U.S. patent number 7,579,469 [Application Number 10/739,208] was granted by the patent office on 2009-08-25 for glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof. This patent grant is currently assigned to Boehringer Ingelheim Pharmaceuticals, Inc.. Invention is credited to Younes Bekkali, Abdelhakim Hammach, Thomas Martin Kirrane, Jr., Daniel Kuzmich, Thomas Wai-Ho Lee, John Robert Proudfoot, Mark Stephen Ralph, John Robinson Regan, David S. Thomson, Renee Zindell.
| United States Patent | 7,579,469 |
| Kuzmich , et al. | August 25, 2009 |
**Please see images for:( Certificate of Correction ) **
Glucocorticoid mimetics, methods of making them, pharmaceuticalcompositions, and uses thereof
Abstract
Compounds of Formula (I) ##STR00001## wherein R.sup.1, R.sup.2,R.sup.3, R.sup.4, R.sup.5, R.sup.6, and X are as defined herein forFormula (IA) and Formula (IB), or a tautomer, prodrug, solvate, orsalt thereof, pharmaceutical compositions containing suchcompounds, and methods of modulating the glucocorticoid receptorfunction and methods of treating disease-states or conditionsmediated by the glucocorticoid receptor function or characterizedby inflammatory, allergic, or proliferative processes in a patientusing these compounds.
| Inventors: | Kuzmich; Daniel (Danbury,CT), Lee; Thomas Wai-Ho (Danbury, CT), Proudfoot; JohnRobert (Newtown, CT), Regan; John Robinson (Larchmont,NY), Thomson; David S. (Ridgefield, CT), Hammach;Abdelhakim (Danbury, CT), Ralph; Mark Stephen (BeaconFalls, CT), Zindell; Renee (New Milford, CT), Bekkali;Younes (Danbury, CT), Kirrane, Jr.; Thomas Martin(Southbury, CT) |
|---|---|
| Assignee: | Boehringer IngelheimPharmaceuticals, Inc. (Ridgefield, CT) |
| FamilyID: | 32717933 |
| Appl.No.: | 10/739,208 |
| Filed: | December 18, 2003 |
Prior Publication Data
| DocumentIdentifier | Publication Date | |
|---|---|---|
| US 20040162321 A1 | Aug 19, 2004 | |
Related U.S. Patent Documents
| ApplicationNumber | Filing Date | Patent Number | Issue Date | ||
|---|---|---|---|---|---|
| 60437925 | Jan 3, 2003 | ||||
| 60445192 | Feb 5, 2003 | ||||
| Current U.S.Class: | 546/113 |
| Current CPCClass: | A61P1/16(20180101); C07D 209/48(20130101); C07D211/18(20130101); C07D 211/74(20130101); C07D241/42(20130101); C07D 295/185(20130101); C07D405/10(20130101); A61P 17/02(20180101); A61P25/28(20180101); C07D 487/08(20130101); A61P3/04(20180101); C07D 209/08(20130101); A61P35/00(20180101); C07D 317/58(20130101); C07D401/14(20130101); C07D 241/38(20130101); C07D409/10(20130101); C07D 295/112(20130101); A61P9/10(20180101); C07D 215/06(20130101); A61P37/06(20180101); A61P 31/04(20180101); C07D215/227(20130101); C07D 279/12(20130101); A61P3/10(20180101); A61P 9/12(20180101); A61P29/00(20180101); C07D 413/06(20130101); A61P5/44(20180101); C07D 211/60(20130101); C07D295/205(20130101); C07D 237/28(20130101); C07D241/08(20130101); C07D 307/24(20130101); A61P9/00(20180101); C07D 211/58(20130101); C07D213/64(20130101); C07D 241/04(20130101); C07D241/44(20130101); C07D 401/06(20130101); C07D307/68(20130101); C07D 401/04(20130101); A61P13/12(20180101); C07D 217/04(20130101); C07D239/42(20130101); C07D 409/06(20130101); C07D413/10(20130101); A61P 11/00(20180101); A61P27/06(20180101); C07D 239/90(20130101); C07D243/14(20130101); C07D 279/16(20130101); C07D215/42(20130101); C07D 231/56(20130101); A61P25/00(20180101); C07D 471/04(20130101); A61P37/02(20180101); C07D 417/06(20130101); A61P1/04(20180101); A61P 27/02(20180101); A61P17/00(20180101); C07D 213/69(20130101); C07D213/74(20130101); C07D 213/85(20130101); C07D243/08(20130101); A61P 19/02(20180101); C07D265/22(20130101); C07D 265/36(20130101); C07D211/62(20130101); C07D 295/092(20130101); A61P9/04(20180101); C07D 209/34(20130101); C07D211/14(20130101); C07D 213/68(20130101); C07D401/10(20130101); A61P 27/16(20180101); A61P37/08(20180101); C07D 209/44(20130101); C07D215/233(20130101); C07D 239/88(20130101); C07D295/15(20130101); C07D 207/14(20130101); C07D211/46(20130101); C07D 405/06(20130101); A61P5/46(20180101) |
| Current InternationalClass: | C07D471/02(20060101) |
| Field ofSearch: | ;546/113,153,225,339,290,304,174,165,164,150 ;514/300 ;540/575,568;548/530,470,240 ;544/106,59,358,349,283,224,235;549/229,32,398 |
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Primary Examiner: Seaman; D. Margaret
Attorney, Agent or Firm: Morris; Michael P. Devlin;Mary-Ellen M. Witkowski; Timothy X.
Parent Case Text
RELATED APPLICATIONS
This application claims benefit of U.S. Ser. No. 60/437,925, filedJan. 3, 2003, and U.S. Ser. No. 60/445,192, filed Feb. 5, 2003,each of which is hereby incorporated by reference in its entirety.
Claims
We claim:
1. A compound of Formula (IA) ##STR00461## wherein: R.sup.1 isphenyl optionally independently substituted with one to threesubstituent groups, wherein each substituent group of R.sup.1 isindependently C.sub.1-C.sub.5 alkyl, C.sub.2-C.sub.5 alkenyl,C.sub.2-C.sub.5 alkynyl, C.sub.3-C.sub.8 cycloalkyl, heterocyclyl,aryl, heteroaryl, C.sub.1-C.sub.5 alkoxy, C.sub.2-C.sub.5alkenyloxy, C.sub.2-C.sub.5 alkynyloxy, aryloxy, acyl,C.sub.1-C.sub.5 alkoxycarbonyl, C.sub.1-C.sub.5 alkanoyloxy,C.sub.1-C.sub.5 alkanoyl, aroyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, aminocarbonyloxy, C.sub.1-C.sub.5alkylaminocarbonyloxy, C.sub.1-C.sub.5 dialkylaminocarbonyloxy,C.sub.3-C.sub.5 cycloalkylaminocarbonyloxy, C.sub.1-C.sub.5alkanoylamino, C.sub.1-C.sub.5 alkoxycarbonylamino, C.sub.1-C.sub.5alkylsulfonylamino, aminosulfonyl, C.sub.1-C.sub.5alkylaminosulfonyl, C.sub.1-C.sub.5 dialkylaminosulfonyl, halogen,hydroxy, oxo, carboxy, cyano, trifluoromethyl, trifluoromethoxy,nitro, or amino wherein the nitrogen atom is optionallyindependently mono- or di-substituted by C.sub.1-C.sub.5 alkyl oraryl; or ureido wherein either nitrogen atom is optionallyindependently substituted with C.sub.1-C.sub.5 alkyl orC.sub.3-C.sub.5 cycloalkyl; or C.sub.1-C.sub.5 alkylthio whereinthe sulfur atom is optionally oxidized to a sulfoxide or sulfone,wherein each substituent group of R.sup.1 is optionallyindependently substituted with one to four substituent groupsselected from aryl or heterocyclyl wherein the heterocycle isoptionally independently substituted with hydroxyl, halogen,methyl, or dialkyl amino; C.sub.1-C.sub.5 alkoxycarbonyl, methyl,methoxy, halogen, hydroxy, oxo, cyano, or amino wherein thenitrogen atom is optionally independently mono- or di-substitutedby C.sub.1-C.sub.5 alkyl or C.sub.1-C.sub.3 dialkylamines or aryl;or ureido wherein either nitrogen atom is optionally independentlysubstituted with C.sub.1-C.sub.5 alkyl; aminosulfonyl, or oximewherein the oxygen atom is optionally substituted byC.sub.1-C.sub.5 alkyl or benzyl; R.sup.2 and R.sup.3 are eachindependently hydrogen, C.sub.1-C.sub.5 alkyl, or C.sub.5-C.sub.15arylalkyl group, or R.sup.2 and R.sup.3 together with the carbonatom they are commonly attached to form a C.sub.3-C.sub.8 spirocycloalkyl ring, or R.sup.1 and R.sup.2 taken together are achromanyl or dihydrobenzofuranyl optionally substituted withC.sub.1-C.sub.5 alkyl, C.sub.2-C.sub.5 alkenyl, C.sub.2-C.sub.5alkynyl, C.sub.3-C.sub.8 cycloalkyl, heterocyclyl, aryl,heteroaryl, C.sub.1-C.sub.5 alkoxy, C.sub.2-C.sub.5 alkenyloxy,C.sub.2-C.sub.5 alkynyloxy, aryloxy, acyl, C.sub.1-C.sub.5alkoxycarbonyl, C.sub.1-C.sub.5 alkanoyloxy, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy,C.sub.1-C.sub.5 alkylaminocarbonyloxy, C.sub.1-C.sub.5dialkylaminocarbonyloxy, C.sub.1-C.sub.5 alkanoylamino,C.sub.1-C.sub.5 alkoxycarbonylamino, C.sub.1-C.sub.5alkylsulfonylamino, aminosulfonyl, C.sub.1-C.sub.5alkylaminosulfonyl, C.sub.1-C.sub.5 dialkylaminosulfonyl, halogen,hydroxy, carboxy, oxo, cyano, trifluoromethyl, trifluoromethoxy,trifluoromethylthio, nitro, or amino wherein the nitrogen atom isoptionally independently mono- or di-substituted by C.sub.1-C.sub.5alkyl; or ureido wherein either nitrogen atom is optionallyindependently substituted with C.sub.1-C.sub.5 alkyl; orC.sub.1-C.sub.5 alkylthio wherein the sulfur atom is optionallyoxidized to a sulfoxide or sulfone; R.sup.4 is carbonyl ormethylene optionally independently substituted with one to twosubstituent groups selected from C.sub.1-C.sub.3 alkyl, hydroxy,and halogen; R.sup.5 is a pyrrolidine, morpholine, thiomorpholine,piperazine, piperidine, 1H-pyridin-4-one, 1H-pyridin-2-one,1H-pyridin-4-ylideneamine, 1H-quinolin-4-ylideneamine, pyran,tetrahydropyran, 1,4-diazepane, 2,5-diazabicyclo[2.2.1]heptane,2,3,4,5-tetrahydrobenzo[b][1,4]diazepine, dihydroquinoline,tetrahydroquinoline, 5,6,7,8-tetrahydro-1H-quinolin-4-one,tetrahydroisoquinoline, decahydroisoquinoline,2,3-dihydro-1H-isoindole, 2,3-dihydro-1H-indole, chroman,1,2,3,4-tetrahydroquinoxaline, 1,2-dihydroindazol-3-one,3,4-dihydro-2H-benzo[1,4]oxazine, 4H-benzo[1,4]thiazine,3,4-dihydro-2H-benzo[1,4]thiazine,1,2-dihydrobenzo[d][1,3]oxazin-4-one,3,4-dihydrobenzo[1,4]oxazin-4-one, 3H-quinazolin-4-one,3,4-dihydro-1H-quinoxalin-2-one, 1H-cinnolin-4-one,1H-quinazolin-4-one, 1H-[1,5]naphthyridin-4-one,5,6,7,8-tetrahydro-1H-[1,5]naphthyridin-4-one,2,3-dihydro-1H-[1,5]naphthyridin-4-one,1,2-dihydropyridol[3,2-d][1,3]oxazin-4-one,pyrrolo[3,4-c]pyridine-1,3-dione,1,2-dihydropyrrolo[3,4-c]pyridin-3-one, ortetrahydro[b][1,4]diazepinone, group, each optionally independentlysubstituted with one to three substituent groups, wherein eachsubstituent group of R.sup.5 is independently C.sub.1-C.sub.5alkyl, C.sub.2-C.sub.5 alkenyl, C.sub.2-C.sub.5 alkynyl,C.sub.3-C.sub.8 cycloalkyl, heterocyclyl, aryl, heteroaryl,C.sub.1-C.sub.5 alkoxy, C.sub.2-C.sub.5 alkenyloxy, C.sub.2-C.sub.5alkynyloxy, aryloxy, acyl, C.sub.1-C.sub.5 alkoxycarbonyl,C.sub.1-C.sub.5 alkanoyloxy, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, aminocarbonyloxy, C.sub.1-C.sub.5alkylaminocarbonyloxy, C.sub.1-C.sub.5 dialkylaminocarbonyloxy,C.sub.1-C.sub.5 alkanoylamino, C.sub.1-C.sub.5 alkoxycarbonylamino,C.sub.1-C.sub.5 alkylsulfonylamino, C.sub.1-C.sub.5alkylaminosulfonyl, C.sub.1-C.sub.5 dialkylaminosulfonyl, halogen,hydroxy, carboxy, oxo, cyano, trifluoromethyl, trifluoromethoxy,trifluoromethylthio, nitro, or amino wherein the nitrogen atom isoptionally independently mono- or di-substituted by C.sub.1-C.sub.5alkyl; or ureido wherein either nitrogen atom is optionallyindependently substituted with C.sub.1-C.sub.5 alkyl; orC.sub.1-C.sub.5 alkylthio wherein the sulfur atom is optionallyoxidized to a sulfoxide or sulfone, wherein each substituent groupof R.sup.5 is optionally independently substituted with one tothree substituent groups selected from C.sub.1-C.sub.3 alkyl,C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 alkoxycarbonyl, acyl, aryl,benzyl, heteroaryl, heterocyclyl, halogen, hydroxy, oxo, cyano,amino wherein the nitrogen atom is optionally independently mono-or di-substituted by C.sub.1-C.sub.5 alkyl; or ureido whereineither nitrogen atom is optionally independently substituted withC.sub.1-C.sub.5 alkyl; or trifluoromethyl; and X is a hydroxy oramino wherein the nitrogen atom is optionally independently mono-or di-substituted by C.sub.1-C.sub.5 alkyl, or a tautomer or saltthereof.
2. The compound of Formula (IA) according to claim 1, wherein: eachsubstituent group of R.sup.1 is independently C.sub.1-C.sub.3alkyl, C.sub.2-C.sub.3 alkenyl, C.sub.2-C.sub.3 alkynyl,C.sub.1-C.sub.3 alkoxy, C.sub.2-C.sub.3 alkenyloxy, C.sub.1-C.sub.3alkanoyl, C.sub.1-C.sub.3 alkoxycarbonyl, C.sub.1-C.sub.3alkanoyloxy, halogen, hydroxy, acyl, oxo, carboxy, cyano,trifluoromethyl, nitro, or C.sub.1-C.sub.3 alkylthio wherein thesulfur atom is optionally oxidized to a sulfoxide or sulfone,wherein each substituent group of R.sup.1 is optionallyindependently substituted with a substituent group selected frommethyl, methoxy, halogen, hydroxy, oxo, cyano, or amino; R.sup.2and R.sup.3 are each independently hydrogen, C.sub.1-C.sub.3 alkyl,benzyl, or phenethyl, or R.sup.2 and R.sup.3 together with thecarbon atom they are commonly attached to form a C.sub.3-C.sub.6spiro cycloalkyl ring; and R.sup.4 is CH.sub.2, or a tautomer orsalt thereof.
3. The compound of Formula (IA) according to claim 1, wherein: eachsubstituent group of R.sup.1 is independently methyl, ethyl,methoxy, ethoxy, fluoro, chloro, bromo, hydroxy, trifluoromethyl,acyl, oxo, C.sub.1-C.sub.5 alkylthio wherein the sulfur atom isoptionally oxidized to a sulfoxide or sulfone, or cyano; R.sup.2and R.sup.3 are each independently methyl, or R.sup.2 and R.sup.3together with the carbon atom they are commonly attached to form aspiro cyclopropyl ring; and R.sup.4 is CH.sub.2, or a tautomer orsalt thereof.
4. The compound of Formula (IA) according to claim 1, wherein: eachsubstituent group of R.sup.1 is independently C.sub.1-C.sub.3alkyl, C.sub.2-C.sub.3 alkenyl, C.sub.2-C.sub.3 alkynyl,C.sub.1-C.sub.3 alkoxy, C.sub.2-C.sub.3 alkenyloxy, C.sub.1-C.sub.3alkanoyl, C.sub.1-C.sub.3 alkoxycarbonyl, C.sub.1-C.sub.3alkanoyloxy, halogen, hydroxy, carboxy, cyano, trifluoromethyl,nitro, or C.sub.1-C.sub.3 alkylthio wherein the sulfur atom isoptionally oxidized to a sulfoxide or sulfone; and R.sup.2 andR.sup.3 are each independently hydrogen or C.sub.1-C.sub.3 alkyl,or a tautomer or salt thereof.
5. A compound selected from:1-{4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpe-ntyl]-2,6-dimethylpiperazin-1-yl}ethanone;4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-2,6-dimethylpiperazine-1-carbaldehyde;1-{5-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpe-ntyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}ethanone;4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3,4-dihydro-2H-quinoxaline-1-carbaldehyde;4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3,4-dihydro-1H-quinoxalin-2-one;4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]piperazine-2,6-dione;2-(2,6-Dimethylthiomorpholin-4-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-me-thoxyphenyl)-4-methylpentan-2-ol;2-(1,1-Dioxo-1H-1.lamda..sup.6-benzo[1,4]thiazin-4-ylmethyl)-1,1,1-triflu-oro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;2-(1,1-Dioxo-2,3-dihydro-1H-1.lamda..sup.6-benzo[1,4]thiazin-4-ylmethyl)--1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;1-{5-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpe-ntyl]-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl}ethanone;5-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1,3,4,5-tetrahydrobenzo[b][1,4]diazepin-2-one;2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]isoindole-1,3-dione;2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]pyrrolo[3,4-c]pyridine-1,3-dione;2-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carbonitrile;2-(2,3-Dihydrobenzo[1,4]thiazin-4-ylmethyl)-1,1,1-trifluoro-4-(4-fluoroph-enyl)-4-methylpentan-2-ol;1-{4-[4-(3-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-2,6--dimethylpiperazin-1-yl}ethanone;2-(3,4-Dihydro-2H-quinoxalin-1-ylmethyl)-1,1,1-trifluoro-4-(4-fluoropheny-l)-4-methylpentan-2-ol;2-(2,6-Dimethylthiomorpholin-4-ylmethyl)-1,1,1-trifluoro-4-(4-fluoropheny-l)-4-methylpentan-2-ol;5-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-2,5-diazabicyclo[2.2.1]heptan-3-one;1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-morpholin-4-ylmet-hylpentan-2-ol;2-(2,6-Dimethylmorpholin-4-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methox-yphenyl)-4-methylpentan-2-ol;2-(2,3-Dihydrobenzo[1,4]oxazin-4-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2--methoxyphenyl)-4-methylpentan-2-ol;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]piperidin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-methoxy-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-2,4-dimethylpentyl]-3,5-dimethy-l-1H-pyridin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3,5-dimethylpiperidin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinazolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-cinnolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-methyl-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-isopropyl-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-2,3-dihydro-1H-quinolin-4-one;1-[4-(4-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]piperidi-n-4-one;1-[4-(4-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]--1H-quinolin-4-one;1-[4-(3-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quin-olin-4-one;1-[4-(2-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quin-olin-4-one;1-[4-(3-Fluoro-4-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one;1-[4-(4-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-(2-Methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quin-olin-4-one;1-[4-(3-Cyanophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quino-lin-4-one;1-[4-(3-Carboxamidophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentyl]-1H-quinolin-4-one;1-[4-(2,6-dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H--quinolin-4-one;1-[4-Phenyl-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one-;1-[4-(4-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-3,5-di-methylpiperidin-4-one;1-[4-(4-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quin-azolin-4-one;1-[4-(4-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-cinn-olin-4-one;1-[4-(4-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-3-methy-l-1H-quinolin-4-one;1-[4-(4-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-3-isopr-opyl-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1,2-dihydrobenzo[d][1,3]oxazin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1,2-dihydrobenzo[d][1,3]oxazin-4-one;4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3,4-dihydrobenzo[1,4]oxazin-2-one;4-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3,4-dihydrobenzo[1,4]oxazin-2-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-[1,5]naphthyridin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-[1,5]naphthyridin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-2,3-dihydro-1H-[1,5]naphthyridin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-2,3-dihydro-1H-[1,5]naphthyridin-4-one;1-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one;1-[4-(2,4-dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H--quinolin-4-one;1-[4-(4-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-(3-Fluoro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1,2-dihydroindazol-3-one;1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-piperazin-1-ylmet-hylpentan-2-ol;1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-methylpiperazi-n-1-ylmethyl)pentan-2-ol;1-{4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpe-ntyl]piperazin-1-yl}ethanone;2-(3,5-Dimethylpiperazin-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methox-yphenyl)-4-methylpentan-2-ol;1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(3,4,5-trimethylp-iperazin-1-ylmethyl)pentan-2-ol;2-(3,4-Dihydro-2H-quinoxalin-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-me-thoxyphenyl)-4-methylpentan-2-ol;1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-methyl-3,4-dih-ydro-2H-quinoxalin-1-ylmethyl)pentan-2-ol;2-[1,4]Diazepan-1-ylmethyl-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4--methylpentan-2-ol;1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-methyl-[1,4]di-azepan-1-ylmethyl)pentan-2-ol;1-{4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpe-ntyl]-[1,4]diazepan-1-yl}ethanone;4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-[1,4]diazepane-1-carbaldehyde;1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-thiomorpholin-4-y-lmethylpentan-2-ol;1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1-oxo-1.lamda..s-up.5-thiomorpholin-4-ylmethyl)pentan-2-ol;2-(1,1-Dioxo-1.lamda..sup.6-thiomorpholin-4-ylmethyl)-1,1,1-trifluoro-4-(-5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;2-(2,3-Dihydrobenzo[1,4]thiazin-4-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2--methoxyphenyl)-4-methylpentan-2-ol;1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1-oxo-2,3-dihydr-o-1H-1.lamda..sup.4-benzo[1,4]thiazin-4-ylmethyl)pentan-2-ol;1-{4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpe-ntyl]-3,4-dihydro-2H-quinoxalin-1-yl}ethanone;1-[2-Hydroxy-4-(2-methoxy-5-thiophen-2-ylphenyl)-4-methyl-2-trifluorometh-ylpentyl]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-methyl-1H-quinolin-4-one;1-[2-Hydroxy-4-(4-hydroxybiphenyl-3-yl)-4-methyl-2-trifluoromethylpentyl]--1H-quinolin-4-one;1-{4-[5-(3,5-Dimethylisoxazol-4-yl)-2-hydroxyphenyl]-2-hydroxy-4-methyl-2--trifluoromethylpentyl}-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-hydroxy-5-thiophen-3-ylphenyl)-4-methyl-2-trifluorometh-ylpentyl]-1H-quinolin-4-one;1-{4-[5-(3,5-Dimethylisoxazol-4-yl)-2-methoxyphenyl]-2-hydroxy-4-methyl-2--trifluoromethylpentyl}-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-[1,5]naphthyridin-4-one;1-[2-Hydroxy-4-methyl-4-(3-pyridin-3-ylphenyl)-2-trifluoromethylpentyl]-1-H-quinolin-4-one;1-[2-Hydroxy-4-(2-hydroxy-5-morpholin-4-ylmethylphenyl)-4-methyl-2-triflu-oromethylpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-methoxy-5-morpholin-4-ylmethylphenyl)-4-methyl-2-triflu-oromethylpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(5-hydroxymethyl-2-methoxyphenyl)-4-methyl-2-trifluorometh-ylpentyl]-1H-quinolin-4-one;4-Methoxy-3-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin--1-ylmethyl)butyl]benzaldehyde;1-[4-(5-[1,3]Dioxan-2-yl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorom-ethylpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-methoxy-5-thiophen-3-ylphenyl)-4-methyl-2-trifluorometh-ylpentyl]-1H-quinolin-4-one;1-[4-(5-Furan-3-yl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylp-entyl]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinazolin-4-one;1-[2-Hydroxy-4-(4-methoxybiphenyl-3-yl)-4-methyl-2-trifluoromethylpentyl]--1H-quinolin-4-one;1-[4-(5-Acetyl-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-(4-{3-[1-(Benzyloxyimino)ethyl]phenyl}-2-hydroxy-4-methyl-2-trifluorome-thylpentyl)-1H-quinolin-4-one;1-[4-(3-Cyclopropanecarbonylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylp-entyl]-1H-quinolin-4-one;1-[4-(5-Acetyl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-(2-Hydroxy-4-{3-[1-(methoxyimino)ethyl]phenyl}-4-methyl-2-trifluorometh-ylpentyl)-1H-quinolin-4-one;1-[4-(5-Bromo-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one;1-(2-Hydroxy-4-{3-[1-(hydroxyimino)ethyl]phenyl}-4-methyl-2-trifluorometh-ylpentyl)-1H-quinolin-4-one;1-[4-(5-Bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one;1-[4-(3,5-Difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H--quinolin-4-one;1-[4-(3,5-Dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H--quinolin-4-one;1-{2-Hydroxy-4-methyl-4-[3-(2-methyl-[1,3]dioxolan-2-yl)phenyl]-2-trifluo-romethylpentyl}-1H-quinolin-4-one;1-[2-Hydroxy-4-(3-hydroxymethylphenyl)-4-methyl-2-trifluoromethylpentyl]--1H-quinolin-4-one;1-[4-(3-[1,3]Dioxan-2-ylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-(3-Acetylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quin-olin-4-one;1-{4-[3-(3,5-Dimethylisoxazol-4-yl)phenyl]-2-hydroxy-4-methyl-2-trifluoro-methylpentyl}-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-3,5-dimethyl-1H-pyridin-4-one;1-{2-Hydroxy-4-[3-(1-hydroxyethyl)phenyl]-4-methyl-2-trifluoromethylpenty-l}-1H-quinolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-2-hydroxymethyl-3,5-dimethyl-1H-pyridin-4-one;3-[4,4,4-Trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1-ylmethyl-)butyl]benzaldehyde;1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-2-(4-imino-4H-quinolin-1-ylm-ethyl)-4-methylpentan-2-ol;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-2-hydroxymethyl-3,5-dimethyl-1H-pyridin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-hydroxymethyl-1H-quinolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-hydroxy-2-methyl-1H-pyridin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-methoxy-2-methyl-1H-pyridin-4-one;1-[4-(3-Bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quino-lin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluorom-ethylpentyl]-6-hydroxy-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-methoxymethyl-1H-quinolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-7-hydroxy-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-7-methoxy-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-6-methoxy-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-6-methyl-1H-quinolin-4-one;
1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-hydroxymethyl-1H-quinolin-4-one;6-Chloro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-[-4-(2-Difluoromethoxy-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-(4-Biphenyl-3-yl-2-hydroxy-4-methyl-2-trifluoromethylpentyl)-1H-quinoli-n-4-one;6-Chloro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-tri-fluoromethylpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-hydroxy-5-methylphenyl)-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-{2-Hydroxy-4-methyl-4-[3-(2-oxopropoxy)phenyl]-2-trifluoromethylpentyl}--1H-quinolin-4-one;1-[2-Hydroxy-4-(3-isopropoxyphenyl)-4-methyl-2-trifluoromethylpentyl]-1H--quinolin-4-one;1-[4-(3-Ethoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quin-olin-4-one;1-[2-Hydroxy-4-(2-methoxy-5-methylphenyl)-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-(2,5-Dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H--quinolin-4-one;1-[2-Hydroxy-4-(3-hydroxyphenyl)-4-methyl-2-trifluoromethylpentyl]-1H-qui-nolin-4-one;1-[2-Hydroxy-4-(3-methoxyphenyl)-4-methyl-2-trifluoromethylpentyl]-1H-qui-nolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1,2-dihydroindazol-3-one;7-Fluoro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3,5-dimethyl-1H-pyridin-4-one;7-Fluoro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-(2-Hydroxy-4-methyl-4-phenyl-2-trifluoromethylhexyl)-1H-quinolin-4-one;2-(3,4-Dihydro-2H-quinolin-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-meth-oxyphenyl)-4-methylpentan-2-ol;1-[4-(4-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]piperidin-4-ol;1-[4-(3,4-Dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H--quinolin-4-one;8-Fluoro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;6-Fluoro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-{4-[5-Fluoro-2-(2-hydroxypropoxy)phenyl]-2-hydroxy-4-methyl-2-trifluoro-methylpentyl}-1H-quinolin-4-one;1-{4-[5-Fluoro-2-(2-oxopropoxy)phenyl]-2-hydroxy-4-methyl-2-trifluorometh-ylpentyl}-1H-quinolin-4-one;7-Chloro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-isopropoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpe-ntyl]-1H-quinolin-4-one;1-[4-(2-Benzyloxy-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpen-tyl]-1H-quinolin-4-one;1-[4-(2-Ethoxy-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one;8-Fluoro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;6-Fluoro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;7-Chloro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]piperidine-4-carboxylic acid amide;1-[4-(2,3-Dihydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H--quinolin-4-one;1-[4-(3-Fluoro-4-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;3-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3H-quinazolin-4-one;4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1-methyl-3,4-dihydro-1H-quinoxalin-2-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-pyridin-2-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-4-methyl-1H-quinolin-2-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-nitro-5-trifluoromethyl-1H-pyridin-2-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-nitro-1H-pyridin-2-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-5-nitro-1H-pyridin-2-one;3-Chloro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-5-trifluoromethyl-1H-pyridin-2-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-4-methyl-1H-pyridin-2-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-4-methyl-3-nitro-1H-pyridin-2-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-4-methyl-5-nitro-1H-pyridin-2-one;2-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-m-ethoxyphenyl)-4-methylpentan-2-ol;2-(1,3-Dihydroisoindol-2-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyp-henyl)-4-methylpentan-2-ol;2-(2,3-Dihydroindol-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphen-yl)-4-methylpentan-2-ol;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1,3-dihydroindol-2-one;1-[4-(3-Dimethylaminomethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpe-ntyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-methyl-4-(3-morpholin-4-ylmethylphenyl)-2-trifluoromethylp-entyl]-1H-quinolin-4-one;1-[4-(3-Diethylaminomethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpen-tyl]-1H-quinolin-4-one;1-[4-(3-{[(2-Dimethylaminoethyl)methylamino]methyl}phenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one;1-{2-Hydroxy-4-[3-(3-hydroxypyrrolidin-1-ylmethyl)phenyl]-4-methyl-2-trif-luoromethylpentyl}-1H-quinolin-4-one;1-[4-(3-Ethylaminomethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[2-Hydroxy-4-methyl-4-(3-pyrrolidin-1-ylmethylphenyl)-2-trifluoromethyl-pentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-methyl-4-(3-piperidin-1-ylmethylphenyl)-2-trifluoromethylp-entyl]-1H-quinolin-4-one;1-{2-Hydroxy-4-methyl-4-[3-(4-methylpiperazin-1-ylmethyl)phenyl]-2-triflu-oromethylpentyl}-1H-quinolin-4-one;1-{4-[3-(3-Dimethylaminopyrrolidin-1-ylmethyl)phenyl]-2-hydroxy-4-methyl--2-trifluoromethylpentyl}-1H-quinolin-4-one;1-[2-Hydroxy-4-methyl-4-(3-methylaminomethylphenyl)-2-trifluoromethylpent-yl]-1H-quinolin-4-one;{4-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpent-yl]piperazin-1-yl}furan-2-ylmethanone;1-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-3-methyl-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-methoxy-3,5-dimethylphenyl)-4-methyl-2-trifluoromethylp-entyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-methoxy-3,5-dimethylphenyl)-4-methyl-2-trifluoromethylp-entyl]-3-methyl-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-hydroxy-3,5-dimethylphenyl)-4-methyl-2-trifluoromethylp-entyl]-3-methyl-1H-quinolin-4-one;1-[4-(3-Acetyl-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-(3-Acetyl-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-methyl-1H-quinolin-4-one;1-[4-(3-Bromo-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-hydroxybiphenyl-3-yl)-4-methyl-2-trifluoromethylpentyl]--1H-quinolin-4-one;1-[4-(2-Acetyl-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methanesulfonylphenyl)-2-hydroxy-4-methyl-2-trifluoromet-hylpentyl]-1H-quinolin-4-one;4-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1--ylmethyl)butyl]benzenesulfonamide;4-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1--ylmethyl)butyl]benzamide;4-Fluoro-N,N-dimethyl-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo--4H-quinolin-1-ylmethyl)butyl]benzamide;1-[4-(5-Fluoro-2-oxazol-2-ylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylp-entyl]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-oxazol-5-ylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylp-entyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-hydroxy-3-oxazol-2-ylphenyl)-4-methyl-2-trifluoromethyl-pentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-hydroxy-3-oxazol-5-ylphenyl)-4-methyl-2-trifluoromethyl-pentyl]-1H-quinolin-4-one;{4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpent-yl]-3,4-dihydro-2H-quinoxalin-1-yl}furan-2-ylmethanone;{4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpent-yl]-3,4-dihydro-2H-quinoxalin-1-yl}thiophen-2-ylmethanone;{4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpent-yl]-3,4-dihydro-2H-quinoxalin-1-yl}phenylmethanone;{4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpent-yl]-3,4-dihydro-2H-quinoxalin-1-yl}-(4-fluorophenyl)methanone;{4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpent-yl]-3,4-dihydro-2H-quinoxalin-1-yl}-(2-fluorophenyl)methanone;{4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpent-yl]-3,4-dihydro-2H-quinoxalin-1-yl}-(3-fluorophenyl)methanone;{4-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpent-yl]-3,4-dihydro-2H-quinoxalin-1-yl}furan-2-ylmethanone;{4-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpent-yl]-3,4-dihydro-2H-quinoxalin-1-yl}thiophen-2-ylmethanone;{4-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpent-yl]-3,4-dihydro-2H-quinoxalin-1-yl}phenylmethanone;{4-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpent-yl]-3,4-dihydro-2H-quinoxalin-1-yl}-(4-fluorophenyl)methanone;{4-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpent-yl]-3,4-dihydro-2H-quinoxalin-1-yl}-(2-fluorophenyl)methanone;{4-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpent-yl]-3,4-dihydro-2H-quinoxalin-1-yl}-(3-fluorophenyl)methanone;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-5,6,7,8-tetrahydro-1H-quinolin-4-one;1-[4-(4-Fluoro-3-morpholin-4-ylmethylphenyl)-2-hydroxy-4-methyl-2-trifluo-romethylpentyl]-1H-quinolin-4-one;1-[4-(3-Fluoro-4-morpholin-4-ylmethylphenyl)-2-hydroxy-4-methyl-2-trifluo-romethylpentyl]-1H-quinolin-4-one;1-[4-(2-{[Ethyl-(2-methoxyethyl)amino]methyl}phenyl)-2-hydroxy-4-methyl-2--trifluoromethylpentyl]-1H-quinolin-4-one;2-[4-(3-Chloro-5-trifluoromethylpyridin-2-yl)piperazin-1-ylmethyl]-1,1,1--trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;{4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpent-yl]piperazin-1-yl}furan-2-ylmethanone;1-(4-{4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethy-lpentyl]piperazin-1-yl}phenyl)ethanone;1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-2-[4-(4-fluorophenyl)piperaz-in-1-ylmethyl]-4-methylpentan-2-ol;1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-phenylpiperazi-n-1-ylmethyl)pentan-2-ol;2-[4-(2,4-Difluorophenyl)piperazin-1-ylmethyl]-1,1,1-trifluoro-4-(5-fluor-o-2-methoxyphenyl)-4-methylpentan-2-ol;4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]piperazine-1-carboxylic acid ethyl ester;{4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpent-yl]piperazin-1-yl}-(tetrahydrofuran-2-yl)methanone;4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]piperazine-1-carboxylic acid benzyl ester;1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-pyrimidin-2-yl-piperazin-1-ylmethyl)pentan-2-ol;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]piperidine-3-carboxylic acid amide;4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-[1,4]diazepane-1-carboxylic acid benzyl ester;1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-[4-(5-pyrazin-2-y-l-[1,3,4]oxadiazol-2-yl)piperidin-1-ylmethyl]pentan-2-ol;1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-pyridin-2-ylpi-perazin-1-ylmethyl)pentan-2-ol;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]piperidine-4-carboxylic acid methyl ester;4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]piperazin-2-one;1-{1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpe-ntyl]piperidin-4-yl}-1,3-dihydrobenzoimidazol-2-one;1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(octahydroisoquin-olin-2-ylmethyl)pentan-2-ol;{4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpent-yl]piperazin-1-yl}acetic acid ethyl ester;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3,3-dimethyl-2,3-dihydro-1H-quinolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3,3-dimethyl-2,3-dihydro-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-3,3-dimethyl-2,3-dihydro-1H-quinolin-4-one;1-[4-(2-Acetyl-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-3,3-dimethyl-2,3-dihydro-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-methoxy-3,5-dimethylphenyl)-4-methyl-2-trifluoromethylp-entyl]-3,3-dimethyl-2,3-dihydro-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-hydroxy-3,5-dimethylphenyl)-4-methyl-2-trifluoromethylp-entyl]-3,3-dimethyl-2,3-dihydro-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-hydroxy-5-thiophen-3-ylphenyl)-4-methyl-2-trifluorometh-ylpentyl]-3,3-dimethyl-2,3-dihydro-1H-quinolin-4-one;1-[4-(3-Ethoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-3,3-dim-ethyl-2,3-dihydro-1H-quinolin-4-one;1-[4-(4-Bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-3-methyl--1H-quinolin-4-one;4-[4,4,4-Trifluoro-3-hydroxy-1,1-dimethyl-3-(3-methyl-4-oxo-4H-quinolin-1--ylmethyl)butyl]benzonitrile;1-[4-(4-Bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quino-lin-4-one;4-[4,4,4-Trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin--
1-ylmethyl)butyl]benzonitrile;2-(4-Benzylpiperazin-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphe-nyl)-4-methylpentan-2-ol;2-(4-Benzo[1,3]dioxol-5-ylmethylpiperazin-1-ylmethyl)-1,1,1-trifluoro-4-(-5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(2-methylpiperidi-n-1-ylmethyl)pentan-2-ol;1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-trifluoromethy-lpiperidin-1-ylmethyl)pentan-2-ol;1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-2-[4-(4-fluorophenyl)piperid-in-1-ylmethyl]-4-methylpentan-2-ol;2-[4-(4-Bromophenyl)piperidin-1-ylmethyl]-1,1,1-trifluoro-4-(5-fluoro-2-m-ethoxyphenyl)-4-methylpentan-2-ol;1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-methylpiperidi-n-1-ylmethyl)pentan-2-ol;4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-[1,4]diazepane-1-carboxylic acid tert-butyl ester;4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]piperazine-1-carboxylic acid tert-butyl ester;1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-2-[4-(2-methoxyphenyl)pipera-zin-1-ylmethyl]-4-methylpentan-2-ol;1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-pyrrolidin-1-y-lpiperidin-1-ylmethyl)pentan-2-ol;2-[1,4']Bipiperidinyl-1'-ylmethyl-1,1,1-trifluoro-4-(5-fluoro-2-methoxyph-enyl)-4-methylpentan-2-ol;2-[4-(2-Ethoxyethyl)piperazin-1-ylmethyl]-1,1,1-trifluoro-4-(5-fluoro-2-m-ethoxyphenyl)-4-methylpentan-2-ol;1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-2-[4-(2-methoxyethyl)piperaz-in-1-ylmethyl]-4-methylpentan-2-ol;2-(4-Benzylpiperidin-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphe-nyl)-4-methylpentan-2-ol;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]piperidine-3-carboxylic acid diethylamide;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]piperidine-3-carboxylic acid ethyl ester;1-{1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpe-ntyl]piperidin-4-yl}-1,3-dihydroindol-2-one;1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-phenylpiperidi-n-1-ylmethyl)pentan-2-ol;2-(4-Benzylpiperidin-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphe-nyl)-4-methylpentan-2-ol;1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-2-[4-(1H-indol-2-yl)piperidi-n-1-ylmethyl]-4-methylpentan-2-ol;5-Chloro-1-{1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluor-omethylpentyl]piperidin-4-yl}-1,3-dihydrobenzoimidazol-2-one;{1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpent-yl]piperidin-4-yl}acetic acid ethyl ester;2-[4-(2,4-Dimethylphenyl)piperazin-1-ylmethyl]-1,1,1-trifluoro-4-(5-fluor-o-2-methoxyphenyl)-4-methylpentan-2-ol;2-(4-Benzyl-[1,4]diazepan-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-metho-xyphenyl)-4-methylpentan-2-ol;4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]piperazine-1-carbaldehyde;4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-methoxycarbonylmethylpiperazine-1-carboxylic acid tert-butylester;2-(4-tert-Butylpiperazin-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methox-yphenyl)-4-methylpentan-2-ol;2-(3-Dimethylaminopyrrolidin-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-me-thoxyphenyl)-4-methylpentan-2-ol;1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-pyrrolidin-1-ylme-thylpentan-2-ol;1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-piperidin-1-ylmet-hylpentan-2-ol; Carbonic acid ethyl ester4-fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1--ylmethyl)butyl]phenyl ester; Ethylcarbamic acid4-fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1--ylmethyl)butyl]phenyl ester; Ethylcarbamic acid4-fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(3-methyl-4-oxo-4H-q-uinolin-1-ylmethyl)butyl]phenyl ester; Ethylcarbamic acid2-[3-(3,3-dimethyl-4-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl)-4,4,4-triflu-oro-3-hydroxy-1,1-dimethylbutyl]-4-fluorophenyl ester;Methylcarbamic acid2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1-ylmethyl-)butyl]phenyl ester; Carbonic acid2-[3-(3,5-dimethyl-4-oxo-4H-pyridin-1-ylmethyl)-4,4,4-trifluoro-3-hydroxy--1,1-dimethylbutyl]-4-fluorophenyl ester methyl ester;Methylcarbamic acid2-[3-(3,5-dimethyl-4-oxo-4H-pyridin-1-ylmethyl)-4,4,4-trifluoro-3-hydroxy--1,1-dimethylbutyl]-4-fluorophenyl ester; Cyclopropylcarbamic acid2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1-ylmethyl-)butyl]phenyl ester;1-Cyclopropyl-3-{2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-qu-inolin-1-ylmethyl)butyl]phenyl}urea;1-Cyclopropyl-3-{2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(3-methyl-4--oxo-4H-quinolin-1-ylmethyl)butyl]phenyl}urea;1-Methyl-3-{2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(3-methyl-4-oxo-4-H-quinolin-1-ylmethyl)butyl]phenyl}urea;1-{2-[3-(3,3-Dimethyl-4-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl)-4,4,4-tri-fluoro-3-hydroxy-1,1-dimethylbutyl]phenyl}-3-methylurea;1-(2,2,3,3-Tetramethylcyclopropyl)-3-{2-[4,4,4-trifluoro-3-hydroxy-1,1-di-methyl-3-(4-oxo-4H-quinolin-1-ylmethyl)butyl]phenyl}urea;(2,2,3,3-Tetramethylcyclopropyl)carbamic acid2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1-ylmethyl-)butyl]phenyl ester; Dimethylcarbamic acid2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1-ylmethyl-)butyl]phenyl ester; Dimethylcarbamic acid2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(3-methyl-4-oxo-4H-quinolin-1--ylmethyl)butyl]phenyl ester; Pyrrolidine-1-carboxylic acid2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1-ylmethyl-)butyl]phenyl ester; Pyrrolidine-1-carboxylic acid2-[3-(3,3-dimethyl-4-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl)-4,4,4-triflu-oro-3-hydroxy-1,1-dimethylbutyl]phenyl ester;1-[2-Hydroxy-4-(2-methoxy-5-pyridin-3-ylphenyl)-4-methyl-2-trifluoromethy-lpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-hydroxy-3,5-dimethylphenyl)-4-methyl-2-trifluoromethylp-entyl]-1H-quinolin-4-one;1-[4-(3-[1,3]Dioxan-2-yl-4-fluorophenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-methoxy-5-pyrimidin-5-ylphenyl)-4-methyl-2-trifluoromet-hylpentyl]-1H-quinolin-4-one;1-[4-(4-[1,3]Dioxan-2-yl-3-fluorophenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-hydroxy-5-pyridin-3-ylphenyl)-4-methyl-2-trifluoromethy-lpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-hydroxy-5-pyrimidin-5-ylphenyl)-4-methyl-2-trifluoromet-hylpentyl]-1H-quinolin-4-one; and Carbonic acid4-fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1--ylmethyl)butyl]phenyl ester methyl ester, or a tautomer or saltthereof.
6. A compound according to claim 5, the compound selected from:4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-2,6-dimethylpiperazine-1-carbaldehyde;2-(1,1-Dioxo-2,3-dihydro-1H-1.lamda..sup.6-benzo[1,4]thiazin-4-ylmethyl)--1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;2-(2,6-Dimethylmorpholin-4-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methox-yphenyl)-4-methylpentan-2-ol;2-(2,3-Dihydrobenzo[1,4]oxazin-4-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2--methoxyphenyl)-4-methylpentan-2-ol;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H -quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3,5-dimethylpiperidin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-cinnolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-methyl-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-2,3-dihydro-1H-quinolin-4-one;1-[4-(4-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quin-olin-4-one;1-[4-(3-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quin-olin-4-one;1-[4-(3-Fluoro-4-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one;1-[4-(4-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-Phenyl-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one-;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpent-yl]-1H-[1,5]naphthyridin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-2,4-dimethylpentyl]-3,5-dimethy-l-1H-pyridin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-[1,5]naphthyridin-4-one;1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1-oxo-2,3-dihydr-o-1H-1.lamda..sup.4-benzo[1,4]thiazin-4-ylmethyl)pentan-2-ol;1-[2-Hydroxy-4-(2-methoxy-5-thiophen-2-ylphenyl)-4-methyl-2-trifluorometh-ylpentyl]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-methyl-1H-quinolin-4-one;1-[2-Hydroxy-4-(4-hydroxybiphenyl-3-yl)-4-methyl-2-trifluoromethylpentyl]--1H-quinolin-4-one;1-{4-[5-(3,5-Dimethylisoxazol-4-yl)-2-hydroxyphenyl]-2-hydroxy-4-methyl-2--trifluoromethylpentyl}-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-hydroxy-5-thiophen-3-ylphenyl)-4-methyl-2-trifluorometh-ylpentyl]-1H-quinolin-4-one;1-{4-[5-(3,5-Dimethylisoxazol-4-yl)-2-methoxyphenyl]-2-hydroxy-4-methyl-2--trifluoromethylpentyl}-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-[1,5]naphthyridin-4-one;1-[2-Hydroxy-4-methyl-4-(3-pyridin-3-ylphenyl)-2-trifluoromethylpentyl]-1-H-quinolin-4-one;1-[2-Hydroxy-4-(2-hydroxy-5-morpholin-4-ylmethylphenyl)-4-methyl-2-triflu-oromethylpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-methoxy-5-morpholin-4-ylmethylphenyl)-4-methyl-2-triflu-oromethylpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(5-hydroxymethyl-2-methoxyphenyl)-4-methyl-2-trifluorometh-ylpentyl]-1H-quinolin-4-one;4-Methoxy-3-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin--1-ylmethyl)butyl]benzaldehyde;1-[4-(5-[1,3]Dioxan-2-yl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorom-ethylpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-methoxy-5-thiophen-3-ylphenyl)-4-methyl-2-trifluorometh-ylpentyl]-1H-quinolin-4-one;1-[4-(5-Furan-3-yl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylp-entyl]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinazolin-4-one;1-[2-Hydroxy-4-(4-methoxybiphenyl-3-yl)-4-methyl-2-trifluoromethylpentyl]--1H-quinolin-4-one;1-[4-(5-Acetyl-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-(4-{3-[1-(Benzyloxyimino)ethyl]phenyl}-2-hydroxy-4-methyl-2-trifluorome-thylpentyl)-1H-quinolin-4-one;1-[4-(3-Cyclopropanecarbonylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylp-entyl]-1H-quinolin-4-one;1-[4-(5-Acetyl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-(2-Hydroxy-4-{3-[1-(methoxyimino)ethyl]phenyl}-4-methyl-2-trifluorometh-ylpentyl)-1H-quinolin-4-one;1-[4-(5-Bromo-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one;1-(2-Hydroxy-4-{3-[1-(hydroxyimino)ethyl]phenyl}-4-methyl-2-trifluorometh-ylpentyl)-1H-quinolin-4-one;1-[4-(5-Bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one;1-[4-(3,5-Difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H--quinolin-4-one;1-[4-(3,5-Dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H--quinolin-4-one;1-{2-Hydroxy-4-methyl-4-[3-(2-methyl-[1,3]dioxolan-2-yl)phenyl]-2-trifluo-romethylpentyl}-1H-quinolin-4-one;1-[2-Hydroxy-4-(3-hydroxymethylphenyl)-4-methyl-2-trifluoromethylpentyl]--1H-quinolin-4-one;1-[4-(3-[1,3]Dioxan-2-ylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-(3-Acetylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quin-olin-4-one;1-{4-[3-(3,5-Dimethylisoxazol-4-yl)phenyl]-2-hydroxy-4-methyl-2-trifluoro-methylpentyl}-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-3,5-dimethyl-1H-pyridin-4-one;1-{2-Hydroxy-4-[3-(1-hydroxyethyl)phenyl]-4-methyl-2-trifluoromethylpenty-l}-1H-quinolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-2-hydroxymethyl-3,5-dimethyl-1H-pyridin-4-one;3-[4,4,4-Trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1-ylmethyl-)butyl]benzaldehyde;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-2-hydroxymethyl-3,5-dimethyl-1H-pyridin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-hydroxymethyl-1H-quinolin-4-one;1-[4-(3-Bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quino-lin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluorom-ethylpentyl]-7-hydroxy-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-6-methyl-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-hydroxymethyl-1H-quinolin-4-one;6-Chloro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-[-4-(2-Difluoromethoxy-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-(4-Biphenyl-3-yl-2-hydroxy-4-methyl-2-trifluoromethylpentyl)-1H-quinoli-n-4-one;6-Chloro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-tri-fluoromethylpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-hydroxy-5-methylphenyl)-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-{2-Hydroxy-4-methyl-4-[3-(2-oxopropoxy)phenyl]-2-trifluoromethylpentyl}--1H-quinolin-4-one;1-[2-Hydroxy-4-(3-isopropoxyphenyl)-4-methyl-2-trifluoromethylpentyl]-1H--quinolin-4-one;1-[4-(3-Ethoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quin-olin-4-one;1-[2-Hydroxy-4-(2-methoxy-5-methylphenyl)-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-(2,5-Dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H--quinolin-4-one;1-[2-Hydroxy-4-(3-hydroxyphenyl)-4-methyl-2-trifluoromethylpentyl]-1H-qui-nolin-4-one;1-[2-Hydroxy-4-(3-methoxyphenyl)-4-methyl-2-trifluoromethylpentyl]-1H-qui-nolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1,2-dihydroindazol-3-one;7-Fluoro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3,5-dimethyl-1H-pyridin-4-one;7-Fluoro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-(2-Hydroxy-4-methyl-4-phenyl-2-trifluoromethylhexyl)-1H-quinolin-4-one;1-[4-(4-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one;1-[4-(3,4-Dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H--quinolin-4-one;8-Fluoro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;6-Fluoro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-{4-[5-Fluoro-2-(2-oxopropoxy)phenyl]-2-hydroxy-4-methyl-2-trifluorometh-ylpentyl}-1H-quinolin-4-one;7-Chloro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-isopropoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpe-ntyl]-1H-quinolin-4-one;1-[4-(2-Benzyloxy-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpen-tyl]-1H-quinolin-4-one;1-[4-(2-Ethoxy-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one;8-Fluoro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;6-Fluoro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;7-Chloro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-[4-(3-Fluoro-4-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-nitro-5-trifluoromethyl-1H-pyridin-2-one;3-Chloro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-5-trifluoromethyl-1H-pyridin-2-one;2-(2,3-Dihydroindol-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphen-yl)-4-methylpentan-2-ol;1-[2-Hydroxy-4-methyl-4-(3-morpholin-4-ylmethylphenyl)-2-trifluoromethylp-entyl]-1H-quinolin-4-one;{4-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpent-yl]piperazin-1-yl}furan-2-ylmethanone;2-[4-(3-Chloro-5-trifluoromethylpyridin-2-yl)piperazin-1-ylmethyl]-1,1,1--trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;{4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpent-yl]piperazin-1-yl}furan-2-ylmethanone;1-[2-Hydroxy-4-(2-methoxy-5-pyridin-3-ylphenyl)-4-methyl-2-trifluoromethy-lpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-hydroxy-3,5-dimethylphenyl)-4-methyl-2-trifluoromethylp-entyl]-1H-quinolin-4-one;1-[4-(3-[1,3]Dioxan-2-yl-4-fluorophenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-methoxy-5-pyrimidin-5-ylphenyl)-4-methyl-2-trifluoromet-hylpentyl]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one;1-[4-(2,4-dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H--quinolin-4-one;1-[4-(4-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-(3-Fluoro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1,2-dihydroindazol-3-one;2-(3,4-Dihydro-2H-quinoxalin-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-me-thoxyphenyl)-4-methylpentan-2-ol;2-(2,3-Dihydrobenzo[1,4]thiazin-4-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2--methoxyphenyl)-4-methylpentan-2-ol;1-{4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpe-ntyl]-3,4-dihydro-2H-quinoxalin-1-yl}ethanone;1-[2-Hydroxy-4-(2-hydroxy-5-thiophen-3-ylphenyl)-4-methyl-2-trifluorometh-ylpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-methoxy-3,5-dimethylphenyl)-4-methyl-2-trifluoromethylp-entyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-hydroxy-5-pyridin-3-ylphenyl)-4-methyl-2-trifluoromethy-lpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-hydroxy-5-pyrimidin-5-ylphenyl)-4-methyl-2-trifluoromet-hylpentyl]-1H-quinolin-4-one; and Carbonic acid4-fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1--ylmethyl)butyl]phenyl ester methyl ester, or a tautomer or saltthereof.
7. A compound according to claim 6, the compound selected from:2-(2,6-Dimethylmorpholin-4-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methox-yphenyl)-4-methylpentan-2-ol;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3,5-dimethylpiperidin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-methyl-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-2,3-dihydro-1H-quinolin-4-one;1-[4-(4-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quin-olin-4-one;1-[4-(3-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quin-olin-4-one;1-[4-(4-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-Phenyl-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one-;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpent-yl]-1H-[1,5]naphthyridin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-2,4-dimethylpentyl]-3,5-dimethy-l-1H-pyridin-4-one;1-[2-Hydroxy-4-(2-methoxy-5-thiophen-2-ylphenyl)-4-methyl-2-trifluorometh-ylpentyl]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-methyl-1H-quinolin-4-one;1-[2-Hydroxy-4-(4-hydroxybiphenyl-3-yl)-4-methyl-2-trifluoromethylpentyl]--1H-quinolin-4-one;1-{4-[5-(3,5-Dimethylisoxazol-4-yl)-2-hydroxyphenyl]-2-hydroxy-4-methyl-2--trifluoromethylpentyl}-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-hydroxy-5-thiophen-3-ylphenyl)-4-methyl-2-trifluorometh-ylpentyl]-1H-quinolin-4-one;1-{4-[5-(3,5-Dimethylisoxazol-4-yl)-2-methoxyphenyl]-2-hydroxy-4-methyl-2--trifluoromethylpentyl}-1H-quinolin-4-one;1-[2-Hydroxy-4-methyl-4-(3-pyridin-3-ylphenyl)-2-trifluoromethylpentyl]-1-H-quinolin-4-one;4-Methoxy-3-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin--1-ylmethyl)butyl]benzaldehyde;1-[2-Hydroxy-4-(2-methoxy-5-thiophen-3-ylphenyl)-4-methyl-2-trifluorometh-ylpentyl]-1H-quinolin-4-one;1-[4-(5-Furan-3-yl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylp-entyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(4-methoxybiphenyl-3-yl)-4-methyl-2-trifluoromethylpentyl]--1H-quinolin-4-one;1-[4-(5-Acetyl-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-(4-{3-[1-(Benzyloxyimino)ethyl]phenyl}-2-hydroxy-4-methyl-2-trifluorome-thylpentyl)-1H-quinolin-4-one;1-[4-(5-Acetyl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-(2-Hydroxy-4-{3-[1-(methoxyimino)ethyl]phenyl}-4-methyl-2-trifluorometh-ylpentyl)-1H-quinolin-4-one;1-[4-(5-Bromo-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one;1-(2-Hydroxy-4-{3-[1-(hydroxyimino)ethyl]phenyl}-4-methyl-2-trifluorometh-ylpentyl)-1H-quinolin-4-one;1-[4-(5-Bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one;1-[4-(3,5-Difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H--quinolin-4-one;1-[4-(3,5-Dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H--quinolin-4-one;1-{2-Hydroxy-4-methyl-4-[3-(2-methyl-[1,3]dioxolan-2-yl)phenyl]-2-trifluo-romethylpentyl}-1H-quinolin-4-one;1-[4-(3-[1,3]Dioxan-2-ylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-{4-[3-(3,5-Dimethylisoxazol-4-yl)phenyl]-2-hydroxy-4-methyl-2-trifluoro-methylpentyl}-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-2-hydroxymethyl-3,5-dimethyl-1H-pyridin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-hydroxymethyl-1H-quinolin-4-one;1-[4-(3-Bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quino-lin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorom-ethylpentyl]-6-methyl-1H-quinolin-4-one;6-Chloro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-[-4-(2-Difluoromethoxy-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-(4-Biphenyl-3-yl-2-hydroxy-4-methyl-2-trifluoromethylpentyl)-1H-quinoli-n-4-one;1-[2-Hydroxy-4-(2-hydroxy-5-methylphenyl)-4-methyl-2-trifluoromet-hylpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(3-isopropoxyphenyl)-4-methyl-2-trifluoromethylpentyl]-1H--quinolin-4-one;1-[4-(3-Ethoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quin-olin-4-one;1-[2-Hydroxy-4-(2-methoxy-5-methylphenyl)-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-(2,5-Dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H--quinolin-4-one;1-[2-Hydroxy-4-(3-methoxyphenyl)-4-methyl-2-trifluoromethylpentyl]-1H-qui-nolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1,2-dihydroindazol-3-one;7-Fluoro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3,5-dimethyl-1H-pyridin-4-one;7-Fluoro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-(2-Hydroxy-4-methyl-4-phenyl-2-trifluoromethylhexyl)-1H-quinolin-4-one;1-[4-(4-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one;1-[4-(3,4-Dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H--quinolin-4-one;8-Fluoro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;6-Fluoro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;7-Chloro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-isopropoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpe-ntyl]-1H-quinolin-4-one;1-[4-(2-Ethoxy-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one;8-Fluoro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;6-Fluoro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;7-Chloro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;3-Chloro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-5-trifluoromethyl-1H-pyridin-2-one;1-[2-Hydroxy-4-(2-methoxy-5-pyridin-3-ylphenyl)-4-methyl-2-trifluoromethy-lpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-hydroxy-3,5-dimethylphenyl)-4-methyl-2-trifluoromethylp-entyl]-1H-quinolin-4-one;1-[4-(3-[1,3]Dioxan-2-yl-4-fluorophenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;2-(1,1-Dioxo-2,3-dihydro-1H-1.lamda..sup.6-benzo[1,4]thiazin-4-ylmethyl)--1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;2-(2,3-Dihydrobenzo[1,4]oxazin-4-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2--methoxyphenyl)-4-methylpentan-2-ol;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-[1,5]naphthyridin-4-one;1-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one;1-[4-(2,4-dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H--quinolin-4-one;1-[4-(4-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-(3-Fluoro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1,2-dihydroindazol-3-one;1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1-oxo-2,3-dihydr-o-1H-1.lamda..sup.4-benzo[1,4]thiazin-4-ylmethyl)pentan-2-ol;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-2-hydroxymethyl-3,5-dimethyl-1H-pyridin-4-one;1-[2-Hydroxy-4-(2-methoxy-3,5-dimethylphenyl)-4-methyl-2-trifluoromethylp-entyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-hydroxy-5-pyridin-3-ylphenyl)-4-methyl-2-trifluoromethy-lpentyl]-1H-quinolin-4-one; and1-[2-Hydroxy-4-(2-hydroxy-5-pyrimidin-5-ylphenyl)-4-methyl-2-trifluoromet-hylpentyl]-1H-quinolin-4-one, or a tautomer or salt thereof.
8. A pharmaceutical composition comprising an effective amount of acompound according to one of claims 1 to 7, or a tautomer or saltthereof, and a pharmaceutically acceptable excipient or carrier.
Description
FIELD OF THE INVENTION
The present invention relates to glucocorticoid mimetics orligands, methods of making such compounds, their use inpharmaceutical compositions, and their use in modulating theglucocorticoid receptor function, treating disease-states orconditions mediated by the glucocorticoid receptor function in apatient in need of such treatment, and other uses.
BACKGROUND OF THE INVENTION
Glucocorticoids, a class of corticosteroids, are endogenoushormones with profound effects on the immune system and multipleorgan systems. They suppress a variety of immune and inflammatoryfunctions by inhibition of inflammatory cytokines such as IL-1,IL-2, IL-6, and TNF, inhibition of arachidonic acid metabolitesincluding prostaglandins and leukotrienes, depletion ofT-lymphocytes, and reduction of the expression of adhesionmolecules on endothelial cells (P. J. Barnes, Clin. Sci., 1998, 94,pp. 557-572; P. J. Barnes et al., Trends Pharmacol. Sci., 1993, 14,pp. 436-441). In addition to these effects, glucocorticoidsstimulate glucose production in the liver and catabolism ofproteins, play a role in electrolyte and water balance, reducecalcium absorption, and inhibit osteoblast function.
The anti-inflammatory and immune suppressive activities ofendogenous glucocorticoids have stimulated the development ofsynthetic glucocorticoid derivatives including dexamethasone,prednisone, and prednisolone (L. Parente, Glucocorticoids, N. J.Goulding and R. J. Flowers (eds.), Boston: Birkhauser, 2001, pp.35-54). These have found wide use in the treatment of inflammatory,immune, and allergic disorders including rheumatic diseases such asrheumatoid arthritis, juvenile arthritis, and ankylosingspondylitis, dermatological diseases including psoriasis andpemphigus, allergic disorders including allergic rhinitis, atopicdermatitis, and contact dermatitis, pulmonary conditions includingasthma and chronic obstructive pulmonary disease (COPD), and otherimmune and inflammatory diseases including Crohn disease,ulcerative colitis, systemic lupus erythematosus, autoimmunechronic active hepatitis, osteoarthritis, tendonitis, and bursitis(J. Toogood, Glucocorticoids, N. J. Goulding and R. J. Flowers(eds.), Boston: Birkhauser, 2001, pp. 161-174). They have also beenused to help prevent rejection in organ transplantation.
Unfortunately, in addition to the desired therapeutic effects ofglucocorticoids, their use is associated with a number of adverseside effects, some of which can be severe and life-threatening.These include alterations in fluid and electrolyte balance, edema,weight gain, hypertension, muscle weakness, development oraggravation of diabetes mellitus, and osteoporosis. Therefore, acompound that exhibited a reduced side effect profile whilemaintaining the potent anti-inflammatory effects would beparticularly desirable especially when treating a chronicdisease.
The effects of glucocorticoids are mediated at the cellular levelby the glucocorticoid receptor (R. H. Oakley and J. Cidlowski,Glucocorticoids, N. J. Goulding and R. J. Flowers (eds.), Boston:Birkhauser, 2001, pp. 55-80). The glucocorticoid receptor is amember of a class of structurally related intracellular receptorsthat when coupled with a ligand can function as a transcriptionfactor that affects gene expression (R. M. Evans, Science, 1988,240, pp. 889-895). Other members of the family of steroid receptorsinclude the mineralocorticoid, progesterone, estrogen, and androgenreceptors. In addition to the effects mentioned above forglucocorticoids, hormones that act on this receptor family have aprofound influence on body homeostasis, mineral metabolism, thestress response, and development of sexual characteristics.Glucocorticoids, N. J. Goulding and R. J. Flowers (eds.), Boston:Birkhauser, 2001, is hereby incorporated by reference in itsentirety to better describe the state of the art. A molecularmechanism which accounts for the beneficial anti-inflammatoryeffects and the undesired side effects has been proposed (e.g., S.Heck et al., EMBO J, 1994, 17, pp. 4087-4095; H. M. Reichardt etal., Cell, 1998, 93, pp. 531-541; F. Tronche et al., Curr. Opin. inGenetics and Dev., 1998, 8, pp. 532-538). Many of the metabolic andcardiovascular side effects are thought to be the result of aprocess called transactivation. In transactivation, thetranslocation of the ligand-bound glucocorticoid receptor to thenucleus is followed by binding to glucocorticoid response elements(GREs) in the promoter region of side effect-associated genes, forexample, phosphoenolpyruvate carboxy kinase (PEPCK), in the case ofincreased glucose production. The result is an increasedtranscription rate of these genes which is believed to result,ultimately, in the observed side effects. The anti-inflammatoryeffects are thought to be due to a process called transrepression.In general, transrepression is a process independent of DNA bindingthat results from inhibition of NF-KB and AP-1-mediated pathways,leading to down regulation of many inflammatory and immunemediators. Additionally, it is believed that a number of theobserved side effects may be due to the cross-reactivity of thecurrently available glucocorticoids with other steroid receptors,particularly the mineralocorticoid and progesterone receptors.
Thus, it may be possible to discover ligands for the glucocorticoidreceptor that are highly selective and, upon binding, candissociate the transactivation and transrepression pathways,providing therapeutic agents with a reduced side effect profile.Assay systems to determine effects on transactivation andtransrepression have been described (e.g., C. M. Bamberger and H.M. Schulte, Eur. J. Clin. Invest., 2000, 30 (suppl. 3), pp. 6-9).Selectivity for the glucocorticoid receptor may be determined bycomparing the binding affinity for this receptor with that of othersteroid family receptors including those mentioned above.
Glucocorticoids also stimulate the production of glucose in theliver by a process called gluconeogenesis and it is believed thatthis process is mediated by transactivation events. Increasedglucose production can exacerbate type II diabetes, therefore acompound that selectivity inhibited glucocorticoid mediated glucoseproduction may have therapeutic utility in this indication (J. E.Freidman et al., J. Biol. Chem., 1997, 272, pp. 31475-31481).
Novel ligands for the glucocorticoid receptor have been describedin the scientific and patent literature. For example, PCTInternational Publication No. WO 99/33786 disclosestriphenylpropanamide compounds with potential use in treatinginflammatory diseases. PCT International Publication No. WO00/66522 describes non-steroidal compounds as selective modulatorsof the glucocorticoid receptor potentially useful in treatingmetabolic and inflammatory diseases. PCT International PublicationNo. WO 99/41256 describes tetracyclic modulators of theglucocorticoid receptor potentially useful in treating immune,autoimmune, and inflammatory diseases. U.S. Pat. No. 5,688,810describes various non-steroidal compounds as modulators ofglucocorticoid and other steroid receptors. PCT InternationalPublication No. WO 99/63976 describes a non-steroidal,liver-selective glucocorticoid antagonist potentially useful in thetreatment of diabetes. PCT International Publication No. WO00/32584 discloses non-steroidal compounds having anti-inflammatoryactivity with dissociation between anti-inflammatory and metaboliceffects. PCT International Publication No. WO 98/54159 describesnon-steroidal cyclically substituted acylanilides with mixedgestagen and androgen activity. U.S. Pat. No. 4,880,839 describesacylanilides having progestational activity and EP 253503 disclosesacylanilides with antiandrogenic properties. PCT InternationalPublication No. WO 97/27852 describes amides that are inhibitors offarnesyl-protein transferase.
A compound that is found to interact with the glucocorticoidreceptor in a binding assay could be an agonist or an antagonist.The agonist properties of the compound could be evaluated in thetransactivation or transrepression assays described above. Giventhe efficacy demonstrated by available glucocorticoid drugs ininflammatory and immune diseases and their adverse side effects,there remains a need for novel glucocorticoid receptor agonistswith selectivity over other members of the steroid receptor familyand a dissociation of the transactivation and transrepressionactivities. Alternatively, the compound may be found to haveantagonist activity. As mentioned above, glucocorticoids stimulateglucose production in the liver. Increased glucose productioninduced by glucocorticoid excess can exacerbate existing diabetes,or trigger latent diabetes. Thus a ligand for the glucocorticoidreceptor that is found to be an antagonist may be useful, interalia, for treating or preventing diabetes.
SUMMARY OF THE INVENTION
The instant invention is directed to compounds of Formula (IA)
##STR00002## wherein: R.sup.1 is an aryl, heteroaryl, orC.sub.5-C.sub.15 cycloalkyl group, each optionally independentlysubstituted with one to three substituent groups, wherein eachsubstituent group of R.sup.1 is independently C.sub.1-C.sub.5alkyl, C.sub.2-C.sub.5 alkenyl, C.sub.2-C.sub.5 alkynyl,C.sub.3-C.sub.8 cycloalkyl, heterocyclyl, aryl, heteroaryl,C.sub.1-C.sub.5 alkoxy, C.sub.2-C.sub.5 alkenyloxy, C.sub.2-C.sub.5alkynyloxy, aryloxy, acyl, C.sub.1-C.sub.5 alkoxycarbonyl,C.sub.1-C.sub.5 alkanoyloxy, C.sub.1-C.sub.5 alkanoyl, aroyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,aminocarbonyloxy, C.sub.1-C.sub.5 alkylaminocarbonyloxy,C.sub.1-C.sub.5 dialkylaminocarbonyloxy, C.sub.3-C.sub.5cycloalkylaminocarbonyloxy, C.sub.1-C.sub.5 alkanoylamino,C.sub.1-C.sub.5 alkoxycarbonylamino, C.sub.1-C.sub.5alkylsulfonylamino, aminosulfonyl, C.sub.1-C.sub.5alkylaminosulfonyl, C.sub.1-C.sub.5 dialkylaminosulfonyl, halogen,hydroxy, oxo, carboxy, cyano, trifluoromethyl, trifluoromethoxy,nitro, or amino wherein the nitrogen atom is optionallyindependently mono- or di-substituted by C.sub.1-C.sub.5 alkyl oraryl; or ureido wherein either nitrogen atom is optionallyindependently substituted with C.sub.1-C.sub.5 alkyl orC.sub.3-C.sub.5 cycloalkyl; or C.sub.1-C.sub.5 alkylthio whereinthe sulfur atom is optionally oxidized to a sulfoxide or sulfone,wherein each substituent group of R.sup.1 is optionallyindependently substituted with one to four substituent groupsselected from aryl or heterocyclyl wherein the heterocycle isoptionally independently substituted with hydroxyl, halogen,methyl, or dialkyl amino; C.sub.1-C.sub.5 alkoxycarbonyl, methyl,methoxy, halogen, hydroxy, oxo, cyano, or amino wherein thenitrogen atom is optionally independently mono- or di-substitutedby C.sub.1-C.sub.5 alkyl or C.sub.1-C.sub.3 dialkylamines or aryl;or ureido wherein either nitrogen atom is optionally independentlysubstituted with C.sub.1-C.sub.5 alkyl; aminosulfonyl, or oximewherein the oxygen atom is optionally substituted byC.sub.1-C.sub.5 alkyl or benzyl. R.sup.2 and R.sup.3 are eachindependently hydrogen, C.sub.1-C.sub.5 alkyl, or C.sub.5-C.sub.15arylalkyl group, or R.sup.2 and R.sup.3 together with the carbonatom they are commonly attached to form a C.sub.3-C.sub.8 spirocycloalkyl ring, or R.sup.1 and R.sup.2 when taken together are achromanyl or dihydrobenzofuranyl optionally substituted withC.sub.1-C.sub.5 alkyl, C.sub.2-C.sub.5 alkenyl, C.sub.2-C.sub.5alkynyl, C.sub.3-C.sub.8 cycloalkyl, heterocyclyl, aryl,heteroaryl, C.sub.1-C.sub.5 alkoxy, C.sub.2-C.sub.5 alkenyloxy,C.sub.2-C.sub.5 alkynyloxy, aryloxy, acyl, C.sub.1-C.sub.5alkoxycarbonyl, C.sub.1-C.sub.5 alkanoyloxy, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy,C.sub.1-C.sub.5 alkylaminocarbonyloxy, C.sub.1-C.sub.5dialkylaminocarbonyloxy, C.sub.1-C.sub.5 alkanoylamino,C.sub.1-C.sub.5 alkoxycarbonylamino, C.sub.1-C.sub.5alkylsulfonylamino, aminosulfonyl, C.sub.1-C.sub.5alkylaminosulfonyl, C.sub.1-C.sub.5 dialkylaminosulfonyl, halogen,hydroxy, carboxy, oxo, cyano, trifluoromethyl, trifluoromethoxy,trifluoromethylthio, nitro, or amino wherein the nitrogen atom isoptionally independently mono- or di-substituted by C.sub.1-C.sub.5alkyl; or ureido wherein either nitrogen atom is optionallyindependently substituted with C.sub.1-C.sub.5 alkyl; orC.sub.1-C.sub.5 alkylthio wherein the sulfur atom is optionallyoxidized to a sulfoxide or sulfone; R.sup.4 is carbonyl ormethylene optionally independently substituted with one to twosubstituent groups selected from C.sub.1-C.sub.3 alkyl, hydroxy,and halogen; R.sup.5 is a pyrrolidine, morpholine, thiomorpholine,piperazine, piperidine, 1H-pyridin-4-one, 1H-pyridin-2-one,1H-pyridin-4-ylideneamine, 1H-quinolin-4-ylideneamine, pyran,tetrahydropyran, 1,4-diazepane, 2,5-diazabicyclo[2.2.1]heptane,2,3,4,5-tetrahydrobenzo[b][1,4]diazepine, dihydroquinoline,tetrahydroquinoline, 5,6,7,8-tetrahydro-1H-quinolin-4-one,tetrahydroisoquinoline, decahydroisoquinoline,2,3-dihydro-1H-isoindole, 2,3-dihydro-1H-indole, chroman,1,2,3,4-tetrahydroquinoxaline, 1,2-dihydroindazol-3-one,3,4-dihydro-2H-benzo[1,4]oxazine, 4H-benzo[1,4]thiazine,3,4-dihydro-2H-benzo[1,4]thiazine, 1,2-dihydrobenzo[d][1,3]oxazin4-one, 3,4-dihydrobenzo[1,4]oxazin4-one,3H-quinazolin-4-one, 3,4-dihydro-1H-quinoxalin-2-one,1H-cinnolin-4-one, 1H-quinazolin-4-one, 1H-[1,5]naphthyridin-4-one,5,6,7,8-tetrahydro-1H-[1,5]naphthyridin-4-one,2,3-dihydro-1H-[1,5]naphthyridin-4-one,1,2-dihydropyrido[3,2-d][1,3]oxazin-4-one,pyrrolo[3,4-c]pyridine-1,3-dione,1,2-dihydropyrrolo[3,4-c]pyridin-3-one, ortetrahydro[b][1,4]diazepinone, group, each optionally independentlysubstituted with one to three substituent groups, wherein eachsubstituent group of R.sup.5 is independently C.sub.1-C.sub.5alkyl, C.sub.2-C.sub.5 alkenyl, C.sub.2-C.sub.5 alkynyl,C.sub.3-C.sub.8 cycloalkyl, heterocyclyl, aryl, heteroaryl,C.sub.1-C.sub.5 alkoxy, C.sub.2-C.sub.5 alkenyloxy, C.sub.2-C.sub.5alkynyloxy, aryloxy, acyl, C.sub.1-C.sub.5 alkoxycarbonyl,C.sub.1-C.sub.5 alkanoyloxy, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, aminocarbonyloxy, C.sub.1-C.sub.5alkylaminocarbonyloxy, C.sub.1-C.sub.5 dialkylaminocarbonyloxy,C.sub.1-C.sub.5 alkanoylamino, C.sub.1-C.sub.5 alkoxycarbonylamino,C.sub.1-C.sub.5 alkylsulfonylamino, C.sub.1-C.sub.5alkylaminosulfonyl, C.sub.1-C.sub.5 dialkylaminosulfonyl, halogen,hydroxy, carboxy, oxo, cyano, trifluoromethyl, trifluoromethoxy,trifluoromethylthio, nitro, or amino wherein the nitrogen atom isoptionally independently mono- or di-substituted by C.sub.1-C.sub.5alkyl; or ureido wherein either nitrogen atom is optionallyindependently substituted with C.sub.1-C.sub.5 alkyl; orC.sub.1-C.sub.5 alkylthio wherein the sulfur atom is optionallyoxidized to a sulfoxide or sulfone, wherein each substituent groupof R.sup.5 is optionally independently substituted with one tothree substituent groups selected from C.sub.1-C.sub.3 alkyl,C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 alkoxycarbonyl, acyl, aryl,benzyl, heteroaryl, heterocyclyl, halogen, hydroxy, oxo, cyano,amino wherein the nitrogen atom is optionally independently mono-or di-substituted by C.sub.1-C.sub.5 alkyl; or ureido whereineither nitrogen atom is optionally independently substituted withC.sub.1-C.sub.5 alkyl;, or trifluoromethyl; and X is a hydroxy oramino wherein the nitrogen atom is optionally independently mono-or di-substituted by C.sub.1-C.sub.5 alkyl, or a tautomer, prodrug,solvate, or salt thereof.
Another aspect of the invention includes compounds of Formula (IA),wherein: R.sup.1 is phenyl, dihydrobenzofuranyl, benzofuranyl,dihydroindolyl, indolyl, benzo[1,3]dioxole, dihydrobenzothienyl,benzothienyl, benzoxazole, benzisoxazole, benzpyrazole,benzimidazole, thienyl, quinolinyl, tetrahydroquinolinone,tetrahydronaphthyridinone, dihydrochromene, pyridinyl, pyrimidinyl,or pyrazinyl, each optionally independently substituted with one tothree substituent groups, wherein each substituent group of R.sup.1is independently C.sub.1-C.sub.3 alkyl, C.sub.2-C.sub.3 alkenyl,C.sub.2-C.sub.3 alkynyl, C.sub.1-C.sub.3 alkoxy, C.sub.2-C.sub.3alkenyloxy, C.sub.1-C.sub.3 alkanoyl, C.sub.1-C.sub.3alkoxycarbonyl, C.sub.1-C.sub.3 alkanoyloxy, halogen, hydroxy,acyl, oxo, carboxy, cyano, trifluoromethyl, nitro, orC.sub.1-C.sub.3 alkylthio wherein the sulfur atom is optionallyoxidized to a sulfoxide or sulfone, wherein each substituent groupof R.sup.1 is optionally independently substituted with asubstituent group selected from methyl, methoxy, halogen, hydroxy,oxo, cyano, or amino; R.sup.2 and R.sup.3 are each independentlyhydrogen, C.sub.1-C.sub.3 alkyl, benzyl, or phenethyl, or R.sup.2and R.sup.3 together with the carbon atom they are commonlyattached to form a C.sub.3-C.sub.6 spiro cycloalkyl ring; andR.sup.4 is CH.sub.2, or a tautomer, prodrug, solvate, or saltthereof.
Yet another aspect of the invention includes compounds of Formula(IA), wherein: R.sup.1 is phenyl, pyridyl, dihydrobenzofuranyl, orbenzofuranyl, each optionally independently substituted with one tothree substituent groups, wherein each substituent group of R.sup.1is independently methyl, ethyl, methoxy, ethoxy, fluoro, chloro,bromo, hydroxy, trifluoromethyl, acyl, oxo, C.sub.1-C.sub.5alkylthio wherein the sulfur atom is optionally oxidized to asulfoxide or sulfone, or cyano; R.sup.2 and R.sup.3 are eachindependently methyl, or R.sup.2 and R.sup.3 together with thecarbon atom they are commonly attached to form a spiro cyclopropylring; and R.sup.4 is CH.sub.2, or a tautomer, prodrug, solvate, orsalt thereof.
Yet another aspect of the invention includes compounds of Formula(IA), wherein: R.sup.1 is phenyl, dihydrobenzofuranyl, orbenzofuranyl, each optionally independently substituted with one tothree substituent groups, wherein each substituent group of R.sup.1is independently C.sub.1-C.sub.3 alkyl, C.sub.2-C.sub.3 alkenyl,C.sub.2-C.sub.3 alkynyl, C.sub.1-C.sub.3 alkoxy, C.sub.2-C.sub.3alkenyloxy, C.sub.1-C.sub.3 alkanoyl, C.sub.1-C.sub.3alkoxycarbonyl, C.sub.1-C.sub.3 alkanoyloxy, halogen, hydroxy,carboxy, cyano, trifluoromethyl, nitro, or C.sub.1-C.sub.3alkylthio wherein the sulfur atom is optionally oxidized to asulfoxide or sulfone; and R.sup.2 and R.sup.3 are eachindependently hydrogen or C.sub.1-C.sub.3 alkyl, or a tautomer,prodrug, solvate, or salt thereof.
An aspect of the invention includes compounds of Formula (IA),wherein: R.sup.5 is a morpholine, thiomorpholine, piperazine,piperidine, 1H-pyridin-4-one, pyran, tetrahydropyran,dihydroquinoline, tetrahydroquinoline, chroman,1,2,3,4-tetrahydroquinoxaline, 3,4-dihydro-2H-benzo[1,4]oxazine,3,4-dihydro-2H-benzo[1,4]thiazine,1,2-dihydrobenzo[d][1,3]oxazin-4-one,3,4-dihydrobenzo[1,4]oxazin-4-one, 3,4-dihydro-1H-quinoxalin-2-one,3,4-dihydro-2H-naphthalen-1-one, 1H-cinnolin-4-one,1H-quinazolin-4-one, 1H-[1,5]naphthyridin-4-one,2,3-dihydro-1H-[1,5]naphthyridin-4-one,3,4-dihydro-2H-isoquinolin-1-one,1,2-dihydropyrido[3,2-d][1,3]oxazin-4-one,pyrrolo[3,4-c]pyridine-1,3-dione, tetrahydro[b][1,4]diazepinone, or1,2-dihydropyrrolo[3,4-c]pyridin-3-one group, each optionallyindependently substituted with one to three substituent groups,wherein each substituent group of R.sup.5 is independentlyC.sub.1-C.sub.5 alkyl, C.sub.2-C.sub.5 alkenyl, C.sub.2-C.sub.5alkynyl, C.sub.3-C.sub.8 cycloalkyl, heterocyclyl, aryl,heteroaryl, C.sub.1-C.sub.5 alkoxy, C.sub.2-C.sub.5 alkenyloxy,C.sub.2-C.sub.5 alkynyloxy, aryloxy, acyl, C.sub.1-C.sub.5alkoxycarbonyl, C.sub.1-C.sub.5 alkanoyloxy, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy,C.sub.1-C.sub.5 alkylaminocarbonyloxy, C.sub.1-C.sub.5dialkylaminocarbonyloxy, C.sub.1-C.sub.5 alkanoylamino,C.sub.1-C.sub.5 alkoxycarbonylamino, C.sub.1-C.sub.5alkylsulfonylamino, C.sub.1-C.sub.5 alkylaminosulfonyl,C.sub.1-C.sub.5 dialkylaminosulfonyl, halogen, hydroxy, carboxy,oxo, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio,nitro, or amino wherein the nitrogen atom is optionallyindependently mono- or di-substituted by C.sub.1-C.sub.5 alkyl; orureido wherein either nitrogen atom is optionally independentlysubstituted with C.sub.1-C.sub.5 alkyl; or C.sub.1-C.sub.5alkylthio wherein the sulfur atom is optionally oxidized to asulfoxide or sulfone, wherein each substituent group of R.sup.5 isoptionally independently substituted with one to three substituentgroups selected from C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy,halogen, hydroxy, oxo, cyano, amino, or trifluoromethyl, or atautomer, prodrug, solvate, or salt thereof.
The following are representative compounds of Formula (IA)according to the invention:
TABLE-US-00001 Compound Name Compound Structure1-{4-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-2,6- dimethylpiperazin-1-yl}ethanone##STR00003## 4-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-2,6- dimethylpiperazine-1-carbaldehyde##STR00004## 1-{5-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2- trifluoromethylpentyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}ethanone ##STR00005##4-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3,4-dihydro-2H- quinoxaline-1-carbaldehyde##STR00006## 4-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3,4-dihydro-1H- quinoxalin-2-one##STR00007## 4-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]piperazine-2,6-dione ##STR00008##2-(2,6-Dimethylthiomorpholin-4-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol ##STR00009##2-(1,1-Dioxo-1H-1.lamda..sup.6-benzo[1,4]thiazin-4- ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methylpentan-2-ol##STR00010## 2-(1,1-Dioxo-2,3-dihydro-1H-1.lamda..sup.6-benzo[1,4]thiazin-4-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4- methylpentan-2-ol##STR00011## 1-{5-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2- trifluoromethylpentyl]-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1- yl}ethanone ##STR00012##5-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1,3,4,5-tetrahydrobenzo[b][1,4]diazepin-2-one ##STR00013##2-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]isoindole-1,3-dione ##STR00014##2-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]pyrrolo[3,4- c]pyridine-1,3-dione##STR00015## 2-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carbonitrile ##STR00016##2-(2,3-Dihydrobenzo[1,4]thiazin-4- ylmethyl)-1,1,1-trifluoro-4-(4-fluorophenyl)-4-methylpentan-2-o1 ##STR00017##4-(2,3-Dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-(4-methyl-3,4- dihydro-2H-quinoxalin-1-ylmethyl)pentan-2-ol ##STR00018##1-{4-[4-(5-Bromo-2,3-dihydrobenzofuran- 7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-3,4-dihydro-2H- quinoxalin-1-yl}ethanone##STR00019## 4-[4-(5-Fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2- trifluoromethylpentyl]-3,4-dihydro-1H-quinoxalin-2-one ##STR00020## 1-{4-[4-(3-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-2,6-dimethylpiperazin-1-yl}ethanone ##STR00021##4-(2,3-Dihydrobenzofuran-7-yl)-2-(2,3-dihydrobenzo[1,4]thiazin-4-ylmethyl)-1,1,1-trifluoro-4-methylpentan-2-ol ##STR00022##2-(3,4-Dihydro-2H-quinoxalin-1- ylmethyl)-1,1,1-trifluoro-4-(4-fluorophenyl)-4-methylpentan-2-ol ##STR00023##2-(2,6-Dimethylthiomorpholin-4- ylmethyl)-1,1,1-trifluoro-4-(4-fluorophenyl)-4-methylpentan-2-ol ##STR00024##2-(1,1-Dioxo-2,3-dihydro-1H-1.lamda..sup.6-benzo[1,4]thiazin-4-ylmethyl)-1,1,1- trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-4-methylpentan- 2-ol ##STR00025##5-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-2,5- diazabicyclo[2.2.1]heptan-3-one##STR00026## 1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-morpholin-4- ylmethylpentan-2-ol##STR00027## 2-(2,6-Dimethylmorpholin-4-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methylpentan-2-ol##STR00028## 2-(2,3-Dihydrobenzo[1,4]oxazin-4-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol ##STR00029##2-(2,3-Dihydrobenzo[1,4]oxazin-4-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-4-methylpentan- 2-ol ##STR00030##1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]piperidin-4-one ##STR00031##1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00032##1-[4-(5-Fluoro-2-hydroxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00033##1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3-methoxy-1H- quinolin-4-one ##STR00034##1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-2,4-dimethylpentyl]-3,5-dimethyl-1H-pyridin-4-one ##STR00035##1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3,5- dimethylpiperidin-4-one ##STR00036##1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinazolin-4- one ##STR00037##1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-cinnolin-4-one ##STR00038##1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3-methyl-1H- quinolin-4-one ##STR00039##1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3-isopropyl-1H- quinolin-4-one ##STR00040##1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-2,3-dihydro-1H- quinolin-4-one ##STR00041##1-[4-(4-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]piperidin- 4-one ##STR00042##1-[4-(4-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H- quinolin-4-one ##STR00043##1-[4-(3-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H- quinolin-4-one ##STR00044##1-[4-(2-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H- quinolin-4-one ##STR00045##1-[4-(3-Fluoro-4-methylphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00046##1-[4-(4-Fluoro-2-hydroxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00047##1-[4-(2-Methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H- quinolin-4-one ##STR00048##1-[4-(3-Cyanophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H- quinolin-4-one ##STR00049##1-[4-(3-Carboxamidophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H- quinolin-4-one ##STR00050##1-[4-(2,6-dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H- quinolin-4-one ##STR00051##1-[4-Phenyl-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00052##1-[4-Cyclohexyl-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00053##1-[4-(Thiophen-2-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4- one ##STR00054##1-[4-(Pyridin-2-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00055##1-[4-(Pyridin-3-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00056##1-[4-(Pyridin-4-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00057##1-[4-(4-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-3,5- dimethylpiperidin-4-one##STR00058## 1-[4-(4-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H- quinazolin-4-one ##STR00059##1-[4-(4-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H- cinnolin-4-one ##STR00060##1-[4-(4-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-3-methyl- 1H-quinolin-4-one##STR00061## 1-[4-(4-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-3- isopropyl-1H-quinolin-4-one##STR00062## 1-[4-(5-Fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2- trifluoromethylpentyl]-1H-quinolin-4-one##STR00063## 1-[4-(5-Fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2- trifluoromethylpentyl]-3-metliyl-1H-quinolin-4-one ##STR00064## 1-[4-(5-Bromo-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2- trifluoromethylpentyl]-1H-quinolin-4-one##STR00065## 1-[4-(5-Cyano-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2- trifluoromethylpentyl]-1H-quinolin-4-one##STR00066## 1-[4-(5-Methyl-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2- trifluoromethylpentyl]-1H-quinolin-4-one##STR00067## 1-[4-(5-Chloro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2- trifluoromethylpentyl]-1H-quinolin-4-one##STR00068## 1-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2- trifluoromethylpentyl]-1H-quinolin-4-one##STR00069## 1-[4-(5-Methoxy-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00070##1-[4-(5-Fluoro-2,3-dihydrobenzofuran-7- yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-3,5- dimethylpiperidin-4-one ##STR00071##1-[4-(5-Fluoro-2,3-dihydrobenzofuran-7- yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinazolin-4- one ##STR00072##1-[4-(5-Fluoro-2,3-dihydrobenzofuran-7- yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-cinnolin-4-one ##STR00073##1-[4-(5-Fluoro-2,3-dihydrobenzofuran-7- yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-2,3-dihydro-1H- quinolin-4-one ##STR00074##1-[4-(5-Bromo-2,3-dihydrobenzofuran-7- yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-2,3-dihydro-1H- quinolin-4-one ##STR00075##1-[4-(5-Cyano-2,3-dihydrobenzofuran-7- yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-2,3-dihydro-1H- quinolin-4-one ##STR00076##1-[4-(4-Fluoro-2,3-dihydrobenzofuran-7- yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-2,3-dihydro-1H- quinolin-4-one ##STR00077##1-[2,2,2-Trifluoro-1-hydroxy-1-(4-methylchroman-4-ylmethyl)ethyl]-1H- quinolin-4-one ##STR00078##1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1,2- dihydrobenzo[d][1,3]oxazin-4-one##STR00079##
1-[4-(5-Fluoro-2-hydroxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1,2- dihydrobenzo[d][1,3]oxazin-4-one##STR00080## 4-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3,4- dihydrobenzo[1,4]oxazin-2-one##STR00081## 4-[4-(5-Fluoro-2-hydroxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3,4- dihydrobenzo[1,4]oxazin-2-one##STR00082## 1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1H- [1,5]naphthyridin-4-one ##STR00083##1-[4-(5-Fluoro-2-hydroxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1H- [1,5]naphthyridin-4-one ##STR00084##1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-2,3-dihydro-1H- [1,5]naphthyridin-4-one##STR00085## 1-[4-(5-Fluoro-2-hydroxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-2,3-dihydro-1H- [1,5]naphthyridin-4-one##STR00086## 1-[4-(5-Fluoro-2-methylphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00087##1-[4-(2,4-dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H- quinolin-4-one ##STR00088##1-[4-(4-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00089##1-[4-(3-Fluoro-4-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00090##1-(4-Benzo[1,3]dioxol-4-yl-2-hydroxy-4-methyl-2-trifluoromethylpentyl)-1H- quinolin-4-one ##STR00091##1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1,2-dihydroindazol- 3-one ##STR00092##1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-piperazin-1- ylmethylpentan-2-ol##STR00093## 1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-methylpiperazin-1-ylmethyl)pentan-2-ol ##STR00094##1-{4-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]piperazin-1- yl}ethanone ##STR00095##2-(3,5-Dimethylpiperazin-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methylpentan-2-ol##STR00096## 1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(3,4,5-trimethylpiperazin-1-ylmethyl)pentan-2-ol ##STR00097##2-(3,4-Dihydro-2H-quinoxalin-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol ##STR00098##1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-(4-methyl-3,4-dihydro-2H-quinoxalin-1- ylmethyl)pentan-2-ol ##STR00099##2-[1,4]Diazepan-1-ylmethyl-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4- methylpentan-2-ol##STR00100## 1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-methyl-[1,4]diazepan-1-ylmethyl)pentan-2-ol ##STR00101##1-{4-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-[1,4]diazepan-1- yl}ethanone ##STR00102##4-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-[1,4]diazepane-1- carbaldehyde ##STR00103##1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-thiomorpholin-4-ylmethylpentan-2-ol ##STR00104##1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1-oxo-1.lamda..sup.4-thiomorpholin-4-ylmethyl)pentan-2-ol ##STR00105##2-(1,1-Dioxo-1.lamda..sup.6-thiomorpholin-4-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol ##STR00106##2-(2,3-Dihydrobenzo[1,4]thiazin-4-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol ##STR00107##1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1-oxo-2,3-dihydro-1H-1.lamda..sup.4-benzo[1,4]thiazin-4- ylmethyl)pentan-2-ol##STR00108## 1-{4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2- trifluoromethylpentyl]-3,4-dihydro-2H-quinoxalin-1-yl}ethanone ##STR00109##1-[2-Hydroxy-4-(2-methoxy-5-thiophen-2- ylphenyl)-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00110##1-[4-(6-Bromobenzo[1,3]dioxol-4-yl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00111##1-[4-(5-Fluoro-2-hydroxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3-methyl-1H- quinolin-4-one ##STR00112##1-[2-Hydroxy-4-(4-hydroxybiphenyl-3-yl)-4-methyl-2-trifluoromethylpentyl]-1H- quinolin-4-one##STR00113## 1-{4-[5-(3,5-Dimethylisoxazol-4-yl)-2-hydroxyphenyl]-2-hydroxy-4-methyl-2-trifluoromethylpentyl}-1H-quinolin-4-one ##STR00114##1-[2-Hydroxy-4-(2-hydroxy-5-thiophen-3- ylphenyl)-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00115##1-{4-[5-(3,5-Dimethylisoxazol-4-yl)-2-methoxyphenyl]-2-hydroxy-4-methyl-2-trifluoromethylpentyl}-1H-quinolin-4-one ##STR00116##1-[4-(5-Fluoro-2-methylphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1H- [1,5]naphthyridin-4-one ##STR00117##1-[2-Hydroxy-4-(5-methanesulfonyl-2,3-dihydrobenzofuran-7-yl)-4-methyl-2- trifluoromethylpentyl]-1H-[1,5]naphthyridin-4-one ##STR00118##1-[2-Hydroxy-4-methyl-4-(3-pyridin-3-ylphenyl)-2-trifluoromethylpentyl]-1H- quinolin-4-one ##STR00119##1-[2-Hydroxy-4-(2-hydroxy-5-morpholin-4-ylmethylphenyl)-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00120##1-[2-Hydroxy-4-(2-methoxy-5-morpholin-4-ylmethylphenyl)-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00121##1-[2-Hydroxy-4-(5-hydroxymethyl-2- methoxyphenyl)-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00122##4-Methoxy-3-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1- ylmethyl)butyl]benzaldehyde##STR00123## 1-[4-(5-[1,3]Dioxan-2-yl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00124##1-[2-Hydroxy-4-(2-methoxy-5-thiophen-3- ylphenyl)-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00125##1-[4-(5-Furan-3-yl-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00126##1-[2-Hydroxy-4-(5-methanesulfonyl-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-trifluoromethylpentyl]-3,5-dimethyl-1H- pyridin-4-one ##STR00127##1-[4-(5-Fluoro-2-hydroxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinazolin-4- one ##STR00128##1-[2-Hydroxy-4-(4-methoxybiphenyl-3-yl)-4-methyl-2-trifluoromethylpentyl]-1H- quinolin-4-one##STR00129## 1-[4-(5-Acetyl-2-hydroxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00130##1-[3,3,3-Trifluoro-2-(6-fluoro-4- methylchroman-4-ylmethyl)-2-hydroxypropyl]-1H-quinolin-4-one ##STR00131## 1-(4-{3-[1-(Benzyloxyimino)ethyl]phenyl}-2- hydroxy-4-methyl-2-trifluoromethylpentyl)-1H-quinolin-4-one ##STR00132##1-[4-(3-Cyclopropanecarbony1phenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00133##1-[4-(5-Acetyl-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00134##1-(2-Hydroxy-4-{3-[1- (methoxyimino)ethyl]phenyl}-4-methyl-2-trifluoromethylpentyl)-1H-quinolin-4-one ##STR00135##1-[4-(5-Bromo-2-hydroxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00136##1-(2-Hydroxy-4-{3-[1- (hydroxyimino)ethyl]phenyl}-4-methyl-2-trifluoromethylpentyl)-1H-quinolin-4-one ##STR00137##1-[4-(5-Bromo-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00138##1-[4-(3,5-Difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H- quinolin-4-one ##STR00139##1-[4-(3,5-Dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H- quinolin-4-one ##STR00140##1-{2-Hydroxy-4-methyl-4-[3-(2-methyl- [1,3]dioxolan-2-yl)phenyl]-2-trifluoromethylpentyl}-1H-quinolin-4-one ##STR00141##1-[4-(2,3-Dihydrobenzofuran-7-yl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-2-hydroxymethyl-3,5-dimethyl-1H-pyridin-4-one ##STR00142##1-[4-(2,3-Dihydrobenzofuran-7-yl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1H- [1,5]naphthyridin-4-one ##STR00143##1-[2-Hydroxy-4-(3- hydroxymethylphenyl)-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00144##1-[4-(3-[1,3]Dioxan-2-ylphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00145##1-[4-(3-Acetylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H- quinolin-4-one ##STR00146##1-{4-[3-(3,5-Dimethylisoxazol-4- yl)phenyl]-2-hydroxy-4-methyl-2-trifluoromethylpentyl}-1H-quinolin-4-one ##STR00147##1-[4-(5-Fluoro-2-methylphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3,5-dimethyl-1H- pyridin-4-one ##STR00148##1-{2-Hydroxy-4-[3-(1- hydroxyethyl)phenyl]-4-methyl-2-trifluoromethylpentyl}-1H-quinolin-4-one ##STR00149##1-[4-(2,3-Dihydrobenzofuran-7-yl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3,5-dimethyl-1H- pyridin-4-one ##STR00150##1-[4-(5-Fluoro-2-hydroxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-2-hydroxymethyl-3,5-dimethyl-1H-pyridin-4-one ##STR00151##3-[4,4,4-Trifluoro-3-hydroxy-1,1- dimethyl-3-(4-oxo-4H-quinolin-1-ylmethyl)butyl]benzaldehyde ##STR00152##1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-2-(4-imino-4H-quinolin-1-ylmethyl)-4-methylpentan-2-ol ##STR00153##1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-2-hydroxymethyl-3,5-dimethyl-1H-pyridin-4-one ##STR00154##1-[4-(5-Fluoro-2-hydroxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3-hydroxymethyl- 1H-quinolin-4-one##STR00155## 1-[4-(5-Fluoro-2-hydroxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3-hydroxy-2- methyl-1H-pyridin-4-one##STR00156## 1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3-methoxy-2- methyl-1H-pyridin-4-one##STR00157##
1-[4-(3-Bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H- quinolin-4-one ##STR00158##1-[4-(5-Fluoro-2-hydroxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-6-hydroxy-1H- quinolin-4-one ##STR00159##1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3-methoxymethyl- 1H-quinolin-4-one##STR00160## 1-[4-(5-Fluoro-2-hydroxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-7-hydroxy-1H- quinolin-4-one ##STR00161##1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-7-methoxy-1H- quinolin-4-one ##STR00162##1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-6-methoxy-1H- quinolin-4-one ##STR00163##1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-6-methyl-1H- quinolin-4-one ##STR00164##1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3-hydroxymethyl- 1H-quinolin-4-one##STR00165## 6-Chloro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00166##1-[-4-(2-Difluoromethoxy-5- fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00167##1-(4-Biphenyl-3-yl-2-hydroxy-4-methyl-2-trifluoromethylpentyl)-1H-quinolin-4-one ##STR00168##6-Chloro-1-[4-(5-fluoro-2- methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00169##1-[2-Hydroxy-4-(2-hydroxy-5- methylphenyl)-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00170##1-{2-Hydroxy-4-methyl-4-[3-(2- oxopropoxy)phenyl]-2-trifluoromethylpentyl}-1H-quinolin-4-one ##STR00171##1-[2-Hydroxy-4-(3-isopropoxyphenyl)-4-methyl-2-trifluoromethylpentyl]-1H- quinolin-4-one ##STR00172##1-[4-(3-Ethoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H- quinolin-4-one ##STR00173##1-[2-Hydroxy-4-(2-methoxy-5- methylphenyl)-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00174##1-[4-(2,5-Dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H- quinolin-4-one ##STR00175##1-[2-Hydroxy-4-(3-hydroxyphenyl)-4-methyl-2-trifluoromethylpentyl]-1H- quinolin-4-one ##STR00176##1-[2-Hydroxy-4-(3-methoxyphenyl)-4-methyl-2-trifluoromethylpentyl]-1H- quinolin-4-one ##STR00177##1-[4-(5-Fluoro-2-hydroxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1,2-dihydroindazol- 3-one ##STR00178##7-Fluoro-1-[4-(5-fluoro-2- hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00179##1-[4-(5-Fluoro-2-hydroxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3,5-dimethyl-1H- pyridin-4-one ##STR00180##7-Fluoro-1-[4-(5-fluoro-2- methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00181##1-(2-Hydroxy-4-methyl-4-phenyl-2-trifluoromethylhexyl)-1H-quinolin-4-one ##STR00182##2-(3,4-Dihydro-2H-quinolin-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methylpentan-2-ol##STR00183## 1-[4-(4-Fluoro-2-methylphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00184##1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]piperidin-4-ol ##STR00185##1-[4-(3,4-Dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H- quinolin-4-one ##STR00186##8-Fluoro-1-[4-(5-fluoro-2- hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00187##6-Fluoro-1-[4-(5-fluoro-2- hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00188##1-{4-[5-Fluoro-2-(2- hydroxypropoxy)phenyl]-2-hydroxy-4-methyl-2-trifluoromethylpentyl}-1H- quinolin-4-one ##STR00189##1-{4-[5-Fluoro-2-(2-oxopropoxy)phenyl]- 2-hydroxy-4-methyl-2-trifluoromethylpentyl}-1H-quinolin-4-one ##STR00190##7-Chloro-1-[4-(5-fluoro-2- hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00191##1-[4-(5-Fluoro-2-isopropoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00192##1-[4-(2-Benzyloxy-5-fluorophenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00193##1-[4-(2-Ethoxy-5-fluorophenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00194##8-Fluoro-1-[4-(5-fluoro-2- methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00195##6-Fluoro-1-[4-(5-fluoro-2- methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00196##1-[2-Hydroxy-4-(5-methanesulfonyl-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00197##1-[2-Hydroxy-4-(5-methanesulfinyl-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00198##1-[2-Hydroxy-4-methyl-4-(5- methylsulfanyl-2,3-dihydrobenzofuran-7-yl)-2-trifluoromethylpentyl]-1H-quinolin- 4-one ##STR00199##7-Chloro-1-[4-(5-fluoro-2- methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00200##1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]piperidine-4- carboxylic acid amide##STR00201## 1-[4-(2,3-Dihydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H- quinolin-4-one ##STR00202##1-[4-(3-Fluoro-4-hydroxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00203##3-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3H-quinazolin-4- one ##STR00204##4-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1-methyl-3,4- dihydro-1H-quinoxalin-2-one##STR00205## 1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-pyridin-2-one ##STR00206##1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile ##STR00207##1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H- quinolin-2-one ##STR00208##1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3-nitro-5- trifluoromethyl-1H-pyridin-2-one##STR00209## 1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3-nitro-1H-pyridin- 2-one ##STR00210##1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-5-nitro-1H-pyridin- 2-one ##STR00211##3-Chloro-1-[4-(5-fluoro-2- methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-5-trifluoromethyl- 1H-pyridin-2-one##STR00212## 1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-1H- pyridin-2-one ##STR00213##1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-3-nitro- 1H-pyridin-2-one##STR00214## 1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-4-methyl-5-nitro- 1H-pyridin-2-one##STR00215## 2-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol ##STR00216##2-(1,3-Dihydroisoindol-2-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4- methylpentan-2-ol##STR00217## 2-(2,3-Dihydroindol-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4- methylpentan-2-ol##STR00218## 1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1,3-dihydroindol-2- one ##STR00219##1-[4-(3-Dimethylaminomethylphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00220##1-[2-Hydroxy-4-methyl-4-(3-morpholin-4-ylmethylphenyl)-2-trifluoromethylpentyl]- 1H-quinolin-4-one##STR00221## 1-[4-(3-Diethylaminomethylphenyl)-2-hydroxy-4-methyl-2- trifluoromethylpentyl]-1H-quinolin-4-one##STR00222## 1-[4-(3-{[(2- Dimethylaminoethyl)methylamino]methyl}phenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00223##1-{2-Hydroxy-4-[3-(3-hydroxypyrrolidin-1-ylmethyl)phenyl]-4-methyl-2-trifluoromethylpentyl}-1H-quinolin-4-one ##STR00224##1-[4-(3-Ethylaminomethylphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00225##1-[2-Hydroxy-4-methyl-4-(3-pyrrolidin-1-ylmethylphenyl)-2-trifluoromethylpentyl]- 1H-quinolin-4-one##STR00226## 1-[2-Hydroxy-4-methyl-4-(3-piperidin-1-ylmethylphenyl)-2-trifluoromethylpentyl]- 1H-quinolin-4-one##STR00227## 1-{2-Hydroxy-4-methyl-4-[3-(4-methylpiperazin-1-ylmethyl)phenyl]-2-trifluoromethylpentyl}-1H-quinolin-4-one ##STR00228##1-{4-[3-(3-Dimethylaminopyrrolidin-1-ylmethyl)phenyl]-2-hydroxy-4-methyl-2-trifluoromethylpentyl}-1H-quinolin-4-one ##STR00229##1-[2-Hydroxy-4-methyl-4-(3- methylaminomethylphenyl)-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00230##{4-[4-(5-Fluoro-2-hydroxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]piperazin-1- yl}furan-2-ylmethanone##STR00231## 1-[2-Hydroxy-4-(5-methanesulfonyl-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-trifluoromethylpentyl]-3-methyl-1H- quinolin-4-one ##STR00232##1-[4-(2,3-Dihydrobenzofuran-7-yl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3-methyl-1H- quinolin-4-one ##STR00233##1-[4-(5-Chloro-2,3-dihydrobenzofuran-7- yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-3-methyl-1H- quinolin-4-one ##STR00234##1-[4-(5-Fluoro-2-methylphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3-methyl-1H- quinolin-4-one ##STR00235##7-[4,4,4-Trifluoro-3-hydroxy-1,1-dimethyl-3-(3-methyl-4-oxo-4H-quinolin-1-ylmethyl)butyl]-2,3-dihydrobenzofuran- 5-sulfonic acid amide##STR00236## 1-[2-Hydroxy-4-(2-methoxy-3,5-dimethylphenyl)-4-methyl-2-
trifluoromethylpentyl]-1H-quinolin-4-one ##STR00237##1-[2-Hydroxy-4-(2-methoxy-3,5- dimethylphenyl)-4-methyl-2-trifluoromethylpentyl]-3-methyl-1H- quinolin-4-one ##STR00238##1-[2-Hydroxy-4-(2-hydroxy-3,5- dimethylphenyl)-4-methyl-2-trifluoromethylpentyl]-3-methyl-1H- quinolin-4-one ##STR00239##1-[4-(3-Acetyl-2-hydroxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00240##1-[4-(3-Acetyl-2-hydroxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3-methyl-1H- quinolin-4-one ##STR00241##1-[4-(3-Bromo-2-hydroxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00242##1-[2-Hydroxy-4-(2-hydroxybiphenyl-3-yl)-4-methyl-2-trifluoromethylpentyl]-1H- quinolin-4-one##STR00243## 1-(4-Chroman-8-yl-2-hydroxy-4-methyl-2-trifluoromethylpentyl)-1H-quinolin-4- one ##STR00244##1-(4-Chroman-8-yl-2-hydroxy-4-methyl-2-trifluoromethylpentyl)-3-methyl-1H- quinolin-4-one ##STR00245##1-[4-(2-Acetyl-5-fluorophenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00246##1-[4-(5-Fluoro-2-methanesulfonylphenyl)- 2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00247##4-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1- ylmethyl)butyl]benzenesulfonamide##STR00248## 4-Fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1- ylmethyl)butyl]benzamide##STR00249## 4-Fluoro-N,N-dimethyl-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1-ylmethyl)butyl]benzamide ##STR00250##1-[4-(5-Fluoro-2-oxazol-2-ylphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00251##1-[4-(5-Fluoro-2-oxazol-5-ylphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00252##1-[2-Hydroxy-4-(2-hydroxy-3-oxazol-2- ylphenyl)-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00253##1-[2-Hydroxy-4-(2-hydroxy-3-oxazol-5- ylphenyl)-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00254##{4-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3,4-dihydro-2H-quinoxalin-1-yl}furan-2-ylmethanone ##STR00255##{4-[(4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3,4-dihydro-2H-quinoxalin-1-yl}thiophen-2-ylmethanone ##STR00256##{4-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3,4-dihydro-2H-quinoxalin-1-yl}phenylmethanone ##STR00257##{4-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3,4-dihydro-2H- quinoxalin-1-yl}-(4-fluorophenyl)methanone ##STR00258##{4-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3,4-dihydro-2H- quinoxalin-1-yl}-(2-fluorophenyl)methanone ##STR00259##{4-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3,4-dihydro-2H- quinoxalin-1-yl}-(3-fluorophenyl)methanone ##STR00260##{4-[4-(5-Fluoro-2-hydroxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3,4-dihydro-2H-quinoxalin-1-yl}furan-2-ylmethanone ##STR00261##{4-[4-(5-Fluoro-2-hydroxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3,4-dihydro-2H-quinoxalin-1-yl}thiophen-2-ylmethanone ##STR00262##{4-[4-(5-Fluoro-2-hydroxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3,4-dihydro-2H-quinoxalin-1-yl}phenylmethanone ##STR00263##{4-[4-(5-Fluoro-2-hydroxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3,4-dihydro-2H- quinoxalin-1-yl}-(4-fluorophenyl)methanone ##STR00264##{4-[4-(5-Fluoro-2-hydroxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3,4-dihydro-2H- quinoxalin-1-yl}-(2-fluorophenyl)methanone ##STR00265##{4-[4-(5-Fluoro-2-hydroxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3,4-dihydro-2H- quinoxalin-1-y1}-(3-fluorophenyl)methanone ##STR00266##1-[4-(5-Fluoro-2-hydroxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-5,6,7,8-tetrahydro- 1H-quinolin-4-one##STR00267## 1-[2-Hydroxy-4-(5-methanesulfonyl-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-trifluoromethylpentyl]-5,6,7,8-tetrahydro- 1H-quinolin-4-one##STR00268## 1-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2- trifluoromethylpentyl]-5-methyl-5,6,7,8-tetrahydro-1H-[1,5]naphthyridin-4-one ##STR00269##1-[2-Hydroxy-4-(5-methanesulfonyl-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-trifluoromethylpentyl]-5,6,7,8-tetrahydro-1H-[1,5]naphthyridin-4-one ##STR00270##1-[4-(4-Fluoro-3-morpholin-4- ylmethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00271##1-[4-(3-Fluoro-4-morpholin-4- ylmethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00272##1-[4-(2-{[Ethyl-(2- methoxyethyl)amino]methyl}phenyl)-2-hydroxy-4-methyl-2- trifluoromethylpentyl]-1H-quinolin-4-one##STR00273## 2-[4-(3-Chloro-5-trifluoromethylpyridin-2-yl)piperazin-1-ylmethyl]-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4- methylpentan-2-ol ##STR00274##{4-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]piperazin-1- yl}furan-2-ylmethanone##STR00275## 1-(4-{4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2- trifluoromethylpentyl]piperazin-1-yl}phenyl)ethanone ##STR00276## 1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-2-[4-(4- fluorophenyl)piperazin-1-ylmethyl]-4-methylpentan-2-ol ##STR00277## 1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-phenylpiperazin-1-ylmethyl)pentan-2-ol ##STR00278##2-[4-(2,4-Difluorophenyl)piperazin-1-ylmethyl]-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol ##STR00279##4-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]piperazine-1-carboxylic acid ethyl ester##STR00280## {4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2- trifluoromethylpentyl]piperazin-1-yl}-(tetrahydrofuran-2-yl)methanone ##STR00281##4-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]piperazine-1- carboxylic acid benzyl ester##STR00282## 1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-pyrimidin-2-ylpiperazin-1-ylmethyl)pentan-2-ol ##STR00283##1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]piperidine-3- carboxylic acid amide##STR00284## 4-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-[1,4]diazepane-1- carboxylic acid benzylester ##STR00285## 1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-[4-(5- pyrazin-2-yl-[1,3,4]oxadiazol-2-yl)piperidin-1-ylmethyl]pentan-2-ol ##STR00286##1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-pyridin-2-ylpiperazin-1-ylmethyl)pentan-2-ol ##STR00287##1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]piperidine-4- carboxylic acid methyl ester##STR00288## 4-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]piperazin-2-one ##STR00289##1-{1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]piperidin-4-yl}-1,3-dihydrobenzoimidazol-2-one ##STR00290##1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-(octahydroisoquinolin-2-ylmethyl)pentan- 2-ol ##STR00291##{4-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]piperazin-1- yl}acetic acid ethyl ester##STR00292## 1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3,3-dimethyl-2,3- dihydro-1H-quinolin-4-one##STR00293## 1-{4-(5-Fluoro-2-hydroxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3,3-dimethyl-2,3- dihydro-1H-quinolin-4-one##STR00294## 1-[4-(5-Fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2- trifluoromethylpentyl]-3,3-dimethyl-2,3-dihydro- 1H-quinolin-4-one ##STR00295##1-[2-Hydroxy-4-(5-methanesulfonyl-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-trifluoromethylpentyl]-3,3-dimethyl-2,3- dihydro-1H-quinolin-4-one##STR00296## 1-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2- trifluoromethylpentyl]-3,3-dimethyl-2,3-dihydro-1H-quinolin-4-one ##STR00297##1-[4-(5-Fluoro-2-methylphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3,3-dimethyl-2,3- dihydro-1H-quinolin-4-one##STR00298## 1-[4-(2-Acetyl-5-fluorophenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3,3-dimethyl-2,3- dihydro-1H-quinolin-4-one##STR00299## 1-[2-Hydroxy-4-(2-methoxy-3,5-dimethylphenyl)-4-methyl-2-trifluoromethylpentyl]-3,3-dimethyl-2,3- dihydro-1H-quinolin-4-one##STR00300## 1-[2-Hydroxy-4-(2-hydroxy-3,5-dimethylphenyl)-4-methyl-2-trifluoromethylpentyl]-3,3-dimethyl-2,3- dihydro-1H-quinolin-4-one##STR00301## 1-[2-Hydroxy-4-(2-hydroxy-5-thiophen-3-ylphenyl)-4-methyl-2- trifluoromethylpentyl]-3,3-dimethyl-2,3-dihydro-1H-quinolin-4-one ##STR00302##1-[4-(3-Ethoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-3,3-dimethyl-2,3-dihydro-1H-quinolin-4-one ##STR00303##7-[4,4,4-Trifluoro-3-hydroxy-1,1-dimethyl-3-(3-methyl-4-oxo-4H-quinolin-1-ylmethyl)butyl]-2,3-dihydrobenzofuran- 5-sulfonic aciddimethylamide ##STR00304## 1-[4-(4-Bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-3-methyl- 1H-quinolin-4-one##STR00305## 4-[4,4,4-Trifluoro-3-hydroxy-1,1-dimethyl-3-(3-methyl-4-oxo-4H-quinolin-1-ylmethyl)butyl]benzonitrile ##STR00306##7-[4,4,4-Trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1-
ylmethyl)butyl]-2,3-dihydrobenzofuran-5- sulfonic aciddimethylamide ##STR00307## 1-[4-(4-Bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H- quinolin-4-one ##STR00308##4-[4,4,4-Trifluoro-3-hydroxy-1,1- dimethyl-3-(4-oxo-4H-quinolin-1-ylmethyl)butyl]benzonitrile ##STR00309##3-Methyl-1-[3,3,3-trifluoro-2-(6-fluoro-4-methylchroman-4-ylmethyl)-2- hydroxypropyl]-1H-quinolin-4-one##STR00310## 3-Methyl-1-[3,3,3-trifluoro-2-(6-fluoro-4-methylchroman-4-ylmethyl)-2- hydroxypropyl]-1H-[1,5]naphthyridin-4-one ##STR00311## 1-[3,3,3-Trifluoro-2-(6-fluoro-4-methylchroman-4-ylmethyl)-2- hydroxypropyl]-1H-[1,5]naphthyridin-4-one ##STR00312## 2-(4-Benzylpiperazin-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4- methylpentan-2-ol##STR00313## 2-(4-Benzo[1,3]dioxol-5-ylmethylpiperazin-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4- methylpentan-2-ol##STR00314## 1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(2-methylpiperidin-1-ylmethyl)pentan-2-ol ##STR00315##1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-(4-trifluoromethylpiperidin-1- ylmethyl)pentan-2-ol ##STR00316##1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-2-[4-(4-fluorophenyl)piperidin-1-ylmethyl]-4- methylpentan-2-ol##STR00317## 2-[4-(4-Bromophenyl)piperidin-1-ylmethyl]-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol ##STR00318##1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methyl-2-(4-methylpiperidin-1-ylmethyl)pentan-2-ol ##STR00319##4-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-[1,4]diazepane-1- carboxylic acid tert-butylester ##STR00320## 4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2- trifluoromethylpentyl]piperazine-1- carboxylicacid tert-butyl ester ##STR00321## 1,1,1 Trifluoro-4-(5-fluoro-2-methoxyphenyl)-2-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]-4-methylpentan-2-ol##STR00322## 1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-pyrrolidin-1-ylpiperidin-1-ylmethyl)pentan-2-ol ##STR00323##2-[1,4']Bipiperidinyl-1'-ylmethyl-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4- methylpentan-2-ol##STR00324## 2-[4-(2-Ethoxyethyl)piperazin-1-ylmethyl]-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol ##STR00325##1,1,1-Trifluoro-4-(5-fluoro-2- methoxyphenyl)-2-[4-(2-methoxyethyl)piperazin-1-ylmethyl]-4- methylpentan-2-ol##STR00326## 2-(4-Benzylpiperidin-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4- methylpentan-2-ol##STR00327## 1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]piperidine-3- carboxylic acid diethylamide##STR00328## 1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]piperidine-3- carboxylic acid ethyl ester##STR00329## 1-{1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2- trifluoromethylpentyl]piperidin-4-yl}-1,3-dihydroindol-2-one ##STR00330## 1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-phenylpiperidin-1-ylmethyl)pentan-2-ol ##STR00331##2-(4-Benzylpiperidin-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4- methylpentan-2-ol##STR00332## 1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-2-[4-(1H-indol-2-yl)piperidin-1-ylmethyl]-4-methylpentan- 2-ol ##STR00333##5-Chloro-1-{1-[4-(5-fluoro-2- methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]piperidin-4-yl}-1,3-dihydrobenzoimidazol-2-one ##STR00334##(1-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]piperidin-4-yl}acetic acid ethyl ester##STR00335## 2-[4-(2,4-Dimethylphenyl)piperazin-1-ylmethyl]-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol ##STR00336##2-(4-Benzyl-[1,4]diazepan-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methylpentan-2-ol##STR00337## 4-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]piperazine-1- carbaldehyde ##STR00338##4-[4-(5-Fluoro-2-methoxyphenyl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3- methoxycarbonylmethylpiperazine-1-carboxylic acid tert-butyl ester ##STR00339##2-(4-tert-Butylpiperazin-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2- methoxyphenyl)-4-methylpentan-2-ol##STR00340## 2-(3-Dimethylaminopyrrolidin-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol ##STR00341##1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-pyrrolidin-1- ylmethylpentan-2-ol##STR00342## 1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-piperidin-1- ylmethylpentan-2-ol##STR00343## Carbonic acid ethyl ester 4-fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3- (4-oxo-4H-quinolin-1-ylmethyl)butyl]phenyl ester ##STR00344## Ethylcarbamic acid4-fluoro-2-[4,4,4- trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1-ylmethyl)butyl]phenyl ester ##STR00345##Ethylcarbamic acid 4-fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(3- methyl-4-oxo-4H-quinolin-1-ylmethyl)butyl]phenyl ester ##STR00346## Ethylcarbamic acid2-[3-(3,3-dimethyl-4- oxo-3,4-dihydro-2H-quinolin-1-ylmethyl)-4,4,4-trifluoro-3-hydroxy-1,1- dimethylbutyl]-4-fluorophenyl ester##STR00347## Methylcarbamic acid 2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H- quinolin-1-ylmethyl)butyl]phenylester ##STR00348## Carbonic acid 2-[3-(3,5-dimethyl-4-oxo-4H-pyridin-1-ylmethyl)-4,4,4-trifluoro-3-hydroxy-1,1-dimethylbutyl]-4- fluorophenyl ester methyl ester##STR00349## Methylcarbamic acid 2-[3-(3,5-dimethyl-4-oxo-4H-pyridin-1-ylmethyl)-4,4,4-trifluoro-3-hydroxy-1,1-dimethylbutyl]-4- fluorophenyl ester##STR00350## Cyclopropylcarbamic acid 2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1-ylmethyl)butyl]phenyl ester ##STR00351##1-Cyclopropyl-3-{2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1-ylmethyl)butyl]phenyl}urea ##STR00352##1-Cyclopropyl-3-{2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(3-methyl-4-oxo-4H-quinolin-1-ylmethyl)butyl]phenyl}urea ##STR00353##1-Methyl-3-{2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(3-methyl-4-oxo-4H-quinolin-1-ylmethyl)butyl]phenyl}urea ##STR00354##1-{2-[3-(3,3-Dimethyl-4-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl)-4,4,4-trifluoro-3-hydroxy-1,1-dimethylbutyl]phenyl}-3- methylurea ##STR00355##1-(2,2,3,3-Tetramethylcyclopropyl)-3-{2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3- (4-oxo-4H-quinolin-1-ylmethyl)butyl]phenyl}urea ##STR00356##(2,2,3,3-Tetramethylcyclopropyl)carbarmic acid2-[4,4,4-trifluoro-3-hydroxy-1,1- dimethyl-3-(4-oxo-4H-quinolin-1-ylmethyl)butyl]phenyl ester ##STR00357## Dimethylcarbamic acid2-[4,4,4-trifluoro- 3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1-ylmethyl)butyl]phenyl ester ##STR00358##Dimethylcarbamic acid 2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(3-methyl-4-oxo-4H-quinolin-1-ylmethyl)butyl]phenyl ester ##STR00359##Pyrrolidine-1-carboxylic acid 2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1-ylmethyl)butyl]phenyl ester ##STR00360##Pyrrolidine-1-carboxylic acid 2-[3-(3,3-dimethyl-4-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl)-4,4,4-trifluoro-3-hydroxy-1,1- dimethylbutyl]phenylester ##STR00361## 1-[2-Hydroxy-4-(2-methoxy-5-pyridin-3-ylphenyl)-4-methyl-2- trifluoromethylpentyl]-1H-quinolin-4-one##STR00362## 1-[2-Hydroxy-4-(2-hydroxy-3,5-dimethylphenyl)-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00363##1-[4-(3-[1,3]Dioxan-2-yl-4-fluorophenyl)- 2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00364##1-[2-Hydroxy-4-(2-methoxy-5-pyrimidin- 5-ylphenyl)-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00365##1-[4-(4-[1,3]Dioxan-2-yl-3-fluorophenyl)- 2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00366##1-[2-Hydroxy-4-(2-hydroxy-5-pyridin-3- ylphenyl)-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00367##1-{2-Hydroxy-4-(2-hydroxy-5-pyrimidin- 5-ylphenyl)-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one ##STR00368## Carbonic acid4-fluoro-2-[4,4,4-trifluoro- 3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1-ylmethyl)butyl]phenyl ester methyl ester ##STR00369##1-[4-(2,3-Dihydrobenzofuran-7-yl)-2- hydroxy-4-methyl-2-trifluoromethylpentyl]-3-methyl-1H- [1,5]naphthyridin-4-one##STR00370## 1-(4-Benzo[1,3]dioxol-4-yl-2-hydroxy-4-methyl-2-trifluoromethylpentyl)-3-methyl-1H-[1,5]naphthyridin-4-one ##STR00371## or a tautomer, prodrug,solvate, or salt thereof.
Preferred compounds of Formula (IA) include the following:4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-2,6-dimethylpiperazine-1-carbaldehyde;2-(1,1-Dioxo-2,3-dihydro-1H-1).sub.6-benzo[1,4]thiazin-4-ylmethyl)-1,1,1--trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;2-(2,6-Dimethylmorpholin-4-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methox-yphenyl)-4-methylpentan-2-ol;2-(2,3-Dihydrobenzo[1,4]oxazin4-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-m-ethoxyphenyl)-4-methylpentan-2-ol;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3,5-dimethylpiperidin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-methyl-H-quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-2,3-dihydro-1H-quinolin-4-one;1-[4-(4-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quin-olin-4-one;1-[4-(3-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quin-olin-4-one;1-[4-(3-Fluoro-4-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one;1-[4-(4-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-Phenyl-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one-;1-[4-(5-Fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluor-omethylpentyl]-H-quinolin-4-one;1-[4-(5-Bromo-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluorom-ethylpentyl]-1H-quinolin-4-one;1-[4-(5-Methyl-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoro-methylpentyl]-1H-quinolin-4-one;1-[4-(5-Chloro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoro-methylpentyl]-1H-quinolin-4-one;1-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpen-tyl]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-[1,5]naphthyridin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-2,4-dimethylpentyl]-3,5-dimethy-l-1H-pyridin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-[1,5]naphthyridin-4-one;1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1-oxo-2,3-dihydr-o-1H-1.lamda..sup.4-benzo[1,4]thiazin-4-ylmethyl)pentan-2-ol;1-[2-Hydroxy-4-(2-methoxy-5-thiophen-2-ylphenyl)-4-methyl-2-trifluorometh-ylpentyl]-1H-quinolin-4-one;1-[4-(6-Bromobenzo[1,3]dioxol-4-yl)-2-hydroxy-4-methyl-2-trifluoromethylp-entyl]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-methyl-1H-quinolin-4-one;1-[2-Hydroxy-4-(4-hydroxybiphenyl-3-yl)-4-methyl-2-trifluoromethylpentyl]--1H-quinolin-4-one;1-{4-[5-(3,5-Dimethylisoxazol-4-yl)-2-hydroxyphenyl]-2-hydroxy-4-methyl-2--trifluoromethylpentyl}-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-hydroxy-5-thiophen-3-ylphenyl)-4-methyl-2-trifluorometh-ylpentyl]-1H-quinolin-4-one;1-{4-[5-(3,5-Dimethylisoxazol-4-yl)-2-methoxyphenyl]-2-hydroxy-4-methyl-2--trifluoromethylpentyl}-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-[1,5]naphthyridin-4-one;1-[2-Hydroxy-4-(5-methanesulfonyl-2,3-dihydrobenzofuran-7-yl)-4-methyl-2--trifluoromethylpentyl]-1H-[1,5]naphthyridin-4-one;1-[2-Hydroxy-4-methyl-4-(3-pyridin-3-ylphenyl)-2-trifluoromethylpentyl]-1-H-quinolin-4-one;1-[2-Hydroxy-4-(2-hydroxy-5-morpholin-4-ylmethylphenyl)-4-methyl-2-triflu-oromethylpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-methoxy-5-morpholin-4-ylmethylphenyl)-4-methyl-2-triflu-oromethylpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(5-hydroxymethyl-2-methoxyphenyl)-4-methyl-2-trifluorometh-ylpentyl]-1H-quinolin-4-one;4-Methoxy-3-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin--1-ylmethyl)butyl]benzaldehyde;1-[4-(5-[1,3]Dioxan-2-yl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorom-ethylpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-methoxy-5-thiophen-3-ylphenyl)-4-methyl-2-trifluorometh-ylpentyl]-1H-quinolin-4-one;1-[4-(5-Furan-3-yl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylp-entyl]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinazolin-4-one;1-[2-Hydroxy-4-(4-methoxybiphenyl-3-yl)-4-methyl-2-trifluoromethylpentyl]--1H-quinolin-4-one;1-[4-(5-Acetyl-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-H-quinolin-4-one;1-[3,3,3-Trifluoro-2-(6-fluoro-4-methylchroman-4-ylmethyl)-2-hydroxypropy-l]-1H-quinolin-4-one;1-(4-{3-[1-(Benzyloxyimino)ethyl]phenyl}-2-hydroxy-4-methyl-2-trifluorome-thylpentyl)-1H-quinolin-4-one;1-[4-(3-Cyclopropanecarbonylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylp-entyl]-1H-quinolin-4-one;1-[4-(5-Acetyl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-H-quinolin-4-one;1-(2-Hydroxy-4-{3-[1-(methoxyimino)ethyl]phenyl}-4-methyl-2-trifluorometh-ylpentyl)-1H-quinolin-4-one;1-[4-(5-Bromo-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one;1-(2-Hydroxy-4-{3-[1-(hydroxyimino)ethyl]phenyl}4-methyl-2-trifluoromethy-lpentyl)-1H-quinolin-4-one;1-[4-(5-Bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-H-quinolin-4-one;1-[4-(3,5-Difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H--quinolin-4-one;1-[4-(3,5-Dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H--quinolin-4-one;1-{2-Hydroxy-4-methyl-4-[3-(2-methyl-[1,3]dioxolan-2-yl)phenyl]-2-trifluo-romethylpentyl}-1H-quinolin-4-one;1-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpen-tyl]-2-hydroxymethyl-3,5-dimethyl-1H-pyridin-4-one;1-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpen-tyl]-1H-[1,5]naphthyridin-4-one;1-[2-Hydroxy-4-(3-hydroxymethylphenyl)-4-methyl-2-trifluoromethylpentyl]--1H-quinolin-4-one;1-[4-(3-[1,3]Dioxan-2-ylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-(3-Acetylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quin-olin-4-one;1-{4-[3-(3,5-Dimethylisoxazol-4-yl)phenyl]-2-hydroxy-4-methyl-2-trifluoro-methylpentyl}-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-3,5-dimethyl-1H-pyridin-4-one;1-{2-Hydroxy-4-[3-(1-hydroxyethyl)phenyl]4-methyl-2-trifluoromethylpentyl-}-1H-quinolin-4-one;1-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpen-tyl]-3,5-dimethyl-1H-pyridin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-2-hydroxymethyl-3,5-dimethyl-1H-pyridin-4-one;3-[4,4,4-Trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1-ylmethyl-)butyl]benzaldehyde;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methy-2-trifluoromethylpentyl-]-2-hydroxymethyl-3,5-dimethyl-1H-pyridin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-hydroxymethyl-1H-quinolin-4-one;1-[4-(3-Bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quino-lin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluorom-ethylpentyl]-7-hydroxy-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-6-methyl-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-hydroxymethyl-1H-quinolin-4-one;6-Chloro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-[-4-(2-Difluoromethoxy-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-(4-Biphenyl-3-yl-2-hydroxy-4-methyl-2-trifluoromethylpentyl)-1H-quinoli-n-4-one;6-Chloro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-tri-fluoromethylpentyl]-H-quinolin-4-one;1-[2-Hydroxy-4-(2-hydroxy-5-methylphenyl)-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-{2-Hydroxy-4-methyl-4-[3-(2-oxopropoxy)phenyl]-2-trifluoromethylpentyl}--1H-quinolin-4-one;1-[2-Hydroxy-4-(3-isopropoxyphenyl)-4-methyl-2-trifluoromethylpentyl]-1H--quinolin-4-one;1-[4-(3-Ethoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-H-quino-lin-4-one;1-[2-Hydroxy-4-(2-methoxy-5-methylphenyl)-4-methyl-2-trifluorom-ethylpentyl]-1H-quinolin-4-one;1-[4-(2,5-Dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H--quinolin-4-one;1-[2-Hydroxy-4-(3-hydroxyphenyl)-4-methyl-2-trifluoromethylpentyl]-1H-qui-nolin-4-one;1-[2-Hydroxy-4-(3-methoxyphenyl)-4-methyl-2-trifluoromethylpentyl]-1H-qui-nolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1,2-dihydroindazol-3-one;7-Fluoro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3,5-dimethyl-1H-pyridin-4-one;7-Fluoro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-(2-Hydroxy-4-methyl-4-phenyl-2-trifluoromethylhexyl)-1H-quinolin-4-one;1-[4-(4-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one;1-[4-(3,4-Dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H--quinolin-4-one;8-Fluoro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;6-Fluoro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-{4-[5-Fluoro-2-(2-oxopropoxy)phenyl]-2-hydroxy-4-methyl-2-trifluorometh-ylpentyl}-H-quinolin-4-one;7-Chloro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-H-quinolin-4-one;1-[4-(5-Fluoro-2-isopropoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpe-ntyl]-1H-quinolin-4-one;1-[4-(2-Benzyloxy-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpen-tyl]-1H-quinolin-4-one;1-[4-(2-Ethoxy-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one;8-Fluoro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;6-Fluoro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(5-methanesulfonyl-2,3-dihydrobenzofuran-7-yl)-4-methyl-2--trifluoromethylpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(5-methanesulfinyl-2,3-dihydrobenzofuran-7-yl)-4-methyl-2--trifluoromethylpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-methyl-4-(5-methylsulfanyl-2,3-dihydrobenzofuran-7-yl)-2-t-rifluoromethylpentyl]-1H-quinolin-4-one;7-Chloro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-[4-(3-Fluoro-4-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-nitro-5-trifluoromethyl-1H-pyridin-2-one;3-Chloro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-5-trifluoromethyl-1H-pyridin-2-one;2-(2,3-Dihydroindol-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphen-yl)-4-methylpentan-2-ol;1-[2-Hydroxy-4-methyl-4-(3-morpholin-4-ylmethylphenyl)-2-trifluoromethylp-entyl]-1H-quinolin-4-one;{4-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpent-yl]piperazin-1-yl}furan-2-ylmethanone;1-[2-Hydroxy-4-(5-methanesulfonyl-2,3-dihydrobenzofuran-7-yl)-4-methyl-2--trifluoromethylpentyl]-3-methyl-1H-quinolin-4-one;2-[4-(3-Chloro-5-trifluoromethylpyridin-2-yl)piperazin-1-ylmethyl]-1,1,1--trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;{4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpent-yl]piperazin-1-yl}furan-2-ylmethanone;1-[2-Hydroxy-4-(2-methoxy-5-pyridin-3-ylphenyl)-4-methyl-2-trifluoromethy-lpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-hydroxy-3,5-dimethylphenyl)-4-methyl-2-trifluoromethylp-entyl]-1H-quinolin-4-one;1-[4-(3-[1,3]Dioxan-2-yl-4-fluorophenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-H-quinolin-4-one;1-[2-Hydroxy-4-(2-methoxy-5-pyrimidin-5-ylphenyl)-4-methyl-2-trifluoromet-hylpentyl]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-H-quinolin-4-one;1-[4-(2,4-dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H--quinolin-4-one;1-[4-(4-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-H-quinolin-4-one;1-[4-(3-Fluoro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-(4-Benzo[1,3]dioxol-4-yl-2-hydroxy-4-methyl-2-trifluoromethylpentyl)-1H--quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-,2-dihydroindazol-3-one;2-(3,4-Dihydro-2H-quinoxalin-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-me-thoxyphenyl)-4-methylpentan-2-ol;1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-methyl-3,4-dih-ydro-2H-quinoxalin-1-ylmethyl)pentan-2-ol;2-(2,3-Dihydrobenzo[1,4]thiazin-4-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2--methoxyphenyl)-4-methylpentan-2-ol;1-{4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpe-ntyl]-3,4-dihydro-2H-quinoxalin-1-yl}ethanone;1-[2-Hydroxy-4-(2-hydroxy-5-thiophen-3-ylphenyl)-4-methyl-2-trifluorometh-
ylpentyl]-1H-quinolin-4-one;1-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpen-tyl]-3-methyl-H-quinolin-4-one;1-[2-Hydroxy-4-(2-methoxy-3,5-dimethylphenyl)-4-methyl-2-trifluoromethylp-entyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-hydroxy-5-pyridin-3-ylphenyl)-4-methyl-2-trifluoromethy-lpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-hydroxy-5-pyrimidin-5-ylphenyl)-4-methyl-2-trifluoromet-hylpentyl]-1H-quinolin-4-one; and Carbonic acid4-fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1--ylmethyl)butyl]phenyl ester methyl ester, or a tautomer, prodrug,solvate, or salt thereof.
More preferred compounds of Formula (IA) include the following:2-(2,6-Dimethylmorpholin-4-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methox-yphenyl)-4-methylpentan-2-ol;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3,5-dimethylpiperidin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-methyl-H-quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-2,3-dihydro-1H-quinolin-4-one;1-[4-(4-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quin-olin-4-one;1-[4-(3-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quin-olin-4-one;1-[4-(4-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-H-quinolin-4-one;1-[4-Phenyl-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one-;1-[4-(5-Fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluor-omethylpentyl]-H-quinolin-4-one;1-[4-(5-Bromo-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluorom-ethylpentyl]-H-quinolin-4-one;1-[4-(5-Methyl-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methy1-2-trifluoro-methylpentyl]-H-quinolin-4-one;1-[4-(5-Chloro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methy1-2-trifluoro-methylpentyl]-1H-quinolin-4-one;1-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpen-tyl]-H-quinolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-[1,5]naphthyridin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-2,4-dimethylpentyl]-3,5-dimethy-l-1H-pyridin-4-one;1-[2-Hydroxy-(2-methoxy-5-thiophen-2-ylphenyl)-4-methyl-2-trifluoromethyl-pentyl]-1H-quinolin-4-one;1-[4-(6-Bromobenzo[1,3]dioxol-4-yl)-2-hydroxy-4-methyl-2-trifluoromethylp-entyl]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-methyl-H-quinolin-4-one;1-[2-Hydroxy-4-(4-hydroxybiphenyl-3-yl)-4-methyl-2-trifluoromethylpentyl]--1H-quinolin-4-one;1-{4-[5-(3,5-Dimethylisoxazol-4-yl)-2-hydroxyphenyl]-2-hydroxy-4-methyl-2--trifluoromethylpentyl}-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-hydroxy-5-thiophen-3-ylphenyl)-4-methyl-2-trifluorometh-ylpentyl]-1H-quinolin-4-one;1-{4-[5-(3,5-Dimethylisoxazol-4-yl)-2-methoxyphenyl]-2-hydroxy-4-methyl-2--trifluoromethylpentyl)}-1H-quinolin-4-one;1-[2-Hydroxy-4-methyl-4-(3-pyridin-3-ylphenyl)-2-trifluoromethylpentyl]-1-H-quinolin-4-one;4-Methoxy-3-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin--1-ylmethyl)butyl]benzaldehyde;1-[2-Hydroxy-4-(2-methoxy-5-thiophen-3-ylphenyl)-4-methyl-2-trifluorometh-ylpentyl]-1H-quinolin-4-one;1-[4-(5-Furan-3-yl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylp-entyl]-H-quinolin-4-one;1-[2-Hydroxy-4-(4-methoxybiphenyl-3-yl)-4-methyl-2-trifluoromethylpentyl]--1H-quinolin-4-one;1-[4-(5-Acetyl-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-H-quinolin-4-one;1-[3,3,3-Trifluoro-2-(6-fluoro-4-methylchroman-4-ylmethyl)-2-hydroxypropy-l]-1H-quinolin-4-one;1-(4-{3-[1-(Benzyloxyimino)ethyl]phenyl}-2-hydroxy-4-methyl-2-trifluorome-thylpentyl)-1H-quinolin-4-one;1-[4-(5-Acetyl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-H-quinolin-4-one;1-(2-Hydroxy-4-{3-[1-(methoxyimino)ethyl]phenyl}4-methyl-2-trifluoromethy-lpentyl)-1H-quinolin-4-one;1-[4-(5-Bromo-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one;1-(2-Hydroxy-4-{3-[1-(hydroxyimino)ethyl]phenyl}4-methyl-2-trifluoromethy-lpentyl)-1H-quinolin-4-one;1-[4-(5-Bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one;1-[4-(3,5-Difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1-H--quinolin-4-one;1-[4-(3,5-Dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1-H--quinolin-4-one;1-{2-Hydroxy-4-methyl-4-[3-(2-methyl-[1,3]dioxolan-2-yl)phenyl]-2-trifluo-romethylpentyl}-1H-quinolin-4-one;1-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpen-tyl]-H-[1,5]naphthyridin-4-one;1-[4-(3-[1,3]Dioxan-2-ylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-{4-[3-(3,5-Dimethylisoxazol-4-yl)phenyl]-2-hydroxy-4-methyl-2-trifluoro-methylpentyl}-1H-quinolin-4-one;1-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpen-tyl]-3,5-dimethyl-1H-pyridin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-2-hydroxymethyl-3,5-dimethyl-1H-pyridin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-hydroxymethyl-1H-quinolin-4-one;1-[4-(3-Bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quino-lin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorom-ethylpentyl]-6-methyl-H-quinolin-4-one;6-Chloro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-[4-(2-Difluoromethoxy-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromet-hylpentyl]-1H-quinolin-4-one;1-(4-Biphenyl-3-yl-2-hydroxy-4-methyl-2-trifluoromethylpentyl)-1H-quinoli-n-4-one;1-[2-Hydroxy-4-(2-hydroxy-5-methylphenyl)-4-methyl-2-trifluoromet-hylpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(3-isopropoxyphenyl)-4-methyl-2-trifluoromethylpentyl]-1-H--quinolin-4-one;1-[4-(3-Ethoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quin-olin-4-one;1-[2-Hydroxy-4-(2-methoxy-5-methylphenyl)-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-(2,5-Dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1-H--quinolin-4-one;1-[2-Hydroxy-4-(3-methoxyphenyl)-4-methyl-2-trifluoromethylpentyl]-1H-qui-nolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1,2-dihydroindazol-3-one;7-Fluoro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3,5-dimethyl-1H-pyridin-4-one;7-Fluoro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-(2-Hydroxy-4-methyl-4-phenyl-2-trifluoromethylhexyl)-1H-quinolin-4-one;1-[4-(4-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-H-quinolin-4-one;1-[4-(3,4-Dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1-H--quinolin-4-one;8-Fluoro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;6-Fluoro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;7-Chloro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-isopropoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpe-ntyl]-H-quinolin-4-one;1-[4-(2-Ethoxy-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one;8-Fluoro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;6-Fluoro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(5-methanesulfonyl-2,3-dihydrobenzofuran-7-yl)-4-methyl-2--trifluoromethylpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-methyl-4-(5-methylsulfanyl-2,3-dihydrobenzofuran-7-yl)-2-t-rifluoromethylpentyl]-1H-quinolin-4-one;7-Chloro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;3-Chloro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-5-trifluoromethyl-1H-pyridin-2-one;1-[2-Hydroxy-4-(5-methanesulfonyl-2,3-dihydrobenzofuran-7-yl)-4-methyl-2--trifluoromethylpentyl]-3-methyl-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-methoxy-5-pyridin-3-ylphenyl)-4-methyl-2-trifluoromethy-lpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-hydroxy-3,5-dimethylphenyl)-4-methyl-2-trifluoromethylp-entyl]-1H-quinolin-4-one;1-[4-(3-[1,3]Dioxan-2-yl-4-fluorophenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;2-(1,1-Dioxo-2,3-dihydro-1H-1.lamda..sup.6-benzo[1,4]thiazin-4-ylmethyl)--1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;2-(2,3-Dihydrobenzo[1,4]oxazin-4-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2--methoxyphenyl)-4-methylpentan-2-ol;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-[1,5]naphthyridin-4-one;1-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one;1-[4-(2,4-dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1-H--quinolin-4-one;1-[4-(4-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-(3-Fluoro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-(4-Benzo[1,3]dioxol-4-yl-2-hydroxy-4-methyl-2-trifluoromethylpentyl)-H--quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1,2-dihydroindazol-3-one;1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1-oxo-2,3-dihydr-o-1H-1.lamda..sup.4-benzo[1,4]thiazin-4-ylmethyl)pentan-2-ol;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-2-hydroxymethyl-3,5-dimethyl-1H-pyridin-4-one;1-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpen-tyl]-3-methyl-H-quinolin-4-one;1-[2-Hydroxy-4-(2-methoxy-3,5-dimethylphenyl)-4-methyl-2-trifluoromethylp-entyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-hydroxy-5-pyridin-3-ylphenyl)-4-methyl-2-trifluoromethy-lpentyl]-1H-quinolin-4-one; and1-[2-Hydroxy-4-(2-hydroxy-5-pyrimidin-5-ylphenyl)-4-methyl-2-trifluoromet-hylpentyl]-1H-quinolin-4-one, or a tautomer, prodrug, solvate, orsalt thereof.
The invention also provides a method of making a compound ofFormula (IA)
##STR00372## where R.sup.1, R.sup.2, R.sup.3, R.sup.5, and X are asdefined above and R.sup.4 is --CH.sub.2--, the method comprising:(a) reacting an ester of Formula (II) with a suitable reducingagent in a suitable solvent to form a diol of Formula (III)
##STR00373## (b) reacting the diol of Formula (III) with a sulfonicacid chloride, R'SO.sub.2Cl to form a sulfonic acid ester ofFormula (IV)
##STR00374## (c) reacting the intermediate of Formula (IV) with asuitable base to form the epoxide of Formula (V)
##STR00375## and (d) reacting the epoxide of Formula (V) with thedesired R.sup.5H to form the compound of Formula (IA)
##STR00376##
In addition, the invention also provides a method of making acompound of Formula (IA)
##STR00377## where R.sup.1, R.sup.2, R.sup.3, R.sup.5, and X are asdefined above and R.sup.4 is --C(O)--, the method comprising: (a)hydrolyzing the ester of Formula (II) to produce the carboxylicacid of Formula (X)
##STR00378## and (b) coupling the carboxylic acid of Formula (X)with R.sup.5H to provide the desired compound of Formula (I)
##STR00379##
The instant invention is directed to compounds of Formula (IB)
##STR00380## wherein: R.sup.1 is an aryl, heteroaryl, orC.sub.5-C.sub.15 cycloalkyl group, each optionally independentlysubstituted with one to three substituent groups, wherein eachsubstituent group of R.sup.1 is independently C.sub.1-C.sub.5alkyl, C.sub.2-C.sub.5 alkenyl, C.sub.2-C.sub.5 alkynyl,C.sub.3-C.sub.8 cycloalkyl, heterocyclyl, aryl, heteroaryl,C.sub.1-C.sub.5 alkoxy, C.sub.2-C.sub.5 alkenyloxy, C.sub.2-C.sub.5alkynyloxy, aryloxy, acyl, C.sub.1-C.sub.5 alkoxycarbonyl,C.sub.1-C.sub.5 alkanoyloxy, C.sub.1-C.sub.5 alkanoyl, aroyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,aminocarbonyloxy, C.sub.1-C.sub.5 alkylaminocarbonyloxy,C.sub.1-C.sub.5 dialkylaminocarbonyloxy, C.sub.1-C.sub.5alkanoylamino, C.sub.1-C.sub.5 alkoxycarbonylamino, C.sub.1-C.sub.5alkylsulfonylamino, aminosulfonyl, C.sub.1-C.sub.5alkylaminosulfonyl, C.sub.1-C.sub.5 dialkylaminosulfonyl, halogen,hydroxy, oxo, carboxy, cyano, trifluoromethyl, trifluoromethoxy,nitro, or amino wherein the nitrogen atom is optionallyindependently mono- or di-substituted by C.sub.1-C.sub.5 alkyl oraryl; or ureido wherein either nitrogen atom is optionallyindependently substituted with C.sub.1-C.sub.5 alkyl; orC.sub.1-C.sub.5 alkylthio wherein the sulfur atom is optionallyoxidized to a sulfoxide or sulfone, wherein each substituent groupof R.sup.1 is optionally independently substituted with one tothree substituent groups selected from aryl or heterocyclyl whereinthe heterocycle is optionally independently substituted withhydroxyl, halogen, methyl, dialkyl amino; methyl, methoxy, halogen,hydroxy, oxo, cyano, or amino wherein the nitrogen atom isoptionally independently mono- or di-substituted by C.sub.1-C.sub.5alkyl or C.sub.1-C.sub.3dialkylamines or aryl; or ureido whereineither nitrogen atom is optionally independently substituted withC.sub.1-C.sub.5 alkyl; aminosulfonyl, oxime wherein the oxygen atomis optionally substituted by C.sub.1-C.sub.5 alkyl or benzyl.R.sup.2 and R.sup.3 are each independently hydrogen,C.sub.1-C.sub.5 alkyl, or C.sub.5-C.sub.15 arylalkyl group, orR.sup.2 and R.sup.3 together with the carbon atom they are commonlyattached to form a C.sub.3-C.sub.8 spiro cycloalkyl ring, orR.sup.1 and R.sup.2 when taken together are a chromanyl ordihydrobenzofuranyl optionally substituted with C.sub.1-C.sub.5alkyl, C.sub.2-C.sub.5 alkenyl, C.sub.2-C.sub.5 alkynyl,C.sub.3-C.sub.8 cycloalkyl, heterocyclyl, aryl, heteroaryl,C.sub.1-C.sub.5 alkoxy, C.sub.2-C.sub.5 alkenyloxy, C.sub.2-C.sub.5alkynyloxy, aryloxy, acyl, C.sub.1-C.sub.5 alkoxycarbonyl,C.sub.1-C.sub.5 alkanoyloxy, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, aminocarbonyloxy, C.sub.1-C.sub.5alkylaminocarbonyloxy, C.sub.1-C.sub.5 dialkylaminocarbonyloxy,C.sub.1-C.sub.5 alkanoylamino, C.sub.1-C.sub.5 alkoxycarbonylamino,C.sub.1-C.sub.5 alkylsulfonylamino, aminosulfonyl, C.sub.1-C.sub.5alkylaminosulfonyl, C.sub.1-C.sub.5 dialkylaminosulfonyl, halogen,hydroxy, carboxy, oxo, cyano, trifluoromethyl, trifluoromethoxy,trifluoromethylthio, nitro, or amino wherein the nitrogen atom isoptionally independently mono- or di-substituted by C.sub.1-C.sub.5alkyl; or ureido wherein either nitrogen atom is optionallyindependently substituted with C.sub.1-C.sub.5 alkyl; orC.sub.1-C.sub.5 alkylthio wherein the sulfur atom is optionallyoxidized to a sulfoxide or sulfone; R.sup.4 is carbonyl ormethylene optionally independently substituted with one to twosubstituent groups selected from C.sub.1-C.sub.3 alkyl, hydroxy,and halogen; R.sup.5 is a pyrrolidine, morpholine, thiomorpholine,piperazine, piperidine, 1H-pyridin-4-one, 1H-pyridin-2-one,1H-pyridin-4-ylideneamine, 1H-quinolin-4-ylideneamine, pyran,tetrahydropyran, 1,4-diazepane, 2,5-diazabicyclo[2.2.1]heptane,2,3,4,5-tetrahydrobenzo[b][1,4]diazepine, dihydroquinoline,tetrahydroquinoline, 5,6,7,8-tetrahydro-1H-quinolin-4-one,tetrahydroisoquinoline, decahydroisoquinoline,2,3-dihydro-1H-isoindole, 2,3-dihydro-1H-indole, chroman,1,2,3,4-tetrahydroquinoxaline, 1,2-dihydroindazol-3-one,3,4-dihydro-2H-benzo[1,4]oxazine, 4H-benzo[1,4]thiazine,3,4-dihydro-2H-benzo[1,4]thiazine,1,2-dihydrobenzo[d][1,3]oxazin4-one,3,4-dihydrobenzo[1,4]oxazin4-one, 3H-quinazolin-4-one,3,4-dihydro-1H-quinoxalin-2-one, 1H-cinnolin-4-one,1H-quinazolin-4-one, 1H-[1,5]naphthyridin-4-one,5,6,7,8-tetrahydro-1H-[1,5]naphthyridin-4-one,2,3-dihydro-1H-[1,5]naphthyridin-4-one,1,2-dihydropyrido[3,2-d][1,3]oxazin4-one,pyrrolo[3,4-c]pyridine-1,3-dione,1,2-dihydropyrrolo[3,4-c]pyridin-3-one, ortetrahydro[b][1,4]diazepinone, group, each optionally independentlysubstituted with one to three substituent groups, wherein eachsubstituent group of R.sup.5 is independently C.sub.1-C.sub.5alkyl, C.sub.2-C.sub.5 alkenyl, C.sub.2-C.sub.5 alkynyl,C.sub.3-C.sub.8 cycloalkyl, heterocyclyl, aryl, heteroaryl,C.sub.1-C.sub.5 alkoxy, C.sub.2-C.sub.5 alkenyloxy, C.sub.2-C.sub.5alkynyloxy, aryloxy, acyl, C.sub.1-C.sub.5 alkoxycarbonyl,C.sub.1-C.sub.5 alkanoyloxy, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, aminocarbonyloxy, C.sub.1-C.sub.5alkylaminocarbonyloxy, C.sub.1-C.sub.5 dialkylaminocarbonyloxy,C.sub.1-C.sub.5 alkanoylamino, C.sub.1-C.sub.5 alkoxycarbonylamino,C.sub.1-C.sub.5 alkylsulfonylamino, C.sub.1-C.sub.5alkylaminosulfonyl, CL-C.sub.5 dialkylaminosulfonyl, halogen,hydroxy, carboxy, oxo, cyano, trifluoromethyl, trifluoromethoxy,trifluoromethylthio, nitro, or amino wherein the nitrogen atom isoptionally independently mono- or di-substituted by C.sub.1-C.sub.5alkyl; or ureido wherein either nitrogen atom is optionallyindependently substituted with C.sub.1-C.sub.5 alkyl; orC.sub.1-C.sub.5 alkylthio wherein the sulfur atom is optionallyoxidized to a sulfoxide or sulfone, wherein each substituent groupof R.sup.5 is optionally independently substituted with one tothree substituent groups selected from C.sub.1-C.sub.3 alkyl,C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 alkoxy carbonyl, acyl,benzyl, heteroaryl, heterocyclyl, halogen, hydroxy, oxo, cyano,amino wherein the nitrogen atom is optionally independently mono-or di-substituted by C.sub.1-C.sub.5 alkyl; or ureido whereineither nitrogen atom is optionally independently substituted withC.sub.1-C.sub.5 alkyl, or trifluoromethyl; and R.sup.6 is hydrogen,C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8alkynyl, carbocycle, heterocyclyl, aryl, heteroaryl,carbocycle-C.sub.1-C.sub.8 alkyl, carboxy, alkoxycarbonyl,aryl-C.sub.1-C.sub.8 alkyl, aryl-C.sub.1-C.sub.8 haloalkyl,heterocyclyl-C.sub.1-C.sub.8 alkyl, heteroaryl-C.sub.1-C.sub.8alkyl, carbocycle-C.sub.2-C.sub.8 alkenyl, aryl-C.sub.2-C.sub.8alkenyl, heterocyclyl-C.sub.2-C.sub.8 alkenyl, orheteroaryl-C.sub.2-C.sub.8 alkenyl, each optionally independentlysubstituted with one to three substituent groups, wherein eachsubstituent group of R.sup.6 is independently C.sub.1-C.sub.5alkyl, C.sub.2-C.sub.5 alkenyl, C.sub.2-C.sub.5 alkynyl,C.sub.3-C.sub.8 cycloalkyl, phenyl, C.sub.1-C.sub.5 alkoxy,phenoxy, C.sub.1-C.sub.5 alkanoyl, aroyl, C.sub.1-C.sub.5alkoxycarbonyl, C.sub.1-C.sub.5 alkanoyloxy, aminocarbonyloxy,C.sub.1-C.sub.5 alkylaminocarbonyloxy, C.sub.1-C.sub.5dialkylaminocarbonyloxy, aminocarbonyl, C.sub.1-C.sub.5alkylaminocarbonyl, C.sub.1-C.sub.5 dialkylaminocarbonyl,C.sub.1-C.sub.5 alkanoylamino, C.sub.1-C.sub.5 alkoxycarbonylamino,C.sub.1-C.sub.5 alkylsulfonylamino, C.sub.1-C.sub.5alkylaminosulfonyl, C.sub.1-C.sub.5 dialkylaminosulfonyl, halogen,hydroxy, carboxy, cyano, oxo, trifluoromethyl, nitro, amino whereinthe nitrogen atom is optionally independently mono- ordi-substituted by C.sub.1-C.sub.5 alkyl; or ureido wherein eithernitrogen atom is optionally independently substituted withC.sub.1-C.sub.5 alkyl; or C.sub.1-C.sub.5 alkylthio wherein thesulfur atom is optionally oxidized to a sulfoxide or sulfone,wherein R.sup.6 cannot be trifluoromethyl, X is a hydroxy or aminowherein the nitrogen atom is optionally independently mono- ordi-substituted by C.sub.1-C.sub.5 alkyl, or a tautomer, prodrug,solvate, or salt thereof.
Another aspect of the invention includes compounds of Formula (13),wherein: R.sup.1 is phenyl, dihydrobenzofuranyl, benzofuranyl,dihydroindolyl, indolyl, benzo[1,3]dioxole, dihydrobenzothienyl,benzothienyl, benzoxazole, benzisoxazole, benzpyrazole,benzimidazole, thienyl, quinolinyl, tetrahydroquinolinone,tetrahydronaphthyridinone, dihydrochromene, pyridinyl, pyrimidinyl,or pyrazinyl, each optionally independently substituted with one tothree substituent groups, wherein each substituent group of R.sup.1is independently C.sub.1-C.sub.3 alkyl, C.sub.2-C.sub.3 alkenyl,C.sub.2-C.sub.3 alkynyl, C.sub.1-C.sub.3 alkoxy, C.sub.2-C.sub.3alkenyloxy, C.sub.1-C.sub.3 alkanoyl, C.sub.1-C.sub.3alkoxycarbonyl, C.sub.1-C.sub.3 alkanoyloxy, halogen, hydroxy,acyl, oxo, carboxy, cyano, trifluoromethyl, nitro, orC.sub.1-C.sub.3 alkylthio wherein the sulfur atom is optionallyoxidized to a sulfoxide or sulfone, wherein each substituent groupof R.sup.1 is optionally independently substituted with asubstituent group selected from methyl, methoxy, halogen, hydroxy,oxo, cyano, or amino; R.sup.2 and R.sup.3 are each independentlyhydrogen, C.sub.1-C.sub.3 alkyl, benzyl, or phenethyl, or R.sup.2and R.sup.3 together with the carbon atom they are commonlyattached to form a C.sub.3-C.sub.6 spiro cycloalkyl ring; R.sup.4is CH.sub.2; and R.sup.6 is C.sub.1-C.sub.5 alkyl, C.sub.2-C.sub.5alkenyl, C.sub.3-C.sub.6 cycloalkyl, phenyl, C.sub.3-C.sub.6cycloalkyl-C.sub.1-C.sub.3 alkyl, phenyl-C.sub.1-C.sub.3 alkyl,phenyl-C.sub.1-C.sub.3 haloalkyl, C.sub.3-C.sub.6cycloalkyl-C.sub.2-C.sub.3 alkenyl, phenyl-C.sub.2-C.sub.3 alkenyl,each optionally independently substituted with one to threesubstituent groups, wherein each substituent group of R.sup.6 isindependently C.sub.1-C.sub.3 alkyl, C.sub.2-C.sub.3 alkenyl,C.sub.2-C.sub.3 alkynyl, C.sub.1-C.sub.3 alkoxy, aminocarbonyl,C.sub.1-C.sub.3 alkylaminocarbonyl, C.sub.1-C.sub.3dialkylaminocarbonyl, halogen, hydroxy, oxo, carboxy, cyano,trifluoromethyl, nitro, or C.sub.1-C.sub.3 alkylthio wherein thesulfur atom is optionally oxidized to a sulfoxide or sulfone,wherein R.sup.6 cannot be trifluoromethyl, or a tautomer, prodrug,solvate, or salt thereof.
Yet another aspect of the invention includes compounds of Formula(BB), wherein: R.sup.1 is phenyl, pyridyl, dihydrobenzofuranyl, orbenzofuranyl, each optionally independently substituted with one tothree substituent groups, wherein each substituent group of R.sup.1is independently methyl, ethyl, methoxy, ethoxy, fluoro, chloro,bromo, hydroxy, trifluoromethyl, acyl, oxo, C.sub.1-C.sub.5alkylthio wherein the sulfur atom is optionally oxidized to asulfoxide or sulfone, or cyano; R.sup.2 and R.sup.3 are eachindependently methyl, or R.sup.2 and R.sup.3 together with thecarbon atom they are commonly attached to form a spiro cyclopropylring; and R.sup.4 is CH.sub.2, or a tautomer, prodrug, solvate, orsalt thereof.
Yet another aspect of the invention includes compounds of Formula(IB), wherein: R.sup.1 is phenyl, dihydrobenzofuranyl, orbenzofuranyl, each optionally independently substituted with one tothree substituent groups, wherein each substituent group of R.sup.1is independently C.sub.1-C.sub.3 alkyl, C.sub.2-C.sub.3 alkenyl,C.sub.2-C.sub.3 alkynyl, C.sub.1-C.sub.3 alkoxy, C.sub.2-C.sub.3alkenyloxy, C.sub.1-C.sub.3 alkanoyl, C.sub.1-C.sub.3alkoxycarbonyl, C.sub.1-C.sub.3 alkanoyloxy, halogen, hydroxy,carboxy, cyano, trifluoromethyl, nitro, or C.sub.1-C.sub.3alkylthio wherein the sulfur atom is optionally oxidized to asulfoxide or sulfone; and R.sup.2 and R.sup.3 are eachindependently hydrogen or C.sub.1-C.sub.3 alkyl, or a tautomer,prodrug, solvate, or salt thereof.
An aspect of the invention includes compounds of Formula (IB),wherein: R.sup.5 is a morpholine, thiomorpholine, piperazine,piperidine, 1H-pyridin-4-one, pyran, tetrahydropyran,dihydroquinoline, tetrahydroquinoline, chroman,1,2,3,4-tetrahydroquinoxaline, 3,4-dihydro-2H-benzo[1,4]oxazine,3,4-dihydro-2H-benzo[1,4]thiazine, 1,2-dihydrobenzo[d][1,3]oxazin4-one, 3,4-dihydrobenzo[1,4]oxazin-4-one,3,4-dihydro-1H-quinoxalin-2-one, 3,4-dihydro-2H-naphthalen-1-one,1H-cinnolin-4-one, 1H-quinazolin-4-one, 1H-[1,5]naphthyridin-4-one,2,3-dihydro-1H-[1,5]naphthyridin-4-one,3,4-dihydro-2H-isoquinolin-1-one,1,2-dihydropyrido[3,2-d][1,3]oxazin4-one,pyrrolo[3,4-c]pyridine-1,3-dione, tetrahydro[b] [1,4]diazepinone,or 1,2-dihydropyrrolo[3,4-c]pyridin-3-one group, each optionallyindependently substituted with one to three substituent groups,wherein each substituent group of R.sup.5 is independentlyC.sub.1-C.sub.5 alkyl, C.sub.2-C.sub.5 alkenyl, C.sub.2-C.sub.5alkynyl, C.sub.3-C.sub.8 cycloalkyl, heterocyclyl, aryl,heteroaryl, C.sub.1-C.sub.5 alkoxy, C.sub.2-C.sub.5 alkenyloxy,C.sub.2-C.sub.5 alkynyloxy, aryloxy, acyl, C.sub.1-C.sub.5alkoxycarbonyl, C.sub.1-C.sub.5 alkanoyloxy, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy,C.sub.1-C.sub.5 alkylaminocarbonyloxy, C.sub.1-C.sub.5dialkylaminocarbonyloxy, C.sub.1-C.sub.5 alkanoylamino,C.sub.1-C.sub.5 alkoxycarbonylamino, C.sub.1-C.sub.5alkylsulfonylamino, C.sub.1-C.sub.5 alkylaminosulfonyl,C.sub.1-C.sub.5 dialkylaminosulfonyl, halogen, hydroxy, carboxy,oxo, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio,nitro, or amino wherein the nitrogen atom is optionallyindependently mono- or di-substituted by C.sub.1-C.sub.5 alkyl; orureido wherein either nitrogen atom is optionally independentlysubstituted with C.sub.1-C.sub.5 alkyl; or C.sub.1-C.sub.5alkylthio wherein the sulfur atom is optionally oxidized to asulfoxide or sulfone, wherein each substituent group of R.sup.5 isoptionally independently substituted with one to three substituentgroups selected from C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy,halogen, hydroxy, oxo, cyano, amino, or trifluoromethyl; andR.sup.6 is C.sub.1-C.sub.5 alkyl, C.sub.3-C.sub.6 cycloalkyl,C.sub.3-C.sub.6 cycloalkylmethyl-, or benzyl, each optionallyindependently substituted with one to three substituent groups,wherein each substituent group of R.sup.6 is independently methyl,methoxy, fluoro, chloro, bromo, cyano, trifluoromethyl, or hydroxy,wherein R.sup.6 cannot be trifluoromethyl, or a tautomer, prodrug,solvate, or salt thereof.
The following are representative compounds of Formula (IB)according to the invention:
TABLE-US-00002 Compound Name Compound Structure1-[2-Cyclopropyl-4-(5-fluoro-2- methoxyphenyl)-2-hydroxy-4-methylpentyl]-1H-quinolin-4-one ##STR00381##1-[2-Difluoromethyl-4-(5-fluoro-2- methoxyphenyl)-2-hydroxy-4-methylpentyl]-1H-quinolin-4-one ##STR00382##1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methylpentyl]-1H-quinolin-4- one ##STR00383##1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-2-isopropyl-4-methylpentyl]-1H- quinolin-4-one ##STR00384##1-[4-(5-Fluoro-2-methoxyphenyl)-2-fluoromethyl-2-hydroxy-4-methylpentyl]- 1H-quinolin-4-one##STR00385## 1-[2-Cyclobutyl-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4- methylpentyl]-1H-quinolin-4-one##STR00386## 1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-2,4-dimethylpentyl]-1H-quinolin- 4-one ##STR00387##1-[2-Ethyl-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methylpentyl]-1H-quinolin-4- one ##STR00388## or atautomer, prodrug, solvate, or salt thereof.
Preferred compounds of Formula (IB) include:1-[2-Cyclopropyl-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methylpentyl]-1--H-quinolin-4-one; and1-[2-Difluoromethyl-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methylpentyl-]-1H-quinolin-4-one, or a tautomer, prodrug, solvate, or saltthereof.
The invention also provides a method of making a compound ofFormula (IB)
##STR00389## where R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, andX are as defined above and R.sup.4 is --CH.sub.2--, the methodcomprising: (a) reacting a compound of Formula (IA) with a suitablebase in a suitable solvent to form a ketone of Formula (IIB)
##STR00390## (b) reacting the ketone of Formula (IIB) with aorganometallic reagent to form a compound of Formula (IB)
##STR00391##
In another aspect of the invention, the compounds according to theinvention are formulated into pharmaceutical compositionscomprising an effective amount, preferably a pharmaceuticallyeffective amount, of a compound according to the invention or atautomer, prodrug, solvate, or salt thereof, and a pharmaceuticallyacceptable excipient or carrier.
The invention also provides a method of modulating theglucocorticoid receptor function in a patient, the methodcomprising administering to the patient an effective amount of acompound according to the invention or a tautomer, prodrug,solvate, or salt thereof.
The invention further provides a method of treating a disease-stateor condition mediated by the glucocorticoid receptor function in apatient in need of such treatment, the method comprisingadministering to the patient an effective amount of apharmaceutically acceptable compound according to the invention ora tautomer, prodrug, solvate, or salt thereof.
In addition, the invention also provides a method of treating adisease-state or condition selected from: type II diabetes,obesity, cardiovascular diseases, hypertension, arteriosclerosis,neurological diseases, adrenal and pituitary tumors, and glaucoma,in a patient in need of such treatment, the method comprisingadministering to the patient an effective amount of apharmaceutically acceptable compound according to the invention ora tautomer, prodrug, solvate, or salt thereof.
The invention provides a method of treating a disease characterizedby inflammatory, allergic, or proliferative processes, in a patientin need of such treatment, the method comprising administering tothe patient an effective amount of a pharmaceutically acceptablecompound according to the invention or a tautomer, prodrug,solvate, or salt thereof. In a preferred embodiment of theinvention, the disease characterized by inflammatory, allergic, orproliferative processes is selected from: (i) lung diseases; (ii)rheumatic diseases or autoimmune diseases or joint diseases; (iii)allergic diseases; (iv) vasculitis diseases; (v) dermatologicaldiseases; (vi) renal diseases; (vii) hepatic diseases; (viii)gastrointestinal diseases; (ix) proctological diseases; (x) eyediseases; (xi) diseases of the ear, nose, and throat (ENT) area;(xii) neurological diseases; (xiii) blood diseases; (xiv) tumordiseases; (xv) endocrine diseases; (xvi) organ and tissuetransplantations and graft-versus-host diseases; (xvii) severestates of shock; (xviii) substitution therapy; and (xix) pain ofinflammatory genesis. In another preferred embodiment of theinvention, the disease characterized by inflammatory, allergic, orproliferative processes is selected from: type I diabetes,osteoarthritis, Guillain-Barre syndrome, restenosis followingpercutaneous transluminal coronary angioplasty, Alzheimer disease,acute and chronic pain, atherosclerosis, reperfusion injury, boneresorption diseases, congestive heart failure, myocardialinfarction, thermal injury, multiple organ injury secondary totrauma, acute purulent meningitis, necrotizing enterocolitis, andsyndromes associated with hemodialysis, leukopheresis, andgranulocyte transfusion.
The invention further provides methods of treating thedisease-states or conditions mentioned above, in a patient in needof such treatment, the methods comprising sequentially orsimultaneously administering to the patient: (a) an effectiveamount of a pharmaceutically acceptable compound according to theinvention or a tautomer, prodrug, solvate, or salt thereof; and (b)a pharmaceutically acceptable glucocorticoid.
The invention further provides a method of assaying theglucocorticoid receptor function in a sample, comprising: (a)contacting the sample with a selected amount of a compoundaccording to the invention or a tautomer, prodrug, solvate, or saltthereof; and (b) detecting the amount of the compound according tothe invention or a tautomer, prodrug, solvate, or salt thereofbound to glucocorticoid receptors in the sample. In a preferredembodiment of the invention, the compound according to theinvention or a tautomer, prodrug, solvate, or salt thereof islabeled with a detectable marker selected from: a radiolabel,fluorescent tag, a chemiluminescent tag, a chromophore, and a spinlabel.
The invention also provides a method of imaging the glucocorticoidreceptor distribution in a sample or patient, the methodcomprising: (a) contacting the sample or administering to a patienta compound according to the invention or a tautomer, prodrug,solvate, or salt thereof having a detectable marker; (b) detectingthe spatial distribution and amount of the compound according tothe invention or a tautomer, prodrug, solvate, or salt thereofhaving a detectable marker bound to glucocorticoid receptors in thesample or patient using an imaging means to obtain an image; and(c) displaying an image of the spatial distribution and amount ofthe compound according to the invention or a tautomer, prodrug,solvate, or salt thereof having a detectable marker bound toglucocorticoid receptors in the sample. In a preferred embodimentof the invention, the imaging means is selected from:radioscintigraphy, nuclear magnetic resonance imaging (MRI),computed tomography (CT scan), or positron emission tomography(PET).
The invention also provides a kit for the in vitro diagnosticdetermination of the glucocorticoid receptor function in a sample,comprising: (a) a diagnostically effective amount of a compoundaccording to the invention or a tautomer, prodrug, solvate, or saltthereof; and (b) instructions for use of the diagnostic kit.
DETAILED DESCRIPTION OF THE INVENTION
Definition of Terms and Conventions Used
Terms not specifically defined herein should be given the meaningsthat would be given to them by one of skill in the art in light ofthe disclosure and the context. As used in the specification andappended claims, however, unless specified to the contrary, thefollowing terms have the meaning indicated and the followingconventions are adhered to.
A. Chemical Nomenclature, Terms, and Conventions
In the groups, radicals, or moieties defined below, the number ofcarbon atoms is often specified preceding the group, for example,C.sub.1-C.sub.10 alkyl means an alkyl group or radical having 1 to10 carbon atoms. The term "lower" applied to any carbon-containinggroup means a group containing from 1 to 8 carbon atoms, asappropriate to the group (i.e., a cyclic group must have at least 3atoms to constitute a ring). In general, for groups comprising twoor more subgroups, the last named group is the radical attachmentpoint, for example, "alkylaryl" means a monovalent radical of theformula Alk-Ar-, while "arylalkyl" means a monovalent radical ofthe formula Ar-Alk- (where Alk is an alkyl group and Ar is an arylgroup). Furthermore, the use of a term designating a monovalentradical where a divalent radical is appropriate shall be construedto designate the respective divalent radical and vice versa. Unlessotherwise specified, conventional definitions of terms control andconventional stable atom valences are presumed and achieved in allformulas and groups.
The terms "alkyl" or "alkyl group" mean a branched orstraight-chain saturated aliphatic hydrocarbon monovalent radical.This term is exemplified by groups such as methyl, ethyl, n-propyl,1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl(tert-butyl), and the like. It may be abbreviated "Alk".
The terms "alkenyl" or "alkenyl group" mean a branched orstraight-chain aliphatic hydrocarbon monovalent radical containingat least one carbon-carbon double bond. This term is exemplified bygroups such as ethenyl, propenyl, n-butenyl, isobutenyl,3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, decenyl, and thelike.
The terms "alkynyl" or "alkynyl group" mean a branched orstraight-chain aliphatic hydrocarbon monovalent radical containingat least one carbon-carbon triple bond. This term is exemplified bygroups such as ethynyl, propynyl, n-butynyl, 2-butynyl,3-methylbutynyl, n-pentynyl, heptynyl, octynyl, decynyl, and thelike.
The terms "alkylene" or "alkylene group" mean a branched orstraight-chain saturated aliphatic hydrocarbon divalent radicalhaving the specified number of carbon atoms. This term isexemplified by groups such as methylene, ethylene, propylene,n-butylene, and the like, and may alternatively and equivalently bedenoted herein as -(alkyl)-.
The terms "alkenylene" or "alkenylene group" mean a branched orstraight-chain aliphatic hydrocarbon divalent radical having thespecified number of carbon atoms and at least one carbon-carbondouble bond. This term is exemplified by groups such as ethenylene,propenylene, n-butenylene, and the like, and may alternatively andequivalently be denoted herein as -(alkylenyl)-.
The terms "alkynylene" or "alkynylene group" mean a branched orstraight-chain aliphatic hydrocarbon divalent radical containing atleast one carbon-carbon triple bond. This term is exemplified bygroups such as ethynylene, propynylene, n-butynylene, 2-butynylene,3-methylbutynylene, n-pentynylene, heptynylene, octynylene,decynylene, and the like, and may alternatively and equivalently bedenoted herein as -(alkynyl)-.
The terms "alkoxy" or "alkoxy group" mean a monovalent radical ofthe formula AlkO-, where Alk is an alkyl group. This term isexemplified by groups such as methoxy, ethoxy, propoxy, isopropoxy,butoxy, sec-butoxy, tert-butoxy, pentoxy, and the like.
The terms "aryloxy", "aryloxy group", mean a monovalent radical ofthe formula ArO-, where Ar is aryl. This term is exemplified bygroups such as phenoxy, naphthoxy, and the like.
The term "oxo" means a double-bonded divalent oxygen radical of theformula (.dbd.O), For instance, one example of an alkyl groupsubstituted by an "oxo" would be a group of the formulaAlk-C(O)-Alk, wherein each Alk is an alkyl.
The terms "alkylcarbonyl", "alkylcarbonyl group", "alkanoyl", or"alkanoyl group" mean a monovalent radical of the formulaAlkC(O)--, where Alk is alkyl or hydrogen.
The terms "arylcarbonyl", "arylcarbonyl group", "aroyl" or "aroylgroup" mean a monovalent radical of the formula ArC(O)--, where Aris aryl.
The terms "acyl" or "acyl group" mean a monovalent radical of theformula RC(O)--, where R is a substituent selected from hydrogen oran organic substituent. Exemplary substituents include alkyl, aryl,arylalkyl, cycloalkyl, heterocyclyl, heteroaryl, heteroarylalkyl,and the like. As such, the terms comprise alkylcarbonyl groups andarylcarbonyl groups.
The terms "acylamino" or "acylamino group" mean a monovalentradical of the formula RC(O)N(R)--, where each R is a substituentselected from hydrogen or a substituent group.
The terms "alkoxycarbonyl" or "alkoxycarbonyl group" mean amonovalent radical of the formula AlkO-C(O)--, where Alk is alkyl.Exemplary alkoxycarbonyl groups include methoxycarbonyl,ethoxycarbonyl, tert-butyloxycarbonyl, and the like.
The terms "aryloxycarbonyl" or "aryloxycarbonyl group" mean amonovalent radical of the formula ArO-C(O)--, where Ar is aryl.
The terms "alkylcarbonyloxy" or "alkylcarbonyloxy group" or"alkanoyloxy" or "alkanoyloxy group" mean a monovalent radical ofthe formula AlkC(O)O--, where Alk is alkyl.
The terms "arylcarbonyloxy" or "arylcarbonyloxy group" or"aroyloxy" or "aroyloxy group" mean a monovalent radical of theformula ArC(O)O--, where Ar is aryl.
The terms "alkylaminocarbonyloxy" or "alkylaminocarbonyloxy group"mean a monovalent radical of the formula R.sub.2NC(O)O--, whereeach R is independently hydrogen or lower alkyl.
The term "alkoxycarbonylamino" or "alkoxycarbonylamino group" meana monovalent radical of the formula ROC(O)NH--, where R is loweralkyl.
The terms "alkylcarbonylamino" or "alkylcarbonylamino group" or"alkanoylamino" or "alkanoylamino groups" mean a monovalent radicalof the formula AlkC(O)NH--, where Alk is alkyl. Exemplaryalkylcarbonylamino groups include acetamido (CH.sub.3C(O)NH--).
The terms "alkylaminocarbonyloxy" or "alkylaminocarbonyloxy group"mean a monovalent radical of the formula AlkNHC(O)O--, where Alk isalkyl.
The terms "amino" or "amino group" mean an --NH.sub.2 group.
The terms "alkylamino" or "alkylamino group" mean a monovalentradical of the formula (Alk)NH--, where Alk is alkyl. Exemplaryalkylamino groups include methylamino, ethylamino, propylamino,butylamino, tert-butylamino, and the like.
The terms "dialkylamino" or "dialkylamino group" mean a monovalentradical of the formula (Alk)(Alk)N--, where each Alk isindependently alkyl. Exemplary dialkylamino groups includedimethylamino, methylethylamino, diethylamino, dipropylamino,ethylpropylamino, and the like.
The terms "substituted amino" or "substituted amino group" mean amonovalent radical of the formula --NR.sub.2, where each R isindependently a substituent selected from hydrogen or the specifiedsubstituents (but where both R.sup.5 cannot be hydrogen). Exemplarysubstituents include alkyl, alkanoyl, aryl, arylalkyl, cycloalkyl,heterocyclyl, heteroaryl, heteroarylalkyl, and the like.
The terms "alkoxycarbonylamino" or "alkoxycarbonylamino group" meana monovalent radical of the formula AlkOC(O)NH--, where Alk isalkyl.
The terms "ureido" or "ureido group" mean a monovalent radical ofthe formula R.sub.2NC(O)NH--, where each R is independentlyhydrogen or alkyl.
The terms "halogen" or "halogen group" mean a fluoro, chloro,bromo, or iodo group.
The term "halo" means one or more hydrogen atoms of the group arereplaced by halogen groups.
The terms "haloalkyl" or "haloalkyl group" mean a branched orstraight-chain saturated aliphatic hydrocarbon monovalent radical,wherein one or more hydrogen atoms thereof are each independentlyreplaced with halogen atoms. This term is exemplified by groupssuch as chloromethyl, 1,2-dibromoethyl, 1,1,1-trifluoropropyl,2-iodobutyl, 1-chloro-2-bromo-3-fluoropentyl, and the like.
The terms "sulfanyl", "sulfanyl group", "thioether", or "thioethergroup" mean a divalent radical of the formula --S--.
The terms "alkylthio" or "alkylthio group" mean a monovalentradical of the formula AlkS--, where Alk is alkyl. Exemplary groupsinclude methylthio, ethylthio, n-propylthio, isopropylthio,n-butylthio, and the like.
The terms "arylthio" or "arylthio group" mean a monovalent radicalof the formula ArS--, where Ar is aryl.
The terms "sulfinyl", "sulfinyl group", "thionyl", or "thionylgroup" mean a divalent radical of the formula --SO--.
The terms "sulfonyl" or "sulfonyl group" mean a divalent radical ofthe formula --SO.sub.2--. The terms "sulfonylamino" or"sulfonylamino group" mean a divalent radical of the formula--SO.sub.2NR--, where R is a hydrogen or a substituent group.
The terms "aminosulfonyl" or "aminosulfonyl group" mean amonovalent radical of the formula NR.sub.2SO.sub.2--, where R iseach independently a hydrogen or a substituent group.
The terms "carbocycle" or "carbocyclic group" mean a stablealiphatic 3- to 15-membered monocyclic or polycyclic monovalent ordivalent radical consisting solely of carbon and hydrogen atomswhich may comprise one or more fused or bridged ring(s), preferablya 5- to 7-membered monocyclic or 7- to 10-membered bicyclic ring.Unless otherwise specified, the carbocycle may be attached at anycarbon atom which results in a stable structure and, ifsubstituted, may be substituted at any suitable carbon atom whichresults in a stable structure. The term comprises cycloalkyl(including spiro cycloalkyl), cycloalkylene, cycloalkenyl,cycloalkenylene, cycloalkynyl, and cycloalkynylene, and thelike.
The terms "cycloalkyl" or "cycloalkyl group" mean a stablealiphatic saturated 3- to 15-membered monocyclic or polycyclicmonovalent radical consisting solely of carbon and hydrogen atomswhich may comprise one or more fused or bridged ring(s), preferablya 5- to 7-membered monocyclic or 7- to 10-membered bicyclic ring.Unless otherwise specified, the cycloalkyl ring may be attached atany carbon atom which results in a stable structure and, ifsubstituted, may be substituted at any suitable carbon atom whichresults in a stable structure. Exemplary cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl, cyclodecyl, norbornanyl, adamantyl,tetrahydronaphthyl (tetralin), 1-decalinyl, bicyclo[2.2.2]octanyl,1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, andthe like.
The terms "cycloalkenyl" or "cycloalkenyl group" mean a stablealiphatic 3- to 15-membered monocyclic or polycyclic monovalentradical having at least one carbon-carbon double bond andconsisting solely of carbon and hydrogen atoms which may compriseone or more fused or bridged ring(s), preferably a 5- to 7-memberedmonocyclic or 7- to 10-membered bicyclic ring. Unless otherwisespecified, the cycloalkenyl ring may be attached at any carbon atomwhich results in a stable structure and, if substituted, may besubstituted at any suitable carbon atom which results in a stablestructure. Exemplary cycloalkenyl groups include cyclopentenyl,cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl,cyclodecenyl, norbornenyl, 2-methylcyclopentenyl,2-methylcyclooctenyl, and the like.
The terms "cycloalkynyl" or "cycloalkynyl group" mean a stablealiphatic 8- to 15-membered monocyclic or polycyclic monovalentradical having at least one carbon-carbon triple bond andconsisting solely of carbon and hydrogen atoms which may compriseone or more fused or bridged ring(s), preferably a 8- to10-membered monocyclic or 12- to 15-membered bicyclic ring. Unlessotherwise specified, the cycloalkynyl ring may be attached at anycarbon atom which results in a stable structure and, ifsubstituted, may be substituted at any suitable carbon atom whichresults in a stable structure. Exemplary cycloalkynyl groupsinclude, cyclooctynyl, cyclononynyl, cyclodecynyl,2-methylcyclooctynyl, and the like.
The terms "cycloalkylene" or "cycloalkylene group" mean a stablesaturated aliphatic 3- to 15-membered monocyclic or polycyclicdivalent radical consisting solely of carbon and hydrogen atomswhich may comprise one or more fused or bridged ring(s), preferablya 5- to 7-membered monocyclic or 7- to 10-membered bicyclic ring.Unless otherwise specified, the cycloalkyl ring may be attached atany carbon atom which results in a stable structure and, ifsubstituted, may be substituted at any suitable carbon atom whichresults in a stable structure. Exemplary cycloalkylene groupsinclude cyclopentylene, and the like.
The terms "cycloalkenylene" or "cycloalkenylene group" mean astable aliphatic 5- to 15-membered monocyclic or polycyclicdivalent radical having at least one carbon-carbon double bond andconsisting solely of carbon and hydrogen atoms which may compriseone or more fused or bridged ring(s), preferably a 5- to 7-memberedmonocyclic or 7- to 10-membered bicyclic ring. Unless otherwisespecified, the cycloalkenylene ring may be attached at any carbonatom which results in a stable structure and, if substituted, maybe substituted at any suitable carbon atom which results in astable structure. Exemplary cycloalkenylene groups includecyclopentenylene, cyclohexenylene, cycloheptenylene,cyclooctenylene, cyclononenylene, cyclodecenylene, norbornenylene,2-methylcyclopentenylene, 2-methylcyclooctenylene, and thelike.
The terms "cycloalkynylene" or "cycloalkynylene group" mean astable aliphatic 8- to 15-membered monocyclic or polycyclicdivalent radical having at least one carbon-carbon triple bond andconsisting solely of carbon and hydrogen atoms which may compriseone or more fused or bridged ring(s), preferably a 8- to10-membered monocyclic or 12- to 15-membered bicyclic ring. Unlessotherwise specified, the cycloalkynylene ring may be attached atany carbon atom which results in a stable structure and, ifsubstituted, may be substituted at any suitable carbon atom whichresults in a stable structure. Exemplary cycloalkynylene groupsinclude cyclooctynylene, cyclononynylene, cyclodecynylene,2-methylcyclooctynylene, and the like.
The terms "aryl" or "aryl group" mean an aromatic carbocyclicmonovalent or divalent radical of from 6 to 14 carbon atoms havinga single ring (e.g., phenyl or phenylene) or multiple condensedrings (e.g., naphthyl or anthranyl). Unless otherwise specified,the aryl ring may be attached at any suitable carbon atom whichresults in a stable structure and, if substituted, may besubstituted at any suitable carbon atom which results in a stablestructure. Exemplary aryl groups include phenyl, naphthyl, anthryl,phenanthryl, indanyl, indenyl, biphenyl, and the like. It may beabbreviated "Ar".
The terms "heteroaryl" or "heteroaryl group" mean a stable aromatic5- to 14-membered, monocyclic or polycyclic monovalent or divalentradical which may comprise one or more fused or bridged ring(s),preferably a 5- to 7-membered monocyclic or 7- to 10-memberedbicyclic radical, having from one to four heteroatoms in thering(s) independently selected from nitrogen, oxygen, and sulfur,wherein any sulfur heteroatoms may optionally be oxidized and anynitrogen heteroatom may optionally be oxidized or be quaternized.Unless otherwise specified, the heteroaryl ring may be attached atany suitable heteroatom or carbon atom which results in a stablestructure and, if substituted, may be substituted at any suitableheteroatom or carbon atom which results in a stable structure.Exemplary and preferred heteroaryls include furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,indolizinyl, azaindolizinyl, indolyl, azaindolyl, diazaindolyl,dihydroindolyl, dihydroazaindoyl, isoindolyl, azaisoindolyl,benzofuranyl, furanopyridinyl, furanopyrimidinyl, furanopyrazinyl,furanopyridazinyl, dihydrobenzofuranyl, dihydrofuranopyridinyl,dihydrofuranopyrimidinyl, benzothienyl, thienopyridinyl,thienopyrimidinyl, thienopyrazinyl, thienopyridazinyl,dihydrobenzothienyl, dihydrothienopyridinyl,dihydrothienopyrimidinyl, indazolyl, azaindazolyl, diazaindazolyl,benzimidazolyl, imidazopyridinyl, benzthiazolyl, thiazolopyridinyl,thiazolopyrimidinyl, benzoxazolyl, oxazolopyridinyl,oxazolopyrimidinyl, benzisoxazolyl, purinyl, chromanyl,azachromanyl, quinolizinyl, quinolinyl, dihydroquinolinyl,tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl,tetrahydroisoquinolinyl, cinnolinyl, azacinnolinyl, phthalazinyl,azaphthalazinyl, quinazolinyl, azaquinazolinyl, quinoxalinyl,azaquinoxalinyl, naphthyridinyl, dihydronaphthyridinyl,tetrahydronaphthyridinyl, pteridinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, benzo[1,3]dioxane,dihydrobenzimidazolone, and the like.
The terms "heterocycle", "heterocycle group", "heterocyclyl", or"heterocyclyl group" mean a stable non-aromatic 5- to 14-memberedmonocyclic or polycyclic, monovalent or divalent, ring which maycomprise one or more fused or bridged ring(s), preferably a 5- to7-membered monocyclic or 7- to 10-membered bicyclic ring, havingfrom one to three heteroatoms in the ring(s) independently selectedfrom nitrogen, oxygen, and sulfur, wherein any sulfur heteroatomsmay optionally be oxidized and any nitrogen heteroatom mayoptionally be oxidized or be quaternized. Unless otherwisespecified, the heterocyclyl ring may be attached at any suitableheteroatom or carbon atom which results in a stable structure and,if substituted, may be substituted at any suitable heteroatom orcarbon atom which results in a stable structure. Exemplary andpreferred heterocycles include pyrrolinyl, pyrrolidinyl,pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, tetrahydropyranyl,tetrahydrothiopyranyl, tetrahydrofuranyl, hexahydropyrimidinyl,hexahydropyridazinyl, and the like.
The term "compounds of the invention" and equivalent expressionsare meant to embrace compounds of Formula (I) as herein described,including the tautomers, the prodrugs, the salts, particularly thepharmaceutically acceptable salts, and the solvates and hydratesthereof, where the context so permits. In general and preferably,the compounds of the invention and the formulas designating thecompounds of the invention are understood to only include thestable compounds thereof and exclude unstable compounds, even if anunstable compound might be considered to be literally embraced bythe compound formula. Similarly, reference to intermediates,whether or not they themselves are claimed, is meant to embracetheir salts and solvates, where the context so permits. For thesake of clarity, particular instances when the context so permitsare sometimes indicated in the text, but these instances are purelyillustrative and it is not intended to exclude other instances whenthe context so permits.
The terms "optional" or "optionally" mean that the subsequentlydescribed event or circumstances may or may not occur, and that thedescription includes instances where the event or circumstanceoccurs and instances in which it does not. For example, "optionallysubstituted aryl" means that the aryl radical may or may not besubstituted and that the description includes both substituted arylradicals and aryl radicals having no substitution.
The terms "stable compound" or "stable structure" mean a compoundthat is sufficiently robust to survive isolation to a useful degreeof purity from a reaction mixture, and formulation into anefficacious therapeutic or diagnostic agent. For example, acompound which would have a "dangling valency" or is a carbanion isnot a compound contemplated by the invention.
The term "substituted" means that any one or more hydrogens on anatom of a group or moiety, whether specifically designated or not,is replaced with a selection from the indicated group ofsubstituents, provided that the atom's normal valency is notexceeded and that the substitution results in a stable compound. Ifa bond to a substituent is shown to cross the bond connecting twoatoms in a ring, then such substituent may be bonded to any atom onthe ring. When a substituent is listed without indicating the atomvia which such substituent is bonded to the rest of the compound,then such substituent may be bonded via any atom in suchsubstituent. For example, when the substituent is piperazinyl,piperidinyl, or tetrazolyl, unless specified otherwise, suchpiperazinyl, piperidinyl, or tetrazolyl group may be bonded to therest of the compound of the invention via any atom in suchpiperazinyl, piperidinyl, or tetrazolyl group. Generally, when anysubstituent or group occurs more than one time in any constituentor compound, its definition on each occurrence is independent ofits definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0 to 2 R.sup.5, then suchgroup is optionally substituted with up to two R.sup.5 groups andR.sup.5 at each occurrence is selected independently from thedefined list of possible R.sup.5. Such combinations of substituentsand/or variables, however, are permissible only if suchcombinations result in stable compounds.
In a specific embodiment, the term "about" or "approximately" meanswithin 20%, preferably within 10%, and more preferably within 5% ofa given value or range.
The yield of each of the reactions described herein is expressed asa percentage of the theoretical yield.
B. Salt, Prodrug, Derivative, and Solvate Terms and Conventions
The terms "prodrug" or "prodrug derivative" mean acovalently-bonded derivative or carrier of the parent compound oractive drug substance which undergoes at least somebiotransformation prior to exhibiting its pharmacologicaleffect(s). In general, such prodrugs have metabolically cleavablegroups and are rapidly transformed in vivo to yield the parentcompound, for example, by hydrolysis in blood, and generallyinclude esters and amide analogs of the parent compounds. Theprodrug is formulated with the objectives of improved chemicalstability, improved patient acceptance and compliance, improvedbioavailability, prolonged duration of action, improved organselectivity, improved formulation (e.g., increasedhydrosolubility), and/or decreased side effects (e.g., toxicity).In general, prodrugs themselves have weak or no biological activityand are stable under ordinary conditions. Prodrugs can be readilyprepared from the parent compounds using methods known in the art,such as those described in A Textbook of Drug Design andDevelopment, Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon& Breach, 1991, particularly Chapter 5: "Design andApplications of Prodrugs"; Design of Prodrugs, H. Bundgaard (ed.),Elsevier, 1985; Prodrugs: Topical and Ocular Drug Deliver, K. B.Sloan (ed.), Marcel Dekker, 1998; Methods in Enzmmology, K. Widderet al. (eds.), Vol. 42, Academic Press, 1985, particularly pp.309-396; Burger's Medicinal Chemistry and Drug Discovery, 5th Ed.,M. Wolff (ed.), John Wiley & Sons, 1995, particularly Vol. 1and pp. 172-178 and pp. 949-982; Pro-Drugs as Novel DeliverySystems, T. Higuchi and V. Stella (eds.), Am. Chem. Soc., 1975;Bioreversible Carriers in Drug Design, E. B. Roche (ed.), Elsevier,1987, each of which is incorporated herein by reference in theirentireties.
The term "pharmaceutically acceptable prodrug" as used herein meansa prodrug of a compound of the invention which is, within the scopeof sound medical judgment, suitable for use in contact with thetissues of humans and lower animals without undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intendeduse, as well as the zwitterionic forms, where possible.
The term "salt" means an ionic form of the parent compound or theproduct of the reaction between the parent compound with a suitableacid or base to make the acid salt or base salt of the parentcompound. Salts of the compounds of the present invention can besynthesized from the parent compounds which contain a basic oracidic moiety by conventional chemical methods. Generally, thesalts are prepared by reacting the free base or acid parentcompound with stoichiometric amounts or with an excess of thedesired salt-forming inorganic or organic acid or base in asuitable solvent or various combinations of solvents.
The term "pharmaceutically acceptable salt" means a salt of acompound of the invention which is, within the scope of soundmedical judgment, suitable for use in contact with the tissues ofhumans and lower animals without undue toxicity, irritation,allergic response, and the like, commensurate with a reasonablebenefit/risk ratio, generally water or oil-soluble or dispersible,and effective for their intended use. The term includespharmaceutically-acceptable acid addition salts andpharmaceutically-acceptable base addition salts. As the compoundsof the present invention are useful in both free base and saltform, in practice, the use of the salt form amounts to use of thebase form. Lists of suitable salts are found in, e.g., S. M. Birgeet al., J. Pharm. Sci., 1977, 66, pp. 1-19, which is herebyincorporated by reference in its entirety.
The term "pharmaceutically-acceptable acid addition salt" meansthose salts which retain the biological effectiveness andproperties of the free bases and which are not biologically orotherwise undesirable, formed with inorganic acids such ashydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuricacid, sulfamic acid, nitric acid, phosphoric acid, and the like,and organic acids such as acetic acid, trichloroacetic acid,trifluoroacetic acid, adipic acid, alginic acid, ascorbic acid,aspartic acid, benzenesulfonic acid, benzoic acid, 2-acetoxybenzoicacid, butyric acid, camphoric acid, camphorsulfonic acid, cinnamicacid, citric acid, digluconic acid, ethanesulfonic acid, glutamicacid, glycolic acid, glycerophosphoric acid, hemisulfic acid,heptanoic acid, hexanoic acid, formic acid, fumaric acid,2-hydroxyethanesulfonic acid (isethionic acid), lactic acid, maleicacid, hydroxymaleic acid, malic acid, malonic acid, mandelic acid,mesitylenesulfonic acid, methanesulfonic acid, naphthalenesulfonicacid, nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid,pamoic acid, pectinic acid, phenylacetic acid, 3-phenylpropionicacid, picric acid, pivalic acid, propionic acid, pyruvic acid,pyruvic acid, salicylic acid, stearic acid, succinic acid,sulfanilic acid, tartaric acid, p-toluenesulfonic acid, undecanoicacid, and the like.
The term "pharmaceutically-acceptable base addition salt" meansthose salts which retain the biological effectiveness andproperties of the free acids and which are not biologically orotherwise undesirable, formed with inorganic bases such as ammoniaor hydroxide, carbonate, or bicarbonate of ammonium or a metalcation such as sodium, potassium, lithium, calcium, magnesium,iron, zinc, copper, manganese, aluminum, and the like. Particularlypreferred are the ammonium, potassium, sodium, calcium, andmagnesium salts. Salts derived from pharmaceutically-acceptableorganic nontoxic bases include salts of primary, secondary, andtertiary amines, quaternary amine compounds, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion-exchange resins, such as methylamine, dimethylarine,trimethylamine, ethylamine, diethylamine, triethylamine,isopropylamine, tripropylamine, tributylamine, ethanolamine,diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, tetramethylammonium compounds,tetraethylammonium compounds, pyridine, N,N-dimethylaniline,N-methylpiperidine, N-methylmorpholine, dicyclohexylamine,dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine,N,N'-dibenzylethylenediamine, polyamine resins, and the like.Particularly preferred organic nontoxic bases are isopropylamine,diethylamine, ethanolamine, trimethylamine, dicyclohexylamine,choline, and caffeine.
The term "solvate" means a physical association of a compound withone or more solvent molecules or a complex of variablestoichiometry formed by a solute (for example, a compound ofFormula (I)) and a solvent, for example, water, ethanol, or aceticacid. This physical association may involve varying degrees ofionic and covalent bonding, including hydrogen bonding. In certaininstances, the solvate will be capable of isolation, for example,when one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. In general, the solvents selecteddo not interfere with the biological activity of the solute.Solvates encompasses both solution-phase and isolatable solvates.Representative solvates include hydrates, ethanolates,methanolates, and the like.
The term "hydrate" means a solvate wherein the solvent molecule(s)is/are H.sub.2O.
The compounds of the present invention as discussed below includethe free base or acid thereof, their salts, solvates, and prodrugsand may include oxidized sulfur atoms or quaternized nitrogen atomsin their structure, although not explicitly stated or shown,particularly the pharmaceutically acceptable forms thereof. Suchforms, particularly the pharmaceutically acceptable forms, areintended to be embraced by the appended claims.
C. Isomer Terms and Conventions
The term "isomers" means compounds having the same number and kindof atoms, and hence the same molecular weight, but differing withrespect to the arrangement or configuration of the atoms in space.The term includes stereoisomers and geometric isomers.
The terms "stereoisomer" or "optical isomer" mean a stable isomerthat has at least one chiral atom or restricted rotation givingrise to perpendicular dissymmetric planes (e.g., certain biphenyls,allenes, and spiro compounds) and can rotate plane-polarized light.Because asymmetric centers and other chemical structure exist inthe compounds of the invention which may give rise tostereoisomerism, the invention contemplates stereoisomers andmixtures thereof. The compounds of the invention and their saltsinclude asymmetric carbon atoms and may therefore exist as singlestereoisomers, racemates, and as mixtures of enantiomers anddiastereomers. Typically, such compounds will be prepared as aracemic mixture. If desired, however, such compounds can beprepared or isolated as pure stereoisomers, i.e., as individualenantiomers or diastereomers, or as stereoisomer-enriched mixtures.As discussed in more detail below, individual stereoisomers ofcompounds are prepared by synthesis from optically active startingmaterials containing the desired chiral centers or by preparationof mixtures of enantiomeric products followed by separation orresolution, such as conversion to a mixture of diastereomersfollowed by separation or recrystallization, chromatographictechniques, use of chiral resolving agents, or direct separation ofthe enantiomers on chiral chromatographic columns. Startingcompounds of particular stereochemistry are either commerciallyavailable or are made by the methods described below and resolvedby techniques well-known in the art.
The term "enantiomers" means a pair of stereoisomers that arenon-superimposable mirror images of each other.
The terms "diastereoisomers" or "diastereomers" mean opticalisomers which are not mirror images of each other.
The terms "racemic mixture" or "racemate" mean a mixture containingequal parts of individual enantiomers.
The term "non-racemic mixture" means a mixture containing unequalparts of individual enantiomers.
The term "geometrical isomer" means a stable isomer which resultsfrom restricted freedom of rotation about double bonds (e.g.,cis-2-butene and trans-2-butene) or in a cyclic structure (e.g.,cis-1,3-dichlorocyclobutane and trans-1,3-dichlorocyclobutane).Because carbon-carbon double (olefinic) bonds, C.dbd.N doublebonds, cyclic structures, and the like may be present in thecompounds of the invention, the invention contemplates each of thevarious stable geometric isomers and mixtures thereof resultingfrom the arrangement of substituents around these double bonds andin these cyclic structures. The substituents and the isomers aredesignated using the cis/trans convention or using the E or Zsystem, wherein the term "E" means higher order substituents onopposite sides of the double bond, and the term "Z" means higherorder substituents on the same side of the double bond. A thoroughdiscussion of E and Z isomerism is provided in J. March, AdvancedOrganic Chemistry: Reactions, Mechanisms, and Structure, 4th ed.,John Wiley & Sons, 1992, which is hereby incorporated byreference in its entirety. Several of the following examplesrepresent single E isomers, single Z isomers, and mixtures of E/Zisomers. Determination of the E and Z isomers can be done byanalytical methods such as x-ray crystallography, .sup.1H NMR, and.sup.13C NMR.
Some of the compounds of the invention can exist in more than onetautomeric form. As mentioned above, the compounds of the inventioninclude all such tautomers.
It is well-known in the art that the biological and pharmacologicalactivity of a compound is sensitive to the stereochemistry of thecompound. Thus, for example, enantiomers often exhibit strikinglydifferent biological activity including differences inpharmacokinetic properties, including metabolism, protein binding,and the like, and pharmacological properties, including the type ofactivity displayed, the degree of activity, toxicity, and the like.Thus, one skilled in the art will appreciate that one enantiomermay be more active or may exhibit beneficial effects when enrichedrelative to the other enantiomer or when separated from the otherenantiomer. Additionally, one skilled in the art would know how toseparate, enrich, or selectively prepare the enantiomers of thecompounds of the invention from this disclosure and the knowledgeof the prior art.
Thus, although the racemic form of drug may be used, it is oftenless effective than administering an equal amount ofenantiomerically pure drug; indeed, in some cases, one enantiomermay be pharmacologically inactive and would merely serve as asimple diluent. For example, although ibuprofen had been previouslyadministered as a racemate, it has been shown that only theS-isomer of ibuprofen is effective as an anti-inflammatory agent(in the case of ibuprofen, however, although the R-isomer isinactive, it is converted in vivo to the S-isomer, thus, therapidity of action of the racemic form of the drug is less thanthat of the pure S-isomer). Furthermore, the pharmacologicalactivities of enantiomers may have distinct biological activity.For example, S-penicillamine is a therapeutic agent for chronicarthritis, while R-penicillamine is toxic. Indeed, some purifiedenantiomers have advantages over the racemates, as it has beenreported that purified individual isomers have faster transdermalpenetration rates compared to the racemic mixture. See U.S. Pat.Nos. 5,114,946 and 4,818,541.
Thus, if one enantiomer is pharmacologically more active, lesstoxic, or has a preferred disposition in the body than the otherenantiomer, it would be therapeutically more beneficial toadminister that enantiomer preferentially. In this way, the patientundergoing treatment would be exposed to a lower total dose of thedrug and to a lower dose of an enantiomer that is possibly toxic oran inhibitor of the other enantiomer.
Preparation of pure enantiomers or mixtures of desired enantiomericexcess (ee) or enantiomeric purity are accomplished by one or moreof the many methods of (a) separation or resolution of enantiomers,or (b) enantioselective synthesis known to those of skill in theart, or a combination thereof. These resolution methods generallyrely on chiral recognition and include, for example, chromatographyusing chiral stationary phases, enantioselective host-guestcomplexation, resolution or synthesis using chiral auxiliaries,enantioselective synthesis, enzymatic and nonenzymatic kineticresolution, or spontaneous enantioselective crystallization. Suchmethods are disclosed generally in Chiral Separation Techniques: APractical Approach (2nd Ed.), G. Subramanian (ed.), Wiley-VCH,2000; T. E. Beesley and R. P. W. Scott, Chiral Chromatography, JohnWiley & Sons, 1999; and Satinder Ahuja, Chiral Separations byChromatography, Am. Chem. Soc., 2000. Furthermore, there areequally well-known methods for the quantitation of enantiomericexcess or purity, for example, GC, HPLC, CE, or NMR, and assignmentof absolute configuration and conformation, for example, CD ORD,X-ray crystallography, or NMR.
In general, all tautomeric forms and isomeric forms and mixtures,whether individual geometric isomers or stereoisomers or racemic ornon-racemic mixtures, of a chemical structure or compound isintended, unless the specific stereochemistry or isomeric form isspecifically indicated in the compound name or structure.
D. Pharmaceutical Administration and Diagnostic and Treatment Termsand Conventions
The term "patient" includes both human and non-human mammals.
The term "effective amount" means an amount of a compound accordingto the invention which, in the context of which it is administeredor used, is sufficient to achieve the desired effect or result.Depending on the context, the term effective amount may include orbe synonymous with a pharmaceutically effective amount or adiagnostically effective amount.
The terms "pharmaceutically effective amount" or "therapeuticallyeffective amount" means an amount of a compound according to theinvention which, when administered to a patient in need thereof, issufficient to effect treatment for disease-states, conditions, ordisorders for which the compounds have utility. Such an amountwould be sufficient to elicit the biological or medical response ofa tissue, system, or patient that is sought by a researcher orclinician. The amount of a compound of according to the inventionwhich constitutes a therapeutically effective amount will varydepending on such factors as the compound and its biologicalactivity, the composition used for administration, the time ofadministration, the route of administration, the rate of excretionof the compound, the duration of treatment, the type ofdisease-state or disorder being treated and its severity, drugsused in combination with or coincidentally with the compounds ofthe invention, and the age, body weight, general health, sex, anddiet of the patient. Such a therapeutically effective amount can bedetermined routinely by one of ordinary skill in the art havingregard to their own knowledge, the prior art, and thisdisclosure.
The term "diagnostically effective amount" means an amount of acompound according to the invention which, when used in adiagnostic method, apparatus, or assay, is sufficient to achievethe desired diagnostic effect or the desired biological activitynecessary for the diagnostic method, apparatus, or assay. Such anamount would be sufficient to elicit the biological or medicalresponse in a diagnostic method, apparatus, or assay, which mayinclude a biological or medical response in a patient or in a invitro or in vivo tissue or system, that is sought by a researcheror clinician. The amount of a compound according to the inventionwhich constitutes a diagnostically effective amount will varydepending on such factors as the compound and its biologicalactivity, the diagnostic method, apparatus, or assay used, thecomposition used for administration, the time of administration,the route of administration, the rate of excretion of the compound,the duration of administration, drugs and other compounds used incombination with or coincidentally with the compounds of theinvention, and, if a patient is the subject of the diagnosticadministration, the age, body weight, general health, sex, and dietof the patient. Such a diagnostically effective amount can bedetermined routinely by one of ordinary skill in the art havingregard to their own knowledge, the prior art, and thisdisclosure.
The term "modulate" means the ability of a compound to alter thefunction of the glucocorticoid receptor by, for example, binding toand stimulating or inhibiting the glucocorticoid receptorfunctional responses.
The term "modulator" in the context of describing compoundsaccording to the invention means a compound that modulates theglucocorticoid receptor function. As such, modulators include, butare not limited to, agonists, partial agonists, antagonists, andpartial antagonists.
The term "agonist" in the context of describing compounds accordingto the invention means a compound that, when bound to theglucocorticoid receptor, enhances or increases the glucocorticoidreceptor function. As such, agonists include partial agonists andfull agonists.
The term "full agonist" in the context of describing compoundsaccording to the invention means a compound that evokes the maximalstimulatory response from the glucocorticoid receptor, even whenthere are spare (unoccupied) glucocorticoid receptors present.
The term "partial agonist" in the context of describing compoundsaccording to the invention means a compound that is unable to evokethe maximal stimulatory response from the glucocorticoid receptor,even at concentrations sufficient to saturate the glucocorticoidreceptors present.
The term "antagonist" in the context of describing compoundsaccording to the invention means a compound that directly orindirectly inhibits or suppresses the glucocorticoid receptorfunction. As such, antagonists include partial antagonists and fullantagonists.
The term "full antagonist" in the context of describing compoundsaccording to the invention means a compound that evokes the maximalinhibitory response from the glucocorticoid receptor, even whenthere are spare (unoccupied) glucocorticoid receptors present.
The term "partial antagonist" in the context of describingcompounds according to the invention means a compound that isunable to evoke the maximal inhibitory response from theglucocorticoid receptor, even at concentrations sufficient tosaturate the glucocorticoid receptors present.
The terms "treating" or "treatment" mean the treatment of adisease-state in a patient, and include: (i) preventing thedisease-state from occurring in a patient, in particular, when suchpatient is genetically or otherwise predisposed to thedisease-state but has not yet been diagnosed as having it; (ii)inhibiting or ameliorating the disease-state in a patient, i.e.,arresting or slowing its development; or (iii) relieving thedisease-state in a patient, i.e., causing regression or cure of thedisease-state. General Synthetic Methods for Making Compounds ofFormula (IA)
The invention also provides processes for making compounds ofFormula (I). In all schemes, unless specified otherwise, R.sup.1 toR.sup.5 in the formulas below shall have the meaning of R.sup.1 toR.sup.5 in the Formula (I) of the invention described hereinabove.Intermediates used in the preparation of compounds of the inventionare either commercially available or readily prepared by methodsknown to those skilled in the art.
Optimum reaction conditions and reaction times may vary dependingon the particular reactants used. Unless otherwise specified,solvents, temperatures, pressures, and other reaction conditionsmay be readily selected by one of ordinary skill in the art.Specific procedures are provided in the Experimental Examplessection. Typically, reaction progress may be monitored by thinlayer chromatography (TLC), if desired, and intermediates andproducts may be purified by chromatography on silica gel and/or byrecrystallization.
Compounds of Formula (IA) may be prepared by the method outlined inScheme I.
Compounds of Formula (IA) in which R.sup.4 is --CH.sub.2-- may beprepared by the method outlined in Scheme I.
##STR00392##
As illustrated in Scheme I, an ester intermediate of Formula (II)where R' is Me or Et, is reduced with a suitable reducing agent,such as lithium aluminum hydride (LiAlH.sub.4), in a suitablesolvent, such as tetrahydrofuran (THF) or diethyl ether(Et.sub.2O), to produce the 1,2-diol of Formula (III). The diol isthen reacted with a reagent, for example R'SO.sub.2Cl (R'=methyl orp-tolyl) that will form a leaving group L, with the primary alcoholof Formula (III) A suitable leaving group would be, for example, asulfonic acid ester such as a mesylate or tosylate (IV, L is--SO.sub.2CH.sub.3 or --SO.sub.2 (p-tolyl)). Intermediate (IV) maybe isolated or reacted in situ with a base such as potassiumcarbonate to produce epoxide (V). Reaction of epoxide (V) with thedesired R.sup.5H, provides the desired product of Formula (IA). Thereaction may take place by heating R.sup.5H and epoxide (V) in asuitable solvent such as DMF, or by heating R.sup.5H and epoxide(V) together in a solvent in the presence of a suitable base suchas sodium ethoxide in EtOH.
Intermediates of Formula (II) may be prepared by methods known inthe art. Two procedures are illustrated in Scheme II.
##STR00393##
For an R.sup.1 group which will undergo a Friedel-Craftsalkylation, one may react a pyruvate (VI) bearing CF.sub.3 andwhere R' is Me or Et, with a bromomethyl olefin (VII) bearing anR.sup.2 and an olefin group (.dbd.CH--R'') that will becomeR.sup.3, in the presence of manganese and a Lewis acid, such aszinc chloride, in a suitable solvent, such as THF, to produce a2-hydroxy ester (VIII). Friedel-Crafts alkylation of R' with thisintermediate (VIII) in the presence of a suitable Lewis acid, suchas aluminum chloride, provides compound (II)(R.sup.3=--CH.sub.2R''). Alternatively, one may perform a Grignardreaction with a pyruvate bearing CF.sub.3 (VI) and an ethylmagnesium halide (IX) bearing R.sup.1, R.sup.2, and R.sup.3 toprovide the desired intermediate of Formula (II).
Compounds in which R.sup.4 is --C(O)-- may be prepared readily fromintermediate (II) as illustrated in Scheme III.
##STR00394##
As illustrated in Scheme III, hydrolysis of intermediate (II), forexample, by refluxing with an aqueous base such as potassiumhydroxide with a suitable co-solvent such as methanol, providescarboxylic acid (X). The resulting carboxylic acid (X) may becoupled with R.sup.5H under standard coupling conditions well-knownin the art (see, for example, M. Bodanszky, The Practice of PeptideSynthesis (Springer-Verlag: 1984), which is hereby incorporated byreference in its entirety). For example, one may couple carboxylicacid (X) and R.sup.5H by treating with1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC)followed by 1-hydroxybenzotriazole hydrate (HOBT) in a suitablesolvent such as DMF.
Compounds of Formula (IB) may be prepared by the method outlined inScheme IV below,
##STR00395## where R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, andX are as defined above and R.sup.4 is --CH.sub.2--, the methodcomprising: (a) reacting a compound of Formula (IA) with a suitablebase in a suitable solvent to form a ketone of Formula (IIB)
##STR00396## and (b) reacting the ketone of Formula (IIB) with aorganometallic reagent to form a compound of Formula (IB)
##STR00397##
In order that this invention be more fully understood, thefollowing examples are set forth. These examples are for thepurpose of illustrating embodiments of this invention, and are notto be construed as limiting the scope of the invention in any waysince, as recognized by one skilled in the art, particular reagentsor conditions could be modified as needed for individual compounds.Starting materials used are either commercially available or easilyprepared from commercially available materials by those skilled inthe art.
EXPERIMENTAL EXAMPLES
Example 1
Synthesis of2-(2,6-dimethylmorpholin-4-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methox-yphenyl)-4-methylpentan-2-ol Hydrochloride
##STR00398##
To a mixture of 8.5 g (49.9 mmol) of ethyl trifluoromethylpyruvate,6.6 g (120 mmol) of manganese, and 0.65 g (4.8 mmol) of zincchloride in 40 mL of THF warmed to reflux was added 200 .mu.L (2mmol) of 1-bromo-2-methylpropene. After 30 minutes, 9.13 mL (90.5mmol) of 1-bromo-2-methylpropene in 30 mL of THF was added dropwiseover a 1 hour period. The mixture was refluxed for 1 hour after theaddition and was then cooled to 0.degree. C. and diluted with 150mL of saturated aqueous ammonium chloride and 100 mL of ethylacetate (EtOAc). The organic phase was separated and the aqueouslayer extracted with three 100 mL portions of EtOAc. The combinedorganic layers were washed with two 50 mL portions of saturatedaqueous ammonium chloride, followed by two 50 mL portions of brine,dried over magnesium sulfate (MgSO.sub.4), filtered, andconcentrated in vacuo. The crude residue was purified by silica gelchromatography eluting with EtOAc-hexanes (5:95) to afford 5.9 g(52%) of 2-hydroxy-4-methyl-2-trifluoromethylpent-4-enoic acidethyl ester.
To a mixture of 5.9 g (26.1 mmol) of the above2-hydroxy-4-methyl-2-trifluoromethylpent-4-enoic acid ethyl esterin 30 mL of 4-fluoroanisole was added in several portions 5.2 g(39.4 mmol) of aluminum chloride. The mixture became exothermic andturned black with the first addition and was cooled with anice-water bath. The mixture was stirred for 3 days and was thenpoured into 200 mL of ice-cold 1N aqueous HCl and extracted withthree 150 mL portions of EtOAc. The combined organic layers werewashed with 50 mL of 1N aqueous hydrochloric acid, three 50 mLportions of brine, dried over magnesium sulfate, filtered, andconcentrated in vacuo. The crude residue was purified by silica gelchromatography eluting with EtOAc-hexanes (1:9, then 2:8, then 3:7,then 4:6) to afford 6.6 g (71%) of4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentanoi-c acid ethyl ester.
To4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenta-noic acid ethyl ester (10.07 g) in 100 mL of anhydrous THF at0.degree. C.-5.degree. C. was added 1.3 g of lithium aluminumhydride portionwise. The mixture slowly warmed to room temperatureand was stirred for two days. The reaction was quenched with 1.3 mLof water, 1.3 mL of 15% aqueous NaOH, and 3.9 mL of water. Themixture was filtered through diatomaceous earth, diluted withdiethyl ether, washed with water and brine, and dried overmagnesium sulfate. The volatiles were removed in vacuo. The product4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethylpentane-1,2-diolwas taken forward without further purification.
To a solution of4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethylpentane-1,2-diol(8.15 g) and pyridine (21.2 mL) in 50 mL of methylene chloride(CH.sub.2Cl.sub.2) at 0.degree. C.-5.degree. C. was added dropwisemethanesulfonyl chloride (2.63 mL). The mixture was warmed to roomtemperature, stirred overnight and methanol (80 mL) andK.sub.2CO.sub.3 (36.2 g) were added. The mixture was stirred 4hours, diluted with diethyl ether, washed with water, dilute HCl,and brine, and dried over magnesium sulfate. Removal of thevolatiles in vacuo provided a residue that was purified by flashsilica gel chromatography using 5% EtOAc in hexanes as the eluent.The product-rich fractions were collected and the volatiles removedin vacuo to provide2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane.
A mixture of2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane(0.219 g) and 2-6-dimethylmorpholine (0.26 mL) in 2 mL anhydrousDMF was heated at 100.degree. C. for 2 hours, cooled to roomtemperature, diluted with diethyl ether, washed with water andbrine, and dried over magnesium sulfate. Removal of the volatilesin vacuo provided an oil which was dissolved in approximately 15 mLdiethyl ether and HCl in dioxane was added. The volatiles wereremoved in vacuo and the resulting solid was triturated withdiethyl ether and dried in vacuo to give the title compound, m.p.133.degree. C.-135.degree. C.
Example 2
Synthesis of2-(2,3-dihydrobenzo[1,4]oxazin-4-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2--methoxyphenyl)-4-methylpentan-2-ol hydrochloride
##STR00399##
A mixture of2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane(see Example 1) (0.139 g) and 3,4-dihydro-2H-benzo[1,4]oxazine(0.76 g) was dissolved in approximately 5 mL of methylene chlorideand 0.55 g of flash silica gel was added. The volatiles wereremoved in vacuo and the residue was microwaved for 60 seconds at150.degree. C. and applied to a column of flash silica gel. Elutionwith EtOAc-hexanes (1:10) and concentration in vacuo of theproduct-rich fractions provided a residue which was dissolved indiethyl ether. HCl in dioxane was added. The volatiles were removedin vacuo and the residue triturated with diethyl ether. Theresulting solid was dried in vacuo to provide the title compound,m.p. 98.degree. C.-99.degree. C.
Example 3
Synthesis of1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one
##STR00400##
A mixture of2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane(see Example 1) (0.21 g) and 4-hydroxyquinoline (0.105 g) andsodium ethoxide (21 wt. % in EtOH) in 4 mL anhydrous EtOH washeated at 85.degree. C. for 6 hours, cooled to room temperature,diluted with EtOAc and acetic acid, washed with water and brine,and dried over magnesium sulfate. Removal of the volatiles in vacuoprovided a residue which was purified with flash silica gel usingEtOAc as the eluent. Concentration in vacuo of the product-richfractions provided the title compound, m.p. 170.degree.C.-172.degree. C.
Example 4
Synthesis of2-(3,4-dihydro-2H-quinoxalin-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-me-thoxyphenyl)-4-methylpentan-2-ol
##STR00401##
A solution of2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane(see Example 1) (54.4 mg) and tetrahydroquinoxaline (124.8 mg) inDMF (0.6 mL) was heated at 100.degree. C. for 6 hours. Theresulting mixture was diluted with diethyl ether, washed with waterand brine, dried over sodium sulfate, filtered, and concentrated invacuo. The residue was purified by preparative TLC (eluted with 25%diethyl ether-benzene) to give the title compound as a clear oil(31.2 mg).
Example 5
Synthesis of1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-methyl-3,4-dih-ydro-2H-quinoxalin-1-ylmethyl)pentan-2-ol
##STR00402##
To a solution of2-(3,4-dihydro-2H-quinoxalin-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-me-thoxyphenyl)-4-methylpentan-2-ol (Example 4) (18.6 mg) inacetonitrile (3 mL) was added formaldehyde solution (37% w/waqueous, 300 .mu.L) followed by sodium cyanoborohydride (13.8 mg).After 30 minutes at room temperature, acetic acid (50.4 .mu.L) wasadded. The resulting mixture was stirred for 3 hours, quenched withsaturated aqueous sodium bicarbonate solution and extracted threetimes with methylene chloride. The combined organic phases weredried over sodium sulfate, filtered, and the volatiles removed invacuo. The residue was purified by preparative TLC (eluted with 25%EtOAc-hexanes) to give the title compound as a pale yellow oil(16.6 mg).
Example 6
Synthesis of1,1,1-trifluoro-4(5-fluoro-2-methoxyphenyl)-4-methyl-2-thiomorpholin-4-yl-methylpentan-2-ol
##STR00403##
A solution of2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane(see Example 1) (130 mg) and thiomorpholine (84.6 .mu.L) indimethylformamide (1 .mu.L) was heated at 100.degree. C. for 15hours. The resulting mixture was diluted with diethyl ether, washedwith water and brine, dried over sodium sulfate, filtered, and thevolatiles removed in vacuo. The residue was purified by silica gelcolumn chromatography using 2% EtOAc-hexanes as the eluent. Theproduct-rich fractions were concentrated in vacuo to provide thetitle compound as a clear oil (161 mg).
Example 7
Synthesis of1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1-oxo-1.lamda..s-up.4-thiomorpholin-4-ylmethylpentan-2-ol
##STR00404##
To a solution of1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-thiomorpholin-4-y-lmethylpentan-2-ol (Example 6) (34 mg) in MeOH (1.5 mL) was added asolution of sodium periodate (20 mg) in water (1.5 mL). After 21hours at room temperature, an additional portion of sodiumperiodate (7 mg) was added to the incomplete reaction. Theresulting mixture was allowed to stir for 15 hours, concentrated invacuo, diluted with water and extracted two times with diethylether. The combined organic phases were washed with brine, driedover sodium sulfate, filtered, and concentrated in vacuo. Theresidue was purified by silica gel column chromatography elutingwith 50% to 70% ethyl acetate-hexanes to give the title compound asa white solid (29 mg), m.p. 135.degree. C.-136.degree. C.
Example 8
Synthesis of2-(1,1-dioxo-1.lamda..sup.6-thiomorpholin-4-ylmethyl)-1,1,1-trifluoro-4-(-5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol
##STR00405##
To a solution of1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-thiomorpholin-4-y-lmethylpentan-2-ol (Example 6) (65 mg) in CH.sub.2Cl.sub.2 (2 mL)was added a solution of hydrogen peroxide (30% w/w aqueous, 46.8.mu.L) in trifluoroacetic acid (0.5 mL). The resulting mixture wasstirred for 3.5 days, quenched with saturated aqueous sodiumbicarbonate, and extracted two times with diethyl ether. Thecombined organic phases were washed with brine, dried overmagnesium sulfate, filtered, and concentrated in vacuo. The residuewas purified by preparative TLC (eluted with 50% ethylacetate-hexanes plus 0.2% triethylamine) to give the title compoundas a clear oil (13.1 mg).
Example 9
Synthesis of2-(2,3-dihydrobenzo[1,4]thiazin-4-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2--methoxyphenyl)-4-methylpentan-2-ol
##STR00406##
A solution of2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane(118 mg) and 3,4-dihydro-2H-1,4-benzothiazine (H. I. El-Subbagh etal., Arch. Pharm. Med. Chem., 1999, 332, pp. 19-24) (122 mg) indimethylformamide (1 mL) was heated at 140.degree. C. for 73 hours.The resulting mixture was diluted with diethyl ether, washed withsaturated aqueous sodium bicarbonate, water and brine, dried overmagnesium sulfate, filtered, and concentrated in vacuo. The residuewas purified by radial chromatography with a chromatotron (elutedwith 0% to 1% ethyl acetate-hexanes) to give the title compound asa white solid (53.5 mg), m.p. 103.degree. C.-104.degree. C.
Example 10
Synthesis of2-(3,5-dimethylpiperazin-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methox-yphenyl)-4-methylpentan-2-ol
##STR00407##
A solution of2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane(98.7 mg) and 2,6-dimethylpiperazine (77.2 mg) in dimethylformamide(1 mL) was heated at 100.degree. C. for 5 hours. The resultingmixture was diluted with diethyl ether, washed with water andbrine, dried over sodium sulfate, filtered, and concentrated invacuo. The residue was purified by column chromatography withsilica gel (eluted with 1:98.5:0.5 methanol-methylenechloride-triethylamine) to give the title compound as a white solid(97.3 mg), m.p. 61.degree. C.-62.degree. C.
Example 11
Synthesis of1-{4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpe-ntyl]-2,6-dimethylpiperazin-1-yl}ethanone
##STR00408##
To a solution of2-(3,5-dimethylpiperazin-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methox-yphenyl)-4-methylpentan-2-ol (18 mg) in methylene chloride (1 mL)was added pyridine (55.8 .mu.L) followed by acetic anhydride (43.4.mu.L). The resulting mixture was stirred overnight, quenched withsaturated aqueous sodium bicarbonate solution and extracted twicewith methylene chloride. The combined organic phases were driedover sodium sulfate, filtered, and concentrated in vacuo. Theresidue was purified by column chromatography with silica gel(eluted with 50% ethyl acetate-hexanes) to give the title compoundas a clear oil (20 mg).
Example 12
Synthesis of4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-2,6-dimethylpiperazine-1-carbaldehyde
##STR00409##
To a solution of2-(3,5-dimethylpiperazin-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methox-yphenyl)-4-methylpentan-2-ol (20 mg) in methylene chloride (1 mL)at 0.degree. C. was added pyridine (60.7 .mu.L) followed by formicanhydride (2M in methylene chloride, 0.5 mL). (Formic anhydride wasfreshly prepared by slow addition of one equivalent of1,3-diisopropylcarbodiimide to 2 equivalents of formic acid inmethylene chloride. The resulting suspension was stirred for 1hour, and filtered). The resulting mixture was stirred overnightfor 20 hours, filtered through a cotton plug, poured intohalf-saturated aqueous sodium bicarbonate solution, and extractedtwice with methylene chloride. The combined organic phases weredried over magnesium sulfate, filtered, and concentrated in vacuo.The residue was purified by chromatography on silica gel (elutedwith 5% methanol-methylene chloride) to give the title compound asa clear oil (19.3 mg).
Example 13
Synthesis of4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3,4-dihydro-1H-quinoxalin-2-one
##STR00410##
A solution of2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane(105 mg) and 3,4-dihydro-1H-quinoxalin-2-one (R. E. TenBrink etal., J. Med. Chem., 1994, 37, pp. 758-768) (267 mg) indimethylformamide (0.75 mL) was heated at 140.degree. C. for 45hours. The resulting mixture was poured into water and extractedtwice with diethyl ether. The combined organic phases were washedwith brine, dried over magnesium sulfate, filtered, andconcentrated in vacuo. The residue was purified by columnchromatography with silica gel (eluted with 30% ethylacetate-hexanes) to give the title compound as a pale yellow solid(67.8 mg), m.p. 69.degree. C.-71.degree. C.
Example 14
Synthesis of4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1-methyl-3,4-dihydro-1H-quinoxalin-2-one
##STR00411##
A solution of2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane(98.8 mg) and 1-methyl-3,4-dihydro-1H-quinoxalin-2-one (prepared asthe minor regioisomer following a similar procedure described for3,4-dihydro-1H-quinoxalin-2-one; R. E. TenBrink et al., J. Med.Chem., 1994, 37, pp. 758-768) (165 mg) in dimethylformamide (0.75mL) was heated at 140.degree. C. for 60 hours. The resultingmixture was poured into saturated aqueous sodium bicarbonatesolution and extracted twice with diethyl ether. The combinedorganic phases were dried over magnesium sulfate, filtered, andconcentrated in vacuo. The residue was purified by columnchromatography with silica gel (eluted with 20% ethylacetate-hexanes) to give the title compound as a pale yellow solid(16.2 mg), m.p. 132.degree. C.-134.degree. C.
Example 15
Synthesis of1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-hydroxymethyl-1H-quinolin-4-one
##STR00412##
A mixture of 4-hydroxyquinoline (5.0 g), aqueous sodium hydroxidesolution (1M, 42 mL) and formaldehyde solution (37% in water, 6 mL)was heated at 45.degree. C. for 18.5 hours. The reaction mixturewas filtered, acidified with 2N HCl (21 mL) and extracted withethyl acetate. The aqueous layer was chilled to afford4-hydroxy-3-hydroxymethylquinoline (2.0 g) as a white solid.
To a suspension of2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane(344 mg) and 4-hydroxy-3-hydroxymethylquinoline (412 mg) inanhydrous ethanol (2.5 mL) was added sodium ethoxide (21 wt. %solution in ethanol, 439 .mu.L). After heating at 85.degree. C. for17 hours, the reaction mixture was poured into saturated aqueoussodium bicarbonate and extracted twice with ethyl acetate. Thecombined organic phases were dried over sodium sulfate, filtered,and concentrated in vacuo. The residue was purified by columnchromatography with silica gel (eluted with 80%-100% ethylacetate-hexanes) to give the title compound as a white solid (405mg), m.p. 183.degree. C.-184.degree. C.
Example 16
Synthesis of1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-methoxymethyl-1H-quinolin-4-one
##STR00413##
To a suspension of1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-hydroxymethyl-1H-quinolin-4-one (51.5 mg) and silver(I) oxide(127 mg) in acetonitrile (3 mL) was added methyl iodide (68.5 p-L).After heating at 50.degree. C. for 15 hours, the reaction mixturewas filtered and concentrated in vacuo. The residue was purified bycolumn chromatography with silica gel (eluted with 50%-70% ethylacetate-hexanes) to give the title compound as a white solid (37.5mg).
Example 17
Synthesis of1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-2-(4-imino-4H-quinolin-1-ylm-ethyl)-4-methylpentan-2-ol
##STR00414##
A mixture of 4-aminoquinoline (H. Shinkai et al., J. Med. Chem.,2000, 43, pp. 4667-4677) (251 mg), chlorotriphenylmethane (533 mg),and triethylamine (266 .mu.L) in methylene chloride (5 mL) wasstirred at room temperature for 24 hours. The reaction mixture wasthen poured into saturated aqueous sodium bicarbonate solution andextracted twice with methylene chloride. The combined organicphases were dried over sodium sulfate, filtered, and concentratedin vacuo. The residue was purified by column chromatography withsilica gel (eluted with 50% ethyl acetate-hexanes) to givequinolin-4-yltritylamine as a pale yellow foam (610 mg).
To a suspension of quinolin-4-yltritylamine (428 mg) in anhydrousdimethylsulfoxide (3.4 mL) and tetrahydrofuran (0.6 mL) was addedsodium hydride (60% dispersion in mineral oil, 44.3 mg) in oneportion. After 30 minutes,2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethy-loxirane (292 mg) was added and the mixture stirred for 3 hours.The mixture was poured into half-saturated aqueous ammoniumchloride and extracted twice with ethyl acetate. The combinedorganic phases were washed with water, brine, dried over sodiumsulfate, filtered, and concentrated in vacuo. The residue waspurified by column chromatography with silica gel (eluted with 0.2%triethylamine-ethyl acetate) to give a 2:1 mixture ofquinolin-4-yltritylamine and product,1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-[4-(tritylimino)--4H-quinolin-1-ylmethyl]pentan-2-ol (480 mg), which was used withoutfurther purification.
To a solution of1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-[4-(tritylimino)--4H-quinolin-1-ylmethyl]pentan-2-ol (470 mg) in methylene chloride(50 mL) was added trifluoroacetic acid (2 mL). After 2 hours,another portion of trifluoroacetic acid (1 mL) was added and themixture was stirred for another 4 hours. The reaction was quenchedby slow addition of saturated aqueous sodium bicarbonate solutionand was extracted twice with ethyl acetate. The combined organicphases were dried over sodium sulfate, filtered, and concentratedin vacuo. The residue was purified by column chromatography withsilica gel (eluted with 8 to 10% methanol-methylene chloride) togive the title compound (84.2 mg), m.p. 137.degree. C.-140.degree.C.
Example 18
Synthesis of1-[2-hydroxy-4-methyl-4-(3-morpholin-4-ylmethylphenyl)-2-trifluoromethylp-entyl]-1H-quinolin-4-one
##STR00415##
To a solution of3-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1-ylmethyl-)butyl]benzaldehyde (0.05 g, 0.12 mmol), dichloroethane (3.0 mL),and acetic acid (0.09 mL, 1.46 mmol) in an ice bath was addedmorpholine (0.26 .mu.L, 3.00 mmol). The solution was warmed to roomtemperature and stirred for 0.5 hours. Triacetoxy sodium borohyride(0.06 g. 0.30 mmol) was added and the reaction stirred at roomtemperature. After 3.0 hours, the solution was partitioned betweenEtOAc and 3% NH.sub.4OH (3 mL). The aqueous layer was extractedwith EtOAc. The combined organic layers were washed with brine,dried over magnesium sulfate, filtered, and the solvent wasevaporated in vacuo. The product was eluted from a flashchromatography column with EtOAc/hexanes, and concentrated in vacuoto afford1-[2-hydroxy-4-methyl-4-(3-morpholin-4-ylmethylphenyl)-2-trifluoro-methylpentyl]-1H-quinolin-4-one as a colorless solid (0.03 g,45%).
Example 19
Synthesis of1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinazolin-4-one
##STR00416##
A solution of2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane(500 mg) and 2-aminobenzamide (1.17 g) in dimethylformamide (2.5mL) was heated at 140.degree. C. for 19.5 hours. The resultingmixture was diluted with diethyl ether, washed with water andbrine, dried over sodium sulfate, filtered, and concentrated invacuo. The residue was purified by column chromatography withsilica gel (eluted with 15 to 30% ethyl acetate-hexanes) to give2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-lamino]benzamide as a white foam (447 mg).
To a solution of2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-lamino]benzamide (106 mg) in trimethylorthoformate (6 mL) was addedtrifluoroacetic acid (0.1 mL). After 1.5 hours, the reactionmixture was concentrated in vacuo. The residue was purified bycolumn chromatography with silica gel (eluted with 70% ethylacetate-hexanes) to give the title compound as a white solid (82mg), m.p. 118.degree. C.-121.degree. C.
Example 20
Synthesis of1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-cinnolin-4-one
##STR00417##
To a suspension of2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane(216 mg) and cinnolin-4-ol (V. G. Chapoulaud et al., Tetrahedron,2000, 56, pp. 5499-5507) (216 mg) in anhydrous ethanol (1.2 mL) wasadded sodium ethoxide (21 wt. % solution in ethanol, 276 .mu.L).After heating at 85.degree. C. for 16 hours, the reaction mixturewas diluted with ethyl acetate, dried over sodium sulfate,filtered, and concentrated in vacuo. The residue was purified bypreparative TLC (eluted with 40% ethyl acetate-hexanes) to give thetitle compound as a pale yellow solid (26 mg), m.p. 122.degree.C.-123.degree. C.
Example 21
Synthesis of1-[4-(2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpen-tyl]-2-hydroxymethyl-3,5-dimethyl-1H-pyridin-4-one
##STR00418##
A mixture of (4-methoxy-3,5-dimethylpyridin-2-yl)methanol (1.0 g)and anhydrous lithium chloride (0.76 mg) in dimethylformamide (10mL) was heated at reflux for 43 hours. Sodium hydroxide solution(10% w/v, 30 mL) was then added and the resulting solution wasextracted twice with diethyl ether. The aqueous phase wasneutralized with 1N HCl (21 mL) and the volatiles were removed invacuo. The resulting solid was purified by column chromatographywith silica gel (eluted with 10% methanol-methylene chloride).Product-rich fractions were combined, concentrated in vacuo, andtriturated with chloroform-acetonitrile (4:1) to afford theproduct, 2-hydroxymethyl-3,5-dimethylpyridin-4-ol, as a white solid(0.78 g).
To a suspension of7-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]-2,3-dihydrobenzofuran(30.0 mg) and 2-hydroxymethyl-3,5-dimethylpyridin-4-ol (32.2 mg) inanhydrous ethanol (0.25 mL) was added sodium ethoxide (21 wt. %solution in ethanol, 39.0 .mu.L). After heating at 85.degree. C.for 18 hours, the reaction mixture was diluted with ethyl acetate,dried over sodium sulfate, filtered, and concentrated in vacuo. Theresidue was purified by column chromatography with silica gel(eluted with 4% to 7% methanol-methylene chloride) to give thetitle compound as a white solid (10.4 mg), m.p. 160.degree.C.-162.degree. C.
Example 22
Synthesis of1-[2-hydroxy-4-(5-methanesulfonyl-2,3-dihydrobenzofuran-7-yl)-4-methyl-2--trifluoromethylpentyl]-3,5-dimethyl-1H-pyridin-4-one
##STR00419##
To a suspension of trimethylsulfoxonium iodide (1.36 g) inanhydrous dimethylsulfoxide (7.7 mL) was added sodium hydride (60%dispersion in mineral oil, 246 mg). The resulting solution wasstirred at room temperature for 30 minutes and was then addeddropwise to a solution of1,1,1-trifluoro-4-methyl-4-(5-methylsulfanyl-2,3-dihydrobenzofuran-7-yl)p-entan-2-one (1.63 g) in anhydrous dimethylsulfoxide (6.5 mL). After2 hours, water (100 mL) was added and the resulting mixture wasextracted with three 100 mL portions of diethyl ether. The combinedorganic phases were washed twice with water, washed with brine,dried over magnesium sulfate, filtered, and concentrated in vacuoto afford7-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]-5-methylsulfanyl-2,3--dihydrobenzofuran as a clear oil (1.64 g) which was used withoutfurther purification.
To a solution of7-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]-5-methylsulfanyl-2,3--dihydrobenzofuran (535 mg) in acetonitrile (30 mL) and water (10mL) was added sodium periodate (1.03 g) followed by ruthenium (III)chloride (1 mg). After 2 hours, the reaction mixture was dilutedwith water and extracted with ethyl acetate. The combined organicphases were dried over magnesium sulfate, filtered, andconcentrated to afford7-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]-5-methanesulfonyl-2,3--dihydrobenzofuran as a tan solid (568 mg) which was used withoutfurther purification.
To a suspension of7-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]-5-methanesulfonyl-2,3--dihydrobenzofuran (51.0 mg) and 3,5-dimethylpyridin-4-ol (B.Boduszek et al., Synthesis, 1979, pp. 452-453) (34 mg) in anhydrousethanol (0.40 mL) was added sodium ethoxide (21 wt. % solution inethanol, 52.0 .mu.L). After heating at 85.degree. C. for 16 hours,the reaction mixture was diluted with ethyl acetate, dried oversodium sulfate, filtered, and concentrated in vacuo.
The residue was purified by column chromatography with silica gel(eluted with 4% methanol-methylene chloride) to give the titlecompound as a white solid (47 mg), m.p. 150.degree. C.-152.degree.C.
Example 23
Synthesis of1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1,2-dihydroindazol-3-one
##STR00420##
To a solution of2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane(0.29 g) and 1,2-dihydroindazol-3-one (0.17 g) in anhydrousdimethylsulfoxide (1 mL) was added sodium bis(trimethylsilyl)amide(1.0M in tetrahydrofuran, 1.0 mL). After 14 days, the reactionmixture was diluted with ethyl acetate and washed twice with water.The organic phase was dried over sodium sulfate, filtered, andconcentrated in vacuo. The residue was purified by preparative TLC(eluted with 1% ethanol-methylene chloride) to give1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1,2-dihydroindazol-3-one as a white solid (91 mg), m.p.141.degree. C.-144.degree. C.
Example 24
Synthesis of1-[2-cyclopropyl-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methylpentyl]-1-H-quinolin-4-one
##STR00421##
To a solution of1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one (2.25 g, 5.14 mmol) in DMF (40 mL) was addedpotassium carbonate (2.13 g, 15.4 mmol) followed by heating to120.degree. C. in a sealed reaction vessel for 14 hours. Thesolution was diluted with 300 mL of diethyl ether, washed with one200 mL portion of saturated aqueous sodium bicarbonate, three 100mL portions of water, one 100 mL portion of brine, dried overanhydrous sodium sulfite (Na.sub.2SO.sub.3), and concentrated invacuo. The crude material was purified by flash columnchromatography (5% MeOH/CH.sub.2Cl.sub.2) to give1-[4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-oxopentyl]-1H-quinolin-4--one as a brown foam (1.07 g, 57%).
##STR00422##
An oven-dried round-bottomed flask charged with cerium chloride(0.27 g, 1.08 mmol) was dried under vacuum and at 140.degree. C.for 1 hour followed by vacuum at room temperature for an additional14 hours. The flask was sealed with a septum, evacuated undervacuum, and charged with argon. THF (3 mL) was added and the slurrywas sonicated for 1 hour to give a yellow suspension. To thisslurry was added1-[4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-oxopentyl]-1H-quinolin-4-one(0.20 g, 0.54 mmol) dissolved in 1 mL of THF resulting in theformation of a dark brown solution. This was stirred for 1 hour atroom temperature followed by the addition of thecyclopropylmagnesium bromide (2.18 mL, 0.5 mol/L) at 0.degree. C.The reaction was allowed to stir at this temperature for 3 hoursfollowed by quenching through the addition of saturated ammoniumchloride (10.0 mL) resulting in the formation of a whiteprecipitate. The biphasic system was filtered and the aqueous layerwas separated. The organic layer was washed with one 25 mL portionof brine, dried over anhydrous sodium sulfite, filtered, and thesolvent was evaporated in vacuo to give a yellow oil. The pureproduct,1-[2-cyclopropyl-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methylpentyl]-1-H-quinolin-4-one (2.0 mg, 1%) was obtained by flash chromatographyon silica gel using mixtures of EtOAc-hexanes as the eluent.
Example 25
Synthesis of1-[2-hydroxy-4-(3-hydroxymethylphenyl)-4-methyl-2-trifluoromethylpentyl]--1H-quinolin-4-one
##STR00423##
To a solution of the3-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1-ylmethyl-)butyl]benzaldehyde (20.0 mg, 0.05 mmol) in methanol (0.50 mL) andTHF (0.50 mL) was added NaBH.sub.4 (20.0 mg, 0.48 mmol). Thereaction vessel was sealed and stirred for 45 minutes. The solventwas evaporated in vacuo and the off-white solid was re-dissolved inEtOAc and water and transferred to a separatory funnel. The aqueouslayer was extracted with two 10 mL portions of EtOAc and thecombined organic layers were washed with one 10 mL portion ofbrine, dried over magnesium sulfate, filtered, and the solvent wasevaporated in vacuo to give a white foam. The material waschromatographed (6% MeOH/CH.sub.2Cl.sub.2, 0.5% NH.sub.4OH) to givethe desired compound,1-[2-hydroxy-4-(3-hydroxymethylphenyl)-4-methyl-2-trifluoromethylpentyl]--1H-quinolin-4-one as a white foam (6.6 mg, 36%).
Example 26
Synthesis of1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-methyl-1H-quinolin-4-one
##STR00424##
A mixture of aniline (10.7 g) and diethyl oxalpropionate (21.7 mL)in 75 mL of methylene chloride was heated at reflux overnight,cooled to room temperature, washed with 1N HCl, water, brine, anddried over magnesium sulfate. The volatiles were removed in vacuoand the residue (2-methyl-3-(phenylimino)succinic acid diethylester) was taken forward without additional purification.
##STR00425##
A mixture of 2-methyl-3-(phenylimino)succinic acid diethyl ester(2.42 g) in silicon oil (7 mL) was heated at 240.degree.C.-245.degree. C. for 20 minutes with removal of ethanol bydistillation, cooled to room temperature, diluted with hexanes, andfiltered. The solid(3-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid ethyl ester)was dried in vacuo. Yield: 0.91 g.
##STR00426##
A mixture of 3-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acidethyl ester (1.42 g) and aqueous NaOH (18.4 mL of a 1N solution)was heated at reflux for 3 hours, cooled to room temperature,acidified with concentrated HCl, filtered, and the solid dried invacuo. The solid (1.1 g) was suspended in 10 mL of silicon oil andheated at 260.degree. C.-265.degree. C. for 10 minutes, cooled toroom temperature, diluted with hexanes, and filtered. The solid(3-methyl-1H-quinolin-4-one) was dried in vacuo.
##STR00427##
A mixture of 3-methyl-1H-quinolin-4-one (0.76 g),2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane(0.089 g) and sodium ethoxide in ethanol (0.18 mL of a 21 wt. %solution) in 2 mL of anhydrous ethanol was heated at 85.degree. C.for 12 hours, cooled to room temperature, and most of the volatilesremoved in vacuo. The residue was diluted with diethyl ether andmethanol and washed with water and brine, and dried over magnesiumsulfate. The residue was purified by flash silica gelchromatography using ethyl acetate as the eluent. The product-richfractions were concentrated in vacuo and dried to afford1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorom-ethylpentyl]-3-methyl-1H-quinolin-4-one, m.p. >225.degree.C.
Example 27
Synthesis of1-[4-(2-ethoxy-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one
##STR00428##
A mixture of1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one (0.053 g), iodoethane (0.011 mL) and powderedpotassium carbonate (0.090 g) in 1 mL of anhydrous DMF was heatedat 80.degree. C. for 18 hours, cooled to room temperature, anddiluted with water and filtered. The solid was purified with flashsilica gel chromatography using ethyl acetate as the eluent. Theproduct rich fraction were concentrated in vacuo and provided1-[4-(2-ethoxy-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one, m.p. 195.degree. C.-196.degree. C.
Example 28
Synthesis of1-[4-(2-difluoromethoxy-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromet-hylpentyl]-1H-quinolin-4-one
##STR00429##
A mixture of1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one (0.05 g), methyl 2-chloro-2,2-difluoroacetate(0.014 mL) and cesium carbonate (0.195 g) in 1.5 mL of DMF washeated at 60.degree. C. for 20 hours, cooled to room temperature,diluted with ethyl acetate, and washed with aqueous acetic acid,water, and brine. The residue was purified by reverse-phase HPLCusing acetonitrile/water as the eluent. The product rich fractionswere concentrated in vacuo and provided1-[4-(2-difluoromethoxy-5-fluorophenyl)-2-hydroxy-4-methyl-2-tri-fluoromethylpentyl]-1H-quinolin-4-one, m.p. 150.degree.C.-155.degree. C.
Example 29
Synthesis of1-[2-hydroxy-4-(2-methoxy-5-thiophen-3-ylphenyl)-4-methyl-2-trifluorometh-ylpentyl]-1H-quinolin-4-one
##STR00430##
To a solution of 2-methoxyphenylmagnesium bromide (131 mL, 65.7mmol, 0.5M solution in THF) at 0.degree. C. was added CuI (12.5 g,65.7 mmol). The reaction mixture was warmed to room temperature andstirred for 1 hour. A solution of4-methyl-1,1,1-trifluoropent-3-en-2-one (10.0 g, 65.74 mmol) (madevia procedure in PCT international application WO03/082280, Example10), in diethyl ether (200 mL) was added and the reaction mixturewas stirred overnight. The reaction was quenched with saturatedaqueous ammonium chloride (50 mL) and extracted with three 300 mLportions of ethyl acetate. The combined organic layers were washedwith water and brine, dried over magnesium sulfate, filtered, andconcentrated in vacuo. The residue was purified by silica gelchromatography using 0%-5% ethyl acetate in hexanes as the eluent.Concentration in vacuo of the product-rich fractions gave 14 g(82%) of1,1,1-trifluoro-4-(2-methoxyphenyl)-4-methylpentan-2-one.
##STR00431##
A mixture of N-bromosuccinimide (6.84 g, 38.42 mmol),benzoylperoxide (catalytic amount) and1,1,1-trifluoro-4-(2-methoxyphenyl)-4-methylpentan-2-one (10.0 g,38.42 mmol) in carbon tetrachloride (120 mL) and was refluxed fortwo days. After cooling, the solution was washed with water (60 mL)and 1.0M NaOH (60 mL), dried over sodium sulfate(Na.sub.2SO.sub.4), and concentrated in vacuo giving1,1,1-trifluoro-4-(5-bromo-2-methoxyphenyl)-4-methylpentan-2-oneand the starting material as 3:1 mixture (13.0 g).
##STR00432## Preparation of ylide Stock Solution:
To trimethylsulfoxonium iodide (8.0 g, 36.3 mmol) in 30 mL ofanhydrous DMSO was added NaH (1.46 g, 36.35 mmol; 60% dispersion inmineral oil) in portions. The mixture was stirred 30 minutes.
Epoxide Formation:
To a solution of1,1,1-trifluoro-4-(5-bromo-2-methoxyphenyl)-4-methylpentan-2-one (5g, 14.7 mmol) in 5 mL of anhydrous DMSO at room temperature wasadded 14.6 mL of the ylide stock solution (17.3 mmol) over 5minutes. The reaction was quenched after 2 hours with water anddiethyl ether. The aqueous layer was extracted with diethyl ether.The combined organic layers were washed with water and brine, driedover magnesium sulfate, filtered, and concentrated in vacuo toafford2-[2-(5-bromo-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxiraneas a dark yellow oil.
##STR00433##
A mixture of2-[2-(5-bromo-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane(5.0 g, 14.2 mmol), 4-hydroxyquinoline (3.08 g, 21.2 mmol) andsodium ethoxide (21 wt. % solution in ethanol, 5.3 mL, 14.2 mmol)in ethanol (120 mL) was heated at 85.degree. C. for 14 hours. Thereaction was quenched with water and concentrated in vacuo toremove most of the ethanol. The residue was diluted with methylenechloride and washed with half saturated sodium bicarbonate(NaHCO.sub.3), dried over magnesium sulfate, filtered, andconcentrated in vacuo. The product was precipitated from diethylether-hexanes to afford1-[4-(5-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one (5.2 g, 73% yield).
##STR00434##
A mixture of1-[4-(5-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one (0.2 g, 0.4 mmol), 3-thiopheneboronic acid (77mg, 0.6 mmol), sodium carbonate (Na.sub.2CO.sub.3; 85 mg, 0.8 mmol)in DME-MeOH-DMF (1:1.5:0.5; 3.0 mL) was stirred for 10 minutes andPd(PPh.sub.3).sub.4 (46.2 mg, 0.04 mmol) was added. The mixture wasmicrowaved for 15 minutes at 120.degree. C., cooled to roomtemperature, and filtered through CELITE.RTM. filter aid. Theresidue was diluted with EtOAc (20 mL) and washed with aqueous NaOH(1.0M, 10 mL), water, and brine, and dried over sodium sulfate, andthe volatiles removed in vacuo. The residue was purified by silicagel chromatography and then by reverse phase HPLC to yield 60 mg(30%) of1-[2-hydroxy-4-(2-methoxy-5-thiophen-3-ylphenyl)-4-methyl-2-trifluorometh-ylpentyl]-1H-quinolin-4-one as a white foam.
Example 30
Synthesis of1-[2-hydroxy-4-(2-hydroxy-5-thiophen-3-ylphenyl)-4-methyl-2-trifluorometh-ylpentyl]-1H-quinolin-4-one
##STR00435##
To a solution of1-[2-hydroxy-4-(2-methoxy-5-thiophen-3-ylphenyl)-4-methyl-2-trifluorometh-ylpentyl]-1H-quinolin-4-one (32 mg, 0.06 mmol) in methylenechloride (1 mL) at 0.degree. C. under an argon atmosphere was addedBBr.sub.3 (0.06 mL, 0.6 mmol). The mixture was warmed to roomtemperature, stirred 3 hours, cooled to 0.degree. C., stirred 2days, and quenched with methanol (5 mL). The volatiles were removedin vacuo and the residue diluted with ethyl acetate (10 mL), washedwith saturated aqueous sodium bicarbonate (5 mL), and brine (5 mL),and dried over magnesium sulfate. The volatiles were removed invacuo and the residue purified by reverse phase HPLC to afford1-[2-hydroxy-4-(2-hydroxy-5-thiophen3-ylphenyl)-4-methyl-2-trifluo-romethylpentyl]-1H-quinolin-4-one (20 mg, 68%).
Example 31
Synthesis of1-[2-hydroxy-4-(4-methoxybiphenyl-3-yl)-4-methyl-2-trifluoromethylpentyl]--1H-quinolin-4-one
##STR00436##
A mixture of1-[4-(5-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one (200 mg, 0.4 mmol), Pd(OAc).sub.2 (9 mg, 0.04mmol), DCyBPP ((2-dicyclohexylphosphino)biphenyl, 28 mg, 0.08mmol), KF (93 mg, 1.6 mmol) in toluene/THF (3/2 mL) at roomtemperature was treated with phenylboronic acid (98 mg, 0.8 mmol).The reaction mixture stirred overnight at room temperature andfiltered through CELITE.RTM. filter aid. The residue was dilutedwith EtOAc (20 mL), washed with aqueous NaOH (11.0M, 10 mL), water,and brine (10 mL). The organic phase was dried over sodium sulfate,filtered, and solvent was evaporated in vacuo. The residue waspurified silica gel chromatography and then by reverse phase HPLCto provide1-[2-hydroxy-4-(4-methoxybiphenyl-3-yl)-4-methyl-2-trifluoromethylpentyl]--1H-quinolin-4-one as white solid.
Example 32
Synthesis of1-[4-(5-Acetyl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one
##STR00437##
A mixture of1-[4-(5-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one (200 mg, 0.4 mmol), 1-vinyloxybutane (0.26 mL,2.0 mmol), Pd(OAc).sub.2 (5 mg, 0.02 mmol),1,3-bis(diphenylphosphino) propane (DPPP) (10.5 mg, 0.03 mmol),K.sub.2CO.sub.3 (66.34 mg, 0.48 mmol), and water (0.1 mL) in DMF (1mL) was microwaved for 1 hour at 122.degree. C. After cooling, themixture was poured into 5 mL of 5% HCl, stirred for 30 minutes andextracted with three 10 mL portions of ethyl acetate. The combinedorganic layers were washed with 10% aqueous K.sub.2CO.sub.3 anddried. The residue was purified silica gel chromatography and thenby reverse phase HPLC to yield 50 mg (27% yield) of1-[4-(5-acetyl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpe-ntyl]-1H-quinolin-4-one as white solid.
Example 33
Synthesis of3-chloro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-5-trifluoromethyl-1H-pyridin-2-one
##STR00438##
A mixture of 3-chloro-5-trifluoromethylpyridin-2-ol (135 mg, 0.68mmol) in 1 mL of EtOH was added to 0.13 mL of a 1M sodium ethoxidesolution in ethanol and was heated to 85.degree. C. for 5 minutesin a sealed vial. The mixture was cooled to room temperature,2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxiranewas added, and the mixture heated to 85.degree. C. overnight in asealed vial. The volatiles were removed in vacuo and the residuediluted with water and extracted with EtOAc. The organic extractswere combined, dried over sodium sulfate and concentrated in vacuo.The residue was purified on PLC plate (hexanes-EtOAc (8:2)) to give125 mg of3-chloro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-5-trifluoromethyl-1H-pyridin-2-one as a solid.
Example 34
Synthesis of1-{4-[3-(3,5-dimethylisoxazol-4-yl)phenyl]-2-hydroxy-4-methyl-2-trifluoro-methylpentyl}-1H-quinolin-4-one
##STR00439##
A solution of 3-bromoacetophenone (9.9 mL, 0.075 mol),methylcyanoacetate (9.8 mL, 0.112 mmol, 1.5 equiv.), benzylamine(0.87 mL, 0.008 mol, 0.1 equiv.), and acetic acid (4.3 mL) in 110mL of toluene was refluxed overnight with azeotropic removal ofwater. The reaction was concentrated in vacuo and purified viaflash chromatography using a hexanes/ethyl acetate gradient toelute product (Z)-3-(3-bromophenyl)-2-cyanobut-2-enoic acid methylester. Yield: 14.13 g (67%).
To a chilled (0.degree. C.) suspension ofSoxhlet-extraction-purified CuI (14.28 g, 0.075 mol, 1.5 equiv.) in150 mL of anhydrous diethyl ether, was added a 1.6M solution ofmethyl lithium (84.4 mL, 0.135 mol, 2.7 equiv.) in diethyl ether.The mixture was stirred for 10 minutes, cooled to -25.degree. C.and a solution of (Z)-3-(3-bromophenyl)-2-cyanobut-2-enoic acidmethyl ester (14.13 g, 0.05 mol) in 150 mL of anhydrous diethylether was added dropwise. The mixture was stirred at -25.degree. C.for 30 minutes, warmed to room temperature, and stirred overnight.The reaction was quenched with saturated aqueous ammonium chloridesolution and extracted with ethyl acetate. The combined organicswere washed with brine, dried with sodium sulfate, filtered, andconcentrated in vacuo to afford a brown oil. The oil was purifiedvia flash chromatography using a hexanes-ethyl acetate gradient toafford 3-(3-bromophenyl)-2-cyano-3-methylbutyric acid methyl ester.Yield: 8.88 g (60%).
A mixture of 3-(3-bromophenyl)-2-cyano-3-methylbutyric acid methylester (8.88 g, 28.6 mmol) and sodium chloride (4.69 g, 80.2 mmol,2.8 equiv.) in 74 mL of dimethyl sulfoxide with 3.5 mL of water wasrefluxed overnight. The reaction was cooled and diluted with brineand extracted with ethyl acetate. The combined organic layers werewashed with water and brine, dried over sodium sulfate, filtered,and concentrated in vacuo to afford an oil which was purified viaflash chromatography. A hexanes-ethyl acetate gradient was used toelute product.
The product fractions were pooled and concentrated in vacuo toafford a dark brown oil, 3-(3-bromophenyl)-3-methylbutyronitrile.Yield: 5.1 g (75%)
To a mixture of 3-(3-bromophenyl)-3-methylbutyronitrile (5.1 g, 21mmol) in anhydrous methylene chloride (94 mL) at -78.degree. C. wasadded diisobutylaluminum hydride (1M in dichloromethane) dropwise.The reaction was stirred 1 hour, slowly warmed to room temperature,and quenched with saturated aqueous solution of Rochelle's salt andextracted with ethyl acetate. The combined organics were washedwith brine, dried over sodium sulfate, filtered, and concentratedin vacuo to afford as an oil. The oil was purified via flashchromatography using a hexanes-ethyl acetate gradient to elute3-(3-bromophenyl)-3-methylbutyraldehyde.
To 3-(3-bromophenyl)-3-methylbutyraldehyde (3.1 g, 12.8 mmol) in a0.5M solution of trimethyl(trifluoromethyl)silane in THF (25.7 mL,12.8 mmol) was added over a 2 minutes tetrabutyl ammonium fluoride(2.6 mL of a 1M solution in THF). The mixture stirred for 30minutes and an additional 10.3 mL of a 1M solution of tetrabutylammonium fluoride was added. The mixture was diluted with water andextracted with ethyl acetate. The combined organics were washedwith brine, dried with sodium sulfate, filtered, and concentratedin vacuo. The residue was purified via flash chromatography using ahexanes-ethyl acetate gradient to elute4-(3-bromophenyl)-1,1,1-trifluoro-4-methylpentan-2-ol. Yield: 2.048g (51%).
To a solution of4-(3-bromophenyl)-1,1,1-trifluoro-4-methylpentan-2-ol (2.05 g, 6.58mmol) in dichloromethane (33 mL) was added the Dess-Martinperiodinane (3.9 g, 9.2 mmol). The mixture stirred for 48 hours andwas then concentrated in vacuo. The residue was diluted withhexanes and filtered. The filtrate was concentrated in vacuo andpurified via flash chromatography using a hexanes-ethyl acetategradient to elute product4-(3-bromophenyl)-1,1,1-trifluoro-4-methylpentan-2-one. Yield: 68mg (34%)
To a solution of4-(3-bromophenyl)-1,1,1-trifluoro-4-methylpentan-2-one (68 mg, 2.2mmol) in 2.9 mL of anhydrous DMSO was added over 5 minutes asolution the ylide of trimethylsulfoxonium iodide (3.3 mL of a 0.8MDMSO solution prepared from 2.66 g (12.1 mmol) oftrimethylsulfoxonium iodide in 15 mL of anhydrous DMSO and 483 mgof 60% NaH in mineral oil (12.1 mmol) added in portions and agedfor 30 minutes). The mixture stirred 2 hours and quenched withwater and ethyl acetate. The organic phase was washed with waterand brine, and dried over sodium sulfate. Removal of the volatilesin vacuo afforded the yellow oil2-[2-(3-bromophenyl)-2-methylpropyl]-2-trifluoromethyloxirane whichwas used without further purification.
A mixture of2-[2-(3-bromophenyl)-2-methylpropyl]-2-trifluoromethyloxirane,4-hydroxyquinoline (2 equiv.), and sodium ethoxide (21 wt. %solution in ethanol, 1 equiv.) in ethanol was heated at 85.degree.C. for 14 hours, quenched with water, and concentrated in vacuo toremove most of the ethanol. The residue was diluted with halfsaturated aqueous sodium bicarbonate solution and methylenechloride. The organic phase was dried over sodium sulfate,filtered, and concentrated in vacuo. Purification of the residue byflash chromatography using ethyl acetate-hexanes gradient andconcentration of the product-rich fractions afforded1-[4-(3-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quino-lin-4-one.
A mixture of1-[4-(3-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1-H-quin-olin-4-one (30 mg, 0.064 mmol), 3,5-dimethylisoxazole-4-boronicacid (9 mg, 0.064 mmol, 1 equiv.),bisdichlorotriphenylphosphinopalladium (II) (catalytic amount) andcesium carbonate (21 mg, 0.064 mmol) in 1.1 mL of ethylene glycoldimethyl ether-water-ethanol (7:3:2) was degassed, sealed in avial, and irradiated twice (microwave) at 160.degree. C. for 300seconds. The reaction was cooled to room temperature and filteredthrough CELITE.RTM. filter aid. The filtrate was diluted with waterand extracted with diethyl ether. The combined organic layers werewashed with brine and dried with sodium sulfate. Removal of thevolatiles in vacuo provided a residue which was purified by HPLC togive1-{4-[3-(3,5-dimethylisoxazol-4-yl)phenyl]-2-hydroxy-4-methyl-2-trifluoro-methylpentyl}-1H-quinolin-4-one.
Example 35
Synthesis of1-[4-(3-cyclopropanecarbonylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylp-entyl]-1H-quinolin-4-one
##STR00440##
To a solution of the Grignard reagent derived from2-(3-bromophenyl)-[1,3]dioxane (52.6 mL of 0.25M in THF, 13.1 mmol)at 0.degree. C. was added copper (I) iodide (25 g, 13.1 mmol).After 45 minutes, 1,1,1-trifluoro-4-methylpent-3-en-2-one (2 g,13.1 mmol) was added and the reaction mixture slowly warmed to roomtemperature and stirred overnight. The mixture was quenched withsaturated aqueous ammonium chloride and extracted with ethylacetate. The combined organic layers were washed with saturatedaqueous sodium chloride solution, dried with sodium sulfate, andconcentrated in vacuo. The residue was triturated with hexanes andfiltered. The filtrate was concentrated in vacuo to give4-(3-[1,3]dioxan-2-ylphenyl)-1,1,1-trifluoro-4-methylpentan-2-one.
To a solution of4-(3-[1,3]dioxan-2-ylphenyl)-1,1,1-trifluoro-4-methylpentan-2-one(1 g, 3 mmol) in 4.1 mL of anhydrous DMSO was added the sodiumylide of trimethylsulfoxonium iodide (3.0 mL of a 0.8M solution inDMSO) over 5 minutes. The reaction was stirred 2 hours and quenchedwith water and ethyl acetate. The organic layer was washed withwater and brine, and dried over sodium sulfate. Removal of thevolatiles in vacuo afforded2-{3-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]phenyl}-[1,3]dioxan-e as a yellow oil.
A mixture of2-{3-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]phenyl}-[1,3]dioxan-e (0.910 g, 2.75 mmol), 4-hydroxyquinoline (806 mg, 5.55 mmol) andsodium ethoxide (21 wt. % solution in ethanol, 1.03 mL, 2.7 mmol)in ethanol (7.7 mL) was capped and heated at 85.degree. C. for 14hours. The mixture was quenched with water and concentrated invacuo to remove most of the ethanol. The residue was diluted withhalf saturated aqueous sodium bicarbonate solution and methylenechloride. The organic layer was dried over sodium sulfate andconcentrated in vacuo. Purification of the residue by flashchromatography using ethyl acetate-hexanes as the eluent. Theproduct-rich fractions were concentrated in vacuo to1-[4-(3-[1,3]dioxan-2-ylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one.
A mixture of1-[4-(3-[1,3]dioxan-2-ylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one (0.99 g, 2.09 mmol), ethanol (66 mL), water(13.2 mL), and pyridinium p-toluenesulfonic acid (262 mg, 1.04mmol) was heated at reflux for 3 hours, cooled to room temperatureand concentrated in vacuo to remove ethanol. The residue wasdiluted with ethyl acetate and water. The aqueous layer wasextracted with ethyl acetate. The combined organic layers werewashed with saturated aqueous sodium bicarbonate and brine, anddried over sodium sulfate. Removal of the volatile in vacuoafforded3-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1--ylmethyl)butyl]benzaldehyde. Yield: 77 mg (89%).
To a solution of3-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1-ylmethyl-)butyl]benzaldehyde (0.10 g, 0.24 mmol) in anhydroustetrahydrofuran (5 mL) and cooled in a ice/isopropanol bath wasadded dropwise cyclopropylmagnesium bromide (0.71 mL of a 0.84Msolution in THF, 0.6 mmol). The mixture was slowly warmed to roomtemperature, quenched with saturated aqueous ammonium chloridesolution, and extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over sodium sulfate, andconcentrated in vacuo. A mixture of the residue and hydrazine resinin THF was agitated for several hours and filtered. Removal of thevolatiles in vacuo afforded alcohol1-{4-[3-(cyclopropylhydroxymethyl)phenyl]-2-hydroxy-4-methyl-2-trifluorom-ethylpentyl}-1H-quinolin-4-one.
A mixture of1-{4-[3-(cyclopropylhydroxymethyl)phenyl]-2-hydroxy-4-methyl-2-trifluorom-ethylpentyl}-1H-quinolin-4-one (26 mg, 0.057 mmol) and MnO.sub.2 (5mg, 0.57 mmol) in methylene chloride (2 mL) was stirred for 48hours at room temperature under an atmosphere of argon and filteredover CELITE.RTM. filter aid. The filtrate was concentrated in vacuoand the residue purified by reversed phase HPLC to afford1-[4-(3-cyclopropanecarbonylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylp-entyl]-1H-quinolin-4-one. Yield: 9 mg (35%).
Example 36a and 36b
Synthesis of1-(2-Hydroxy-4-{3-[1-(hydroxyimino)ethyl]phenyl}4-methyl-2-trifluoromethy-lpentyl)-1H-quinolin-4-one and1-(2-Hydroxy-4-{3-[1-(methoxyimino)ethyl]phenyl}-4-methyl-2-trifluorometh-ylpentyl)-1H-quinolin 4-one
##STR00441##
A mixture of 3-bromoacetophenone (10 mL, 75.6 mmol), ethyleneglycol (10.1 mL, 181 mmol), and p-toluenesulfonic acid hydrate intoluene (120 mL) was heated with azeotropic removal of water. After4 hours, a second portion of ethylene glycol was added and themixture heated at refluxed for 48 hours. The reaction was cooled toroom temperature and washed with saturated aqueous sodiumbicarbonate solution and brine, and dried over sodium sulfate.Removal of the volatiles in vacuo provided a residue that waspurified by flash chromatography. Concentration of the product-richfractions afforded 2-(3-bromophenyl)-2-methyl-[1,3]dioxolane as aclear oil. Yield: 2.44 g.
To a solution of 2-(3-bromophenyl)-2-methyl-[1,3]dioxolane (1 g) inTHF (5 mL) was added portionwise magnesium metal (0.2 g) and thereaction heated at refluxed for 30 minutes. The mixture was cooledto room temperature and CuBr-DMS complex (846 mg, 4.11 mmol) wasadded. The mixture was stirred 3 minutes at room temperature,cooled to 0.degree. C. and 1,1,1-trifluoro-4-methylpent-3-en-2-one(62 mg, 4.11 mmol) in 20 mL of THF was added dropwise. The mixturewas stirred for 30 minutes at 0.degree. C., warmed to roomtemperature, stirred overnight and quenched with aqueous ammoniumchloride solution and ethyl acetate. The organic layer was washedwith brine, dried over sodium sulfate, and concentrated in vacuo toafford a residue that was purified by flash chromatography.Concentration in vacuo of the product-rich fractions afforded 0.56g of1,1,1-trifluoro-4-methyl-4-[3-(2-methyl-[1,3]dioxolan-2-yl)phenyl]pentan--2-one.
To a solution of1,1,1-trifluoro-4-methyl-4-[3-(2-methyl-[1,3]dioxolan-2-yl)phenyl]pentan--2-one (0.56 g, 1.8 mmol) in anhydrous DMSO (2.3 mL) was added thesodium ylide of trimethylsulfoxonium iodide (2.6 mL of a 0.8Msolution in DMSO) over 5 minutes. The mixture was stirred 2 hours,quenched with water, and extracted with ethyl acetate. The combinedorganic layers were washed with water and brine, and dried oversodium sulfate. The solution was concentrated in vacuo to affordthe yellow oil,2-{3-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]phenyl}-2-methyl-[1-,3]dioxolane, which was used without further purification.
A mixture of2-{3-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]phenyl}-2-methyl-[1-,3]dioxolane (0.514 g, 1.55 mmol), 4-hydroxyquinoline (0.433 g,2.98 mmol), and sodium ethoxide (21 wt. % solution in ethanol, 0.55mL, 1.49 mmol) in ethanol (4.2 mL) was heated at 85.degree. C. for14 hours, cooled to room temperature, quenched with water, andconcentrated in vacuo to remove most of the ethanol. The residuewas diluted with half saturated aqueous sodium bicarbonate solutionand extracted with methylene chloride. The organic layers werecombined, dried over sodium sulfate, and concentrated in vacuo. Theresidue was purified by flash chromatography using ethylacetate-hexanes as the eluent. The product-rich fractions wereconcentrated in vacuo to afford1-{2-hydroxy-4-methyl-4-[3-(2-methyl-[1,3]dioxolan-2-yl)phenyl]-2-trifluo-romethylpentyl}-1H-quinolin-4-one. Yield: 0.35 g.
A mixture of1-{2-hydroxy-4-methyl-4-[3-(2-methyl-[1,3]dioxolan-2-yl)phenyl]-2-trifluo-romethylpentyl}-1H-quinolin-4-one (0.35 g, 0.75 mmol), ethanol (24mL), water (4.8 mL), and pyridinium p-toluenesulfonic acid (95 mg,0.37 mmol) was heated to reflux for 3 hours, cooled to roomtemperature, and concentrated in vacuo to remove most of theethanol. The residue was diluted with ethyl acetate and water. Theaqueous layer was extracted with ethyl acetate. The combinedorganic layers were washed with saturated aqueous sodiumbicarbonate and brine, and dried over sodium sulfate. Removal ofthe volatiles in vacuo afforded1-[4-(3-acetylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1-H-qui-nolin-4-one. Yield: 0.27 g (84%).
A mixture of1-[4-(3-acetylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1-H-qui-nolin-4-one (60 mg, 0.14 mmol), potassium carbonate (79 mg, 0.57mmol), and hydroxylamine hydrochloride (39 mg, 0.55 mmol) inmethanol (1 mL) was heated at 65.degree. C. for 3 hours, cooled toroom temperature, and concentrated in vacuo. The residue wasdiluted with water and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over sodium sulfate,and concentrated in vacuo. The residue was purified by flashchromatography to afford1-(2-hydroxy-4-{3-[1-(hydroxyimino)ethyl]phenyl)}-4-methyl-2-trifluoromet-hylpentyl)-1H-quinolin-4-one. Yield: 38 mg.
A mixture of1-[4-(3-acetylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1-H-qui-nolin-4-one (55 mg, 0.12 mmol), potassium carbonate (72 mg, 0.52mmol), and methoxyamine hydrochloride (42 mg, 0.51 mmol) in 1 mL ofmethanol was heated at 65.degree. C. for 3 hours, cooled to roomtemperature, and concentrated in vacuo. The residue was dilutedwith water and extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over sodium sulfate, andconcentrated in vacuo. The residue was purified by flashchromatography to afford1-(2-hydroxy-4-{3-[1-(methoxyimino)ethyl]phenyl}-4-methyl-2-trifluorometh-yl-pentyl)-1H-quinolin-4-one. Yield: 48 mg.
Example 37
Synthesis of1-[2-hydroxy-4-(5-methanesulfonyl-2,3-dihydrobenzofuran-7-yl)-4-methyl-2--trifluoromethylpentyl]-1H-quinolin-4-one
##STR00442## ##STR00443##
To a solution of 10 g (29 mmol) of4-(2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentan-oic acid ethyl ester in 20 mL of acetic acid (HOAc) was addeddropwise a solution of 1.55 mL (30 mmol) of bromine in 10 nL ofHOAc. The reaction was monitored by proton NMR. An additional 0.5mL of Br.sub.2 was added. The mixture was diluted with saturatedaqueous sodium bicarbonate and extracted with diethyl ether. Theorganic layer was dried over magnesium sulfate and concentrated invacuo to afford 11.7 g (95%) of4-(5-bromo-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluorometh-ylpentanoic acid ethyl ester.
To a suspension of 1.25 g (33 mmol) of lithium aluminum hydride in50 nL of THF at 0.degree. C. was added dropwise a solution of 11.7g (27.5 mmol) of4-(5-bromo-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trif-luoromethylpentanoic acid ethyl ester in 20 mL of THF. The reactionwas warmed to room temperature, stirred 2 hours, cooled to0.degree. C., carefully quenched with water, followed by 1N HCl,and extracted with EtOAc. The organic layers were combined, driedover magnesium sulfate, and concentrated in vacuo. The residue wastriturated with hexanes and the solid collected by filtration toafford 7.6 g (72%) of4-(5-bromo-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-trifluoromethylpentane--1,2-diol.
A mixture of 7.6 g (20 mmol) of4-(5-bromo-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-trifluoromethylpentane--1,2-diol and 0.754 g (4 mmol) of p-toluenesulfonic acid monohydratein 200 mL of acetone was stirred at room temperature for 6 days andthe volatiles removed in vacuo. The residue was dissolved in EtOAc,washed with saturated aqueous sodium bicarbonate, dried overmagnesium sulfate, and concentrated in vacuo. The residue wasextracted with diethyl ether and the filtrate concentrated in vacuoto afford 6.3 g (75%) of5-bromo-7-[2-(2,2-dimethyl-4-trifluoromethyl-[1,3]dioxolan-4-yl)-1,1-dime-thylethyl]-2,3-dihydrobenzofuran.
To a solution of 1 g (2.4 mmol) of5-bromo-7-[2-(2,2-dimethyl-4-trifluoromethyl-[1,3]dioxolan-4-yl)-1,1-dime-thylethyl]-2,3-dihydrobenzofuran in 20 mL of THF at -78.degree. C.was added 1.05 mL (2.6 mmol) of 2.5M solution n-BuLi in hexanes.After 20 minutes, 0.255 mL (2.8 mmol) of methyl disulfide was addedand the reaction was warmed to room temperature. The reaction wasmonitored by TLC. The mixture was cooled to -78.degree. C. andquenched with saturated ammonium chloride, and extracted withdiethyl ether. The combined organic layers were dried overmagnesium sulfate, and concentrated in vacuo to afford 0.89 g of anoil which was purified by silica gel chromatography using 5% to 40%methylene chloride in hexanes as the eluent. Concentration in vacuoof the product-rich fractions gave 0.31 g (34%) of7-[2-(2,2-dimethyl-4-trifluoromethyl-[1,3]dioxolan-4-yl)-1,1-dimethylethy-l]-5-methylsulfanyl-2,3-dihydrobenzofuran.
A solution of 0.31 g of7-[2-(2,2-dimethyl-4-trifluoromethyl-[1,3]dioxolan-4-yl)-1,1-dimethylethy-l]-5-methylsulfanyl-2,3-dihydrobenzofuran and 0.015 g ofp-toluenesulfonic acid (p-TsOH) monohydrate in methanol (10 mL) wasstirred at room temperature for 7 days, heated to reflux for 1minute, and the volatiles removed in vacuo. The residue was dilutedwith saturated aqueous sodium bicarbonate and filtered. The solidwas washed with water and hexanes, and dried to give 0.235 g of4-methyl-4-(5-methylsulfanyl-2,3-dihydrobenzofuran-7-yl)-2-trifluoromethy-lpentane-1,2-diol.
To a solution of 0.313 g (0.8 mmol) of4-methyl-4-(5-methylsulfanyl-2,3-dihydrobenzofuran-7-yl)-2-trifluoromethy-lpentane-1,2-diol and 0.06 mL of methanesulfonyl chloride in 10 mLof MeOHCH.sub.2Cl.sub.2 at 0.degree. C. was added 0.015 g (0.08mmol) of p-TsOH monohydrate. The mixture was warmed to roomtemperature, stirred overnight, and additional (0.01 g) p-TsOHmonohydrate was added. The mixture was stirred 3 days andconcentrated in vacuo. The residue was diluted with saturatedaqueous sodium bicarbonate and the solid was collected byfiltration. The solid was washed with water and hexanes, and driedto afford 0.235 g (84%) of a solid which was dissolved in 10 mL ofTHF and cooled to 0.degree. C. NaH (0.064 g of 60% oil dispersion)was added and the mixture warmed to room temperature and stirredovernight. The mixture was quenched with saturated aqueous ammoniumchloride (NH.sub.4Cl) and extracted with diethyl ether. Thecombined organic layers were dried over magnesium sulfate andconcentrated in vacuo. The residue was purified on PLC plate(hexanes-EtOAc (95:5)) to give 0.145 g of7-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]-5-methylsulfanyl-2-,3-dihydrobenzofuran.
7-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]-5-methylsulfanyl-2,3--dihydrobenzofuran was reacted with 4-hydroxyquinoline and sodiumethoxide according to Example 35 to give1-[2-hydroxy-4-methyl-4-(5-methylsulfanyl-2,3-dihydrobenzofuran-7-yl)-2-t-rifluoromethylpentyl]-1H-quinolin-4-one.
To a solution of 0.03 g (0.06 mmol) of1-[2-hydroxy-4-methyl-4-(5-methylsulfanyl-2,3-dihydrobenzofuran-7-yl)-2-t-rifluoromethylpentyl]-1H-quinolin-4-one and 0.04 g (0.18 mmol) ofNaIO.sub.4 in 3 mL of acetonitrile and 1 mL of water at roomtemperature was added a catalytic amount of RuCl.sub.3. The mixturewas stirred 30 minutes, diluted with water, and extracted withEtOAc. The organic layers were combined, dried over sodium sulfate,and concentrated in vacuo. The residue was purified on a PLC plateeluting with dichloromethane-methanol (CH.sub.2Cl.sub.2/MeOH, 95:5)to afford 0.008 g (27%) of1-[2-hydroxy-4-(5-methanesulfonyl-2,3-dihydrobenzofuran-7-yl)-4-methyl-2--trifluoromethylpentyl]-1H-quinolin-4-one.
Example 38
Synthesis of1,1,1-trifluoro-3-(6-fluoro-4-methylchroman4-yl)propan-2-one
##STR00444##
A mixture of 10.0 g (60 mmol) of 6-fluorochroman4-one, 7.9 mL (90mmol) of methyl cyanoacetate, 0.54 mL (5 mmol) of benzylamine, and3 mL of acetic acid in 100 mL of toluene was heated to reflux withazeotropic removal of water. After 18 hours, additional methylcyanoacetate and acetic acid was added. The reaction was monitoredby TLC and then the reaction was concentrated under a stream ofnitrogen. The residue was passed through a pad of silica gel usingEtOAc-hexanes (1:9) to afford 3.4 g (22%) ofcyano-[6-fluorochroman-(4E/Z)-ylidene]acetic acid methyl esterwhich was a mixture of geometric isomers.
To a chilled (0.degree. C.) suspension of 4.3 g (22.6 mmol) ofcopper (I) iodide in 75 mL of diethyl ether was added 26 mL (41.6mmol) of a 1.6M solution of methyl lithium in diethyl ether. After5 minutes, the mixture was cooled to -20.degree. C. and a solutionof 3.36 g (13.6 mmol) ofcyano-[6-fluorochroman-(4E/Z)-ylidene]acetic acid methyl ester in20 mL of diethyl ether was added. The mixture slowly warmed to roomtemperature, and was monitored by proton NMR. The reaction wascooled -78.degree. C. and quenched with saturated aqueous ammoniumchloride and warmed to room temperature. The mixture was thenfiltered through diatomaceous earth and the aqueous layer wasseparated and extracted with diethyl ether. The combined organiclayers were dried over magnesium sulfate and concentrated in vacuoto afford 3.1 g (86%) of cyano-(6-fluoro-4-methylchroman4-yl)aceticacid methyl ester as a mixture of diastereomers which was usedwithout further purification.
A mixture of 3.1 g (11.8 mmol) ofcyano-(6-fluoro-4-methylchroman4-yl)acetic acid methyl ester and2.47 g (42.4 mmol) of sodium chloride in 30 mL of wet DMSO waswarmed to reflux. The reaction was monitored by TLC. After 4 hours,the reaction was cooled and diluted with water and extracted withdiethyl ether. The combined organic layers were washed with fourportions of water, brine, dried over magnesium sulfate, andconcentrated in vacuo to afford 2.1 g (87%) of(6-fluoro-4-methylchroman-4-yl)acetonitrile as an oil.
To a chilled (-40.degree. C.) solution of 2.1 g (10.2 mmol) of(6-fluoro-4-methylchroman-4-yl)acetonitrile in 30 mL ofdichloromethane was added 11.4 mL (11.4 mmol) of a 1M solution ofdiisobutylaluminum hydride in dichloromethane. The mixture waswarmed to room temperature. After 1 hour, the mixture wascautiously quenched with minimal water, dried over magnesiumsulfate, filtered through diatomaceous earth, and concentrated invacuo to afford 1.7 g (80%) of(6-fluoro-4-methylchroman4-yl)acetaldehyde as an oil which was usedwithout further purification.
To 1.7 g (8.16 mmol) of (6-fluoro-4-methylchroman-4-yl)acetaldehydeand 1.69 mL (11.4 mmol) of trimethyl(trifluoromethyl)silane in 15mL of tetrahydrofuran was added 1 mL (1 mmol) of a 1M solution oftetrabutylammonium fluoride in tetrahydrofuran. The mixture stirredfor 1 hour and then an additional 9 mL (9 mmol) of a 1M solution oftetrabutylammonium fluoride in tetrahydrofuran was added. After 18hours, the mixture was concentrated in vacuo and diluted with 1Naqueous HCl and extracted with three 50 mL portions of diethylether. The combined organic layers were dried over magnesiumsulfate and concentrated in vacuo to afford 2.4 g of crude1,1,1-trifluoro-3-(6-fluoro-4-methylchroman4-yl)propan-2-ol as amixture of diastereomers. The crude oil was used without furtherpurification.
To a solution of 2.4 g (8.62 mmol) of1,1,1-trifluoro-3-(6-fluoro-4-methylchroman-4-yl)propan-2-ol in 20mL of dichloromethane was added 11.8 mmol of Dess-Martinperiodinane. After 18 hours, the mixture was adsorbed onto silicagel and passed through a pad of silica gel, washing withEtOAc-hexanes (1:9) to afford 1.05 g (44%) of the title compound asan oil.
The following trifluoromethyl ketones were also prepared by themethod of Example 34:1,1,1-Trifluoro-3-(1-methylindan-1-yl)propan-2-one;1,1,1-Trifluoro-3-(6-fluorochroman4-yl)propan-2-one (prepared byforegoing the methyl cuprate step and reducing the double bondunder standard hydrogenation conditions (Pd/C, H.sub.2 atmosphere);3-Chroman4-yl-1,1,1-trifluoropropan-2-one; and4-Benzo[1,3]dioxol-4-yl-1,1,1-trifluoro-4-methylpentan-2-one.
Example 39
Synthesis of 1-benzol[1,3]dioxol-4-ylethanone
##STR00445##
To a chilled (-78.degree. C.) solution of 10 g ofbenzo[1,3]dioxole4-carbaldehyde in 200 mL of THF was added byaddition funnel 43.7 mL of a 1.6M MeLi solution in diethyl ether.The reaction was slowly warmed to room temperature and stirredovernight. The reaction was monitored by TLC. The mixture was thencooled to -78.degree. C. and quenched with saturated aqueousammonium chloride and concentrated in vacuo. The residue wasextracted with EtOAc. The combined organic layers were dried overmagnesium sulfate and concentrated in vacuo to give 11 g of1-benzo[1,3]dioxol-4-ylethanol as a brown oil that crystallizedupon standing.
To a solution of 11 g of 1-benzo[1,3]dioxol-4-ylethanol in 100 mLof THF was added 17.26 g of MnO.sub.2 in one portion and reactionwas monitored by TLC. After several hours, TLC showed a new productand starting material. Additional MnO.sub.2 was added. TLCindicated still the reaction was incomplete. The mixture wasfiltered through CELITE.RTM. filter aid and concentrated in vacuoto afford an oil that partially crystallized. To a chilled(-60.degree. C.) solution of 9.24 mL of oxalyl chloride in 120 mLof methylene chloride was added a solution of 15 mL of DMSO in 20mL of methylene chloride. After 10 minutes, a solution of abovealcohol/ketone mixture (53 mmol) in 20 mL of methylene chloride wasadded. After 15 minutes, 44.3 mL of triethylamine was added. Thereaction was allowed to slowly warm to room temperature overnightand was then poured onto ice. The organic layer was separated andwashed with five 100 mL portions of water, washed with brine, driedover magnesium sulfate, filtered, and concentrated in vacuo toafford a tan solid. Trituration with hexanes gave 9.33 g of thetitle compound.
1-Benzo[1,3]dioxol-4-ylethanone was converted to the correspondingtrifluoromethyl ketone according to Example 34.
Example 40
Synthesis of 2-Hydroxy-4-methyl-4-phenyl-2-trifluoromethylhexanoicacid ethyl ester
##STR00446##
To a solution of 5 g (38 mmol) of 2-phenylpropionitrile in 50 mL ofDMSO was added 42 mL of a 1M solution of NaHMDS in THF. After 15minutes, the reaction was cooled to 0.degree. C. and 4.6 mL ofethyl iodide was added. The reaction was monitored by TLC. After 30minutes, the mixture was poured into water and extracted withdiethyl ether. The combined organics were washed with four portionsof water, washed with brine, dried over magnesium sulfate,filtered, and concentrated in vacuo to afford 6.1 g of2-methyl-2-phenylbutyronitrile as an oil.
To a solution of 6.1 g of 2-methyl-2-phenylbutyronitrile in 50 mLof methylene chloride at room temperature was added dropwise 57 mLof a 1M solution of DIBAI in methylene chloride. The reaction wasmonitored by TLC. After 30 minutes, the reaction was carefullypoured into 100 mL of 1N aqueous HCl and the organic layerseparated and concentrated in vacuo. The residue was diluted withdiethyl ether, combined with the aqueous layer, and extracted withdiethyl ether. The combined organic layers were dried overmagnesium sulfate and concentrated in vacuo. The residue waspurified on silica gel column eluting with ethyl acetate-hexanes(0-2%) to afford 4.2 g of 2-methyl-2-phenylbutyraldehyde as acolorless oil.
To a chilled (0.degree. C.) solution of 7.4 g of(diethoxyphosphoryl)ethoxy acetic acid ethyl ester in 30 mL of THFwas added 16 mL of a 1.8M solution of LDA. After 30 minutes, 4.2 gof 2-methyl-2-phenylbutyraldehyde in 30 mL of THF was addeddropwise by syringe. The mixture was warmed to room temperature,quenched with saturated aqueous ammonium chloride, and extractedwith diethyl ether. The combined organic layers were dried overmagnesium sulfate and concentrated in vacuo to afford 8.3 g of2-ethoxy4-methyl-4-phenylhex-2-enoic acid ethyl ester as an orangeoil and a mixture of geometric isomers (2:1).
To a solution of 8.3 g of 2-ethoxy-4-methyl-4-phenylhex-2-enoicacid ethyl ester in 25 mL of acetic acid was added 116 mL of 1Maqueous sulfuric acid (H.sub.2SO.sub.4). The reaction was stirredat room temperature for several hours. The reaction was monitoredby TLC. The reaction was warmed at 100.degree. C. overnight. Anadditional 2 mL of concentrated sulfuric acid and 20 mL of aceticacid was added. After 1 hour, the reaction was cooled to roomtemperature and extracted with diethyl ether. The combined organicswere washed with four portions of water, washed with brine, driedover magnesium sulfate, filtered, and concentrated in vacuo toafford 2.5 g of an orange oil. A proton NMR indicated 1:1 mixtureof minor isomer and aldehyde. The aqueous layer was extracted withEtOAc. The combined ethyl acetate layers were dried over magnesiumsulfate and concentrated in vacuo to afford a brown liquid. NMRshowed a mixture of the desired product as the ketoacid. Themixture was diluted with 200 mL of ethanol, 1 mL of concentratedHCl was added, and the mixture was refluxed overnight. The reactionwas cooled to room temperature and concentrated in vacuo. Theresidue was diluted with water and extracted with diethyl ether.The combined organics were dried over magnesium sulfate, filtered,and concentrated in vacuo to afford 4.3 g of4-methyl-2-oxo-4-phenylhexanoic acid ethyl ester as an orangeoil.
To a solution of 4.3 g of 4-methyl-2-oxo-4-phenylhexanoic acidethyl ester and 3.6 mL of trifluoromethyltrimethylsilane in 50 mLof THF was added 1.5 mL (0.1 equiv.) of 1M TBAF in THF. Thereaction stirred until ketoester was consumed by TLC. After 30minutes, 17.5 mL of TBAF was added. After 1 hour, the mixture wasconcentrated in vacuo and the residue was diluted with 1N aqueousHCl and extracted with diethyl ether. The combined organic layerswere dried over magnesium sulfate, filtered, and concentrated invacuo to afford a brown oil. The residue was diluted with hexanes(cloudy), treated with activated charcoal, filtered throughCELITE.RTM. filter aid, and concentrated in vacuo to afford 3.8 gof 2-hydroxy-4-methyl-4-phenyl-2-trifluoromethylhexanoic acid ethylesters as a mixture of diastereomers as a light green oil.
The diastereomeric mixture of esters was converted to thecorresponding epoxides according to Example 1.
Example 41
Synthesis f6-bromo4-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]benzo[1,3]dioxo-le
##STR00447##
To a solution of 0.1 g (0.35 mmol) of4-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]benzo[1,3]dioxolein 5 mL of THF was added 0.06 g (0.35 mmol) of N-bromosuccinimide.The reaction was monitored by TLC. After stirring overnight, TLCshowed starting material and a new slightly more polar spot. Thereaction was concentrated in vacuo and the residue was diluted withhexanes. The resulting suspension was filtered to remove insolublematerial and the filtrate was purified by chromatography oversilica gel eluting with ethyl acetate-hexanes (0-10%) to afford anoil as a mixture of starting material and product (3.5:1) by protonNMR. The residue was dissolved in 3 mL of acetonitrile and 0.06 g(0.35 mmol) of N-bromosuccinimide was added. After 3 hours, a TLCindicated the reaction was complete and it was worked up as aboveto afford 0.07 g (54%) of6-bromo-4-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]benzo[1,3]diox-ole as a yellow oil.
Example 42
Synthesis1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1,3-dihydroindol-2-one
##STR00448##
To a solution of 42 mg (0.31 mmol) of oxindole in 1 mL of DMF wasadded 10 mg (0.39 mmol) of 60% sodium hydride in mineral oil. Afterhydrogen evolution ceased, 50 mg (0.17 mmol) of2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxiranewas added and the mixture was warmed to 75.degree. C. The reactionwas monitored by TLC (ethyl acetate-hexanes (15:85)). After 40minutes, the mixture was cooled and diluted with saturated aqueousammonium chloride and extracted with three 5 mL portions of ethylacetate. The combined organic layers were washed with three 5 mLportions of brine, dried over magnesium sulfate, and concentratedin vacuo. The crude material was chromatographed on silica gel prepplates (2.times.1 mm, ethyl acetate-hexanes (15:85)). The materialfrom the prep plate was recrystallized fromdichloromethane-hexanes-ether to afford 14 mg of the titlecompound.
Example 43
Synthesis of1-[2-difluoromethyl-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methylpentyl-]-1H-quinolin-4-one
##STR00449##
To a solution of the 4-fluorophenol (25.3 g) and dimethylacryloylchloride (25.9 g) in diisopropyl ether (500 mL) cooled in an icebath was added triethylamine (35 mL) dropwise over a period of 20minutes. After 1 hour, the reaction mixture was washed with waterand brine, dried over sodium sulfate, and the organic solvent wasevaporated in vacuo to give crude ester. Distillation under vacuumgave dimethylacrylate 4-fluorophenyl ester (38.20 g, 87%).
##STR00450##
To a stirred suspension of aluminum trichloride (18.0 g) in carbondisulfide (30 mL) was added dimethylacrylate 4-fluorophenyl ester(18.0 g, 92.7 mmol) dropwise over a 0.5 hour period. The reactionmixture was stirred at room temperature for 14.0 hours. Thereaction was poured onto ice and extracted with ethylacetate-hexanes (1:10, 200 mL). The organic phase was washed withsaturated sodium bicarbonate, dried over anhydrous sodium sulfate,and evaporated in vacuo. Trituration of the residue with coldhexane gave a colorless crystalline6-fluoro-4,4-dimethylchroman-2-one (13.9 g, 77%).
##STR00451##
To a solution of 6-fluoro-4,4-dimethylchroman-2-one (5.40 g)dissolved in DMSO (20.0 mL) was added a solution of potassiumhydroxide (6.00 g) dissolved in water (10.0 mL) over 5 minutes.After 20 minutes, methyl iodide (4.0 mL) was added portionwise over15 minutes and the mixture was stirred at room temperature for 14.0hours. The mixture was diluted with hexanes, washed with water,dried, filtered, and evaporated in vacuo. Distillation yielded themethyl 3-methyl-3-(2-methoxy-5-fluorophenyl)butanoate (4.2 g,63%).
##STR00452##
To a suspension of lithium aluminum hydride (0.75 g) in THF (20 mL)stirred under nitrogen was added dropwise a solution of methyl3-methyl-3-(2-methoxy-5-fluorophenyl)butanoate (4.2 g) dissolved inTHF (10 mL). The mixture was stirred at room temperature for 4hours. The reaction was quenched by cautious addition of water (1mL) and diluted with ether (100 mL). The mixture was filteredthrough FLORISIL.RTM. selective adsorbent and evaporated to drynessin vacuo to give 3-methyl-3-(2-methoxy-5-fluorophenyl)butan-1-ol asan oil (3.30 g, 89%).
##STR00453##
To a solution of 3-methyl-3-(2-methoxy-5-fluorophenyl)butan-1-ol(3.30 g) in methylene chloride (40 mL) stirred at room temperaturewas added pyridinium chlorochromate (4.2 g) portionwise over 5minutes. The mixture was stirred for 3 hours and then filteredthrough CELITE.RTM. filter aid. The solvent was evaporated in vacuoand the residue was fractionated by chromatography over silica gel(methylene chloride-hexane (1:3 to 1:1 gradient)) to give3-methyl-3-(2-methoxy-5-fluorophenyl)butyraldehyde an oil (2.5 g,76%).
##STR00454##
To a solution of the difluoromethylphosphonic acid diethyl ester(1.35 g) in THF (5.0 mL) cooled in a dry ice/acetone bath was addedLDA (5.0 mL, 1.5M in cyclohexane) dropwise over 5.0 minutes. After10.0 minutes, a solution of3-methyl-3-(2-methoxy-5-fluorophenyl)butyraldehyde (0.94 g) in THF(5.0 mL) was added dropwise. After an additional 20.0 minutes,acetic acid (1 mL) was added and the mixture was warmed to roomtemperature. The mixture was diluted with ethyl acetate, washedwith water, dried, filtered, and evaporated in vacuo. Fractionationof the residue over silica gel (eluent: methylene chloride-ethylacetate (1:4)) gave the desired[1,1-difluoro-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methylpentyl]phosp-honic acid diethyl ester (1.15 g, 40%) as an oil that crystallizedon treatment with hexanes.
##STR00455##
A solution of oxalyl chloride (2.2 mL, 2.0M in dichloromethane) wasdiluted with dichloromethane (3.0 mL) and cooled in a dryice/acetone bath. To this solution was added a solution of DMSO(0.7 mL) in dichloromethane (2.5 mL) dropwise. After 10 minutes, asolution of the[1,1-difluoro-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methylpentyl]phosp-honic acid diethyl ester (1.10 g) in dichloromethane (3 mL) wasadded and the mixture was stirred for 15 minutes. Triethylamine(4.0 mL) was added, the cooling bath was removed, the reactionmixture was allowed to warm to room temperature and quenched withwater and diluted with hexanes. The organic layer was separated,washed with water, dried, filtered, and concentrated in vacuo. Theresidue was purified by chromatography over silica gel (eluent:hexanes to hexanes-ethyl acetate (2:1) gradient) to give[1,1-difluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-oxopentyl]phos-phonic acid diethyl ester as an oil (1.0 g, 91%).
##STR00456##
To a solution of[1,1-difluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-oxopentyl]phosphoni-c acid diethyl ester (1.0 g) in methanol (12.0 mL) was added asolution of sodium hydroxide (0.04 g) in water (1 mL). The mixturewas stirred at room temperature for 30 minutes. The mixture wasdiluted with hexanes (50 mL) and water (50 mL) and the organicphase was separated, dried, filtered, and evaporated in vacuo togive1,1,-difluoro-4-methyl-4-(2-methoxy-5-fluorophenyl)pentan-2-one(0.63 g) as an oil which was used without additionalpurification.
##STR00457##
To suspension of trimethylsulfoxonium iodide (0.22 g) in DMSO (0.5mL) and THF (0.5 mL) stirred under nitrogen and cooled on ice wasadded sodium hexamethyldisilazide (1.0 mL, 1.0M in THF) dropwiseover 5 minutes. After 15 minutes, a solution of1,1,-difluoro-4-methyl-4-(2-methoxy-5-fluorophenyl)pentan-2-one(0.23 g) in THF (0.6 mL) was added dropwise and the mixture wasallowed to come to room temperature over 2 hours. The mixture wasdiluted with hexane, washed with water, dried, filtered, andevaporated in vacuo to give2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-difluoromethyloxiraneas an oil (0.25 g).
##STR00458##
To a solution of the 4-hydroxyquinoline and2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-difluoromethyloxiranein DMSO (1.0 mL) stirred under nitrogen was added NaHMDS (1.2 mL,1.0M in THF) dropwise. The mixture was stirred at room temperaturefor 15 days. The mixture was diluted with ethyl acetate, washedwith water, dried, filtered, and evaporated in vacuo. Triturationof the residue with diethyl ether gave the product1-[2-difluoromethyl-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methylpentyl-]-1H-quinolin-4-one as a crystalline solid that was collected byfiltration and air dried (77.7 mg, 20%).
Example 44
Synthesis of1,1,1-Trifluoro-4(2-methoxy-5-methylphenyl)-4-methylpentan-2-one
##STR00459##
To a yellow solution of 20 g of 4-methylanisole and 1.7 mL ofconcentrated sulfuric acid was added dropwise 19.17 mL of3-chloro-2-methylpropene. The reaction became warm and turned darkpurple and after 20 minutes a precipitate formed. The reactions wasmonitored by TLC indicating a new less polar product. After 18hours, the reaction was poured onto ice and extracted with diethylether. The combined organic layers were dried over magnesiumsulfate, filtered, and concentrated in vacuo to leave an oil. Theresidue was diluted with hexanes, cooled to -78.degree. C., and thesolids collected by filtration to afford 14 g of2-(2-chloro-1,1-dimethylethyl)-1-methoxy-4-methylbenzene whichmelted upon warming to room temperature. The filtrate wasconcentrated in vacuo to afford 15.5 g of product and startinganisole (4:1 mixture).
To a suspension of 1.87 g of Mg turnings in 30 mL of dry diethylether under argon in a water bath was added 1.62 mL ofdibromoethane slowly by syringe while maintaining the temperaturebelow 27.degree. C. A solution of 4 g of2-(2-chloro-1,1-dimethylethyl)-1-methoxy4-methylbenzene andadditional dibromoethane (1.62 mL) in 20 mL of diethyl ether wasadded by addition funnel at a rate that kept the internal tempbelow 25.degree. C. The reaction became green and a fineprecipitate formed. After 1 hour, the reaction was cooled to-78.degree. C., solids formed on the bottom, stirring stopped, anda solution of 3.98 mL of trifluoroacetic anhydride in 4 mL diethylether was added by addition funnel while swirling the reaction byhand. The reaction was warmed to room temperature and stirringresumed above 40.degree. C. The reaction was monitored by TLCindicating a new slightly more polar product and starting material.The reaction was poured onto cold 1N aqueous HCl and extracted withdiethyl ether. The combined organic layers were dried overmagnesium sulfate and concentrated in vacuo. The residue waspurified on silica gel column eluting with ethyl acetate-hexanes(0%-5%) to afford 1.7 g of1,1,1-trifluoro-4-(2-methoxy-5-methylphenyl)-4-methylpentan-2-oneas a clear oil.
Example 45
Synthesis of{4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpent-yl]-3,4-dihydro-2H-quinoxalin-1-yl}furan-2-ylmethanone
##STR00460##
To a solution of2-(3,4-dihydro-2H-quinoxalin-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-me-thoxyphenyl)-4-methylpentan-2-ol (0.50 g, 0.117 mmol) indichloromethane (10 mL) was added pyridine (0.24 mL, 0.129 mmol)and 2-furoyl chloride (0.012 mL, 0.129 mmol). The reaction wasstirred at room temperature for 14 hours. The reaction mixture wasdiluted with dichloromethane, washed with two 25 mL portions of asaturated aqueous sodium bicarbonate, dried over sodium sulfate,filtered, and the solvent was evaporated in vacuo. Purification byflash column chromatography (5% MeOH/CH.sub.2Cl.sub.2) yielded thetitle compound as a white solid (14.5 mg).
Assessment of Biological Properties
Compounds of the invention were evaluated for binding to thesteroid receptor by a fluorescence polarization competitive bindingassay. Detailed descriptions for preparation of recombinantglucocorticoid receptor (GR) complex used in the assay is describedin U.S. Patent Application Publication No. 2003/00175503 andincorporated herein by reference in its entirety. Preparation ofthe tetramethyl rhodamine (TAMRA)-labeled dexamethasone probe wasaccomplished using a standard literature procedure (M. Pons et al.,J. Steroid Biochem., 1985, 22, pp. 267-273).
A. Glucocorticoid Receptor Competitive Binding Assay
Step 1. Characterization of the Fluorescent Probe
The wavelengths for maximum excitation and emission of thefluorescent probe should first be measured. An example of such aprobe is rhodamine (TAMRA)-labeled dexamethasone.
The affinity of the probe for the steroid receptor was thendetermined in a titration experiment. The fluorescence polarizationvalue of the probe in assay buffer was measured on an SLM-8100fluorometer using the excitation and emission maximum valuesdescribed above. Aliquots of expression vector lysate were addedand fluorescence polarization was measured after each additionuntil no further change in polarization value was observed.Non-linear least squares regression analysis was used to calculatethe dissociation constant of the probe from the polarization valuesobtained for lysate binding to the probe.
Step 2. Screening for Inhibitors of Probe Binding
This assay uses fluorescence polarization (FP) to quantitate theability of test compounds to compete with tetramethyl rhodamine(TAMRA)-labeled dexamethasone for binding to a human glucocorticoidreceptor (GR) complex prepared from an insect expression system.The assay buffer was: 10 mM TES, 50 mM KCl, 20 mMNa.sub.2MoO.sub.4.2H.sub.20, 1.5 mM EDTA, 0.04% w/v CHAPS, 10% v/vglycerol, 1 mM dithiothreitol, pH 7.4. Test compounds weredissolved to 1 mM in neat DMSO and then further diluted to10.times. assay concentration in assay buffer supplemented with 10%v/v DMSO. Test compounds were serially diluted at 10.times. assayconcentrations in 10% DMSO-containing buffer in 96-wellpolypropylene plates. Binding reaction mixtures were prepared in96-well black Dynex microtiter plates by sequential addition of thefollowing assay components to each well: 15 .mu.L of 10.times. testcompound solution, 85 .mu.L of GR-containing baculovirus lysatediluted 1:170 in assay buffer, and 50 .mu.L of 15 nM TAMRA-labeleddexamethasone. Positive controls were reaction mixtures containingno test compound; negative controls (blanks) were reaction mixturescontaining 0.7 .mu.M to 2 .mu.M dexamethasone. The bindingreactions were incubated for 1 hour at room temperature and thenread for fluorescence polarization in the LJL Analyst set to 550 nmexcitation and 580 nm emission, with the Rhodamine 561 dichroicmirror installed. IC.sub.50 values were determined by iterativenon-linear curve fitting of the FP signal data to a 4-parameterlogistic equation.
Compounds found to bind to the glucocorticoid receptor may beevaluated for binding to the progesterone receptor (PR), estrogenreceptor (ER), and mineralocorticoid receptors to evaluate thecompound's selectivity for GR. The protocols for PR and MR areidentical to the above GR method, with the following exceptions: PRinsect cell lysate is diluted 1:7.1 and MR lysate diluted 1:9.4. PRprobe is TAMRA-labeled mifepristone, used at a final concentrationof 5 nM in the assay, and the negative controls (blanks) werereactions containing mifepristone at 0.7 .mu.M to 2 .mu.M.
The ER protocol is similar to the above protocols, but uses PanVerakit receptor, fluorescein-labeled probe. The assay components aremade in the same volumes as above, to produce final assayconcentrations for ER of 15 nM and ES2 probe of 1 nM. In addition,the component order of addition is modified from the above assays:probe is added to the plate first, followed by receptor and testcompound. The plates are read in the LJL Analyst set to 485 nmexcitation and 530 nm emission, with the Fluorescein 505 dichroicmirror installed.
Compounds found to bind to the glucocorticoid receptor may beevaluated for dissociation of transactivation and transrepressionby assays cited in the Background of the Invention (C. M. Bambergerand H. M. Schulte, Eur. J. Clin. Invest., 2000, 30 (suppl. 3) 6-9)or by the assays described below.
B. Glucocorticoid Receptor Cell Assays
1. Induction of Aromatase in Fibroblasts (Cell Assay forTransactivation)
Dexamethasone, a synthetic ligand to the glucocorticoid receptor(GR), induces expression of aromatase in human foreskin fibroblastcells. The activity of aromatase is measured by the conversion oftestosterone to estradiol in culture media. Compounds that exhibitbinding to GR are evaluated for their ability to induce aromataseactivity in human foreskin fibroblasts.
Human foreskin fibroblast cells (ATCC Cat. No. CRL-2429,designation CCD112SK) are plated on 96 well plates at 50,000 cellsper well 5 days before use, in Iscove's Modified Dulbecco's Media(GibcoBRL Life Technologies Cat No. 12440-053) supplemented with10% charcoal filtered FBS (Clonetech Cat No. SH30068) andGentamycin (GibcoBRL Life Technologies Cat. No. 15710-064). On theday of the experiment, the media in the wells is replaced withfresh media. Cells are treated with test compounds to finalconcentrations of 10.sup.-5 M to 10.sup.-8 M, and testosterone to afinal concentration of 300 ng/mL. Each well has a total volume of100 .mu.L. Samples are made in duplicates. Control wells include:(a) wells that receive testosterone only, and (b) wells thatreceive testosterone plus 2 .mu.M of dexamethasone to providemaximum induction of aromatase. Plates are incubated at 37.degree.C. overnight (15 to 18 hours), and supernatants are harvested atthe end of incubation. Estradiol in the supernatant is measuredusing ELISA kits for estradiol (made by ALPCO, obtained fromAmerican Laboratory Products Cat. No. 020-DR-2693) according to themanufacture's instruction. The amount of estradiol is inverselyproportional to the ELISA signals in each well. The extent ofaromatase induction by test compounds is expressed as a relativepercentage to dexamethasone. EC.sub.50 values of test compounds arederived by non-linear curve fitting.
2. Inhibition of IL-6 Production in Fibroblasts (Cell Assay forTransrepression)
Human foreskin fibroblast cells produce IL-6 in response tostimulation by pro-inflammatory cytokine IL-1. This inflammatoryresponse, as measured by the production of IL-6, can be effectivelyinhibited by dexamethasone, a synthetic ligand to theglucocorticoid receptor (GR). Compounds that exhibit binding to GRare evaluated for their ability to inhibit IL-6 production in humanforeskin fibroblasts.
Human foreskin fibroblast cells (ATCC Cat. No. CRL-2429) are platedon 96 well plates at 5,000 cells per well the day before use, inIscove's Modified Dulbecco's Media (GibcoBRL Life Technologies Cat.No. 12440-053) supplemented with 10% charcoal filtered FBS(Clonetech Cat. No. SH30068) and Gentamycin (GibcoBRL LifeTechnologies Cat. No. 15710-064). On the next day, media in thewells is replaced with fresh media. Cells are treated with IL-1(rhIL-1.alpha., R&D Systems Cat. No. 200-LA) to a finalconcentration of 1 ng/mL, and with test compounds to finalconcentrations of 10.sup.-5 M to 10.sup.-8 M, in a total volume of200 .mu.L per well. Samples are done in duplicates. Backgroundcontrol wells do not receive test compounds or IL-1. Positivecontrol wells receive IL-1 only and represent maximum (or 100%)amount of IL-6 production. Plates are incubated at 37.degree. C.overnight (15 to 18 hours), and supernatants are harvested at theend of incubation. IL-6 levels in the supernatants are determinedby the ELISA kits for IL-6 (MedSystems Diagnostics GmbH, Vienna,Austria, Cat. No. BMS213TEN) according to manufacture'sinstructions. The extent of inhibition of IL-6 by test compounds isexpressed in percentage relative to positive controls. IC.sub.50values of test compounds are derived by non-linear curvefitting.
Evaluation of agonist or antagonist activity of compounds bindingto the glucocorticoid receptor may be determined by any of theassays.
3. Modulation of Tyrosine Aminotransferase (TAT) Induction in RatHepatoma Cells
Testing of compounds for agonist or antagonist activity ininduction of tyrosine aminotransferase (TAT) in rat hepatomacells.
H4-II-E-C.sup.3 cells were incubated overnight in 96 well plates(20,000 cells/100 .mu.L/well) in MEM medium containing 10% heatinactivated FBS and 1% nonessential amino acids. On the next day,cells were stimulated with the indicated concentrations ofdexamethasone or test compound (dissolved in DMSO, final DMSOconcentration 0.2%) for 18 hours. Control cells were treated with0.2% DMSO. After 18 hours, the cells were lysed in a buffercontaining 0.1% Triton X-100 and the TAT activity was measured in aphotometric assay using tyrosine and alpha-ketoglutarate assubstrates.
For measuring antagonist activity, the hepatoma cells werepre-stimulated by addition of dexamethasone (concentration rangesfrom 3.times.10.sup.-9 M to 3.times.10.sup.-8 M) shortly before thetest compound was applied to the cells. The steroidal non-selectiveGR/PR antagonist mifepristone was used as control.
4. Modulation of MMTV-Luc Induction in HeLa Cells
Testing of compounds for agonist or antagonist activity instimulation of MMTV-(mouse mammary tumor virus) promoter in HeLacells. HeLa cells were stably co-transfected with thepHHLuc-plasmid containing a fragment of the MMTV-LTR (-200 to +100relative to the transcription start site) cloned in front of theluciferase gene (Norden, 1988) and the pcDNA3.1 plasmid(Invitrogen) constitutively expressing the resistance for theselective antibiotic GENETICIN.RTM.. Clones with best induction ofthe MMTV-promoter were selected and used for furtherexperiments.
Cells were cultured overnight in DMEM medium without phenol red,supplemented with 3% CCS (charcoal treated calf serum) and thentransferred to 96 well plates (15,000 cells/100 .mu.L/well). On thenext day, activation of the MMTV-promoter was stimulated byaddition of test compound or dexamethasone dissolved in DMSO (finalconcentration 0.2%). Control cells were treated with DMSO only.After 18 hours, the cells were lysed with cell lysis reagent(Promega, Cat. No. E1531), luciferase assay reagent (Promega, Cat.No. E1501) was added and the glow luminescence was measured using aluminometer (BMG, Offenburg).
For measuring antagonist activity, the MMTV-promoter waspre-stimulated by adding dexamethasone (3.times.10.sup.-9 M to3.times.10.sup.-8 M) shortly before the test compound was appliedto the cells. The steroidal non-selective GR/PR antagonistmifepristone was used as control.
5. Modulation of IL-8 Production in U937 Cells
Testing of compounds for agonist or antagonist activity inGR-mediated inhibition of LPS-induced IL-8 secretion in U-937cells.
U-937 cells were incubated for 2 to 4 days in RPM11640 mediumcontaining 10% CCS (charcoal treated calf serum). The cells weretransferred to 96 well plates (40,000 cells/100 .mu.L/well) andstimulated with 1 .mu.g/mL LPS (dissolved in PBS) in the presenceor absence of dexamethasone or test compound (dissolved in DMSO,final concentration 0.2%). Control cells were treated with 0.2%DMSO. After 18 hours, the IL-8 concentration in the cellsupernatant was measured by ELISA, using the "OptEIA human IL-8set" (Pharmingen, Cat. No. 2654KI).
For measuring antagonist activity, the LPS-induced IL-8 secretionwas inhibited by adding dexamethasone (3.times.10.sup.-9 M to3.times.10.sup.-8 M) shortly before the test compound was appliedto the cells. The steroidal non-selective GR/PR antagonistmifepristone was used as control.
6. Modulation of ICAM-Luc Expression in HeLa Cells
Testing of compounds for agonist or antagonist activity ininhibition of TNF-alpha-induced activation of the ICAM-promoter inHeLa cells.
HeLa cells were stably co-transfected with a plasmid containing a1.3 kb fragment of the human ICAM-promoter (-1353 to -9 relative tothe transcription start site, Ledebur and Parks, 1995) cloned infront of the luciferase gene and the pcDNA3.1 plasmid (Invitrogen)which constitutively expresses the resistance for the antibioticGENETICIN.RTM.. Clones with best induction of the ICAM-promoterwere selected and used for further experiments. Cells weretransferred to 96 well plates (15,000 cells/100 .mu.L/well) in DMEMmedium supplemented with 3% CCS. On the following day theactivation of the ICAM-promoter was induced by addition of 10 ng/mLrecombinant TNF-alpha (R&D System, Cat. No. 210-TA).Simultaneously the cells were treated with the test compound ordexamethasone (dissolved in DMSO, final concentration 0.2%).Control cells were treated with DMSO only. After 18 hours, thecells were lysed with cell lysis reagent (Promega, Cat. No. E1531),luciferase assay reagent (Promega, Cat. No. E1501) was added andglow luminescence was measured using a luminometer (BMG,Offenburg).
For measuring antagonist activity, the TNF-alpha-induced activationof the ICAM-promoter was inhibited by adding dexamethasone(3.times.10.sup.-9 M to 3.times.10.sup.-8 M) shortly before thetest compound was applied to the cells. The steroidal non-selectiveGR/PR antagonist mifepristone was used as control.
Representative compounds of the invention have been tested and haveshown activity as modulators of the glucocorticoid receptorfunction in one or more of the above assays. For example, thefollowing compounds of the invention of Formula (IA) and Formula(IB) have demonstrated potent activity in the GR binding assay:4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-2,6-dimethylpiperazine-1-carbaldehyde;2-(1,1-Dioxo-2,3-dihydro-1H-1.lamda..sup.6-benzo[1,4]thiazin-4-ylmethyl)--1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;2-(2,6-Dimethylmorpholin-4-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methox-yphenyl)-4-methylpentan-2-ol;2-(2,3-Dihydrobenzo[1,4]oxazin4-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3,5-dimethylpiperidin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-cinnolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-methyl-H-quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-2,3-dihydro-1H-quinolin-4-one;1-[4-(4-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quin-olin-4-one;1-[4-(3-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quin-olin-4-one;1-[4-(3-Fluoro-4-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one;1-[4-(4-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-Phenyl-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one-;1-[4-(5-Fluoro-2-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluorom-ethylpentyl]-1H-quinolin-4-one;1-[4-(5-Bromo-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluorom-ethylpentyl]-1H-quinolin-4-one;1-[4-(5-Methyl-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoro-methylpentyl]-1H-quinolin-4-one;1-[4-(5-Chloro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoro-methylpentyl]-1H-quinolin-4-one;1-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpen-tyl]-H-quinolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-[1,5]naphthyridin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-2,4-dimethylpentyl]-3,5-dimethy-l-1H-pyridin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-[1,5]naphthyridin-4-one;1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1-oxo-2,3-dihydr-o-1H-1.lamda..sup.4-benzo[1,4]thiazin-4-ylmethyl)pentan-2-ol;1-[2-Hydroxy-4-(2-methoxy-5-thiophen-2-ylphenyl)-4-methyl-2-trifluorometh-ylpentyl]-1H-quinolin-4-one;1-[4-(6-Bromobenzo[1,3]dioxol-4-yl)-2-hydroxy-4-methyl-2-trifluoromethylp-entyl]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-methyl-H-quinolin-4-one;1-[2-Hydroxy-4-(4-hydroxybiphenyl-3-yl)-4-methyl-2-trifluoromethylpentyl]--1H-quinolin-4-one;1-{4-[5-(3,5-Dimethylisoxazol-4-yl)-2-hydroxyphenyl]-2-hydroxy-4-methyl-2--trifluoromethylpentyl}-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-hydroxy-5-thiophen-3-ylphenyl)-4-methyl-2-trifluorometh-ylpentyl]-1H-quinolin-4-one;1-{4-[5-(3,5-Dimethylisoxazol-4-yl)-2-methoxyphenyl]-2-hydroxy-4-methyl-2--trifluoromethylpentyl}-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-[1,5]naphthyridin-4-one;1-[2-Hydroxy-4-(5-methanesulfonyl-2,3-dihydrobenzofuran-7-yl)-4-methyl-2--trifluoromethylpentyl]-1H-[1,5]naphthyridin-4-one;1-[2-Hydroxy-4-methyl-4-(3-pyridin-3-ylphenyl)-2-trifluoromethylpentyl]-1--H-quinolin-4-one;1-[2-Hydroxy-4-(2-hydroxy-5-morpholin-4-ylmethylphenyl)-4-methyl-2-triflu-oromethylpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-methoxy-5-morpholin-4-ylmethylphenyl)-4-methyl-2-triflu-oromethylpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(5-hydroxymethyl-2-methoxyphenyl)-4-methyl-2-trifluorometh-ylpentyl]-1H-quinolin-4-one;4-Methoxy-3-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin--1-ylmethyl)butyl]benzaldehyde;1-[4-(5-[1,3]Dioxan-2-yl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorom-ethylpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-methoxy-5-thiophen-3-ylphenyl)-4-methyl-2-trifluorometh-ylpentyl]-H-quinolin-4-one;1-[4-(5-Furan-3-yl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylp-entyl]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-H-quinazolin-4-one;1-[2-Hydroxy-4-(4-methoxybiphenyl-3-yl)-4-methyl-2-trifluoromethylpentyl]--1H-quinolin-4-one;1-[4-(5-Acetyl-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-H-quinolin-4-one;1-[3,3,3-Trifluoro-2-(6-fluoro-4-methylchroman-4-ylmethyl)-2-hydroxypropy-l]-1H-quinolin-4-one;1-(4-{3-[1-(Benzyloxyimino)ethyl]phenyl}-2-hydroxy-4-methyl-2-trifluorome-thylpentyl)-1H-quinolin-4-one;1-[4-(3-Cyclopropanecarbonylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylp-entyl]-H-quinolin-4-one;1-[4-(5-Acetyl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-(2-Hydroxy-4-{3-[1-(methoxyimino)ethyl]phenyl}4-methyl-2-trifluoromethy-lpentyl)-1H-quinolin-4-one;1-[4-(5-Bromo-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one;1-(2-Hydroxy-4-{3-[1-(hydroxyimino)ethyl]phenyl}4-methyl-2-trifluoromethy-lpentyl)-1H-quinolin-4-one;1-[4-(5-Bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one;1-[4-(3,5-Difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1-H--quinolin-4-one;1-[4-(3,5-Dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1-H--quinolin-4-one;1-{2-Hydroxy-4-methyl-4-[3-(2-methyl-[1,3]dioxolan-2-yl)phenyl]-2-trifluo-romethylpentyl}-1H-quinolin-4-one;1-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpen-tyl]-2-hydroxymethyl-3,5-dimethyl-1H-pyridin-4-one;1-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpen-tyl]-H-[1,5]naphthyridin-4-one;1-[2-Hydroxy-4-(3-hydroxymethylphenyl)-4-methyl-2-trifluoromethylpentyl]--1-H-quinolin-4-one;1-[4-(3-[1,3]Dioxan-2-ylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-(3-Acetylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quin-olin-4-one;1-{4-[3-(3,5-Dimethylisoxazol-4-yl)phenyl]-2-hydroxy-4-methyl-2-trifluoro-methylpentyl}-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-3,5-dimethyl-1H-pyridin-4-one;-{2-Hydroxy-4-[3-(1-hydroxyethyl)phenyl]4-methyl-2-trifluoromethylpentyl}--1H-quinolin-4-one;1-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpen-tyl]-3,5-dimethyl-1H-pyridin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-2-hydroxymethyl-3,5-dimethyl-1H-pyridin-4-one;3-[4,4,4-Trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1-ylmethyl-)butyl]benzaldehyde;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-2-hydroxymethyl-3,5-dimethyl-1H-pyridin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-hydroxymethyl-1H-quinolin-4-one;1-[4-(3-Bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quino-lin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluorom-ethylpentyl]-7-hydroxy-H-quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-6-methyl-H-quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-hydroxymethyl-1H-quinolin-4-one;6-Chloro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-[-4-(2-Difluoromethoxy-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-H-quinolin-4-one;1-(4-Biphenyl-3-yl-2-hydroxy-4-methyl-2-trifluoromethylpentyl)-H-quinolin--4-one;6-Chloro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trif-luoromethylpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-hydroxy-5-methylphenyl)-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-{2-Hydroxy-4-methyl-4-[3-(2-oxopropoxy)phenyl]-2-trifluoromethylpentyl}--1H-quinolin-4-one;1-[2-Hydroxy-4-(3-isopropoxyphenyl)-4-methyl-2-trifluoromethylpentyl]-1-H--quinolin-4-one;1-[4-(3-Ethoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-H-quino-lin-4-one;1-[2-Hydroxy-4-(2-methoxy-5-methylphenyl)-4-methyl-2-trifluorom-ethylpentyl]-1H-quinolin-4-one;1-[4-(2,5-Dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1-H--quinolin-4-one;1-[2-Hydroxy-4-(3-hydroxyphenyl)-4-methyl-2-trifluoromethylpentyl]-1H-qui-nolin-4-one;1-[2-Hydroxy-4-(3-methoxyphenyl)-4-methyl-2-trifluoromethylpentyl]-1H-qui-nolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1,2-dihydroindazol-3-one;7-Fluoro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3,5-dimethyl-1H-pyridin-4-one;7-Fluoro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-(2-Hydroxy-4-methyl-4-phenyl-2-trifluoromethylhexyl)-1H-quinolin-4-one;1-[4-(4-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-H-quinolin-4-one;1-[4-(3,4-Dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1-H--quinolin-4-one;8-Fluoro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;6-Fluoro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-{4-[5-Fluoro-2-(2-oxopropoxy)phenyl]-2-hydroxy-4-methyl-2-trifluorometh-ylpentyl}-1H-quinolin-4-one;7-Chloro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-isopropoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpe-ntyl]-H-quinolin-4-one;1-[4-(2-Benzyloxy-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpen-tyl]-H-quinolin-4-one;1-[4-(2-Ethoxy-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-1H-quinolin-4-one;8-Fluoro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;6-Fluoro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(5-methanesulfonyl-2,3-dihydrobenzofuran-7-yl)-4-methyl-2--trifluoromethylpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(5-methanesulfinyl-2,3-dihydrobenzofuran-7-yl)-4-methyl-2--trifluoromethylpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-methyl-4-(5-methylsulfanyl-2,3-dihydrobenzofuran-7-yl)-2-t-rifluoromethylpentyl]-1H-quinolin-4-one;7-Chloro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-[4-(3-Fluoro-4-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-3-nitro-5-trifluoromethyl-1H-pyridin-2-one;3-Chloro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-5-trifluoromethyl-1H-pyridin-2-one;2-(2,3-Dihydroindol-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphen-yl)-4-methylpentan-2-ol;1-[2-Hydroxy-4-methyl-4-(3-morpholin-4-ylmethylphenyl)-2-trifluoromethylp-entyl]-H-quinolin-4-one;{4-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpent-yl]piperazin-1-yl}furan-2-ylmethanone;1-[2-Hydroxy-4-(5-methanesulfonyl-2,3-dihydrobenzofuran-7-yl)-4-methyl-2--trifluoromethylpentyl]-3-methyl-1H-quinolin-4-one;2-[4-(3-Chloro-5-trifluoromethylpyridin-2-yl)piperazin-1-ylmethyl]-1,1,1--trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol;{4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpent-yl]piperazin-1-yl}furan-2-ylmethanone;1-[2-Hydroxy-4-(2-methoxy-5-pyridin-3-ylphenyl)-4-methy-2-trifluoromethyl-pentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-hydroxy-3,5-dimethylphenyl)-4-methyl-2-trifluoromethylp-entyl]-1H-quinolin-4-one;1-[4-(3-[1,3]Dioxan-2-yl-4-fluorophenyl)-2-hydroxy-4-methy-1-2-trifluorom-ethylpentyl]-1H-quinolin-4-one; 1-[2-Hydroxy-4-(2-methoxy-5-pdin-5-ylphenyl)-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl-]-H-quinolin-4-one;1-[4-(2,4-dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1-H--quinolin-4-one;1-[4-(4-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-H-quinolin-4-one;1-[4-(3-Fluoro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-(4-Benzo[1,3]dioxol-4-yl-2-hydroxy-4-methyl-2-trifluoromethylpentyl)-1--H-quinolin-4-one;1-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1,2-dihydroindazol-3-one;2-(3,4-Dihydro-2H-quinoxalin-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-me-thoxyphenyl)-4-methylpentan-2-ol;1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-methyl-3,4-dih-ydro-2H-quinoxalin-1-ylmethyl)pentan-2-ol;2-(2,3-Dihydrobenzo[1,4]thiazin-4-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2--methoxyphenyl)-4-methylpentan-2-ol;
1-{4-[4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpe-ntyl]-3,4-dihydro-2H-quinoxalin-1-yl}ethanone;1-[2-Hydroxy-4-(2-hydroxy-5-thiophen-3-ylphenyl)-4-methyl-2-trifluorometh-ylpentyl]-1H-quinolin-4-one;1-[4-(2,3-Dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpen-tyl]-3-methyl-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-methoxy-3,5-dimethylphenyl)-4-methyl-2-trifluoromethylp-entyl]-H-quinolin-4-one;1-[2-Hydroxy-4-(2-hydroxy-5-pyridin-3-ylphenyl)-4-methyl-2-trifluoromethy-lpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(2-hydroxy-5-pyrimidin-5-ylphenyl)-4-methyl-2-trifluoromet-hylpentyl]-H-quinolin-4-one; Carbonic acid4-fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4-H-quinolin--1-ylmethyl)butyl]phenyl ester methyl ester;1-[2-Cyclopropyl-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methylpentyl]-H--quinolin-4-one; and1-[2-Difluoromethyl-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methylpentyl-]-H-quinolin-4-one. 7. Inhibition of Osteocalcin Production fromOsteoblast Cell Line MG-63
Human osteosarcoma MG-63 cells (ATCC, Cat. No. CRL-1427) are platedon 96 well plates at 20,000 cells per well the day before use in200 .mu.L media of 99% D-MEM/F-12 (Gibco-Invitrogen, Cat. No.11039-021), supplemented with 1% penicillin and streptomycin(Gibco-Invitrogen, Cat. No. 15140-122), 10 .mu.g/mL Vitamin C(Sigma, Cat. No. A4544), and 1% charcoal filtered Fetal BovineSerum (HyClone, Cat. No. SH30068.02). The next day, wells arereplaced with fresh media. Cells are treated with Vitamin D (Sigma,Cat. No. D1530) to a final concentration of 10 nM, and with thetest compounds in concentrations of 10.sup.-6 M to 10.sup.-9 M, ina total volume of 200 .mu.L per well. Samples are done induplicates. Background control wells do not receive Vitamin D orcompounds. Positive control wells receive Vitamin D only, withoutcompounds, and represent maximum (100%) amount of osteocalcinproduction. Plates are incubated at 37.degree. C. incubator for 48hours and supernatants are harvested at the end of incubation.Amounts of osteocalcin in the supernatants are determined by theGlype osteocalcin ELISA kit (Zymed, Cat. No. 99-0054) according tomanufacture's protocol. Inhibition of osteocalcin by test compoundsis expressed in percentage relative to positive controls. IC.sub.50values of the test compounds are derived by non-lineal curvefitting.
The following compounds of Formula (IA) inhibit the vitamin Dstimulated production of osteocalcin:7-Fluoro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluorome-thylpentyl]-1H-quinolin-4-one;1-[2-Hydroxy-4-(5-methanesulfonyl-2,3-dihydrobenzofuran-7-yl)-4-methyl-2--trifluoromethylpentyl]-1H-quinolin-4-one;1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-1H-quinolin-4-one;1-[4-(5-Bromo-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluorom-ethylpentyl]-1H-quinolin-4-one;1-(4-Biphenyl-3-yl-2-hydroxy-4-methyl-2-trifluoromethylpentyl)-1H-quinoli-n-4-one; and1-[4-(5-Fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpenty-l]-H-[1,5]naphthyridin-4-one.
The invention also provides methods of modulating theglucocorticoid receptor function in a patient comprisingadministering to the patient a compound according to the invention.If the purpose of modulating the glucocorticoid receptor functionin a patient is to treat a disease-state or condition, theadministration preferably comprises a therapeutically orpharmaceutically effective amount of a pharmaceutically acceptablecompound according to the invention. If the purpose of modulatingthe glucocorticoid receptor function in a patient is for adiagnostic or other purpose (e.g., to determine the patient'ssuitability for therapy or sensitivity to various sub-therapeuticdoses of the compounds according to the invention), theadministration preferably comprises an effective amount of acompound according to the invention, that is, the amount necessaryto obtain the desired effect or degree of modulation.
Methods of Therapeutic Use
As pointed out above, the compounds of the invention are useful inmodulating the glucocorticoid receptor function. In doing so, thesecompounds have therapeutic use in treating disease-states andconditions mediated by the glucocorticoid receptor function or thatwould benefit from modulation of the glucocorticoid receptorfunction.
As the compounds of the invention modulate the glucocorticoidreceptor function, they have very useful anti-inflammatory andantiallergic, immune-suppressive, and anti-proliferative activityand they can be used in patients as drugs, particularly in the formof pharmaceutical compositions as set forth below, for thetreatment of disease-states and conditions.
The agonist compounds according to the invention can be used inpatients as drugs for the treatment of the following disease-statesor indications that are accompanied by inflammatory, allergic,and/or proliferative processes: (i) Lung diseases: chronic,obstructive lung diseases of any genesis, particularly bronchialasthma and chronic obstructive pulmonary disease (COPD); adultrespiratory distress syndrome (ARDS); bronchiectasis; bronchitis ofvarious genesis; all forms of restrictive lung diseases,particularly allergic alveolitis; all forms of lung edema,particularly toxic lung edema; all forms of interstitial lungdiseases of any genesis, e.g., radiation pneumonitis; andsarcoidosis and granulomatoses, particularly Boeck disease. (ii)Rheumatic diseases or autoimmune diseases or joint diseases: allforms of rheumatic diseases, especially rheumatoid arthritis, acuterheumatic fever, and polymyalgia rheumatica; reactive arthritis;rheumatic soft tissue diseases; inflammatory soft tissue diseasesof other genesis; arthritic symptoms in degenerative joint diseases(arthroses); traumatic arthritis; collagenoses of any genesis,e.g., systemic lupus erythematosus, scleroderma, polymyositis,dermatomyositis, Sjogren syndrome, Still disease, and Feltysyndrome; (iii) Allergic diseases: all forms of allergic reactions,e.g., angioneurotic edema, hay fever, insect bites, allergicreactions to drugs, blood derivatives, contrast agents, etc.,anaphylactic shock (anaphylaxis), urticaria, angioneurotic edema,and contact dermatitis; (iv) Vasculitis diseases: panarteritisnodosa, polyarteritis nodosa, arteritis temporalis, Wegnergranulomatosis, giant cell arthritis, and erythema nodosum; (v)Dermatological diseases: atopic dermatitis, particularly inchildren; psoriasis; pityriasis rubra pilaris; erythematousdiseases triggered by various noxa, e.g., rays, chemicals, burns,etc.; bullous dermatoses; diseases of the lichenoid complex;pruritus (e.g., of allergic genesis); seborrheic dermatitis;rosacea; pemphigus vulgaris; erythema multiforme exudativum;balanitis; vulvitis; hair loss, such as occurs in alopecia areata;and cutaneous T cell lymphomas; (vi) Renal diseases: nephroticsyndrome; and all types of nephritis, e.g., glomerulonephritis;(vii) Hepatic diseases: acute liver cell disintegration; acutehepatitis of various genesis, e.g., viral, toxic, drug-induced; andchronically aggressive and/or chronically intermittent hepatitis;(viii) Gastrointestinal diseases: inflammatory bowel diseases,e.g., regional enteritis (Crohn disease), colitis ulcerosa;gastritis; peptic esophagitis (refluxoesophagitis); andgastroenteritis of other genesis, e.g., nontropical sprue; (ix)Proctological diseases: anal eczema; fissures; hemorrhoids; andidiopathic proctitis; (x) Eye diseases: allergic keratitis,uveitis, or iritis; conjunctivitis; blepharitis; neuritis nervioptici; choroiditis; and sympathetic ophthalmia; (xi) Diseases ofthe ear, nose, and throat (ENT) area: allergic rhinitis or hayfever; otitis extema, e.g., caused by contact eczema, infection,etc.; and otitis media; (xii) Neurological diseases: brain edema,particularly tumor-related brain edema; multiple sclerosis; acuteencephalomyelitis; meningitis; acute spinal cord injury; stroke;and various forms of seizures, e.g., nodding spasms; (xiii) Blooddiseases: acquired hemolytic anemia; and idiopathicthrombocytopenia; (xiv) Tumor diseases: acute lymphatic leukemia;malignant lymphoma; lymphogranulomatoses; lymphosarcoma; extensivemetastases, particularly in mammary, bronchial, and prostaticcarcinoma; (xv) Endocrine diseases: endocrine ophthalmopathy;endocrine orbitopathia; thyrotoxic crisis; Thyroiditis de Quervain;Hashimoto thyroiditis; Morbus Basedow; granulomatous thyroiditis;struma lymphomatosa; and Grave disease; (xvi) Organ and tissuetransplantations and graft-versus-host diseases; (xvii) Severestates of shock, e.g., septic shock, anaphylactic shock, andsystemic inflammatory response syndrome (SIRS); (xviii)Substitution therapy in: congenital primary adrenal insufficiency,e.g., adrenogenital syndrome; acquired primary adrenalinsufficiency, e.g., Addison disease, autoimmune adrenalitis,post-infection, tumors, metastases, etc.; congenital secondaryadrenal insufficiency, e.g., congenital hypopituitarism; andacquired secondary adrenal insufficiency, e.g., post-infection,tumors, metastases, etc.; (xix) Pain of inflammatory genesis, e.g.,lumbago; and (xx) various other disease-states or conditionsincluding type I diabetes (insulin-dependent diabetes),osteoarthritis, Guillain-Barre syndrome, restenosis followingpercutaneous transluminal coronary angioplasty, Alzheimer disease,acute and chronic pain, atherosclerosis, reperfusion injury, boneresorption diseases, congestive heart failure, myocardialinfarction, thermal injury, multiple organ injury secondary totrauma, acute purulent meningitis, necrotizing enterocolitis andsyndromes associated with hemodialysis, leukopheresis, andgranulocyte transfusion.
In addition, the compounds according to the invention can be usedfor the treatment of any other disease-states or conditions notmentioned above which have been treated, are treated, or will betreated with synthetic glucocorticoids (see, e.g., H. J. Hatz,Glucocorticoide: Immunologische Grundlagen, Pharmakologie undTherapierichtlinien [Glucocorticoids: Immunological Fundamentals,Pharmacology, and Therapeutic Guidelines], Stuttgart:Verlagsgesellschaft mbH, 1998, which is hereby incorporated byreference in its entirety). Most or all of the indications (i)through (xx) mentioned above are described in detail in H. J. Hatz,Glucocorticoide: Immunologische Grundlagen, Pharmakologie undTherapierichtlinien. Furthermore, the compounds of the inventioncan also be used to treat disorders other than those listed aboveor mentioned or discussed herein, including in the Background ofthe Invention.
The invention include use of a compound according to the inventionfor the preparation of a pharmaceutical composition. The inventionalso includes use of a compound according to the invention incombination with a pharmaceutically acceptable glucocorticoid forthe preparation of a pharmaceutical composition. The inventionadditionally includes use of a compound according to the inventionin combination with other pharmaceutically acceptable excipientsand ingredients as set forth herein for the preparation of apharmaceutical composition. The invention also includes the use ofa compound according to the invention for the preparation of apharmaceutical composition as described herein for the treatment ofa disease-state or condition mediated by the glucocorticoidreceptor function; type II diabetes, obesity, cardiovasculardiseases, hypertension, arteriosclerosis, neurological diseases,adrenal and pituitary tumors, and glaucoma; a disease characterizedby inflammatory, allergic, or proliferative processes, (i) lungdiseases; (ii) rheumatic diseases/autoimmune diseases/jointdiseases; (iii) allergic diseases; (iv) vasculitis diseases; (v)dermatological diseases; (vi) renal diseases; (vii) hepaticdiseases; (viii) gastrointestinal diseases; (ix) proctologicaldiseases; (x) eye diseases; (xi) diseases of the ear, nose, andthroat (ENT) area; (xii) neurological diseases; (xiii) blooddiseases; (xiv) tumor diseases; (xv) endocrine diseases; (xvi)organ and tissue transplantations and graft-versus-host diseases;(xvii) severe states of shock; (xviii) substitution therapy; and(xix) pain of inflammatory genesis.
The antagonist compounds according to the invention, whether fullantagonists or partial antagonists, can bemused in patients asdrugs for the treatment of the following disease-states orindications, without limitation: type II diabetes(non-insulin-dependent diabetes); obesity; cardiovascular diseases;hypertension; arteriosclerosis; neurological diseases, such aspsychosis and depression; adrenal and pituitary tumors; glaucoma;and Cushing syndrome based on an ACTH secreting tumor likepituitary adenoma. In particular, the compounds of the inventionare useful for treating obesity and all disease-states andindications related to a deregulated fatty acids metabolism such ashypertension, atherosclerosis, and other cardiovascular diseases.Using the compounds of the invention that are GR antagonists, itshould be possible to antagonize both the carbohydrate metabolismand fatty acids metabolism. Thus, the antagonist compounds of theinvention are useful in treating all disease-states and conditionsthat involve increased carbohydrate, protein, and lipid metabolismand would include disease-states and conditions leading tocatabolism like muscle frailty (as an example of proteinmetabolism).
Methods of Diagnostic Use
The compounds of the invention may also be used in diagnosticapplications and for commercial and other purposes as standards incompetitive binding assays. In such uses, the compounds of theinvention may be used in the form of the compounds themselves orthey may be modified by attaching a radioisotope, luminescence,fluorescent label or the like in order to obtain a radioisotope,luminescence, or fluorescent probe, as would be known by one ofskill in the art and as outlined in Handbook of Fluorescent Probesand Research Chemicals, 6th Edition, R. P. Haugland (ed.), Eugene:Molecular Probes, 1996; Fluorescence and Luminescence Probes forBiological Activity, W. T. Mason (ed.), San Diego: Academic Press,1993; Receptor-Ligand Interaction, A Practical Approach, E. C.Hulme (ed.), Oxford: IRL Press, 1992, each of which is herebyincorporated by reference in their entireties.
General Administration and Pharmaceutical Compositions
When used as pharmaceuticals, the compounds of the invention aretypically administered in the form of a pharmaceutical composition.Such compositions can be prepared using procedures well known inthe pharmaceutical art and comprise at least one compound of theinvention. The compounds of the invention may also be administeredalone or in combination with adjuvants that enhance stability ofthe compounds of the invention, facilitate administration ofpharmaceutical compositions containing them in certain embodiments,provide increased dissolution or dispersion, increased inhibitoryactivity, provide adjunct therapy, and the like. The compoundsaccording to the invention may be used on their own or inconjunction with other active substances according to theinvention, optionally also in conjunction with otherpharmacologically active substances. In general, the compounds ofthis invention are administered in a therapeutically orpharmaceutically effective amount, but may be administered in loweramounts for diagnostic or other purposes.
In particular, the compounds of the invention are useful incombination with glucocorticoids or corticosteroids. As pointed outabove, standard therapy for a variety of immune and inflammatorydisorders includes administration of corticosteroids, which havethe ability to suppress immunologic and inflammatory responses. (A.P. Truhan et al., Annals of Allergy, 1989, 62, pp. 375-391; J. D.Baxter, Hospital Practice, 1992, 27, pp. 111-134; R. P. Kimberly,Curr. Opin. Rheumatol., 1992, 4, pp. 325-331; M. H. Weisman, Curr.Opin. Rheumatol., 1995, 7, pp. 183-190; W. Sterry, Arch. Dermatol.Res., 1992, 284 (Suppl.), pp. S27-S29). While therapeuticallybeneficial, however, the use of corticosteroids is associated witha number of side effects, ranging from mild to possibly lifethreatening, especially with prolonged and/or high dose steroidusage. Accordingly, methods and compositions that enable the use ofa lower effective dosage of corticosteroids (referred to as the"steroid sparing effect") would be highly desirable to avoidunwanted side effects. The compounds of the invention provide sucha steroid sparing effect by achieving the desired therapeuticeffect while allowing the use of lower doses and less frequentadministration of glucocorticoids or corticosteroids.
Administration of the compounds of the invention, in pure form orin an appropriate pharmaceutical composition, can be carried outusing any of the accepted modes of administration of pharmaceuticalcompositions. Thus, administration can be, for example, orally,buccally (e.g., sublingually), nasally, parenterally, topically,transdermally, vaginally, or rectally, in the form of solid,semi-solid, lyophilized powder, or liquid dosage forms, such as,for example, tablets, suppositories, pills, soft elastic and hardgelatin capsules, powders, solutions, suspensions, or aerosols, orthe like, preferably in unit dosage forms suitable for simpleadministration of precise dosages. The pharmaceutical compositionswill generally include a conventional pharmaceutical carrier orexcipient and a compound of the invention as the/an active agent,and, in addition, may include other medicinal agents,pharmaceutical agents, carriers, adjuvants, diluents, vehicles, orcombinations thereof. Such pharmaceutically acceptable excipients,carriers, or additives as well as methods of making pharmaceuticalcompositions for various modes or administration are well-known tothose of skill in the art. The state of the art is evidenced, e.g.,by Remington: The Science and Practice of Pharmacy, 20th Edition,A. Gennaro (ed.), Lippincott Williams & Wilkins, 2000; Handbookof Pharmaceutical Additives, Michael & Irene Ash (eds.), Cower,1995; Handbook of Pharmaceutical Excipients, A. H. Kibbe (ed.),American Pharmaceutical Ass'n, 2000; H. C. Ansel and N. G.Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systems,5th ed., Lea and Febiger, 1990; each of which is incorporatedherein by reference in their entireties to better describe thestate of the art.
As one of skill in the art would expect, the forms of the compoundsof the invention utilized in a particular pharmaceuticalformulation will be selected (e.g., salts) that possess suitablephysical characteristics (e.g., water solubility) that is requiredfor the formulation to be efficacious.
Pharmaceutical compositions suitable for buccal (sub-lingual)administration include lozenges comprising a compound of thepresent invention in a flavored base, usually sucrose, and acaciaor tragacanth, and pastilles comprising the compound in an inertbase such as gelatin and glycerin or sucrose and acacia.
Pharmaceutical compositions suitable for parenteral administrationcomprise sterile aqueous preparations of a compound of the presentinvention. These preparations are preferably administeredintravenously, although administration can also be effected bymeans of subcutaneous, intramuscular, or intradermal injection.Injectable pharmaceutical formulations are commonly based uponinjectable sterile saline, phosphate-buffered saline, oleaginoussuspensions, or other injectable carriers known in the art and aregenerally rendered sterile and isotonic with the blood. Theinjectable pharmaceutical formulations may therefore be provided asa sterile injectable solution or suspension in a nontoxicparenterally acceptable diluent or solvent, including1,3-butanediol, water, Ringer's solution, isotonic sodium chloridesolution, fixed oils such as synthetic mono- or diglycerides, fattyacids such as oleic acid, and the like.
Such injectable pharmaceutical formulations are formulatedaccording to the known art using suitable dispersing or settingagents and suspending agents. Injectable compositions willgenerally contain from 0.1 to 5% w/w of a compound of theinvention.
Solid dosage forms for oral administration of the compounds includecapsules, tablets, pills, powders, and granules. For such oraladministration, a pharmaceutically acceptable compositioncontaining a compound(s) of the invention is formed by theincorporation of any of the normally employed excipients, such as,for example, pharmaceutical grades of mannitol, lactose, starch,pregelatinized starch, magnesium stearate, sodium saccharine,talcum, cellulose ether derivatives, glucose, gelatin, sucrose,citrate, propyl gallate, and the like. Such solid pharmaceuticalformulations may include formulations, as are well-known in theart, to provide prolonged or sustained delivery of the drug to thegastrointestinal tract by any number of mechanisms, which include,but are not limited to, pH sensitive release from the dosage formbased on the changing pH of the small intestine, slow erosion of atablet or capsule, retention in the stomach based on the physicalproperties of the formulation, bioadhesion of the dosage form tothe mucosal lining of the intestinal tract, or enzymatic release ofthe active drug from the dosage form.
Liquid dosage forms for oral administration of the compoundsinclude emulsions, microemulsions, solutions, suspensions, syrups,and elixirs, optionally containing pharmaceutical adjuvants in acarrier, such as, for example, water, saline, aqueous dextrose,glycerol, ethanol and the like. These compositions can also containadditional adjuvants such as wetting, emulsifying, suspending,sweetening, flavoring, and perfuming agents.
Topical dosage forms of the compounds include ointments, pastes,creams, lotions, gels, powders, solutions, sprays, inhalants, eyeointments, eye or ear drops, impregnated dressings and aerosols,and may contain appropriate conventional additives such aspreservatives, solvents to assist drug penetration and emollientsin ointments and creams. Topical application may be once or morethan once per day depending upon the usual medical considerations.Furthermore, preferred compounds for the present invention can beadministered in intranasal form via topical use of suitableintranasal vehicles. The formulations may also contain compatibleconventional carriers, such as cream or ointment bases and ethanolor oleyl alcohol for lotions. Such carriers may be present as fromabout 1% up to about 98% of the formulation, more usually they willform up to about 80% of the formulation.
Transdermal administration is also possible. Pharmaceuticalcompositions suitable for transdermal administration can bepresented as discrete patches adapted to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time.To be administered in the form of a transdermal delivery system,the dosage administration will, of course, be continuous ratherthan intermittent throughout the dosage regimen. Such patchessuitably contain a compound of the invention in an optionallybuffered, aqueous solution, dissolved and/or dispersed in anadhesive, or dispersed in a polymer. A suitable concentration ofthe active compound is about 1% to 35%, preferably about 3% to15%.
For administration by inhalation, the compounds of the inventionare conveniently delivered in the form of an aerosol spray from apump spray device not requiring a propellant gas or from apressurized pack or a nebulizer with the use of a suitablepropellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, tetrafluoroethane, heptafluoropropane,carbon dioxide, or other suitable gas. In any case, the aerosolspray dosage unit may be determined by providing a valve to delivera metered amount so that the resulting metered dose inhaler (MDI)is used to administer the compounds of the invention in areproducible and controlled way. Such inhaler, nebulizer, oratomizer devices are known in the prior art, for example, in PCTInternational Publication Nos. WO 97/12687 (particularly FIG. 6thereof, which is the basis for the commercial RESPIMAT.RTM.nebulizer); WO 94/07607; WO 97/12683; and WO 97/20590, to whichreference is hereby made and each of which is incorporated hereinby reference in their entireties.
Rectal administration can be effected utilizing unit dosesuppositories in which the compound is admixed with low-meltingwater-soluble or insoluble solids such as fats, cocoa butter,glycerinated gelatin, hydrogenated vegetable oils, mixtures ofpolyethylene glycols of various molecular weights, or fatty acidesters of polyethylene glycols, or the like. The active compound isusually a minor component, often from about 0.05 to 10% by weight,with the remainder being the base component.
In all of the above pharmaceutical compositions, the compounds ofthe invention are formulated with an acceptable carrier orexcipient. The carriers or excipients used must, of course, beacceptable in the sense of being compatible with the otheringredients of the composition and must not be deleterious to thepatient. The carrier or excipient can be a solid or a liquid, orboth, and is preferably formulated with the compound of theinvention as a unit-dose composition, for example, a tablet, whichcan contain from 0.05% to 95% by weight of the active compound.Such carriers or excipients include inert fillers or diluents,binders, lubricants, disintegrating agents, solution retardants,resorption accelerators, absorption agents, and coloring agents.Suitable binders include starch, gelatin, natural sugars such asglucose or .beta.-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes, and the like.Lubricants include sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride, and thelike. Disintegrators include starch, methyl cellulose, agar,bentonite, xanthan gum, and the like.
Generally, a therapeutically effective daily dose is from about0.001 mg to about 15 mg/kg of body weight per day of a compound ofthe invention; preferably, from about 0.1 mg to about 10 mg/kg ofbody weight per day; and most preferably, from about 0.1 mg toabout 1.5 mg/kg of body weight per day. For example, foradministration to a 70 kg person, the dosage range would be fromabout 0.07 mg to about 1050 mg per day of a compound of theinvention, preferably from about 7.0 mg to about 700 mg per day,and most preferably from about 7.0 mg to about 105 mg per day. Somedegree of routine dose optimization may be required to determine anoptimal dosing level and pattern.
Pharmaceutically acceptable carriers and excipients encompass allthe foregoing additives and the like.
Examples of Pharmaceutical Formulations
TABLE-US-00003 A. TABLETS Component Amount per tablet (mg) activesubstance 100 lactose 140 corn starch 240 polyvinylpyrrolidone 15magnesium stearate 5 TOTAL 500
The finely ground active substance, lactose, and some of the cornstarch are mixed together. The mixture is screened, then moistenedwith a solution of polyvinylpyrrolidone in water, kneaded,wet-granulated and dried. The granules, the remaining corn starchand the magnesium stearate are screened and mixed together. Themixture is compressed to produce tablets of suitable shape andsize.
TABLE-US-00004 B. TABLETS Component Amount per tablet (mg) activesubstance 80 lactose 55 corn starch 190 polyvinylpyrrolidone 15magnesium stearate 2 microcrystalline cellulose 35sodium-carboxymethyl starch 23 TOTAL 400
The finely ground active substance, some of the corn starch,lactose, microcrystalline cellulose, and polyvinylpyrrolidone aremixed together, the mixture is screened and worked with theremaining corn starch and water to form a granulate which is driedand screened. The sodium-carboxymethyl starch and the magnesiumstearate are added and mixed in and the mixture is compressed toform tablets of a suitable size.
TABLE-US-00005 C. COATED TABLETS Component Amount per tablet (mg)active substance 5 lactose 30 corn starch 41.5 polyvinylpyrrolidone3 magnesium stearate 0.5 TOTAL 90
The active substance, corn starch, lactose, andpolyvinylpyrrolidone are thoroughly mixed and moistened with water.The moist mass is pushed through a screen with a 1 mm mesh size,dried at about 45.degree. C. and the granules are then passedthrough the same screen. After the magnesium stearate has beenmixed in, convex tablet cores with a diameter of 6 mm arecompressed in a tablet-making machine. The tablet cores thusproduced are coated in known manner with a covering consistingessentially of sugar and talc. The finished coated tablets arepolished with wax.
TABLE-US-00006 D. CAPSULES Component Amount per capsule (mg) activesubstance 50 corn starch 268.5 magnesium stearate 1.5 TOTAL 320
The substance and corn starch are mixed and moistened with water.The moist mass is screened and dried. The dry granules are screenedand mixed with magnesium stearate. The finished mixture is packedinto size 1 hard gelatine capsules.
TABLE-US-00007 E. AMPOULE SOLUTION Component Amount per ampouleactive substance 50 mg sodium chloride 50 mg water for inj. 5mL
The active substance is dissolved in water at its own pH oroptionally at pH 5.5 to 6.5 and sodium chloride is added to make itisotonic. The solution obtained is filtered free from pyrogens andthe filtrate is transferred under aseptic conditions into ampouleswhich are then sterilized and sealed by fusion. The ampoulescontain 5 mg, 25 mg, and 50 mg of active substance.
TABLE-US-00008 F. SUPPOSITORIES Amount per Component suppository(mg) active substance 50 solid fat 1650 TOTAL 1700
The hard fat is melted. At 40.degree. C., the ground activesubstance is homogeneously dispersed therein. The mixture is cooledto 38.degree. C. and poured into slightly chilled suppositorymolds.
TABLE-US-00009 G. METERING AEROSOL Component Amount activesubstance 0.005 sorbitan trioleate 0.1 monofluorotrichloromethaneand to 100 difluorodichloromethane (2:3)
The suspension is transferred into a conventional aerosol containerwith a metering valve. Preferably, 50 .mu.L of suspension aredelivered per spray. The active substance may also be metered inhigher doses if desired (e.g., 0.02% by weight).
TABLE-US-00010 Component Amount H. POWDER FOR INHALATION activesubstance 1.0 mg lactose monohydrate to 25 mg I. POWDER FORINHALATION active substance 2.0 mg lactose monohydrate to 25 mg J.POWDER FOR INHALATION active substance 1.0 mg lactose monohydrateto 5 mg K. POWDER FOR INHALATION active substance 2.0 mg lactosemonohydrate to 5 mg
In Examples H, I, J, and K, the powder for inhalation is producedin the usual way by mixing the individual ingredients together.
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