia or athero- -non-human . , . . . -non-human sclerosis in a/mammal comprising administering to the/mammaT an v Pi "" 35 effective ACAT inhibiting or antiatherosclerotic amount of the ' o^ compound of Claim 27. , "V\ : o\\ *2 9 OCT 1992 "7 / * (J t> o o 85

87. A method of treating hypercholesterolemia or athero- /non-human . . , . . . , non-human sclerosis in a/mammal comprising administering to the/mammal an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 28.

88. A method of treating hypercholesterolemia or athero- . . /non-human . . , . ' . ^ _ /ion-human sclerosis in a/mammai comprising administering to the/mammaT an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 29.

89. A process for preparing a compound of Formula (I): optionally substituted with -F, -CI, -Br, -I, -CF3, -C0NH2, -NO2, -CHO, -C02Et, -CN, -O2CR9, -SCH3, -SCF3, -so2cf3, -so2ch3, 5-tetrazolyl, -N(0) (0*3)2, OH, C1-c7 alkoxy, N-piperidyl, C1-C10 alkyl, c3-c7 cycloalkyl, or C3-C10 substituted cycloalkyl, or Ar* may be Cj-Cio alkyl, c3-c7 cycloalkyl, or c4.-c7 substituted cycloalkyl substituted as above, where R9 is H or alkyl, alkenyl, or alkynyl of 1 to 20 carbon atoms; Q is 0 or X-R2 wherein X is bonded to W, provided that when Q is 0, a is a double bond; X is N, NR6, CH, CHR6, or S and R6 is H, or alkyl, alkenyl, or alkynyl; W is C or CH provided that when a is a single bond, X is NR6, S, or CHR6 and W is CH, and when a is a double 2 bond, W is C, and Q is 0 or XR and X is N or CH; Y is N or NR7, and R7 is H or C1-C3 alkyl; (I) wherein Ar* is phenyl, or mono-, di-, or tri-substituted phenyl, 'v v 23 86 Z is C or CH, provided that when b is a single bond, Y is NR7 and Z is CH, and when b is a double bond, Y is N and Z is C; and, a and b are, independently, single or double bonds; 5 R* is H or C1-C3 alkyl, alkenyl, or alkynyl; R2 is C4 to C15 alkyl, C4 to C15 alkynyl, or C4 to C15 alkenyl, which may be straight or branched (optionally with a terminal COOH or OH group) or 2 3 3 cyclic; or R is COR where R is C^ to C^ alkyl; 10 C2 to C^j. alkynyl, or to C^ alkenyl, which may be straight or branched (optionally with a 2 . 2 terminal COOH or OH group) or cyclic; R is COAr , CH2Ar2, C02Ar2, CONR8Ar2, where R8 is H or alkyl, S02Ar2, S02NHAr2 or S02R3; 15 9 Ar is N-morpholyl; 2- or 3-thienyl; 2- or 3-pyrrolyl; 3-furyl; or is ethyl, ethenyl, ethynyl, a carboaromatic moiety of up to 11 ring atoms or a saturated or unsaturated, straight, branched or 20 nonaromatic cyclic C^-C^ moiety, which may be substituted with 0-3 F, CI, Br, I, CF3, p-N02, CN, CHO, N3, C^-C^alkyl, C^-C^alkoxy, phenyl, or NR^R^, where R4 and R^ are independently H, C^-C3 25 alkyl or R4 and R^ may be C3~C5 alkyl taken together to form a ring with N; 2 . 2 1 provided that: when X is CH or CH9 and R is COAr , Ar 2 and Ar are independently, phenyl or substituted phenyl 2 . 2 2 2 and when X is CH2, R is COAr , CH2Ar or C02Ar ; or 30 a resolved optical antipode of any chiral form thereof; of a pharmaceutically acceptable salt thereof; comprising the steps of: # 2383HO 87 a) reacting in an inert solvent an imidazole of the formula C(CF3)2NH2 10 where Ar*, Ar2 and R* are defined above, with an organic peracid, such as m-chloroperoxybenzoic acid; or 15 20 b) reacting in an organic acid an imidazole of the formula c(cf3)2nh2 25 where Ar*, Ar2 and R* are defined above, with monoperoxyphthalic acid magnesium salt to yield a compound of Formula (I) above; 30 c) reacting in an inert solvent a pyrrole of the formula H Af2 i XV 35 cfcfaknhj where Ar*, Ar2 and R* are as defined above, witH an ? "-ja organic peracid, such as m-chloroperoxybenzoic acid or 88 oxidizing with singlet oxygen followed by acid treatment, to yield a compound of Formula (I) above where 0 is X-R2 and X is CH; d) and, optionally, reacting the product of a) or b) with a reducing agent such as lithium aluminum hydride in an inert solvent with sodium borohydride in a protic organic solvent to yield a compound of the Formula (I) where Y, 1, Ar*, R*, W, Q and b are as defined above and where a_ is a single bond; e) and, optionally, reacting the product of d) with (1) sodium hydride in dimethylformamide and iodomethane followed by, (2) potassium tert-butoxide in an inert solvent followed by, (3) reaction of the resultant amine with an acylating reagent, such as a benzoyl chloride, Jn the presence of an organic base to yield a compound of Formula (I) where Y, Z, Ar*, R*, W, Q and b are as defined above and where i is a single bond; f) and optionally, reducing the product of c) where X is CH with an appropriate reducing agent, preferably zinc dust in acetic acid, to yield a compound of Formula (I) where X is CH2.

90. A crystalline form of the compound of Claim 23 which has melting point of 131-134*C.

91. A crystalline form of the compound of Claim 23 which has melting point of 181-183#C. THE DU PONT MERCK PHARMACEUTICAL COMPANY By their attorneys BALDWIN, SON & CAREY !in7 if c if liJ- r- • > </div>