CA2006306A1 - Antiatherosclerotic and antithrombotic 1-benzopyran-4-ones and 2-amino-1,3-benzoxazine-4-ones - Google Patents

Abstract

ABSTRACT
This invention relates to compounds of Formula I

Description

~00~30~i ANTIATHEROSCLEROTIC AND ANTITHROMBOTIC l-BENZOPYRAN-4-ONES
AND 2-AMIN0-1,3-BENZ0XAZINE-4-ONES
BACKGROUND OF THE INVENTI0~
The present specification provides methods for use of pharmacologically active substances. Further the present specification provides novel compositions of matter and novel methods of their preparation.
Atherosclerosis in mammals is a disease characterized by the deposition of atherosclerotic plaque on arterial walls. While atherosclerosis e~hibits many varied forms and consequences, typical consequences of atherosclerotic diseases include angina pectoris, myocardial infarction, stroke and transient cerebral ischemic attacks. Other forms of atherosclerotic diseases include certain peripheral vascular diseases and other ischemias (e.g., bowel and renal).
Medical science now recognizes that certain forms of athero-sclerosis may be preventable or reversible. Agents capable of preventing or reversing atherosclerosis are characterized as exhibit-ing antiatherosclerotic activity. Since serum lipids have a recogni~ed associatisn with atherogenesis, an important class of antiatherosclerotic agents are those with serum lipid-modifying effects. Serum lipids implicated in atherogenesis include serum cholesterol, serum triglycerides, and serum lipoproteins.
With respect to serum lipoproteins, at least three different classes of these substances have been characterized; high density l~poproteins (HDL's), low density lipoproteins (LDL's), and very low density lipoproteins (VLDL's). HDL's are often referred to as alphalipoproteins, while LDL's and VLDL's are referred to as beta-lipoproteins. The enhancement of HDL levels ~hyperalphalipoprotein-emic activity) is postulated to have direct antiatheroscleroticeffects. See Eaton, R.P., J. Chron. Dis 31:131-135 (1978). In contrast, agents which reduce serum LDL's and serum VLDL's (hypobeta-lipoproteinemic agents) are also associated with antiathero~enic effects See Haust, M.D., "Reaction Patterns of Intimal Mesenchyme to Ir.jury and Repair in Atherosclerosis", Adv. Exp. Med. Biol. 43:35-57 (1974), which postulates that serum LDL is a factor in athero-sclerotic lesion formation.
Numerous animal models have been developed for assessin~

20()~306 antiatherosclerotic actlv~ty. Prlnclpal amon~ these are models for assesslng hypollpoprotelnemlc sctlvlty ln the rat and antlatherosclerotic activlty ln the Japanese quall. For a description of the operation of the hypobetalipoproteinemlc rat model, refer to the known methods of Schurr, P.E., e~ al., ~Hlgh Volume Screening Procedure for Lypobetalipoproteinemia Activity in Rats~, Adv. Exp. Med. Biol. 67: Atherosclerotic Drug Discovery, pp.
215-229, Plenum Press (1975). For a description of the Japanese quail model, see Day, C.E. et al., ~Utility of a Selected Line (SEA) of the Japanese Quail (Corturnic Corturnix ~aponica) for the Discovery of New Anti-Atherosclerosis Drugs~, Laboratory Animal Science 27:817-821 (1977).
2-Aminochromones (4H-l-benzopyran-4-ones) are known in the literature. For example, the antiallergic activity of 2-aminochromones has been described in the literature by Mazzei, Balbi,Ermili, Sottofattori and Roma (Mazzei, M., Ballbi, A., Ernili, A., Sottofattorl, E., Roma, G., Farmaco. Ed. Sci., (1985) 40, 895 and Mazzei, M., Ermili, A., Balbi, A., Di Braccio, M., Farmaco. Ed. Sci,, (1986), 41, 611; CA 106:18313w). The CNS activity of 2-amino-chromones has also been described (Balbi, A., Roma, G., Ermili, A., Farmaco. Ed. Sci., (1982) 37, 582; Ermili, A., Mazzei, M., Roma, G., Cacciatore, C., Farmaco. Ed. Sci., (1977), 32, 375 and 713). The nitro derivatives of various 2-aminochromones have recently been described (Balbi, A., Roma, G., Mazzei, M., Ermili, A., Farmaco. Ed.
25 Sci., (1983) 38, 784) and Farmaco. Ed. Sci., 41(7), 548-57. 2-Amino-3-hydroxychromones are described in DE 2205913 and GB 1389186.
U.S. Patent 4,092,416 ~see also DE 2555290 and CA 87:102383r) discloses various benzopyrone derivatives exhibiting anti-allergic activity, including 2-(2-[4-(2-methoxyphenyl)-piperazinyl-1~-ethyl)-30 5-methoxy-4-oxo-4H-l-benzopyran and 2-(2-[4-(2-methoxyphenyl)-piperazinyl-l]-ethyl)-5-(2-hydroxypropoxy)-4-oxo-4H-l-benzopyran.
JA-025657 and JP-259603 descrive various 2-amino-3-carboxamide derivatives and 3-phanyl (optionally substituted)-2-aminochromone derivatives as useful as oncostatic and immunosuppressive agents.
The pharmacomodulation of ~-adrenergic blocking agents by a series of benzopyrans, including 2-(1-piperidinylmethylene)-4H-l-benzopyran-4-one, is described in Eur. J. Med. Chem., 1987, 22(6), 539-44; CA 109:92718k.

Structurally, the closest compounds in the llterature to 2-(4-morpholinyl)-4H-l-benzopyra~-4-one (Cpd 2) i9 belie~ed to be the 3-hydroxy, 3-methoxy snd 3-acetyloxy analogues (l.e., 2-(4-morpholinyl)-3-hydroxychromono, 2-(4-morpholinyl)-3-methoxychromone and 3-(acetyloxy)-2-(4-morpholinyl)chromone) reportod by Elden and Docher (Eiden, F., Dolchor, D., Arch. Pharm. (Wo~nhelm Gor.) (197S) 308, 385) and DE 2205913; CA 83(11):96942w and CA79(19):115440s.
6,7-dimethoxy-2-(4-morphollnyl)chromone is disclosod in J. Chem.
Soc., Perklns Trans. 1, (2), 173-4; CA78(9);58275v. 3-Acetyl-2-(4-morpholinyl)chromone is disclosed in Arch. Pharm. 316(1), 34-42;
CA98(15):12915g.
3-hydroxy-2-[4-(2-hydroxyethyl)-1-piperazinyl]-4H-l-benzopyran-4-one and 3-hydroxy-2-(4-methyl-1-plperazlnyl)-4H-l-benzopyran-4-one are disclosed in Arch. Pharm 308(5), 385-8; CA83(11):96942w. 5,8-lS dlmethoxy-2-(4-methyl-1-piperazinyl)-4H-l-benzopyran-4-one is disclosed in J. Heterocycl. Chem., 18(4), 679-84; CA95(17):150348v.
The synthesis of 2-amlnochromones from the correspondln~ 2-sulphonyl and 2-sulphinyl analogues has been reported by Bantick and Suschitzky (Bantick, J.R., Suschitzky, J.L., J. Heterocyclic Chem., (1981) 18, 679). Also described in this report is the preparation of the HCL and H2S04 salts of several 2-aminochromones.
The anti-platelet activity of some 2-(dialkylamino)chromones, namely: 2-(diethylamino~-5,6-dimethyl-4H-l-benzopyran-4-one, 2-(diethylamino)-6,7-dimethyl-4H-l-benzopyran-4-one, 2-(diethyl-amino)-7-hydroxy-5-methyl-4H-l-benzopyran-4-one, 2-(diethylamino)-5-hydroxy-7-methyl-4H-l-benzopyran-4-one, 2-(diethylamino)-6-chloro-8-isopropyl-4H-l-benzopyran-4-one, 2-(diethylamino)-5,7-methoxy-4H-l-benzopyran-4-one, 2-(ethylamino)-5-hydroxy-4H-l-benzopyran-4-one, 2-(ethylamino)-7-hydroxy-4H-l-benzopyran-4-one, 2-~diethylamino)-7-hydroxy-6-nitro-4H-l-benzopyran-4-one, 2-(diethylamino)-4H-l-benzo-pyran-4-one, 2-(dimethylamino)-7-methoxy-4H-L-benzopyran-4-one, 2-(diethylamino)-7-methoxy-4H-l-benzopyran-4-one, 2-(1-pyrrolidinyl)-7-methoxy-4H-l-benzopyran-4-one, 2-(1-piperidinyl)-7-methoxy-4H-l-benzopyran-4-one, 2-(diethylamino)-7-hydroxy-4H-l-benzopyran-4-one, 2-(1-piperdinyl)-7-hydroxy-4H-l-benzopyran-4-one, 2-(ethylamino)-7-methoxy-4H-l-benzopyran-4-one, 2-(diethylamino)-5-hydroxy-4H-l-benzopyran-4-one, 2-(diethylamino)-5-methyl-8-isopropyl-4H-l-benzo-pyran-4-one, and 2-(diethylamino)-3-~4-morpohoinomethyl)-7-methoxy-200~306 4H-l-benzopyran-4-one, was reported by Mazzei et al. in Eur. J. Med.
Chem. 23, 237-242 (May-June 1988); CA 110:75246h.
The literature on the use of an yn~mlne in the Jynthesi- o a 2--~ aminochromones has been reported by Tronchet, Bachler and Bonenfant (Tronchet, J.M. J., Bachler, B., Bonenfant, A., Hel~. Chim. Acta.
(1976), 59, 941). In this report, a 2-amino-3-glycosylchromone ~as prepared.
'~ 2-A~ino-1,3-benzoxazin-4-ones are also known in the literature.
Specifically, 2-morpholinyl-4H-1,3-benzoxazln-4-one (Cpd 98) and 8-10 methyl-2-(4-morpholinyl)-4H-1,3-benzoxazin-4-one (Cpd 84) are described in Netherlants patent application 6,412,966 (see also U.S.
3,491,092), and in the literature (Grigat, E., Putter, R., Schneider, K., WedeDeyer, K., Chem. Ber., (1964) 97, 3036).
The fungicide and analgesic activity of 2-amino-1,3-benzoxazin-15 4-ones are also claimed by Sankyo in Japn. Tokkyo Roho 79 20,504 (CA
91:157755b) and in Japan (Kokai 72, 17,781 (CA 77:140107e). These patents appear to cover 2-(4-morpholinyl)-4H-1,3-benzoxazin-4-one (Cpd 98) and 6,7-substituted-2-(4-morpholinyl) analogues for the above indications.
The synthesis of 2-dialkylamino-1,3-benzoxazin-4-ones has been described by Kokel et al (see Tet. Letters (1984) 3837).
2-N-Alkyl and 2-N-aryl-1,3-benzoxazin-4-ones have been described by Palazzo and Giannola (Palazzo, S., Giannola, L.I., Atti. Accad.
Sci. Lett. Arti Palermo, Parte 1, (1976) 34(2), 83-7).
2-~enzamidino-1,3-benzoxazin-4-one have been described by Brunetti, H., and Luthi, C.E. (in Helv. Chim. Acta., (1972) 55, 1566).
BRIEF DESCRIPTION OF THE INVENTION
This invention relates to compounds of the Formula I which are useful in association with a pharmaceutical carrier as antiatherosclerotic agents. In addition, various compounds of the Formula I are useful inhibitors of cell proliferation and/or platelet aggregation.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of this invention are represented by Formula I
wherein X is N, or CZ where Z is H, Cl-C5 alkyl, amino (-NH2) or a halogen atom;

~006306 .s.
when X is CZ, Y i9 selected from the group consisting of -(CH2)nNRgRlo wherein Rg and Rlo, being the same or different, are selected from the ~roup consisting of (8) hydrogen, with the provisio that Rg and Rlo are not both hYdr8en; (b) Cl-C12 alXyl; (c) phenyl optionally substituted with one, 2 or 3 Cl-C4 alkyl, Cl-C4 alkoxy, halo, OH, trifluoromethyl or -C02(Cl-C4 alkyl); (d) -(CH2)nphenyl [wherein phenyl is optionally substituted with one, 2 or 3 Cl-C4 alkyl, Cl-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(Cl-C4alkyl)], (e) -(CH2)npyridinyl or (f) wherein Rg and Rlo, taken together with N, form a saturated or unsaturated heterocyclic amine ring selected fron the group consisting of (aa) 4-morpholine optionally substituted with one or two members selected from the group consisting of Cl-C4 alkyl, Cl-C4 alkoxy, halo or trifluoromethyl (bb) 4-thiomorpholine optionally substituted with one or two members selected from the group consisting of Cl-C4 alkyl, Cl-C4 alkoxy, halo or trifluoromethyl (cc) 3-amiro-1-pyrrolidine, (dd) l-pyrrolidine optionally substituted with one or two members selected from the group consisting of Cl-C4 alkyl, Cl-C4 alkoxy, halo, OH, -CH2OH, or trifluoromethyl (ee) l-piperidine optionally substituted with one or two members selected from the group consisting of Cl-C4 alkyl, Cl-C4 alkoxy, halo, trifluoromethyl, -(CH2)qOH, -CO2H, -CO2CH3 -CO2CH2CH3 or phenyl (wherein phenyl is optionally substituted with one, 2 or 3 Cl-C4 alkyl, Cl-C4 alkoxy, halo or trifluoromethyl), (ff) l-piperazine, 4-methyl-l-piperazine, 4-(cycloC3-C6alkyl)-l-piperazine, 4-phenyl-1-piperazine (wherein phenyl is optionally substituted with one, 2 or 3 Cl-C4 alkyl, Cl-C4 alkoxy, halo or trifluoromethyl) or 4-pyridinyl-l-piperazine optionally substituted with one or two members selected from the group consisting of Cl-C4 alkyl, Cl-C4 alkoxy, halo, OH, trifluoromethyl, -CH2OH~ -CO2H, -Co2cH3 or -CO2CH2CH3, and .. . _ .. . . . . .

(gg) thiazolldlns, thlazolldlne-4-carboxyllc acid, plpecollnlc acld, p-plperazinaceto-phenone, l-homopiperazlne, 1-methylhomoplperazlne, 4-phenyl-1,2-3,6-S tetrahydropyridine, proline, tetra-hydrofurylamine, 1-(3-hydroxy)pyrrol~dine, nipecota~ide, 1,2,3,4-tetrahydroisoquinoline or imidszole;
and R5, R6, R7 and Rg, being the same or dlfferent, are æelected from the group consisting of hydrogen, Cl-C8 alkyl, -(cH2)nphenyl Iwherein phenyl is optionally substituted with one, 2 or 3 Cl-C4 alkyl, Cl-C4 alkoxy, halo, OH, trifluoromethyl or -C02(Cl-C4alkyl)], -(CH2)nnaphthyl, -(CH2)npyridinyl, -(CH2)qNRgRlo, -CH-CH-phenyl [wherein phenyl i8 optionally sub-stituted with one, 2 or 3 Cl-C4 alkyl, Cl-C4 alkoxy, halo, OH, trifluoromethyl or -C02(Cl-C4alkyl)], -CH2-CH-CH2, -CH-CH-CH3, -O-CH2-CH-CH2, -C C-phenyl [wherein phenyl i8 optionally sub-stituted wlth one, 2 or 3 Cl-C4 alkyl, Cl-C4 alkoxy, halo, OH, trifluoromethyl or -C02(Cl-C4alkyl)], -O(CH2)p(N-methylpiperdin-3-yl) -o (CH2)pNR9Rlo~ -o-CH2CH(OCH3)2. --(cH2)PoRl5 [wherein R15 ls selected from Cl-C5 alkyl, -(CH2)nphenyl [phenyl optionally substituted with one, 2 or 3 Cl-C4 alkyl, Cl-C4 alkoxy, halo, OH, trlfluoromethyl or -C02(Cl-C4alkyl)], -(CH2)npyridin-1-yl or -(CH2)ppiperidin-l-yl]~ -(CH2)nC(O)-(CH2)nRg~ ~(CH2)nC(O)O~(CH2)pR9~ -(cH)nc(o)o-(cH2)pNR9R
- (CH2)nC(O) (CH2)nNRgRlo ~ N2 . -O- (CH2)nC() ~ (CH2)pR9 (CH2)nC()o-(CH2)pR9~ -O-(CH2) * (0)-(CH2)nNRgRlo~ -NRgR
-N(Rg)(CH2)nC(O)~(cH2)nRlo~ -N(Rg)-(CH2)nC(O)O~(cH2)nRlo~
N(R9)(CH2)nC(O)~(CH2)nNRgRlo, -O-(CH2)nphenyl [wherein phenyl ls optionally substituted with one, 2 or 3 Cl-C4 alkyl, Cl-C4 alkoxy, halo, OH, trifluoromethyl or -C02(Cl-C4alkyl)], -O-(CH2)npyrldine, -O(CH2)nC(O)-(CH2)npyridine, -O-(CH2)nC(O)O-(cH2)npyridine, ~o(cH2)nc(o)-N(Rg)(cH2)npyridine~
-O-(CH2)nqulnoxallnyl, -0-(CH2)nqulnolinyl, -0-(CH2)npyrazinyl, -o-(cH2)nnaphthyl~ ~-(CH2)nc()~(cH2)nnaPhthyl~
-O-(CH2)nC(O)O-(CH2)nnaphthyl, -O-(CH2)nC(O)NRg-(CH2)nnaphthyl, halo (fluoro, chloro, bromo, iodo), OH, ~(CH2)q~0H~
(CH2)qOC(O~Rg, -~CH2)qOC(O)-NRgRlo, (l-cyclohexyl-lH-tetrazol-5-yl)Cl~C4 alkoxy, -[l-(cl-csalkyl)-lH-tetrszol-5-yl]cl-c4 alkoxy, -[l-(phenyl)-lH-tetrazol-5-yl]cl-c4 alkoxy [wherein phenyl is optionally substituted with one, 2 or 3 Cl-C4 alkyl, Cl-C4 alkoxy, halo, OH, trifluoromethyl or -C02(Cl-C4alkyl)], -[1-(pyridinyl)-lH-tetrazol-5-yl~Cl-C4 alkoxy, -[l-(l-phenylethyl)-lH-tetrazol-5-yl]Cl-C4 alkoxy, -Cl-C4 alkoxyl, or a group of Formula Il (see Formula Sheet) wherein R' is methyl or carboxy, R'' is hydrogen and R''' is selected from benzyl [optionally substituted with one, two or three groups selected from hydroxy, halogen or phenoxy (optionally substituted with one, two or three groups selected from hydroxy or halo~en)], Cl-C5 alkyl, -(CH2)nC02H, -CH2SH, -CH2SCH3, imidazolinylmethylens, indolinylmethylene, CH3CH(OH), CH20H. H2N(CH2)4-(optionally in protected form) or H2NC(NN)NH(CH2)3 (optionally in protected form); with the overall pro~iso that when Y is other than -(CH2)nmorpholinyl, at least one member of Rs, R~, R7 or R8 is other than hydrogen, Cl-C8 alkyl, N02, OH, Cl-C4 alkoxy, a halogen atDm, phenyl, benzyl, 4-morpholinylmethyl, NH2, or dimethyamino; with the further proviso that when Y is 4-morpholinyl, the compound is other than:

6,7-dimethoxy-2-(4-morpholinyl)^4H-l-benzopyran-4-one, 7,8-(Bis)-(3-trifluoromethyl)phenylmethoxy-2-(4-morpholinyl)-4H-l-benzopyran-4-one, N-cyclohexyl-2-[[8-methyl-2-(4-morpholinyl)-4-oxo-4H-l-benzopyran-7-yl]oxy]-acetamide, 2-[[8-methyl-2-(4-morpholinyl)-4-oxo-4H-l-benzopyran-7-yl]oxy]-N-phenyl-acetamide, 6-[(1-cyclohexyl-lH-tetrazol-5-yl)methoxy]-2-(4-mor-pholinyl)-4H-l-Benzopyran-4-one, 2-[lô-methyl-2-(4-morpholinyl)-4-oxo-4H-l-benzopyran-7-yl]oxy]-N-(l-phenylethyl)-acetamide;
with the further provisio that when Y is dimethylamino, the compound is other than:
2-(Dimethylamino)-8-methyl-4-oxo-4H-l-benzopyran-7-yl carbamic acid dimethyl ester, (Dimethylamino)-4-oxo-4H-l-benzopyran-6-yl carbamic acid dimethyl ester, 200~.306 2-(Dimethylamino)-4-oxo-4H-l-benzopyran-7-yl carbamic acid dlmethyl ester;
when X is N, Y is selected from the group consisting of -NRgRlo wherein Rg snd Rlo, being the sa~e or dlfferent, are selected from the group consisting of (a) hydrogen, with the provisio that Rg and Rlo are not both hydrogen;
(b) Cl-C12 slkyl; (c) phenyl optionally substituted with one, 2 or 3 Cl-C4 alXyl, Cl-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(Cl-C4alkyl); (d) -(CH2)nphenyl [wherein phenyl is optionally substituted with one, 2 or 3 Cl-C4 alkyl, Cl-C4 alkoxy, halo, OH, trifluoromethyl or-CO2(Cl-C4alkyl)], (e) -(CH2)npyridinyl or (f) wherein Rg and Rlo, taXen together with N, form a saturated or unsaturated heterocyclic amine ring selected from the group consisting of (aa) 4-morpholine optionally substituted with one or two members selected from the group consisting of Cl-C4 alkyl, Cl-C4 alkoxy, halo or trifluoromethyl (bb) 4-thiomorpholine optionally substituted with one or two members selected from the group consisting of Cl-C4 alkyl, Cl-C4 alkoxy, halo or trifluoromethyl (cc) 3-amino-1-pyrrolidine, (dd) l-pyrrolidine optionally substituted with one or two members selected from the group consisting of Cl-C4 alkyl, Cl-C4 alkoxy, halo, OH, -CH2OH, or trifluoromethyl (ee) l-piperidine optionally substituted with one or two members selected from the group consisting of Cl-C4 alXyl, Cl-C4 alXoxy, halo, trifluoromethyl, -(CH2)qOH, -CO2H, -CO2CH3 -CO2CH2CH3 or phenyl (wherein phenyl is optionally substituted with one, 2 or 3 Cl-C4 alXyl, Cl-C4 alkoxy, halo or trifluoromethyl), (ff) l-piperazine, 4-methyl-1-piperazine, 4-phenyl-1-piperazine (wherein phenyl is optionally substituted with one, 2 or 3 Cl-C4 alkyl, Cl-C4 alXoxy, halo or trifluoromethyl) or 4-pyridinyl-1-piperazine optionally substituted with one or two .. . , . . . .. . . . ... ,~, . . . . . ., "._ . . . . ..

;;i ~) O ~ii 3 ~

members selected from the group consisting of Cl-C4 alkyl, Cl-C4 alkoxy, halo, OH, trifluoromethyl, -CH2OH -CO2H, -CO2CH3 or -CO2CH2CH3~ and ~g~) thiazolidine, thiazolidine-4-csrboxyllc acid, pipecolinic acid, p-piperazinaceto-phenone, l-homopiperazine, 1-methylhomopiperazine, 4-phenyl-1,2-3,6-tetrahytropyridine, proline, tetra-hydrofurylamine, 1-(3-hydroxy)pyrrolidine, nipecotamide, 1,2,3,4-tetrahydroisoquinoline or imidazole;
and R5, R6, R7 and Rg, being the same or different, are selected from the group consisting of hydrogen, Cl-Cg ~lkyl, -(CH2)nphenyl [wherein phenyl is optionally substituted with one, 2 or 3 Cl-C4 alkyl, Cl-C4 alkoxy, halo, OH, trifluoromethyl or -CO2~Cl-C4alkyl)], -(CH2)nnaphthyl, -(CH2)npyridinyl, -(CH2)qNRgRlo, -CH-CH-phenyl [wherein phenyl is optionally sub-~tituted with one, 2 or 3 Cl-C4 alkyl, Cl-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(Cl-C4alkyl)], -CH2-CH-CH2, -CH-CH-CH3, -O-CH2-CH-CH2, -C~C-phenyl [wherein phenyl is optionally sub-stituted wi~h one, 2 or 3 Cl-C4 alkyl, Cl-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(Cl-C4alkyl)], -O(CH2)p(N-methylpiperdin-3-yl) -O-(CH2)pNR9Rlo, -O-cH2CH(0cH3)2. --(cH2)PoRls [wherein Rls is selected from Cl-C5 slkyl, -(CH2)nphenyl [phenyl optionally substituted with one, 2 or 3 Cl-C4 alkyl, Cl-C4 ~lkoxy, halo, OH, trifluoromethyl or -CO2(Cl-C4alkyl)], -(CH2)npyridin-1-yl or -(CH2)ppiperidin-l-yl]~ -(CH2)nc(o) (CH2)nRg~ -(CH2)n(;(0)0-(CH2)pRg, -(CH)nC(O)O-(CH2)pNRgRlo, ~ (CH2)nC() (CH2)nNR9R10. N02 . -O- (CH2)nC(O) - (CH2)pRg, -O-(CH2)nC(0)0-(cH2)pRg~ --(CH2)nC()-(CH2)nNR9~10~ NR9R10--N(Rg)(CH2)nc(0)-(cH2)nRlo~ -N(Rg~-(CH2)nc(O)o-(cH2)nRlo~
N(R9)(CH2)nC()~(CH2)nN~9R10. -O-(CH2)nphenyl [wherein phenyl is optionally substituted with one, 2 or 3 Cl-C4 alkyl, Cl-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(Cl-C4alkyl), -O-(CH2)npyridine, -O(CH2)nC(O)-(CH2)npyridine, -O-(CH2)nC(O)O-(CH2)npyridine, -o(cH2)nc(o)-N(R9)(cH2)npyridine~
-O-(CH2)nquinoxalinyl, -O-(CH2)nquinolinyl, -O-(CH2)npyrazinyl, -O-(CH2)nnaphthyl, -O-(CH2)nC(O)~(CH2)nnaPhthyl~

. ..

~00~306 -O-(CH2)nC(O)O-(CH2)nnaphthyl, -O-(CH2)nC(O)NRg-(CH2)nnaphthyl, halo (fluoro, chloro, bromo, iodo), OH, ~(CH2)q~0H~
(CH2)qOC(O)~g, -(CH2)qOC(O)-NRgRlo, (l-cyclohexyl-lH-tetrazol-5-yl)Cl~C4 alkoxy, -[1-(Cl-Csalkyl)-lH-tetrazol-5-yl]C1-C4 alkoxy, -[l-(phenyl)-lH-tetrazol-5-yl]cl-c4 alkoxy [whereln phenyl is optionally substituted with one, 2 or 3 Cl-C4 alkyl, Cl-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(Cl-C4alkyl)], -[l-(pyridinyl)-lH-tetrazol-5-yl]Cl-C4 alkoxy, -[l-(l-phenylethyl)-lH-tetrazol-5-yl]Cl-C4 alkoxy, or -Cl-C4 alkoxyl, or a group of Formula II (see Formula Sheet) wherein R' is methyl or carboxy, R'' is hydrogen and R''' is selected from benzyl [optionally substituted with one, two or three groups selected from hydroxy, halogen or phenoxy (optionally substituted with one, two or three groups selected from hydroxy or halogen)], Cl-Cs alkyl, ~(CH2)ncO2H~ -CH2SH~
-CH2SCH3, imidazolinylmethylene, indolinylmethylene, CH3CH(OH~, CH2OH, H2N(CH2)4-(optionally in protected form) or H2NC(NH)NH(CH2)3 (optionally in protected form);
n is 0-5, preferably 0 or one;
p is 2-5, preferably 2 or 3;
q is 1-5, preferably 1 or 2;
and pharmaceutically acceptable salts thereof.
X is preferably CZ where Z is H or Cl-C5 alkyl, more preferably H or methyl, most preferably H.
When X is CZ, Y is ?referably selected from the group consiting of -(CH2)nNRgR1o wherein Rg and Rlo, taken together with N, form a saturated or unsaturated heterocyclic amine ring selected from the group consisting of:
(a,a) 4-morpholine optionally substituted with one or two members selected from the group consisting of Cl-C4 alkyl, Cl-C4 alkoxy, halo or trifluoromethyl (bb) 4-thiomorpholine optionally substituted with one or two members selected from the group consisting of C1-C4 alkyl, Cl-C4 alkoxy, halo or trifluoromethyl ~cc) 3-amino-1-pyrrolidine, (dd) 1-pyrrolidine optionally substituted with one or two members selected from the group consisting of Cl-C4 `' 2006306 alkyl, Cl-C4 alkoxy, halo, OH, -CH2OH, or trifluoromethyl (ee) l-piperitine optionally substituted with one or two members selected from the group consisting of Cl C4 alkyl, Cl-C4 alkoxy, halo, trifluoromeehyl, -(CH2)qOH, -CO2H, -CO2CH3 -CO2CH2CH3 or phenyl ~wherein phenyl is optionally subctituted with one, 2 or 3 Cl-C4 alkyl, Cl-C4 alkoxy, halo or trifluoromethyl), and (ff) l-piperazine, 4-methyl-l-pipera~ine, 4-phenyl-l-piperazine (wherein phenyl is optionally substituted with one, 2 or 3 Cl-C4 alkyl, Cl-C4 alkoxy, halo or trifluoromethyl) or 4-pyridinyl-1-piperazine optionally substituted with one or two members selected from the group consisting of Cl-C4 alkyl, Cl-C4 alkoxy, halo, trifluoromethyl, -CH2OH,-CO2H, -CO2CH3 or -CO2CH2CH3 When X is CZ wherein Z is H or Cl-C5 slkyl (most preferably H), Y is more preferably selected from the group consisting of -(CH2)nNRgRlo wherein n is O or 1 (most preferably 1) and Rg and Rlo, taken together with N, form:
(aa) morpholine (preferably 4-morpholine) optionally substituted with one or two members selected from the group consisting of Cl-C4 alkyl or phenyl (wherein phenyl is optionally subseituted with one or 2 Cl-C4 alkyl, Cl-C4 alkoxy, halo or trifluoromethyl);
and preferably, at least one member selected from R5, R6, R7 or R8 is selected from:
the group consisting of -(CH2)pphenyl [wherein phenyl is optionally substituted with one, 2 or 3 Cl-C4 alkyl, Cl-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(Cl-C4alkyl)], -(CH2)nnaphthyl, -(CH2)npyridinyl, -(CH2)qNRgRlo, -CH-CH-phenyl [wherein phenyl is optionally substituted with one, 2 or 3 Cl-C4 alkyl, Cl-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(Cl-C4alkyl)], -CH2-CH CH2, -CH CH-CH3, -O-CH2-CH~CH2, -C-C-phenyl [wherein phenyl is optionally substituted wlth one, 2 or 3 Cl-C4 alkyl, Cl-C4 alkoxy, halo, OH, trifluoromethyl or -C~2(Cl-C4alkyl) ], 2006:~06 -O(CH2)p(N-methylpiperdin-3-yl), -O (CH2)pNR9Rlo, -O-CH2CH(0CH3)2~ -O-(CH2)pOal5 [wherein Rls is selected from Cl-Cs alkyl, -(CH2)nphenyl [phenyl optionally substituted with one, 2 or 3 Cl-C4 alkyl, Cl-C4 alkoxy, halo, OH, trlfluoromethyl or -CO2(Cl-C4alkyl)], -(CH2)npyridin-l-yl or -(CH2)ppipe~ldin-l-yl], - (CH2)nC(O) - (CH2)nRg, - (CH2)nC(O)O- (CH2)pR9 ~, - (CH)nC(O)O~
(CH2)pNRgRlo, -(CH2)nC(O)(CH2)nNRgRlo, -O-(CH2)nC(O)-(CH2)pRg, -O- (CH2)nC(O)O- (CH2)pRg, -O- (CH2)nC(O) - (CH2)nNRgR
-~RgRlo, -N(Rg)(CH2)nC(O)~(cH2)nRlo~ -N(~g)-(CH2)nC(O
(CH2)nR10~ N(Rg)~CH2)nC(O)-(CH2)nNR9R10. -O-(CH2)nphenYl [wherein phenyl is optionally substitut~d with one, 2 or 3 Cl-C4 alkyl, Cl-C4 alkoxy, halo, OH, trifluoromethyl or -C02(Cl-C4alkyl)]~ -O-(CH2)nPyridine~ -o(cil2)nc(o) (CH2)npyridine, -O-(CH2)nC(O)O-(CH2)npyridine, -O(CH2)nC(O)-N(Rg)(CH2)npyridine, -O-(CH2)nquinoxalinyl, -O-(CH2)nquinolinyl, -O-(CH2)npyrazinyl, -O-(CH2)nnaphthyl, -O-(CH2)nC(O)~(CH2)nnaPhthYl~
-O-(CH2)nC(O)O-(CH2)nnaphthyl, -O-(CH2)nC(O)NRg-(CH2)nnaphthyl, ~(CH2)q~0H~ (CH2)qOC(O)Rg, -(CH2)qOC(O)-~RgRlo, (l-cyclohexyl-lH-tetrazol-5-yl)Cl-C4 alkoxy, -[1-(Cl-C5alkyl)-lH-tetrazol-5-yl]Cl-C4 alkoxy, -[l-(phenyl)-lH-tetrazol-5-yl]cl-c4 alkoxy [wherein phenyl is optionally substituted with one, 2 or 3 Cl-C4 alkyl, Cl-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(Cl-C4alkyl)], -[l-(pyridinyl)-lH-tetrazol-5-yl]Cl-C4 alkoxy, -[l-(l-phenylethyl)-lH-tetrazol-5-yl]Cl-C4 alkoxy, or -Cl-C4 alkoxyl;
more preferably, (i) R5, R6, R7 and R8 are each hydrogen; or (ii) R5, R6, and R8 are each hydrogen, and R7 is selected from:
-O-(CH2)nphenyl twherein phenyl is optionally substituted with one, 2 or 3 Cl-C4 alkyl, Cl-C4 alkoxy, halo or tri-fluoromethyl), -C-C-phenyl ~wherein phenyl is optionally substituted with one, 2 or 3 Cl-C4 alkyl, Cl-C4 alkoxy, halo or trifluoromethyl), or -(CH2)nphenyl (wherein phenyl is optionally substituted with one, 2 or 3 Cl-C4 alkyl, Cl-C4 alkoxy, halo or trifluoromethyl); or (iii) R5 and R6 are hydrogen, R8 is hydrogen, halo or Cl-Cs alkyl, and R7 is selected from: -O-(CH2)nphenyl (wherein phenyl is optionally substituted with one, 2 or 3 Cl-C4 2001i306 alkyl, Cl-C4 alkoxy, halo or trifluoromethyl), -O-(CH2)npyridinyl (wherein pyridinyl is optlonally substituted with one, 2 or 3 Cl-C4 alkyl, Cl-C4 alkoxy, halo or trifluoromethyl), -O-(CH2)nnaphthyl, -(CH2)nphenyl (wherein phenyl ls optionally substituted with one, 2 or 3 Cl-C4 alkyl, Cl-C4 alkoxy, halo or trifluoromethyl), -(CH2)ppyridinyl (wherein pyridinyl is optionally substituted with one, 2 or 3 Cl-C4 alkyl, Cl-C4 alkoxy, halo or trifluoromethyl), -(CH2)p(1-piperidinyl)~
-(CH2)p(1-pyrrolidinyl) or -~(1-cyclohexyl-lH-tetrazol-5-yl)Cl-C4 alkoxy; or (iv) Rs, R7 and R8 are each hydrogen, and R6 is -NH-C(O)-O-CH2phenyl.
X is most preferably CH.
Y is ~ost preferably 4-morpholinyl.
R8 is preferably hydrogen or Cl-Cs alkyl, more preferably hydrogen or methyl.
Accordingly the present invention includes the novel 2-amino(4H)-l-benzopyran-4-ones and 2-aminoalkyl(4H)-l-benzopyran-4-ones of Formula I when X is CZ and the antiatherosclerotic utility of said compounds as well as the antiatherosclerotic utility of the known compounds of Formula I, including the 2-amino-1,3-benzoxazine-4-ones of Formula IB.
The carbon content of various hydrocarbon containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix Ci-C; indicates a carbon atoms content of the integer "in to the integer ~;n carbon atoms, inclusive. Thus, Cl-C3 alkyl refers to alkyl of 1-3 carbon atoms, inclucive, or methyl, ethyl, propyl, and isopropyl.
With respect to the above, Cl-C4 alkyl is methyl, ethyl, propyl, or butyl, including isomeric forms thereof. Similarly, Cl-C6 alkyl is methyl, ethyl, propyl, butyl, pentyl, hexyl, and isomeric forms thereof.
The term "halo" includes fluoro, chloro, bromo and iodo.
Examples of Cl-Cg alkylthiomethyl are methylthiomethyl, ethylthiomethyl, propylthiomethyl, butylthiomethyl, pentylthiomethyl, hexylthiomethyl, and heptylthiomethyl, and isomeric forms thereof.
Examples of Cl-Cg alkoxymethyl are methoxymethyl, ethoxymethyl, propoxyoothyl, butoxymethyl, pentoxyoothyl, butoxyoothyl, pentoxymothyl, hexoxymethyl, and heptoxy~othyl, nd lsomerlc forms thereof - Exa~plos of h-t-rocyllc ~lnos corro-pondlng to heterocycllc amine rlngs accordlng to -NRgNlo are 4-morphollne, 4-phenyl-1-piperazino, 4-(2-pyrldlnyl)-1-plperazlno, 2,6-dimethyl-4-morpholine, l-pyrrolidine, 4-methyl-1-piperazine, l-piperidino, 4-phenyl-1-piperidine thiazolidine, 3-piporidine methanol, 2-piperidino methanol, pipecolic acid, 3-piperidino othanol, 2-piperidine ethanol, l-piperazine propanol, p-piperazinoacetophenone, 4-phenyl-1,2,3,6-tetrahydropyridin , 4-phonylpiperidine, proline, 1-(3-hydroxy)pyrrolidine, tetrahydrofurylamine, pyrrolidioethanol, 3-pyrroline, thiazolidine-4-carboxylic acid, thiomorpholine, nipecotamide, 2-methylpiperidine, 3-metbylpiperidine, 4-methylpiperidine, N-methylpiperazine, l-methylhomopiperazine, l-acetylpiperazine, N-carboethoxypiperazine, 3-methylpiperazine-2-carboxylic acid, 2-methylpiperazine, 2,3,5,6,-tetra~ethylpiperazine, 1,4-dimethylpiperazine, 2,6-dimethylpiperazine, 2-methyl-1-phenylpiperazine, l-(l-phenylethyl)piperazine, 1-(2-pyrazinyl)piperszine, 1-cyclopropylpiperazine, l-cyclobutylpiperazine, 1,2,3,4-tetrahydroisoquinoline, imidazole, homopiperdine, and pharmaceutically acceptable salts and hydrates thereof.
Examples of -O(CH2)p(N-oethylpiperdin-3-yl) include (2-(N-methylpipordin-3-yl)ethyl)oxy, (3-(N-nethylpiperdin-3-yl)propy)loxy, (4-(N-methylpiperdin-3-yl)butyl)oxy.
Examples of -o~(cH2)pNR9Rlo include (2-(1-piperidinyl)ethyl)oxy, (2-(4-morpholinyl)ethyl)oxy, (2-(1-pyrrolidinyl)ethyl)oxy, (3-(N-methylpiperazinyl)propyl)oxy, (4-(N-ethyl-N-phenylamino)butyl)oxy, (5-(diethylanino)pentyl)oxy, (2-(4-benzylpiperazinyl)ethyl)oxy, and (3-~N,N-diisopropyl)propyl)oxy.
Examples of 0-(CH2)pORls include (2-methoxyethyl)oxy, (3-butoxypropyl)oxy, (4-phenoxybutyl)oxy, (2-benzyloxyethyl)oxy, (2-(2-(l-piperidinyl)ethoxy)ethyl)oxy and (3-(3-picolylmethoxy)propyl)oxy.
Examples of -(CH2)npyridinyl include 2-pyridyl, 3-pyridylmethyl and 4-pyridylethyl.
Examples of -(CH2)npiperdinyl include l-piperidinyl, 1-peiperidinylmethyl, 2-(1-piperidinyl)ethyl and 3-(1-piperidinyl)propyl.
Examples of -(CH2)qNR9R10 include (l-piperidinyl)methyl, 2-(4-morpholinyl)ethyl, 3-(1-pyrrolindinyl)propyl and 4-(1-piperazinyl)butyl.
Examples of -(CH2)nC(0)-(CH2)nRg include acetyl, acetylmethyl, methylacetylmethyl, methylacetylethyl, phenylacetyl, phenylacetylmethyl, 2-(phenylacetyl)ethyl, 2-pyridylacetyl, 3-pyridylacetylmethyl, 3-(t-butylacetyl)propyl and 4-(ethylacetyl)butyl.

-16~
Examples of -(CH2)nC(O)O-(CH2)pRg include carbomethoxy, carbomethoxymethyl, 2-(carbomethoxy)ethyl, carbophenylmethoxy, carbophenylmethoxymethyl, 2-(carbo(3-pyridyl)methoxy)ethyl, carboethoxymethyl and 3-(carbopropoxy)propoxy.
Exa~ples of (cH2)nC(o)o-(cH2)pNR9Rlo include -C(0)0-(CH2)2N(ethyl)2~ -(CH2)C(O)O-(CH2)2N(CH3)(phenyl)~ -(CH2)3c(o)o-(CH2)3(1-pyrrolidine), -(CH2)3C(O)O-(CH2)2(1-piperidinyl), and -(CH2)C(O)O-(CH2)2(4-morpholinyl).
Examples of -(cH2)nc(o)(cH2)nNR9Rlo ~nclude 10 -(CH2)C(O)(CH2)N(ethyl)2, -(CH2)2C(O)(CH2)2N(~ethyl)(phenyl), -C(O)(l-pyrrolidine), -(CH2)2C(O)(CH2)3(1-piperidine), and -(CH2)3C(O)(CH2)(4-morpholine).
Examples of -0-(CH2)nC(0)-(CH2)pRg include -0-(CH2)C(0)-(CH2)(CH3), -O C(0)-(CH2)2(CH3), -O-(CH2)3C(O)-(CH2)phenyl, 15 -O-(CH2)2C(O)-(CH2)3(2-pyridyl), -O-(CH2)C(O)-(CH2)2(3-pyridyl) and -O- (CH2)4C(O) - (CH2)4(t-butyl) -Examples of -0-(CH2)nC(O)0-(CH2)pRg include -O-(CH2)C(0)0-(CH2)(CH3)~ -O-C(O)0-(CH2)2(CH3). -O-(cH2)2c(o)o-(cH2)3(phenyl) and -O- (CH2)3C(O)O- (CH2)2(3-pyridyl) -Examples Of - (CH2)nc(O)~(cH2)nNRgRlo include -0-(CH2)C(O)-(CH2)N(CH3)2~ -0-C(0)-(CH2)(1-pyrrolidine), -O-(CH2)C(O)-(l-plperidine), -O-(CH2)2C(O)-(CH2)(1-N-methylpiperazine), (CH2)2C()-(cH2)2(4-morpholine), -O-(CH2)C(O)-(CH2)3(cyclohexylamine), -0-(CH2)2C(O)-(CH2)3(t-butylamine), -O-(CH2)C(O)-(CH2)2(1-phenylethylamine), -O-(CH2)C(O)-(CH2)2(aniline), -0-(CH2)C(0)-(CH2)(L-phenylalanine ethyl ester) and -O- (CH2)2nC() - (cH2)3(3-pyridylamine) .
Examples of -N(Rg)(cH2)nc(O)-(cH2)nRlo include -N(CH3)C(O)-(CH3), -N(H)(CH2)2C(0)-(CH2)(PhenYl). -N(H)(CH2)C(0)-(CH2)2(3-30 pyridyl) and -N(CH3)~CH2)3C(0)-(CH2)(CH3).
Examples of -N(Rg)-(CH2)nC(0)0-(CH2)nRlo include -N(H)-(CH2)C(O)O-(CH3), -N(H)-(CH2)2C(O)O-(CH2)(benzyl), -N(H)-(CH2)2C(O)O-(CH2)(3-pyridyl) and -N(CH3)-(CH2)C(O)O-(CH2)2(t-butyl).
Examples of -N(R9)(cH2)nc(o)-(cH2)nNR9Rlo incl~de -N(H)(CH2)C(0)-(cH2~N(cH3)2. ~N~H)c(o)-(cH2)(l-pyrrolidine)~
-N(H)(CH2)2C(0)-(CH2)2(1-piperidine), and -N(CH3)(CH2)C(O)-(CH2)2(4-morpholine), Examples of -0-(CH2)nphenyl include 2-(4-trlfluoromethylphenyl)ethoxy, 4-chlorophenoxy, 4-fluorophenylmethoxy, 3-(4-methoxyphenyl)propoxy, 4-(2-methyl-4-fluorophenyl)butoxy, 2-(2-methoxyphenyl)ethoxy, 3-methoxyphenylmethoxy,4-carbooethoxyphenylmethoxy, 2-(3,4-5 dichlorophenyl)ethoxy, 4-ethoxyphenylmethoxy, 3-(4-nitrophenyl)propoxy, 4-t-butylphenylmethoxy, 4-benzyloxyphenylmothoxy and 2-(3-triflouro-ethylphenyl~ethoxy.
Examples of -O-(CH2)npyridine include 2-pyridyloxy, 3-pyridyl~ethoxy and 2-(4-pyridyl)ethoxy.
Examplos of -O(CH2)nC~O)-(CH2)npyridine include -O(CH2)C(O)-(CH2)(2-pyridine), -O(CH2)3C(O)-(CH2)(3-pyridine) and -O(CH2)2C(O)-(CH2)3(4-pyridine), Examples of -O-(CH2)nC(O)O-(CH2)npyritine include -O(CH2)C(O)0-(CH2)(2-pyritine), -O(CH2)3C(O)O-(CH2)(3-pyridine) and lS -O(CH2)2C(O)O-(CH2)3(4-pyridine).
Examples of -O(CH2)nC(O)-N(Rg)(CH2)npyridine include ~(CH2)C()~N(CH3)(CH2)(2-pyridine), -o(CH2)2C(O)-N(CH3)(cH2)(3-pyridine) and -O(CH2)C(O)-N(benzyl)(CH2)2(4-pyridine).
Examples of -O-(CH2)nquinoxalinyl include 2-quinoxalinyloxy, 2-quinoxalinylmethoxy and 2-(2-quinoxalinyl)ethoxy.
Examples of -O-(CH2)nquinolinyl include 2-quinolinyloxy, 2-quinolinylDethoxy and 2-(2-quinollnyl)ethoxy.
Examples of -O-(CH2)npyrazinyl include 2-pyrazinyloxy, 2-pyrazinylmethoxy and 2-(2-pyrazinyl)ethoxy.
Examples of -O-(CH2)nnaphthyl include l-naphthyloxy, 2-naphthylmethoxy and 2-(1-naphthyl)ethoxy.
Examples of -O-(CH2)nC(O)-(CH2)nnaphthyl include -O-(CH2)C(O)-(CH2)(1-naphthyl), -O-(CH2)2C(O)-(CH2)(2-naphthyl), -0-C(O)-(CH2)(1-naphthyl) and -O-(CH2)2C(O)-(CH2)2(2-naphthyl).
Examples of -O-(CH2)nC(O)O-(CH2)nnaphthyl include -O-(CH2)C(O)O-(CH2)(1-naphthyl), -O-(CH2)2C(O)0-(CH2)(2-naphthyl), -O-C(0)0-(CH2)(1-naphthyl) and -0-(CH2)2C(O)O-(CH2)2(2-naphthyl).
Examples of -O-(CH2)nC(O)NRg-(CH2)nnaphthyl include -O-(CH2)C(O)N(H)(CH2)(1-naphthyl), -O-(CH2)C(O)N(CH3)(CH2)2(2-naphthyl) and -O-(CH2)C(O)N(benzyl)tCH2)3(1-naphthyl).
Examples of -(CH2)q-OH include hydroxymethyl, hydroxyethyl and hydroxybutyl.
Examples of (CH2)qOC(O)Rg include (CH2)OC(O)methyl, 20()6306 18~
(CH2)2OC(O)ethyl, (CH2)30C(O)phenyl, (CH2)40C(0)(3-pyridyl) and (CH2)OC(O)thiophene.
Examples of -(CH2)qOC(O)-NRgRlo include -(CH2)0C(O)-N(CH2)2, -(CH2)2OC(0)-N(ethyl)2, -(CH2)30C(O)-(l-pyrrolidine), -(CH2)40C(0)-(l-piperidine) and -(CH2)OC(O)-N-benzylamine.
Examples of (l-cyclohexyl-lH-tetrazol-5-yl)Cl-C4 alkoxy, -[1-(Cl-C5alkyl)-lH-tetrazol-5-yllCl-C4 alkoxy lnclude .(l-cyclohexyl-lH-tetrazol-5-yl)oethoxy, (1-cyclohexyl-lH-tetrazol-5-yl)ethoxy, -11-(methyl)^lH-tetrazol-5-yl]methoxy, -Il-(cyclopropyl)-lH-tetrazol-5-yl]etboxy, -Il-(l-tert-butyl)-lH-tetrazol-5-yl~propoxy and -[1-(cyclopenyl)-lH-tetrazol-5-yl]methoxy.
Examples of -[l-(phenyl)-lH-tetrazol-5-yllcl-c4 alkoxy (wherein phenyl is optionally subs~ituted with one, 2 or 3 Cl-C4 alkyl, Cl-C4 alkoxy, halo or trifluoromethyl) include -[l-(phenyl)-lH-tetrazol-5-yl]methoxy, -[1-(*enyl)-lH-tetrazol-5-yl]ethoxy, -[1-(4-methoxyphenyl)-lH-tetrazol-5-yl]methoxy~ -l1-(4-fluorophenyl)-lH
tetrazol-5-yl]propoxy.
Examples of -Il-(pyridinyl)-lH-tetrazol-S-yllCl-C4 alkoxy or -[l-(l-phenylethyl)-lH-tetrazol-5-yl]Cl-C4 alkoxy include -[1-(2-pyridinyl)-lH-tetrazol-5-yl]methoxy, -[1-(3-pyridinyl~-lH-tetrazol-5-yl]ethoxy, -[1-(4-pyridinyl)-lH-tetrazol-5-yl]propoxy, -[1-(1-phenylethyl)-lH-tetrazol-5-yl]methoxy, -[l-(l-phenylethyl)-lH-tetrazol-5-yl]ethoxy.
The tertiary amines and aromatic heterocyclic amines of the sub~ect specification and claims include the N-oxides thereof.
Pharmaceutically acceptable salts means salts useful for administering the compounds of this invention and include hydrochlor-ide, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propion-ate, lactate, maleate malate, succinate, tartrate, and the like.
These salts may be in hydrated form.
The compounds of Formula 1 are all characterized by pronounced antiatherogenic activity, rendering these compounds useful in the treatment and prophylaxis of atherosclerosis.
- Various compounds including 2-t4-morpholinyl)-4H-benzopyran-4-35 one (Cpd #2), 2-(4-morpholinyl)-4H-1,3-benzoxazin-4-one (Cpd #98), 8-methyl-2-(4-morpholinyl)-4H-1,3-benzoxazin-4-one (Cpd #84), 2-(1-(4-th~omorpholinyl))-4H-1,3-benzoxazin-4-one (Cpd #95) and 2-(4-methyl-l-piperazinyl)-4H-1,3-benzoxazin-4-one (Cpd #96) reduced arterial 200~S3()6 -19~
cholesterol accumulation in the SEA Japanese quail model. The reduction in arterial cholesterol was accompanied with reduced serum cholesterol levels with Compounds 84 and 95, but not with Compounds 2, 98 and 96. In normal cholesterolemic SEA Japanese quail, Co~pound 84 also lowered ~erum cholesterol. For a descriptlon of the Japanese quail model, see Day, C.E. et al., ~Utlllty of a Selected Line (SEA) of the Japanese Quall (Coturnic Coturnlx ~aponlca) for the Dlscovery of New Anti-Atherosclerosls Drugsn, Laboratory Animal Science 27:817-821 (1977).
Preferred antiatherosclerotic compounds include Compounds 2, 3, 19, 51, 72, 76, 84, 95, 96, 98, 112, 139, 163, 164, 171 and 204.
In additlon, various compounds of Formula I are also potent lnhibitors of cell proliferation and are contemplated as useful in the treatment of proliferative diseases such as cancer, rheumatoid arthritis, psoriasis, pulmonary fibrosis, scleroderma, cirrhosis of the liver and for the improved utilizatlon of artificial prosthetic devices such as arterial grafts. These agents may also be useful in the prevention or treatment of obstruction or restenosis of arteries by subsequent administration of drug in cases such as by-pass surgery, coronary by-pass surgery, balloon angioplasty (and other procedures directed at re-establishing patency in occluded or partly occluded vessels, i.e atherectomy, laser or ultrasonic procedures), transplants, and post-thrombotic re-stenosis.
Compounds of Formula I which are inhibitors of cell prollferation are those active in the test procedure described in Pledger W.J., Stiles C.D., Antniades H.N., Scher C.D., [Proc. Natl.
Acad. Sci (USA) tl977). Examples of inhibitors of cell proliferation include Compounds 1-14; 16-17; 19-23; 25 and 26; 28; 30-34; 36-39;
42; 46-48; 51, 52; 54-56; 58-76; 81, 100-103; 105-112; 120-122; 125-133; 135-145; 149; 155 and 156; 158-160; 163; 165 and 166; 171; 173-180, 183-190, 193, 204, 206 and 207.
In addition, various compounds of Formula I are also inhibitors of ADP induced platelet aggregation and are useful in the prevention or treatment of thrombotic diseases and related complications by, for example, inhibition or reversal of platelet aggregation, or platelet adhesion or blood coagulation.
Compounds of Formula I which are inhibitors of platelet aggregation are those active in the test procedure described in Born, ~20-G.R., Cross M.J., J. Physiol., 168, p. 178 (1963). EXaOple9 of lnhib~tiors of ADP lnduced platelet aggreation include: Compounds 2-3, 5-6, 9-11, 13, 20-22, 25-26, 28, 31-32, 34, 36-39, 31, 36-38, 51-53, 56, 58-59, 63, 65, 69, 72-76, 80, 100, 102, 104, 106-107, 109-113, 115, 116, 118, 120-123, 125-131, 133, 136-140, 147, 149, 154-160, 162-167, 169, 171, 172, 178, 181-188, 192-198, and 207.
Accordingly, in using coDpounds of Formula I for the prHvention or treatment of atherosclerotic diseAso or thrombot1c diseases, an oral route of administration, either by conventional oral dosage forms or by mixture with food, represents the preferred method of their systemic administration. Alternatively, however, these compounds may be administered by other comenient routes of administration whereby systemic activity is obtained. These other routes of administration would include rectal, vaginal, subcutaneous, intramuscular, intravenous, and like routes.
In u~ing compounds of Formula I for use in angioplasty, an oral route of administratlon represents the preferred method of their ; systemic adminstration. Alternatively, however, these compounds ay be administered by other convenient routes of adninistration whereby systemic activity is obtained.
The patient or animal being treated must be given periodic doses of the drug in amounts effective to reduce serum and/or srterial cholesterol, and reduce arterial atherosclerotic lesion size (as determined by angiogram, ultrasound, NMR, etc.); or, by the inhibi-tion or reversal of platelet aggregation, platelet adhesion or bloodcoagulation; or, by preventing arterial occlusion in vascular trauma associated with procedures such as by-pass grafts, coronary by-passes, angioplasty, post-thrombotic re-stenosis and transplants.
Such effective dosages are readily determined by methods known in the art. For example, small daily doses of the drug ( e.g., O.01-200 mg/kg) may be administered initially with higher succeeding doses until levels of serum and/or arterial cholesterol are favorably affected. By this regimen, a compound of Formula I is administered initially at doses as low-as about 0.01 mg/kg per patient per day, with increasing doses up to about 200 mg/kg per patient per day. In the event the antiatherogenic response in a patient being treated at a dose of 200 mg/kg per day is insufficient, higher doses are also utili~ed to the extent patient tolerance 20Cll~306 permlts further increases in dose.
Whils the preferred dosage regimen is with sin~le dally doslng of patlents, also preferred for obtainlng more uniform serum levels of drug are multiple dosages per day (e.g., up to 4-6 times daily).
Accordingly, when 4 daily doses of drug are to be administered, each such dose may be about 50 mg/kg per patient per dose, or hlgher dependlng on tolerance.
Similar doses are employed in hon-human mam~als, e.g. 0.01-200 mg/kg/day.
Charts A-I herein describe various methods by which the compounds of Formula I are prepared. Ulth respect to these Charts, X, Y, R5, R6, R7, Rg, Rg and Rlo are as defined above.
With respect to Chart A, the compounds of Formula I are prepared by mixing the salicylic acid ester with the morpholine ynamine ne~t, or in an organic solvent, with stirring. After several minutes, a tertiary amine base, e.g. TEA (triethylamine), is added and she reaction stirred for a period of time. The product can be isolated by recrystallization or column chromatography.
~ith respect to Chart B, the compounds of Formula I are prepared by reaction of a ortho-hydroxyacetophenone with an amideacetal, e.g., N,N-dimethylformamide dimethylacetal, to yield a vinylogous amide.
Treatment of that amide with a halo~en (Br, Cl, I or F) in an organic solvent such as CHC13 or CHCN then affords a 3-halochromone.
Treatment of that halochromone with amines, either neat or in the presence of organic solvents, then yields the desired 2-amino-chromone.
Uith respect to Chart C, the compounds of Fsrmula I are prepared by treating a ortho-hydroxyacetophenone with carbon disulfide in the presence of base followed by treatment with acid which yields the 2-mercaptochromone. Treatment of the resulting mercaptan with theappropriate amine then affords the desired 2-aminochromone.
Uith respect to Chart D, the compounds of Formula I are prepared by hydrogenation of the corresponding benzylmethoxy analogues which are prepared by the methods described in Charts A,B and C, followed by alkylation of the resulting phenol.
With respect to Chart E, these compounds can be prepared by treatment of a o-hydroxy acetophenone with an iminium salt such as morpholine-4-phosgene iminium chloride, in the presence of boron .. . .. .. .. ... .

;~0063~:)6 trifluoride etherate. Subsequent hydrolysis and alkylatlon yields the desired compounds.
With respect to Chart F, these co~pounts can bo prepared by the treatment of an o-hydroxy acetophenone containing a trlfluorooethyl sulfonate group with an iminiuo salt ~uch as 4-morpholine dichloromethyleniminium chlorlde, in the presence of boron trifluoride etherate. Subsequent hydrolysic and alkylstlon ylelds the 2-amlnochromone. Treatment of the 2-aminochromone with an acetylene in the presence of a palladiuo catalyst such as (bis)triphenylphosphine palladium dlchlorlde and copper iodide yields a 2-aminochromone with a substituted acetylene. Hydrogenatlon of the acetylene yields the desired derivatlve.
Wlth respect to Chart G, the treatment of an o-hydroxy acetophenone containing a halogen group with an lmlnium salt uch as 4-morphollne dichloromethylenimlnlum chloride, ln the presenco of boron trlfluoride etherate. Subse~uent hydrolysis and alkylation yields the 2-aminochromone. Treatment of the 2-aminochromone with a tetraalkyl tin reagent in the presence of a palladium catalyst such as (bis)triphenylphosphine palladium dichloride and a salt such as lithlum chlorlde affords a 2-amlnochromone substltuted with an alkyl substltuent.
Wlth respect to Chart H, the compounds of formula I are prepared by treatlng 4-benzyloxy-2-hydroxy-3-methylacetophenone with sodium hydride, then ethyl ~-methylthloacetate and finally acid to yleld 7-benzy;oxy-8-methyl-2-oethylthiomethyl-4H-[l]-benzopyran-4-one.
Treatment of that compound with methyl lodide affords the corresponding 7-benzyloxy-8-methyl-2-iodomethyl-4H-[l]-benzopyran-4-one. Treatment of that compound with the appropiate amine then afforded the compounds of fsrmula I. Compounds of formula I were also prepared by treating a formula I compound such as 7-benzyloxy-8-methyl-2-(4-morpholiniylmethyl)-4H-[l~-benzopyran-4-one with a transition metal catalyst in an atmosphere of hydrogen to yield 7-hydroxy-8-methyl-2-(4-morpholiniylmethyl)-4H-[l]-benzopyran-4-one.
Alkylation of that phenol with the appropiate group also afforded compounds of formula I.
Alternatively, compounds of formula I can also be prepared by hydrogenation of a R5 8 benzyloxy 2-amino-4H-l-benzopyran-4-one followed by alkylation of the resulting phenol as illustrated in chart I.
The synthesis of the compounds of the present invention is morecompletely understood by the following examples:
Procedure l: Preparation of l-ethynyl morpholine.
Part A: Preparation of trichloroscetylmorpholine.
Norpholine (4.0 mL, 45 mmol) is dissolved in EtOAc (50 oL) and saturated K2C03 (40 mL) added. The mixture is cooled in an ice bath and trichloroacetyl chloride (5.0 mL, 45 mmol) added drop-wise. The reaction is stirred for 20 min then diluted with EtOAc (200 DL) and washed with aq. K2CO3 (20 mL), water (2 X 50 mL) and brlne (30 mL).
The organic layer i~ dried over MgSO4. Rotary evaporation gives trichloroacetylmorpholine.
Mp - 80-l'C
lH NMR (300 MHz, CDC13) 3.81-3.76 (m) W (EtOH) 224 (4.520) IR (mull) 2955, 2926, 2859, 1657, 1431, 1270, 1239, 1116, 962, 852, 848, 842, 810, 777 MS m/e (relative intensity) 233 (12), 231 (12), 115 (8), 114 (100), 86 (10), 70 (67), 56 (26), 42 (20), 28 (18), 27 (8) HRMS calc'd. for C6H8NO2C13: 230.9621; found: 230.9629; anal.
calc'd. for C6H8NO2C13: C, 31.00, H, 3.47, N, 6.02, Cl, 45.75;
FOUND: C, 31.15, H, 3.43, N, 6.07, Cl, 45.88.
Part B: Preparation of tricholorvinylmorpholine.
TrichloroacetylDorpholine (8.3 g, 36 mmol) is dissolved in toluene and triphenylphosphine (9.44 g, 36 mmol) added. The mixture is brought to reflux for 1.5 h, then cooled and solvent removed in vacuo. The residue is fractionally distilled at reduced pressure to give trichlorovinylmorpholine. BP - 85-7 C, 20 mm Hg.
Part C: Preparation of the morpholine ynamine.
Trichlorovinylmorpholine (5.50 g, 24.5 mmol) is dissolved in an-hydrous ether (30 mL) under a nitrogen atmosphere. The mixture is cooled to -30C and butyllithium (50 mL, 1.5 M, 75 mmol) added slowly, then the mixture is allowed to warm to 23 oC for 2 h. The mixture is cooled to -30 oC again and poured into cold 20 ~ ammonium hydroxide (20 mL), ether (50 mL) added and the solutions quickly separated. The organic layer is filtered through anhydrous R2CO3 (5 cm) and concentrated in vacuo to a yellow orange oil that is 200~306 fractlonally dlstilled ~0.9 mu Hg, BP - 53-C) to glve tho ynamine, 1-ethynyl morpholine, as a colorless oll (1.1 g, 40~).
IR (fllm) 2970, 2940, 2870, 2137, 1647, 1458, 1382, 1272, 1123cm~l. lH-NMR (CDC13, 6) 3.81, 3.12, 2.36.
Example 1: Preparation of 6-chloro-2-(4 morphollnyl)-4H-l-benzo-pyran-4-one, Compound 1 The methyl ester of 5-chlorosalicylic acid (2.00 g, 10.7 mmol) i9 mixed with ethynyl morpholine (naat, 1.00 g, 9.00 mmol) dropwise.
The roaction is exothermic. When the mixturo c0018, triethylamine (TEA, 1 drop) is added and the liquid oixture immediately crystall-ized. The mixture is chromatographed (flash, SiO2, CH2C12/EtOH, 95:5) to yield 6-chloro-2-(4-morpholinyl)-4H-lbenzopyran-4-one (1.07 g, 45~). Mp 194-5C; IR (mull) 2949, 2946, 2869, 2855, 1640, 1615, 1566, 1464, 1450, 1437, 1345, 1246, 1118, 822, 787 cm~l; lH-NMR
15 (CDC13, 200 MHz, ~) 8.11 (d, J - 2.5 Hz, 1 H), 7.49 (dd, J - 8.7, 2.5 Hz, 1 H), 7.23 (d, J - 8.7 Hz, 1 H), 5.49 (s, 1 H), 3.85-3.82 (m, 4 H), 3.S3-3.50 (m, 4 H); W (EtOH) ~ max () 217 (31,360), 230 (24,900), 245sh (12,100), 290sh (11,170), 301 (15,810), 315 (16,070);
Mass Spectrum: ions at m/e (relative intensity) 267 (35), 265 (100), 20 210 (24) 209 (22), 208 (74), 207 (31), 180 (47), 154 (27), 126 (19), 52 (21); High resolution MS calc'd. for C13H12N03Cl: 265.0506. Found:
265.0512. Anal. calc'd. for C13H14NO3Cl: C, 58.77; H, 4.55; N, 5.27; Cl, 13.34. Found: C, 58.52; H, 4.66; N, 5.11; Cl, 13.58.
Following the general procedure of Example 1, bue employing the appropriate o-hydroxy salicylic methyl ester in place of the methyl ester of 5-chlorosalicylic acid and, depending upon the reactivity of the methyl ester, carried out either neat, in methylene chloride, toluene or triethylamine, there are prepared the following products:
Cpd 2 2-(4-morpholinyl)-4H-l-benzopyran-4-one, Mp 160-61C;
30 Cpd 4 7-Chloro-2-(4-morphol~nyl)-4H-l-benzopyran-4-one, Mp 160-l-C (from CH2C12/EtOH);
Cpd 5 8-Chloro-2-(4-morpholinyl)-4H-l-benzopyran-4-one, Mp 190-l-C (from CH2C12/Et20);
Cpd 6 6-Bromo-2-(4-morpholinyl)-4H-l-benzopyran-4-one, Mp 164-5C (from CH2C12/Et20);
Cpd 7 6-Fluoro-2-(4-morpholinyl)-4H-l-benzopyran-4-one, Mp 198-9~C (from CH2C12/Et20);
Cpd 8 6-Methyl-2-(4-morpholinyl)-4H-l-benzopyran-4-one, Mp J

166-7-C (from CH2C12/Et2O);
Cpd 9 7-Methyl-2-(4-morpholinyl)-4H-l-benzopyran-4-one, Mp 163-4-C (from CH2C12/Et2O);
Cpd 10 8-M~thyl-2-~4-morpholinyl)-4H-l-benzopyr~n-4-one, Mp 169-70C (from EtOAc/hexane);
Cpd 11 6-Methoxy-2-(4-morpholinyl)-4H-l-benzopyran-4-one, Mp 148-9C (from EtOH/CH2C12);
Cpd 12 7-Methoxy-2-(4-morpholinyl)-4H-l-benzopyran-4-one, Mp 173-4C (from EtOH/hexane);
Cpd 13 6-~Phenylmethoxy)-2-(4-morpholinyl)-4H-l-benzopyran-4-one, Mp 210-12-C;
Cpd 14 8-(Phenylmethoxy)-2-(4-morpholinyl)-4H-l-benzowran-4-one, Mp 192-4C;
Cpd 15 [2-(4-morpholinyl)-4-oxo-4H-l-benzopyran-6-yl]-1,1-dimethylethyl carbamic acid ester;
Cpd 16 6-(3-pyridinecarboxamide)-2-(4-morpholinyl)-4H-l-benzopyran-4-one.
Example 17 Preparation of 2-(Morpholinyl)-6-nitro-4H-l-benzo-pyran-4-one, Compound #17 The ethyl ester of 5-nitro salicylic acid (634 mg, 3.0 mmol) is dissolved in TEA (2.0 mL) and the morpholine ynamine added. The mixture is then stirred for 48 h. The reaction is diluted with EtOAc (200 mL) and washed with water (5 X 25 mL), brine (30 mL) and dried (MgSO4). Evaporation of the solvent yields product which is chromat-ographed (silica gel [50 g]; 4% EtOH/CH2C12) to afford 182 mg (22%) of the desired product. MP - 258-9~C; lH NMR (CDC13, 300 MHz) 9.05 (d, J - 2.9 Hz, 1 H~, 8.44 (dd, J - 8.7, 2.9 Hz, 1 H), 7.46 (d, J -9.3 Hz, 1 H), 5.69 (s, 1 H), 3.91-3.86 (m, 4 H), 3.61-3.56 (m, 4 H);
W (EtOH) 226 (23,700), 234sh (19,000), 282 (17,600), 316 (15,000);
LRMS m/e (rel. intensity) 277 (28), 276 (100~, 261 (38), 219 (80), 218 (53), 191 (38), 172 (19), 55 (30), 53 (35), 41 ~31); IR (mull) 2954, 2924, 2856, 1637, 1627, 1604, 1565, 1447, 142~, 1347, 1253, 1126, 740, 638; HRMS calc'd. for C13H12N205: 276.0746; found:
276.0742; anal calc'd. for C13H12N205: C, 56.52, H, 4.38, N, 10.14;
found: C, 56.32, H, 4.52, N, 10.16.
Example 18: Preparation of 2-(4-Morpholinyl)-4H-pyrano[2,3b]
pyridin-4-one, Compound 18 The methyl ester of 2-hydroxy-3-carboxypyridine (300 mg, 1.9 20063~)6 mmol) is dissolved in toluene (2.0 mL) and a solution of the morpholine ynamine (250 ~g, 2.2 ~mol) in toluene (2.0 ~L) added dropwise st 23C. The reaction is then warDed to 100C for 24 h.
The mixture is cooled and purifiat by fl-sh chrom~tography (CH2C12/
EtOH, 95:5) to give the chromone as pale yellow crystals (270 g, 63 ~). Mp l90-l-C; IR (mull) 2924, 2868, 2855, 1652, 1639, 1611, lS90, 1557, 1463, 1405, 1250, 1120, 788, 602 cm-l; lH NMR ~C W 13, 200 MHz, S) 8.60 (s, 1 H), 8.57 (dd, J - 3.2, 2.4 Hz, 1 N), 7.45 (o, 1 H), 5.56 (s, 1 H), 3.92-3.87 (m, 4 H), 3.68-3.63 (o, 4 H); W (EtOH) ~
max (t) 215 (16,740), 243 (10,250), 281sh (8,330), 289 (10,500), 320 (15,320); Mass spectrum: ions at m/e (rolative intensity3 233 (14), 232 (100), 217 (17), 175 (37), 174 (39), 146 (15), 122 (17), 79 (34), 53 ~15), 42 (14); Anal. calc'd. for C12H12N203: C, 62.06; H, 5.21; N, 12.06. Found: C, 61.85; H, 5.15; N, 11.88. 5 Example 19 PreparAtion of 6-(~[phenyimethoxy]carbonyl]amino)-2-(4-Dorpholinyl)-4H-l-benzopyran-4-one, Compound 19 2-Hydroxy-5-(~[phenylmethoxy]carbonyl]amino)benzoic acid methyl ester (1.0 g, 3.3 ,lol) ls added to CH2C12 (1 ml) and cooled to O-C.
To that solution is added the ynamine (366 mg) neat and dropwise followed by several drops of TEA. The reaction solut~on turns yellow and after stirring at room temperature for 18 hr is heated at 80C
(oil bath) for 6 hr. A solid fills the flas~. The reaction is diluted with CH2C12 and the solid collected on a filter to yield 350 mg (19.4~) of the desired product. An analytical sample was prepared 25 by recrystallization from CH3CN. Mp 245-SO-C; IR (mull) 3263, 2947, 2925, 2921, 2867, 2854, 1716, 1638, 1623, 1577, 1564, 1558, 1464, 1456, 1453, 1404, 1246, 1231, 1121, 731 cm~l; lH-NMR (CDC13, ~) 8.15 (d, lH, J-2 Hz), 7.95 (s, lH), 7.87 (s, lH), 7.3 (m, 7H), 5.42 (s, lH, vinyl), 5.2 (s, 2H), 3.7 (m, 4H), 3.4 (m, 4H); W (EtOH ~ max () 30 231 (27,520), 246 (34,960), 300 sh (16,300), 307 (17,830), 320 sl sh (12,800); Mass spectrum: ions at m/e (relative intensity) 380 (17), 335 (12~, 272 (100), 215 (69), 187 (44), 161 (32), 108 (79), 91 (87), 79 (99), 53 (32), 44 (50);
Anal. Calc'd. for: C21H20N2os: C, 66.31; H, 5.26; N, 7.36.
Found: C, 66.40; H, 5.28; N, 7.30.
Example 20: Preparation of ~-Methoxy-2-(4-morpholinyl)-4H-l-benzopyran-4-one, Compound 20 Method A: 3-Methoxy salicyl chloride (750 mg, 4 mmol) is 200G3()6 dissolved ln THF (4mL) and cooled to 0-C. The morphollne ynamine (44S mg, 4~0 mmol) is dissolved in THF (4 mL) and then added dropwise to the cooled solution of the acit chloride. A whlte precipitate forms lmmediately and after stirring for 20 mlnutes, TEA (0.60 mL), 4.5 omol) is added and the reaction temperature raised to 23C.
After refluxing for 20 oinutes the reaction is cooled to room temperature and the THF removed ~ vac~o. The crute reaction Dixture is filtered and the filtrate chromatographed over silica gel (5~
EtOH/CH2C12) to affort, after recrystallization, 115 mg (12~) of the desired product. Mp 184-6C; IR 2952, 2925, 2870, 2855, 1642, 1625, 1618, 1581, 1575, 1463, 1455, 1410, 1350, 1250, 1244, 1116, 773 cm~l;
W (EtOH) ~ max () 212 sh (20,710), 236 (25,000), 250 sh (12,000), 301 (17,800); lH-NMR (CDC13) 7.74 (dd, lH, J - 2 and 8 Hz), 7.27 (t, lH, J - 8 Hz), 7.10 (dd, lH, J - 2 and 8 Hz), 5.52 (s, lH), 3.96 (s, 3H), 3.88 (m, 4H), 3.55 (m, 4H); Mass spectrum: ions at m/e (relative intensity) 261 (100), 204 (63), 203 (19), 176 (27), 122 (33), 77 (26), 55 (26), 57 (32), 43 (37); Anal. calc'd. for C14HlsNO4; C, 64.35; H, 5.76; N, 5.36. Found: Ç, 64.39; H, 5.83; N, 5.74.
Method B: 3-Methoxy methyl salicylate (547 mg, 3.0 mmol) is dissolved in TEA (4.0 mL) and the oorpholine ynamine (400 mg, 3.7 mmol) is added. The mixture is stirred for 48 h, then diluted with EtOAc (200 mL) and washed with water (5 X 20 mL), brine (30 mL) and dried (MgS04). Evaporation in vacuo affords 690 mg of crude product.
Chromatography (silica gel [50 g]; 44 EtOH/CH2C12) affords the desired product (160 mg; 20~).
Exa~ple 21: Preparation of 3-Amino-2-(4-morpholinyl)-4H-l-benzo-pyran-4-one, Compound 21 Part A: 2-(4-morpholinyl)-4H-benzopyran-4-one (2.00g, 8.00 mmol) is dissolved in CH2C12 (12 mL) and nitric acid (5.00 mL, 24 mmol) added dropwise with stirring at 23C. After 2H, the mixture is warmed to 60 C and three drops of sulfuric acid added. The reaction gradually turns red and a brown gas is evolved. After about 4 hrs the starting material is consumed as evidenced by TLC (EtOAc/CH30H, 9/1). The reaction mixture is poured onto ice (30 mL) and yellow crystals precipitated almost immediately. The crystals are filtered and washed with cold water. The crude product is dissolved in ethyl acetate (200 mL) and the remaining precipitate is removed by filtration. The EtOAc layer is washed with saturated NaHCO3 (2 X 30 . . , . , . . . . .. .,, _ _, .. ... . . .

~006306 mL) and ~rlne (50 mL) then dried (MgS04). Rotary evaporation yields 1.44g (60~) of 2-(4-morpholinyl)-3-nitro-4H-lbenzopryan-4-one. The 2-(4-morpholinyl)-3-nitro-4H-l-benzopyran-4-one l- further purlfled by column chromatography over 9ilic- gel (etoAc) to give analytical material. Mp 206-8C; IR (mull) 2954, 2925, 2869, 2856, 1646, 1620, 1599, 1575,1487, 1467, 1445, 1435, 1422, 1379, 1341, 1325, 1116 co~l;
lH-NMR (CDC13, ~) 8.23 (dd, J - 1.9, 8.9 Hz, lH), 7.65 (ddd, J - 2.1, 7.3, 10.2, lH), 7.39 (m, 2H), 3.90 (m, 4H), 3.62 (m, 4H); MS m/e (rel intensity) 276 (78), 201 (36), 187 (38), 121 (100), 120 (56), 92 (30), 79 (23), 77 (21), 73 (22), 42 (25); W (EtOH) ~ max (~) 230 (15,730), 286 (17,000), 295sh (14,760), 360sh (1,840); Anal. calc'd.
for C13H12N2O5: C, 56.52; H 4.38; N, 10.14. Fount: C, 56.53; H, 4.56; N, 9.79.
Part B: 2-(4-Morpholinyl)-3-nitro-4H-l-benzopyran-4-one (500 mg) is dissolved in EtOAc (30 mL). Palladium on carbon (10 ~, 100 mg) is added under a nitrogen atnosphere. The oixture 1Y fixed to a Parr hydrogenator at 30 psi for 4 hr, then filtered (Celite, 1 CD) and solvent removed in vacuo. The product is purified by flash chromatography (EtOAc) to give 3-Amino-2-(morpholinyl)-4H-l-benzo-pyran-4-one (419 mg, 94%). Mp 140-1C; IR (mull) 2954, 2925, 2856, 1621, 1607, 1551, 1466, 1423, 1382, 1277, 1271, 1240, 1115, 952, 762 cm l; lH NMR (CDC13, ~) 8.24 (dd, J - 7.8, 2.0 Hz, 1 H), 7.60 (ddd, J
- 6.8, 6.7, 1.8 Hz, 1 H), 7.38 (br.d, J - 7.8 Hz, 2 H), 3.91-3.76 (m, 4 H), 3.52-3.47 (~, 4 H), 3.43 (br.s, 2 H); W (EtOH) ~ max (~) 212 (19,150), 233 (15,180), 255sh (9,900), 300 (3,000), 356 (12,100);
Mass spectrum:ions at m/e (relative intensity) 262 (21), 246 (100), 201 (21), 188 (18), 187 (40), 148 (88), 121 (52), 114 (21), 70 (36), 42 (17); Anal. calc'd. for C13Hl4N2O3: C, 63.40, H, 5.73, N, 11.38;
found: C, 63.48; H, 5.84; N, 11.46.
Example 22: Preparation of 3-Chloro-2-(4-morpholinyl)-4H-l-benzopyran-~-one, Compound 22 2-(4-Morpholinyl)-4H-benzopyran-4-one (2.0 g, 8.0 mmol) is dissolved in CH2C12 (20 mL). t-Butyl hypochlorite (1.0 mL, 8.5 mmol) is added dropwise at 23C. The reaction mixture is warmed slightly snd ls finished almost instantaneously. The solvent is removed in vacuo and the residue is taken up in EtOAc (200 mL). The organic layer is washed with water (2 X 50 mL) and brine (80 mL), then dried (Mg~04). The solution is concentrated in vacuo giving colorless crystals which are recrystallized from EtOAc to give the desired product (1.86 g, 91~) Mp 127-8C; IR (oull) 2962, 2923, 2856, 1635, 1612, 1597, 1562, 1555, 1466, 1457, 1325, 1233, 1119, 872, 762 cm'l;
lH NMR (200 Mhz, CDC13, 6) 8.20 (br d, J - 7.5 Hz, lH), 7.60 (ddd, J
- 9.1, 6.7, 1.7 Hz, lH), 7.36 (m, 2 H), 3.88 (m, 4H), 3.74 (m, 4H) MS m/e (rel intensity) 267 (33), 266 (15), 265 (100), 231 (15), 230 (98), 209 (16), 207 (45), 120 (27), 110 (19), 41 (16); W (EtOH) max (~) 214 (18,900), 238 (18,160), 300 sh (11,530); Anal. calc'd.
for C13H12NO3Cl: C, 58.76; H, 4.55; N, 5.27. Found: C, 58.82; H, 4.58; N, 5.37.
Example 23: Preparation of 3-Bromo-2-(4-morpholinyl)-4H-l benzopyran-4-one, Compound 23 2-(4-morpholinyl)-4H-benzopyran-4-one ~2.0 g, 8.0 mmol) is dissolved in CH2C12 (20 mL). N-Bromosuccininide (1.6 g, 8.2 mmol) is added and the reaction mixture warmed slightly and the starting material disappears immediately as evidenced by TLC. The solvent ls removod in vacuo and the colorless residue i9 taken up in EtOAc (200 mL) and washed with water (4 X 30 mL), brine (50 mL) and driod (MgSO4). Rotary evaporation gives the desired product (2.27 g, 92~) 20 as colorless crystals. mp: 145-6C; IR (mull) 3337, 3016, 2922, 2871, 2855, 1698, 1609, 1585, 1502, 1462, 1378, 1367, 1341, 1303, 1295, 1260, 1234, 996, 812 c~-l; lH NMR (CDC13, 6) 8.22 (dd, J - 7.9, 1.8 Hz, lH), 7.63 (ddd, J - 8.2, 7.4, 1.4 Hz, lH), 7.44-7.28 (m, 2H), 3.90-3.84 (m, 4H), 3.76-3.69 (m, 4H); LRMS m/e (rel intensity) 311 (55), 309 (55), 253 (14), 231 (17), 230 (lOO), 172 (21), 121 (20), 120 (15), 110 (61), 41 (16); W (EtOH) ~ ~ax (~) 216 (18,400), 238 (18,600), 317 (17,040); High resolution HS calc'd. for C13H12N03Br:
309.0001. Found: 308.9990. Anal. calc'd. for C13H12NO3Br: C, 50.34; H, 3.90; N,4.52. Found: C, 50.40; H,4.05; N, 4.46.
Relating to Chart B:
Example 24 Preparation of 8-methyl-2-(4-morpholinyl)-7-(phenyl-methoxy)-4H-l-benzopyran-4-one (Cpd 24).
Part A: 3-(D~methylamino)-1-(2-hydroxy-3-methyl-4-benzyloxyphenyl)-Propen-l-one.
2-Hydroxy-3-methyl-4-(phenylmethoxy)-acetophenone (25 g, 98 mmol) and DMF-DMA (17.9 g, 150 mmol) is heated at 95-100C for 2.75 h. The reaction is cooled to room temperature and excess reagent and CH30H removed in vacuo to leave a dark solid. That solid is tritura-ted wlth ether at 0C and flltered to yleld 19.64 g ~64.4 %) of the product as a yellow solld. The mother llquors (9.91 g) also con-talned product but ls not lsolated. An an~lytlcal s~plo ls prepared by recrystalllzatlon from EtOAc/ Skelly-B.
Part B: 3-Bromo-8-methyl-7-(phenylmethoxy)-~4H]-l-benzopyran-4-one.
The vlnylogous a~lde of Part A (19.0 8, 61 unol) i9 dl~solvet in CHC13 and cooled to 0C. Br2 (9-75 g, 61 mol), ln CHC13 (50 L), i8 added dropwise over a 5 Dlnute perlod. After complete addltion, the reaction i8 diluted with H20 (200 L) and vlgorously ~tirred for 5 minutes. The CHC13 layer ls separated, dried (MgS04) and solvent evaporated in vacuo to yield 23.1 g of crude product. Recrystalliza-tion from EtOAc afforded 15.2 g (66a) of analytically pure product.
Part C: 8-Methyl-2-(4-morpholinyl)-7-(phenylmethoxy)-4H-l-ben-zopyran-4-one.
The 3-bromochromone of Part B (1.0 g, 2.9 mDOl) i8 dissolved in acetonitrile (35 mL). Anhydrous potassiun carbonate i9 added (371 mg, 2.9 mmol). Then morpholine (0.252 mg, 2.9 mmol) is added dropwise. Stirring is begun and the reaction warmed to reflux for 36 h. The acetonltrile is removed in vacuo and the organic material is taken up in ethyl acetate. The organic phase is washed with water and brine then dried (MgS04). The solvent is removed in vacuo and the residue is chromatographed over silica gel ( CH2C12/Et20; 2/1) to give two main fractlons. The first contained a 3-amlno substltuted product.
rne second fraction is a mixture of a ring contracted product and the desired 2-morpholinyl chromone. That mixture is rechromatographed (EtOAc/CH30H; 95/5) giving two fractions, the faster moving containing the ring-contracted product (211 Dg, 21~), Hp 171-2-C; IR (mull) 2954, 2924, 2867, 2855, 1693, 1632, 1613, 1597, 1260, 1166, 1140, 1108, 1099, 749 cm~l; lH-NMR (200 MHz, CDC13, ~) 7.64 (dd, J - 8.57 Hz, 1.27, 1 H), 7.49-7.41 (m, 5 H), 6.89 (s, vinyl, 1 H), 8.84 (d, J - 8.57 Hz, lH), 5.22 (s, 2 H), 3.89-3.84 (m, 4 H), 3.79-3.76 (m, 4 H), 2.30 (s, 3 H); W (EtOH) ~ max (t) 204 (25,300), 205sh (24,500), 252 (8,550), 258 (8,670), 321 (18,900), 377 (33,100), 391 (29,300); High resolution MS calc'd. for C21H21N04:
351.1470. Found: 351.1470. Anal. calc'd. for C21H21N04: C, 71.78;
H, 6.02; N, 3.99. Found: C, 71.60; H, 6.15; N, 3.96.
On further elution, the desired 2-morpholinyl chromone (Cpd #24) is isolated (127 mg, 12~). Mp 181.5-182.5C; IR (mull) 2953, 2925, 2864, 2857, 1637, 1612, 1592, 1575, 1413, 1274, 1272, 1251, 1240, 1119, 782 cm~l; lH-NMR (200 MHz, CDC13, ~) 8.00 (d, J - 9.1 Hz, 1 H), 7.47-7.38 (m, 5 H) 6.98 (d, J - 9.1 Hz, 1 H), 5.44 (s, 1 H), 5.19 (s, 2 H), 3.89-3.84 (m, 4 H), 3.54-3.49 (m, 4 H), 2.33 (s, 3 H); W
(EtOH) ~ max (~) 217 (33,610) 239 (23,660), 291sh (13,980), 312 (26,160), 376 (509); High resolution MS calc'd. for C21H21NO4:
351.1470. Found: 351.1464. Anal. calc'd. for C21H21NO4: C, 71.78;
H, 6.02; N, 3.99. Found: C, 71.79; H, 5.99; N, 3.98.
Exa~ple 25 Preparation of 2-(4-morpholinyl)-5-(phenylmethoxy)-4H-l-benzopyran-4-one Compound 25 Part A: 6-Benzyloxy-2-hydroxyacetophenone 2,6-Dihydroxyacetophenone (84.48 g, 0.55 M), benzyl bromide (95 g, 0.55 M), and K2C03 (120 g) is added to acetone (750 mL). That mixture i8 heated at reflux under nitrogen with vigorous stirring (overhead stirrer~ for 18 h. The reaction is then cooled to room tempsrature and filtered. The filtrate is evaporated in vacuo to yield an oily semi-solid. That material is dissolved in CH2C12 and washed with 1 N HCL. The CH2C12 solution is dried (MgSO4) and solvent removed in vacuo to yield a pale oil. That material is chromatographed over silica gel (400 g~ eluting with CH2C12 to afford 72.8 g (54.5~) of the product. An analytical sample is prepared by recrystallization from EtOAc/Skelly-B.
Part B: 3-(Dimethylamino)-1-(2-hydroxy-6-benzyloxyphenyl)-Propen-l-one A mixture of 6-benzyloxy-2-hydroxyacetophenone (15.0 g, 62 ~mol) and N,N-dimethylfor~amide dimethylacetal (DMF-DMA; 10.71 g, 90 mmol) is heated under nitrogen at 100-10C for 2 h. Within several minutes of placing the reaction vessel in the oil bath (already at 100C) the initial heterogeneous mixture became homogeneous and very dark in color. After several additional minutes a solid began to separate from this solution and at the end of the reaction time the flask is filled with a yellow solid. The reaction is cooled to room tempera-ture and excess DMF-DMA and methanol is removed in vacuo. The resulting solid is filtered with the aid of ether and air dried to yield 15.41 g (83.7~) of pure product. An analytical sample is prepared by recrystallization from EtOAc.
Part C: 5-Benzyloxy-3-bromo-[4H]-l-benzopyran-4-one ;2006306 The vinylogous amide of Part B (10.0 8, 33.6 mnol) is dlsJolvedin CHC13 (150 mL) and coolet to 0C. Br2 (5.38 g, 33.6 n~ol) i9 added to the aforementioned solution ln CHC13 (50 mL) dropwiJe over 10 minutes. After complete addition tho r~actlon i~ dilutod w~th H20 and vigorously stirred for 5 minutes. The or~anic layer i9 sepArated and washed ~ith brine, dried (MgS04), and ovaporated to give a dark red oil. Chromatography over silica gol (400 g) eluting with 1 CH30H/CH2C12 afforded, after recrystallizat~on from EtOAc/Skelly-B, 4.76 g (42.8~) of the product.
The 5-benzyloxy-3-bromochromone of Part B (3.31g, 10.0 ol) ~s dissolved in acetonitrile (50 mL). Anhydrous potassiu~ carbonate (1.38g, 10.0 mmol) is added, then morpholine (1.02 mL, 11.0 mmol) is added. The mixture is heated to reflux for 72 h. The solvent is removed under vacuo and the residue is taken up in EtOAc (400 ~L) and washed with water (3 X 50 mL) and brine (100 ~L), then dried (MgSO*4). The solvent is removed ~ vacuo and the residue purified by flash chromatography (CHC13/CH30H, 99/1) giving three main fractions. The first fraction contained a 3-~or~pholinyl chromone (0.92g, 51%). Mp 122.5-124C; IR (mull) 2956, 2924, 2856, 1641, 1604, 1464, 1459, 1269, 1235, 1180, 1115, 1070, 1064, 772, 699 cm~l;
H-NMR (200 MHz, CDC13, ~) 7.61 (dd, J - 6.7, 1.5 Hz, 1 H), 7.59-7.29 (m, 5 H), 6.98 (dd, J - 8.2, 1.5 Hz, 1 H), 6.77 (dd, J - 8.2, 1.5 Hz, 1 H), 5.31 (s, 2 H), 3.94-3.90 (m, 4 H), 3.08-3.04 (D, 4 H); W
(EtOH) ~ max (~) 244 (22,700), 249 (21,500), 336 (6,270); Anal.
calc'd. for C20HlgN04: C, 71.20, H, 5.68, N, 4.15; found: C, 70.84, H, 5.75, N, 4.05.
The second fraction contained a ring contracted product (0.60g, 33%). Mp 179-181C.
The last fraction contains the desired 2-morpholinyl chromone (Cpd #25) (0.29g, 16%). Mp 139-40C; IR (mull) 2954, 2926, 2870, 2855, 1640, 1623, 1615, 1600, 1470, 1449, 1407, 1239, 1122, 745, 740 cm~l; lH-NMR (CDC13, 200 MHz, ~) 7.65 (broad doublet, J - 7.2 Hz, 2 H), 7.47-7.30 (m, 4 H), 6.92 (dd, J - 8.1, 0.9 Hz, 1 H), 6.85 (br.d, J - 8.1 Hz, 1 H) 5.45 (s, 1 H), 5.32 (s,-2 H), 3.89-3.85 (m, 4 H), 3.52-3.47 (m, 4 H); W (EtOH) ~ max (~) 210 (32,900~, 238 (23,500), 252sh (8,040), 260sh (5,650), 313 (18,460); Mass Spectrum: ions at m/e (rel intensity) 91 (100), 337 (66), 231 (36), 174 (33), 173 (16), 338 (16) 336 (15), 218 (15), 65 (14), 146 (12); High resolution MS

.33 calc'd. for C20HlgNO4: 337.1314. Found: 337.1312. Anal. calc't, for C20HlgNO4: C, 71.20, H, 5.58, N, 4.16. Found: C, 71.05, H, 5.56, N, 4.17.
Exam~le 26: Preparation of 7,8-dimethoxy-2(4-morpholinyl)-4H-l-benzopyran-4-one, Compound 26 Part A: The 7,8-dimethoxy-3-bromochromone, R.B. Gammill, SYntho~is (1979), p. 901, (3.42g, 12.0 mmol) is dlssolved in acotonitrile (100 mL) and anhydrous potassi~m carbonate (1.66g, 12.0 mmol) is atted.
Morpholine (l.lO mL, 12.5 ~L) is attet tropwise ant the reaction is warmet to reflux (82 C bath temperature) for 24 h. The acetonitrile is removed in vacuo, ant th~ mixture i~ taken up in ethyl acetate (400 mL~. The solution is washed with w~ter (2 x 50 mL) ant brine (100 mL), then driet (M~S04) and concentratet in vacuo to give a yellow solid. Flash chromatography over silica gel (EtOAc/MeOH, 15 95/5) gave the 3-morpholinyl adtuct (2.77g, 79%~, the ring contracted product (0.24 g, 6.9 %) and 0.23 g of a mlxture of the ring contracted and the 2-substituted product (79%) Mp 168-9C; IR (mull) 2952, 2924, 2866, 2854, 1639, 1619, 1509, 1456, 1441, 1433, 1322, 1291, 1200, 1171 cm~l; lH-NMR (200 MHz, CDC13, 6) 8.0 (d,lH, 7.56 (s,lH,-C(H)OAr), 7.02 (d,lH,J-8 .9Hz), 4.0 (s,3 H, OCH3), 3.98 (g, 3 H, OCH3), 3.91 (m, 4 H), 3.08 (m, 4 H), W (EtOH) ~ max (~) 247 (30,060), 303 (7,490), 326 (3,990); High resolution MS calc'd. for ClsH17NOs: 291.1107. Found: 291.1110. Anal. calc'd. for ClsH17NOs:
C, 61.85; H, 5.88; N, 4.81. Found: C, 61.79; H, 5.86; N, 4.74.
Part B: The mixture of ring contracted and 2-morpholinyl chromone are rechromatographed (SiO2, CH2C12/CH30H, 98/2). The ring-contrac-ted product is recrystallized from EtOH to give pale yellow crystals, Mp 180-181C.
The 2-morpholinyl chromone is recrystallized from EtOH to give the desired product (Cpd #26) (colorless crystals); Mp 194.5-5.5C;
lH-NMR (CDC13, ~) 7.88 (d, J - 8.8 Hz, 1 H), 6.97 (d, J - 8.8 Hz, 1 H), 5.43 (s, 1 H), 3.98 (s, 3 H), 3.94 (s, 3 H), 3.86 (m, 4 H), 3.55 (m, 4 H). W (EtOH) ~ max (~) 217 (27,140), 239 (23,530), 270 (6,700), 311 (23,530); High resolution MS calc'd. for C15H17NO5:
291.1107. Found: 291.1093. Anal. calc'd. for C15H17NO5: C, 61.85;
H, 5.88; N, 4.81. Found: C, 61.85; H, 5.83; N, 4.78.
Example 27: Preparation of 2-(4-methyl-1-piperaæinyl)-4H-l-benzopyran-4-one, Compound 27 ~00~;306 Follow~ng the general procedure outlined ln Chart B, the title compound is prepared.
Relatine to Chart C:
Example 28: Preparation of 8-msthyl-7 (phenyl~ethoxy)-2-~4-(2-pyridinyl)-1-piperazinyl]-4H-benzopyran-4-one, Compound 28 Part A: Preparation of 8-Methyl-7-(Phenylmethoxy)-2-mercapto-4H-l-benzopyran-4-one.
Potassium t-butoxide (65.5 g) is covered ~ith 500 mL of benzene under nitrogen and that solution i9 placed in a water bath. 4'-Benzyloxy-2'hydroxy-3'-methylacetophenone (50.0 g) and carbon disulfide (14.82 g) are dissolved in 500 mL of benzene and added dropwise to the potassium t-butoxide solution over a one hour per~od.
After co~plete addition the dark red paste is stirred at room temperature over night and then diluted with one liter of water.
That ~ixture i8 poured into a separatory funnel and the organic layer discarded. The aqueous is diluted with 300 mL of 20~ H2SO4 and the solid that separated is collected on a filter and air dried to yield 31.0g of a yellow powder. MP 245~C [D]; 2954, 2916, 2869, 2855, 20 1619, 1602, 1542, 1499, 1462, 1455, 1377, 1305, 1280, 1113, 1076, 822 cm~l; W (EtOH) ~ max (~) 208 (34260), 231 (24940), 252 (15070), 263 sl sh (9470), 285 sl sh (5030), 299 (4930), 353 (18200), 392 (6840);
H-NMR (DMSO-d6) ~ 7.73 (d, lH, J - 8.9 Hz), 7.45 (m, 5H, aromatic), 7.24 (d, lH, J - 8.9 Hz), 6.58 (s, lH, vinyl at C-3), 5.29 (8, 2H), 25 2.29 (s, 3H, -CH3); Mass spectrum: ions at m/e (relative intensity) 298 (12), 207 (1), 179 (1), 149 (1), 121 (1), 91 (100), 65 (6), 43 (1). See Bantick, J.R. and Suschitzky, J.L., J. Heterocyclic Chem.
18, 679 (1981).
Part B: 8-Methyl-7-(phenylmethoxy)-2-mercapto-4H-l-benzopyran-4-one (2.0 g, 6.7 mmol), 1-(2-pyridyl)piperazine (1.19 g, 7.3 mmol) and TsOH (25 mg) is added to toluene and heated at reflux for 20 hours.
The reaction temperature is lowered to room temperature and the toluene removed in vacuo. The resulting dark oil is diluted with EtOAc and the resulting crystals collected on a filter to afford 2.42 g of product. MP 148-9~C.
Following the general procedure of Example 28, but employing the appropriate amine in place of l-(2-pyridyl)piperazlne there are prepared the following products:

Z00~i306 Cpd 29 8-Nethyl-7-(phenylmethoxy)-2-(1-piperazlnyl)-4H-benzopyran-4-one, Mp 165-70-C;
Cpd 30 8-Methyl-7-(phenylmethoxy)-2-~1-pyrrolidinyl)-4H-benzopyran-4-one, Mp 190-3-C;
Cpd 31 8-Methyl-7-tphenylmethoxy)-2-(1-piperid1nyl)-4H-benzopyran-4-one, Hp 172-4'C;
Cpd 32 8-Methyl-2-(4-methyl-1-piperazinyl)-7-(phenyl~ethoxy)-4H-benzopyran-4-one, Mp 180-1C;
Cpd 33 8-Methyl-7-(phenylmethoxy)-2-(2,6-dimethyl-4-morpholinyl)-4H-benzopyran-4-one, Mp 166-8-C;
Cpd 34 2-[4-(Hydroxyethyl)-1-piperazinyl]-8-methyl-7-(phenyl-methoxy)-4H-benzopyran-4-one monohydrochloride, N p 253-5 C;
Cpd 35 2-[4-(Diphenylmethyl)-l-piperazinyl]-8-methyl-7-(phenylmethoxy)-4H-benzopyran-4-on~, Mp 90-5~C;
Cpd 36 8-ffethyl-7-(phenylmethoxy)-2-(4-phenyl-1-piperidinyl)-4H-benzopyran-4-one, Mp 193-4~C;
Cpd 37 8-Methyl-7-(phenylmethoxy)-2-(4-phenyl-1-piperazinyl)-4H-benzopyran-4-one, Mp 153-4C; and Cpd 38 2-(4-Hydroxy-l-piperdinyl)-8-methyl-7-(phenylmethoxy)-4H-benzopyran-4-one.
Relat~ to Chart D and E:
Example 39: Preparation of 7-hydroxy-2-(4-morpholinyl)-8-oethyl-4H-l-benzopyran-4-one, Compound 39 (according to Chart D).
Part A: 8-Methyl-2-(4-morpholinyl)-7-(phenylmethoxy)-4H-l-ben-zopyran-4-one (8.59g, 24.4 ~mol.~ is suspended in 250ml of ethyl acetate. 9.9 ml of cyclohexene is added followed by 0.85g of 10%
Palladium on carbon. The mixture is heated at reflux for 18 hours.
The reaction is allowed to cool and filtered, the solid is taken up in methanol, decanted and filtered. The methanol is evaporated to give 4.71g (74~) of the phenol (mp > 250 C).
Alternate Part A: 2',4',-Dihydroxy-3'-methyl-acetophenone (90%
purity, 1.108g, 6 mmole) is suspen~ed in 25ml 1,2-dichloroethans and the mixture is treated with boron trifluoride etherate (1.48ml, 12 mmole) while stirring in a 50ml one neck round bottom flask under nitrogen. The mixture is stirred for 30 min at room temperature and is subsequently treated with morpholine-4-phosgene iminium chloride 2006~06 (2.70g, 13.2 mmole). The reactlon mixture i9 waroed to 70 C for 3h.
The reaction i9 cooled to room temperature and the insolublo orange solid is collected by f~ltration and the fllter cake i8 WaDhed vell with dlethylether, Tho solld i8 taken up ln 25-1 ac-tonitrile ln a 50ml one neck round bottom flask under nltrogon and the solution i9 cooled to 0 C. The mixture i8 treated with 2.Sml water ant the reaction ls stirred for 48h aC the coollng b-th exp~rod. The ac-tonl-trile is removed in vacuo and the residue i9 c-refully dilutet with 75ml 2:1 saturated sodiu~ bicarbonate/-odiun chloride. The mixture is extracted with 4 X 35~1 dichloromethane. The coobined or~anics ~re dried over ~agnesium sulfate and are concentrated in vacuo to an amber ~olid. The solid is washed successively with othylacetate and diethylether to afford 980mg (44~) of [8-methyl-2-(4-~orpholinyl)-4-oxo-4H-l-benzopyran-7-yl]4-morpholinyl carboxylic ac~d ester (Cpd 100) H.P. 232-234'C. The carbamate (945~g, 2.51 ole) i~ suspended in 9ml 2/1 methanol/water in a 25ml on neck round bottom flask under nitrogen. The suspension is treated with lithium hydroxide (236Og, 5.62 ~mole) and the reaction ~ixture ls stirred for 48h at room temperature. The methanol is removed in vacuo and the pH of the aqueous residue is ad~usted to pH - 4.9 by the addition of 5%
hydrochloric acid. The precipltated ~sterial i8 collected by filtra-tion and is dried in vacuo at 25 C to afford 56g g (87%) of phenol 39 ~M.P. > 250 C) as a chalky grayish solid.
Second Alternate Part A: 2',4'-Dihydroxy-3'-Dethyl-acetophenone (90%
purity, 18.46g, 100 mmole) is suspended in 50ml diethylether in a lOOml one neck round bottom flask under nitrogen. The mixture is treated with boron trifluoride etherate (18.4SD1~ 150 ole) and the reaction is stirred overnight at room temperature. The precipitated material is collected by filtration and the filter cake is washed well with fresh diethylether. The filtered material is air dried to afford 10.45g (47%) of difluoroboronate salt as a yellow solid.
- The difluoroboronate salt (10.45g, 47 mmole) i~ combined with morpholine-4-phosgene iminium chloride (21.2g, 104 mmole) in 125ml 1,2-dichloroethane in a 250ml one neck round bottom flask under argon. The reaction mixture ls warmed to 70 C for 3h and is cooled to room temperature. The orange-yellow precipitate is collected by i'iltration and is washed successively with 1,2-dichloroethane and diethylether to provide 25.3g of an orange solid. The solid is Juspented ln 200ml acotonltrllo ln 500O1 one neck round bottoo flask and tho ulxturo ls coolod to 0 C. Tho cooled xlxturo 15 tre-ted with 20O1 wator and fter stlrring 20 mln at 0 C, the roactlon mixturo 19 ~tirrod ovornight t rooo teoperaturo. Tho olxture ls sub~oquently cooled to -33 C for 2h and tho preclpltated hydro chloride salt i9 collected by flltration and i9 washed with 125O1 lce cold acetonitrile. The filter cake is dried to provido 13.25g (69~) of tho carba~ato-chrooone hydrochloride as a whlte solid. The filtrato is concontrated in vacuo to n ambor syrup. Tho syrup iS
; 10 dilutod with lOOml saturatod odiu~ blcarbonate and the mixture is extractod with 4 X 50ml dichloromethane. The combinod organics are dried ovor ~agnesium ulfate and aro concontratod ln vacuo to a reddish oil which upon crystallization with othylacotato yielded 875mg (5~) of carbamate-chromone as a yellow solid. Hydrolysis of the carbamate-chromono as doscribed in mothod B affords the desired phonol.
Part B: 7-Hydroxy-8-mothyl-2-(4-morpholinyl)-4H-l-benzopyran-4-one (0.50g, l.91o~ol) is suspendod in lSol of acetonitrile. 1.3g of potassium carbonate is added followed by 0.39g (2.1m~ol) of alphabromo-p-xylene. The mixture is refluxed for 5 ho~rs. 0.04 g of ~ adtitional al~ylating agent is added and the oixture i9 refluxed for : 2 hours. The coolod mixturo is diluted with 5ml of water and filtored. The white solid is washed ~ith water and dried. The solid is recrystallized from ethyl acetato to afford 0.59g (84a) of the 25 product 48 (mp 167.5-168-C).
Following the general procedure of ExaDple 39 but omploying the ,~ appropriate phenylmethoxy aminochromone in place of (7-phenyl-methoxy)-8-methyl-2-(4-morpholinyl)-4H-l-benzopyran-4-ono there are prepared the following products:
30 Cpd 40 6-Hydroxy-2-(4-morpholinyl)-4H-l-benzopyran-4-one, Mp 290-2-C;
Cpd 41 7-Hydroxy-2-(4-morpholinyl)-4H-l-benzopyran-4-one;
Cpd 42 5-Hydroxy-2-(4-morpholinyl)-4H-l-benzopyran-4-one, Mp 295-7-C;
~;~ 35 Cpd 43 8-Hydroxy-2-(4-morpholinyl)-4H-l-benzopyran-4-one, ~` Np 300-C;
Cpd 44 7-Methoxy-8-methyl-2-(4-morpholinyl)-4H-l-benzopyran-~; 4-one, Mp 224.5-225.5'C;

,:

;~ ~006~06 Cpd 45 [(8-methyl-2-(4-morphollnyl)-4H-l-benzopyran-7-yl)oxy) acetic acid lithi~m salt;
Cpd 46 1[8-Methyl-2-(4-morpholinyl)-4-oxy-4H-l-benzopyran-7 yl]oxy]acetic scid methyl ester, Hp 181-2-C;
Cpd 47 7-[(4-Methoxyphenyl)methoxy]-8-methyl-2-(4-morpho l~nyl)-4H-l-benzopyran-4-one, Hp 171-2-C;
Cpd 48 8-Methyl-7-[(4-methylphenyl)methoxy]-2-(4-morpho linyl)-4H-l-benzopyran-4-one, Mp 167.5-8C;
Cpd 49 7-[(4-Chlorophenyl)methoxy]-8-methyl-2-(4-morpho linyl)-4H-l-benzopyran-4-one, Mp 226-7-C;
Cpd 50 7-[(4,5-Dichlorophenyl)methoxy]-8-methyl-2-(4-morpho llnyl)-4H-l-benzopyran-4-ons, Mp 243-4C;
Cpd 51 8-Methyl-2-(4-morpholinyl)-7-(2-pyridinylmethoxy)-4H-l-benzopyran-4-one; Mp 174-175.5; and Cpd 52 8-Methyl-7-1[(phenyl)carbonyl]oxy]-2-(4-morpho linyl)-4H-l-benzopyran-4-one, Hp 223.5-25'C.
Cpd 53 8-Methyl-7-(2-(4-methyl-(1-piperizinyl))ethyl)oxy-2-(4-morpholinyl)-4H-l-benzopyran-4-one, Mp lS9.0-159 . 5~ C .
Cpd 54 7-[[4-(1,1-Dimethylethyl~phenyl]methoxy]-8-methyl-2-(4-morpholinyl)-4H-l-benzopyran-4-one, Mp 218.5-220C;
Cpd 55 8-Nethyl-2-(4-morpholinyl)-7-[[4-phenylmethoxy)-phenyl]methoxy]-4H-l-benzopyran-4-one, Mp llO-lll-C;
Cpd 56 7-l(3-Methoxyphenyl)methoxy]-8-methyl-2-(4-morpho-linyl)-4H-l-benzopyran-4-one, Mp 153.5-155.5C;
Cpd 57 7-[(4-Nitrophenyl)methoxy]-8-metbyl-2-(4-morpholinyl)-4H-l-benzopyran-4-one, Hp 285C dec.;
Cpd 58 7-[(2-Phenylethyl)methoxy]-8-methyl- 2-(4-morpholinyl)-4H-l-benzopyran-4-one, Mp 200.5-201.5C dec.;
Cpd 59 7-[(2-Methoxyphenyl)methoxy]-8-methyl-2-(4-morpho-linyl)-4H-l-benzopyran-4-one, Mp 202-2~3-C;
Cpd 60 7-[(4-Ethoxyphenyl)methoxy]-8-methyl-2-(4-morpho-linyl)-4H-l-benzopyran-4-one, Mp 186-188~C;
Cpd 61 8-(4-Ethoxy-benzyloxy)-2-~4-morpholinyl)-4H-l-benzo-pyran-4-one, Mp 149.5-151.S-C;
Cpd 62 2-(4-Morpholinyl)-8-(4-nitro-benzyloxy)-4H-l-benzo-pyran-4-one, Mp 240-241C;
Cpd 63 8-(2-Methoxy-benzyloxy)-2-(4-morpholinyl)-4H-l-ben7Opyran-4-one, Mp 149-150-C;
Cpd 64 2-(4-Morpholinyl)-8-(2-phenyl-ethoxy)-4H-l-benzopyran-4-one, Mp 131-132-C;
Cpd 65 2-(4-Morphollnyl)~(2-oxo-2-phenyl-ethoxy)-4H-l-S benzopyran-4-one, Mp 200-201. 5'C;
Cpd 66 8-(4-Benzyloxy-benzyloxy)-2-(4-morpholinyl)-4H-l-benzopyran-4-one, Mp 143.5-145-C;
Cpd 67 8-(4-Chloro-benzyloxy)-2-(4-morpholinyl)-4H-l-benzo-pyran-4-one, Mp 208-209-C;
10 Cpg 68 8-(4-t-Butyl-benzyloxy)-2-(4-morpholinyl)-4H-l-benzopyran-4-one, Mp 165.5-166.5-C;
Cpd 69 8-(3-Msthoxy-benzyloxy)-2-(4-morpholinyl)-4H-l-benzopyran-4-one, Mp 177-178'C;
Cpd 70 8-(3,4-Dichloro-benzyloxy)-2-(4-morpholinyl)-4H-l-benzopyran-4-one, Mp 207-208C;
Cpd 71 8-(4-Methyl-benzyloxy~-2-(4-morpholinyl)-4H-l-benzo-pyran-4-one, Mp 177-178-C;
Cpd 72 8-(4-Methoxy-benzyloxy~-2-(4-morpholinyl)-4H-l-benzopyran-4-one, Mp 173.5-174.5'C;
20 Cpd 73 2-(4-Morpholinyl)-8-(naphthyl-2-methyloxy)-4H-l-benzopyran-4-one, Mp 200.5-201.5-C;
Cpd 74 2-(4-Morpholinyl)-8-(naphthyl-1-methyloxy)-4H-l-benzopyran-4-one, ~p 192.5-193.5-C;
Cpd 75 8-Methyl-2-(4-morphollnyl)-7-(naphthyl-2-methyloxy)-4H-l-benzopyran-4-one, Mp 158.5-159.5C;
Cpd 76 8-Methyl-2-(4-morpholinyl)-7-(naphthyl-1-methyloxy)-4H-l-benzopyran-4-one, Mp 205.5-207C;
Cpd 77 2-(Dimethylamino)-8-methyl-4-oxo-4H-l-benzopyran-7-yl carbamic acid dimethyl ester.
30 Cpd 7B 2-(Dimethylamino)-4-oxo-4H-l-benzopyran-6-yl carbamic acid dimethyl ester, Mp 179.5-80C;
Cpd 79 2-(Dimethylamino)-4-oxo-4H-l-benzopyran-7-yl carbamic acid dimethyl ester, Mp 158-9C;
Cpd 80 2-(Dimethylamino)-4H-l-benzopyran-4-one, Mp 122-23.5C;
Cpd 81 2-(Dimethylamino)-8-methyl-7-(phenylmethoxy)-4H-l-benzopyran-4-one, Mp 165-6C.
Cpd 102 8-Methyl-2-(4-morpholinyl)-7-(2-oxo-2-phenylethoxy)-.. . --, . -- , 7 .. ~ .. ... . . . . .. . . .... . . . .. . .

~00~306 4H-l-benzopyran-4-ono mp. 226.5-227.5 Cpd 103 6-Chloro-8-methyl-2-(4-morpholinyl)-7-(phenylmethoxy)-4H-l-benzopyran-4-one mp. 207-209 Cpd 104 [[2-(4-Morpholinyl)-4-oxo-4H-l-benzopyran-8-yl]oxy]-acetlc acid, methyl ester mp. 192.5-193 Cpd 105 4-[[[8-Methyl-2-(4-morpholinyl)-4-oxo-4H-l-benzopyran-7-yl]oxylmethyl]-benzoic acid, methyl ester mp. 226-Cpd 106 4-1~[2-(4-Morpholinyl~-4-oxo-4H-l-benzopyran-8-yl]oxy]methyl]-benzoic acid, Dethyl e~ter ~p. 207-Cpd 107 8 - M a t h y l - 2 - ( 4 - m o r p h o l i n y l ) -7 - 1 [ 3 -(trifluoromethyl)phenyl]methoxy]-4H-l-benzopyran-4-one mp. 194.5-195.5 Cpd 108 2-(4-Morpholinyl)-8-[[3-(trifluoromethyl)-phenyl~methoxyl-4H-l-benzopyran-4-one mp. 204-204.5 Cpd 109 7-(Cyclohexylmethoxy~-8-methyl-2-(4-morpholinyl)-4H-l-benzopyran-4-one mp. 184.5-185.5 Cpd 110 8-Methyl-2-(4-morpholinyl)-7-(2-propenyloxy)-4H-l-benzopyran-4-one mp. 191-192 Cpd 111 2-(4-Norpholinyl)-7-(1-naphthalenylmethoxy~-4H-l-benzopyran-4-one mp. 195.2-195.8 Cpd 112 8-Methyl-2-(4-morpholinyl)-7-(3-pyrindinylmethoxy)-4H-l-benzopyran-4-one mp. 182.5-184 Cpd 113 8-Methyl-2-(4-morpholinyl)-7-(4-pyrindinylmethoxy)-4H-l-benzopyran-4-one mp. 253.5-255.5 Cpd 115 8-~ethyl-2-(4-morpholinyl)-7-(2-quinoxalinylmethoxy)-4H-l-Benzopyran-4-one, mp. 250.5-252.5 Cpd 116 8-methyl-2-(4-morpholinyl)-7-(pyrazinlymethoxy)-4H-l-Benzopyran-4-one, mp. 236-237 Cpd 117 8-methyl-2-(4-morpholinyl)-7-(2-pyridinylmethoxy)-4H-l-Benzopyran-4-one, N-oxide mp. 248-249.5 Cpd 118 8-methyl-2-(4-morpholinyl)-7-(3-pyridinylmethoxy)-4H-l-Benzopyran-4-one, N-oxide mp. 233.5-234 Cpd 119 8-Iodo-2-(4-morpholinyl)-7-~3-pyrindinylmethoxy)-4H-l-bPnzopyran-4-one mp. 214-215 Cpd 120 3,3-D~methyl-1-[[8-methyl-2-(4-morpholinyl)-4-oxo-4H-; l-benzopyran-7-yl]oxy]-butan-2-one mp. 197-198 Cpd 121 1-~[8-Methyl-2-(4-morpholinyl)-4-oxo-4H-l-benzopyran-7-yl]oxy]-propan-2-one mp. 206.5 Cpd 122 1-[[8-~ethyl-2-~4-morphol~nyl)-4-oxo-4H-l-benzopyran-7-yl]oxy]-butan-2-one mp. 183-184 Cpd 123 8-Methyl~2-(4-morpholinyl)-7-~2-oxo-2-~2-naphthyl)ethoxy)-4H-l-benzopyrsn-4-one mp. 214.5-215.5 Cpd 125 2-(4-Morpholinyl)-7-~2-pyrindinylmethoxy)-4H-l-benzopyran-4-one mp. 274-276 Cpd 126 2-(4-Norpholinyl)-7-(3-pyrindinylmethoxy)-4H-l-benzopyran-4-one mp. 193-194 Cpd 127 2-(4-Morpholinyl)-8-(2-pyrindinylmethoxy)-4H-l-benzopyran-4-one mp. 199-200 Cpd 128 2-(4-Morpholinyl)-8-(3-pyrindinylmethoxy)-4H-l-i 15 benzopyran-4-one mp. 160-161 Cpd 129 8-methyl-2-(4-morpholinyl)-7-~2-quinolinylmethoxy)-4H-l-Benzopyr~n-4-one, mp. 223.5-224.5 Cpd 130 7,8-~is)-phenylmethoxy-2-~4-morpholinyl)-4H-l-benzopyran-4-one mp. 165.5-167 Cpd 131 7,8-(Bis~-acetyloxy-2-(4-morphol~nyl)-4H-l-benzopyran-4-one mp. 231.5-233 Cpd 132 7,8-(Bis)-hydroxy-2-~4-morpholinyl)-4H-l-benzopyran-4-one mp. >300 Cpd 133 7-Hydroxy-2-~4-morpholinyl)-8-phenylmethoxy-4H-l-benzopyran-4-one ~p. 198~1~9 Cpd 134 7,8-(Bis)-(3-trifluoromethyl)phenylmethoxy-2-(4-morpholinyl)-4H-l-benzopyran-4-one mp. 178.5-17905 Cpd 135 8 - H y d r o x y - 2 - ( 4 - m o r p h o 1 i n y 1 ) - 7 - ( 3 -trifluoromethyl)phenylmethoxy-4H-l-ben~opyran-4-one mp. 262-262.5 Cpd 136 7 - H y d r o x y - 2 - ( 4 - m o r p h o 1 i n y 1 ) - 8 - ( 3 -trifluoromethyl)phenylmethoxy-4H-l-benzopyran-4-one mp. 236-237 Cpd 137 7-[3-(1-cyclohexyl-lH-tetrazol-5-yl)propoxyl-8-methyl-2-(4-morpholinyl)-4H-l-Benzopyran-4-one, mp. 228-Cpd 138 8-[3-(1-cyclohexyl-lH-tetrazol-5-yl)propoxy~-2-(4-mor-pholinyl)-4H-l-Benzopyran-4-one, mp. 185-186 1 200~306 Cpd 139 7-[(1-cyclohexyl-lH-tetrazol-5-yl)methoxy]-8-methyl-2-(4-morpholinyl)-4H-l-Benzopyran-4-one, mp. 228 Cpd 140 8-[(1-cyclohexyl-lH-tetrazol-5-yl)methoxy]-2-(4-mor-pholinyl)-4H-l-Benzopyran-4-one, ~p. 218 Cpd 141 2-(4-morpholinyl)-8-[(1-phenyl-lH-tetrazol-5-yl)oxy]-4H-l-Benzopyran-4-one, mp. 214-215 Cpd 142 N-cyclohexyl-2-l~2-(4-morpholinyl)-4-oxo-4H-l-benzopyran-8-yl]oxy]-acetamide mp. 238-241 Cpd 143 N-(l,l-dimethylethyl)-2-[[2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-8-yl]oxy]-acetamide Dp. 219-220 Cpd 144 2-[[2-(4-morpholinyl)-4-oxo-4H-l-benzopyr~n-8-yl]-N-phenyl-acet&mide ~p. 225-228 Cpd 145 2-[12-(4-morpholinyl)-4-oxo-4H-l-benzopyran-8-yl~oxy]-N-(l-phenylathyl)-acetamide op. 178-180 lS Cpd 146 N-cyclohexyl-2-[[8-methyl-2-(4-morpholinyl)-4-oxo-4H-l-benzopyran-7-yl]oxy]-aceta~ide ~p. 255-256 Cp~ 147 N-1118-methyl-2-(4-morphol~nyl)-4-oxo-4H-l-benzopyran-7-yl]oxy]acotyl]-Phenylalan~ne, ethyl ester op. 173-Cpd 148 2-[[8-methyl-2-(4-morpholinyl)-4-oxo-4H-l-benzopyran-7-yl]oxy]-N-phenyl-acetamide mp. 242-244 Cpd 149 8-msthyl-2-(4-morpholinyl)-7-[(1-phenyl-lH-tetrazol-S-yl)oxy]-4H-l-Benzopyran-4-one, mp. 209-211 Cpd 150 6-[(1-cyclohexyl-lH-tetrazol-5-yl)methoxy]-2-(4-mor-pholinyl)-4H-l-Benzopyran-4-one, mp. 215-217 Cpd 151 2-[[8-methyl-2-(4-morpholinyl)-4-oxo-4H-l-benzopyrsn-7-yl]oxy]-N-(l-phenylethyl)-acetamide mp. 203-205 Cpd 152 2-[[8-methyl-2-(4-morpholinyl)-4-oxo-4H-l-benzopyran-7-yl]oxy]-N-3-pyridinyl-acetamide mp. 243-245 Cpd 153 N-[[[8-methyl-2-(4-morpholinyl)-4-oxo-4H-l-benzopyran-7-yl]oxy]acetyl]-Phenylalanine mp. 259-262 Cpd 154 7-(2,2-dimethoxyethoxy)-8-methyl-2-(4-morpholinyl)-4H-l-Benzopyran-4-one, mp. 168-169 Cpd 155 2-(4-Morpholinyl)-8-(2-propenyl)-4H-l-benzopyran-4-one mp. 145.5-146.5 Cpd 156 2-(4-Morpholinyl)-8-(1-propenyl)-4H-l-benzopyran-4-one ~p. 163-164 Cpd 157 8-Formyl-2-(4-Morpholinyl)-4H-l-benzopyran-4-one mp.

~ 2006306 209-209.5 Cpd 158 2-(4-morpholinyl)-8-(phenylamino)methyl-4H-l-benzopyr~n-4-one, mp. 226-227 Cpd 159 2-~4-morpholinyl)-8-(2E-phenyl)ethenyl-4H-l-benzopyran-4-one, mp.209-209.5 Cpd 160 8-Hydroxymethyl-2-(4-Morpholinyl)-4H-l-benzopyran-4-one, mp. 243-243.5 Cpd 162 8-methyl-7-[(1-methyl-3-piperidinyl)methoxy]-2-(4-mor-pholinyl)-4H-l-Benzopyran-4-one, mp. 159-161 Cpd 163 8-Methyl-2-(4-morpholinyl)-7-(2-(1-piperi-dinyl)ethyl)oxy-4H-l-benzopyran-4-one mp. 154-156 Cpd 164 8 - M e th y l - 2 - ( 4 - m o r p h o liny l) -7 - (2- (1-pyrrolidinyl)ethyl)oxy-4H-l-benzopyran-4-one mp.

Cpd 165 8-Methyl-2-(4-morpholinyl)-7-(2-(4-morpholinyl)ethyl)-oxy-4~-1-benæopyran-4-ono mp. 170.5-172.5 Cpd 166 8-Methyl-2-(4-morpholinyl)-7-(3-(1-piperi-dino)propyl)oxy-4H-l-benzopyran-4-one ~p. 144-145 Cpd 167 7-(2-Diethylaminoethyl)oxy-8-methyl-2-(4-morpholinyl)-4H-l-benzopyran-4-one mp. 162-162.5 Cpt 16B 7-[2-(ethylphenylamino)ethoxy3-8-methyl-2-(4-mor-pholinyl)-4H-l-B~nzopyran-4-one, mp. 146-147 Cpd 169 7-(2-Diisopropylaminoethyl)oxy-8-methyl-2-(4-morpholinyl)-4H-l-benzopyran-4-one mp. 136.5-138.5 Cpd 170 7-Hydroxy-8-methyl-2-(1-plperidinyl)-4H-l-benzopyran-4-one mp. 278-234 Cpd 171 8-Methyl-2-(1-piperidinyl)-7-(3-pyrindinylmethoxy)-4H-l-benzopyran-4-one mp. 144-158 Cpd 172 7-(2-(4-Penzyl-(l-piperizinyl))ethyl)oxy-8-methyl-2-(4-morpholinyl)-4H-l-benzopyran-4-one mp. 138-139 Example 82: Preparation of 2-(4-~orpholinyl)-4H-l-benzopyran-4-one, Compound 2 Part A: Potassium t-butoxide (134 g, 1.2 mole) is covered with benzene (1 L) in a flame dried round bottom flask equipped with an overhead stirrer, addition funnel, thermometer, and a nitrogen inlet.
This suspension is maintained at lS~C. A solution of o-hydroxyaceto-phenone (54.4 g, 48.1 ml, 0.4 mole) and carbon disulfide (30.4, 24 2()06306 ; -44-ml, 0.4 mole) in benzene (700 ml) l- 510wly added over 1.3 hours, applying an ice bath periodically in order to oaintain the temperature 18-C. The slurry whlch foros i9 stlrret t ~blent - temperature for one day. The reactlon mlxtur- ls tr-nsferred to aseparatory funnel containing water (4 L) and extractet with other (4 x 250 ml) and EtOAc t3 x 250 ml). The aqueous layer is acidifled with 10~ H2S04 (1 L) and stlrred t anblent temperature overnight.
The resultlng solld ls flltered off and dried ln vacuo at 50-C
overnlght to yield 22.07 g of 2-mercapto-4H-l-benzopyran-4-one. Mp 207-8'C.
Part B:
Tosic acid (0.4g, 2 n~ol) i8 added to a solution of 2-mercapto-4H-l-bonzopyran-4-one (3.56 g, 20 omol) and morpholine (2.44 g, 2.44ml, 28 mmol) in benzene (400ml). After refluxing for 4 hours, the reaction mixture is transferred to a separatory funnel containing EtOAc and water. Extracting with EtOAc (2x), washing with combined organic layers with water and brine, and filtering through sodium sulfate yields 4.56 of crude material after evaporation of the solvent. Flssh chromatography over silica gel (300 g, 2.5 MeOH/CHC13, 50 ml fractions) yields 2.07 g of 2-(4-Morpholinyl)-4H-l-benzopyran-4-one (44.8~, fractions 22-32). Mp 160-l-C.
Example ~3 Preparation of 6-Methyl-2-(4-morpholinyl)-4a-1,3-benzoxazin-4-one, Compound 83 The sethyl ester of 5-methylsalicylic acid (2.73 g; 16.4 mmol) is dissolved in acetone (50 ml), cyanogen bromide (1.81g; 17.2 ~mol) is added and the solution is cooled to O~C. Triethylamine (1.73 8;
18.2 m~ol) is dissolved in acetone (5 ml) and added dropwise.
Precipitation occurred rapidly and the solid ls removed by filtration. The filtrate is concentrated in vacuo to afford 3.41 g of the intermediate cyanoether. The cyanoether is dissolved in acetonitrile (50 ,1), morpholine (1.43 g; 16.4 mmol) is added in 5 ml of acetonitrile and the reaction is stirred for two hours at room temperature. Crystals form and the reaction mixture is cooled to 0C, and washed with cold acetonitrile to afford 1.65 g (40.8%).
Mother liquors are recrystallized from acetonitrile to afford 0.54 g (13.4~); mp 197-197.9~C; IR (mull) 2955, 2923, 2858, 1674, 1619, 1576, 1466, 1453, 1433, 1424, 1333, 1325, 1315, 1112, 817 cm~l; lH-NMR (CDC13, 6) 7.91 (d, J-1.4 Hz, 1 H, aromatic), 7.40 (d of d's, . . _ . . . . . .. ~ . .. . . . .... . . . . . . ... ...... .

2~)06306 J-8.3 Hz, 1.9 Hz, 1 H, aromatlc), 7.09 (d, J-8.4 Hz, 1 H, arooatlc), 3~81 (broad s, 8H, morpholine methylenes), 2.40 ~s, 3 H, methyl); W
max (~) 217sh(26,550), 223sh(26,350), 259~15,100), 296(4,250), 304~h(3,550); MaQs spectrum, ions at o/e ~relatlve intensity) 246(parent, 29), 218(10), 189(20), 134(base, 100), 106~18), 105~10), 78(12), 77(8), 28(19);
Anal. Calc'd. for: C13H14N203: C, 63.40; H, 5.73; N, 11-38-Found: C, 63.29; H, 5.92; N, 11.31.
Following the general proceture of Example 83, but employing the appropriate o-hydroxy salicylic methyl ester in place of the methyl ester of 5-methylsalicylic acid there are prepared the following products:
Cpt 84 8-Methyl-2-(4-morphollnyl)-4H-1,3-benzoxazin-4-one, Mp 229-231-C;
15Cpd 85 6-Bromo-2-(4-morpholinyl)-4H-1,3-benzoxazin-4-one, Mp 207-214-C;
Cpd 86 7-Chloro-2-(4-morpholinyl)-4H-1,3-benzoxazin-4-one ; Mp 207-214-C;
Cpd 87 6,8-Bis(l-methylethyl)-2-(4-morpholinyl)-4H-1,3-benzoxazin-4-one, Mp 120-120.5C;
Cpd 88 6-Fluoro-2-(4-morpholinyl)-4H-1,3-benzoxazin-4-one, Mp 220-231-C;
Cpd 89 6-Dimethoxymethyl-2-(4-morpholinyl)-4H-1,3-benzoxazin-4-one; MplOl-108-C;
25Cpd 90 7-Methoxy-2-(4-morpholinyl)-4H-1,3-benzoxazin-4-one, Mp 197-200-C; and Cpd 91 6-(Morpholin-l-yl)-pyrido(2,3-e)-1,3-oxazine-8-one Mp 181-184C.
Following the general procedure of Example 83, but employing the appropriate o-hydroxy salicylic methyl ester in place of the methyl ester of S-methylsalicylic acid and the appropriate heterocylic compound in place of morpholine there are prepared the following products:
Cpd 92 8-Methyl-2-(1-piperidinyl)-4H-1,3-benzoxazin-4-one,Mp 35214.5-217.5C;
Cpd 93 8-Methyl-2-(1-pyrrolidinyl)-4H-1,3-benzoxazin-4-one, Mp 199.5-200.5~C;
Cpd 94 2-(1-pyrrolidinyl)-4H-1,3-benzoxazin-4-one, Mp 163-.. . ..... . . . . . ., . . .. . ... . . . . . .. . .. . .. , = . _, . ~ , , ~ , .

;~00630~;

164-C;
Cpd 95 2~ (4-Thiomorpholinyl))-4H-1,3-benzoxazin-4-one, Mp 179-180'C;
Gpd 96 2-(4-Methyl-l-piperazinyl)-4H-1,3-benzoxaz~n-4-one;
5Example 98: Preparation of 2-(4-Morpholinyl)-4H-1,3-benzoxazin-4-one, Compound 98 (Method A) Nethyl salicylate (25 g, 0.164 M) and BrCN (18.08 B, 0.172 M) is added to dry acetone (500 mL) and cooled to O-C. That mixture is then treated with TEA (17.37 g, 0.172M) ~n acetone (50 ~L) dropwise over 20 minutes. A white precipitate separates from the solution.
After stirring 1 hr the acetone i~ decanted and the precipitate washed with acetone. The filtrate is concentrated in vacuo and used without further purification. The above cyanoether (29.0 g, 0.164 M) is added to acetonitrile (300 mL) und~r an atmosphero of nitrogen.
15 An acetonitrile solution of morpholinQ (14.26 g, 0.164 M) is then added dropwise over 30 minutes. The reaction becomes warm during addition. After stirring a total of 3 hrs the solvent ~8 remo~ad in vacuo to yield a tan olid which is washed w~th ether to yield 22 g (58%) of pure product. An analytical sample is prepared by re-20 crystallization from EtOAc. MP 184.5-86.0C (lit. MP 187-9C);6 IR
(CHC13) 2950, 2825, 2750, 1670, 1620, 1600, 1560, 1460, 1440, 1420, 1340, 1260, 1110, 980, 850 cm~l; lH-NMR (CDC13) 8.25 ~dd, lH, J-1.5 and 6.0 Hz), 7.8-7.2 (m, 3H, aromatic), 3.80 (8, 8H); Mass spectrum:
ions at m/e (relative intensity) 232 (47), 215 (13), 204 (20), 189 25 (11), 176 (14), 175 (56), 121 (35), 120 (100), 92 (46), 64 (14); W
(EtOH) ~ max (~) 210 (24,000), 218 (24,200), 240sh (11,200), 258 (14,750), 286 (4,850), 295 (3,900); Anal. calc't. for C12H12N203: C, 62.06; H, 5.17; N, 12.06. Found: C, 61.70; H, 5.22; N, 11.99.
Example 99 Preparation of 2-(4-Morpholinyl)-4M-1,3-benzoxazin-4-.

one, Compound 98 (Method B) Tosic acid (0.4g, 2 mmol) is added to a solution of 2-mercapto-4H-l-benzopyran-4-one (3.56 g, 20 mmol) and piperidine ~2.38 g, 2.77 ml, 28 mmol) in benzene (400ml). After refluxing for 5 hours, the reaction solution is evaporated in vacuo. The residue is transferred to a separatory funnel with methylene chloride and water. Extracting with methylene chloride, washing the organic layer twice with water, and filtering through sodium sulfate affords 2.80 g of crude material after evaporation of the solvent. Flash chromatography over silica ZOOG3()6 gel (300 g, 7~ MeOH/CH2C12) affords 0.39 g of 2-(4-Horpholinyl)-4H-1,3-benzoxazin-4-one.
Example 101 2-(4-Morpholinyl)-7-(phenylmethoxy)-4H-l-benzopyran-4-one, Compound 101 Prepared by the method outlined in Chart C.
Example 173 Preparation of 4'-Acetoxy-3'-methyl-2'-hydroxy-propiophenone (Relating to Chart E~
Part A
2',4'-Dihydroxy-3'methyl-propiophenone (7.21 g, 40 mmole) is suspended in 200ml dichloromethane in a 500 ml one neck round bottom flask under nitrogen. The suspension is treated with diisopropyl-ethylamine (6.97 ml, 40 mnole) and the solution is cooled to O-C.
Acetyl chloride (3.26 ml, 46 mmole), in 80 ml dichloromethane, is added slowly dropwise to the reaction mixture (1 h~ at 0 C. The mixture is warmed to room temperature and is stirred 20 min. The reaction is washed with 1 X 150 ml 5a hydrochloric acid and the organics are dried over magnesiu~ sulfate. The mixture is concentrated in vacuo to a yellow oil which i8 crystallized and then recrystallized from ethanol to afford 7.2 g (81~) of the acetate as a white solid. Melting Point: 59-61 C.
Part B
Preparation of 7-Acetoxy-3,8-dimethyl-2-(4-morpholinyl)-4H-l-benzopyran-4-one (Cpd 173) 4'-Acetoxy-2'-hydroxy-3'-methyl-propiophenone (6.2 g, 27.9 mmole) is dissolved in 60 ml diethyl ether in a 100 ml one neck round bottom flask under nitrogen. The solution is treated with boron trifluoride etherate and the reaction mixture is stirred overnight at room temperature. The precipitate is collected by filtration and is washed with 150 ml diethyl ether to afford 6.8 g (~0~) of the boron difluoride complex as a yellow solid. The boron difluoride complex (1.05 g, 5.13 mmole) and 4-morpholine phosgene iminium chloride (1.25 g, 4.63 mmole) are combined in 12 ml 1,2-dichloroethanein a 25 ml one neck round bottom flask under nitrogen. The reaction mixture is warmed to 60 C for 3 h. The reaction is cooled to room temperature and the dichloroethane is removed in vacuo. The residual oil is taken up in 12ml acetonitrile in a 25 ml one neck round bottom flask.
The mixture is warmed to 60C, is diluted with 10 ml water, and is stirred for 5 min. The reaction mixture is immediately neutralized with 25 ml saturated sodlum bicarbonate and the acetonitrile i9removed in vacuo. The aqueous residue ls extracted with 4 X 25 ml dichloromethane The combined organics are driot over magnesium sulfate and are concentrated in vacuo to afford 750mg (51~) of Cpd 173 as an orange solid.
Melting Po~nt: 142.5-144.5'C.
Part C
Preparation of 3,8-di~ethyl-7-hydroxy-2-(4-morpholinyl)-4H-l-benzopyran-4-one (Cpd 174) The boron difluoride complex (prepared as in Part A above, 3.0 g, 11.1 mmole) is combined with 4-morpholine phosgene iminium chloride (2.S g, 12.2 mmole) in 29 ol 1,2-dichloroethane in a 50 ml one neck round bottom flask under nitrogen. The reaction mixture is warmed to 60-C for 3.5 h and is cooled to room temperature. The dichloroethane is removed in vacuo and the oily residue is dissoved in 30 ml acetonitrile in a 100 ml ono neck round bottom flask under nitrogen. The solution is ~armed to 60C, is diluted with 25 ml ; water, and iQ rtirred for 5 oin. The reactio~ oixture is immediately quenched with 30 ml saturated sodium bicarbonate and the acetonitrile is reDoved in vacuo. The aqueous residue is extracted with 4 X 25 ml dichloromethane and the combined organics are dried over Dagnesiuo sulfat~. The dried organics are concentrated in vacuo to a yellow solid (2.82 g) which is dissolved in 30 ml oethanol in 100 Dl one neck round bottom flask under nitrogen. The solution is diluted wlth 15 ml water and the mixture is treated ~ith lithiuD hydroxide (800 mg, 19.1 mmole). The reaction mixture is stirred lh at room tempera-ture. The ~ethanol is removed in vacuo and the pH of the aqueous residue is ad~usted to 5 with 5~ hydrochloric acid (pH meter). The precipitated phenol is collected by filtration and is dried to afford 1.2g (40~) of Cpd 174.
Melting Point: >300 C
Part D
Preparation of 7-benzyloxy-3,8-dimethyl-2-(4-morpholinyl)-4H-l-benzopyran-4-one (Cpd 175).
3,8-Dimethyl-7-hydroxy-2-(4-morpholinyl)-4H-l-benzopyran-4-one (355 mg, 1.29 mmole) is suspended in 9 ml dry acetonitrile in a 25 ml one neck round bottom flask under nitrogen. The suspsnsion is treated successively with potassium carbonats (1.1 g, 8.0 mmole) and .... . . ~ .. .

200~i306 49.
benzyl bromlde (213 mg, 1.79 ~mole). The reaction mixture is warmed to 60-C for 16 h and is cooled to room temperatur0. The volatlles are removed in vacuo snd the residue i5 washed with 25 ml dichloro-methane. The insoluable material is romoved by flltratlon ant the filtrate i9 consentrated to a pale oil. The oil is crystallized from diethyl ether to afford 323 mg (69~) of Cpd 175 as a white solid.
Melting Point: 136-137.5-C.
Following the general procedure of Example 173, but starting with the sppropriate 2'-hydroxypropiophenone, there are prepared the following products:
Cpd 176 3,8-Dimethyl-2-(4-morpholinyl)-7-(naphthyl-1-methyloxy)-4H-l-benzopyran-4-one mp. 204-206 Cpd 177 3,8-Dimethyl-7-(4-methoxy-benzyloxy)-2-(4-morpho-- linyl)-4H-l-benzopyran-4-one mp. 141-142 lS Cpd 178 3,8-Dimethyl-2-(4-morpholinyl)-7-(2-phenyl-ethyloxy)-4H-l-benzopyran-4-one mp. 160-161.5 Cpd 179 3,8-Dimethyl-7-(4-chlorobenzyloxy)-2-(4-morpholinyl)-4H-l-benzopyran 4-one mp. 166-167.5 Cpd 180 3,8-Dimethyl-2-(4-morpholinyl)-7-(3-trifluoromethyl-benzyloxy)-4H-l-benzopyran-4-one mp. 158.5-160 Cpd 181 7-(Carbomethoxy-methoxyl)-3,8-dimethyl-2-(4-morpholinyl)-4H-l-benzopyran-4-one mp. 174-17S
Cpd 182 8-Hydroxy-3-methyl-2-(4-morpholinyl)-4H-l-benzopyran-4-one mp. 239-240 2S Cpd 183 8-Benzyloxy-3-methyl-2-(4-morpholinyl)-4H-l-benzo-pyran-4-one mp. 134-13S
Cpd 184 3-methyl-2-(4-morpholinyl)-8-(m-trifluoromethyl-benzyloxy)-4H-l-benzopyran-4-one mp. 160.S-161 Example 185 Preparation of C-7 alkyl, alkenyl and alkynylaryl substituents. (relating to Chart F) Part A
Preparation of 2'-Hydroxy-3'-methyl-4'-trifluormethanesul-fonyloxy-acetophenone.
3S 2',4'-Dihydroxy-3'methyl-acetophenone (11 g, 60.2 mmole) is suspended in 300 ml dichloromethane in a 1000 ml one neck round bottom flask under nitrogen. The suspension is treated successively with pyridine (4.4 ml, 54 m~ole) and N,N, dimethylamino-pyridine (730 ~00~306 mg, 6 mmole) and the solution ls cooled to O-C. Tr~fllc anhydrlde (11 ml, 66.2 mmole), ln 1 X 100 ml dichloromethane, i~ sdded 910wly dropwise to the reaction mixture (30 min). The reaction is stirred for 1 h at room temperature for 1 h and the mixture is washed with 2 X 200 ml 5~ hydrochloric acid. The organics are dried over magnesium sulfate and are concentrated in vacuo to a yellow oil. The oil is distilled via kugelrhor under high vacuum (165 C) to provide 16.4 (91~) of triflate as a white solid.
Melting Point: 60-64-C
Part B
Preparation of 8^methyl-2-(4-morpholinyl)-7-trifluormethane-sulfonyloxy-4H-l-benzopyran-4-one.
2'-Hydroxy-3'-methyl-4'-triflouromethanesulfonyloxy-acetophenone (1.5 g, 5.03 mmole) ls dissolved in 10 ml dlethyl ether ln a 25 ml one neck round bottom flask under nitrogen. The solutlon i9 treated with boron trifluoride etherate (0.9 ml, 7.5 mmole) and the react~on mixture is stirred for 6 h at room temperature. Approximately 1/2 the ether is removed in vacuo and the precipitate is collected by filtration. The pale solid is washed with cold diethyl ether to afford 1.1 g (63%) of difluoroboronate. Boron difluoride complex (1.1 g, 3.2 ~mole) is combln~d wlth 4-morpholinophosgeniminlum chloride (0.72 g, 3.5 ~mole) in 12 ml 1,2-dichloroethane in a 50 ml one neck round bottom flask under nitrogen. The reaction mixture is warmed to 65C for 3 h and is cooled to room temperature. The precipitate is removed by filtration and ic washed with diethyl ether to provide 1.35 g. The solid is supended in 12 ml acetonitrile in a 25 ml one neck round bottom flask under nitrogen. The suspension is stirred with 1.2 ml water for 48 h. The colorless solution is diluted with 10 ml satursted sodium bicarbonate and the acetonitrile is removed in vacuo. The aqueous residue is extracted with 4 X 25 ml dichloromethane. The combined organics are dried over magnesium sulfate and are concentrated in vacuo to a red solid. The solid is recrystallized from ethyl acetate to afford 566 mg (45~) of chromone-triflate as an off white solid.
Melting Point: 151-155C.
Part C
Preparation of 8-methyl-7-(2-phenyl)ethynyl-2-(4-morpholinyl)-4H-l-benzopyran-4-one (Cpd 185).

a -Methyl-7-(trifluoromethanesulfonyloxy)-2-(4-oorphollnyl)-4H-l-benzopyran-4-one (190 mg, 0.48 mmole) iq suspended in 6 ml 1:1 ben-zene/triethylamine in a 15 ml screw cap preqsure tube. The suspension is treated successively with phenyl acetylene (100 ul, 0.91 mmole), bis (triphenylphosphine) palladiuD dichloride ~14 mg, 0.02 mmole), and cuprous iodide (2 mg, 0.01 onole). The reaction mixture is warmed to 100-llO-C overnight. The reaction mixture is cooled to room temperature and is again treated successively with phenyl acetylene (100 ul, 0.91 m~ole), bis (triphenylphosphlne) palladium dichloride (14 mg, 0.02 mole), and cuprous iodide (2 mg, 0.01 ~s ole). The reaction is heated to llO-C for 4 h and is cooled to room temperature. The volatiles are removed in vacuo to a black - residue. The residue is chromatographed over 12 8 silica gel (230-400 mesh) eluting with 1~ methanol/dichloromethane and collecting 3 ml fraction s for 48 fractions. Thereafter elution is carried out with 2a methanol/dichloromethane and 5 ml fractions are collected.
Fractions 55-72 are combined and concentrated to provide 153 mg of a dark brown solid. The solid is recrystallized from ethyl acetate to afford 94 mg (56%) of Cpd 185 as a pale grey solid.
Melting Point: 228.5-229.5-C.
Exa~ple 186 Preparation of 3-methyl-2-(4-morpholinyl)-7-(2-phenyl)ethyl-4H-l-benzopyran-4-one (Cpd 186).
8-Methyl-2-(4-morpholinyl)-7-(2-phenyl-ethynyl)-4H-l-benzopyran-4-one (90 mg, 0.261 mmole) is dissolved in 90 ml 8:1 methanol/acetone in a Parr shaker bottle. The solution is treated with 18 mg 10~
palladium on carbon and the reaction mixture is hydrogenated at 40 PS~ for 2 h. The catalyst is removed by filtration through a 1~ bed of celite and the filter cake is washed well with methanol. The filtrate is concentrated in vacuo to a yellow oil which crystallized from hexane to give 70 mg (77~) of Cpd 186 as a tan solid. Melting Point: 162-163-C.
Following the general procedures of Example 185, but starting with the appropriate 2'-hydroxyacetophenone, there are prepared the following products:
Cpd 187 2-(4-Morpholinyl)-8-(2-phenyl)ethynyl-4H-l-benzopyran-4-one mp. 196-197 Cpd 188 2-(4-Mo~pholinyl)-8-(2-phenyl)ethyl-4H-l-benzopyran-4-one mp. 110-112 Cpd 189 2-(4~orpholinyl)-8 (2-(3-trifluorooethyl-)phenyl~ethynyl-4H-l-benzopyran-4-one mp. 157.5-158.5 Cpd 190 2-(4-Morpholinyl)-8-(2-(3-trifluoromethyl)phenyl)-ethyl-4H-l-benzopyran-4-one mp. 130-131 Cpd 192 8-Methyl-2-(4-morpholinyl)-7-(2-(1-naphthyl))ethyl-4H-l-benzopyran-4-one mp. 188.5-189.5 Cpd 193 8-Methyl-2-(4-morpholinyl)-7-phenyl-4H-l-benzopyran-4-one mp. 194.5-195 Example 194 (Relating to Chart G) Part A
Preparation of 4'-acetoxy-3'-iodo-2'-hydroxy-propiophenone 2',4'-dihydroxy-3'-iodoacetophenone (55.6 g, 0.2 mol) is suspended ln 600 ml of methylene chloride. Triethylamine (27.8 ml, 0.2 mol) is added and the cooled mixture (0C) is treated dropwise with acetyl chloride (16.35 ml, 0.23 mol). The mixture is stirred at 0C for 1 h and at ambient temperature for 2 h. The mixture is washed with 53 hydrochloric acid, dried owver magnesium sulfste and evaporated. The solid is recrystallized from ethanol to provide 48.39 g of the product.
Part B
Preparation of 7-acetyloxy-8-iodo-2-(4-morpholinyl)-4H-l-benzopyran-4-one (Cpd 194) 4'-Acetoxy-3'-iodo-2'-hydroxy-propiophenone (43.4 g, 0.15 mol) is suspended in 750 ml of ether and treated with boron trifluoride etherate (27.9 ml, 0.22 mol). The mixture is stirred overnight at ambient temperature, filtered and the solid is washed well with ether to afford 47.0 g of the boron difluoride complex. The complex is eombined with 4-morpholine dichloromethyleniminium chloride in 400 ml of ethylene dichloride and heated at 70C for 5 h and at 50C for 16 h. The reaction is cooled to 0C and the solid is filtered and washed well with ether (45 g). The solid is suspended in 400 ml of acetonitrile, 40 ml of water is added and the mixture is stirred overnight at room temperature, heated at 50C for 2 h and finally heated at 60C for 30 min. The solvent is evaporated and the material is taken up in methylene chloride/ saturated sodium bicar-bonate. The aqueous layer is extracted twice with methylene chloride and the combined organics are dried over magnesium sulfate. Evapora-;~006306 tion of the solvent and recrystalllzatlon from methanol gave 20.8 g (398) of the chromone. The mother liquors contalned 5.8 g of crude product from whlch a second recrystallization yielded 0.7 g. mp.
201.5-202.5 Part C
Preparation of 8-ethyl-7-hydroxy-2-(4-morpholinyl)-4H-l-benzo-pyran-4-one 7-Acetyloxy-8-lodo-2-(4-morpholinyl)-4H-l-benzopyran-4-one (2.07 g, 5.0 mmol) is combined with lithlum chloride (0.64 g, 15 ~mol) 10 tetraethyltin (1.04 ml, 5.25 mmol) and (bis)trlphenylphosphine palladium dichloride (70 mg, 0.10 mmol) in 20 ml of dimethylfor-mamide. The mixture is heated a 100C for 40 min., poured into half saturated sodi~m chlorlde and extracted twice with methylene chlor-ide. The organics are washed twlce with half saturated ~odium chloride, dried over magnesium sulfate and evaporated. The material is ta~en up in 20 ml of methanol and 10 ml of water and treated with 0.63 g (15 mmol) of lithium hydroxide. The mixture is stirred at room temperature for 30 min. The solvent i8 evaporated, the mixture is diluted with water and extracted twice with ethyl acetate. The aqueous layer is acidified to pH 6.1 qirh 5% hydrochloric acld and the solid is filtered, washed with ether and dried to afford 0.98 gt (71%) of the product.
Part D
Preparation of 8-ethyl-2-(4-morpholinyl)-7-(3-pyrindinyl-25 methoxy)-4H-l-benzopyran-4-one (Cpd 195) 8-Ethyl-7-hydroxy-2-(4-morpholinyl)-4H-l-benzopyran-4-one (0.176 g, 0.64 mmol) and sodium hydride (0.105 g, 60%, 2.6 mmol) are combine in 4 ml of dimethylformamide and heated to 60C for 20 min. 3-Picoyl chloride hydrochloride (0.321 g, 1.76 mmol) is added and the mixture is heated at 60C for 1 h. The cooled mixture is poured into 2N
sodium hydroxlde and ice. The solid ls flltered, washed well wlth water and ether and recrystallzed form ethyl acetate to provide 0.156 g of the product. mp.178-179 Following the general procedure of Example 194, but starting with the 2'-hydroxyacetophonone, there are prepared the following products:
Cpd 196 8-Ethyl-2-(4-morpholinyl)-7-phenylmethoxy-4H-l-benzopyran-4-one mp. 153-154.5 . . .. . . .... . . . . .. . . .. .. . ... .. _, _, . . . . .. . . _ . _ . .. .. . _ _ _ . . .

Cpd 197 8-Iodo-2-(4-morphollnyl)-7-phenyloethoxy-4H-l-benzopyran-4-one mp. 155-157 Cpd 198 8-Ethyl-2-(4-morpholinyl)-7-(2-(1-piperi-dinyl)ethyl)oxy-4H-l-benzopyran-4-one mp. 151-152 Cpd l99 8-Iodo-2-(4-morpholinyl)-7-(3-pyrindinylmethoxy)-4H-l-benzopyran-4-one mp. 214-215 Cpd 200 8-Iodo-7-hydroxy-2-(4-morpholinyl)-4H-l-benzopyran-4-one mp. 224-225 Example 201 (Relating to Chart H) Part A
Preparation of 7-hydroxy-8-methyl-2-(1-piperidinyl)-4H-l-benzopyran-4-one (Cpd 201).
Palladiu~ black (225 mg) is added to a solution of the benzyl ether Gpd 31 (1.00 g, 2.86 mmol) in EtOAc (80 ml). After sh~klng in a Parr hydrogenation apparatus under 50 lbs pressure of hydrogen for 2 days, the catalyst is filtered off through a cintered glass funnel rinsing with EtOAc and MeOH. Evaporation of the solvent afforded 0.99 g of crude material. Flash chromatography (~0 g silica gol, 10~
MeOH/CH2C12) afforded 0.83 g of the phenol. Recrystallization from 20 MeOH~EtOAc at 4C afforded 0.65 g (88~) of white crystalline title product. mp 278-284C.
Part B
Preparation of 7-(3-pyridinylmethoxy)-2-(l~piperidinyl)-8-methyl-4H-l-benzopyran-4-one, Cpd 202.
A suspension of phenol Cpd 170 (130 mg, 0.5 mmol), 3-picolinyl chloride-HCl (161 mg, 1.0 mmol), and potassiu~ carbonate (277 mg, 2.0 mmol) in dimethylformamide (5 ml) is stixred at 90C. After 7 days, the reaction mixture is evaporated down and then CRC13 added. The solids are filtered off and the filtrate evaporated. Flash 30 chromatography of the residue (15 ~ silica gel, 2~ MeOH/CH2C12, 6 ml fractions) afforded 18 mg (10%, fractions 37-52) of Cpd 202. mp 144-58C.
Example 203 Preparation of 7-phenylmethoxy-2-methylthiomethyl-8-methyl-4H-l-benzopyran-4-one, Cpd 203 (Relating to Chart I) Part A: Sodium hydride (50% oil dispers$on washed 3x in hexane, 23.2 g, 0.48 mol) is stirred in THF (195 ml) under nitrogen in a flame dried 2 1 three-necked round bottom flask equipped with an addition funnel and a condensor. A solution of the 2-hydroxyaceto-_, . ... . .. . ~ .,, .. , . . , . , . .. .. , .. , . , ..... . .. , . , , , . . . _ , . . . .. .
.

~55 phenone (25 g, 97.6 mmol) and ethyl o-thlomethyl- acetate (130.4 g, 123 ol, 0.9 mol) ln THF (164 ml) i9 slowly dropped lnto the sodlum hydrlde slurry. After about half of th~ reagent solutlon had beon added the reaction ls heated with a heatlng gun untll th~ reactlon had begun to reflux on lts own. The remalnder of the reagent solutlon ls slowly added wlth stlrrlng. After 10 nin at amblent temperature and 1 h 40 mln at reflux, the solution i~ evaporatod in vacuo. The solution i8 transferred to a separatory funnel with methylene chloride/2N HCl and shaken for about 10 oin. E~traction wlth methylene chloride (2x) and drying over magnesium sulfate affords the crude ~-diketone which is not further purlfied.
A biphasic solution of the ~-dikeone and 6N HCl (250 ml) is stirred at ambient temperature overnight. Extraction with methylene chloride and drying over magnesium sulfate afforded 127.13g of crude material after evaporation of the solvent. Flash chromatography (700 g silica gel, 30-50% EtOAc/hexane) afforded 122 g of a mixture of the starting acetophenone, the thiomethylacetate, and some ~-diketone and 4-94 8 Cpd 203 (15~). An analytical sample is recrystallized from ether/hexane to afford white crystalline title product. mp 110-114 C.
Part B
Preparation of 7-phenylmethoxy-2-iodomethyl-8-methyl-4H-l-benzopyran-4-one A solution of Cpd 203 (4.0 g, 12.3 mmol) in methyl iodide (12.5 ml) and CH2C12 (8 ml) is stirred under reflux. After 3 days, the solution is cooled to 0DC and the yellow precipitate filtered off.
The filtrate is evaporated down and the residue flash chromato~raphed (100 g silica gel, 40~D EtOAc/hexane) to afford 1.48 g of 7-phenylmethoxy-2-iodomethyl-8-methyl-4H-l-benzopyran-4-one (30~). An analytical sample is prepared by recrystallization from CH2C12/EtOAc/hexane to afford white crystalline title product. mp 144-7C;
Part C
Preparation of 8-Methyl-2-(4-morpholinylmethyl)-7-(phenylmethoxy)-4H-l-benzopyran-4-one (Cpd 204) Morpholine (0.21 g, 2.5 mmol) is added to a stirring solution of 7-phenylmethoxy-2-iodomethyl-8-methyl-4H-l-benzopyran-4-one (1.0 g, 2.5 mmol) and triethylamine (0.25 ml, 2.5 mmol) in CHC13 (12 ml).

... . . . . . .. . . . . .. ...

After seirrlng at ambient temperature for 2.5 h, the solvent i9 evaporated in vacuo. The residue is flash chrooatographed (100 g silica gel, 50-100~ EtOAc/CH2C12, 45 ml fractions) to afford 0.72 g (79~) of the product. Recrystallization froo ether affordet a white solid tltlo product. MP 130-3-C.
Part D
Preparation of 7-hydroxy-2-(4-morpholinyloethyl)-8-nethyl-4H-l-benzopyran-4-one, Cpd 205 Palladium black (140 og) i8 added to a solutlon of the benzyl ether Cpd 204 (0.65 g, 1.78 mmol) ln EtOAc (50 ml). After shaking in a Parr hydrogenation apparatus under 50 lbs pressure of hydrogen for 23 h, the catalyst is filtered off through a cintered slass funnel rinsing with EtOAc and MeOH. Evaporation of the solvent afforded 0-49 8 of crude material. Flash chromatography (100 g silica gel, 4~
MeOH/CH2C12, 50 ml fractions) afforded 35 ng (5~, fractions 6-7) of the starting material and 0.33 g (688, fractions 11-16) of the phenol. An analytical sample i9 prepared by recrystallization from EtOAc/ether/hexane st 4-C to afford white crystalline title product.
MP 144-6-C;
Part E
Preparation of 7-[(1-cyclohexyl-lH-tetrazol-5-yl)methyoxy]-8-methyl-2-(4-morpholinylmethy)-4H-l-benzopyran-4-one, Cpd 206 A suspension of Cpd 205 (100 mg, 0.36 mmol), 5-(4-chloromethyl)-l-cyclohexyltetrazole [see e.g. Chem. Pharm. Bull. 31, 1151 (1983~] (146 mg, 0.73 mmol), and potassium carbonate (201 mg, 1.45 ~nol) in acetonitrile (3 ml) is stirred at 60OC. After 17 h, the reaction mixture is evaporated down and then CHC13 added. The solids are filtered off and the filtrate evaporated. Flash chromatography of the residue (25 g silica gel, 3~ MeOH/CH2C12, 15 ml fractions) afforded 134 mg (85~, fractions 5-6) of white crystalline title product. MP 193-5C;
Part F
Preparation of 8-Methyl-2-(4-morpholinylmethyl)-7-(3-pyridinylmethoxy)-4H-l-benzopyran-4-one, Cpd 207 A suspension of Cpd 205 (50 mg, 0.18 mmol), 3-picolinyl chloride-HCl (58 mg, 0.36 mmol), and potassium carbonate (100 mg, 0.72 mmol) in acetonitrile (2 ml) is stirred at 60C. After 2 days, the reaction mixture is evaporated down and then CHC13 added. The ~olids aro filtorod off and tho flltrato o~aporatod. Fl-sh chromatography of tha residue (20 8 silica eol, 3~ MeOH/CH2C12, 10 ml fractions) afforded 45 mg (680, fractions 17-25) of white crystalline title product which is recrystallized fron othor. ~p 105-8-C.

.___ . . . , , . . . . . . .. . . _ . . .. . . , . . ._ . , . _ . _ . ~ _ ... .. _ __..... .
... .

R6~C2 R? ~ OH

R5 o R5 o R6~ halogell ~halo R7~\o NR9R10 R7~\o NR9R10 R5 o R5 0 R6 ~N2 R6 ~NH2 R7~--0 NR9R10 R7 \~ NR9R10 _ ._.. . .

CHART B

R5 o R6 ~CH3 R7 ~0H

¦ (CH3)2N CH(OCH3)2 R6~ ~ H(CH3)2 ¦ halogen/organic solvent R6~ 9R9Rlo ~0~
R7 \~/ o NR9R10 . _ _ . .. . . .. . .. .. . . . ..... .. . .. .. ... . .. . . _ .. . . _ _ _ _ .. .. .

CHART C

R6~` ~-- [ ~ --~ base ~ CS2 organic acid R7~ \I~OH solvent _ .
a8 R5 o a6~J~
I O I ~
R7 ~\ SH

¦ Hl;RgRIo R6~

R7 R8 NRgR10 CHART D

(BZ)n ~
O ~:RgR10 ~J~
~HO)n ~) ¦ ~
\/ \ o NR9R10 Base (R5 R6/R7 or R8 ) ~~
(R5/R6/R7 ~

o NR9R10 .. . . . . .. . . . .. ..

~0~6306 ~62 CHART 1~

HO ~oll --AcO J~3~ Cl Cl-1. Q

1 2. H20 O 1. LiOH

~ 2. Ph/~ Br j~
0~0 N/\l base o~ N~l CH3 ~ CH3 ~O

CHI~RT F

HO~L~ F3C--SO~ F3C--~1 J~F

C~

Cl Cl---/

F3C--3~ J~N~

Ph----H _ PtII, CuI

~ U~ N~

~64~
CHART G

NoJ~3~ ACO~ + C

1 2. H20 NO~ ICOJ~
Et 1~, o 2 . LiOH I ~

~';'`1 Et ~O

~N

ZC)~t~306 ~6S-CI~RT H

~O~`l~RsRlo ~o~R9R10 c~3 CH3 RO ~ NR9Rlo 200630~;
~66~
CHART I

O O

CH3 ~ ~ SCH3 ~V~~' ~ 9RgRlo O O

HO ~ NR9R10 RO ~ NR9R10 CH3 C~3 ~67-FORMIJIA

R6~x ~ O 1 R6 ~Z
1 O ¦ ~ IA
R7 \~o Y

~ IB
R7 o Y

FORMUI~ (Contlnued) N\ ~ II

R' ¦ ~R' ' '

Claims (17)

1. A compound of Formula I

I

wherein X is CZ where Z is H, C1-C5 alkyl, amino (-NH2) or a halogen atom;
Y is selected from the group consisting of -(CH2)nNR9R10 wherein R9 and R10, being the same or different, are selected from the group consisting of (a) hydrogen, with the provisio that R9 and R10 are not both hydrogen; (b) C1-C12 alkyl; (c) phenyl optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(C1-C4alkyl); (d)-(CH2)nphenyl [wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, tri-fluoromethyl or -CO2(C1-C4alkyl)], (e) -(CH2)npyridinyl or (f) wherein R9 and R10, taken together with N, form a saturated or unsaturated heterocyclic amine ring selected from the group consisting of (aa) 4-morpholine optionally substituted with one or two members selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl, (bb) 4-thiomorpholine optionally substituted with one or two members selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl, (cc) 3-amino-1-pyrrolidine, (dd) 1-pyrrolidine optionally substituted with one or two members selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, OH, -CH2OH, or trifluoromethyl, (ee) 1-piperidine optionally substituted with one or two members selected fron the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, trifluoromethyl, -(CH2)qOH, -CO2H, -CO2CH3, -CO2CH2CH3 or phenyl (wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl), (ff) 1-piperazine, 4-methyl-1-piperazine, 4-phenyl-1-piperazine (wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl) or 4-pyridinyl-1-piperazine optionally substituted with one or two members selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, trifluoromethyl, -CH2OH, -CO2H-, -CO2CH3 or -CO2CH2CH3, and (gg) thiazolidine, thiazolidine-4-carboxylic acid, pipecolinic acid, p-piperazinaceto-phenone, 1-homopiperazine, 1-methylhomopiperazine, 4-phenyl-1,2-3,6-tetrahydropyridine, proline, tetra-hydrofurylamine, 1-(3-hydroxy)pyrrolidine, nipecotamide, 1,2,3,4-tetrahydroisoquinoline or imidazole;
and R5, R6, R7 and Rg, being the same or different, are selected from the group consisting of hydrogen, C1-C8 alkyl, -(CH2)nphenyl [wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(C1-C4alkyl)], -(CH2)nnaphthyl, -(CH2)npyridinyl, -(CH2)qNR9R10, -CH=CH-phenyl [wherein phenyl as optionally sub-stituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(C1-C4alkyl)], -CH2-CH=CH2, -CH=CH-CH3, -O-CH2-CH=CH2, -C=C-phenyl [wherein phenyl is optionally sub-stituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(C1-C4alkyl)], -O(CH2)p(N-methylplperdin-3-yl), -O-(CH2)pNR9R10, -O-CH2CH(OCH3)2, -O-(CH2)pOR15, -(CH2)nC(O)-(CH2)nR9, -(CH2)nC(O)O-(CH2)pR9, -(CH)nC(O)O-(CH2)pNR9R10, -(CH2)nC(O)(CH2)nNR9R10, NO2,-O-(CH2)nC(O)-(CH2)pR9, -O-(CH2)nC(O)O-(CH2)pR9, -O-(CH2)nC(O)-(CH2)nNR9R10, -NR9R10, -N(R9)(CH2)nC(O)-(CH2)nR10, -N(R9)-(CH2)nC(O)O-(CH2)nR10, N(R9)(CH2)nC(O)-(CH2)nNR9R10, -O-(CH2)nphenyl [whereln phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trlfluorooethyl or -CO2(C1-C4alkyl)], -O-(CH2)npyrldine, -O(CH2)nC(O)-(CH2)npyridine, -O-(CH2)nC(O)O-(CH2)npyrldine, -O(CH2)nC(O)-N(R9)(CH2)npyridine, -O-(CH2)nquinoxalinyl, -O-(CH2)nquinolinyl -O-(CH2)npyrazinyl, -O-(CH2)nnaphthyl, -O-(CH2)nC(O)-(CH2)nnaphthyl, -O-(CH2)nC(O)O-(CH2)nnaphthyl, -O-(CH2)nC(O)NR9-(CH2)nnaphthyl, halo (fluoro, chloro, bromo, iodo), OH, -(CH2)q-OH, (CH2)qOC(O)R9, -(CH2)qOC(O)-NR9R10, (1-cyclohexyl-1H-tetrazol-5-yl)C1-C4 alkoxy, -[1-(C1-C5alkyl)-1H-tetrazol-5-yl]C1-C4 alkoxy, -[1-tphenyl)-1H-tetrazol-5-yl]C1-C4 alkoxy [wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(C1-C4alkyl)], -[1-(pyridinyl)-1H-tetrazol-5-yl]C1-C4 alkoxy, -[1-(1-phenylethyl)-1H-tetrazol-5-yl]C1-C4 alkoxy, -C1-C4 alkoxyl, a group of Formula II wherein R' is methyl or carboxy, R'' is hydrogen and R''' is selected from benzyl [optionally substituted with one, two or three groups selected from hydroxy, halogen or phenoxy (optionally substituted with one, two or three groups selected from hydroxy or halogen)], C1-C5 alkyl, -(CH2)nCO2H, -CH2SH, -CH2SCH3, ioidazolinylmethylene, indolinylmethylene, CH3CH(OH), CH2OH, H2N(CH2)4-(optionally in protected form) or H2NC(NH)NH(CH2)3 (optionally in protected form); with the overall proviso that when Y is other than -(CH2)nmorpholinyl, at least one member of R5, R6, R7 or R8 is other than hydrogen, C1-C8 alkyl, NO2, OH, C1-C4 alkoxy, a halogen atom, phenyl, benzyl, 4-morpholinylmethyl, NH2, or dimethyamino; with the further proviso that when Y is 4-morpholinyl, the compound is other than:
6,7-dimethoxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one, 7,8-(Bis)-(3-trifluoromethyl)phenylmethoxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one, N-cyclohexyl-2-[[8-methyl-2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-7-yl]oxy]-acetamide,

2-[[8-methyl-2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-7-yl]oxy]-N-phenyl-acetamide, 6-[(1-cyclohexyl-1H-tetrazol-5-yl)methoxy]-2-(4-mor-pholinyl)-4H-1-Benzopyran-4-one, 2-[[8-methyl-2-(4-morphollnyl)-4-oxo-4H-1-benzopyran-7-yl]oxy]-N-(1-phenylethyl)-acetamide;
with the further provisio that when Y is dimethylamino, the compound is other than:
2-(Dimethylamino)-8-methyl-4-oxo-4H-1-benzopyran-7-yl carbamic acid dimethyl ester, (Dimethylamino)-4-oxo-4H-1-benzopyran-6-yl carbamic acid dimethyl ester, 2-(Dimethylamino)-4-oxo-4H-1-benzopyran-7-yl carbamic acid dimethyl ester;
R15 is selected from C1-C5 alkyl, -(CH2)nphenyl [phenyl optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(C1-C4alkyl)], -(CH2)npyridin-1-yl or -(CH2)ppiperidin-1-yl;
n is 0-5;
p is 2-5;
q is 1-5;
and pharmaceutically acceptable salts and hydrates thereof.

2. A compound according to Claim 1 wherein Y is selected from the group consiting of -(CH2)nNR9R10 wherein R9 and R10, taken together with N, form a saturated or unsaturated heterocyclic amine ring selected from the group consisting of:
(aa) 4-morpholine optionally substituted with one or two members selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl, (bb) 4-thiomorpholine optionally substituted with one or two members selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl, (cc) 3-amino-1-pyrrolidine, (dd) 1-pyrrolidine optionally substituted with one or two members selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, OH, -CH2OH, or trifluoromethyl, (ee) 1-piperidine optionally substituted with one or two members selected from the group consisting of Cl-C4 alkyl, C1-C4 alkoxy, halo, trifluoromethyl, -(CH2)qOH, -CO2H, -CO2CH3 -CO2CH2CH3 or phenyl (wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl), (ff) 1-piperazine, 4-methyl-1-piperazine, 4-phenyl-1-piperazine (wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl) or 4-pyridinyl-1-piperazine optionally substituted with one or two members selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, trifluoromethyl, -CH2OH, -CO2H, -CO2CH3 or -CO2CH2CH3.

3. A compound according to Claim 1 wherein Z is H or C1-C5 alkyl.

4. A compound according to Claim 3 wherein Y is selected from the group consisting of -(CH2)nNR9R10 wherein n is 0 or 1, and R9 and R10, taken together with N, form 4-morpholine.

5. A compound according to Claim 4 wherein Z is H.

6. A compound according to Claim 5 wherein n is 0.

7. A compound according to Claim 2 wherein at least one member selected from R5, R6, R7 or R8 is selected from:
the group consisting of -(CH2)pphenyl [wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(C1-C4alkyl)], -(CH2)nnaphthyl, -(CH2)npyridinyl, -(CH2)qNR9R10, -CH=CH-phenyl [wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(C1-C4alkyl)], -CH2-CH=CH2, -CH-CH-CH3, -O-CH2-CH=CH2, -C=C-phenyl [wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, trifluoromethyl or -CO2(C1-C4alkyl)], -O(CH2)p(N-methylpiperdin-3-yl), -O-(CH2)pNR9R10, -O-CH2CH(OCH3)2, -O-(CH2)pOR15, -(CH2)nC(O)-(CH2)nR9, -(CH2)n-C(O)O-(CH2)pR9, -(CH)nC(O)O-(CH2)pNR9R10, -(CH2)nC(O)(CH2)n-NR9R10, -O-(CH2)nC(O)-(CH2)pR9, -O-(CH2)nC(O)O-(CH2)pR9, -O-(CH2)nC(O)-(CH2)nNR9R10, -NR9R10, -N(R9)(CH2)nC(O)-(CH2)nR10, -N(R9)-(CH2)nC(O)O-(CH2)nR10, N(R9)(CH2)nC(O) (CH2)nNR9R10, -O-(CH2)nphenyl [wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(C1-C4alkyl)], -O-(CH2)npyridine, -O(CH2)nC(O)-(CH2)npyridine, -O-(CH2)nC(O)O-(CH2)npyridine, -O(CH2)nC(O)-N(R9)(CH2)npyridine, -O-(CH2)nquinoxa1inyl, -O-(CH2)npyrazinyl, -O-(CH2)nnaphthyl, -O-(CH2)nC(O)-(CH2)nnaphthyl, -O-(CH2)nC(O)O-(CH2)nnaphthyl, -O-(CH2)nC(O)NR9-(CH2)nnaphthyl, -(CH2)q-OH, (CH2)qOC(O)R9, -(CH2)qoC(O)-NR9R10, (1-cyclohexyl-1H-tetrazol-5-yl)C1-C4 alkoxy, -[1-(C1-C5alkyl)-1H-tetrazol-5-yl)C1-C4 alkoxy, -[1-(phenyl)-1H-tetrazol-5-yl]C1-C4 alkoxy [wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(C1-C4alkyl)], -[1-(pyridinyl)-1H-tetrazol-5-yl]C1-C4 alkoxy, -[1-(1-phenylethyl)-1H-tetrazol-5-yl]C1-C4 alkoxy, or -C1-C4 alkoxyl.

8. A compound according to Claim 2, 3, 4 or 6 wherein R5, R6, R7 and R8 are selected from the following groups:
(i) R5, R6, R7 and R8 are each hydrogen; or (ii) R5, R6, and R8 are each hydrogen, and R7 is selected from:
-O-(CH2)nphenyl (wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo or tri-fluoromethyl), -C=C-phenyl (wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl), or -(CH2)nphenyl (wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl); or (iii) R5 and R6 are hydrogen, R8 is hydrogen, halo or C1-C5 alkyl, and R7 is selected from: -O-(CH2)nphenyl (wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl), -O-(CH2)npyridinyl (wherein pyridinyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C -C4 alkoxy, halo or trifluoromethyl), -O-(CH2)nnaphthyl, -(CH2)nphenyl (wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl), -(CH2)ppyridinyl (wherein pyridinyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl), -(CH2)p(1-piperidinyl), -(CH2)p(1-pyrrolidinyl) or -[(1-cyclohexyl-1H-tetrazol-5-yl)C1-C4 alkoxy; or (iv) R5, R7 and R8 are each hydrogen, and R6 is -NH-C(O)-O-CH2phenyl.

9. A compound according to Claim 1 selected from the group consisting of:
Cpd 1 6-Chloro-2-(4-morpholinyl)-4H-1-benzo pyran-4-one;
Cpd 2 2-(4-morpholinyl)-4H-bonzopyran-4-one;
Cpd 3 8-Methyl-2-(4-morpholinyl)-(7-phenylmethoxy)-4H-benzopyran-4-one;
Cpd 4 7-Chloro-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 5 8-Chloro-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 6 6-Bromo-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 7 6-Fluoro-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 8 6-Methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 9 7-Methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 10 8-Methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 11 6-Methoxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 12 7-Methoxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 13 6-(Phenylmethoxy)-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 14 8-(Phenylmethoxy)-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 15 [2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-6-yl]-1,1-dimethylethyl carbamic acid ester;
Cpd 16 6-(3-pyridinecarboxamide)-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 17 2-(4-Morpholinyl)-6-nitro-4H-1-benzopyran-4-one;
Cpd 19 6-([[Phenylmethoxy]carbonyl]amino)-2-(4-morpholinyl)-4H-l-benzopyran-4-one;
Cpd 20 8-Methoxy-2-(4-morpholinyl)-4H-1- benzopyran-4-one;
Cpd 21 3-Amino-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 22 3-Chloro-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 23 3-Bromo-2-(4-morpholinyl)-4H-1-benzopyran-4-one;

Cpd 24 8-Methyl-2-(4-morpholinyl)-7-(phenylmethoxy)-4H-1-benzopyran-4-one;
Cpd 25 2-(4-Morpholinyl)-5-(phenylmethoxy)-4H-1-benzopyran-4-one;
Cpd 26 7,8-Dimethoxy-2-(4-morphollnyl)-4H-1-benzopyran-4-one;
Cpd 27 2-(4-Methyl-2-piperazinyl)-4H-1-benzopyran-4-one;
Cpd 28 8-Methyl-7-(phenylmethoxy)-2-14-(2-pyridinyl)-1-piperazinyl]-4H-benzopyran-4-one;
Cpd 29 8-Methyl-7-(phenylmethoxy)-2-(1-piperazinyl)-4H-benzopyran-4-one;
Cpd 30 8-Methyl-7-(phenylmethoxy)-2-(1-pyrrolidinyl)-4H-benzopyran-4-one;
Cpd 31 8-Methyl-7-(phenylmethoxy)-2-(1-piperidinyl)-4H-benzopyran-4-one;
Cpd 32 8-Methyl-2-(4-methyl-1-piperazinyl)-7-(phenylmethoxy)-4H-benzopyran-4-one;
Cpd 33 8-Methyl-7-(phenylmethoxy)-2-(2,6-dimethyl-4-morpholinyl)-4H-benzopyran-4-one;
Cpd 34 2-[4-(Hydroxyethyl)-1-piperazinyl]-8-methyl-7-(phenyl-methoxy)-4H-benzopyran-4-one monohydrochloride;
Cpd 35 2-[4-(Diphenylmethyl)-1-piperazinyl]-8-methyl-7-(phenylmethoxy)-4H-bsnzopyran-4-one;
Cpd 36 8-Methyl-7-(phenylmethoxy)-2-(4-phenyl-1-piperidinyl)-4H-benzopyran-4-one;
Cpd 37 8-Methyl-7-(phenylmethoxy)-2-(4-phenyl-1-piperazinyl)-4H-benzopyran-4-one;
Cpd 38 2-(4-Hydroxy-1-piperdinyl)-8-methyl-7-(phenylmethoxy)-4H-benzopyran-4-one;
Cpd 39 7-Hydroxy-8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 40 6-Hydroxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 41 7-Hydroxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 42 8-Hydroxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 43 8-Hydroxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 44 7-Methoxy-8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 45 [(8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-7-yl)oxy]
acetic acid lithium salt;

Cpd 46 [[8-Methyl-2-(4-morpholinyl)-4-oxy-4H-1-benzopyran-7-yl]oxy]acetic acid methyl ester;
Cpd 47 7-[(4-Methoxyphenyl)methoxy]-8-oethyl-2-(4-morpho linyl)-4H-1-benzopyran-4-one;
Cpd 48 8-Methyl-7-[(4-methylphenyl)methoxy]-2-(4-morpho linyl)-4H-1-benzopyran-4-one;
Cpd 49 7-[(4-Chlorophenyl)methoxy]-8-methyl-2-(4-morpho linyl)-4H-1-benzopyran-4-one;
Cpd 50 7-[(4,5-Dichlorophenyl)methoxy]-8-methyl-2-(4-morpho linyl)-4H-1-benzopyran-4-one;
Cpd 51 8-Methyl-2-(4-morpholinyl)-7-(2-pyridinylmethoxy)-4H-1-benzopyran-4-one;
Cpd 52 8-Methyl-7-[[(phenyl)carbonyl]oxy]-2-(4-morpho linyl)-4H-1-benzopyran-4-one;
Cpd 53 7-Methoxy-8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 54 7-[[4-(1,1-Dimethylethyl)phenyl]methoxy]-8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 55 8-Methyl-2-(4-morpholinyl)-7-[[4-phenylmethoxy)-phenyl]methoxy]-4H-1-benzopyran-4-one;
Cpd 56 7-[(3-Methoxyphenyl)methoxy]-8-methyl-2-(4-morpho-linyl)-4H-1-benzopyran-4-one;
Cpd 57 7-[(4-Nitrophenyl)methoxy]-8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 58 7-[(2-Phenylethyl)methoxy]-8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 59 7-[(2-Methoxyphenyl)methoxy]-8-methyl-2-(4-morpho-linyl)-4H-1-benzopyran-4-one;
Cpd 60 7-[(4-Ethoxyphenyl)methoxy]-8-methyl-2-(4-morpho-linyl)-4H-1-benzopyran-4-one;
Cpd 61 8-(4-Ethoxy-benzyloxy)-2-(4-morpholinyl)-4H-1-benzo-pyran-4-one;
Cpd 62 2-(4-Morpholinyl)-8-(4-nitro-benzyloxy)-4H-1-benzo-pyran-4-one;
Cpd 63 8-(2-Methoxy-benzyloxy)-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 64 2-(4-Morpholinyl)-8-(2-phenyl-ethoxy)-4H-1-benzopyran-4-one;

Cpd 65 2-(4-Morpholinyl)-(2-oxo-2-phenyl-ethoxy)-4H-1-benzopyran-4-one;
Cpd 66 8-(4-Benzyloxy-benzyloxy)-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 67 8-(4-Chloro-benzyloxy)-2-(4-morpholinyl)-4H-1-benzo-pyran-4-one;
Cpd 68 8-(4-t-Butyl-benzyloxy)-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 69 8-(3-Methoxy-benzyloxy)-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 70 8-(3,4-Dichloro-benzyloxy)-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 71 8-(4-Methyl-benzyloxy)-2-(4-morpholinyl)-4H-1-benzo-pyran-4-one;
Cpd 72 8-(4-Methoxy-benzyloxy)-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 73 2-(4-Morpholinyl)-8-(naphthyl-2-methyloxy)-4H-1-benzopyran-4-one;
Cpd 74 2-(4-Morpholinyl)-8-(naphthyl-1-methyloxy)-4H-1-benzopyran-4-one;
Cpd 75 8-Methyl-2-(4-morpholinyl)-7-(naphthyl-2-methyloxy)-4H-1-benzopyran-4-one;
Cpd 76 8-Methyl-2-(4-morpholinyl)-7-(naphthyl-1-methyloxy)-4H-1-benzopyran-4-one;
Cpd 80 2-(Dimethylamino)-4H-1-benzopyran-4-one; and Cpd 81 2-(Dimethylamino)-8-methyl-7-(phenylmethoxy)-4H-1-benzopyran-4-one;
Cpd 100 [8-methyl-2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-7-yl]4-morpholinyl carboxylic acid ester;
Cpd 101 2-(4-morpholinyl)-7-(phenylmethoxy)-4H-1-benzopyran-4-one;
Cpd 102 8-Methyl-2-(4-morpholinyl)-7-(2-oxo-2-phenylethoxy)-4H-1-benzopyran-4-one;
Cpd 103 6-Chloro-8-methyl-2-(4-morpholinyl)-7-(phenylmethoxy)-4H-1-benzopyran-4-one;
Cpd 104 [[2-(4-Morpholinyl)-4-oxo-4H-1-benzopyran-8-yl]oxy]-acetic acid methyl ester;
Cpd 105 4-[[[8-Methyl-2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-7-yl]oxy]methyl]-benzoic acid methyl ester;
Cpd 106 4-[[[2-(4-Morpholinyl)-4-oxo-4H-1-benzopyran-8-yl]oxy]methyl]-benzoic acid methyl ester;
Cpd 107 8 - M e t h y l - 2 - ( 4 - m o r p h o l i n y l ) - 7 - [ [ 3 -(trifluoromethyl)phenyl]methoxy]-4H-1-benzopyran-4-one;
Cpd 108 2-(4-Morpholinyl)-8-[[3-(trifluoromethyl)-phenyl]methoxy]-4H-1-benzopyran-4-one;
Cpd l09 7-(Cyclohexylmethoxy)-8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 110 8-Methyl-2-(4-morpholinyl)-7-(2-propenyloxy)-4H-1-benzopyran-4-one;
Cpd 111 2-(4-Morpholinyl)-7-(1-naphthalenylmethoxy)-4H-1-benzopyran-4-one;
Cpd 112 8-Methyl-2-(4-morpholinyl)-7-(3-pyrindinylmethoxy)-4H-1-benzopyran-4-one;
Cpd 113 8-Methyl-2-(4-morpholinyl)-7-(4-pyrindinylmethoxy)-4H-1-benzopyran-4-one;
Cpd 115 8-methyl-2-(4-morpholinyl)-7-(2-quinoxalinylmethoxy)-4H-1-benzopyran-4-one;
Cpd 116 8-methyl-2-(4-morpholinyl)-7-(pyrazinlymethoxy)-4H-1-benzopyran-4-one;
Cpd 117 8-methyl-2-(4-morpholinyl)-7-(2-pyridinylmethoxy)-4H-1-benzopyran-4-one N-oxide;
Cpd 118 8-methyl-2-(4-morpholinyl)-7-(3-pyridinylmethoxy)-4H-1-benzopyran-4-one N-oxide;
Cpd 119 8-Iodo-2-(4-morpholinyl)-7-(3-pyrindinylmethoxy)-4H-1-benzopyran-4-one;
Cpd 120 3,3-Dimethyl-1-[[8-methyl-2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-7-yl]oxy]-butan-2-one;
Cpd 121 1-[[8-Methyl-2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-7-yl]oxy]-propan-2-one;
Cpd 122 1-[[8-Methyl-2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-7-yl]oxy]-butan-2-one;
Cpd 123 8-Methyl-2-(4-morpholinyl)-7-(2-oxo-2-(2-naphthyl)ethoxy)-4H-1-benzopyran-4-one;
Cpd 125 2-(4-Morpholinyl)-7-(2-pyrindinylmethoxy)-4H-1-benzopyran-4-one;

Cpd 126 2-(4-Morpholinyl)-7-(3-pyrindinylmethoxy)-4H-1-benzopyran-4-one;
Cpd 127 2-(4-Morpholinyl)-8-(2-pyrindinylmethoxy)-4H-1-benzopyran-4-one;
Cpd 128 2-(4-Morpholinyl)-8-(3-pyrindinylmethoxy)-4H-1-benzopyran-4-one;
Cpd 129 8-methyl-2-(4-morpholinyl)-7-(2-quinolinylmethoxy)-4H-1-benzopyran-4-one;
Cpd 130 7,8-(Bis)-phenylmethoxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 131 7,8-(Bis)-acetyloxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 132 7,8-(Bis)-hydroxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 133 7-Hydroxy-2-(4-morpholinyl)-8-phenylmethoxy-4H-1-benzopyran-4-one, Cpd 135 8- H y d r o x y - 2 - ( 4 - m o r p h o 1 i n y l ) - 7 - ( 3 -trifluoromethyl)phenylmethoxy-4H-1-benzopyran-4-one;
Cpd 136 7 - H y d r o x y - 2 - ( 4 - m o r p h o 1 i n y 1 ) - 8 - ( 3 -trifluoromethyl)phenylmethoxy-4H-1-benzopyran-4-one;
Cpd 137 7-[3-(1-cyclohexyl-1H-tetrazol-5-yl)propoxyl-8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 138 8-[3-(1-cyclohexyl-1H-tetrazol-5-yl)propoxy]-2-(4-mor-pholinyl) - 4H-1-benzopyran-4-one;
Cpd 139 7-[(1-cyclohexyl-1H-tetrazol-5-yl)methoxy]-8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 140 8-[(1-cyclohexyl-1H-tetrazol-5-yl)methoxy]-2-(4-mor-pholinyl)-4H-1-benzopyran-4-one;
Cpd 141 2-(4-morpholinyl)-8-[(1-phenyl-1H-tetrazol-5-yl)oxy]-4H-1-benzopyran-4-one;
Cpd 142 N-cyclohexyl-2-[[2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-8-yl]oxy]-acetamide;
Cpd 143 N-(1,1-dimethylethyl)-2-1[2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-8-yl]oxy]-acetamide;
Cpd 144 2-[[2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-8-yl]-N-phenyl-acetamide;
Cpd 145 2-[[2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-8-yl]oxy]-N-(1-phenylethyl)-acetamide;

Cpd 147 N-[[[8-methyl-2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-7-yl]oxy]acetyl]-phenyalanine, ethyl ester;
Cpd 149 8-methyl-2-(4-morpholinyl)-7-[(1-phenyl 1H-tetrazol-5-yl)oxy]-4H-1-Benzopyran-4-one;
Cpd 152 2-[[8-methyl-2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-7-yl]oxy]-N-3-pyridinyl-acetamide;
Cpd 153 N-[[[8-methyl-2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-7-yl]oxy]acetyl]-Phenylalanine;
Cpd 154 7-(2,2-dimethoxyethoxy)-8-methyl-2-(4-morpholinyl)-4H-1-Benzopyran-4-one;
Cpd 155 2-(4-Morpholinyl)-8-(2-propenyl)-4H-1-benzopyran-4-one;
Cpd 156 2-(4-Morpholinyl)-8-(1-propenyl)-4H-1-benzopyran-4-one;
Cpd 157 8-Formyl-2-(4-Morpholinyl)-4H-1-benzopyran-4-one;
Cpd 158 2-(4-morpholinyl)-8-(phsnylamino)methyl-4H-1-benzopyran-4-one;
Cpd 159 2-(4-morpholinyl)-8-(2E-phenyl)ethenyl-4H-1-benzopyran-4-one;
Cpd 160 8-Hydroxymethyl-2-(4-Morpholinyl)-4H-1-benzopyran-4-one;
Cpd 162 8-methyl-7-[(1-methyl-3-piperidinyl)methoxy]-2-(4-mor-pholinyl)-4H-1-Benzopyran-4-one;
Cpd 163 8-Methyl-2-(4-morpholinyl)-7-(2-(1-piperi-dinyl)ethyl)oxy-4H-1-benzopyran-4-one;
Cpd 164 8 - M e th y l - 2 - ( 4 - m o r p h o l i n y l) -7- (2- (1 -pyrrolidinyl)ethyl)oxy-4H-1-benzopyran-4-one;
Cpd 165 8-Methyl-2-(4-morpholinyl)-7-(2-(4-morpholinyl)ethyl)-oxy-4H-1-benzopyran-4-one;
Cpd 166 8-Methyl-2-(4-morpholinyl)-7-(3-(1-piperi-dino)propyl)oxy-4H-1-benzopyran-4-one;
Cpd 167 7-(2-Diethylaminoethyl)oxy-8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 168 7-[2-(ethylphenylamino)ethoxy]-8-methyl-2-(4-mor-pholinyl)-4H-1-Benzopyran-4-one;
Cpd 169 7-(2-Diisopropylaminoethyl)oxy-8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 170 7-Hydroxy-8-methyl-2-(1-piperidinyl)-4H-1-benzopyran-4-one;
Cpd 171 8-Methyl-2-(1-piperidinyl)-7-(3-pyrindinylmethoxy)-4H-1-benzopyran-4-one;
Cpd 172 7-(2-(4-Benzyl-(1-piperizinyl))ethyl)oxy-8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 173 7-Acetoxy-3,8-dimethyl-2-(4-morpholinyl)-4H-1-ben-zopyran-4-one;
Cpd 174 3,8-dimethyl-7-hydroxy-2-(4-morpholinyl)-4H-1-benzo-pyran-4-one;
Cpd 175 7-benzyloxy-3,8-dimethyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 176 3,8-Dimethyl-2-(4-morpholinyl)-7-(naphthyl-1-methyloxy)-4H-1-benzopyran-4-one;
Cpd 177 3,8-Dimethyl-7-(4-methoxy-benzyloxy)-2-(4-morpho-linyl)-4H-1-benzopran-4-one;
Cpd 178 3,8-Dimethyl-2-(4-morpholinyl)-7-(2-phenyl-ethyloxy)-4H-1-benzopyran-4-one;
Cpd 179 3,8-Dimethyl-7-(4-chlorobenzyloxy)-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 180 3,8-Dimethyl-2-(4-morpholinyl)-7-(3-trifluoromethyl-benzyloxy)-4H-1-benzopyran-4-one;
Cpd 181 7-(Carbomethoxy-methoxyl)-3,8-dimethyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 182 8-Hydroxy-3-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one, Cpd 183 8-Benzyloxy-3-methyl-2-(4-morpholinyl)-4H-1-benzo-pyran-4-one;
Cpd 184 3-methyl-2-(4-morpholinyl)-8-(m-trifluoromethyl-benzyloxy)-4H-1-benzopyran-4-one, Cpd 185 8-methyl-7-(2-phenyl)ethynyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 186 8-methyl-2-(4-morpholinyl)-7-(2-phenyl)ethyl-4H-1-benzopyran-4-one;
Cpd 187 2-(4-Morpholinyl)-8-(2-phenyl)ethynyl-4H-1-benzopyran-4-one;
Cpd 188 2-(4-Morpholinyl)-8-(2-phenyl)ethyl-4H-1-benzopyran-4-one;
Cpd 189 2-(4-Morpholinyl)-8-(2-(3-trifluoromethyl-)phenyl)ethynyl-4H-1-benzopyran-4-one;
Cpd 190 2-(4-Morpholinyl)-8-(2-(3-trifluoromethyl)phenyl)-ethyl-4H-l-benzopyran-4-one;
Cpd 192 8-Methyl-2-(4-morpholinyl)-7-(2-(1-naphthyl))ethyl-4H-1-benzopyran-4-one;
Cpd 193 8-Methyl-2-(4-morpholinyl)-7-phenyl-4H-1-benzopyran-4-one;
Cpd 194 7-acetyloxy-8-iodo-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 195 8-ethyl-2-(4-morpholinyl)-7-(3-pyrindinylmethoxy)-4H-1-benzopyran-4-one;
Cpd 196 8-Ethyl-2-(4-morpholinyl)-7-phenylmethoxy-4H-1-benzopyran-4-one;
Cpd 197 8-Iodo-2-(4-morpholinyl)-7-phenylmethoxy-4H-1-benzopyran-4-one;
Cpd 198 8-Ethyl-2-(4-morpholinyl)-7-(2-(1-piperi-dinyl)ethyl)oxy-4H-1-benzopyran-4-one;
Cpd 199 8-Iodo-2-(4-morpholinyl)-7-(3-pyrindinylmethoxy)-4H-1-benzopyran-4-one;
Cpd 200 8-Iodo-7-hydroxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 202 7-(3-pyridinylmethoxy)-2-(1-piperidinyl)-8-methyl-4H-1-benzopyran-4-one;
Cpd 204 8-Hethyl-2-(4-morpholinylmethyl)-7-(phenylmethoxy)-4H-1-benzopyran-4-one;
Cpd 205 7-hydroxy-2-(4-morpholinylmethyl)-8-methyl-4H-1-benzopyran-4-one;
Cpd 206 7-[(1-cyclohexyl-1H-tetrazol-5-yl)methyoxy]-8-methyl-2-(4-morpholinylmethy)-4H-1-benzopyran-4-one;
Cpd 207 8- Methyl-2-(4-morpholinylmethyl)-7-(3-pyridinylmethoxy)-4H-1-benzopyran-4-one or a pharmaceutically acceptable salt or hydrate thereof.

10. A compound according to Claim 1 selected from the group consisting of:
Cpd 2 2-(4-morpholinyl)-4H-benzopyran-4-one;
Cpd 3 8-Methyl-2-(4-morpholinyl)-(7-phenylmethoxy)-4H-benzopyran-4-one;

Cpd 19 6-([[Phenylmethoxy]carbonyl]amino)-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 51 8-Methyl-2-(4-morpholinyl)-7-(2-pyridinylmethoxy)-4H-1-benzopyran-4-one;
Cpd 72 8-(4-Methoxy-benzyloxy)-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 76 8-Methyl-2-(4-morpholinyl)-7-(naphthyl-1-methyloxy)-4H-l-benzopyran-4-one;
Cpd 112 8-Methyl-2-(4-morpholinyl)-7-(3-pyrindinylmethoxy)-4H-1-benzopyran-4-one;
Cpd 139 7-[(1-cyclohexyl-1H-tetrazol-5-yl)methoxy]-8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 163 8-Methyl-2-(4-morpholinyl)-7-(2-(1-piperi-dinyl)ethyl)oxy-4H-1-benzopyran-4-one;
Cpd 164 8 - M e t h y l - 2 - ( 4 - m o r p h o l i n y l) - 7 - (2- (1-pyrrolidinyl)ethyl)oxy-4H-1-benzopyran-4-one;
Cpd 171 8-Methyl- 2-(1-piperidinyl)-7-(3-pyrindinylmethoxy)-4H-1-benzopyran-4-one;
or a pharmaceutically acceptable salt or hydrate thereof.

11. Use of a compound selected from the group consisting of a compound of Formula I

I

wherein X is N, or CZ where Z is H, C1-C5 alkyl, amino (-NH2) or a halogen atom;
when X is CZ, Y is selected from the group consisting of -(CH2)nNR9R10 wherein R9 and R10, being the same or different, are selected from the group consisting of (a) hydrogen, with the provisio that R9 and R10 are not both hydrogen; (b) C1-C12 alkyl; (c) phenyl optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(C1-C4alkyl); (d) -(CH2)nphenyl (wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or carboC1-C4 alkoxy), (e) -(CH2)npyridinyl or (f) wherein R9 and R10, taken together with N, form a saturated or unsaturated heterocyclic amine ring selected from the group consisting of (aa) 4-morpholine optionally substituted with one or two members selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl, (bb) 4-thiomorpholine optionally substituted with one or two members selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl, (cc) 3-amino-1-pyrrolidine, (dd) 1-pyrrolidine optionally substituted with one or two members selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, OH, -CH2OH, or trifluoromethyl, (ee) 1-piperidine optionally substituted with one or two members selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, trifluoromethyl, -(CH2)qOH, -CO2H, -CO2CH3 -CO2CH2CH3 or phenyl (wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl), (ff) 1-phenyl-1-piperazine (wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl) or 4-pyridinyl-1-piperazine optionally substituted with one or two members selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, trifluoromethyl, -CH2OH, -CO2H-, -CO2CH3 or -CO2CH2CH3, and (gg) thiazolidine, thiazolidine-4-carboxylic acid, pipecolinic acid, p-piperazinaceto-phenone, 1-homopiperazine, 1-methylhomopiperazine, 4-phenyl-1,2-3,6-tetrahydropyridine, proline, tetra-hydrofurylamine, 1-(3-hydroxy)pyrrolidine, nipecotamide, 1,2,3,4-tetrahydroisoquinoline or imidazole;

and R5, R6, R7 and R8, being the same or different, are selected from the group consisting of hydrogen, C1-C8 alkyl, -(CH2)nphenyl [wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(C1-C4alkyl)], -(CH2)nnaphthyl, -(CH2)npyridinyl, -(CH2)qNR9R10, -CH-CH-phenyl [wherein phenyl is optionally sub-stituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(C1-C4alkyl)], -CH2-CH-CH2, -CH-CH-CH3,-O-CH2-CH-CH2, -C=C-phenyl [wherein phenyl is optionally sub-stituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(C1-C4alkyl)], -O(CH2)p(N-methylpiperdin-3-yl), -O-(CH2)pNR9R10, -O-CH2CH(OCH3)2, -O-(CH2)pOR15, - (CH2)nC(O) - (CH2)nR9, -(CH2)nC(O)O- (CH2)pR9, -(CH)nC(O)O-(CH2)pNR9R10, -(CH2)nC(O)(CH2)nNR9R10, NO2,-O-(CH2)nC(O)-(CH2)pR9, -O-(CH2)nC(O)O-(CH2)pR9, -O-(CH2)nC(O)-(CH2)nNR9R10, -NR9R10, -N(R9)(CH2)nC(O)-(CH2)nR10, -N(R9)-(CH2)nC(O)O-(CH2)nR10, N(R9)(CH2)nC(O)-(CH2)nNR9R10, -O-(CH2)nphenyl [wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(C1-C4alkyl)], -O-(CH2)npyridine, -O(CH2)nC(O)-(CH2)npyridine, -O-(CH2)nC(O)O-(CH2)npyridine, -O(CH2)nC(O)-N(R9)(CH2)npyridine, -O-(CH2)nquinoxalinyl, -O-(CH2)nquinolinyl -O-(CH2)npyrazinyl, -O-(CH2)nnaphthyl, -O-(CH2)nC(O)-(CH2)nnaphthyl, -O-(CH2)nC(O)O-(CH2)nnaphthyl, -O-(CH2)nC(O)NR9-(CH2)nnaphthyl, halo (fluoro, chloro, bromo, iodo), OH, -(CH2)q-OH-(CH2)qOC(O)R9, -(CH2)qOC(O)-NR9R10, (1-cyclohexyl-1H-tetrazol-5-yl)C1-C4 alkoxy, -[1-(C1-C5alkyl)-1H-tetrazol-5-yl]C1-C4 alkoxy, -[1-(phenyl)-1H-tetrazol-5-yl]C1-C4 alkoxy [wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(C1-C4alkyl)], -[1-(pyridinyl)-1H-tetrazol-5-yl]C1-C4 alkoxy, -[1-(1-phenylethyl)-1H-tetrazol-5-yl]C1-C4 alkoxy, -C1-C4 alkoxyl, a group of Formula II wherein R' is methyl or carboxy, R'' is hydrogen and R''' is selected from benzyl [optionally substituted with one, two or three groups selected from hydroxy, halogen or phenoxy (optionally substituted with one, two or three groups selected from hydroxy or halogen)], C1-C5 alkyl, -(CH2)nCO2H, -CH2SH, -CH2SCH3, imidazolinylmethylene, indolinylmethylene, CH3CH(OH), CH2OH, H2N(CH2)4-(optionally in protected form) or H2NC(NH)NH(CH2)3 (optionally in protected form); with the overall proviso that when Y is other than -(CH2)nmorpholinyl, at least one member of R5, R6, R7 or R8 is other than hydrogen, C1-C8 alkyl, NO2, OH, C1-C4 alkoxy, a halogen atom, phenyl, benzyl, 4-morpholinylmethyl, NH2, or dimethyamino; with the further proviso that when Y is 4-morpholinyl, the compound is other than:
6,7-dimethoxy-2-(4-morpholinyl)-4H-1-benzopran-4-one, 7,8-(Bis)-(3-trifluoromethyl)phenylmethoxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one, N-cyclohexyl-2-[[8-methyl-2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-7-yl]oxy]-acetamide, 2-[[8-methyl-2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-7-yl]oxy]-N-phenyl-acetamide, 6-[(1-cyclohexyl-1H-tetrazol-5-yl)methoxy]-2-(4-mor-pholinyl)-4H-1-Benzopyran-4-one, 2-[[8-methyl-2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-7-yl]oxy]-N-(1-phenylethyl)-acetamide;
with the further provisio that when Y is dimethylamino, the compound is other than:
2-(Dimethylamino)-8-methyl-4-oxo-4H-1-benzopyran-7-yl carbamic acid dimethyl ester, (Dimethylamino)-4-oxo-4H-1-benzopyran-6-yl carbamic acid dimethyl ester, 2-(Dimethylamino)-4-oxo-4H-1-benzopyran-7-yl carbamic acid dimethyl ester;
when X is N, Y is selected from the group consisting of -NR9R10 wherein R9 and R10, being the same or different, are selected from the group consisting of (a) hydrogen, with the provisio that R0 and R10 are not both hydrogen;
(b) C1-C12 alkyl; (c) phenyl optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(C1-C4alkyl); (d) -(CH2)nphenyl (wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or carboC1-C4 alkoxy), (e) -(CH2)npyridinyl or (f) wherein R9 and R10, taken together with N, form a saturated or unsaturated heterocyclic amine ring selected from the group consisting of (aa) 4-morpholine optionally substituted with one or two members selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl (bb) 4-thiomorpholine optionally substituted with one or two members selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl (cc) 3-amino-1-pyrrolidine, (dd) 1-pyrrolidine optionally substituted with one or two members selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, OH, -CH2OH, or trifluoromethyl, (ee) 1-piperidine optionally substituted with one or two members selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, trifluoromethyl, -(CH2)qOH, -CO2H, -CO2CH3 -CO2CH2CH3 or phenyl (wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl), (ff) 1-piperazine, 4-methyl-1-piperazine, 4-phenyl-1-piperazine (wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl) or 4-pyridinyl-1-piperazine optionally substituted with one or two members selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, trifluoromethyl, -CH2OH, -CO2H, -CO2CH3 or -CO2CH2CH3, and (gg) thiazolidine, thiazolidine-4-carboxylic acid, pipecolinic acid, p-piperazinaceto-phenone, 1-homopiperazine, 1-methylhomopiperazine, 4-phenyl-1,2-3,6-tetrahydropyridine, proline, tetra-hydrofurylamine, 1-(3-hydroxy)pyrrolidine, nipecotamide, 1,2,3,4-tetrahydroisoquinoline or imidazole;
and R5, R6, R7 and R8, being the same or different, are selected from the group consisting of hydrogen, C1-C8 alkyl, -(CH2)nphenyl [wherein phenyl is optlonally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(C1-C4alkyl)], -(CH2)nnaphthyl, -(CH2)npyridinyl, -(CH2)qNR9R10, -CH=CH-phenyl [wherein phenyl is optionally sub-stituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(C1-C4alkyl)], -CH2-CH=CH2, -CH-CH-CH3, -O-CH2-CH=CH2, -C=C-phenyl [wherein phenyl is optionally sub-stituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(C1-C4alkyl)], -O(CH2)p(N-methylpiperdin-3-yl), -O-(CH2)PNR9R10, -O-CH2CH(OCH3)2, -O-(CN2)pOR15, -(CH2)nC(O)-(CH2)nR9, -(CH2)nC(O)O-(CH2)pR9, -(CH)nC(O)O-(CH2)pNR9R10, -(CH2)nC(O)(CH2)nNR9R10, NO2,-O-(CH2)nC(O)-(CH2)pR9, -O-(CH2)nC(O)O, (CH2)pR9, -O-(CH2)nC(O)-(CH2)nNR9R10, -NR9R10, -N(R9)(CH2)nC(O)-(CH2)nR10, -N(R9)-(CH2)nC(O)O-(CH2)nR10, N(R9)(CH2)nC(O)-(CH2)nNR910, -O-(CH2)nphenyl wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(C1-C4alkyl)], -O-(CH2)npyridine, -O(CH2)nC(O) - (CH2)npyridine, -O-(CH2)nC(O)O-(CH2)npyridine, -O(CH2)nC(O)-N(Rg)(CH2)npyridine, -O-(CH2)nquinoxalinyl, -O-(CH2)nquinolinyl, -O-(CH2)npyrazinyl, -O-(CH2)nnaphthyl, -O-(CH2)nC(O)-(CH2)nnaphthyl, -O-(CH2)nC(O)O-(CH2)nnaphthyl, -O-(CH2)nC(O)NR9-(CH2)nnaphthyl, halo (fluoro, chloro, bromo, iodo), OH, -(CH2)q-OH, (CH2)qOC(O)R9, -(CH2)qOC(O)-NR9R10, (1-cyclohexyl-1H-tetrazol-5-yl)C1-C4 alkoxy, -[1-(C1-C5alkyl)-1H-tetrazol-5-yl]C1-C4 alkoxy, -[1-(phenyl)-1H-tetrazol-5-yl]C1-C4 alkoxy [wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(C1-C4alkyl)], -[1-(pyridinyl)-1H-tetrazol-5-yl]C1-C4 alkoxy, -[1-(1-phenylethyl)-1H-tetrazol-5-yl]C1-C4 alkoxy, or -C1-C4 alkoxyl;
R15 is selected from C1-C5 alkyl, -(CH2)nphenyl [phenyl optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(C1-C4alkyl)], -(CH2)npyridin-1-yl or -(CH2)ppiperidin-1-yl]
n is 0-5;
p is 2-5;
q is 1-5;
and pharmaceutically acceptable salts or hydrates thereof; to prepare a medicament for preventing or treating atherosclerosis.

12. A method according to Claim 11 where Y is selected from the group consiting of -(CH2)nNR9R10 wherein R9 and R10, taken together with N, form a saturated or unsaturated heterocyclic amine ring selected from the group consisting of:
(aa) 4-morpholine optionally substituted with one or two members selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo or trlfluoromethyl, (bb) 4-thiomorpholine optionally substituted with one or two members selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl, (cc) 3-amino-1-pyrrolidine, (dd) 1-pyrrolidine optionally substituted with one or two members selected fron the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, OH, -CH2OH, or trifluoromethyl, (ee) 1-piperidine optionally substituted with one or two members selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, trifluoromethyl, -(CH2)qOH, -CO2H, -CO2CH3 -CO2CH2CN3 or phenyl (wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl), (ff) 1-piperazine, 4-methyl-1-piperazine, 4-phenyl-1-piperazine (wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl) or 4-pyridinyl-1-piperazine optionally substituted with one or two members selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, trifluoromethyl, -CH2OH, -CO2H, -CO2CH3 or -CO2CH2CH3.

13. A method according to Claim 12 wherein X is CZ where Z is H or methyl.

14. A method according to Claim 12 wherein X is N.

15. A method according to Claim 13 or 14 wherein R5, R6, R7 and R8 are selected from the following groups:
(i) R5, R6, R7 and R8 each hydrogen (ii) R5, R6, and R8 are each hydrogen, and R7 is selected from:
-O-(CH2)nphenyl (wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo or tri-fluoromethyl), -C=C-phenyl (wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl), or -(CH2)nphenyl (wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl);
(iii) R5 and R6 are hydrogen, R8 is hydrogen, halo or C1-C5 alkyl, and R7 is selected from: -O-(CH2)nphenyl (wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl), -O-(CH2)npyridinyl (wherein pyridinyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl), -O-(CH2)nnaphthyl, -(CH2)nphenyl (wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl), -(CH2)ppyridinyl (wherein pyridinyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl), -(CH2)p(1-pyrrolidinyl) or -[(1-cyclohexyl-1H-tetrazol-5-yl)C1-C4 alkoxy; or (iv) R5, R7 and R8 are each hydrogen, and R6 is -NH-C(O)-O-CH2phenyl.

16. The method according to Claim 11 where the compound is selected from the group consisting of:
Cpd 1 6-Chloro-2-(4-morpholinyl)-4H-1-benzo pyran-4-one;
Cpd 2 2-(4-morpholinyl)-4H-benzopyran-4-one;
Cpd 3 8-Methyl-2-(4-morpholinyl)-(7-phenylmethoxy)-4H-benzopyran-4-one;
Cpd 4 7-Chloro-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 5 8-Chloro-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 6 6-Bromo-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 7 6-Fluoro-2-(4-morpholinyl)-4H-1-benzopyran-4-one;

Cpd 8 6-Methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 9 7-Methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 10 8-Methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 11 6-Methoxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 12 7-Methoxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 13 6-(Phenylmethoxy)-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 14 8-(Phenylmethoxy)-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 15 [2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-6-yl]-1,1-dimethylethyl carbamic acid ester;
Cpd 16 6-(3-pyridinecarboxamide)-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 17 2-(4-Morpholinyl)-6-nitro-4H-1-benzopyran-4-one;
Cpd 19 6-([[Phenylmethoxy]carbonyl]amino)-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 20 8-Methoxy-2-(4-morpholinyl)-4H-1- benzopyran-4-one;
Cpd 21 3-Amino-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 22 3-Chloro-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 23 3-Bromo-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 24 8-Methyl-2-(4-morpholinyl)-7-(phenylmethoxy)-4H-1-benzopyran-4-one;
Cpd 25 2-(4-Morpholinyl)-5-(phenylmethoxy)-4H-1-benzopyran-4-one;
Cpd 26 7,8-Dimethoxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 27 2-(4-Methyl-2-piperazinyl)-4H-1-benzopyran-4-one;
Cpd 28 8-Methyl-7-(phenylmethoxy)-2-[4-(2-pyridinyl)-1-piperazinyl]-4H-benzopyran-4-one;
Cpd 29 8-Methyl-7-(phenylmethoxy)-2-(1-piperazinyl)-4H-benzopyran-4-one;
Cpd 30 8-Methyl-7-(phenylmethoxy)-2-(1-pyrrolidinyl)-4H-benzopyran-4-one;
Cpd 31 8-Methyl-7-(phenylmethoxy)-2-(1-piperidinyl)-4H-benzopyran-4-one;
Cpd 32 8-Methyl-2-(4-methyl-1-piperazinyl)-7-(phenylmethoxy)-4H-benzopyran-4-one;
Cpd 33 8-Methyl-7-(phenylmethoxy)-2-(2,6-dimethyl-4-morpholinyl)-4H-benzopyran-4-one;

Cpd 34 2-[4-(Hydroxyethyl)-1-piperazinyl]-8-methyl-7-(phenyl-methoxy)-4H-benzopyran-4-one monohydrochloride;
Cpd 35 2-[4-(Diphenylmethyl)-1-piperazinyl]-8-methyl-7-(phenylmethoxy)-4H-banzopyran-4-one;
Cpd 36 8-Methyl-7-(phenylmethoxy)-2-(4-phenyl-1-piperidinyl)-4H-benzopyran-4-one;
Cpd 37 8-Methyl-7-(phenylmethoxy)-2-(4-phenyl-1-piperazinyl)-4H-benzopyran-4-one;
Cpd 38 2-(4-Hydroxy-1-piperdinyl)-8-methyl-7-(phenylmethoxy)-4H-benzopyran-4-one;
Cpd 39 7-Hydroxy-8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 40 6-Hydroxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 41 7-Hydroxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 42 5-Hydroxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 43 8-Hydroxy-2-(4-morpholinyl)-4a-1-benzopyran-4-one;
Cpd 44 7-Methoxy-8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 45 [(8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-7-yl)oxy]
acetic acid lithium salt;
Cpd 46 [[8-Methyl-2-(4-morpholinyl)-4-oxy-4H-1-benzopyran-7-yl]oxy]acetic acid methyl ester;
Cpd 47 7-[(4-Methoxyphenyl)methoxy]-8-methyl-2-(4-morpho linyl)-4H-1-benzopyran-4-one;
Cpd 48 8-Methyl-7-[(4-methylphenyl)methoxy]-2-(4-morpho linyl)-4H-1-benzopyran-4-one;
Cpd 49 7-[(4-Chlorophenyl)methoxy]-8-methyl-2-(4-morpho linyl)-4H-1-benzopyran-4-one;
Cpd 50 7-[(4,5-Dichlorophenyl)methoxy]-8-methyl-2-(4-morpho linyl)-4H-1-benzopyran-4-one;
Cpd 51 8-Methyl-2-(4-morpholinyl)-7-(2-pyridinylmethoxy)-4H-1-benzopyran-4-one;
Cpd 52 8-Methyl-7-[[(phenyl)carbonyl]oxy]-2-(4-morpho linyl)-4H-1-benzopyran-4-one;
Cpd 53 7-Methoxy-8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 54 7-[[4-(1,1-Dimethylethyl)phenyl]methoxy]-8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one;

Cpd 55 8-Methyl-2-(4-morpholinyl)-7-[[4-phenylmethoxy)-phenyl]methoxy]-4H-1-benzopyran-4-one;
Cpd 56 7-[(3-Methoxyphenyl)methoxy]-8-methyl-2-(4-morpho-linyl)-4H-1-benzopyran-4-one;
Cpd 57 7-[(4-Nitrophenyl)methoxy]-8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 58 7-[(2-Phenylethyl)methoxy]-8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 59 7-[(2-Methoxyphenyl)methoxy]-8-methyl-2-(4-morpho-linyl)-4H-1-benzopyran-4-one;
Cpd 60 7-[(4-Ethoxyphenyl)methoxy]-8-methyl-2-(4-morpho-linyl)-4H-1-benzopyran-4-one;
Cpd 61 8-(4-Ethoxy-benzyloxy)-2-(4-morpholinyl)-4H-1-benzo-pyran-4-one;
Cpd 62 2-(4-Morpholinyl)-8-(4-nitro-benzyloxy)-4H-1-benzo-pyran-4-one;
Cpd 63 8-(2-Methoxy-benzyloxy)-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 64 2-(4-Morpholinyl)-8-(2-phenyl-ethoxy)-4H-1-benzopyran-4-one;
Cpt 65 2-(4-Morpholinyl)-(2-oxo-2-phenyl-ethoxy)-4H-1-benzopyran-4-one;
Cpd 66 8-(4-Benzyloxy-benzyloxy)-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 67 8-(4-Chloro-benzyloxy)-2-(4-morpholinyl)-4H-1-benzo-pyran-4-one;
Cpd 68 8-(4-t-Butyl-benzyloxy)-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 69 8-(3-Methoxy-benzyloxy)-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 70 8-(3,4-Dichloro-benzyloxy)-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 71 8-(4-Methyl-benzyloxy)-2-(4-morpholinyl)-4H-1-benzo-pyran-4-one;
Cpd 72 8-(4-Methoxy-benzyloxy)-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 73 2-(4-Morpholinyl)-8-(naphthyl-2-methyloxy)-4H-1-benzopyran-4-one;

Cpd 74 2-(4-Morpholinyl)-8-(naphthyl-1-methyloxy)-4H-1-benzopyran-4-one;
Cpd 75 8 Methyl-2-(4-morpholinyl)-7-(naphthyl-2-methyloxy)-4H-1-benzopyran-4-one;
Cpd 76 8-Methyl-2-(4-morpholinyl)-7-(naphthyl-1-methyloxy)-4H-l-benzopyran-4-one;
Cpd 80 2-(Dimethylamino)-4H-1-benzopyran-4-one; and Cpd 81 2-(Dimethylamino)-8-methyl-7-(phenylmethoxy)-4H-1-benzopyran-4-one;
Cpd 83 6-Methyl-2-(4-morpholinyl)-4H-1,3-benzoxazin-4-one;
Cpd 84 8-Methyl-2-(4-morpholinyl)-4H-1,3-benzoxazin-4-one;
Cpd 85 6-Bromo-2-(4-morpholinyl)-4H-1,3-benzoxazin-4-one;
Cpd 86 7-Chloro-2-(4-morpholinyl)-4H-1,3-benzoxazin-4-one;
Cpd 87 6,8-Bis(1-methylethyl)-2-(4-morpholinyl)-4H-1,3-benzoxazin-4-one;
Cpd 88 6-Fluoro-2-(4-morpholinyl)-4H-1,3-benzoxazin-4-one;
Cpd 89 6-Dimethoxymethyl-2-(4-morpholinyl)-4H-1,3-benzoxazin-4-one;
Cpd 90 7-Methoxy-2-(4-morpholinyl)-4H-1,3-benzoxazin-4-one;
Cpd 91 6-(Morpholin-1-yl)-pyrido(2,3-e)-1,3-oxazine-8-one;
Cpd 92 8-Methyl-2-(1-piperidinyl)-4H-1,3-benzoxazin-4-one;
Cpd 93 8-Methyl-2-(1-pyrrolidinyl)-4H-1,3-benzoxazin-4-one;
Cpd 94 2-(1-pyrrolidinyl)-4H-1,3-benzoxazin-4-one;
Cpd 95 2-(1-(4-Thiomorpholinyl))-4H-1,3-benzoxazin-4-one;
Cpd 96 2-(4-Methyl-1-piperazinyl)-4H-1,3-benzoxazin-4-one;
Cpd 98 2-(4-Morpholinyl)-4H-1,3-benzoxazin-4-one;
Cpd 100 [8-methyl-2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-7-yl]4-morpholinyl carboxylic acid ester;
Cpd 101 2-(4-morpholinyl)-7-(phenylmethoxy)-4H-1-benzopyran-4-one;
Cpd 102 8-Methyl-2-(4-morpholinyl)-7-(2-oxo-2-phenylethoxy)-4H-1-benzopyran-4-one;
Cpd 103 6-Chloro-8-methyl-2-(4-morpholinyl)-7-(phenylmethoxy)-4H-1-benzopyran-4-one;
Cpd 104 [[2-(4-Morpholinyl)-4-oxo-4H-1-benzopyran-8-yl]oxy]-acetic acid methyl ester;

Cpd 105 4 [[[8-Methyl-2-(4-morphollnyl)-4-oxo-4H-l-benzopyran-7-yl]oxylmethyl]-benzoic acld methyl ester;
Cpd 106 4-[[[2-(4-Morpholinyl)-4-oxo-4H-l-benzopyran-8-yl]oxy]methyl]-benzoic acid methyl ester;
Cpd 107 8 - M e t h y 1 - 2 - ( 4 - m o r p h o 1 i n y 1 ) - 7 - [ [ 3 -(trifluoromethyl)phenyl]methoxy]-4H-l-benzopyran-4-one;
Cpd 108 2-(4-Morpholinyl)-8-[[3-(trifluoromethyl)-phenyl]methoxy]-4H-l-benzopyran-4-one;
Cpd 109 7-(Cyclohexylmethoxy)-8-methyl-2-(4-morpholinyl)-4H-l-benzopyran-4-one;
Cpd 110 8-Hethyl-2-(4-morpholinyl)-7-(2-propenyloxy)-4H-l-benzopyran-4-one;
Cpd 111 2-(4-Morpholinyl)-7-(1-naphthalenylmethoxy)-4H-l-benzopyran-4-one;
Cpd 112 8-Methyl-2-(4-morpholinyl)-7-(3-pyrindinylmethoxy)-4H-l-benzopyran-4-one;
Cpd 113 8-Methyl-2-(4-morpholinyl)-7-(4-pyrindlnylmethoxy)-4H-l-benzopyran-4-one;
Cpd 115 8-methyl-2-(4-morpholinyl)-7-(2-quinoxalinylmethoxy)-4H-l-benzopyran-4-one;
Cpd 116 8-methyl-2-(4-morpholinyl)-7-(pyrazinlymethoxy)-4H-l-benzopyran-4-one;
Cpd 117 8-methyl-2-(4-morpholinyl)-7-(2-pyridinylmethoxy)-4H-l-benzopyran-4-one N-oxide;
Cpd 118 8-methyl-2-(4-morpholinyl)-7-(3-pyridinylmethoxy)-4H-l-benzopyran-4-one N-oxide;
Cpd 119 8-lodo-2-(4-morpholinyl)-7-(3-pyrindinylmethoxy)-4H-l-benzopyran-4-one;
Cpd 120 3,3-Dimethyl-1-[[8-methyl-2-(4-morpholinyl)-4-oxo-4H-l-benzopyran-7-yl]oxy]-butan-2-one;
Cpd 121 1-[18-Methyl-2-(4-morpholinyl)-4-oxo-4H-l-benzopyran-7-yl]oxy]-propan-2-one;
Cpd 122 1-[[8-Methyl-2-(4-morpholinyl)-4-oxo-4H-l-benzopyran-7-yl]oxy]-butan-2-one;
Cpd 123 8-Methyl-2-(4-morpholinyl)-7-(2-oxo-2-(2-naphthyl)ethoxy)-4H-l-benzopyran-4-one;
Cpd 125 2-(4-Morpholinyl)-7-(2-pyrindinylmethoxy)-4H-l-benzopyran-4-one;
Cpd 126 2-(4-Morpholinyl)-7-(3-pyrindinylnethoxy)-4H-l-benzopyran-4-one;
Cpd 127 2-(4-Morpholinyl)-8-(2-pyrindlnylnethoxy)-4H-l-benzopyran-4-one;
Cpd 128 2-(4-Morpholinyl)-8-(3-pyrindinylmethoxy)-4H-l-benzopyran-4-one;
Cpd 129 8-methyl-2-(4-morpholinyl)-7-(2-quinolinylmethoxy)-4H-l-benzopyran-4-one;
Cpd 130 7,8-(Bis)-phenylmethoxy-2-(4-morpholinyl)-4H-l-benzopyran-4-one;
Cpd 131 7,8-(Bis)-acetyloxy-2-(4-morpholinyl)-4H-l-benzopyran-4-one;
Cpd 132 7,8-(Bis) -hydroxy-2-(4-morpholinyl)-4H-l-benzopyran-4-one;
Cpd 133 7-Hydroxy-2-(4-morpholinyl)-8-phenylmethoxy-4H-l-benzopyran-4-one;
Cpd 135 8 - H y d r o x y - 2 - ( 4 - m o r p h o 1 i n y 1 ) - 7 - ( 3 -trifluoromethyl)phenylmethoxy-4H-l-benzopyran-4-one;
Cpd 136 7 - H y d r o x y - 2 - ( 4 - m o r p h o 1 i n y 1 ) - 8 - ( 3 -trifluoromethyl)phenylmethoxy-4H-l-benzopyran-4-one;
Cpd 137 7-[3-(1-cyclohexyl-lH-tetrazol-S-yl)propoxyl-8-methyl-2-(4-morpholinyl)-4H-l-benzopyran-4-one;
Cpd 138 8-[3-(1-cyclohexyl-lH-tetrazol-5-yl)propoxy]-2-(4-mor-pholinyl)-4H-l-benzopyran-4-one;
Cpd 139 7-[(1-cyclohexyl-lH-tetrazol-5-yl)methoxy]-8-methyl-2-(4-morpholinyl)-4H-l-benzopyran-4-one;
Cpd 140 8-[(1-cyclohexyl-lH-tetrazol-5-yl)methoxy]-2-(4-mor-pholinyl)-4H-l-benzopyran-4-one;
Cpd 141 2-(4-morpholinyl)-8-[(1-phenyl-lH-tetrazol-5-yl)oxy]-4H-l-benzopyran-4-one;
Cpd 142 N-cyclohexyl-2-[[2-(4-morpholinyl)-4-oxo-4H-l-benzopyrsn-8-yl]oxy]-acetamide;
Cpd 143 N-(l,l-dimethylethyl)-2-[[2-(4-morpholinyl)-4-oxo-4H-l-benzopyran-8-yl]oxy]-acetamide;
Cpd 144 2-[[2-(4-morpholinyl)-4-oxo-4H-l-benzopyran-8-yl]-N-phenyl-acetamide;
Cpd 145 2-[[2-(4-morpholinyl)-4-oxo-4H-l-benzopyran-8-yl]oxy]-N- phenylethyl)-acetaoide;
Cpd 147 N-[[[8-methyl-2-(4-morpholinyl)-4-oxo-4H-l-benzopyran-7-yl]oxy]acetyl]-phenyalanine, ethyl ester;
Cpd 149 8-methyl-2-(4-morpholinyl)-7-[(1-phenyl-lH-tetrazol-5-yl)oxy]-4H-l-Benzopyran-4-one;
Cpd 152 2-[[8-methyl-2-(4-morpholinyl)-4-oxo-4H-l-benzopyran-7-yl]oxy]-N-3-pyridinyl-acetanide;
Cpd 153 N-[[[8-methyl-2-(4-morpholinyl)-4-oxo-4M-l-benzopyran-7-yl]oxy]acetyl]-Phenylalanine;
Cpd 154 7-(2,2-dimethoxyethoxy)-8-methyl-2-(4-morpholinyl)-4H-l-Benzopyran-4-one;
Cpd 155 2-(4-Morpholinyl)-8-(2-propenyl)-4H-l-benzopyran-4-one;
Cpd 156 2-(4-Morpholinyl)-8-(1-propenyl)-4H-l-benzopyran-4-one;
Cpd 157 8-Formyl-2-(4-Morpholinyl)-4H-l-benzopyran-4-one;
Cpd 158 2-(4-morpholinyl)-8-(phenylamino)methyl-4H-l-benzopyran-4-one;
Cpd 159 2-(4-morpholinyl)-8-(2E-phenyl)ethenyl-4H-l-benzopyran-4-one;
Cpd 160 8-Hydroxymethyl-2-(4-Morpholinyl)-4H-l-benzopyran-4-one;
Cpd 162 8-methyl-7-[(l-methyl-3-piperidinyl)methoxy]-2-(4-mor-pholinyl)-4H-l-Benzopyran-4-one;
Cpd 163 8-Methyl-2-(4-morpholinyl)-7-(2-(1-piperi-dinyl)ethyl)oxy-4H-l-benzopyran-4-one;
Cpd 164 8 - M e t h y l - 2 - ( 4 - m o r p h o liny l) -7 - (2 - (1 -pyrrolidinyl)ethyl)oxy-4H-l-benzopyran-4-one;
Cpd 165 8-Methyl-2-(4-morpholinyl)-7-(2-(4-morpholinyl)ethyl)-oxy-4H-l-benzopyran-4-one;
Cpd 166 8-Methyl-2-(4-morpholinyl)-7-(3-(1-piperi-dino)propyl)oxy-4H-l-benzopyran-4-one;
Cpd 167 7-(2-Diethylaminoethyl)oxy-8-methyl-2-(4-morpholinyl)-4H-l-benzopyran-4-one;
Cpd 168 7-[2-(ethylphenylamino)ethoxy]-8-methyl-2-(4-mor-pholinyl)-4H-l-Benzopyran-4-one;
Cpd 169 7-(2-Diisopropylaminoethyl)oxy-8-methyl-2-(4-morpholinyl)-4H-l-benzopyran-4-one;

Cpd 170 7-Hydroxy-8-methyl-2-(1-piperidinyl)-4H-1-benzopyran-4-one;
Cpt 171 8-Methyl-2-(1-piperidlnyl) 7-(3-pyrindinylmethoxy)-4H-1-benzopyran-4-one;
Cpd 172 7-(2-(4-Benzyl-(1-piperizinyl))ethyl)oxy-8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 173 7-Acetoxy-3,8-dimethyl-2-(4-morpholinyl)-4H-1-ben-zopyran-4-one;
Cpd 174 3,8-dimethyl-7-hydroxy-2-(4-morpholinyl)-4H-1-benzo-pyran-4-one;
Cpd 175 7-benzyloxy-3,8-dimethyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 176 3,8-Dimethyl-2-(4-morpholinyl)-7-(naphthyl-1-methyloxy)-4H-1-benzopyran-4-one;
Cpd 177 3,8-Dimethyl-7-(4-methoxy-benzyloxy)-2-(4-morpho-linyl)-4H-1-benzopyran-4-one;
Cpd 178 3,8-Dimethyl-2-(4-morpholinyl)-7-(2-phenyl-ethyloxy)-4H-1-benzopyran-4-one;
Cpd 179 3,8-Dimethyl-7-(4-chlorobenzyloxy)-2- (4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 180 3,8-Dimethyl-2-(4-morpholinyl)-7-(3-trifluoromethyl-benzyloxy)-4H-1-benzopyran-4-one;
Cpd 181 7-(Carbomethoxy-methoxyl)-3,8-dimethyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 182 8-Hydroxy-3-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one, Cpd 183 8-Benzyloxy-3-methyl-2-(4-morpholinyl)-4H-1-benzo-pyran-4-one;
Cpd 184 3-methyl-2-(4-morpholinyl)-8-(m-trifluoromethyl-benzyloxy)-4H-1-benzopyran-4-one, Cpd 185 8-methyl-7-(2-phenyl)ethynyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one;
Cpd 186 8-methyl-2-(4-morpholinyl)-7-(2-phenyl)sthyl-4H-1-benzopyran-4-one;
Cpd 187 2-(4-Morpholinyl)-8-(2-phenyl)ethynyl-4H-1-benzopyran-4-one;
Cpd 188 2-(4-Morpholinyl)-8-(2-phenyl)ethyl-4H-1-benzopyran-4-one;

Cpd 189 2-(4-Horpholinyl)-8-(2-(3-trifluoromethyl-)phenyl)ethynyl-4H-l-benzopyran-4-one;
Cpd 190 2-(4-Morpholinyl)-8-(2-(3-trifluoromethyl)phenyl)-ethyl-4H-l-benzopyran-4-one;
Cpd 192 8-Methyl-2-(4-morpholinyl)-7-(2-(1-naphthyl))ethyl-4H-l-benzopyran-4-one;
Cpd 193 8-Methyl-2-(4-morpholinyl)-7-phenyl-4H-l-benzopyran-4-one;
Cpd 194 7-acetyloxy-8-iodo-2-(4-morpholinyl)-4H-l-benzopyran-4-one;
Cpd 195 8-ethyl-2-(4-morpholinyl)-7-(3-pyrindinylmethoxy-4H-l-benzopyran-4-one;
Cpd 196 8-Ethyl-2-(4-morpholinyl)-7-phenylmethoxy-4H-l-benzopyran-4-one;
Cpd 197 8-Iodo-2-(4-morpholinyl)-7-phenylmethoxy-4H-l-benzopyran-4-one;
Cpd 198 8-Ethyl-2-(4-morpholinyl)-7-(2-(1-piperi-dinyl)ethyl)oxy-4H-l-benzopyran-4-one;
Cpd 199 8-Iodo-2-(4-morpholinyl)-7-(3-pyrindinylmethoxy)-4H-l-benzopyran-4-one;
Cpd 200 8-Iodo-7-hydroxy-2-(4-morpholinyl)-4H-l-benzopyran-4-one;
Cpd 202 7-(3-pyridinylmethyleneoxy)-2-(1-piperidinyl)-8-methyl-4H-l-benzopyran-4-one;
Cpd 204 8-Methyl-2-(4-morpholinylmethyl)-7-(phenylmethoxy)-4H-l-benzopyran-4-one;
Cpd 205 7-hydroxy-2-(4-morpholinylmethyl)-B-methyl-4H-l-benzopyran-4-one;
Cpd 206 7-[(l-cyclohexyl-lH-tetrazol-5-yl)methyoxy]-8-methyl-2-(4-morpholinylmethy)-4H-l-benzopyran-4-one;
Cpd 207 8- Me thy l-2 - (4-morpholinylmethyl)-7-(3-pyridinylmethoxy)-4H-l-benzopyran-4-one;
or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a compound selected from he group consisting of compounds of Formula I

I

wherein X is N, or CZ where Z is H, C1-C5 alkyl, amino (-NH2) or a halogen atom;
when X is CZ, Y is selected from the group consisting of -(CH2)nNR9R10 wherein R9 and R10 being the same or different, are selected from the group consisting of (a) hydrogen, with the provisio that R9 and R10 are not both hydrogen; (b) C1-C12 alkyl; (c) phenyl optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(Cl-C4alkyl); (d)-(CH2)nphenyl [wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, tri-fluoromethyl or -CO2(C1-C4alkyl)], (e) -(CH2)npyridinyl or (f) wherein R9 and R10, taken together with N, form a saturated or unsaturated heterocyclic amine ring selected from the group consisting of (aa) 4-morpholine optionally substituted with one or two members selected from the group consisting of C1-C4 alkyl, Cl-C4 alkoxy, halo or trifluoromethyl (bb) 4-thiomorpholine optionally substituted with one or two members selected from the group consisting of C1-C4 alkyl, Cl-C4 alkoxy, halo or trifluoromethyl (cc) 3-amino-1-pyrrolidine, (dd) l-pyrrolidine optionally substituted with one or two members selected from the group consisting of Cl-C4 alkyl. Cl-C4 alkoxy, halo, OH, -CH20H, or trifluoromethyl (ee) l-piperidine optionally substituted with one or two members selected from the group consisting of Cl-C4 alkyl, Cl-C4 alkoxy, halo, trifluoromethyl, -(CH2)qOH, -C02H, -C02CH3 -C02CH2CH3 or phenyl (wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl), (ff) l-piperazine, 4-methyl-1-piperazine, 4-phenyl-1-piperazine (wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl) or 4-pyridinyl-1-piperazine optionally substituted with one or two members selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, trifluoromethyl, -CH20H, -CO2H- -CO2CH3 or -CO2CH2CH3, and (gg) thiazolidine, thiazolidine-4-carboxylic acid, pipecolinic acid, p-piperazinaceto-phenone, l-homopiperazine, 1-methylhomopiperazine, 4-phenyl-1, 2 - 3, 6 -tetrahydropyridine, proline, tetra-hydrofurylamine, l-(3-hydroxy)pyrrolidine, nipecotamide, 1,2,3,4-tetrahydroisoquinoline or imidazole;
and R5, R6, R7 and R8, being the same or different, are selected from the group consisting of hydrogen, C1-C8 alkyl, -(CH2)nphenyl [wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(C1-C4alkyl)], -(CH2)nnaphthyl, -(CH2)npyridinyl, -(CH2)qNR9R10, -CH-CH-phenyl [wherein phenyl is optionally sub-stituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(C1-C4alkyl)], -CH2-CH-CH2, -CH-CH-CH3, -O-CH2-CH-CH2, -C-C-phenyl [wherein phenyl is optionally sub-stituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(C1-C4alkyl)], -O(CH2)p(N-methylpiperdin-3-yl), -O-(CH2)pNR9R10, -O-CH2CH(OCH3)2, -O-(CH2)pOR15, - (CH2)nC(O) - (CH2)nR9, - (CH2)nC(O)O- (CH2)pR9,- (CH)nC(O)O-(CH2)pNR9R10, -(CH2)nC(O)(CH2)nNR9R10, N02,-O-(CH2)nC(O)-(CH2)pR9, O-(CH2)nC(O)O-(CH2)pR9, -O-(CH2)nC(O)-(CH2)nNR9R10 -NR9R10, -N(R9)(CH2)nC(O)-(CH2)nR10, -N(R9)-(CH2)nC(O)O-(CH2)nR10, N(R9)(CH2)nC(O)-(CH2)nNR9R10,-O-(CH2)nphenYl [wherein phenyl is optionally substituted with one, 2 or 3 Cl-C4 alkyl, Cl-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(Cl-4 alkyl)], -O-(CH2)npyridine, -O(CH2)nC(O)-(CH2)npyridine, -O-(CH2)nC(O)O-(CH2)npyridine, -O(CH2)nC(O)-N(Rg)(CH2)npyridine, -O-(CH2)nquinoxalinyl, -O-(CH2)nquinolinyl, -O-(CH2)npyrazlnyl, -O-(CH2)nnaphthyl, -O-(CH2)nC(O)-(CH2)nnaphthyl, -O-(CH2)nC(O)O-(CH2)nnaphthyl, -O-(CH2)nC(O)NRg-(CH2)nnaphthyl, halo (fluoro, chloro, bromo, iodo), OH, -(CH2)q-OH, (CH2)qOC(O)R9, -(CH2)qOC(O)-NR9R10, (1-cyclohexyl-1H-tetrazol-5-yl)C1-C4 alkoxy, -[1-(C1-C5alkyl)-1H-tetrazol-5-yl]C1-C4 alkoxy, -[1-(phenyl)-1H-tetrazol-5-yl]C1-C4 alkoxy [wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -C02(C1-C4alkyl) , -[l-(pyridinyl)-lH-tetrazol-5-yl]C1-C4 alkoxy, -[1-(1-phenylethyl)-1H-tetrazol-5-yl]C1-C4 alkoxy, -C1-C4 alkoxyl, a group of Formula II wherein R' is methyl or carboxy, R'' is hydrogen and R''' is selected from benzyl [optionally substituted with one, two or three groups selected from hydroxy, halogen or phenoxy (optionally substituted with one, two or three groups selected from hydroxy or halogen)], Cl-Cs alkyl,-(CH2)ncO2H, -CH2SH, -CH2SCH3, imidazolinylmethylene, indolinylmethylene, CH3CH(OH), CH2OH, H2N(CH2)4-(optionally in protected form) or H2NC(NH)NH(CH2)3 (optionally in protected form); with the overall proviso that when Y is other than -(CH2)nmorpholinyl, at least one member of R5, R6, R7 or R8 is other than hydrogen, C1-C8 alkyl, NO2, OH, C1-C4 alkoxy, a halogen atom, phenyl, benzyl, 4-morpholinylmethyl, NH2, or dimethyamino; with the further proviso that when Y is morpholinyl, the compound is other than:
6,7-dimethoxy-2-(4-morpholinyl)-4H-l-benzopyran-4-one, 7,8-(Bis)-(3-trifluoromethyl)phenylmethoxy-2-(4-morpholinyl)-4H-l-benzopyran-4-one, N-cyclohexyl-2-[[8-methyl-2-(4-morpholinyl)-4-oxo-4H-l-benzopyran-7-yl]oxy]-acetamide, 2-[[8-methyl-2-(4-morpholinyl)-4-oxo-4H-l-benzopyran-7-yl]oxyl-N-phenyl-acetamide, 6-[(1-cyclohexyl-lH-tetrazol-5-yl)methoxy]-2-(4-mor-pholinyl)-4H-l-Benzopyran-4-one, 2-[18-methyl-2-(4-morpholinyl)-4-oxo-4H-l-benzopyran-7-yl]oxy]-N-(l-phenylethyl)-acetamide;

with the further provisio that when Y is dimethylamino, the compound is other than:
2-(Dlmethylamino)-8-methyl-4-oxo-4H-l-benzopyran-7-yl carbamic acid dimethyl ester, (Dimethylamino)-4-oxo-4H-l-benzopyran-6-yl carbamic acid dimethyl ester, 2-(Dimethylamino)-4-oxo-4H-l-benzopyran-7-yl carbamic acid dimethyl ester;
when X is N, Y is selected from the group cons1sting of -NR9R10 wherein R9 and R10, being the same or different, are selected from the group consisting of (a) hydrogen, with the provisio that R9 and R10 are not both hydrogen;
(b) Cl-C12 alkyl; (c) phenyl optionally substituted with one, 2 or 3 Cl-C4 alkyl, Cl-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(Cl-C4alkyl); (d) -(CH2)nphenyl (wherein phenyl is optionally substituted with one, 2 or 3 Cl-C4 alkyl, Cl-C4 alkoxy, halo, OH, trifluoromethyl or carboCl-C4 alkoxy), (e) -(CH2)npyridinyl or (f) wherein Rg and Rlo, taken together with N, form a saturated or unsaturated heterocyclic amine ring selected from the group consisting of (aa) 4-morpholine optionally substituted with one or two members selected from the group consisting of Cl-C4 alkyl, Cl-C4 alkoxy, halo or trifluoromethyl (bb) 4-thiomorpholine optionally substituted with one or two members selected from the group consisting of C1-C4 alkyl, Cl-C4 alkoxy, halo or trifluoromethyl (cc) 3-amino-1-pyrrolidine, (dd) l-pyrrolidine optionally substituted with one or two members selected from the group consisting of Cl-C4 alkyl, C1-C4 alkoxy, halo, OH, -CH2OH, or trifluoromethyl (ee) l-piperidine optionally substituted with one or two members selected from the group consisting of Cl-C4 alkyl, C1-C4 alkoxy, halo, trifluoromethyl, -(CH2)qOH, -CO2H, -CO2CH3 -C02CH2CH3 or phenyl (wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl), (ff) 1-piperazine, 4-nethyl-1-piperazine, 4-phenyl-1-piperazino (wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl) or 4-pyridinyl-1-piperazine optionally substituted with one or two members selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, trifluoromethyl, -CH2OH,-CO2H- -CO2-CH3 or -CO2CH2CH3, and (gg) thiazolidine, thiazolidine-4-carboxylic acid, pipecolinic acid, p-piperazinaceto-phenone, 1-homopiperazino, 1-methylhomopiperazine, 4-phenyl-1,2-3,6-tetrahydropyrldlne, proline, tetra-hydrofurylamine, 1-(3-hydroxy)pyrrolidine, nipecotamide, 1,2,3,4-tetrahydroisoquinoline or imidazole;
and R5, R6, R7 and R8, being the same or different, are selected from the group consisting of hydrogen, C1-C8 alkyl, -(CH2)nphenyl [wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(C1-C4alkyl)], -(CH2)nnaphthyl, -(CH2)npyridinyl, -(CH2)qNR9R10o, -CH-CH-phenyl [wherein phenyl is optionally sub-stituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(C1-C4alkyl)], -CH2-CH-CH2, -CH-CH-CH3, -O-CH2-CH-CH2, -C-C-phenyl [wherein phenyl is optionally sub-stituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(C1-C4alkyl)], -O(CH2)p(N-methylpiperdin-3 yl), -O-(CH2)PNR9R10, -O-CH2CH(OCH3)2, -O-(CH2)pOR15, -(CH2)nC(O)-(cH2)nR9, -(CH2)nC(O)O-(CH2)pR9, -(CH)nC(O)O-(CH2)pNR9R10, -(CH2)nC(O)(CH2)nNR9R10, NO2,-O-(CH2)nC(O)-(CH2)pR9, -O-(CH2)nC(O)O)(CH2)pR9, -O-(CH2)nC(O)-(CH2)nNR9R10, -NR9R10, -N(R9)(CH2)nC(O)-(CH2)nR10, -N(R9)-(CH2)nC(O)O-(CH2)nR10, N(R9)(CH2)nC(O)-(CH2)nNR9R10, -O-(CH2)nphenyl [wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(C1-C4alkyl)], -O-(CH2)npyridine, -O(CH2)nC(O)-(CH2)npyridine, -O-(CH2)nC(O)O-(CH2)npyridine, -O(CH2)nC(O)-N(R9)(CH2)npyridine, -O-(CH2)nquinoxalinyl, -O-(CH2)nquinolinyl, -O-(CH2)npyrazinyl, -O- (CH2)nnaphthyl, -O- (CH2)nC(O) - (CH2)nnaphthyl, -O-(CH2)nC(O)O-(CH2)nnaphthyl, -0-(CH2)nC(O)NR9-(CH2)nnaphthyl, halo (fluoro, chloro, bromo, iodo), OH, -(CH2)q-OH, (CH2)qOC(O)Rg, -(CH2)qOC(O)-NR9R10, (l-cyclohexyl-lH-tetrazol-5-yl)C1-C4 alkoxy, -[1-(Cl-Csalkyl)-lH-tetrazol-5-yl]C1-C4 alkoxy, -[l-(phenyl)-1H-tetrazol-5-yl]C1-C4 alkoxy [wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(C1-C4alkyl)], -[l-(pyridinyl)-lH-tetrazol-5-yl]C1-C4 alkoxy, wherein X is CZ where Z is H, Cl-C5 alkyl, amino (-NH2) or a halogen atom;
Y is selected from the group consisting of -(CH2)nNR9R10 wherein R9 and R10, being the same or different, are selected from the group consisting of (a) hydrogen, with the provisio that R9 and R10 are not both hydrogen; (b) C1-C12 Alkyl; (c) phenyl optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(C1-C4alkyl); (d)-(CH2)nphenyl (wherein phenyl is optionally substltuted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, tri-fluoromethyl or carboCl-C4 alkoxy), (e) -(CH2)npyridlnyl or (f) wherein R9 and R10, taken together with N, form a saturated or unsaturated heterocyclic amine ring selected from the group consisting of (aa) 4-morpholine optionally substituted with one or two members selected from the group consisting of Cl-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl (bb) 4-thiomorpholine optionally substituted with one or two members selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl (cc) 3-amino-1-pyrrolidine, (dd) l-pyrrolidine optionally substituted with one or two members selected from the group consisting of Cl-C4 alkyl, C1-C4 alkoxy, halo, OH, -CH2OH, or trifluoromethyl (ee) 1-piperidine optionally substituted with one or two members selected from the group consisting of Cl-C4 alkyl, C1-C4 alkoxy, halo, trifluoromethyl, -(CH2)qOH, -CO2H, -CO2CH3 -CO2CH2CH3 or phenyl (wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl), (ff) l-piperazine, 4-methyl-1-piperazine, 4-phenyl-1-piperazine (wherein phenyl is optionally substituted with one, 2 or 3 Cl-C4 alkyl, C1-C4 alkoxy, halo or trifluoromethyl) or 4-pyridinyl-1-piperazine optionally substituted with one or two members selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, trifluoromethyl, -CH2OH,-CO2H- -CO2CH3 or -CO2CH2CH3, and (gg) thiazolidine, thiazolidine-4-carboxylic acid pipecolinic acid, p-piperazinsceto-phenone, l-homopiperazine, 1-methylhomopiperazine, 4-phonyl-1,2-3,6-tetrihydropyridine, proline, tetra-hydrofurylamine, 11-(3-hydroxy)pyrrolidine, nipecotamide, 1,2,3,4-tetrahydroisoquinoline or imidazole;
and R5, R6, R7 and R9, being the same or different, are selected from the group consisting of hydrogen, C1-C9 alkyl, -(CH2)nphenyl [wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(C1-C4alkyl)], -(CH2)nnaphthyl, -(CH2)npyridinyl, -(CH2)qNR9R10, -CH-CH-phenyl [wherein phenyl is optionally sub-stituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(Cl-C4alkyl), -CH2-CH-CH2, -CH-CH-CH3, -O-CH2-CH-CH2, -C-C-phenyl [wherein phenyl is optionally sub-stituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -C02(C1-C4alkyl)], -O(CH2)p(N-methylpiperdin-3-yl), -O-(CH2)pNRgRlo, -O-CH2CH(OCH3)2, -O-(GH2)pORls, - (CH2)nC(O) - (CH2)nR9 - (CH2)nC(O)O- (CH2)pR9, - (CH)nC(O)O-(CH2)pNR9R10, -(CH2)nC(o)(cH2)nNR9R10, N02,-0-(CH2)nC(O)-(CH2)PR9' -O-(CH2)nc(O)O-(cH2)pR9, -o-(CH2)nc(o)-(CH2)nNR9R10, -NR9R10, -N(R9)(CH2)nc(O)-(CH2)nR10, -N(R9)-(CH2)nC(O)O-(CH2)nR10, N(R9)(CH2)nC(O)-(cH2)nNR9R10, -O-(CH2)nphenyl [wherein phenyl is optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoroDethyl or -CO2(C1-C4alkyl)], -O-(CH2)npyridine, -O(CH2)nC(O)-(CH2)npyridine, -O-(CH2)nC(O)O-(CH2)npyridine, -O(CH2)nC(O)-N(Rg)(CH2)npyridine, -O-(CH2)nquinoxalinyl, -O-(CH2)nquinolinyl, -O-(CH2)npyrazinyl, -O-(CH2)nnaphthyl, -O-(CH2)nC(O)-(CH2)nnaphthyl, -O-(CH2)nC(O)O-(CH2)nnaphthyl, -O-(CH2)nC(O)NRg-(CH2)nnaphthyl, halo (fluoro, chloro, bromo, iodo), OH, -(CH2)q-OH-(CH2)qOC(O)R9, -(CH2)qOC(O)-NR9R10, (l-cyclohexyl-lH-tetrazol-5-yl)C1-C4 alkoxy, -[1-(C1-C5alkyl)-1H-tetrazol-5-yl]C1-C4 alkoxy, -[l-(phenyl)-1H-tetrazol-5-yl]C1-C4 alkoxy [wherein phenyl is optionally substituted with one, 2 or 3 Cl-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(C1-C4alkyl)], -[l-(pyridinyl)-lH-tetrazol-5-yl]C1-C4 alkoxy, -[1-(1-phenylethyl)-1H-tetrazol-5-yl]C1-C4 alkoxy, -C1-C4 alkoxyl, or a group of Formula II (see Formula Sheet) wherein R' is methyl or carboxy, R'' is hydrogen and R''' is selected from benzyl [optionally substituted with one, two or three groups selected from hydroxy, halogen or phenoxy (optlonally substituted with one, two or three groups selected from hydroxy or halogen)], C1-C5 alkyl, -(CH2)nC02H, -CH2SH, -CH2SCH3, imidazollnylmethylene, indolinylmethylene, CH3CH(OH), CH20H, H2N(CH2)4-(optionally ln protected form) or H2NC(NH)NH(CH2)3 (optionally in protected form); with the overall proviso that when Y is other than -(CH2)nmorpholinyl, at least one member of R5, R6, R7 or R8 is other than hydrogen, C1-C9 alkyl, NO2, OH, C1-C4 alkoxy, a halogen atom, phenyl, benzyl, 4-morpholinylmethyl, NH2, or dimethyamino; with the further proviso that when Y is 4-morpholinyl, the compound is other than:
6,7-dimethoxy-2-(4-morpholinyl)-4H-l-benzopyran-4-one, 7,8-(Bis)-(3-trifluoromethyl)phenylmethoxy-2-(4-morpholinyl)-4H-l-benzopyran-4-one, N-cyclohexyl-2-[[8-methyl-2-(4-morpholinyl)-4-oxo-4H-l-benzopyran-7-yl]oxy]-acetamide, 2-[[8-methyl-2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-7-yl]oxy]-N-phenyl-acetamide, 6-[(1-cyclohexyl-1H-tetrazol-5-yl)methoxyl-2-(4-mor-pholinyl)-4H-l-Benzopyran-4-one, 2-[[8-methyl-2-(4-morpholinyl)-4-oxo-4H-l-benzopyran-7-yl]oxy]-N-(l-phenylethyl)-acetamide;
with the further provisio that when Y is dimethylamino, the compound is other than:
2-(Dimethylauino)-8-methyl-4-oxo-4H-l-benzopyran-7-yl carbamic acid dimethyl ester, (Dimethylamino)-4-oxo-4H-l-benzopyran-6-yl carbamic acid dimethyl ester, 2-(Dimethylamino)-4-oxo-4H-l-benzopyran-7-yl carbamic acid dimethyl ester;
R15 is selected from C1-C5 alkyl, -(CH2)nphenyl [phenyl optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, OH, trifluoromethyl or -CO2(C1-C4alkyl)], -(CH2)npyridin-1-yl or (CH2)ppiperidin-l-yl];
is 0-5;
is 2-5;

q is 1-5;
which comprises reacting a salicylic acld ester of Formula A

with an ynamine of Formula B