HK1066796B

HK1066796B - Pyranone compounds useful to treat retroviral infections

Info

Publication number: HK1066796B
Application number: HK04109663.3A
Authority: HK
Inventors: K．R．罗米尼斯; G．L．邦迪; T．M．施瓦茨; R．A．托马西; J．W．斯特罗巴克; S．R．特纳; S．塞斯里冯斯; P．A．阿里斯托夫; P.D.约翰逊; H．I．斯库尼克; L．L．斯卡勒茨基; D.J.安德森; J．默里斯; R．B．甘米尔; G．P．鲁克
Original assignee: 法玛西雅厄普约翰美国公司
Priority date: 1994-05-06
Filing date: 2004-12-07
Publication date: 2008-01-18

Description

Compounds for the treatment of retroviral infections

This application is a divisional application of the chinese patent application filed on 4.5.1995 under application No. 95193553.4 entitled "compound for treating retroviral infections".

Technical Field

The present invention relates to compounds useful for inhibiting retroviruses in retrovirus-infected human cells. More particularly, the present invention provides pyran-2-ones, 5, 6-dihydropyran-2-ones, 4-hydroxy-benzopyran-2-ones, 4-hydroxy-cycloalkyl [ b ] pyran-2-ones, and derivatives thereof, useful as HIV-protease inhibitors.

Background

Acquired Immune Deficiency Syndrome (AIDS) has developed over the last decade from a medical dilemma affecting only a few individuals into a medically and economically significant problem. John Saunders and Richard Storer, "New developments in RT inhibitors", DN & P5(3), 4 months 1992, pp 153-169. WHO's data reveal that more than 360000 cases of AIDS have been reported worldwide, of which about 175000 in the united states. Of these, approximately 100000 cases worldwide (50000 in the united states) were reported during the first 12 months. The number of seropositive individuals in the united states is about two million, and it is estimated that five to ten million people worldwide are seropositive. Saunders and Storer, page 153.

Since the first description of the disease in the early decades, acquired immunodeficiency syndrome (AIDS) and its catastrophic consequences have been the subject of continuing and extensive scientific publications. Indeed, there is a edition of Scientific American that is completely concerned with AIDS [ Scientific American 289, #4(1988) ] and the literature on this disease and virus is so extensive that it is not fully cited.

On 20/3 of 1987, the FDA approved the compound zidovudine (AZT) for the treatment of AIDS patients with recent initial onset of pneumocystis carinii pneumonia, AIDS patients with symptoms other than pneumocystis carinii pneumonia, or absolute CD in peripheral blood₄The number of lymphocytes is less than 200/mm³Of a patient infected with the virusUse is provided. AZT is a known viral reverse transcriptase, an inhibitor of the enzymes required for replication of the human immunodeficiency virus. Us patent 4724232 claims a method of treating patients with acquired immunodeficiency syndrome using 3 '-azido-3' -deoxy-thymidine (azidothymidine, AZT).

With the discovery of AZT anti-HIV activity, a great deal of effort has been focused on various other dideoxynucleoside analogs to find better drugs. In the 2 ', 3' -dideoxy series, ddC and ddI showed potent anti-HIV in vitro activity and have been evaluated in clinical trials. Saunders and Storer, page 160. Hoffman-La Roche has recently developed compound ddC as a potential anti-AIDS drug. Its limiting toxicity in humans is peripheral neuropathy, which is reversible at low doses. Raymond R.Schinazi, Jan R.Mead and Paul M.Feorino, "instruments Into HIV Chemotherapy", AIDS Research and human Retroviruses, Vol.8(6), 1992, page 963-. It has been approved by the FDA for use in combination with AZT in the treatment of AIDS. Compound ddI has also been evaluated in clinical trials. Its limiting toxicities are peripheral neuropathy and pancreatitis. It has also been shown to stimulate hepatic glycolysis to cause irreversible liver damage. Schinazi, Mead and Feorino, page 966. The FDA has recently approved it for the treatment of HIV-1 infection in adults and pediatric patients who cannot tolerate AZT or have significantly deteriorated health when AZT is treated. Schinazi, Mead and Feorino, page 966.

Of these approved drugs, AZT is currently the only drug that has been shown to reduce mortality and the frequency of opportunistic infections associated with AIDS, schiinazi, Mead and Feorino, page 963.

Human Immunodeficiency Virus (HIV) has long been recognized as the causative agent of AIDS, although there are a few opposite views (e.g., p. duesberg, proc. natl. acad. sci., USA, 86: 755, 764 (1989). Sequence analysis of the complete genome of many infectious and non-infectious HIV isolates elucidates the composition and molecular type of the virus (important for the virus to replicate and mature into infectious species). HIV protease is important for the development of viral gag and gag-pol polypeptides into mature viral proteins. Ratner et al, Nature, 313: 277-284 (1985); L.H.Pearl and W.R.Taylor, Natuer, 329-E351 (1987). HIV exhibits the same gag/pol/env organization as in other retroviruses. Ratner et al, supra. Wainhobson et al, Cell, 40: 9-17 (1985); sanchez-Pescador et al, Science, 227: 484-492 (1985); m.a. muesing et al, Nature, 313: 450-458(1985).

Reverse Transcriptase (RT) is an enzyme specific to retroviruses that catalyzes the conversion of viral RNA to double-stranded DNA. Blocking any point in the transcription process by AZT or any other abnormal deoxynucleoside triphosphate (which cannot be extended) will produce dramatic results associated with viral replication. Much of the progress in work on RT targets is based in large part on the fact that nucleosides such as AZT are readily transported into cells. However, the ineffectiveness, lack of specificity and thus toxicity of the phosphorylation step on triphosphates, form the major disadvantage of using AZT and similar nucleosides with blocked or missing 3' -hydroxyl groups.

The T4 cell receptor for HIV, the so-called CD4 molecule, has also been the target of intervention in AIDS therapy. R.a. fisher et al, Nature, 331: 76-78 (1988); r.e. hussey et al, Nature, 331: 78-81 (1988); deen et al, Nature, 331: 82-84(1988). The outer membrane portion of the transmembrane protein, a 371 amino acid molecule (sCD4), has been expressed in Chinese Hamster Ovary (CHO) cells and genetic engineering (Genentech) [ d.h. smith et al, Science, 238: 1704-. CD4 has been found to have a narrow spectrum of activity against wild-type (wild-type) virus and thus cannot control HIV infection in humans. Schinazi, Mead and Feorino, page 963. The idea of CD 4-based therapy is based on the fact that this molecule can neutralize HIV by interfering with viral attachment to T4 and other cells expressing CD4 on their surface. A variation on this topic is to deliver cytotoxins with specific binding to infected cells that are attached to CD4 and that express the glycoprotein gp-120 on the surface. M.a. till et al, Science, 242: 1166-1168 (1988); chaudhary et al, Nature, 335: 369-372(1988).

Another target of AIDS therapy involves the inhibition of viral proteases, which are important for the processing of precursors of HIV fusion polypeptides. In HIV and many other retroviruses, proteolytic maturation of the gag and gag/pol fusion polypeptides, a process essential for the production of infectious viral particles, is regulated by proteases, which themselves are encoded by the pol region of the viral genome. Y.yosbinaka et al, proc.natl.acad.sci.usa, 82: 1618-; y.yoshinaka et al, j.virol., 55: 870-873 (1985); y.yoshinaka et al, j.virol., 57: 826-832 (1986); and k.von der Helm, proc.natl.acad.sci., USA, 74: 911-915(1977). Inhibition of proteases has been shown to inhibit the progression of HIVp55 in mammalian cells and HIV replication in T lymphocytes. T.j.mcquadre et al, Science, 247: 454(1990).

A protease containing only 99 amino acids is one of the smallest known enzymes, which has been shown to be homologous to aspartyl proteases, such as pepsin and renin [ l.h. pearl and w.r. taylor, Nature, 329: 351-354 (1987); katoh et al, Nature, 329: 654-656(1987), led to conclusions about the three-dimensional structure and mechanism of the enzyme (L.H.Pearl and W.R.Taylor, supra) and have been experimentally confirmed. Active HIV protease has been expressed in bacteria [ see, e.g., p.l.darke et al, j.biol.chem., 264: 2307-: 363-368 (1988); r.f. nutt et al, proc.natl.acad.sci., USA, 85: 7129-. Site-specific mutagenesis [ p.l.darke et al, supra; n.e.kohl et al, proc.natl.acad.sci., USA, 85: 4686-4690(1988) and pepstatin inhibition [ p.l.darke et al, j.biol.chem., 264: 2307 and 2312 (1989); s.seelmeier et al, proc.natl.acad.sci., USA, 85: 6612 and 6616 (1988); C. giam and i.borsos, j.biol.chem., 263: 14617-14720 (1988); hansen et al, EMBO j., 7: 1785-1791(1988) provides evidence for the mechanistic function of the HIV protease as an aspartyl protease. One study demonstrated that during virus maturation, proteases are cleaved at the expected polypeptide site and are mimicked by the enzyme within the gag and pol precursor proteins after the region has actually cleaved. P.l.darke et al, Biochem, biophysis.res.commans, 156: 297-303(1988). For HIV protease [ m.a. navia et al, Nature, 337: 615 (1989) and related retroviral enzymes from the rous sarcoma virus [ m.miller et al, Nature, 337: 576-579(1989) revealed that the active site in the protease dimer is completely identical to that seen in other aspartyl proteases, supporting the hypothesis that the HIV enzyme is active as a dimer (L.H.Pearl and W.R.Taylor, supra). See also Joseph A. Martin, "a new development in the design of HIV protease inhibitors," anti Research, 17(1992)265- "278.

Today, the scientific search for a completely effective and safe method of inhibiting retroviruses in human hosts, and thus effectively treating diseases caused by such viruses, such as Acquired Immune Deficiency Syndrome (AIDS), continues.

Disclosing information

JO 3227-H-923A (Sawai Seiyaku KK) discloses the use of 4-hydroxy-coumarins as therapeutic agents for HIV-infected patients; however, unsubstituted 4-hydroxy-coumarin is the only compound specifically disclosed for this use.

WO 91/04663(univ. of Calif, Oakland) discloses 6-amino-1, 2-benzopyranones for the treatment of viral diseases.

WO 91/12804(Kabi pharmaceutical), published 5.9.1991, discloses the use of N-phenyl-N-methyl-1, 2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide (Linomide) for the treatment of retroviral infections.

International publication No. WO89/07939, published 1989 on 8.9, discloses specific coumarin compounds which are inhibitors of reverse transcriptase.

U.S. Pat. Nos. 3489774 and 3493586 disclose the production of 3 (. beta. -aryl-. beta. -arylthio) (or arylseleno)) propionyl-coumarins and pyrones as parasiticidal agents.

Biochemical and Biophysical Research Communications, 188(2), 1992, 631-637, disclose chromones with a hydroxyl substituent and a 2-phenolic group (flavone) having anti-HIV-1 protease activity.

Gamma-pyrones, gamma-pyridones, gamma-thio-pyrones are disclosed as antiviral drugs on 9, 4, weekends of 1992.

International publication Nos. WO 92/04326, 92/04327 and 92/04328, all published 3/19.1992, disclose heterocyclic antiviral derivatives such as quinolinones and benzopyrones as replication inhibitors for the treatment of herpes simplex types 1 and 2, cytomegalovirus and Epstein-Barr virus.

C.a.selects: antitumor Agents, Issue 19, 1992, p.25, No. 117: 90147q (PCT international application WO 9206687) discloses the preparation of 5-iodo-5-amino-1, 2-benzopyranone and analogs as cytostatic and antiviral agents.

There is no literature describing the use of 4-hydroxy-alpha-pyrones as HIV protease inhibitors or with antiviral activity.

Phytochemistry, 31 (3): 953-956(1992) discloses compounds such as methyl 4-hydroxy- α - (4-methoxyphenyl) -6- [2- (4-methoxyphenyl) vinyl ] -2-oxo- (E) - (-) 2H-pyran-3-acetate.

Tetrahedron, 48 (9): 1695-: 3109-12(1989), disclosed, for example, 3- [1- (4-chlorophenyl) -3- (4-nitrophenyl) -2-propenyl ] -4-hydroxy-6-methyl-2H-pyran-2-one; 3- [3- (4-chlorophenyl) -1- (4-nitrophenyl) -2-propenyl ] -4-hydroxy-6-methyl-2H-pyran-2-one; 4-hydroxy-3- [3- (4-methoxyphenyl) -1- (4-nitrophenyl) -2-propenyl ] -6-methyl-2H-pyran-2-one; and 4-hydroxy-3- [1- (4-methoxyphenyl) -3- (4-nitrophenyl) -2-propenyl ] -6-methyl-2H-pyran-2-one.

Tennen Yuki Kagobutsu Toronkai Koen Yoshishu, 30: 17-24(1988) to describe compounds such as methyl 4-hydroxy- β - (4-methoxyphenyl) -6- [2- (4-methoxyphenyl) vinyl ] -2-oxo- (E) - (-) -2H-pyran-3-propionate.

Chem. absts.53: 15072f discloses compounds such as alpha-1, 3-dihydroxy-2-butenylene-beta-ethylhydrocinnamic acid delta-lactone.

Chem. absts.53: 15072c discloses compounds such as α -1, 3-dihydroxy-2-butenylene- β -isopropyl hydrocinnamic acid δ -lactone.

Arch, pharm, (Weinheim, Ger.), 316 (12): 988-94(1983) which discloses, for example, 3- [1- (4-chlorophenyl) -3-oxobutyl ] -4-hydroxy-6-methyl-2H-pyran-2-one; and 3- [1- (4-chlorophenyl) propyl ] -4-hydroxy-6-methyl-2H-pyran-2-one.

Cam, be., 110 (3): 1047-57(1977), discloses, for example, 6- (3, 4-dimethoxyphenyl) -3- [2- (3, 4-dimethoxyphenyl) -1- (4-methoxy-2-oxo-2H-pyran-6-yl) ethyl ] -4-hydroxy-2H-pyran-2-one; and 3- [2- (3, 4-dimethoxyphenyl) -1- (4-methoxy-2-oxo-2H-pyran-6-yl) ethyl ] -4-hydroxy-6- [2- (4-methoxyphenyl) ethyl ] -2H-pyran-2-one.

J.heterocyclic. chem., 23 (2): 413-16(1986) to describe compounds such as 3- [ (4-chlorophenyl) -1-piperidinylmethyl ] -4-hydroxy-6-methyl-2H-pyran-2-one.

The following published PCT applications disclose peptides useful as retroviral protease inhibitors: international publication No. WO 91/06561, published 5/16/1991; and International publication No. WO92/17490, published 10/15.1992;

the following references disclose pyrone compounds, which are believed to be representative of compounds known in the art.

EP-443449 (German) discloses 3-hexyl-5, 6-dihydro-6-pentyl-2H-pyran-2-one and 3-ethyl-6-hexadecyl-5, 6-dihydro-4-hydroxy-2H-pyran-2-one. Pesticide, sci., 27 (1): 45-63(1989) discloses 5, 6 dihydro-4-hydroxy-6-methyl- (1-methyl-1-propenyl) -3- (1-oxobutyl) -2H-pyran-2-one; and 6-cyclopropyl-5, 6-dihydro-4-hydroxy-6-methyl-3- (1-oxobutyl) -2H-pyran-2-one. Acta. chem.scand., 43 (2): 193-95(1989) discloses 4- (acetoxy) -5, 6-dihydro-3, 6 dimethyl-2H-pyran-2-one. Chem., 54 (14): 3383-9(1989) to describe 5, 6-dihydro-4-hydroxy-3, 6, 6-trimethyl-2H-pyran-2-one. Chem., 53 (6): 1218-21 (1988); and Tetrahedron lett, 34 (2): 277-80(1993), discloses (6R) -3-hexyldihydro-6-undecyl-2H-pyran-2, 4(3H) -dione. Chem.soc.perkins trans, 1 (6): 1157-9(1985) discloses dihydro-3-methyl-6-nonyl-6- [ [ (methyl-hydrogen-2H-pyran-2-yl) oxy ] methyl ] -2H-pyran-2, 4(3H) -dione. Chem. ecol., 9 (6): 703-14(1983), 5, 6-dihydro-4-hydroxy-3, 6-dimethyl-2H-pyran-2-one is disclosed. Chem., 48 (7): 1123-5(1983) discloses (Z) - (+ -) 6- (2-chloro-1-methylvinyl-5, 6-dihydro-4-hydroxy-3-methyl-2H-pyran-2-one, acta, chem, Scand, 43(2) 193-95(1989) and Tetrahedron Lett, 21(6) 551-4(1980) discloses 5, 6-dihydro-4-hydroxy-3, 6-dimethyl-2H-pyran-2-one, Helv, chem, acta, 59(7) 2393-2401(1976) discloses 4- [ (3, 6-dihydro-4-hydroxy-5-methyl-6-oxo-2H-pyran-2-yl) methyl ] -2, 6-piperidinedione. Acta. chem.scand., 30 (7): 613-18 (1976); and Tetrahedron lett, 22: 1903-4(1976), discloses (E) -5, 6-dihydro-4-hydroxy-3-methyl-6- (1-methyl-1-propenyl) -2H-pyran-2-one. In synth. commun, 20 (18): 2827 2836, 1990 discloses 3, 3' - [ (4-nitrophenyl) methylene ] bis [5, 6-dihydro-4-hydroxy-6-methyl-2H-pyran-2-one; and 3, 3' - (phenylmethylene) bis [5, 6-dihydro-4-hydroxy-6-methyl-2H-pyran-2-one.

WO 93/07868, published 1993 on month 4 and 29, discloses novel nitroso-benzopyranone, -benzamide and-isoquinolinone derivatives useful as inhibitors of adenosine diphosphate ribosyltransferase for the treatment of viral infections and cancer.

WO 93/07128, published 1993 at 4/15, relates to substituted cyclic ketones and derivatives thereof useful as retroviral protease inhibitors.

J.indian chem.soc., 69: 397-398 (month 7 1992), discloses the determination of the anti-cancer and anti-AIDS activity of coumarin-4-acetic acids, which were found to be inactive.

The Journal of Antibiotics, 46 (7): 1126(1993, 7 months) discloses bacteriocin (germicidin), 6- (2-butyl) -3-ethyl-4-hydroxy-2-pyrone, which is an autoregulation germination inhibitor of streptomyces viridis NRRL B-1551.

Derwent Abstract, 93-168920/21 of EP543201 discloses the use of coumarin derivatives, such as 1- (N-morphinol) -6- (4-ethylhydroxybenzoate) hexane, for the treatment of viral infections, such as influenza or acute rhinitis.

Chem., 48 (22): 3945-7 (1983); chem. pharm. bull, 29 (10): 2762-8(1981) discloses compounds such as 4-hydroxy-6- (3-pyridyl) -2H-pyran-2-one.

Labelled composite. radiopharm, 28 (10): 1143-8(1990) compounds such as 4-hydroxy-6-methyl-2H-pyran-2-one are disclosed.

Am chem.soc., 113 (25): 9585-95(1991), compounds such as 3- (3-phenyl-2-propen-1-yl) -6-methyl-4-hydroxy-2H-pyran-2-one are disclosed.

CA 54: 14239d and CA 53: 4272c discloses compounds such as α - (α, γ -dihydroxycinnamylidene) -hydrocinnamic acid δ -lactone.

CA 53: 15072f discloses compounds such as α -1, 3-dihydroxy-2-butenylene- β -ethyl-hydrocinnamic acid δ -lactone.

Commun, 20 (18): 2827-36(1990) compounds such as 3, 3 '- [ (4-nitrophenyl) methylene ] bis [5, 6-dihydro-4-hydroxy-6-methyl-2H-pyran-2-one, and 3, 3' - (phenylmethylene) bis [5, 6-dihydro-4-hydroxy-6-methyl-2H-pyran-2-one, are disclosed.

Chem., 54 (14): 3383-9(1989) to describe compounds such as 5, 6-dihydro-4-hydroxy-3, 6, 6-trimethyl-2H-pyran-2-one.

Derwent Abstract, 92-166863/20 of EP 553248 discloses novel optionally substituted 5-iodo-6-amino-1, 2 benzopyrone derivatives, which are inhibitors of adenosine diphosphate ribose, for the treatment and prevention of viruses and tumors involved in AIDS.

Synthesis of heterocycles, xv.4-hydroxy-2-pyranone cycloolefins, e.ziegler, h.juneek, and e.nolken, monatsh, 89: 678-82(1958) (CA 53: 12283-4) discloses the following compounds: 4-hydroxy-3-benzyl-5, 6-octylidene-2-pyrone; 4-hydroxy-3-benzyl-5, 6-pentylidene-2-pyrone; 4-hydroxy-3-benzyl-5, 6-heptylidene-2-pyrone; 4-hydroxy-3-benzyl-5, 6-hexylidene-2-pyrone; 4-hydroxy-3-benzyl-5, 6-tridecylidene-2-pyrone.

R.effenberger, t.ziegler, k.h.schonwalder, t.kesmarszky, b.bauer, chem.ber 119: 3394-3404(1986) disclose pyrone intermediates, for example of formula J-1 (wherein n is 4; see Table J below).

Money, chem., 119 (6-7): 727-37(1988) (CA 110 (13): 114430k) discloses the compound 10-hydroxy-9- (phenylmethyl) -; and indeno [2, 1-b ] pyran-3 (5H) -one, 1-hydroxy-2- (phenylmethyl) -8H-acenaphtho [1, 2-b ] pyran-8-one.

CA 54: 14239b discloses the compound 3-benzyl-4-hydroxy-2-oxoindeno [1, 2-b ] pyran.

Breast, chem., 113 (4): 475-84(1982) discloses, for example, 6, 7-dihydro-4-hydroxy-6- (3-methylphenyl) -7-phenyl-3- (phenylmethyl) -pyrano [2, 3-c ] pyrrole-2, 5-dione; and 6, 7-dihydro-4-hydroxy-6, 7-diphenyl-3- (phenylmethyl) -pyrano [2, 3-c ] pyrrole-2, 5-dione.

Breast, chem, 90: 594-9(1959) (CA 54: 14238g, H) discloses, for example, α -benzyl-6, 7-dihydro- β -9-dihydroxy-5H-benzocycloheptene-8-propenoic acid δ -lactone; and 3-benzyl-5, 6, 7, 8-tetrahydro-4-hydroxy-8-isopropyl-5-methylcoumarin.

Bull, soc, chim, fr.5: 1719-23(1969) (Fr) (CA 71 (21): 101655p) discloses the compound 3-benzyl-5, 6, 7, 8-tetrahydro-4-hydroxycoumarin.

WO 8804652 (equivalent to AU 8810440(Jap.)) discloses the compound 3- (4-chloro-2-nitrobenzoyl) -5, 6, 7, 8-tetrahydro-4-hydroxy-2H-1-benzopyran-2-one.

Monatsh.92: 246-53(1961) (Gr) (CA 55: 27296d) discloses the compound 3- (3, 5-dimethylsalicyl) -5, 6, 7, 8-tetrahydro-4-hydroxy-coumarin.

CA 94 (9): 65472r discloses 5, 6, 7, 8-hexahydro-3-phenyl-2-H-cycloocta [ b ] pyran-2-one; and 6, 7, 8, 9-tetrahydro-4-hydroxy-3-phenyl-2-H-cyclohepta [ b ] pyran-2 (5H) -one.

Chem.28 (11): 3112-14(1963) (CA 59: 15185e) discloses the compound 2- [ hydroxy (2-hydroxy-1-cyclopenten-1-yl) methylene ] adipate delta lactone.

Cyclic ureas and analogs useful as retroviral protease inhibitors are disclosed by Antimicrobial Patent Fast-Alert, 1993 on 30/4, weekend.

Many compounds of the 4-hydroxy-coumarin type are known. For example, these documents-CA 54: 577e, g, h (1960); U.S. patent 2872457(CA 53: 12305e (1959)); CA 51: 14826f, h (1957); U.S. Pat. No. 2723276(CA 52: 5480g, h (1958)); CA 51: 14827a, b (1957); CA 51: 16453a (1957); CA 54: 5699d (1960); CA 54: 16450f (1960); CA 53: 22454a (1959); CA 53: 20046a- -discloses the following compounds: 4-hydroxy-3- (1-phenylbutyl) -coumarin; 4-hydroxy-3- (1-phenylpentyl) -coumarin; 3- (cyclohexylphenylmethyl) -4-hydroxycoumarin; 4-hydroxy-3- (2-methyl-1-phenylpropyl) -coumarin; 4-hydroxy-3- (2-phenylpropyl) coumarin; 4-hydroxy-3- (1, 3-diphenylpropyl) -coumarin; 4-hydroxy-3- (1- (4-methylphenyl) -butyl) -coumarin; 4-hydroxy-3- (1- (1-naphthyl) -propyl) coumarin; 4-hydroxy-7-methyl-3- (1-phenylpropyl) -coumarin; 7-chloro-4-hydroxy-3- (1-phenylpropyl) coumarin; 4-hydroxy-3- [1- (4-methoxyphenyl) propyl ] -coumarin; 3- (α -ethyl-p-fluorobenzyl) -4-hydroxy-coumarin; 3- (α -ethyl-p-methoxybenzyl) -4-hydroxy-coumarin; 3- (1-phenyl-propenyl) -4-hydroxy-coumarin.

To the best of our knowledge, these references do not disclose the use of these compounds as HIV protease inhibitors. They are disclosed as rodenticides, lowering blood prothrombin levels, blood anticoagulants, and insecticides.

Other 4-hydroxy-coumarin compounds of similar utility are disclosed in the following references.

Indian j.chem., sec.b, 25B: 1167-70(1986) (CA 107 (17): 154201f) and CA93 (23): 220546t discloses the compound 4-hydroxy-3- (1-phenyl-2-propenyl) -coumarin.

CA 96 (19): 157432 x; CA 90 (1): 1707 f; CA 84 (9): 55338 f; CA 79 (13): 74969 a; and CA 71 (15): 69677j discloses the compound 4-hydroxy-3- [1- (1, 2, 3, 4-tetrahydro) naphthyl ] -coumarin; CA 54: 579e discloses the compound 4-hydroxy 3- [1- (2, 3-indanyl) ] -coumarin; CA 63: 14743c discloses the compound 4-hydroxy-3- (1-naphthylmethyl) -coumarin; CA 63: 5589c discloses the compound 3- (1' - (2-methoxy, 3-methyl, 5-chloro-phenyl) propyl) -4-hydroxy-coumarin; CA 64: 12969b discloses the compound 3- (α -acetonyl- α -acetylbenzyl) -4-hydroxy-coumarin.

CA 79 (13): 74969 a; him.7 (4): 300-6(1972) (Fr) (CA78 (7): 38016 h); CA 52: 5399 b; CA 54: 5699 e; CA 54: 579 e; and CA72 (15): 78882v disclose 4-hydroxycoumarin compounds substituted at the 6-or 7-position with, for example, methyl, methoxy and chloro.

Mulder, U.S. Pat. No. 3835161, 1974, 9/10, discloses the compound 3- [1- [4- (2-bromoethyl) phenyl ] ethyl ] -4-hydroxy-2H-1-benzopyran-2-one.

Merck Index, 11 th edition (1989); entry 9950, disclosing warfarin, the chemical name of which-3- α -phenyl- β -acetyl ethyl-4-hydroxycoumarin-which is used as a rodenticide and anticoagulant. Med, chem, 1978, 21 (2): 231, 234, discloses warfarin activity against vitamin K and discusses certain 3-substituted 4-hydroxycoumarins such as 4-hydroxy-3- (1-phenylbutyl) -coumarin; and anticoagulant activity of 4-hydroxy-3- (alpha-methylbenzyl) -coumarin. J.am.chem.soc.83: 2676-9(1961) (CA 55: 22306e (1961)) discusses the resolution and absolute configuration of warfarin and discloses the preparation of compounds such as 4-hydroxy-3- (1-phenylbutyl) -coumarin.

Journal of laboratory Compounds and radiopharmaceuticals XXIII (2): 137-148(1986), discloses deuterium-labeled warfarin metabolites and phenylpropanoids, such as the tritium-labeled compound 4-hydroxy-7-methoxy-3- (1-phenylpropyl) -coumarin.

J48023942 discloses compounds such as 4-hydroxy-3- (α -methylbenzyl) -coumarin; 4-hydroxy-3- (3-methyl-1-phenylbutyl) coumarin; 4-hydroxy-7-methoxy-3- (1-phenylpropyl) -and 2H-1-benzopyran-2-one (cited in the previous literature) and their use as rodenticides.

Tr. voronezh. teckhnol. inst.19 (2): 27-30(1971), abstract number lzh274 (russian), discloses the compound 4-hydroxy-3-phenethylcoumarin. This document, and helv. chim. acta74 (7): 1451-8(1991) discloses 4-hydroxy-3- (3-phenylpropyl) coumarin.

Chem.33 (1): 437-8 (1968); and eur.j.med.chem. -chimther.12 (2): 125-30(1977) disclose compounds such as 4-hydroxy-3-diphenylmethylcoumarin.

U.S.3764693 discloses the compound 4-hydroxy-3- (3-hydroxy-1-phenylbutyl) -coumarin and its anticoagulant and rodenticidal activity.

Med chem.18 (5): 513-19(1975) (CA 83 (5): 37913 q); chromatogr.338 (2): 325-34 (1985); chromatogr.562 (1-2): 31-8 (1991); lablledcompds. radiopharm.23 (2): 137-48(1986) (cited above); chromatogr.529 (2): 479-85(1990) compounds such as 4-hydroxy-3- [1- [3- (phenylmethoxy) phenyl ] propyl ] -2H-1-benzopyran-2-one; 4-hydroxy-8- (phenylmethoxy) -3- (1-phenylpropyl) -2H-1-benzopyran-2-one; 4-hydroxy-3- [1- (4-hydroxyphenyl) propyl ] -coumarin; 4-hydroxy-6-methoxy-3- (1-phenylpropyl) -coumarin; 4, 7-dihydroxy-3- (1-phenylpropyl) coumarin; 4, 6-dihydroxy-3- (1-phenylpropyl) -coumarin; 4-hydroxy-3- [1- (3-hydroxyphenyl) propyl ] -coumarin; and p-chlorophenyl hydroxycoumarin.

AIDS 1993, 7(1), 129, 130, discloses the effect of warfarin on the replication and spread of HIV-1.

CA Selects: AIDS & Related Immunodeficiencies, Issue 24, 1993, Abstract 119: 195147j discloses the single dose coumarin derivatives, warfarin, 4-hydroxy-coumarin, 7-hydroxycoumarin, have inhibitory effects on HIV-1 replication and cell-regulated or cell-free viral infection.

In First National Conference on Human Retroviruses and relatedinfestations, 12.16.1993, Washington, d.c., it was disclosed that coumarins, such as warfarin, and pyrones, such as 3- (thienyl) -6-phenyl-4-hydroxy-pyrones, exhibit HIV protease inhibition in one assay.

Biochemial and Biophysical Research Communications, 201(1), 290-.

Med chem.37: 2664-2677(1994) discloses 4-hydroxy-3- (3-phenoxypropyl) -2H-1-benzopyran-2-one and structural analogues as HIV-1 protease inhibitors, particularly 4, 7-dihydroxy-3- [4- (2-methoxyphenyl) butyl ] -2H-1-benzopyran-2-one.

Biochemical and Biophysical Research Communications, 200(3), 1658, 1664 (5.16, 1994) disclose 4-hydroxy-3- (3-phenoxypropyl) -1-benzopyran-2-one and 4-hydroxy-6-phenyl-3- (phenylthio) -pyran-2-one, and structural analogs of these compounds are HIV-1 protease inhibitors.

J.am.chem.soc.116: 6989 (1994) discloses that 4-hydroxy-6-phenyl-3- (phenylthio) -pyran-2-one and its structural analogues are HIV-1 protease inhibitors.

Acta.virol.37: 241-250(1993) discloses the anti-HIV activity of a coumarin derivative, warfarin, 4-hydroxy-coumarin, 7-hydroxycoumarin.

Anti viral Research 24: 275- "1994" discloses bicyclic imidazo derivatives (imidazothiazoles and imidazopyridines) inhibiting HIV-1 by interaction with Reverse Transcriptase (RT).

U.S. Pat. No. 3325515(J.Schmitt et al) discloses coumarin derivatives, such as methyl 3- (4-hydroxy-3-coumarinyl) -3-phenyl-1-propionate, which exhibit anticoagulant activity.

Us patent 2723277(a. grussner et al) discloses malonic acid derivatives as anticoagulants, such as 3- [ 1' - (p-chloro-phenyl) -propyl ] -4-hydroxy-coumarin.

FR, a, 1276654 discloses 4-hydroxy-coumarins, such as (2' -hydroxy) -3-benzyl-4-hydroxycoumarin, having anticoagulant, antibacterial or antimycotic properties.

BE, a, 674997 discloses 4-hydroxy-coumarin derivatives, such as 3- (5-methoxytetrahydronaphthyl- (1)) -4-hydroxycoumarin, as rodenticides.

GB, a, 734142 discloses the preparation of 3-substituted-4-hydroxycoumarins, such as 3- (1-phenyl-2-acetyl) -ethyl-4-hydroxycoumarin and 3- (1-furan-2-acetyl) -ethyl-4-hydroxycoumarin, which are potent anticoagulants and rodenticides.

"computer-aided drug design for the discovery of non-peptide HIV-1 protease inhibitors", Parke-Davis pharm. Res., Keystone Symposia, 1994, 3.3.11 days, Santa Fe, NM, discloses 4-hydroxy-3- (3-phenoxypropyl) -1-benzopyran-2-one as HIV protease inhibitors.

Structural Biology, 1 (1): 199- "200 (month 4 1994) discloses that mouse toxic warfarin is a useful lead to the search for HIV protease inhibitors.

CA 85: 78002b (1976) discloses 3- (2, 4, 6-trihydroxybenzyl) -4-hydroxy-2H-pyran-2-one derivatives having antibacterial activity.

FR, A, 1092278(Hoffman) (1955) discloses the preparation of coumarin derivatives, such as 3- [1 '-phenyl-propene- (1') -yl ] -4-hydroxycoumarin.

International publication No. WO 94/11361, published 26.5.1994, discloses pyran-2-ones and 5, 6-dihydroxypyran-2-ones useful as retroviral protease inhibitors.

International publication No. WO 94/18188, published 8/18 in 1994, discloses 4-hydroxy-chromen-2-ones and 4-hydroxy-cycloalkyliden-2-ones as retroviral protease inhibitors.

The following references are cited for the closest parent application to disclose the state of the art:

U.S. Pat. No. 3651091(Boschetti et al); U.S. Pat. No. 4262013(Mistui et al); U.S. Pat. No. 4900754(Regan et al); U.S. Pat. No. 5294724(Jendralla et al); australian patent specification 219371(Enders et al); canadian patent No. 1171424 (Willad et al); british patent specification 836740 (Bayer); european patent application 0024348 (Willad et al); european patent application 0588137(Fischer et al); french patent 1276654(Molho) (cited above); and International publication No. WO94/1136(Thaisrivongs et al) (cited above).

Crystalline complexes of HIV-1 and HIV-2 protease with compounds such as 3- (. alpha. -ethylbenzyl) -6- (. alpha. -ethylphenylethyl) -4-hydroxy-2H-pyran-2-one are disclosed in "colloidal Structure-Based Design of Small organic molecules as Inhibitors of HIV Proteases" Keystone Symposia, SantaFe, NM, (3.3.5-11.1994).

"Discovery and Properties of Small Organic Molecules inhibiting HIV-1 Protease" Keystone Symposia, Santa Fe, NM, (1994, 3, 5-11), discloses an assay for determining the inhibitory activity of a compound, such as 3- (. alpha. -ethylbenzyl) -6- (. alpha. -ethylphenylethyl) -4-hydroxy-2H-pyran-2-one.

"Structure-based Design of Non-peptide HIV protease inhibitors", 35th Annual Baffalo medical Chemistry Symposium, Buffalo, NY (5.5.25.1994), discloses compounds useful as potential anti-HIV therapeutic agents, for example 3- (. alpha. -ethylbenzyl) -6- (. alpha. -ethylphenylethyl) -4-hydroxy-2H-pyran-2-one.

Chem., 58(26) in j.org.chem.: 7567(1993) (Hruby et al) describes the copper catalyzed addition of an aryl Grignard reagent to an unsaturated chiral amide, 3- (2-butenoyl) -4-phenyl-2-oxazolidinone. In j.am.chem.soc., 112: 8215(1990) (Evans et al) discloses the reaction of a chiral amide with 2-methoxy-2-methyl-1, 3-dioxoline. In j.am.chem.soc., 110 (9): 2910(1988) (Santry et al) discloses the preparation of 2-methoxy-2-methyl-1, 3-dioxoline. Reactions between enolated esters and ketones, see Dongala et al, Tetrahedron Letters, 4983(1973), and Mitsui et al, Tetrahedron, 23: 4271(1967). The reaction between enolated amides and ketones, see Viteva et al, Tetrahedron 50: 7193 (1994); oare et al, j.org.chem.55: 132 (1990); hullot et al, Can.J.chem.55: 266 (1977); woodbury et al, j. org. chem.42: 1688 (1977); stefanovsky et al, Tetrahedron 42: 5355 (1986); mathew et al, U.S. Pat. No. 5284975.

G.carganico, p.cozzi, g.orini, j.med.chem., 26: 1767-1769(1983) disclose synthetic compounds having a methyl group and a hydroxyl group at the 4-position of the dihydropyrone ring and no substitution at the 3-position. The compounds of the present invention have a keto group at the 4-position (which may be in the form of an enol) and a substituent at the 3-position.

D.t.witiak et al, j.med.chem., 31: 1437-1445(1988) discloses benzopyran-2-ones having a hydroxyl group at the 3-position. The compounds of the present invention have an alkyl substituent at this position.

Tait, Winter Conference on biological medicinal Chemistry, 1 month 29 day-2 month 2 day 1995, Steamboat Springs, Colorado, discloses in the field of HIV proteases the presence of a phenyl and a pentyl group in the 6-position and an-S-CH in the 3-position₂-CH₂-phenyl dihydropyrones.

J.v.n.vara Prasad et al, j.med.chem., 38: 898 (1995) discloses 4-hydroxy-6-phenyl-2-oxo-2H-pyran-3-yl-thiomethanes, such as (+) -3- [ cyclopentyl (cyclopentylthio) methyl ] -4-hydroxy-6-phenyl-2H-pyran-2-one, useful as HIV-1 protease inhibitors.

Summary of The Invention

The present invention provides:

a compound of formula I

Wherein R is₁Is H-;

wherein R is₂Is that

a)C₃-C₅An alkyl group, a carboxyl group,

b) phenyl- (CH)₂)₂-，

c)het-SO₂NH-(CH₂)₂-，

d) Cyclopropyl- (CH) ₂)₂-，

e) F-phenyl- (CH)₂)₂-，

f)het-SO₂NH-phenyl-, or

g)F₃C-(CH₂)₂-；

Or wherein R is₁And R₂Taken together are a double bond;

wherein R is₃Is a radical of the formula X

Wherein R is₄Is that

a) A phenyl group,

b)het，

c) the compound of the cyclopropyl group is shown in the figure,

d)H₃C-[O(CH₂)₂]₂-，

e)het-SO₂NH-

f)Br，

g)N₃-or

h)HO₃S(CH₂)₂-N(CH₃)-C(O)-(CH₂)₆-C(O)-NH-；

Wherein R is₅is-H;

wherein R is₆Is that

a)R₄-(CH₂)n-CH(R₈)-，

b)H₃C-[O(CH₂)₂]₂-CH₂-，

c)C₃-C₅An alkyl group, a carboxyl group,

d) phenyl- (CH)₂)₂-，

e)het-SO₂NH-(CH₂)₂-，.

f)(HOCH₂)₃-C-NH-C(O)-NH-(CH₂)₃-，

g)(HO₂C)(H₂N)CH-(CH₂)₂-CO-NH-(CH₂)₃-，

h) piperazin-1-yl-C (O) -NH- (CH)₂)₃-，

i)HO₃S(CH₂)₂-N(CH₃)-C(O)-(CH₂)₆-C(O)-NH-(CH₂)₃-；

j) Cyclopropyl- (CH)₂)₂-，

k) F-phenyl- (CH)₂)₂-，

l)het-SO₂NH-phenyl, or

m)F₃C-(CH₂)₂-；

Wherein n is zero (0), one (1) or two (2);

wherein R is₇Is that

a) The compound of the cyclopropyl group is shown in the figure,

b)CH₃-CH₂-, or

c) A tertiary butyl group;

wherein R is₈Is that

a)-CH₂-CH₃Or is or

b)-CH₂-a cyclopropyl group;

wherein R is₉Is that

a)-NR₁₂SO₂-het，

b) Zero (0) or one (1) R₁₁substituted-NR₁₂SO₂-a phenyl group,

c) zero (0) or one (1) R₁₁substituted-CH₂SO₂-a phenyl group,

d)-CH₂SO₂-het；

wherein het is a 5-, 6-, or 7-membered saturated or unsaturated ring containing one (1) to three (3) heteroatoms selected from nitrogen, oxygen and sulfur; also included are any bicyclic groups in which any of the above heterocycles are fused to a benzene ring or other heterocycle; by zero (0) or one (1) R₁₀Substitution;

wherein R is₁₀Is that

a)-CH₃，

b)-CN，

c)-OH，

d)-C(O)OC₂H₅，

e)-CF₃，

f)-NH₂Or is or

g)-C(O)-NH₂；

Wherein R is₁₁Is that

a)-CN，

b)-F，

c) -OH, or

d)-NO₂；

Wherein R is₁₂Is that

a) -H, or

b)-CH₃；

Or a pharmaceutically acceptable salt thereof.

The present invention more specifically provides:

a compound of formula I

Wherein R is₁Is H-;

wherein R is₂Is that

a)C₃-C₅An alkyl group, a carboxyl group,

b) phenyl- (CH)₂)₂-, or

c)het-SO₂NH-(CH₂)₂-；

Or wherein R is₁And R₂Taken together are a double bond;

wherein R is₃Is a radical of the formula X

Wherein R is ₄Is that

a) A phenyl group,

b)het，

c) the compound of the cyclopropyl group is shown in the figure,

d)H₃C-[O(CH₂)₂]₂-，

e)het-SO₂NH-

f)Br，

g)N₃-, or

h)HO₃S(CH₂)₂-N(CH₃)-C(O)-(CH₂)₆-C(O)-NH-；

Wherein R is₅is-H;

wherein R is₆Is that

a)R₄-(CH₂)n-CH(R₈)-，

b)H₃C-[O(CH₂)₂]₂-CH₂-，

c)C₃-C₅An alkyl group, a carboxyl group,

d) phenyl- (CH)₂)₂-，

e)het-SO₂NH-(CH₂)₂-，

f)(HOCH₂)₃C-NH-C(O)-NH-(CH₂)₃-，

g)(HO₂C)(H₂N)CH-(CH₂)₂-CO-NH-(CH₂)₃-，

h) piperazin-1-yl-C (O) -NH- (CH)₂)₃Or is or

i)HO₃S(CH₂)₂-N(CH₃)-C(O)-(CH₂)₆-C(O)-NH-(CH₂)₃-; wherein n is zero (0), one (1) or two (2);

wherein R is₇Is that

a) The compound of the cyclopropyl group is shown in the figure,

b)CH₃-CH₂-, or

c) A tert-butyl group;

wherein R is₈Is that

a)-CH₂-CH₃-, or

b)-CH₂-a cyclopropyl group;

wherein R is₉Is that

a)-NR₁₂SO₂-het，

b) Zero (0) or one (1) R₁₁substituted-NR₁₂SO₂-a phenyl group,

c) zero (0) or one (1) R₁₁substituted-CH₂SO₂-phenyl, or

d)-CH₂SO₂-het；

wherein R is₁₀Is that

a)-CH₃，

b)-CN，

c) -OH, or

d)-C(O)OC₂H₅，

Wherein R is₁₁Is that

a)-CN，

b)-F，

c) -OH, or

d)-NO₂；

Wherein R is₁₂Is that

a) -H, or

b)-CH₃；

Or a pharmaceutically acceptable salt thereof.

The present invention provides compounds wherein het is represented by zero (0) or one (1) R₁₀The substitution is carried out by the following steps,

a) a 2-pyridyl group,

b) an imidazol-2-yl group, which is a cyclic moiety,

c) an imidazol-4-yl group, which is selected from the group consisting of,

d) a benzimidazol-2-yl group, which is a phenyl group,

e) a quinoline-8-yl group, which is a cyclic quinoline,

f) a quinolin-2-yl group, a naphthalen-2-yl group,

g) a pyrimidin-2-yl group, a pyrimidine-2-yl group,

h) a quinazolin-2-yl group, a pharmaceutically acceptable salt thereof,

i) a purin-6-yl group which,

j) a thiazol-2-yl group, a pharmaceutically acceptable salt thereof,

k) a thiazol-4-yl group, or a pharmaceutically acceptable salt thereof,

l) a 2-pyrazolyl group which is,

m) a 2-pyrazinyl group, and,

n) tetrahydropyran-4-yl, or

o) tetrahydropyran-3-yl.

More particularly, the invention also provides compounds of formula I

Wherein R is₁Is H-;

wherein R is₂Is that

a)H₃C-(CH₂)₂-；

b) Phenyl- (CH)₂)₂-，

c)(CH₃)₂CH-CH₂-, or

d) A pentyl group;

or wherein R is₁And R₂Taken together are a double bond;

wherein R is₃Is a radical of the formula X

Wherein R is₄Is that

a) A phenyl group,

b)het，

c) the compound of the cyclopropyl group is shown in the figure,

d)H₃C-[O(CH₂)₂]₂-，

e)het-SO₂NH-

f)Br-，

g)N₃-, or

h)HO₃S(CH₂)₂-N(CH₃)-C(O)-(CH₂)₆-C(O)-NH-；

Wherein R is₅is-H;

wherein R is₆Is that

a)R₄-(CH₂)n-CH(R₈)-，

b)H₃C-[O(CH₂)₂]₂-CH₂-，

c)H₃C-(CH₂)₂-；

d) Phenyl- (CH)₂)₂-，

e)(CH₃)₂CH-CH₂-, or

f) A pentyl group;

wherein n is zero (0), one (1) or two (2);

wherein R is₇Is that

a) Cyclopropyl, or

b)CH₃-CH₂-，

Wherein R is₈Is that

a)-CH₂-CH₃Or is or

b)-CH₂-a cyclopropyl group;

wherein R is₉Is that

a)-NHSO₂-het, or

b) Zero (0) or one (1) R₁₁substituted-NHSO₂-a phenyl group;

where het is as follows, substituted by zero (0) or one (1) R₁₀The substitution is carried out by the following steps,

a) a 2-pyridyl group,

b) an imidazol-2-yl group, which is a cyclic moiety,

c) an imidazol-4-yl group, which is selected from the group consisting of,

d) a quinoline-8-yl group, which is a cyclic quinoline,

e) a tetrahydropyran-4-yl group, or a tetrahydropyran-4-yl group,

f) tetrahydropyran-3-yl, or

g) Benzimidazol-2-yl;

wherein R is₁₀Is that

a)-CH₃，

Wherein R is₁₁Is that

a)-CN，

b) -F, or

c)-NO₂；

Or a pharmaceutically acceptable salt thereof.

Most particularly, the invention provides compounds of formula VI

Wherein R is₂Is that

a)H₃C-(CH₂)₂-；

b) Phenyl- (CH)₂)₂-，

c)(CH₃)₂CH-CH₂-, or

d) A pentyl group;

wherein R is₃Is a radical of the formula X

Wherein R is₆Is that

a)H₃C-(CH₂)₂-；

b) Phenyl- (CH)₂)₂-，

c)(CH₃)₂CH-CH₂-, or

d) A pentyl group;

wherein R is₇Is that

a)CH₃-CH₂-, or

b) The compound of the cyclopropyl group is shown in the figure,

wherein R is₉Is that

a) One (1) R₁₁substituted-NHSO ₂-phenyl, or

b)-NHSO₂-het，

Wherein het is as follows, and the head is as follows,by zero (0) or one (1) R₁₀The substitution is carried out by the following steps,

a) imidazol-4-yl, or

b) A quinoline-8-yl group, which is a cyclic quinoline,

wherein R is₁₀is-CH₃，

Wherein R is₁₁Is that

a) -CN, or

b)-F。

Most particularly, the invention also provides compounds of formula VII wherein R₃Is a radical of the formula X

Wherein R is₄Is that

a) A phenyl group,

b)het，

c) the compound of the cyclopropyl group is shown in the figure,

d)H₃C-[O(CH₂)₂]₂-，

e)het-SO₂NH-，

f)Br-，

g)N₃-, or

h)HO₃S(CH₂)₂-N(CH₃)-C(O)-(CH₂)₆-C(O)-NH-；

Wherein R is₆Is that

a)R₄-(CH₂)n-CH(R₈) -, or

b)H₃C-[O(CH₂)₂]₂-CH₂-；

Wherein R is₇Is cyclopropyl;

wherein R is₈Is that

a)-CH₂-CH₃Or is or

b)-CH₂-a cyclopropyl group;

wherein R is₉Is that

a)-NHSO₂-het, or

b) One (1) R₁₁substituted-NHSO₂-a phenyl group,

wherein n is zero (0), one (1) or two (2);

a) an imidazol-4-yl group, which is selected from the group consisting of,

b) an imidazol-2-yl group, which is a cyclic moiety,

c) a quinoline-8-yl group, which is a cyclic quinoline,

d) a tetrahydropyran-3-yl group,

e) a tetrahydropyran-4-yl group, or a tetrahydropyran-4-yl group,

f) 2-pyridyl, or

g) Benzimidazol-2-yl;

wherein R is₁₀is-CH₃；

Wherein R is₁₁Is that

a)-NO₂，

b) -F, or

c)-CN；

Or a pharmaceutically acceptable salt thereof.

The present invention also provides:

a compound of formula II

Wherein R is₁₀And R₂₀Taken together are

a) A radical of the formula III, or

b) A group of formula IV;

wherein p is four (4);

wherein R is₁is-H;

wherein R is₂Is that

a)H-，

b)CH₃O-, or

c)CH₃O-[(CH₂)₂O]₃-；

Wherein R is₃Is a radical of the formula V

Wherein R is₄Is that

a) Cyclopropyl, or

b)CH₂-CH(CH₃)₂；

Wherein R is₅Is that

a) Zero (0) or (1) R₆substituted-NR₉SO₂-a phenyl group,

b)-NR₉SO₂-het，

c) zero (0) or (1) R₆substituted-CH ₂-SO₂-phenyl, or

d)-CH₂-SO₂-het

Wherein R is₆Is that

a)-CN，

b)-F，

c)-CH₃，

d) -COOH, or

e)-OH；

Wherein het is a 5-, 6-, or 7-membered saturated or unsaturated ring containing one (1) to three (3) heteroatoms selected from nitrogen, oxygen and sulfur; also included are any bis wherein any of the above heterocycles are fused to a benzene or other heterocycleA cyclic group; by zero (0), one (1) or two (2) R₇Substitution;

wherein R is₇Is that

a)-CH₃，

b)-CN，

c)-C(O)OC₂H₅Or is or

d)-OH；

Wherein R is₈Is that

a)-H，

b)-(CH₂)₂-CH₃，

c)-CH₂-a cyclopropyl group; or

d)-CH₂-a phenyl group;

wherein R is₉Is that

a) -H, or

b)-CH₃；

Or a pharmaceutically acceptable salt thereof.

The present invention provides compounds wherein het is substituted with zero (0) or one (1) R₇The substitution is carried out by the following steps,

a) a 2-pyridyl group,

b) an imidazol-2-yl group, which is a cyclic moiety,

c) an imidazol-4-yl group, which is selected from the group consisting of,

d) a benzimidazol-2-yl group, which is a phenyl group,

e) a quinoline-8-yl group, which is a cyclic quinoline,

f) a quinolin-2-yl group, a naphthalen-2-yl group,

g) a pyrimidin-2-yl group, a pyrimidine-2-yl group,

h) a quinazolin-2-yl group, a pharmaceutically acceptable salt thereof,

i) a purin-6-yl group which,

j) a thiazol-2-yl group, a pharmaceutically acceptable salt thereof,

k) a thiazol-4-yl group, or a pharmaceutically acceptable salt thereof,

l) a 2-pyrazolyl group which is,

m) a 2-pyrazinyl group, and,

n) tetrahydropyran-4-yl, or

o) tetrahydropyran-3-yl.

More particularly, the invention provides compounds of formula II

Wherein R is₁₀And R₂₀Taken together are

a) A radical of the formula III, or

b) A group of formula IV;

wherein p is four (4);

wherein R is₁is-H;

wherein R is₂Is that

a)CH₃O-, or

b)CH₃O[(CH₂)₂O]₃-；

Wherein R is₃Is a radical of the formula V

Wherein R is₄Is that

a) Cyclopropyl, or

b)-CH₂-CH(CH₃)₂；

Wherein R is ₅Is that

a) Zero (0) or (1) R₆substituted-NR₉SO₂-a phenyl group,

b)-NR₉SO₂-het，

c) zero (0) or (1) R₆substituted-CH₂-SO₂-phenyl, or

d)-CH₂-SO₂-het；

Wherein R is₆Is that

a)-CN，

b)-F，

c)-CH₃Or is or

d)-COOH；

Where het is as follows, substituted by zero (0) or one (1) R₇The substitution is carried out by the following steps,

a) an imidazol-4-yl group, which is selected from the group consisting of,

b) a quinoline-8-yl group, which is a cyclic quinoline,

c) 2-pyridyl, or

d) 4-pyridyl;

wherein R is₇is-CH₃；

Wherein R is₈Is that

a) -H, or

b)-(CH₂)₂-CH₃；

Wherein R is₉Is that

a) -H, or

b)-CH₃；

Or a pharmaceutically acceptable salt thereof.

Most particularly, the invention provides compounds of formula VIII

Wherein R is₃Is a radical of the formula V

Wherein R is₄Is that

a) Cyclopropyl, or

b)-CH₂-CH(CH₃)₂；

Wherein R is₅Is that

a) Zero (0) or (1) R₆substituted-NR₉SO₂-a phenyl group,

b)-NR₉SO₂-het, or

c)-CH₂-SO₂-het；

Wherein R is₆Is that

a) -CN, or

b)-F；

a) a 2-pyridyl group,

b) 4-pyridyl, or

c) Imidazol-4-yl;

wherein R is₇is-CH₃；

Wherein R is₈Is that

a) -H, or

b)-(CH₂)₂-CH₃；

Wherein R is₉Is that

a) -H, or

b)-CH₃；

Or a pharmaceutically acceptable salt thereof.

Most particularly, the invention also provides compounds of formula IX

Wherein R is₁is-H;

wherein R is₂Is that

a)CH₃O-, or

b)CH₃O-[(CH₂)₂O]₃-；

Wherein R is₃Is a group of formula V;

wherein R is₄Is cyclopropyl;

wherein R is₅is-NHSO₂-het；

a) an imidazol-4-yl group, which is selected from the group consisting of,

b) 2-pyridyl, or

c) Quinolin-8-yl;

wherein R is₇is-CH₃。

The invention also provides compounds of formula VI

Wherein R is₂Is that

a)H₃C-CH₂-，

b)H₃C-(CH₂)₂-，

c) Cyclopropyl- (CH)₂)₂-，

d) F-phenyl- (CH)₂)₂-，

e)het-SO₂NH-phenyl-,

f)(H₃C)₂HC-CH₂，

g) phenyl- (CH)₂)₂-, or

h)F₃C-(CH₂)₂-；

Wherein R is₃Is a group of formula X;

wherein R is₆Is that

a)H₃C-CH₂-，

b)H₃C-(CH₂)₂-，

c) Cyclopropyl- (CH)₂)₂-，

d) F-phenyl- (CH)₂)₂-，

e)het-SO₂NH-phenyl-,

f)(H₃C)₂HC-CH₂，

g) phenyl- (CH)₂)₂-, or

h)F₃C-(CH₂)₂-；

Wherein R is₇Is that

a)CH₃-CH₂-，

b) Tert-butyl, or

c) A cyclopropyl group;

wherein R is₉Is that

a)-NHSO₂-het, or

b) One (1) R₁₁substituted-NHSO₂-a phenyl group;

a) an imidazol-4-yl group, which is selected from the group consisting of,

b) 2-pyridyl, or

c) Quinolin-8-yl;

wherein R is₁₀Is that

a)-CH₃，

b)-CN，

c)-CF₃

d)-NH₂Or is or

e)-(CO)-NH₂；

Wherein R is₁₁Is CN.

The present invention also provides:

a compound of formula XI

Wherein R is₁Is- (CH)₂)p-CH(R₂)-(CH₂)o-Ar₁；

Wherein R is₂Is that

a)-C₁-C₅Alkyl, or

b)-(CH₂) q-cycloalkyl;

wherein Ar is₁Is that

a) Zero (0) or one (1) R₃Substituted phenyl, or

b) -m-NHSO₂Ar₂Substituted phenyl;

wherein Ar is₂Is that

a) Zero (0) or one (1) R₃Substituted phenyl, or

b)het；

Wherein het is a 5-, 6-, or 7-membered saturated or unsaturated ring containing one (1) to three (3) heteroatoms selected from nitrogen, oxygen and sulfur; also included are any bicyclic groups in which any of the above heterocycles are fused to a benzene ring or other heterocycle; by zero (0) or one (1) R₄Substitution;

wherein R is₃Is that

a)-CN，

b)-F，

c) -OH, or

d)-NO₂；

Wherein R is₄Is that

a)-CH₃，

b)-CN，

c)-OH，

d)-C(O)OC₂H₅，

e)-CF₃Or is or

f)-NH₂；

Wherein n is zero (0) to eight (8), inclusive;

wherein o is zero (0) to three (3), inclusive;

Wherein p is zero (0) to three (3), inclusive;

wherein q is zero (0) to three (3), inclusive; or

Pharmaceutically acceptable salts thereof.

More specifically, the present invention provides:

a compound of the formula wherein R₁is-CH (R)₂)-Ar₁；

Wherein R is₂Is that

a)-CH₂-CH₃Or is or

b) -tert-butyl;

wherein Ar is₁is-m-NHSO₂Ar₂Substituted phenyl;

wherein Ar is₂Is one (1) R₄Substituted 2-pyridyl;

wherein R is₄Is that

a) -CN, or

b)-CF₃；

Where n is two (2) to four (4), inclusive.

The present invention also provides:

preparation method of compound of formula W-10

Wherein R is₁Is that

a) N-propyl, or

b) A phenethyl group;

the method comprises the following steps:

a) reacting a compound of formula W-9

Wherein X_AAs defined above, with TiCl₄Processing;

b) treating the product of step a) with an amine base; and is

c) Reacting the product of step b) with 4-heptanone or propylphenethylketone to produce a compound of formula W-10;

the method additionally comprises the steps of:

d) treating the compound of formula W-10 with sodium hydride or potassium tert-butoxide to give the compound of formula W-11

Wherein R is₁Is that

a) N-propyl, or

b) A phenethyl group;

e) hydrogenation of a compound of formula W-11 to a compound of formula W-12

Wherein R is₁As defined above;

f) treating a compound of formula W-12 with a sulfonyl chloride of formula D-7 in an organic solvent in the presence of an organic base

Wherein R is₄Is 5-trifluoromethyl-2-pyridyl to give the compound of the formula W-13

Wherein R is₁As defined above.

The present invention also provides:

preparation method of compound of formula X-10

Wherein R is₁Is that

a) N-propyl, or

b) A phenethyl group;

the method comprises the following steps:

a) reacting a compound of formula X-9

Wherein X_AAs defined above, with TiCl₄Processing;

b) treating the product of step a) with an amine base; and is

c) Reacting the product of step b) with 4-heptanone or propylphenethylketone to produce a compound of formula X-10;

the method additionally comprises the steps of:

d) treating the compound of formula X-10 with sodium hydride or potassium tert-butoxide to give the compound of formula X-11

Wherein R is₁Is that

a) N-propyl, or

b) A phenethyl group;

e) hydrogenation of a compound of formula X-11 to give a compound of formula X-12

Wherein R is₁As defined above;

f) treating a compound of formula X-12 with a sulfonyl chloride of formula D-7 in an organic solvent in the presence of an organic base

Wherein R is₄Is 5-trifluoromethyl-2-pyridyl to give the compound of the formula X-13

Wherein R is₁As defined above.

The present invention also provides:

preparation method of compound of formula GGG-10

Wherein R is₁Is that

a) N-propyl, or

b) A phenethyl group;

the method comprises the following steps:

a) Reacting a compound of formula GGG-9

Wherein X_AAs defined above, with TiCl₄Processing;

b) treating the product of step a) with an amine base; and is

c) Reacting the product of step b) with 4-heptanone or 1-phenyl-3-hexanone to produce a compound of formula GGG-10;

the method additionally comprises the steps of:

d) treating a compound of formula GGG-10 with sodium hydride or potassium tert-butoxide to give a compound of formula GGG-11

Wherein R is₁Is that

a) N-propyl, or

b) A phenethyl group;

e) hydrogenation of a compound of formula GGG-11 to give a compound of formula GGG-12

Wherein R is₁As defined above;

f) treating a compound of formula GGG-12 with a sulfonyl chloride of formula D-7 in an organic solvent in the presence of an organic base

Wherein R is₄Is that

a) 5-trifluoromethyl-2-pyridyl; or

b) 5-cyano-2-pyridinyl to give compounds of formula GGG-13A

Wherein R is₁As defined above.

Preparation method of compound of formula HHH-10

Wherein R is₁Is that

a) N-propyl, or

b) A phenethyl group;

the method comprises the following steps:

a) reacting a compound of formula HHH-9 with TiCl₄Treatment of

Wherein X_AAs defined above;

b) treating the product of step a) with an amine base; and is

c) Reacting the product of step b) with 4-heptanone or 1-phenyl-3-hexanone to produce a compound of formula HHH-10;

The method additionally comprises the steps of:

d) treatment of a compound of formula HHH-10 with sodium hydride or potassium tert-butoxide gives a compound of formula HHH-11

Wherein R is₁Is that

a) N-propyl, or

b) A phenethyl group;

e) hydrogenation of a compound of formula HHH-11 to give a compound of formula HHH-12

Wherein R is₁As defined above;

f) treating a compound of formula HHH-12 with a sulfonyl chloride of formula D-7 in an organic solvent in the presence of an organic base

Wherein R is₄Is that

a) 5-trifluoromethyl-2-pyridyl; or

b) 5-cyano-2-pyridinyl to give compounds of formula HHH-13A

Wherein R is₁As defined above.

Preparation method of compound of formula III-10

Wherein R is₁Is that

a) N-propyl, or

b) A phenethyl group;

the method comprises the following steps:

a) the compound of formula III-9 is reacted with TiCl₄Treatment of

Wherein X_AAs defined above;

b) treating the product of step a) with an amine base; and is

c) Reacting the product of step b) with 4-heptanone or 1-phenyl-3-hexanone to produce a compound of formula III-10;

the method additionally comprises the steps of:

d) treating the compound of formula III-10 with sodium hydride or potassium tert-butoxide to give the compound of formula III-11

Wherein R is₁Is that

a) N-propyl, or

b) A phenethyl group;

e) hydrogenation of the compound of formula III-11 to give the compound of formula III-12

Wherein R is₁As defined above;

f) treating a compound of formula III-12 with a sulfonyl chloride of formula D-7 in an organic solvent in the presence of an organic base

Wherein R is₄Is that

a) 5-trifluoromethyl-2-pyridyl; or

b) 5-cyano-2-pyridinyl to give compounds of formula III-13A

Wherein R is₁As defined above.

Preparation method of compound of formula JJJ-10

Wherein R is₁Is that

a) N-propyl, or

b) A phenethyl group;

the method comprises the following steps:

a) the compound of formula JJJ-9 is reacted with TiCl₄Treating wherein X_AAs defined above;

b) treating the product of step a) with an amine base; and is

c) Reacting the product of step b) with 4-heptanone or 1-phenyl-3-hexanone to produce a compound of formula JJJ-10;

the method additionally comprises the steps of:

d) treating the compound of formula JJJ-10 with sodium hydride or potassium tert-butoxide to give the compound of formula JJJ-11

Wherein R is₁Is that

a) N-propyl, or

b) A phenethyl group;

e) hydrogenating the compound of formula JJJ-11 to provide a compound of formula JJJ-12

Wherein R is₁As defined above;

f) treating a compound of formula JJJ-12 with a sulfonyl chloride of formula D-7 in an organic solvent in the presence of an organic base

Wherein R is₄Is that

a) 5-trifluoromethyl-2-pyridyl;

b) 5-cyano-2-pyridinyl to give compounds of formula JJJ-13A

Wherein R is₁As defined above.

The present invention most preferably provides:

a compound of formula VI wherein R₂Is that

a)H₃C-(CH₂)₂-, or

b) Phenyl- (CH)₂)₂-；

Wherein R is₃Is a group of formula X;

wherein R is₆Is that

a)H₃C-(CH₂)₂-, or

b) Phenyl- (CH)₂)₂-；

Wherein R is₇Is that

a)H₃C-CH₂-, or

b) A tert-butyl group;

wherein R is₉is-NH₂SO₂-het；

Where het is as follows, by one (1) R₁₀The substitution is carried out by the following steps,

a) imidazol-4-yl, or

b) 2-pyridyl;

wherein R is₁₀Is that

a)-CH₃，

b) -CN, or

c)-CF₃。

The compounds of the invention are named according to the IUPAC or CAS nomenclature system.

The carbon atom content of the various hydrocarbon-containing groups is indicated by the prefix designating the minimum and maximum number of carbon atoms in the group, i.e., the prefix Ci-Cj indicates a group containing the integer "i" to the integer "j" (inclusive) carbon atoms. Thus, for example, C₁-C₃Alkyl means alkyl of one to three carbon atoms, inclusive, i.e. AEthyl, propyl, and isopropyl, their linear and branched forms.

The carbon atom content of the various hydrocarbon-containing groups of the present invention can also be represented by subscripted integers representing the number of carbon and hydrogen atoms in the group, e.g., "CnH₂n "represents a group containing the integer" n "carbon atoms and the integer" 2n "hydrogen atoms, inclusive. Thus, for example, "CnH₂n ", wherein n is one to three carbon atoms, inclusive, and two to six hydrogen atoms, inclusive, i.e., methyl, ethyl, propyl, and isopropyl, and all linear and branched isomers thereof.

Examples of alkyl groups of one to nine carbon atoms, inclusive, are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and nonyl, all isomeric forms thereof, and straight and branched chain forms thereof.

Examples of alkenyl of one to five carbon atoms, inclusive, are ethenyl, propenyl, butenyl, pentenyl, all their isomeric forms and their straight-chain and branched forms.

"halogen" means a general halogen atom such as fluorine, chlorine, bromine and iodine.

The compounds of formula I and II of the present invention inhibit retroviral proteases and thereby inhibit viral replication. They are useful in the treatment of Human Immunodeficiency Virus (HIV) infected patients, which causes acquired immunodeficiency syndrome (AIDS) and related diseases.

More particularly, the compounds of the present invention are useful as novel human retroviral protease inhibitors. Thus, the compounds inhibit retroviral proteases and thereby inhibit replication of the virus. They are useful in the treatment of human retroviruses, such as human immunodeficiency virus (HIV-1 or HIV-2 strain) or human T-cell leukemia virus (HTLV-I or HTLV-II) infected patients, which cause acquired immunodeficiency syndrome (AIDS) and/or related diseases.

The capsid and replicase of the retrovirus (i.e., protease, reverse transcriptase, integrase) are converted from the viral gag and pol genes in multiple proteins and further processing by viral Proteases (PR) produces the mature proteins that can be found in the viral capsid and are necessary for the function and replication of the virus. If PR is absent or inoperative, the virus will not be able to replicate. Retroviral PR, such as HIV-1PR, has been found to be an aspartic protease with an active site with characteristics similar to those of the more complex aspartic protease, renin.

The term Human Retrovirus (HRV) includes human immunodeficiency virus type I, human immunodeficiency virus type II, or strains thereof, and human T-cell leukemia viruses 1 and 2(HTLV-1 and HTLV-2) or strains apparent to those skilled in the art, which belong to the same or related virus families and produce similar physiological effects in humans as the various human retroviruses.

The following conditions should be met for a patient to be treated: 1) infection with one or more human retroviruses, determined by the presence of measurable viral antibodies or antigens in serum and 2) in the case of HIV, with asymptomatic HIV infection or a symptomatic AIDS-determined infection, such as i) disseminated histoplasmosis, ii) psoriasis (isoporiasisis), iii) bronchial and pulmonary candidiasis, including interstitial plasmacytic pneumonia, iv) non-hodgkin's lymphoma or v) kaposi's sarcoma and an age of less than 60 years; or an absolute count of CD4+ lymphocytes in peripheral blood of less than 500/mm ³. The composition of the treatment is as follows: the compounds according to the invention used are maintained in the patient at inhibitory concentrations and are continued until the occurrence of a second established infection with symptomatic AIDS indicates a need for a change in the treatment regimen.

More specifically, an example of one such human retrovirus is the human immunodeficiency virus (HIV, also known as HTLV-III or LAV), which is recognized to be the causative agent of acquired human immunodeficiency syndrome (AIDS), p.duesberg, proc.natl.acad.sci.usa, 86: 755(1989). HIV contains a retrovirus-encoded protease, HIV-I protease, which cleaves the fused polypeptide into functional proteins of mature viral particles, e.p. lillehoj et al, j.virology, 62: 3053 (1988); debuck et al, proc.natl.acad.sci., 84: 8903(1987). This enzyme, HIV-I protease, is classified as an aspartyl protease and has been shown to be homologous to other aspartyl proteases, such as renin, l.h. pearl et al, Nature 329: 351 (1987); katoh et al, Nature 329: 654(1987). Inhibition of HIV-I protease blocks HIV replication and is therefore useful in the treatment of human AIDS, e.d. clerq, j.med. chem.29: 1561(1986). Inhibitors of HIV-I protease are useful in the treatment of asymptomatic or symptomatic AIDS patients infected with HIV-I.

Pepstatin a, a commonly used aspartyl protease inhibitor, has been disclosed as an inhibitor of HIV-I protease, s.seelmeier et al,

proc.natl.acad.sci.usa, 85: 6612(1986). Other isostere or statin inhibitors derived from substrates containing a reducing bond at the scissle position are also disclosed, m.l. moore et al, biochem. biophysis, res.commun.159: 420(1989): billch et al, J.biol.chem.263: 17905 (1988); sandoz, D.E.3812-576-A.

Accordingly, the compounds of the present invention are useful in the treatment of diseases caused by retroviruses, such as Acquired Immune Deficiency Syndrome (AIDS) in humans.

The compounds are also useful for treating retroviral-infected non-human animals, such as feline leukemia virus-infected cats. Other feline-infecting viruses include, for example, feline infectious peritonitis virus, sepal virus, rabies virus, feline immunodeficiency virus, feline parvovirus (feline infectious agranulocytosis virus), and feline chlamydia. The exact dosage, dosage form and mode of administration of the compounds of the invention for non-human animals will be readily apparent to those of ordinary skill in the art, e.g., veterinarians.

The compounds of formula I and II of the present invention are prepared as described in the tables, preparations and examples below, or by methods analogous thereto, which are known and available to those of ordinary skill in the art of organic synthesis.

TABLE A

Nitration of the cyclopropylphenyl ketone of formula A-1 (commercially available) with fuming nitric acid at-40 ℃ yields an approximately 2: 1 mixture of isomers. The desired meta-nitro compound of formula A-2 can be conveniently isolated from the crude mixture by recrystallization from methanol. Cyclopropyl- (3-nitrophenyl) methanone was catalytically hydrogenated in methanol with 10% palladium on charcoal to give the aniline of formula A-3. The aniline is then coupled with benzenesulfonyl chloride in dichloromethane with pyridine to produce the sulfonamide derivative of formula A-4. Reduction of the ketone with sodium borohydride in tetrahydrofuran and ethanol yields methanol of formula A-5.

The divalent anion of the cyclooctylpyrone of formula A-6 (prepared as described in Table B) was formed with lithium diisopropylamide in tetrahydrofuran at 0 deg.C, then alkylated with iodopropane to produce the 10-propyl-cyclooctylpyrone of formula A-7. The cyclooctylpyranone of formula A-7 was then coupled with methanol of formula A-5 with p-toluenesulfonic acid in dichloromethane to give the sulfonamide derivative of formula A-8.

TABLE B

Commercially available amines of formula B-1 were protected with benzyl chloroformate and sodium bicarbonate in THF/water solution to give compounds of formula B-2. The aldehyde of formula B-2 is then reacted with a Grignard reagent to produce a secondary alcohol of formula B-3, wherein, for example, R ₁Is an isobutyl group. Known cyclooctylpyrones of formula B-4 are prepared by acylation of the trimethylsilylenol ether of cyclooctanone with malonyl dichloride, such as r.effenberger, t.ziegler, k.h.schonwalder, t.kesmarszky, b.bauer chem.ber.119: 3394 and 3404 (1986). The cyclooctylpyranone of formula B-4 is then alkylated with an alcohol of formula B-3 in refluxing toluene and p-toluenesulfonic acid to give compounds of formula B-5, wherein, for example, R₁Is an isobutyl group. At this point, the enantiomer of formula B-5 was separated using a chiral HPLC column. The benzyloxy protecting group is then deprotected in cyclohexene with 10% Pd/C to yield an amine of formula B-6 wherein,for example R₁Is isobutyl, an amine is reacted with an arylsulfonyl chloride to form a compound of formula B-7, wherein, for example, R₁Is isobutyl, R₂Is 1-methylimidazole.

Watch C

Commercially available 3-bromobenzyl alcohol of formula C-1 was treated successively with methyllithium, n-butyllithium and cyclopropanecarboxaldehyde in tetrahydrofuran at-78 ℃. The resulting solution is gradually warmed to room temperature and then heated to reflux to form the alcohol of formula C-2. The resulting alcohol was treated with 4-hydroxy-5, 6, 7, 8, 9, 10-hexahydrocycloocta [ B ] pyran-2-one of formula C-8 (prepared as described in Table B) and p-toluenesulfonic acid in dichloromethane in the presence of molecular sieves. The solution is heated to reflux to produce the alcohol of formula C-3. The benzyl alcohol is treated with carbon tetrabromide and triphenylphosphine in dichloromethane at 0 ℃ to give, after treatment with brine, compounds of the formulae C-4 and C-5, which are inseparable mixtures. The mixture is then treated with any mercaptan (e.g., thiophenol) and an organic base and heated to reflux to provide the sulfide of formula C-6. Finally, the compound of formula C-6 is treated with oxone in a mixture of tetrahydrofuran, methanol and water to form the sulfone of formula C-7.

Table D

The table describes the reaction of aluminum trichloride (AlCl)₃) General procedure for the preparation of C-3 alpha branched 5, 6-dihydropyrones by modified condensation with 3-nitrobenzaldehyde. Thus, compounds of formula D-1, prepared as described in the preparations below, (e.g., wherein R is₁Is phenethyl or propyl, R₂Is phenethyl or propyl) in AlCl₃With a commercially available 3-nitrobenzaldehyde (formula D-2) to produce a compound of formula D-3 (e.g., wherein R is₁Is phenethyl or propyl; r₂Is phenethyl or propyl). Followed by reaction with trialkylaluminum or Grignard reagents in cuprous bromide-dimethyl sulfide complex (CuBr-Me)₂S) to a compound of formula D-4 (e.g., wherein R is₁Is phenethyl or propyl; r₂Is phenethyl or propyl; r₃Is ethyl or cyclopropyl). With transfer hydrogenation of Pd/C and ammonium formate to form compounds of formula D-5Compounds (e.g., wherein R₁Is phenethyl or propyl; r₂Is phenethyl or propyl; r₃Is ethyl or cyclopropyl). Reacting a compound of formula D-5 with a sulfonyl chloride of formula D-7, wherein R is₄Is defined below, and pyridine in dichloromethane (CH)₂Cl₂) To give a compound of formula D-6 (e.g., wherein R is₁Is phenethyl or propyl; r₂Is phenethyl or propyl; r₃Is ethyl or cyclopropyl; r ₄Is 4-cyanophenyl, 4-fluorophenyl, 1-methylimidazol-4-yl, quinolin-8-yl, 2-pyridyl, 4-cyano-2-pyridyl, quinolin-2-yl, 2-hydroxyphenyl, 2-pyrimidinyl, 2-quinazoline, 7H-purin-6-yl, 1H-imidazol-2-yl, 1H-benzimidazol-2-yl or thiazol-2-yl).

TABLE E

Commercially available 4-hydroxy-6-methyl-2-pyrone of formula E-1 is treated with three equivalents of lithium diisopropylamide in tetrahydrofuran and hexamethylphosphoramide, followed by bromomethylcyclopropane to yield the compound of formula E-2. The compound of formula E-2 was reacted with the compound of formula F-5, prepared as described in Table F, in benzene in the presence of a molecular sieve catalyzed by p-toluenesulfonic acid to produce the compound of formula E-3. Hydrogenolysis of the compound of formula E-3 with hydrogen and palladium on charcoal in methanol produces the free amine of formula E-4. Treatment of a compound of formula E-4 with two equivalents of pyridine in dichloromethane, followed by one equivalent of 4-fluorobenzenesulfonyl chloride, yields a compound of formula E-5 (wherein, for example, R is 4-fluorophenyl), i.e. the compound: n- (3- { cyclopropyl- [6- (2-cyclopropyl-1-cyclopropylmethyl-ethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] -methyl } -phenyl) 4-fluoro-benzenesulfonamide.

Under similar conditions, the amine E-4 is reacted with alkyl, aryl, and heteroaryl sulfonyl chlorides in the presence of pyridine to provide compounds of the general formula E-5, wherein R is alkyl, aryl, or heteroaryl. Similarly, enantiomers of compounds such as formula E-9 are chromatographed using chiral HPLC to provide compounds of formulae E-10 and E-11. The final compounds of the invention of formulas E-6, E-7, E-8, and E-12-E-16 were also prepared using similar conditions.

TABLE F

The commercially available cyclopropylphenylketone of formula F-1 is nitrated with fuming nitric acid to produce the compound of formula F-2. The compound of formula F-2 is reduced in methanol with hydrogen catalyzed by platinum on carbon to produce the amine of formula F-3. The compound of formula F-3 is treated with benzyl chloroformate and diisopropylethylamine in dichloromethane to yield a compound of formula F-4. The compound of formula F-4 is reduced with sodium borohydride in tetrahydrofuran and ethanol to produce the compound of formula F-5.

Watch G

The commercially available dianion of 4-hydroxy-6-methyl-2-pyrone of formula G-0 is generated by deprotonation with two equivalents of lithium diisopropylamide in tetrahydrofuran and hexamethylphosphoramide. Alkylation with 2- (2-methoxy-ethoxy) -ethyl iodide (prepared by standard methods from commercially available alcohols) produces compounds of formula G-1. The compound of formula G-1 and the compound of formula F-5, m-benzyloxycarbonylaminophenyl cyclopropylmethanol (prepared as described in Table F) were reacted in dichloromethane in the presence of molecular sieves catalyzed with p-toluenesulfonic acid to produce the compound of formula G-2. Hydrogenolysis of the compound of formula G-2 on palladium on charcoal with hydrogen in ethanol yields the free amine of formula G-3. The free amine of formula G-3 is treated with two equivalents of pyridine in dichloromethane, followed by one equivalent of methylimidazole-4-sulfonyl chloride to produce the compound of formula G-4, i.e. the compound: n- (3- { cyclopropyl- [ 4-hydroxy-6- (3- { 2-methoxy-ethoxy } -propyl) -2-oxo-2H-pyran-3-yl ] -methyl } -phenyl) -1-methyl-1H-imidazole-4-sulfonamide.

Watch H

Commercially available 4-hydroxy-6-methyl-2-pyrone of formula H-0 is catalytically reacted with m-benzyloxycarbonylaminophenyl cyclopropylmethanol (the title compound of formula F-5, prepared as described in Table F) in dichloromethane in the presence of molecular sieves to produce the compound of formula H-1 using p-toluenesulfonic acid. The trivalent anion of the compound of formula H-1, produced from three equivalents of lithium diisopropylamide in tetrahydrofuran, is alkylated with ethyl bromide to produce the compound of formula H-2. The compound of formula H-2 is treated with lithium diisopropylamide and 2- (2-methoxy-ethoxy) -ethyl iodide in tetrahydrofuran to produce a compound of formula H-3. Hydrogenolysis of the compound of formula H-3 with hydrogen and palladium on charcoal in ethanol produces the free amine of formula H-4. Treatment of the free amine of formula H-4 with two equivalents of pyridine in dichloromethane, followed by one equivalent of 1-methylimidazole-4-sulfonyl chloride, yields the compound of formula H-5, i.e. the compound: n- (3- { cyclopropyl- [6- (1-ethyl-3- { 2-methoxy-ethoxy } -propyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] -methyl } -phenyl) -1-methyl-1H-imidazole-4-sulfonamide. Under similar conditions, other sulfonamide compounds of formula H-5 of the present invention are obtained by reacting amines of formula H-4 with alkyl, aryl and heteroarylsulfonyl chlorides in the presence of pyridine.

TABLE I

The compound of formula H-2, prepared as described in Table H, was treated with three equivalents of lithium diisopropylamide in tetrahydrofuran and ethylene oxide to produce the compound of formula I-1. The compound of formula I-1 is reacted with triphenylphosphine and carbon tetrabromide in tetrahydrofuran to produce the compound of formula I-2. The compound of formula I-2 is treated with sodium azide in aqueous ethanol to produce the compound of formula I-3. The compound of formula I-3 is reacted with hydrogen and palladium on charcoal in ethanol to produce the compound of formula I-4. Treatment of a compound of formula I-4 with diisopropylethylamine in dichloromethane followed by treatment with 1-methylimidazole-4-sulfonyl chloride yields a compound of formula I-5. Reacting a compound of formula I-5 with ammonia in methanol to produce a compound of formula I-6, i.e., a compound: n- (3- { cyclopropyl- [6- (1-ethyl-3- { 1-methyl-1H-imidazole-4-sulfonylamino } -propyl-) -4-hydroxy-2-oxo-2H-pyran-3-yl ] -methyl } -phenyl) -1-methyl-1H-imidazole-4-sulfonamide.

TABLE J

The compound of formula I-1, prepared as described in Table I, was hydrogenolyzed in ethanol with hydrogen and palladium on charcoal to produce the compound of formula J-1. The compound of formula J-1 is treated with triphenylphosphine and carbon tetrabromide in tetrahydrofuran to produce a compound of formula J-2. Reacting a compound of formula J-2 with pyridine in dichloromethane, followed by reaction with 1-methylimidazole-4-sulfonyl chloride to produce a compound of formula J-3, i.e., the compound: n- (3- { [6- (3-bromo-1-ethyl-propyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] -cyclopropyl-methyl } -phenyl) -1-methyl-1H-imidazole-4-sulfonamide. Treating a compound of formula J-3 with sodium azide in aqueous ethanol to produce a compound of formula J-4, i.e., the compound: n- (3- { [6- (3-azido-1-ethyl-propyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] -cyclopropyl-methyl } -phenyl) -1-methyl-1H-imidazole-4-sulfonamide. The compound of formula J-4 is reacted with hydrogen and palladium on charcoal in ethanol to produce a compound of formula J-5. Compound of formula J-5 was purified using the sultanic acid salt of triethylamine [ Anderson, b.d.; conradi, r.a.; knuth, k.e.; J.pharm.Sci.74: 365(1985), and diisopropylcarbodiimide to produce a compound of formula J-6: n- (3- { cyclopropyl- [6- (1-ethyl-3- { N- [8- (methyl- { 2-sulfoethyl } -amino) -1, 8-dioxooctyl ] -amino-propyl }) -4-hydroxy-2-oxo-2H-pyran-3-yl ] -methyl } -phenyl) -1-methyl-1H-imidazole-4-sulfonamide sodium salt.

Watch K

A compound of formula K-8, i.e. a compound: the preparation of N- (3- { cyclopropyl- [6- (1- (tetrahydropyran-4-ylmethyl) propyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] -methyl } -phenyl) -1-methyl-1H-imidazole-4-sulfonamide is shown in Table K. Commercially available tetrahydropyran-4-carboxylic acid of formula K-1 is reduced with borane in tetrahydrofuran to yield the compound of formula K-2. Treatment of a compound of formula K-2 with p-toluenesulfonyl chloride gives the corresponding tosylate of formula K-3, which is converted to the iodide of formula K-4 by treatment with potassium iodide in refluxing acetone. The commercially available dianion of 4-hydroxy-6-methyl-2-pyrone of formula K-10 is alkylated with ethyl bromide in tetrahydrofuran and hexamethylphosphoric triamide to produce the propyl derivative of formula K-9. Alkylation of the 6 alpha position of the compound of formula K-9 with a compound of formula K-4 produces a compound of formula K-5. Prepared as described in Table F using methanol of formula F-5, the 3-position of the compound of formula K-5 is further alkylated to produce the compound of formula K-6. Removal of the benzyloxycarbonyl protecting group by catalytic transfer hydrogenation affords the amine of formula K-7. Treatment of an amine of formula K-7 with 1-methylimidazole-4-sulfonyl chloride in the presence of pyridine affords a compound of formula K-8.

Watch L

As shown in Table L, the commercially available dianion of 4-hydroxy-6-methyl-2-pyrone of formula L-1 is generated by deprotonation with two equivalents of lithium diisopropylamide in tetrahydrofuran and hexamethylphosphoramide. Alkylation with benzyl bromide to produce a compound of formula L-2, which is then treated with two equivalents of lithium diisopropylamide in tetrahydrofuran and hexamethylphosphoramide, followed by treatment with ethyl iodide to produce a compound of formula L-3. The compound of formula L-2 was prepared as described in Table F with the compound of formula F-5 in benzene in the presence of molecular sieves catalyzed with p-toluenesulfonic acid to give the compound of formula L-4. Namely, the compound: 3- [ (3-benzyloxycarbonylaminophenyl) -cyclopropyl-methyl ] -6- (1-ethylphenylethyl) -4-hydroxy-2H-pyran-2-one. Hydrogenolysis of a compound of formula L-4 in methanol with a catalyst of palladium on carbon and ammonium formate or hydrogen to produce a free amine of formula L-5, i.e., the compound: 3- [ (3-aminophenyl) -cyclopropyl-methyl ] -6- (1-ethylphenylethyl) -4-hydroxy-2H-pyran-2-one. The compound of formula L-5 is reacted with the appropriate sulfonyl chloride to form the final compound of the present invention.

Watch M

As shown in Table M, commercially available triethylene glycol monomethyl ether was treated with p-toluenesulfonyl chloride and pyridine to provide a tosylate of formula M-2, which was then used to alkylate commercially available 2, 4-dihydroxyacetophenone to produce a compound of formula M-3. Condensation with diethyl carbonate to produce the compound of formula M-4. The compound of formula M-4 is ring closed by refluxing in acetic acid to produce the compound of formula M-5. Prepared as described in Table F using methanol of formula F-5, and the catalyst p-toluenesulfonic acid to alkylate the 3-position of the compound of formula M-5 to produce the compound of formula M-6. Removal of the benzyloxycarbonyl protecting group by catalytic transfer hydrogenation affords amines of formula M-7. Treatment of the amine with 1-methylimidazole-4-sulfonyl chloride in the presence of pyridine affords the final compound of formula M-8, i.e. the compound: n- (3- { cyclopropyl- [7- (2- (2- (2-methoxyethoxy) -ethoxy) -4-hydroxycoumarin-3-yl ] -methyl } -phenyl) -1-methyl-1H-imidazole-4-sulfonamide.

TABLE N

The nitration of a commercially available cyclopropylphenyl ketone of formula N-1 with fuming nitric acid at-40 ℃ produces an approximately 2: 1 mixture of isomers. The desired meta-nitro compound of formula N-2 can be conveniently isolated from the crude mixture by recrystallization from methanol. Cyclopropyl- (3-nitrophenyl) methanone of formula N-2 was catalytically hydrogenated in methanol with 10% palladium on charcoal at 0 ℃ to produce aniline of formula N-3. The product was isolated by filtration and concentration. The amino group is then protected with benzyl chloroformate and diisopropylethylamine in dichloromethane to yield a ketone of formula N-4. The ketone is then reduced with sodium borohydride in 5: 1THF and ethanol to produce the alcohol of formula N-5.

4-hydroxy-5, 6, 7, 8, 9, 10-hexahydrocycloocta [ b ] pyran-2-one was then reacted as described in r.effenberger, t.ziegler, k.h.sch _ nanoalder, t.kesmarsky, b.bauer chem.ber.119: 3394 preparation described in 3404(1986) alkylation with a compound of formula N-5 to produce a compound of formula N-6. The preferred conditions for the alkylation reaction are the use of p-toluene sulfonic acid in refluxing dichloromethane and a soxhlet extractor containing molecular sieves. Finally, the benzyl protecting group is removed by transfer hydrogenation to give the compound of formula N-7. Best results were obtained when 10% Pd/C was used in the reaction in pure cyclohexene.

Watch O

An amine of formula O-1, prepared as described in Table N, is treated with a sulfonyl chloride and a base, such as pyridine, in methylene chloride to produce a sulfonamide of formula O-2, wherein R₆₀Is, for example, 4-nitrophenyl. These sulfonamides are further modified using standard literature procedures readily apparent to those of ordinary skill in the art to produce sulfonamides of the formula O-3, wherein R is₆₁Are, for example, 4-aminophenyl and other functional groups which are not readily available via readily available sulfonyl chlorides. For example, N- [3- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ]]Pyran-3-yl) methyl]Phenyl radical]Catalytic hydrogenation reduction of nitro group of (E) -4-nitro-benzenesulfonamide with palladium on charcoal in ethyl acetate to give amine, 4-amino-N- [3- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b]Pyran-3-yl) methyl]Phenyl radical]-a benzenesulfonamide. Similarly, a carboxylic acid such as 3- [ [ [3- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ]]Pyran-3-yl) methyl]Phenyl radical]Amino group]Sulfonyl radical]Sulfation of benzoic acid with methanol and a catalyst to form the methyl ester, 3- [ [ [3- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ] ]Pyran-3-yl) methyl]Phenyl radical]Amino group]Sulfonyl radical]-benzoic acid methyl ester. Sulfonamides of the formula O-3 can also be obtained from compounds of the formula O-2 by further processing of the active functional groups. For example, 3-amino-N- [3- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ]]Pyran-3-yl) methyl]Phenyl radical]Reaction of benzenesulfonamides with benzoyl chlorides and bases such as pyridine to form benzamides, N- [3- [ [ [3- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b [)]Pyran-3-yl) methyl]Phenyl radical]Amino group]Sulfonyl radical]henyl]-benzamide. Further compounds of the invention of formula II, wherein R is₁₀And R₂₀Is a radical of the formula IV.

The sulfonyl chlorides used to prepare the compounds of the present invention can be conveniently prepared by one skilled in the art by methods described in the literature, as illustrated by the following examples₂In water/methanol with chlorine to give sulfonyl fluorides [ d.j.brown, j.a.hoskins, aust.j.chem.25: 2641(1972), which is subsequently converted to the desired sulfonyl chloride [ t. norris, j. chem. soc., Perkin trans.1 (11): 1378 (english) (1978). Adding appropriate mercaptan into iron chloride (FeCl) with chlorine ₃) To the desired sulfonyl chloride [ g.pala, ed.sci.13: (461 1958); close, j, amer, chem, soc, 82: 1132 (1960). Reacting the heteroaromatic compound with oleum to form a heteroaromatic sulfonic acid, followed by phosphorus oxychloride (POCl)₃) And phosphorus pentachloride (PCl)₅) Treatment yielded the desired sulfonyl chloride [ v.georgian, r.j.harrison, l.l.skaletzky, j.org.chem.27: 4571 (1962). Heteroaromatic compound and manganese dioxide (MnO)₂) And sodium sulfite (Na)₂SO₃) Reaction in water to give the desired sulfonic acid, followed by POCl₃And PCl₅Work-up to give the desired sulfonyl chloride [ N.A. Andova, Izvest.455 (1972); j.o.morley, j.chem.comm.88 (1976). Treatment of the appropriate heteroaromatic chloride with sodium sulfate and HCl in water to form the desired sulfonic acid, followed by POCl₃And PCl₅Treatment yielded the desired sulfonyl chloride [ t.r.norton, j.amer.chem.soc.68: 1330 (1946). Treating the appropriate hydroxy compound with N, N-dimethylthiocarbonyl chloride

[ m.s.newman, f.w.hetzel, org.synth.col.vol.iv: 824 (1988); m.s.newman, h.a.karnes, j.org.chem.31: 3980(1966), and the resulting thiol is then treated as described above to form the desired sulfonyl chloride. Treatment of an appropriately protected thio-heteroaromatic compound with chlorine in acetic acid to form the desired sulfonyl chloride

[ can.j.chem.55: 421 (1977). The heteroaromatic sulfonyl chlorides of the present invention were prepared using the literature methods described above.

Watch P

A preferred method for preparing heteroaryl sulfonamides of formula P-2 is described in Table P. Amines of formula P-1, prepared in schemes N, P-1, are sulfonated with various heteroaryl sulfonyl chlorides of formula P-3, wherein R is, for example, 2-pyridyl, 4-pyridyl, 5-cyanopyridin-2-yl, 2-pyrazinyl, 2-pyrimidinyl, 4, 6-dimethylpyrimidin-2-yl, 4-methylpyrimidin-2-yl to form sulfonamides of formula P-2, wherein R is the corresponding substituent.

Watch Q

The commercially available divalent anion of methyl acetoacetate was formed by deprotonation of sodium hydride and n-butyllithium in this order in tetrahydrofuran at 0 deg.C and reacted with a ketone of formula Q-1, prepared as described in Table S (formula S-4). The resulting hydroxy-ester intermediate is cyclized with dilute aqueous hydroxide followed by treatment with aqueous hydrochloric acid to produce the compound of formula Q-2. The compound of formula Q-2 is condensed with commercially available 3-nitrobenzaldehyde in tetrahydrofuran under the catalysis of aluminum trichloride, followed by reaction of the intermediate benzylidene adduct with triethylaluminum in the presence of cuprous bromide-dimethylsulfide to produce the compound of formula Q-3. By using Pd/C and ammonium formate are catalytically transfer hydrogenated in methanol to give the compound of formula Q-4. Treatment of a compound of formula Q-4 with the appropriate sulfonyl chloride and pyridine in methylene chloride yields the desired compound of formula Q-5 (wherein, for example, R₁Is 5-cyano-2-pyridyl or 1-methylimidazol-4-yl).

TABLE R

Commercially available 3-nitrophenylethyl ketones of formula R-1 are catalytically hydrogenated to give amines of formula R-2. Treatment of an amine of formula R-2 with diisopropylethylamine and benzyl bromide produces a compound of formula R-3. The divalent anion of methyl acetoacetate, produced by treating commercially available methyl acetoacetate in tetrahydrofuran with sodium hydride and n-butyllithium at 0 deg.C, was reacted with a ketone of the formula R-3. The intermediate hydroxy-ester is cyclized with dilute aqueous hydroxide followed by treatment with aqueous hydrochloric acid to yield the compound of formula R-4. The compound of formula R-4 is condensed with 3-nitrobenzaldehyde in tetrahydrofuran under the catalysis of aluminum trichloride, followed by reaction of the intermediate benzylidene adduct with triethylaluminum in the presence of cuprous bromide-dimethylsulfide to produce the compound of formula R-5. Catalytic hydrogenation with Pd/C gives diamines of the formula R-6. Treatment of a compound of formula R-6 with the appropriate sulfonyl chloride and pyridine in dichloromethane affords a desired compound of formula R-7 (wherein, for example, R1 is 5-cyano-2-pyridyl or 1-methylimidazol-4-yl).

Watch S

Commercially available 4-pentenoic acid of formula S-1 is coupled with bis (2-oxo-3-oxazolidinyl) phosphinic chloride with N, O-dimethylhydroxylamine to give the amide of formula S-2. The amide of formula S-2 is reacted with 3-butenyl magnesium bromide in tetrahydrofuran to produce the ketone of formula S-3. Treatment of the ketone of formula S-3 with metallic zinc, cuprous chloride and diiodomethane produces a ketone of formula S-4 (also formula Q-1, see Table Q above).

Watch T

A compound of formula T-2 (also of formula D-1) [ preparation thereof from commercially available methyl acetoacetate and 1-phenyl-3-hexanone (formula T-1) is described in detail in Table D and preparation 17 above ] with 3-nitrobenzaldehyde in the presence of aluminum trichloride in tetrahydrofuranFollowed by reaction of the intermediate benzylidene adduct with tert-butyl cu (cn) ZnI (an organometallic reagent prepared from metallic zinc, 2-iodo-2-methyl-propane, copper cyanide and lithium chloride) to produce a compound of formula T-3. (the preparation of organometallic reagents is further described in the above-mentioned article corresponding to preparation J). Catalytic transfer hydrogenation with Pd/C and ammonium formate in methanol gives the compounds of the formula T-4. Treatment of a compound of formula T-4 with the appropriate sulfonyl chloride and pyridine in methylene chloride yields the desired compound of formula T-5 (wherein, for example, R ₁Is 5-cyano-2-pyridyl or 1-methylimidazol-4-yl).

Watch U

Commercially available 4-fluorohydrocinnamic acids of formula U-1 are coupled with diethyl cyanophosphonate and N, O-dimethylhydroxylamine to give amides of formula U-2. Treatment of the amide with n-propylmagnesium chloride produces a ketone of formula U-3. Condensation of the ketone with the divalent anion of methyl acetoacetate followed by hydrolysis of the intermediate ester and ring closure yields the dihydropyrone of formula U-4. Dihydropyrones and aldehydes of formula B-2, prepared as described in Table B above, in AlCl₃In the presence of a catalyst to produce a benzylidene compound of formula U-5; followed by reaction with a Grignard reagent or a trialkylaluminum in the presence of cuprous bromide-dimethyl sulfide complex to produce a compound of formula U-6 (wherein, for example, R₁Is ethyl, t-butyl, or cyclopropyl). Removal of the benzyloxycarbonyl (CBZ) protecting group with ammonium formate and palladium on charcoal yields amines of the formula U-7 (wherein, for example, R₁Is ethyl, t-butyl, or cyclopropyl). Treatment of amines with sulfonyl chlorides and pyridines in methylene chloride affords sulfonamides of formula U-8 (wherein, for example, R₁Is ethyl, t-butyl, or cyclopropyl, and R is alkyl, aryl, or heteroaryl).

TABLE V

Commercially available 4-fluorobenzaldehyde of the formula V-1 is condensed with acetone under basic conditions to produce 1, 5-bis- (4-fluorophenyl) -penta-1, 4-dien-3-one of the formula V-2. Reduction of the dienone with magnesium in methanol gives the ketone of formula V-3. The ketone of formula V-3 is converted to the dihydropyrone product of formula V-8 using a chemistry similar to that described in the reaction sequence from U-3 to U-8 in Table U.

Watch W

Commercially available trans-2-pentenoic acid of formula W-1 is converted to the corresponding acid chloride in dichloromethane with oxalyl chloride to yield the product of formula W-2. The lithium amide of formula W-3 can be conveniently obtained by treating commercially available (S) - (+) -4-phenyl-2-oxazolidinone with tert-butyllithium in tetrahydrofuran at-78 deg.C to form the unsaturated amide of formula W-4 by treatment with an acid chloride of formula W-2. The amide of formula W-4 is added to a solution containing commercially available CuBr/(CH) at-20 deg.C₃)₂S and chlorinated 3- [ bis (trimethylsilyl) amino]In a solution of phenylmagnesium in tetrahydrofuran, after treatment with acid, a compound of formula W-5 [ Hruby et al, J.org.Chem., 58 (26): 7567 (1993). Refluxing an aniline of formula W-5 with benzyl bromide and sodium carbonate in a water/dichloromethane mixture; or reflux treatment with potassium carbonate in acetonitrile to give the compound of formula W-6. Reacting an amide of the formula W-6 with TiCl₄Followed by treatment with a base of the amine type in a solvent such as dichloromethane at below-20 ℃, preferably-78 ℃, followed by addition of 2-methoxy-2-methyl-1, 3-dioxoline of formula W-7 (as per Santry et al, j.am.chem.soc., 110 (9)): 2910(1988) to produce a compound of formula W-8. Simple treatment of the compound of formula W-8 with a protic acid affords the β -ketoamide of formula W-9. The compound of formula W-9 is successively reacted with TiCl ₄Alkali treatment of amines followed by further treatment with 4-heptanone or propylphenethylketone gives compounds of the formula W-10, wherein R₁Respectively n-propyl or phenethyl. Treatment of a compound of formula W-10 in ethereal solution with sodium hydride or preferably potassium tert-butoxide yields a pyrone of formula W-11. Hydrogenation of a compound of formula W-11 using, for example, palladium on carbon as a catalyst produces a compound of formula W-12. Finally, the compound of formula W-12 is reacted with a sulfonyl chloride of formula D-7, wherein R is₄Is 5-trifluoromethyl-2-pyridyl to produce the final compound of formula W-13, wherein R₁Is n-propyl or phenethyl (when R is₁Is phenethyl, it is a pair of diastereomers).

Table X

The (R) enantiomer of formula X-13 was prepared according to the method in Table W, where R is₁Is n-propyl or phenethyl.

Watch Y

The addition of acetyl chloride of formula Y-1 to lithium amide of formula Y-2 [ also X-3, conveniently obtained by treatment of commercially available (R) - (-) -4-phenyl-2-oxazolidinone with n-butyllithium in tetrahydrofuran at-78 ℃ affords the product of formula Y-3. The compound of formula Y-3 is first reacted with TiCl₄Treatment in dichloromethane at below room temperature followed by addition of a tertiary amine base and then addition of an aldehyde of formula Y-4 (the aldehyde of formula Y-4 is conveniently obtained by reacting a commercially available 3-aminobenzaldehyde with benzyl bromide and potassium carbonate or sodium carbonate in acetonitrile or a water/dichloromethane mixture) gives compounds of formula Y-5. The amine of formula Y-5 is added to a solution containing commercially available CuBr/(CH) at-20 deg.C ₃)₂S and ethylmagnesium chloride in tetrahydrofuran to produce the compound of formula Y-6. Alternatively, a commercially available compound of formula Y-7 is treated with oxalyl chloride to produce a compound of formula Y-8. The compound of formula Y-8 is then added to a solution of a compound of formula Y-2 [ also X-3, conveniently obtained by treatment of commercially available (R) - (-) -4-phenyl-2-oxazolidinone with n-butyllithium in tetrahydrofuran at-78 ℃ to yield a compound of formula Y-9. The compound of formula Y-9 is reduced with metallic iron in an ethanol/water mixture to produce a compound of formula Y-10. The compound of formula Y-10 is treated with benzyl bromide and potassium carbonate or sodium carbonate in acetonitrile or a water/dichloromethane mixture to produce a compound of formula Y-5, which is converted to a compound of formula Y-6 as described above. Converting a Compound of formula Y-6A compound of formula W-6 is converted to a compound of formula W-13 (wherein R is₁Propyl or phenethyl) into the final product.

Watch Z

The preparation of the (3S) amide of formula Z-6 is accomplished in the same manner as described in Table Y above, except that a compound of formula Z-2 (also W-3) is used. Converting the compound of formula X-6 as in Table ZIs a compound of the formula X-13 (wherein R is ₁Is propyl or phenethyl) converts the compound of formula Z-6 into the final product.

TABLE AA

Preparation of (3S), (6S) diastereomers AA-12 and AA-14: unsaturated amides of formula AA-1 (also Y-5) are added to a solution containing commercially available CuBr/(CH) at-20 deg.C₃)₂S and ethylmagnesium chloride in tetrahydrofuran to produce a compound of formula AA-2 (the same as Y-6). The compound of formula AA-2 is reduced with a metal hydride (sodium borohydride, lithium aluminum hydride) to produce a compound of formula AA-3. Oxidation of a compound of formula AA-3 (Swern oxidation) produces an aldehyde of formula AA-4, which is treated with trimethylsilyl cyanide to produce a trimethylsilyl protected cyanohydrin of formula AA-5. In addition, compounds of formula AA-2 are treated sequentially with trimethylaluminum, N-methyl-O-methylhydroxylamine to produce amides of formula AA-6, which are treated with lithium aluminum hydride to produce aldehydes of formula AA-4. Reaction of a trimethylsilyl cyanohydrin of formula AA-5 with a strong base (e.g., n-butyllithium) followed by addition of a chiral epoxide of formula AA-7 (also BB-12; the synthesis of which is described in Table BB) produces a compound of formula AA-8. Dissolving the compound of formula AA-8 in dichloromethane and cooling to-78 deg.C, adding TiCl in sequence₄And tertiary amine bases. To this solution were added sequentially trimethyl orthoformate and TiCl ₄To produce the compound of formula AA-9. The compound of formula AA-9 is treated sequentially with base, trimethylsilyl chloride, and then sequentially with an oxidizing agent (ozone), tetrabutylammonium fluoride, potassium tert-butoxide or sodium hydride in an ether solvent to produce a compound of formula AA-10. Hydrogenation of a compound of formula AA-10 produces a compound of formula AA-11. Finally, the compound of formula AA-11 is dissolved in an organic solvent, such as methylene chloride, in the presence of an organic base, such as pyridine, with a sulfonyl chloride of formula D-7 in Table D (wherein R is₄Is for example 5-trifluoromethyl-2-pyridyl) to give the final compound of formula AA-12.

In addition, the compound of formula AA-1 was added to a solution containing commercially available CuBr/(CH) at-20 deg.C₃)₂S and tert-butylmagnesium chloride in tetrahydrofuran to produce a compound of formula AA-13. Will be provided withThe compound of formula AA-13 is converted to the final product, a compound of formula AA-14, using the chemistry described in the synthesis of AA-12.

Table BB

Table BB describes the asymmetric synthesis of epoxides of formulas BB-7 and BB-12. 2-methyl-2-propen-1-ol (BB-1) is alkylated with commercially available benzyl bromide to produce an allyl alcohol of formula BB-2 (see Lipshutz, B.H., et al, Synthesis 1992, 191). Sharpless epoxidation was carried out with commercially available (+) diethyl L-tartrate to form the epoxy alcohol of formula BB-8 (see (a) Pphenniger, A; Synthesis 1986, 89. (b) Johnson, R.A.; Sharpless, K.B. InCatalytic asymmetry Synthesis; Ojima, I., Ed.; VCH: New York, 1993; Chapter 4.1, 103). Alkylation of a compound of formula BB-8 with benzyl bromide (see: Lipshutz, B.H., et al; Synthesis 1992, 191) produces a compound of formula BB-9. The compound of formula BB-9 is reacted with commercially available ethylmagnesium bromide to produce a tertiary alcohol of formula BB-10 (see: Hanson, R.M.chem.Rev.1991, 91, 437). The compound of formula BB-10 is subjected to catalytic hydrogenolysis to produce a diol of formula BB-11. Compounds of formula BB-11 are converted to chiral epoxides of formula BB-12 using standard methods (for a discussion of the conversion of vicinal diols to epoxides see:

Mitsunobu，O.In Comprehensive Organic Synthesis；Trost，B.M.Ed.；Pergamon Press：Oxford，1991：Vol.6；Chapter 1.1，1)。

In a similar manner, the epoxide of formula BB-7 is finally obtained from the epoxy alcohol of formula BB-3, the compound of formula BB-3 being obtained by Sharpless epoxidation of allyl alcohol of formula BB-2 with commercially available (-) diethyl D-tartrate.

Alternatively, an epoxy alcohol of formula BB-8 is reacted with commercially available 4-toluenesulfonyl chloride under standard conditions to produce a tosylate of formula BB-13. The compound of formula BB-13 is reacted with ethylmagnesium bromide under similar conditions as described for the nucleophilic cleavage of arylsulphonate derivatives of glycidol (see: Klender, J.M.; Onami.T.; Sharpless, K.B.J.Org.Chem.1989, 54, 1295) to form the desired ring of formula BB-12A mixture of an oxide and a hydroxytoluene sulfonate ester of formula BB-14. Hydroxy tosylate of formula BB-14 with K₂CO₃The reaction in methanol can be conveniently converted to the epoxide of formula BB-12.

Watch CC

Preparation of the 3(S), 6(R) diastereomers of CC-12 and CC-14: these diastereomers were prepared in the same manner as described in Table AA, except that the epoxide of formula CC-7 (identical to BB-7) was used.

Table DD

Preparation of the 3(R), 6(S) diastereomer of DD-12 and DD-14: these diastereomers were prepared in the same manner as described in Table AA, except that the amide of formula DD-1 (identical to Z-5) was used.

TABLE EE

Preparation of the 3(R), 6(R) diastereomer of EE-12 and EE-14: these diastereomers were prepared in the same manner as described in Table DD, except that the epoxide of formula EE-7 (identical to BB-7) was used.

Watch FF

The lithium amide of formula FF-2 can be conveniently obtained by treating commercially available (S) - (+) -4-phenyl-2-oxazolidinone in tetrahydrofuran with n-butyllithium at-78 ℃ to form the amide of formula FF-3 with acetyl chloride of formula FF-1. The compound of formula FF-3 is successively reacted with TiCl₄Trialkylamine treatment followed by the addition of commercially available trimethylacetaldehyde to produce a compound of formula FF-4. The amide of formula FF-4 is added at-20 ℃ to a solution containing commercially available CuBr/(CH)₃)₂S and chlorinated 3- [ bis (trimethylsilyl) amino]A solution of phenylmagnesium in tetrahydrofuran, after treatment with an acid, gives a compound of formula FF-5. Refluxing an aniline of formula FF-5 with benzyl bromide and sodium carbonate in a water/dichloromethane mixture; or refluxing potassium carbonate in acetonitrile to produce the compound of formula FF-6.

Lithium amide of formula FF-7 can be prepared by reacting a commercially available (S) - (-) -4-phenyl-2-oxazolidone in tetrahydroTreatment of furan with n-butyllithium at-78 ℃ conveniently gives an amide of formula FF-8 by treatment with an acetyl chloride of formula FF-1. The compound of formula FF-8 is successively reacted with TiCl ₄Trialkylamine treatment followed by the addition of commercially available trimethylacetaldehyde to produce a compound of formula FF-9. The amide of formula FF-9 is added to a solution containing commercially available CuBr/(CH) at-20 deg.C₃)₂S and chlorinated 3- [ bis (trimethylsilyl) amino]In tetrahydrofuran solution of phenylmagnesium, a mixture of compounds of formula FF-10a and FF-10b is produced. Refluxing an aniline of formula FF-10b with benzyl bromide and sodium carbonate in a water/dichloromethane mixture; or refluxing potassium carbonate in acetonitrile to produce the compound of formula FF-11. The compound of formula FF-11 is reacted with TiCl₄Treatment in dichloromethane followed by the sequential addition of a tertiary amine base and 2-methyl-2-methoxy-1, 3-dioxolane gives a dioxolane intermediate (see W-8 in Table W) which is treated with a weak acid to give a compound of formula FF-12. The compound of formula FF-12 is successively reacted with TiCl₄Alkali treatment with a tertiary amine followed by the addition of 4-heptanone or 1-phenyl-3-hexanone produces a 3-hydroxybutanal product of formula FF-13. Treating a compound of formula FF-13 with sodium hydride or potassium tert-butoxide in an ether solvent to produce a compound of formula FF-14. Hydrogenating the compound of formula FF-14 in a hydrogen atmosphere in the presence of a palladium on carbon catalyst to produce a compound of formula FF-15. Finally, a compound of formula FF-15 is reacted with a sulfonyl chloride of formula D-7 in Table D (wherein R is R) in an organic solvent such as dichloromethane in the presence of an organic base such as pyridine ₄Is, for example, 5-trifluoromethyl-2-pyridyl) to produce a final compound of the formula FF-16, wherein R is₁Is for example propyl or phenethyl.

Table GG

Intermediates of formula GG-6 and final products of formula GG-16 were prepared as described in Table FF, except that (R) - (-) -4-phenyl-2-oxazolidinone and (R) - (+) -4-benzyl-2-oxazolidinone chiral auxiliary were used.

Table HH

A compound of formula HH-1(W-6), prepared as described in Table W, was converted to an ester of formula HH-2 by adding potassium tert-butoxide at 0 deg.C to a solution of the compound of formula HH-1 in tetrahydrofuran, where R is t-Bu. Compounds of formula HH-2, wherein R is t-Bu, can also be prepared in two steps from HH-1. First, a compound of formula HH-1 is treated with lithium hydroxide and hydrogen peroxide in tetrahydrofuran and water at 0 deg.C to remove the oxazolidinone group. The intermediate acid is then treated with N, N-dimethylformamide tert-butyl acetal in refluxing benzene to produce the ester of formula HH-2 (R is t-Bu). Esters of formula HH-2, wherein R is Me, are prepared by heating a mixture of titanium tetrachloride and HH-1 in methanol. A compound of formula HH-3 is formed by treating an ester of formula HH-2 with lithium diisopropylamide or sodium hexamethyldisilylazide to form an enolate which is subsequently captured by ethyl formate to yield a compound of formula HH-3. This intermediate is treated with tosyl chloride in 1, 2-dimethoxyethane to produce a compound of formula HH-4 which is then converted to a sulphur containing derivative of formula HH-5 by treatment with a mixture of potassium hydride and thiophenol in tetrahydrofuran. The compound of formula HH-5 is then deprotonated with tert-butyllithium in tetrahydrofuran at low temperature. An epoxide of the formula HH-6(BB-7) was added, prepared as described in Table BB, and one equivalent of boron trifluoride etherate to produce a compound of the formula HH-7. This intermediate is cyclized in situ to the compound of formula HH-8, or it is isolated and treated with sodium hydride in tetrahydrofuran to yield the cyclic compound of formula HH-8. The sulfur-containing group is then hydrolyzed with sodium hydroxide in acetonitrile or with aqueous copper chloride to produce a dihydropyrone derivative of the formula HH-9. The benzyl protecting group was then removed by catalytic hydrogenation with 10% palladium on charcoal in ethyl acetate. The resulting amine of formula HH-10 is converted to the desired sulfonamide derivative of formula HH-11 by treatment with 5-cyanopyridine-2-sulfonyl chloride (prepared as described in Table O) and pyridine in dichloromethane.

TABLE II-OO

The diastereomer of formula II-7 was prepared according to Table II by a procedure analogous to that described for the preparation of the diastereomer product in Table HH. Likewise, stereoisomers of formulae JJ-11, KK-7, LL-11, MM-7, NN-11, and OO-7 were prepared according to tables JJ, KK, LL, MM, NN, and OO, respectively, by methods analogous to those described in Table HH.

Watch PP

Compounds of formula PP-4(HH-8) were also prepared as described in Table PP. The tert-butyl ester of formula PP-1(HH-5), prepared as described in Table HH, was treated with an acidic aqueous solution to produce an acid of formula PP-2. The compound of formula PP-2 was then treated with t-butyllithium in tetrahydrofuran at low temperatures to produce a dianionic intermediate, which was prepared as described in Table BB with an epoxide of formula PP-3(BB-7), and one equivalent of boron trifluoride etherate to produce a compound of formula PP-4 (HH-8).

Watch QQ-WW

The diastereomer of formula QQ-3(II-4) was prepared according to Table QQ by a procedure analogous to that described for the preparation of the diastereomer product in Table PP. Likewise, stereoisomers of formulae RR-4(JJ-8), SS-3(KK-4), TT-4(LL-8), UU-3(MM-4), VV-4(NN-8), and WW-3(OO-4) were prepared according to tables RR, SS, TT, UU, VV, and WW, respectively, by methods analogous to those described in Table PP.

Table XX

Compounds of formula XX-6(HH-9) are also prepared as described in Table XX. A compound of formula XX-1(HH-2), prepared as described in Table HH, was heated alone in commercially available tris (dimethylamino) methane, bis (dimethylamino) -methoxymethane or tert-butoxy-bis (dimethylamino) methane to produce an intermediate of formula XX-2. One equivalent of tert-butyllithium was added to a solution of the ester in tetrahydrofuran at low temperature to form an anionic intermediate, which was prepared as described in Table BB with the epoxide of formula XX-3(BB-7), and one equivalent of boron trifluoride etherate was treated to form the compound of formula XX-4. The intermediate of formula XX-4 is cyclised in situ to the compound of formula XX-5 or it is isolated and cyclised by treatment with potassium tert-butoxide or sodium hydride in tetrahydrofuran. The intermediate of the same pattern XX-5 is hydrolyzed in situ to produce a compound of formula XX-6(HH-9) or it is isolated and treated with aqueous acidic or basic solutions to convert it to a dihydropyrone of formula XX-6 (HH-9).

TABLE YY-EEE

The diastereomer of formula YY-5(II-5) was prepared according to Table YY by a procedure analogous to that described for the preparation of the diastereomer product in Table XX. Similarly, stereoisomers of formula ZZ-6(JJ-9), AAA-5(KK-5), BBB-6(LL-9), CCC-5(MM-5), DDD-6(NN-9), and EEE-5(OO-5) are prepared according to tables ZZ, AAA, BBB, CCC, DDD, and EEE, respectively, by methods analogous to those described in Table XX.

Table FFF

The diastereomers of formula FFF-5 and FFF-7 are also prepared by separation of the diastereomeric intermediates. The diastereomeric mixture of formula FFF-1(W-11) was prepared as described in Table W and separated into the single diastereomers of formula FFF-2 (the less polar diastereomer) and FFF-3 (the more polar diastereomer) using a preparative chiral HPLC column. The benzyl protecting groups of the compounds FFF-2 and FFF-3 were then removed by catalytic hydrogenation with 10% palladium on charcoal in ethyl acetate to yield amines of the formulae FFF-4 and FFF-6, respectively. The intermediate amine is then converted to the desired sulfonamide derivatives of formula FFF-5(HH-11) and FFF-7(II-7) by treatment with 5-cyanopyridine-2-sulfonyl chloride (prepared as described in Table O) and pyridine in methylene chloride.

Watch GGG

Meta-nitrocinnamoyl chloride of formula GGG-1 (obtained by treating a commercially available acid with oxalyl chloride) is added to a solution of lithio-oxazolidinone of formula GGG-2 (conveniently prepared by treating a commercially available (R) - (+) -4-benzyl-2-oxazolidinone with n-butyl lithium) in ether to produce a compound of formula GGG-3. SnCl for compounds of formula GGG-3₂·2H₂Treatment of O in ethanol or iron powder in an ethanol/water mixture containing ammonium chloride reduces the nitro group to the corresponding amine in the compound of formula GGG-4. A compound of formula GGG-4 is treated with excess benzyl bromide in the presence of potassium carbonate or sodium carbonate in an organic solvent (with the addition of dichloromethane/water) to produce a compound of formula GGG-5. A THF solution of a compound of formula GGG-5 is added to a THF/dimethyl sulfide mixture containing a cuprate reagent prepared from ethyl magnesium bromide and a copper bromide/dimethyl sulfide complex to produce a compound of formula GGG-6. General formula GGG-6 compounds successively with TiCl₄Treatment with a tertiary amine followed by addition of a 2-methyl-2-methoxy-1, 3-dioxolane of formula GGG-7 affords a compound of formula GGG-8. The compound of formula GGG-8 is treated with perchloric acid to produce a compound of formula GGG-9. Alternatively, a compound of formula GGG-6 may be treated with a strong base such as lithium diisopropylamide in an ether solvent at below room temperature and added to a solvent of acetyl chloride (also in an ether solvent and cooled to below room temperature) to produce a compound of formula GGG-9. The compound of formula GGG-9 is successively treated with TiCl in dichloromethane₄And tertiary amine treatment, followed by the addition of 4-heptanone or 1-phenyl-3-hexanone to produce a compound of formula GGG-10. Treating a compound of formula GGG-10 with sodium hydride or potassium tert-butoxide in an ether solvent to produce a compound of formula GGG-11. Hydrogenating a compound of formula GGG-11 to produce a compound of formula GGG-12. Finally, the compound of formula GGG-12 is reacted with a sulfonyl chloride of formula D-7 in Table D (wherein R is R) in an organic solvent, such as dichloromethane, in the presence of an organic base, such as pyridine₄Is, for example, 5-trifluoromethyl-2-pyridyl) to produce a final compound of the formula GGG-13, wherein R is₁Is, for example, propyl or phenethyl.

In addition, the compound of formula GGG-5 is added to a THF/dimethylsulfide solution containing a mixture of t-butylmagnesium chloride and copper bromide/dimethylsulfide complex at 0 ℃ or lower to produce a mixture of compounds of formulae GGG-14a and GGG-14 b. Compounds of formula GGG14a and GGG-14b are converted to final products of formula GGG-19 and formula GGG-20 using the methods described for the synthesis of C-3 ethyl compounds of formula GGG-13 in Table GGG.

Watch HHH

The final compounds of formulas HHH-13, HHH-19 and HHH-20 were prepared in the same manner as described for the preparation of the final compounds in Table GGG.

TABLE III

The commercially available acid of formula III-1 is converted to the compound of formula III-2 by treatment with oxalyl chloride. Acyl chlorides of formula III-3 and lithio oxazolidinones of formula III-3 (prepared by treating commercially available (S) - (-) -4-benzyl-2-oxazolidinone with n-butyllithium in ethereal solvents) Coupling to produce the compound of formula III-4. The amide of formula III-4 is added at-20 ℃ to a solution containing a commercially available copper bromide/dimethyl sulfide complex and 3- [ bis (trimethylsilyl) amino chloride]In tetrahydrofuran solution of phenylmagnesium, after treatment with acid, the compounds of the formulae III-5a and III-5b are obtained. These compounds can be isolated by chromatography on silica gel. Treatment of the compound of formula III-5a with benzyl bromide in acetonitrile or a dichloromethane/water mixture in the presence of potassium carbonate or sodium carbonate yields the compound of formula III-6. The compound of formula III-6 is then treated with TiCl in dichloromethane₄Treatment followed by the sequential addition of a tertiary amine and 2-methyl-2-methoxy-1, 3-dioxolane of formula III-7 affords compounds of formula III-8. The compound of formula III-8 is treated with an acid (e.g., perchloric acid) to produce a compound of formula III-9. The compound of formula III-9 is reacted with TiCl in dichloromethane ₄Treatment followed by the sequential addition of a tertiary amine and 4-heptanone or 1-phenyl-3-hexanone produces a compound of formula III-10. The compound of formula III-10 is treated with sodium hydride or potassium tert-butoxide to produce the compound of formula III-11. The compound of formula III-11 is hydrogenated to produce the compound of formula III-12. Finally, the compound of formula III-12 is dissolved in an organic solvent, such as dichloromethane, in the presence of an organic base, such as pyridine, with a sulfonyl chloride of formula D-7 in Table D (wherein R is₄Is, for example, 5-trifluoromethyl-2-pyridyl) to produce the final compound of the formula III-13, wherein R is₁Is, for example, propyl or phenethyl.

In a similar manner, starting from the compound of formula III-5b, the final compound of formula III-14 is prepared.

TABLE JJJ

Final compounds of formula JJJ-13 and JJJ-14 were prepared as described in Table III.

Watch KKK

A compound of formula KKK-1 (same as JJJ-9) is dissolved in dichloromethane with TiCl₄Treatment followed by addition of a tertiary amine. To this solution is added commercially available hydrocinnamaldehyde to produce a compound of formula KKK-2. Oxidation of compounds of formula KKK-2 (e.g. Me)₂SO-SO₃Pyridine) formationA compound of formula KKK-3. Treating a compound of formula KKK-3 with propylmagnesium chloride (wherein R is₁Is, for example, phenyl) to form compounds of the formulae KKK-4a and KKK-4 b. The ratio of KKK-4a/KKK-4b varies depending on the particular reaction conditions. In addition, in TiCl ₄Or n-Bu₄NF Compounds of the formulae KKK-4a and KKK-4b can also be produced by adding allylzinc bromide or allylsilane to a compound of the formula KKK-3 in the presence of NF (see Chemistry Letters2135, 1992, Taniguchi et al) followed by hydrogenation. The ratio of KKK-4a and KKK-4b varies depending on the particular reaction conditions. Treatment of a compound of formula KKK-4a with sodium hydride or potassium tert-butoxide produces a compound of formula KKK-5. It is also possible to produce KKK-5 directly after hydrogenation of the metal alkoxide intermediate (magnesium, zinc and titanium) produced by treating the compound of formula KKK-3 with allylzinc bromide, allylsilane or propylmagnesium chloride with simultaneous cyclization to give the unsaturated intermediate without isolation of KKK-4 a. Hydrogenating the compound of formula KKK-5 to produce a compound of formula KKK-6. Finally, the compound of formula KKK-6 is dissolved in an organic solvent, e.g. dichloromethane, in the presence of an organic base, e.g. pyridine, with a sulfonyl chloride of formula D-7 in Table D (wherein R is₄Is, for example, 5-trifluoromethyl-2-pyridyl) to give the final compound of the formula KKK-7a, in which, for example, R₁And R₂Respectively propyl or phenyl.

The compound of formula KKK-4b is converted into the final compound of formula KKK-7b in a similar manner as described for the conversion of the compound of formula KKK-4a into the compound of formula KKK-7 a.

Starting from a compound of formula KKK-8 (identical with III-6), compounds of formulae KKK-14a and KKK-14b are prepared in a similar manner as described for the conversion of a compound of formula KKK-1 into the final compounds of formulae KKK-7a and KKK-7b, wherein R is₁And R₂For example methyl or phenethyl, respectively.

In a similar manner to that described for the conversion of compounds of the formula KK-1 and KKK-8, which in each case contain a 4-benzyl-2-oxazolidinone auxiliary group, into the final compounds of the formulae KK-7a and KKK-7b and KKK-14a and KKK-14b, respectivelyThe compounds of K-15 and of the formula KKK-19, which both contain a 4-phenyl-2-oxazolidinone auxiliary group, are converted into the final compounds of the formulae KKK-7a and KKK-7b and the final compounds of the formulae KKK-14a and KKK-14b, respectively, wherein R is₁And R₂For example methyl or phenethyl, respectively.

TABLE LLL

A compound of formula LLL-1 (the same as AA-1 wherein R is phenyl; GGG-5 wherein R is benzyl) is added below 0 ℃ to a solution of commercially available copper bromide/dimethyl sulfide complex and t-butylmagnesium chloride in tetrahydrofuran to yield a compound of formula LLL-2 as the major diastereomeric product. When R is defined as benzyl in the compound of formula LLL-2, the compound is treated with TiCl in dichloromethane ₄Treating at 0 deg.C or below, and sequentially adding tertiary amine and 2-methyl-2-methoxy-1, 3-dioxolane to obtain LLL-3 compound. The compound of formula LLL-3 is treated with a protonic acid to produce a compound of formula LLL-4. The compound of formula LLL-4 is reacted with TiCl in dichloromethane₄Treating below 0 deg.C, and sequentially adding amine base and 4-heptanone or 1-phenyl-3-hexanone to obtain LLL-5 compound₁Respectively, for example n-propyl or phenethyl. Treating the compound of formula LLL-5 with sodium hydride or potassium tert-butoxide in an ether solvent to produce the pyrone of formula LLL-6. Hydrogenation of a compound of formula LLL-6 using, for example, palladium on charcoal as a catalyst produces a compound of formula LLL-7. Finally, a compound of formula LLL-7 is dissolved in an organic solvent, such as dichloromethane, in the presence of an organic base, such as pyridine, with a sulfonyl chloride of formula D-7 in Table D (wherein R is₄Is, for example, 5-trifluoromethyl-2-pyridyl) to produce a final compound of the formula LLL-8, wherein R is₁Is, for example, propyl or phenethyl.

Reacting a compound of formula LLL-2, wherein R is phenyl, with TiCl in dichloromethane₄Processing to produce the compound of formula LLL-9. The compound of formula LLL-9 is treated with a base to produce a compound of formula LLL-10. Treatment of the acid of formula LLL-10 with methyllithium in an ether solvent produces a compound of formula LLL-11. The ketone of the formula LLL-11 is dissolved in dichloromethane with TiCl ₄Treatment at below 0 ℃ followed by addition of an amine base and4-heptanone or 1-phenyl-3-hexanone to produce a compound of formula LLL-12, wherein R is₁Respectively, for example n-propyl or phenethyl. The compound of formula LLL-12 is reacted with TiCl in dichloromethane₄Treatment at below 0 ℃ followed by the sequential addition of an amine base and trimethyl orthoformate produces a compound of formula LLL-13. The compound of formula LLL-13 is treated with a base in an organic solvent such as THF or dichloromethane, followed by the addition of trimethylsilyl chloride. The solvent in the preceding reaction is removed and the resulting protected tertiary alcohol is oxidized [ e.g., Ru cat./t-BuOH (see Murahashi et al Chemistry Letters2237, 1992); triphenylmethyl perchlorate/methylene chloride (see Mukaiyama et al chemistry letters 1255, 1985); ozone/methylene chloride (see Can.J. chem.49, 2465, 1971)) either directly or via a two-step reaction (wherein the intermediate ester is reacted with sodium hydride, potassium tert-butoxide or n-Bu₄Lactonization in ether solvents with the aid of NF) to produce the lactone of LLL-6. The compound of formula LLL-6 is converted to the final product as described above.

The same procedure is followed to convert the compound of formula LLL-16 to the final product of formula LLL-23, wherein R is₁Is propyl or phenethyl.

Table MMM

Diastereomers of the two compounds obtained by separating a mixture of diastereomers of the compounds of formulae MMM-5 and MMM-7. In addition, a diastereomeric mixture of formula MMM-1 (X-11, wherein R is₁Is, for example, phenethyl) prepared as described in table X and separated into the single diastereomers of formulae MMM-2 and MMM-3 using a preparative chiral HPLC column. The benzyl protecting groups of the compounds of formula MMM-2 (the less polar diastereomer) and MMM-3 (the more polar diastereomer) are then removed by catalytic hydrogenation with 10% palladium on charcoal in ethyl acetate to yield the amines of formula MMM-4 and MMM-6, respectively. This intermediate amine was then prepared using 5-trifluoromethyl-2-pyridylsulfonyl chloride, using the method described in Table O, and pyridine was treated in dichloromethane to convert to the desired sulfonamide derivatives of formula MMM-5 and MMM-7, respectively.

TABLE NNN

The commercially available (1R, 2S) - (-) ephedrine of formula NNN-2 was treated with triethylamine and the acid chloride of formula NNN-1 (W-2) (prepared as described in Table W) to produce the amide of formula NNN-3. The tert-butyl methyl ether solution of the amide was treated with 1.1 equivalents of propylmagnesium chloride and 2.0 equivalents of 3- [ bis (trimethylsilyl) amino ] phenylmagnesium chloride at 0 deg.C, stirred for 3 hours at 0 deg.C, washed with ammonium chloride solution and concentrated in vacuo. The residue is stirred with silica gel in chloroform to yield the compound of formula NNN-4. Alternatively, the above reaction mixture may be washed with a 1N hydrochloric acid solution instead of an ammonium chloride solution during work-up to produce a compound of formula NNN-4. A mixture of the compound of formula NNN-4, 2.2 equivalents of benzyl bromide and 2.2 equivalents of sodium carbonate in acetonitrile is then heated to convert the amine to the derivative of formula NNN-5. The derivative of formula NNN-5 is treated with 2 equivalents of lithium diisopropylamide in tetrahydrofuran to form the lithium salt of the enol, which is captured with acetyl chloride to form the b-ketoamide of formula NNN-6. A solution of the amide in methylene chloride can be treated with 1 equivalent of titanium tetrachloride and 1 equivalent of diisopropylethylamine at low temperature, followed by treatment with 4-heptanone to produce a compound of formula NNN-7. The amides of formula NNN-7 can be converted to the dihydropyrones of formula NNN-8 with sodium hydride in tetrahydrofuran or with an acidic aqueous solution. The benzyl protecting group can then be removed by catalytic hydrogenation with 10% palladium on charcoal in ethyl acetate. The resulting amine of formula NNN-9 was prepared using 5-trifluoromethyl-2-pyridylsulfonyl chloride, the procedure described in Table O, and pyridine was treated in dichloromethane to convert to the desired sulfonamide derivative of formula NNN-10 (W-12).

Table OOO

Compounds of formula OOO-7(NNN-8) were also prepared as described in Table OOO. The amide of formula OOO-1(NNN-5) is treated with an acidic aqueous solution to produce a compound of formula OOO-2. The compound of formula OOO-2 is acid catalyzed in methanol to form a methyl ester of formula OOO-3. The methyl ester of formula OOO-3 is treated sequentially with lithium diisopropylamide, trimethylsilyl chloride to produce a compound of formula OOO-4. The intermediate is treated with 2-methoxy-2-methyl-1, 3-dioxolane followed by hydrolysis, or treatment with acetyl chloride, to form a β -keto ester of the formula OOO-5. The beta-ketoester is converted to the compound of formula OOO-6 by treatment with a titanium salt of an enol (formed at low temperature with 1 equivalent of titanium tetrachloride and 1 equivalent of diisopropylethylamine in dichloromethane) or a divalent anion of lithium (formed at low temperature with 2 equivalents of lithium diisopropylamide in tetrahydrofuran) and 4-heptanone. The compound of formula OOO-6 is treated with sodium hydride in tetrahydrofuran or with an aqueous base to produce a dihydropyrone of formula OOO-7 (NNN-8).

Table PPP

Commercially available ethyl 4, 4, 4-trifluorobutyrate of formula PPP-1 is reduced with DiBAL-H and alkylated in situ with 2-phenylethylmagnesium bromide or chloride to produce an alcohol of formula PPP-2. Swern oxidation of the alcohol produces a ketone of the formula PPP-3. The ketone is alkylated with the divalent anion of methyl acetoacetate, subsequently saponified to the acid and lactonized with a base to convert it to the dihydropyrone of the formula PPP-4.

Watch QQQ

Dihydropyrones of formula QQQ1(PPP-4), prepared as described in Table PPP, are reacted with a CBZ-protected 3-aminobenzaldehyde of formula QQQ-2, obtainable by reaction of benzyl chloroformate with commercially available 3-aminobenzaldehyde, in the presence of aluminum trichloride, and then with trialkylaluminum or Grignard reagents in the presence of cuprous bromide-dimethyl sulfide complex to produce compounds of formula QQQ-3. Each stereoisomer was separated by HPLC using a chiral stationary phase to give four possible stereoisomers of the formulae QQQ-4, QQQ-5, QQQ-6 and QQQ-7. Each stereoisomer was subjected to transfer hydrogenation with Pd/C and ammonium formate to form amines of the formulae QQQ-8, QQQ-9, QQQ-10 and QQQ-11. Treatment of amines with sulfonyl chlorides of the formula QQQ-12 and pyridine in methylene chloride produces compounds of the formulae QQQ-13, QQQ-14, QQQ-15 and QQQ-16, wherein R is₂Is, for example, 5-cyano-2-pyridyl, 1-methyl-4-imidazolyl, or 5-amino-2-pyridyl.

TABLE RRR

The preparation of the compounds of formulae RRR-11 to RRR-15 is described in Table RRR. Adding AlCl into benzaldehyde RRR-B protected by pyrone RRR-A and Cbz₃Is coupled in THF of (1),the intermediate obtained is then used with R₁MgX (wherein X ═ Br or Cl) in the presence of CuBr ₂S in THF to obtain RRR-1. The resulting intermediate was deprotected with 10% Pd/C in methanol with ammonium formate added to form RRR-2. The racemic compound RRR-1 is resolved into four enantiomers thereof to obtain RRR-3 to RRR-6. The resulting intermediate was deprotected with 10% Pd/C in methanol with ammonium formate to form free amines RRR-7 to RRR-10. Treatment of the amines of RRR-7 through RRR-10 and RRR-2 with the appropriate sulfonyl chlorides produced sulfonamides of RRR-11 through RRR-14 and RRR-15, respectively.

Watch SSS

The preparation of the compounds of formulae SSS-7 to SSS-9 is described in Table SSS. Pyranone SSS-A and Cbz protected benzaldehyde SSS-B in the presence of AlCl₃In THF, followed by coupling of the resulting intermediate with R₁MgX (wherein X ═ Br or Cl) in the presence of CuBr₂S in THF to give SSS-1. The resulting intermediate was deprotected with 10% Pd/C in methanol with ammonium formate to form SSS-2. The racemic compound SSS-1 is resolved into two enantiomers thereof to obtain SSS-3 to SSS-4. The resulting intermediate was deprotected with 10% Pd/C in methanol with ammonium formate to yield free amines SSS-5 to SSS-6. Treatment of the amine with the appropriate sulfonyl chloride generates the sulfonamides of SSS-7 to SSS-9.

Watch TTT

The preparation of the compounds of formulae TTT-6 and TTT-7 is described in Table TTT. Pyranone TTT-A and Cbz protected benzaldehyde TTT-B in the presence of AlCl ₃In THF, followed by coupling of the resulting intermediate with R₁MgX (wherein X ═ Br or Cl) in the presence of CuBr₂Treatment of S in THF afforded TTT-1. Resolving racemic compound TTT-1 into its two enantiomers to obtain TTT-2 to TTT-3. The resulting intermediate was deprotected with 10% Pd/C in methanol with ammonium formate to form the free amines TTT-4 and TTT-5. Treatment of the amine with the appropriate sulfonyl chloride produces TTT-6 and TTT-7 sulfonamides, respectively.

Watch UUU

Commercially available thioureas and commercially available formulae2-chloro-5-nitropyridine of UUUU-1 is reacted in hot ethanol to produce an isothiourea compound of formula UU-2. The compound of formula UUU-2 is treated with an aqueous solution of sodium carbonate and sodium hydroxide to produce the thiol compound of formula UU-3. The compound of formula UUU-3 is oxidized with chlorine to produce the sulfonyl chloride compound of formula UU-4. A compound of formula D-5 (e.g., a compound of formula T-4, wherein R is₁Is 2-phenylethyl, R₂Is propyl, R₃Is t-butyl) in methylene chloride with two equivalents of pyridine followed by one equivalent of the compound of formula UUU-4 to produce the sulfonamide compound of formula UUU-5 (wherein R is₁Is 2-phenylethyl, R₂Is propyl, R₃Is a tert-butyl group). Reducing a compound of formula UUU-5 with palladium on charcoal and ammonium formate to produce a compound of formula UU-6, i.e., a compound: 5-amino-N- [3- (1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6-propyl-2H-pyran-3-yl ]-2, 2-dimethylpropyl) phenyl]-2-pyridinesulfonamide (formula UUUU-6: R)₁Is 2-phenylethyl, R₂Is propyl, R₃Is tert-butyl)

Watch VVV

The compound of formula VVV-1, 2-mercapto-5-carbamoylpyridine, was prepared by a published method (J.chem.Soc.1948, 1939-. A suspension of this compound in dilute hydrochloric acid is treated with chlorine at 0 ℃ to give the sulfonyl chloride of the formula VVV-2.

Table WWW

Amine with the general formula WWW-1 reacts with benzyl chloroformate to generate CBZ derivative WWW-2. The individual stereoisomers of the formula WWW-2 are separated by chiral HPLC and subsequently converted back to the free amines of WWW-3 by hydrogenolysis. The amine is sulfonated by conventional methods known to those of ordinary skill in the art to produce a stereochemically pure final compound of the formula WWW-4.

Watch XXX

Dihydropyrone XXX-1, prepared in a manner analogous to that described for preparations 17 and 84, is condensed with m-nitrobenzaldehyde in the presence of aluminum trichloride to form benzylidene intermediate XXX-2. The double bond is reduced conjointly with sodium cyanoborohydride followed by catalytic hydrogenation of the nitro group to give an amine of formula XXX-4 which is converted to the sulfonamide XXX-5 by treatment with the appropriate sulfonyl chloride in dichloromethane and pyridine.

Watch YYY

Dihydropyrones of the formula YYY-1, wherein R₁And R₂Is propyl or phenethyl, synthesized as described in preparation 84, condensed with an aldehyde of formula B-2 with aluminum trichloride to produce a benzylidene intermediate of formula YYY-2. Conjugated addition with t-butyl magnesium chloride in the presence of cuprous bromide-dimethyl sulfide to produce a compound of formula YYY-3. The deprotection by hydrogenation yields amines of formula YYY-4 which are converted to sulfonamides of formula YYY-5 by treatment with the appropriate sulfonyl chloride in pyridine plus dichloromethane. The method is similar to that described in table D.

TABLE ZZZ

The polymerized meta-aminobenzaldehyde is protected by reflux treatment with benzyl bromide and potassium carbonate in acetonitrile to produce a compound of formula ZZZ-2. Treatment of 2-bromovinyltrimethylsilane of formula ZZZ-3 with t-butyllithium at-78 deg.C to-20 deg.C produces the vinyl anion. The vinyl anion formed is cooled to-78 ℃ and the bis-protected m-aminobenzaldehyde of formula ZZZ-2 is added to produce the desired propenol of formula ZZZ-3. This alcohol can be conveniently converted to the acetate or carbonate of formula ZZZ-5 (e.g., CH) using standard procedures₃COCl, pyridine, CH₂Cl₂0 ℃ C. These substrates precipitated in the palladium-catalyzed allylic substitution as described in Table AAAA-CCCC

〔C.G.Frost；J.Howarth；J.M.J.Williams，Tetrahedron：Asymmetry(1992)3：1089-1122〕。

TABLE AAAA

The sodium salt of methyl acetoacetate of formula AAAA-1 formed by treating methyl acetoacetate with sodium hydride at 0 ℃ in DMF or THF acts as a nucleophile in the palladium-catalyzed allylic substitution. If the reaction is carried out in the presence of allylpalladium chloride dimer of formula AAAA-3 as palladium source and a chiral phosphine ligand [ P.von Mitt; pfaltz, angelw.chem.int.ed.engl. (1993) 32: 566-. If the reaction with the nucleophile is slow, the acetate produced from the pi-allylpalladium intermediate will isomerize the two possible diastereomeric pi-allyl complexes and allow the stereoselective synthesis of the allylated product.

(b.m.trost; p.e.j.strege, am.chem.soc. (1977) 99: 1649 ]. The resulting vinylsilane of formula AAAA-4 is treated with p-toluenesulfonic acid under reflux in acetonitrile to yield the desilylated olefin of formula AAAA-5. Dihydropyrones of formula AAAA-7 are prepared by reacting a beta-ketoester under standard conditions to form a dianion [ j.r.peterson; t.j.winger; miller, syn.comm. (1988)18 (9): 949-963), (NaH, n-butyllithium, THF) and quenched with an appropriate symmetrical ketone of formula AAAA-6 (e.g., 4-heptanone). The ester is hydrolyzed (0.1N NaOH/THF) and treated with acid to produce the dihydropyrone product of formula AAAA-7. The olefin is reduced and the amine deprotected using standard hydrogenation conditions. The amine is then reacted with the appropriate sulfonyl chloride (pyridine, CH) of formula AAAA-8 ₂Cl₂) Treatment produces the desired sulfonamide protease inhibitor of formula AAAA-9.

Table BBBB

In addition, the palladium-catalyzed allylic substitution reaction can also be carried out with the desired sodium anion of the dihydropyrone of the formula BBBB-1 (J.R.Peterson; T.J.Winger; C.P.Miller, Syn.Comm (1988)18 (90: 946-963) (dihydropyrone, NaH, THF or DMF, 0 ℃) as nucleophile likewise, if an allylpalladium chloride dimer of the formula BBBB-3 and a chiral phosphine ligand [ P.von Mitt ], A.Pfaltz, Angew.Chem.int.Ed.Engl. (1993) 32: 566-568 ] are used as catalysts, the kinetic resolution will lead to the synthesis of an optically pure allylated dihydropyrone of the formula BBBB-4, and if the reaction with the nucleophile is carried out relatively slowly compared to the isomerization of the two possible diastereomeric pi-allylic complexes of the acetates produced from the pi-allylpalladium intermediate, an allylic stereocomplex of the allylated allyl would occurAnd (4) selective synthesis. Followed by desilylation (p-TsOH, CH)₃CN), olefin reduction and amine deprotection (H)₂Pd/C), and sulfonylation of the amine with a compound of formula BBBB-5 (ArSO)₂Cl, pyridine, CH₂Cl₂) To produce the desired dihydropyrone protease inhibitor of formula BBBB-6.

TABLE CCCC

Treatment of m-bis (benzyl) aminobenzoic acid of formula CCCC-1 with oxalyl chloride to yield acid chloride and reaction with bis (trimethylsilyl) acetylene and AlCl₃Reaction in dichloromethane produces propargyl acetone of formula CCCC-2. The ketones are substituted with chiral boranes, e.g. DIP [ (+) -or (-) -beta-chlorodiisopinocampheyl borane]Performing asymmetric reduction [ h.c.brown; bereraraghavanramachandran, p.acc.chem.res. (1992) 25: 16-24 and reduction of the acetylene with REDAL to produce an allyl alcohol of the formula CCCC-3, predominantly a single enantiomer. The carbonate of the formula CCCC-4 (methyl chloroformate, pyridine, CH) formed₂Cl₂Palladium catalyzed allylic substitution at 0 ℃) with a dihydropyrone of the desired formula CCCC-5 as nucleophile yields predominantly one enantiomer of the allylated dihydropyrone of the formula CCCC-6 (configuration retention) [ t.hayashi; t. Hagihara; m.konishi; m.j.kumada, am.chem.soc (1983) 105: 7768-7770 ]. The product was converted to the desired protease inhibitor of formula CCCC-7 as described in Table BBBB above.

Table DDDD

Known cycloalkylpyranones of formula DDDD-1 are prepared by reacting the corresponding trimethylsilylenol ether of a cycloalkylketone as described in r.effenberger, t.ziegier, k. — h.schonwalder, t.kesmarszky, b.bauer chem.be.119: 3394 preparation by acylation with malonyl chloride is described in 3404 (1986). Contacting a cycloalkylpyrone of formula DDDD-1 with platinum dioxide (PtO) ₂) Catalytic hydrogenation in acetic acid produces a cycloalkyldihydropyrone of formula DDDD-2. A compound of formula DDDD-2 is reacted with 3-nitrobenzaldehyde (commercially available) in aluminum trichloride (AlCl)₃) To form an intermediate of formula DDDD-3. The intermediate of formula DDDD-3 is then reacted with a trialkylaluminum in the presence of cuprous bromide-dimethyl sulfideComplex (CuBr-Me)₂S) or a zinc reagent formed from metallic zinc, an alkyl halide, copper cyanide (CuCN) and lithium chloride (LiCl) to form a compound of formula DDDD-4 containing a C-3 alpha branched substituent. The compound of formula DDDD-4 is catalytically hydrogenated with Pd/C in ethanol to produce the amine derivative of formula DDDD-5. A compound of formula DDDD-5 is reacted with a sulfonyl chloride of formula DDDD-6 and pyridine in methylene Chloride (CH)₂Cl₂) To produce a compound of formula DDDD-7 (e.g., wherein n is 1, 2 or 3; r1 is ethyl or tert-butyl; r₂Is 4-cyanophenyl or 5-cyano-2-pyridyl).

Processes for the preparation of the compounds of the invention are also described in International application, PCT/US93/10645, filed 1993 at 11/9 (WO94/11361, published 1994 at 5/26), and International application, PCT/US94/00938, filed 1994 at 2/3 (WO94/18188, published 1994 at 8/18), both of which are incorporated herein by reference.

As will be apparent to those of ordinary skill in the art, the compounds of the present invention may occur in many diastereomeric forms depending on the configuration around the asymmetric carbon atom. All such diastereomeric forms are included within the scope of the invention.

In addition, the dihydropyrones of the present invention can be resolved into the individual stereoisomers or prepared as individual diastereomers. One diastereomeric pair can be prepared where C-3 α is the center of the structural identity and C-6 is mixed. All such enantiomeric and diastereomeric forms, as well as mixtures thereof, are intended to be included within the scope of the invention.

The compounds of formula I of the present invention may exist in a variety of tautomeric forms, including the particular enol forms depicted in formulas I and IA and the keto form of formula IB. (for formulas I, IA and IB, the dashed lines indicate that a double bond may or may not be present.) all of these tautomeric forms are included within the scope of the invention. The 4-hydroxy-pyran-2-one compound of the formula VII of the present invention is mainly in the form of an enol. For the 5, 6-dihydro-4-hydroxy-pyran-2-one compounds of formula VI of the present invention, it is generally considered to be in the form of a mixture of an enol and a ketone.

In addition, the compounds of formula II of the present invention may exist in a variety of tautomeric forms of the 4-hydroxy-pyrone ring, including the specific enol forms described in formula II and IIA and the specific keto forms described in formula IIB, and mixtures thereof. All such tautomeric forms are included within the scope of the present invention.

The compounds of the invention may be in free form or may be in a form in which one or more of the carboxyl, amino, hydroxyl, or other reactive groups remaining (not previously protected) are protected. The protecting group may be any known in the art. Examples of nitrogen and oxygen Protecting Groups are described in T.W.Greene, Protecting Groups in Organic Synthesis, Wiley, New York, (1981); McOmie, ed.protective Groups in organic chemistry, Plenum Press (1973); fuhrhop and G.Benzlin, organic Synthesis, Verlag Chemie (1983). Included among the nitrogen protecting groups are t-Butoxycarbonyl (BOC), benzyloxycarbonyl, acetyl, allyl, phthaloyl, benzyl, benzoyl, trityl and the like.

The present invention provides compounds of formulae I and II or their pharmacologically acceptable salts and/or hydrates. Pharmacologically acceptable salts are those salts which are significantly equivalent to the parent compound in properties such as formulation, stability, patient acceptance and bioavailability for the pharmaceutical chemist producing the drug. Examples of salts of compounds of formula I include acid salts, such as sodium, potassium, lysine, arginine, and calcium salts, and base salts, such as hydrochloride salts, wherein the R substituent in formula I contains a basic moiety. Examples of salts of compounds of formula II include hydrohalic salts, such as hydrochloride and hydroiodide salts; and sodium, potassium, calcium, lysine and arginine salts.

If the compounds of the formulae I and II according to the invention contain, for example, -NHSO₂-，-SO₃H, -CONH-, -OH or COOH, and salts thereof also include disalts, such as, for example, dilargyl, dilysine, disodium, dipotassium and dicalcium salts.Disodium salts are most preferred.

The compounds of the present invention are useful in treating human patients infected with Human Immunodeficiency Virus (HIV), which causes acquired immunodeficiency syndrome (AIDS) and related diseases. For this indication, the compounds may be administered by the oral, intranasal, transdermal, subcutaneous and parenteral (including intramuscular and intravenous) routes at doses ranging from 0.1mg to 100mg per kg of body weight per day.

One skilled in the art will know how to formulate the compounds of the present invention into appropriate pharmaceutical dosage forms. Examples of dosage forms include oral preparations, such as tablets and capsules, or parenteral preparations, such as sterile solutions.

When the compound of the present invention is administered orally, the effective dose is about 0.1mg to 100mg per kg body weight per day. Both solid and liquid dosage forms may be used for oral administration. Solid compositions, for example, tablets, are prepared by mixing a compound of the invention with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methylcellulose, or functionally similar pharmaceutical diluents and carriers. Capsules are prepared by mixing a compound of the invention with an inert pharmaceutical diluent and placing the mixture in hard gelatin capsules of appropriate size. Soft capsules are prepared by machine encapsulation of a slurry or solution of the compounds of the invention with an acceptable inert oil such as vegetable oil or light liquid paraffin.

Pharmaceutically acceptable formulations of the disodium salt of the compounds of the present invention include: soft Elastic Capsules (SEC) containing a suspension of salt; a tablet of salt; salt-sprayed sucrose pellets; or a salt spray dried matrix containing an enteric or non-enteric polymer.

The formulations of the compounds of the present invention, wherein the compounds are present in the free acid form, preferably contain the free acid in amorphous form. Examples of such agents include: soft elastic capsules containing free acid solutions; a non-crystalline spray-dried matrix of free acid and enteric or non-enteric polymer; or a solid non-crystalline matrix of the free acid in polyethylene glycol (PEG) or Gelucire 44/14 (Gattefose, Saint Priest, France).

Syrups are prepared by dissolving a compound of the invention in an aqueous vehicle and adding sugar, aromatic flavoring and preservative. Elixirs are prepared with an aqueous alcoholic excipient, for example ethanol, a suitable sweetening agent, for example sugar or saccharin and an aromatic flavoring agent. Suspending agents are prepared with aqueous excipients and suspending agents such as acacia, tragacanth, or methylcellulose.

When the compounds of the present invention are administered parenterally, they may be administered by injection or intravenous infusion. An effective dose is about 0.1mg to 100mg/kg body weight per day. Parenteral solutions are prepared by dissolving the compound of the invention in a liquid vehicle and filter sterilizing the solution prior to filling into a sealable vial or ampoule. Parenteral suspensions are prepared in substantially the same manner except that sterile suspension vehicles are used and the compounds of the invention are sterilized by ethylene oxide or a suitable gas prior to suspension in the vehicle.

The exact route of administration, dosage, or frequency of administration will be determined by one skilled in the art and will depend on the age, weight, general physical condition, or other clinical condition of the patient being treated.

The following conditions should be met for a patient to be treated: 1) infection with one or more human retroviruses, determined by the presence of measurable viral antibodies or antigens in serum and 2) in the case of HIV, with asymptomatic HIV infection or a symptomatic AIDS-determined infection, such as i) disseminated histoplasmosis, ii) psoriasis, iii) bronchial and pulmonary candidiasis, including interstitial plasmacytic pneumonia, iv) non-hodgkin's lymphoma or v) kaposi's sarcoma and an age of less than 60 years; or an absolute count of CD4+ lymphocytes in peripheral blood of less than 500/mm³. The composition of the treatment is as follows: the compounds according to the invention used are maintained in the patient at inhibitory concentrations and are continued until the occurrence of a second established infection with symptomatic AIDS indicates a need for a change in the treatment regimen.

The utility of representative compounds of the present invention has been demonstrated in the following biological experiments:

screening assays for HIV protease are based on a fluorescently labeled substrate that can be separated from unlabeled cleavage products by using a special bead of streptavidin envelope. The substrate was biotinylated with arginine at the amino terminus and the carboxy-terminal lysine was fluorescently labeled with Fluorescein Isothiocyanate (FITC). This test has been used to determine novel, non-peptide inhibitors of HIV-1 protease. Substrate (0.2. mu.M, 20. mu.l), sample (desired concentration, 10. mu.l), enzyme (0.1. mu.M, 10. mu.l) were added to a 96-well pandex plate. The assay was performed in 0.1M sodium acetate buffer at pH5.5 in the presence of 1.0M sodium chloride and 0.05% NP-40 and incubated for one hour at room temperature in the dark. Streptavidin-coated polystyrene beads { 0.1% (w/v), 40. mu.l } were added and incubation continued in the dark for half an hour. The labeled cleavage product was separated from the unreacted substrate by filtration and read on an Idexx screener. The data was analyzed by appropriate computer mathematical calculations to determine percent inhibition values.

K_iThe same materials and equipment used in the study of percent inhibition were used for the determination of the values. Serial dilutions of 2, 3 or 4 starting concentrations for a given multiple ratio of inhibitor, totaling 24, 36 or 48 inhibitor concentrations. The Biomek robotics system was used for these dilutions. The assay consisted of 10. mu.L of 40nM HIV-1 protease, 10. mu.L of various inhibitor concentrations, 20. mu.L of 200. mu.M substrate (40. mu.L total). The reaction was carried out at room temperature for 90 minutes, quenched with 40. mu.L of avidin beads and worked up (see above). Parallel experiments were performed with an inhibitor of known Ki to verify the validity of the assay. K is derived by data processing using a computer program for non-linear least square error analysis of data_iThe value is obtained.

The% inhibition value and/or K of representative compounds of the invention in HIV protease screening assays_iThe values are listed in table I below.

In the enzyme inhibition assay described above, K for compounds with high binding capacity_iThe sensitivity of value determination is limited in part by the ability to continuously reduce enzyme concentration. To prevent dimerisation at low enzyme concentrations, a tandem enzyme was prepared by appropriate extension of the amino acid residues, in which the two monomers were covalently linked. The sensitivity of the inhibition assay is improved when the latter enzyme is used, since a much lower enzyme concentration can be used, compared to the conditions when the wild-type enzyme is used.

K Using tandem HIV protease_iMethod of value determination: since the single-chain-tethered (tandem) HIV protease has greater stability (does not dimerize), where two monomer units are linked by a stretch of the polypeptide, K of the inhibitor is determined_iMethod of value very low enzyme concentration (0.2nM) and extended incubation time at room temperature (96 hours) were used to increase K of very potent inhibitors_iThe sensitivity of the value measurement. The initial inhibitor concentration depends on the initial enzyme inhibition screen, which indicates the expected potency of the inhibitor. Inhibitor concentrations were then formulated with Biomek 1000(Beckman) and Quadra96 (Tomtec). The substrate (arginine biotinylation at the amino terminus and lysine fluorescence labeling at the carboxy terminus with fluorescein), inhibitor and tandem enzyme were reacted in a solution at pH5.5 (same buffer as used for the native dimer enzyme) protected from light for 96 hours. The reaction was stopped by adding streptavidin-coated polystyrene beads. The labeled cleavage product is separated from the unreacted substrate by filtration. The residual fluorescence was quantified using Idexx SM2000(Idexx) and the resulting data analyzed using NLLSF program.

The% inhibition value and/or K in an HIV protease screening assay and/or a tandem HIV protease assay for representative compounds of the invention _iThe values are listed in table II below.

Some of the compounds of the invention, for example N- [3- (1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6-propyl-2H-pyran-3-yl]-2, 2-dimethylpropyl) phenyl]-1-methyl-1H-imidazole-4-sulfonamides in known human cellsLines, e.g. human T cell lines, e.g. MT4 and H9 (which are HIV-1-infected)_IIIBInfection), some of these compounds were also tested in peripheral blood mononuclear cells (PBBMC) [ they are HIV-1-infected_JRCSF(clinical isolates) infection ] further experiments were performed. These compounds were found to inhibit retroviral replication.

The following compounds of the invention are preferred:

5-cyano-N- [3- (1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6-propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl) phenyl ] -2-pyridine-sulfonamide

N- [3- {1- (4-hydroxy-5, 6-dihydro-2-oxo-6-phenethyl-6-propyl-2H-pyran-3-yl) propyl } phenyl ] -5-cyanopyridine-2-sulfonamide

N- [3- (1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6-propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl) phenyl ] -1-methyl-1H-imidazole-4-sulfonamide

N- [3- [1- (4-hydroxy-2-oxo-6-phenethyl-6-propyl-5, 6-dihydro-2H-pyran-3-yl) -propyl ] phenyl ] -1-methyl-1H-imidazole-4-sulfonamide

N- [3- {1- (4-hydroxy-5, 6-dihydro-2-oxo-6- (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl ] -5-cyanopyridine-2-sulfonamide

N- [3- {1- (4-hydroxy-5, 6-dihydro-2-oxo-6- (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) propyl } phenyl ] -5-cyanopyridine-2-sulfonamide

N- [3- {1- (4-hydroxy-5, 6-dihydro-2-oxo-6- (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl ] -1-methyl-1H-imidazole-4-sulfonamide

N- [3- {1- (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-dipropyl-2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl ] -5-cyanopyridine-2-sulfonamide

N- [3- {1- (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-dipropyl-2H-pyran-3-yl) propyl } phenyl ] -5-cyanopyridine-2-sulfonamide

N- [3- {1- (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-dipropyl-2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl ] -1-methyl-1H-imidazole-4-sulfonamide

N- [3- {1- (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-bis (2- (4-fluorophenyl) ethyl) -2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl ] -5-cyanopyridine-2-sulfonamide

N- [3- {1- (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-bis (2- (4-fluorophenyl) ethyl) -2H-pyran-3-yl) propyl } phenyl ] -5-cyanopyridine-2-sulfonamide

N- [3- {1- (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-bis (2- (4-fluorophenyl) ethyl) -2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl ] -1-methyl-1H-imidazole-4-sulfonamide

N- [3- (1- [6, 6-bis- (2-cyclopropyl-ethyl) -5, 6-dihydro-4-hydroxy-2-oxo-2H-pyran-3-yl ] -2, 2-dimethylpropyl) phenyl ] -5-cyano-2-pyridinesulfonamide

N- [3- (1- [6, 6-bis- (2-cyclopropyl-ethyl) -5, 6-dihydro-4-hydroxy-2-oxo-2H-pyran-3-yl ] -propyl) -phenyl ] -5-cyano-2-pyridinesulfonamide

N- [3- (1- [6, 6-bis- (2-cyclopropyl-ethyl) -5, 6-dihydro-4-hydroxy-2-oxo-2H-pyran-3-yl ] -2, 2-dimethylpropyl) phenyl ] -1-methyl-1H-imidazole-4-sulfonamide

5-cyano-N- [3- (R or S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6- (R or S) - (3, 3, 3-trifluoropropyl) -2H-pyran-3-yl ] -2, 2-dimethylpropyl ] phenyl ] -2-pyridinesulfonamide,

n- [3- (R or S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (R or S) - (2-phenylethyl) -6- (3, 3, 3-trifluoropropyl) -2H-pyran-3-yl ] -2, 2-dimethylpropyl ] phenyl ] -1-methyl-1H-imidazole-4-sulfonamide,

5-amino-N- [3- (R or S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6- (R or S) - (3, 3, 3-trifluoropropyl) -2H-pyran-3-yl ] -2, 2-dimethylpropyl ] phenyl ] -2-pyridinesulfonamide,

N- [3- (R or S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) - [6- (R or S) -propyl) -2H-pyran-3-yl ] -2, 2-dimethylpropyl ] phenyl ] -2-pyridinesulfonamide,

5-trifluoromethyl-N- [3- [1- [ 4-hydroxy-2-oxo-6, 6-di-N-propyl-5, 6-dihydro-2H-pyran-3-yl ] -propyl ] phenyl ] -2-pyridinesulfonamide,

5-trifluoromethyl-N- [3- (R or S) - [1- [ 4-hydroxy-2-oxo-6, 6-di-N-propyl-5, 6-dihydro-2H-pyran-3-yl ] -propyl ] phenyl ] -2-pyridinesulfonamide, or (3R or S) -N- [3- [1- (5, 6-dihydro-4-hydroxy-2-oxo-6, 6-dipropyl-2H-pyran-3-yl) propyl ] phenyl ] -5- (trifluoromethyl) -2-pyridinesulfonamide

5-trifluoromethyl-N- [3- (R or S) - [1- [ 4-hydroxy-2-oxo-6, 6-diphenylethyl-5, 6-dihydro-2H-pyran-3-yl ] -propyl ] phenyl ] -2-pyridinesulfonamide,

5-trifluoromethyl-N- [3- [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6-N-propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl ] -phenyl ] -2-pyridinesulfonamide,

5-trifluoromethyl-N- [3(R or S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (R or S) - (2-phenylethyl) -6(R or S) -N-propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl ] phenyl ] -2-pyridinesulfonamide,

5-trifluoromethyl-N- [3(R or S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (R or S) - (2-phenylethyl) -6(R or S) -N-propyl-2H-pyran-3-yl ] -propyl ] -phenyl ] -2-pyridinesulfonamide, or (3R or S, 6R or S) -N- [3- [1- (5, 6-dihydro-4-hydroxy-2-oxo-6-propyl-6-phenethyl-2H-pyran-3-yl) propyl ] phenyl ] -5- (trifluoromethyl) -2-pyridinesulfonamide.

5-amino-N- [3- (1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6-propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl) -phenyl ] -2-pyridinesulfonamide,

5-cyano-N- [3(R or S) - (1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (R or S) - (2-phenylethyl) -6-propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl) -phenyl ] -2-pyridinesulfonamide,

5-cyano-N- [3- (1- [5, 6-dihydro-6, 6-diisobutyl-4-hydroxy-2-oxo-2H-pyran-3-yl ] -2, 2-dimethylpropyl) phenyl ] -2-pyridinesulfonamide,

n- [3(R or S) - [1- (5, 6-dihydro-4-hydroxy-2-oxo-6 (R or S) - [ 2-phenylethyl ] -6-propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl ] -phenyl ] -1-methyl-1H-imidazole-4-sulfonamide,

5-cyano-N- [3- (1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6-propyl-2H-pyran-3-yl ] -cyclopropylmethyl) phenyl ] -2-pyridinesulfonamide,

5-amino-N- [3(R or S) - (1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (R or S) - (2-phenylethyl) -6-propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl) phenyl ] -2-pyridinesulfonamide,

5-amino-N- [3(R or S) - (1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (R or S) - (2-phenylethyl) -6-propyl-2H-pyran-3-yl ] -propyl) phenyl ] -2-pyridinesulfonamide,

5-amino-N- [3(R or S) - (1- [6(R or S) - (2- [ 4-fluorophenyl ] ethyl) -5, 6-dihydro-4-hydroxy-2-oxo-6-propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl) phenyl ] -2-pyridinesulfonamide,

n- [3(R or S) - (1- [5, 6-dihydro-6, 6-dipropyl-4-hydroxy-2-oxo-2H-pyran-3-yl ] -2, 2-dimethylpropyl) phenyl ] -1-methyl-1H-imidazole-4-sulfonamide,

5-amino-N- [3(R or S) - (1- [5, 6-dihydro-6, 6-dipropyl-4-hydroxy-2-oxo-2H-pyran-3-yl ] -2, 2-dimethylpropyl) phenyl ] -2-pyridinesulfonamide,

5-cyano-N- [3(R or S) - (1- [5, 6-dihydro-6, 6-dipropyl-4-hydroxy-2-oxo-2H-pyran-3-yl ] -2, 2-dimethylpropyl) phenyl ] -2-pyridinesulfonamide,

n- [3(R or S) - (1- [6, 6-bis (2-phenylethyl) -5, 6-dihydro-4-hydroxy-2-oxo-2H-pyran-3-yl ] propyl) phenyl ] -1-methyl-1H-imidazole-4-sulfonamide,

n- [3(R or S) - (1- [6, 6-bis (2-phenylethyl) -5, 6-dihydro-4-hydroxy-2-oxo-2H-pyran-3-yl ] propyl) phenyl ] -5-cyano-2-pyridinesulfonamide,

n- [3- {1- (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-bis (2-phenylethyl) -2H-pyran-3-yl) propyl } phenyl ] -5-cyanopyridine-2-sulfonamide,

n- [3- {1(R or S) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (R or S) -phenethyl-6-propyl-2H-pyran-3-yl) propyl } phenyl ] -5-cyanopyridine-2-sulfonamide,

N- [3- {1(R or S) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (S or R) -phenethyl-6-propyl-2H-pyran-3-yl) propyl } phenyl ] -1-methyl-1H-imidazole-4-sulfonamide,

n- [3- {1- (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-bis (2-phenylethyl) -2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl ] -1-methyl-1H-imidazole-4-sulfonamide,

n- [3- {1(R or S) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (R or S) - (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl ] -5-cyanopyridine-2-sulfonamide,

n- [3- {1(R or S) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (R or S) - (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl ] -1-methyl-1H-imidazole-4-sulfonamide,

n- [3- {1(R or S) - (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-bis (2-phenylethyl) -2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl ] -5-aminopyridine-2-sulfonamide,

n- [3- {1(R or S) - (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-bis (2-phenylethyl) -2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl ] -1-methyl-1H-imidazole-4-sulfonamide,

n- [3- {1(R or S) - (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-bis (2-phenylethyl) -2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl ] -5-cyanopyridine-2-sulfonamide,

N- [3- {1(R or S) - (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-dipropyl-2H-pyran-3-yl) -propyl } phenyl ] -5-cyanopyridine-2-sulfonamide

The following compounds of the invention are more preferred:

n- [3(R or S) - [1- (5, 6-dihydro-4-hydroxy-2-oxo-6 (R or S) - [ 2-phenylethyl ] -6-propyl-2H-pyran-3-yl) -2, 2-dimethylpropyl ] -phenyl ] -1-methyl-1H-imidazole-4-sulfonamide,

n- [3- {1(R or S) - (5, 6-dihydro-4-hydroxy-2-oxo-6 (S or R) -phenethyl-6-propyl-2H-pyran-3-yl) propyl } phenyl ] -5-cyanopyridine-2-sulfonamide,

n- [3- {1(R or S) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (R or S) - (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl ] -1-methyl-1H-imidazole-4-sulfonamide, and

n- [3- {1(R or S) - (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-dipropyl-2H-pyran-3-yl) -propyl } phenyl ] -5-cyanopyridine-2-sulfonamide.

The following compounds of the invention are most preferred (see table EEE):

n- [3- {1(R or S) - (5, 6-dihydro-4-hydroxy-2-oxo-6 (S or R) -phenethyl-6-propyl-2H-pyran-3-yl) propyl } phenyl ] -5-cyanopyridine-2-sulfonamide of the formula EEE-1,

N- [3- {1(R or S) - (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-dipropyl-2H-pyran-3-yl) -propyl } phenyl ] -5-cyanopyridine-2-sulfonamide of formula EEE-2.

N- [3(R or S) - [1- (5, 6-dihydro-4-hydroxy-2-oxo-6 (R or S) - [ 2-phenylethyl ] -6-propyl-2H-pyran-3-yl) -2, 2-dimethylpropyl ] -phenyl ] -1-methyl-1H-imidazole-4-sulfonamide of formula EEE-3,

5-trifluoromethyl-N- [3(R or S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (R or S) - (2-phenylethyl) -6(R or S) -N-propyl-2H-pyran-3-yl ] -propyl ] -phenyl ] -2-pyridinesulfonamide of formula EEE-4, or (3R or S, 6R or S) -N- [3- [1- (5, 6-dihydro-4-hydroxy-2-oxo-6-propyl-6-phenethyl-2H-pyran-3-yl) propyl ] phenyl ] -5- (trifluoromethyl) -2-pyridinesulfonamide.

5-trifluoromethyl-N- [3- (R or S) - [1- [ 4-hydroxy-2-oxo-6, 6-di-N-propyl-5, 6-dihydro-2H-pyran-3-yl ] -propyl ] phenyl ] -2-pyridinesulfonamide or (3R or S) -N- [3- [1- (5, 6-dihydro-4-hydroxy-2-oxo-6, 6-dipropyl-2H-pyran-3-yl) propyl ] phenyl ] -5- (trifluoromethyl) -2-pyridinesulfonamide of formula EEE-5.

Furthermore, the following compounds of the invention, which are prepared by the synthetic methods set forth herein, are also most preferred:

(3R) -N- [3- [1- (5, 6-dihydro-4-hydroxy-2-oxo-6, 6-dipropyl-2H-pyran-3-yl) propyl ] phenyl ] -5- (trifluoromethyl) -2-pyridinesulfonamide

(3R) -N- [3- [1- (5, 6-dihydro-4-hydroxy-2-oxo-6-propyl-6-phenethyl-2H-pyran-3-yl) propyl ] phenyl ] -5- (trifluoromethyl) -2-pyridinesulfonamide.

Description of the preferred embodiments

In the following preparations and examples and throughout:

DEG C is centigrade.

¹H-NMR is proton nuclear magnetic resonance spectrum.

¹³C-NMR is a carbon nuclear magnetic resonance spectrum.

δ is the chemical shift (parts per million) relative to TMS.

AlCl₃Is aluminum chloride.

Anal is analytical data.

Br is benzyl.

CBZ is benzyloxycarbonyl.

CDCl₃Is tritiated chloroform.

CD₃OD is tritiated methanol.

CH₂Cl₂Is methylene chloride.

cm^-1Is the reciprocal of a centimeter.

CuBr₂Is copper bromide.

DMSO is dimethyl sulfoxide.

DMSO_D6Is tritiated dimethyl sulfoxide.

EI MS is electron impact mass spectrometry.

EtOAc was ethyl acetate.

Et₃Al is triethylaluminum.

FAB MS is fast atom bombardment mass spectrometry.

HCl is hydrochloric acid.

H₂O is water.

HOBT is hydrated 1-hydroxybenzotriazole.

HRMS is high resolution mass spectrometry.

KOH is potassium hydroxide.

M is molar.

MeOH is methanol.

Me₂S is dimethyl sulfide.

mg is mg.

MgSO₄Is magnesium sulfate.

mL is mL.

mmHg is millimeter Hg.

MP is the melting point.

N is the equivalent (concentration).

NaCl is sodium chloride.

NaOH is sodium hydroxide.

NaH is sodium hydride.

NaHCO₃Is sodium bicarbonate.

Na₂CO₃Is sodium carbonate.

Na₂SO₄Is sodium sulfate.

NH₄Cl is ammonium chloride.

Pd/C is palladium-supported carbon.

R_fIs a chromatographic shift relative to the front of the solvent.

TFA is trifluoroacetic acid.

THF is tetrahydrofuran.

TMS is tetramethylsilane.

The following preparations and examples illustrate the invention:

preparation of 1 cyclopropyl- (3-nitrophenyl) methanone (formula A-2), see Table A.

To a 500 ml three-neck round-bottom flask with gas outlet and 250 ml isobaric addition funnel was added cyclopropylphenylketone of formula A-1 (30 ml) and cooled to-40 ℃. The addition funnel was charged with nitric acid (180 ml) which was added dropwise to the reaction mixture over 2 hours. The reaction mixture was stirred at-40 ℃ to 0 ℃ for another 3.5 hours and then poured into 500 ml of ice to terminate the reaction. The mixture was extracted with three portions of 150 ml ethyl acetate. The organic layers were combined, washed with two 250 ml portions of saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated to give 41.117 g of a yellow solid in orange oil. Recrystallization from 65 ml of methanol gave 20.664 g of the title product as pale yellow crystals.

The physical properties were as follows:

¹H NMR(CDCl₃)δ8.85，8.43，8.33，7.70，2.72，1.36-1.31，1.20-1.14ppm。

preparation of 2 cyclopropyl- (3-aminophenyl) methanone (formula A-3), see Table A.

A 500 ml Parr hydrogenation bottle was charged with 2.1 g of 10% platinum loaded carbon and a solution of the title product of preparation 1 (20.6 g) in 250 ml of methanol. The reaction mixture was shaken under 44psi hydrogen atmosphere for 50 minutes and then filtered twice through celite. The pale green solution was then concentrated to give 15.744 g of the title product as a green oil.

The physical properties were as follows:

¹H NMR(CDCl₃)δ7.42，7.30-7.23，6.88，3.83，2.63，1.24-1.19，1.05-0.99ppm。

preparation of 3N- [ 3-cyclopropyl methanone ] benzenesulfonamide (formula A-4), see Table A.

To a 500 ml three neck round bottom flask with nitrogen inlet was added the title product of preparation 2 (15.7 g) and 200 ml dichloromethane. Benzenesulfonyl chloride (12 ml) and pyridine (7.8 ml) were added, and the reaction mixture was stirred at room temperature for 45 minutes. The reaction was terminated by the addition of 10% hydrochloric acid (200 ml). The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated to give 28.638 g of an orange solid. Recrystallization from 75 ml of hot dichloromethane afforded the title product as a pink solid (22.264 g).

The physical properties were as follows:

MP 98-101℃.

¹H NMR(CDCl₃)δ7.81-7.73，7.62，7.55-7.35，2.60，1.30-1.25，1.10-1.03ppm.

¹³C NMR(CDCl₃)δ200.4，138.8，137.2，133.0，129.5，129.0，127.0，125.1，124.7，120.5，17.3，12.1ppm.

IR (mineral oil) 3239, 3222, 1653, 1449, 1339, 1259, 1176, 1165, 1093, 939, 687cm^-1。

Elemental analysis, found: c, 63.70; h, 5.01; n, 4.78.

MS(EI)m/e 301，206，160，141，77。

Measured values of high resolution mass spectrometry: 301.0772.

preparation of 4N- [ 3-cyclopropylmethanol ] benzenesulfonamide (formula A-5), see Table A.

To a 500 ml three neck round bottom flask with nitrogen inlet was added the title compound of preparation 3 (21.133 g), 200 ml tetrahydrofuran and 100 ml ethanol. The flask was cooled to 0 ℃ in an ice bath and sodium borohydride (10.6 g) was added in small portions over 20 minutes. The reaction mixture was stirred at room temperature for about 18 hours and then cooled to 0 ℃ in an ice bath. 10% hydrochloric acid (100 ml) was added dropwise over 45 minutes and the mixture was stirred at 0 ℃ for a further 1 hour. The reaction mixture was then extracted with three 100 ml portions of dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give 25.015 g of a pale yellow oil. Column chromatography on 150 g silica gel (eluting with 50-65% diethyl ether in hexanes then 2-5% methanol in dichloromethane) afforded 18.692 g of the title product as a white solid.

The physical properties were as follows:

MP 112-114℃.

¹H NMR(CDCl₃)δ7.69，7.42，7.32，7.25，7.12，7.05-6.96，3.82，3.19，1.03-0.94，0.51-0.46，0.39-0.29，0.19-0.16ppm.

¹³C NMR(DMSO)δ147.0，139.7，137.4，132.9，129.3，128.6，126.8，121.8，118.5，117.8，75.0，19.2，3.1，2.3ppm.

IR (mineral oil) 3523, 3249, 1449, 732cm^-1。

Elemental analysis, found: c, 63.41; h, 5.79; and N, 4.86.

MS(EI)m/e 303，275，262，77。

Measured values of high resolution mass spectrometry: 303.0935.

preparation of 54-hydroxy-10-propyl-2H-cycloocta [ b ] pyran-2-one (formula A-7), see Table A.

To a 250 ml three-neck round bottom flask with nitrogen inlet and 125 ml isobaric addition funnel were added diisopropylamine (3.6 ml) and 15 ml tetrahydrofuran. The charging funnel is filled with 4-hydroxy-2H-cycloocta [ b ] of formula A-6]Pyran-2-one (2.292 g) and 35 ml of tetrahydrofuran. The flask was cooled to 0 ℃ in an ice bath, n-butyllithium (16.3 ml of a 1.6M solution in hexane) was added dropwise over 3 minutes, and the reaction mixture was stirred at 0 ℃ for another 15 minutes. 4-hydroxy-2H-cycloocta [ b ] in THF was added dropwise over 35 minutes]Pyran-2-one solution and the reaction mixture was stirred at 0 ℃ for a further 25 minutes. Hexamethylphosphoramide (4 ml) was added in one portion and iodopropane (1.3 ml) was added dropwise over 2 minutes. The reaction mixture was allowed to warm to room temperature and stirred for about 18 hours. 30 ml of 10% hydrochloric acid was added, and the aqueous layer was separated. The pH of the aqueous layer was lowered from 10 to 2 with concentrated HCl and the aqueous layer was extracted with two 50ml portions of dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give an orange oil which was partitioned between 100ml 1N NaOH and 50ml diethyl ether. The pH of the aqueous layer was adjusted from 14 to 1 with concentrated HCl and then two 50ml portions of CH were added₂Cl₂And (4) extracting. The organic layers were then combined and MgSO₄Drying and concentration gave an orange oil which was diluted with 100ml of diethyl ether and washed with three 25 ml portions of 10% hydrochloric acid. The organic layer was then dried over magnesium sulfate, filtered, and concentrated to give 1.829 g of an orange solid. Column chromatography on 100 g silica gel (eluting with 0-10% methanol in dichloromethane) afforded 1.358 g of a light orange solid. Further column chromatography on 150 g silica gel (eluting with 10% diethyl ether and 1% acetic acid in dichloromethane) afforded 0.705 g of the title product as a yellow solid.

The physical properties were as follows:

¹H NMR(CDCl₃)δ11.38，5.68，3.02-2.93，2.20，1.98-1.82，1.73-1.58，1.46-1.25，1.24-1.08，0.89ppm.

¹³C NMR(CDCl₃)δ172.3，168.3，165.3，114.8，89.7，38.6，36.0，33.3，30.1，27.2，25.5，22.9，21.0，13.9ppm.

IR (mineral oil) 1679, 1641, 1617, 1492cm^-1。

Elemental analysis, found: c, 70.90; h, 8.36.

MS(EI)m/e 236，208，166。

Measured values of high resolution mass spectrometry: 236.1414.

example 1N- [3- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-10-propyl-2H-cycloocta [ b ] pyran-3-yl) methyl ] phenyl ] benzenesulfonamide (formula A-8), see Table A.

To a 100 ml three-neck round-bottom flask with a 35 ml isobaric addition funnel containing 3A molecular sieve, reflux condenser and nitrogen inlet was added the title compound of preparation 5 (0.196 g), p-toluenesulfonic acid (0.040 g) and 30 ml dichloromethane. The title product of preparation 4 (0.252 g) was added and the reaction mixture was heated to reflux for 2 hours and then stirred at room temperature for an additional 1 hour. The reaction mixture was diluted with 20 ml of dichloromethane and washed with 60 ml of 1: 1 saturated sodium bicarbonate and brine, 30 ml of water and 30 ml of brine. The aqueous layers were combined and extracted with 30 ml of dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give 0.576 g of crude product. Column chromatography on 35 g silica gel (eluting with 20-80% diethyl ether in hexanes) afforded 0.096 g of the title compound as a white solid.

The physical properties were as follows:

melting point 87-90 deg.C (decomposition).

MS(EI)m/e521，493，380，275，262，249，144，77。

Measured values of high resolution mass spectrometry: 521.2236.

examples 2 to 7

The following other compounds of the invention were prepared according to a similar procedure as described above:

2) 4-cyano-N- [3- (R or S) - [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo- (R or S) -10-propyl-2H-cycloocta [ b ] pyran-3-yl) methyl ] phenyl ] benzenesulfonamide

3) 4-cyano-N- [3- (R or S) - [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro- (R or S) -10-cyclopropylmethyl-4-hydroxy-2-oxo-2H-cycloocta [ b ] pyran-3-yl) methyl ] phenyl ] benzenesulfonamide

4) 4-cyano-N- [3- (R or S) - [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro- (R or S) -10-benzyl-4-hydroxy-2-oxo-2H-cycloocta [ b ] pyran-3-yl) methyl ] phenyl ] benzenesulfonamide

5) N- [3- (R or S) - [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo- (R or S) -10-propyl-2H-cycloocta [ b ] pyran-3-yl) methyl ] phenyl ] -1-methyl-1H-imidazole-4-sulfonamide

6) N- [3- (R or S) - [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro- (R or S) -10-cyclopropylmethyl-4-hydroxy-2-oxo-2H-cycloocta [ b ] pyran-3-yl) methyl ] phenyl ] -1-methyl-1H-imidazole-4-sulfonamide

7) Preparation of 6 (3-benzaldehyde) -carbamic acid phenylmethyl ester (formula B-2) from N- [3- (R or S) - [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro- (R or S) -10-benzyl-4-hydroxy-2-oxo-2H-cycloocta [ B ] pyran-3-yl) methyl ] phenyl ] -1-methyl-1H-imidazole-4-sulfonamide is shown in Table 8.

A flask with nitrogen inlet was charged with sodium bicarbonate (10.4 g) in 200 mL THF and 200 mL water, followed by m-aminobenzaldehyde of formula B-1 (10.0 g) and benzyl chloroformate (13.6 mL). The mixture was stirred at room temperature for 40 minutes. Diethyl ether was then added and the organic layer was separated, washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated to give a brown oil. Column chromatography on 300 g silica gel gave 16.3 g of the title compound as a pale yellow oil. The analytical sample was crystallized from ethyl acetate-hexane.

The physical properties were as follows:

MP 100-104℃.

¹H NMR(CDCl₃)δ9.98，7.91，7.69，7.59，7.43-7.35，6.83，5.23ppm.

¹³C NMR(CDCl₃)δ191.8，153.0，138.6，137.1，135.6，129.7，128.6，128.4，128.3，124.6，124.2，119.1，67.2ppm.

IR (mineral oil) 3269, 2954, 2925, 2868, 2855, 1729, 1682, 1597, 1560, 1465, 1455, 1326, 1294, 1237, 1229, 1170, 1155, 1048, 695cm-1.

Elemental analysis, found: c, 70.74; h, 5.14; n, 5.33.

MS(EI)m/e 255，211，91。

Measured values of high resolution mass spectrometry: 255.0900.

preparation of 7[3- (1-hydroxy-3-methylbutyl) phenyl]Phenyl methyl carbamate (formula B-3, wherein R₁Is isobutyl) as shown in table 8.

A flask with nitrogen inlet was charged with the title compound of preparation 6 (4.0 g) and 60 mL of anhydrous tetrahydrofuran. The mixture was cooled to 0 ℃ and isobutylmagnesium chloride (17.2 ml) was added. The reaction mixture was then warmed to room temperature and stirred for 2 hours. The reaction was quenched by the addition of saturated ammonium chloride and the mixture was partitioned between ether and water. The organic layer was washed with water and concentrated to give 5.78 g of a pale yellow oil. The crude product was crystallized from ethyl acetate-hexane to give 4.13 g of the title compound as white crystals.

The physical properties were as follows:

MP 73-77℃.

¹H NMR(CDCl₃)δ7.41-7.33，7.25，7.05，6.74，5.19，4.73-4.65，1.91，1.73-1.65，1.47，0.93ppm.

IR (liquid paraffin) 3400, 3249, 3085, 2953, 2925, 2869, 2855, 1697, 1615, 1602, 1563, 1450, 1283, 1245, 1177, 1067, 1017, 798, 773, 740, 696cm^-1.

Elemental analysis, found: c, 72.58; h, 7.25; and N, 4.55.

MS(EI)m/z 313，257，213，91。

Preparation of 8[3- [1- (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ]]Pyran-3-yl) -3-methylbutyl]Phenyl radical]Phenyl methyl carbamate (formula B-5, wherein R₁Is isobutyl) as shown in table B.

To a 200 ml three-neck round bottom flask with dean-stark trap and nitrogen inlet was added p-toluenesulfonic acid (0.66 g) and toluene (100 ml) and warmed to reflux to collect 20 ml in dean-stark trap. The reaction mixture was cooled to room temperature and the trap was evacuated. To the reaction mixture were added 4-hydroxy-2H-cycloocta [ B ] pyran-2-one of formula B-4 (2.48 g) and the title compound of preparation 7 (4.0 g), followed by heating under reflux for 6.5 hours. The reaction mixture was left at room temperature overnight and then poured into 350 ml of ethyl acetate and washed with two portions of 25 ml of water, 25 ml of saturated sodium bicarbonate and 25 ml of water. The organic layer was concentrated to give 7.9 g of a yellow oil. Column chromatography on 150 g silica gel (eluting with 10-50% ethyl acetate in hexanes) afforded 0.217 g of the title product as a beige foam.

The physical properties were as follows:

melting point 73-78 deg.C (decomposition).

¹H NMR(CDCl₃)δ7.38-7.25，7.13，6.72，6.01，5.19，4.48，2.58，2.41，1.93，1.74，1.62-1.33，0.96ppm.

Preparation of 9(R or S) - [3- [1- (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ]]Pyran-3-yl) -3-methylbutyl]Phenyl radical]Phenyl methyl carbamate (formula B-5, wherein R₁Is isobutyl) as shown in table B.

Stock solutions (32 mg/ml) of the title compound of preparation 8 in 30% isopropanol and 0.1% acetic acid in hexane were chromatographed on a 2.0X 25cm (R, R) Whelk-O1 column, injecting 2 ml each time using an automated chromatography system. The eluate was monitored at 310nm with a flow rate of 10 ml/min, and the appropriate fractions from multiple injections were combined and concentrated in vacuo to give a snow-white solid.

The physical properties were as follows:

the residence time of the title compound was 18.8 minutes.

Preparation of 10(R or S) - [3- [1- (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ]]Pyran-3-yl) -3-methylbutyl]Phenyl radical]Phenyl methyl carbamate (formula B-5, wherein R₁Is isobutyl) as shown in table B.

The title compound of preparation 8 was isolated as described above for preparation 9.

The physical properties were as follows:

the residence time of the title compound was 22.1 minutes.

Preparation of 11(R or S) -3- [1- (3-aminophenyl) -3-methylbutyl]-5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2H-cycloocta [ b ] ]Pyrones (formula B-6, wherein R₁Is isobutyl) as shown in table B.

A flask equipped with a nitrogen inlet was charged with a solution of the title compound of preparation 9 (0.637 g) in 6 mL of ethanol. Cyclohexene (6 ml) and 10% palladium on carbon (0.16 g) were added and the reaction mixture was heated to reflux for 2 hours. The mixture was filtered through celite and concentrated to give 0.205 g of the title compound as a beige foam.

The physical properties were as follows:

MP158-162℃

MS(EI)m/z 355，312，299，161，106

measured values of high resolution mass spectrometry: 355.2144.

example 8(R or S) -N- [3- [1- (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ]]Pyran-3-yl) -3-methylbutyl]Phenyl radical]-1-methyl-1H-imidazole-4-sulfonamide (formula B-7, wherein R is₁Is isobutyl, R₂Is 1-methylimidazole) as shown in table B.

A flask equipped with a nitrogen inlet was charged with the title compound of preparation 11 (0.095 g), 1-methylimidazole-4-sulfonyl chloride (0.048 g), and 5 mL of dichloromethane. Pyridine (0.53 ml) was added, and then the reaction mixture was stirred at room temperature for about 18 hours. The precipitate formed was filtered to give 0.097 g of a white solid. Recrystallization from methanol-chloroform gave 0.065 g of the title compound as a white powder.

The physical properties were as follows:

MP 207-210℃

¹H NMR(CDCl₃)δ10.4，10.0，7.70，7.11，7.05，6.92，4.21，3.64，2.54，2.16，1.62，1.53，1.43，1.34，0.85ppm.

MS(EI)m/z 499，456，443，306，251，160，145

measured values of high resolution mass spectrometry: 499.2151.

Preparation of 12(R or S) -3- [1- (3-aminophenyl) -3-methylbutyl]-5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2H-cycloocta [ b ]]Pyrones (formula B-6, wherein R₁Is isobutyl) as shown in table B.

Prepared according to the general procedure for preparation 11 with non-critical changes except that the title product of preparation 10 was used instead of the title product of preparation 9 to give 0.189 g of the title compound as a grey solid.

The physical properties were as follows:

MS(EI)m/z 355，312，299，161。

measured values of high resolution mass spectrometry: 355.2135.

example 9(R or S) -N- [3- [1- (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ]]Pyran-3-yl) -3-methylbutyl]Phenyl radical]-1-methyl-1H-imidazole-4-sulfonamide (formula B-7, wherein R is₁Is isobutyl, R₂Is 1-methylimidazole) as shown in table B.

Following the general method of example 8 and making non-critical changes, except substituting the title product of preparation 12 for the title product of preparation 11, 0.047 g of the title compound was obtained as a white solid.

The physical properties were as follows:

¹H NMR(CDCl₃)δ10.45，10.06，7.70，7.11，7.05，6.94，4.21，3.64，2.55，2.16，1.62，1.53，1.42，1.35，0.86ppm.

MS(EI)m/z 499，456，443，354，306，160，145

measured values of high resolution mass spectrometry: 499.2146.

preparation of 13[3- (cyclopropyl-hydroxymethyl) -phenyl ] methanol (formula C-2), see Table C.

To a solution of 6.5 ml of 3-bromobenzyl alcohol of formula C-1 in 900 ml of tetrahydrofuran, 46 ml of a 1.4M solution of methyllithium in diethyl ether were added at-78 ℃ under a nitrogen atmosphere. The solution was stirred for 20 minutes, then 66 ml of a 1.6M solution of n-butyllithium in hexane were added. The solution was stirred for 25 minutes, then 6 ml of cyclopropanecarboxaldehyde was added. The solution was stirred for 1.5 hours, warmed to 0 ℃ and stirred for 40 minutes. The solution was then warmed to room temperature and stirred for 30 minutes. Finally the solution was heated to reflux for 1 hour. The solution was poured into 800 ml of water, acidified with concentrated hydrochloric acid and then adjusted to a pH of about 6 with 5% aqueous hydrochloric acid. The layers were separated and the aqueous layer was extracted with two portions of ethyl acetate. The combined organics were dried (sodium sulfate) and concentrated to give a yellow oil which was chromatographed on 900 g 230-400 mesh silica gel (2: 1 ethyl acetate: hexane) to give 6.61 g (68%) of the desired alcohol as a yellow oil.

The physical properties were as follows:

¹H NMR(CDCl₃)δ7.41-7.26，4.67，3.99-3.96，2.18，1.28-1.14，0.68。

preparation of 143- [ cyclopropyl [3- [ hydroxymethyl ] phenyl ] methyl ] -5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2H-cycloocta [ b ] pyran-2-one (formula C-3), see Table C.

To a solution of 501 mg of the title product of preparation 13 in 50 ml of dichloromethane in the presence of 3A molecular sieve and nitrogen were added 492 mg of 4-hydroxy-5, 6, 7, 8, 9, 10-hexahydrocycloocta [ b ] pyran-2-one, followed by 49 mg of p-toluenesulfonic acid monohydrate. The solution was heated to reflux for 2 hours, then 105 mg of p-toluenesulfonic acid monohydrate was added and heating was continued for 1 hour. The solution was concentrated in vacuo to give a white foam which was treated with water, then 1N potassium hydroxide and extracted with one portion of ethyl acetate. The organic layer was washed with one portion of 1N potassium hydroxide. The combined aqueous layers were acidified with 5% aqueous hydrochloric acid and extracted with three portions of ethyl acetate. The combined organics were dried over sodium sulfate and concentrated in vacuo to give a yellow oil which was chromatographed on 180 g 230-400 mesh silica gel (2: 1 ethyl acetate: hexane) to give 436 mg of the desired benzyl alcohol as a white foam.

The physical properties were as follows:

melting point of 65-70 deg.C

¹H NMR(CDCl₃)δ7.25-7.03，4.36，3.70-3.67，2.41-2.37，2.24-2.23，1.53-1.50，1.35-1.05，0.54-0.43，0.42-0.21，0.07-0.02。

Preparation of 153- [ cyclopropyl [3- [ bromomethyl ] phenyl ] methyl ] -5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2H-cycloocta [ b ] pyran-2-one; and 3- [ cyclopropyl [3- [ chloromethyl ] phenyl ] methyl ] -5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2H-cycloocta [ b ] pyran-2-one (formula C-4, 5), see Table C.

To a solution of 1.01 g of the title product of preparation 14 in 70 ml of dichloromethane were added 2.00 g of triphenylphosphine and 2.58 g of carbon tetrabromide in that order at 0 ℃ under a nitrogen atmosphere. The solution was stirred for 1 hour and then poured into brine. The layers were separated and the aqueous layer was extracted with three portions of ethyl acetate. The combined organics were dried over sodium sulfate and concentrated to give a yellow oil which was triturated with ether. The solid was filtered off, the filtrate was concentrated and purified by chromatography on 180 g of 230-400 mesh silica gel (1: 1 hexane: ethyl acetate) to give 374 mg of a mixture of bromide and chloride of the desired title product. The solid isolated from the filtrate was chromatographed as described above to give an additional 699 mg of the title product as a mixture of chloride and bromide.

The physical properties were as follows:

mass Spectrometry M/e 418, 416 (M for bromine)⁺) 388, 374, 372 (M for chlorine)⁺)，337，246，233，220，207，195，179，153，143，129。

Preparation of 163- [ cyclopropyl [3- [ (phenylthio) methyl ] phenyl ] methyl ] -5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2H-cycloocta [ b ] pyran-2-one (formula C-6), see Table C.

To a solution of 138 mg of the title product of preparation 15 in 5 ml of dichloromethane were added 0.04 ml of thiol phenol and 0.17 ml of diisopropylethylamine in succession. The solution was heated to reflux for 1 hour and then left overnight at room temperature. The solution was poured into brine and treated with 5% aqueous hydrochloric acid. The layers were separated and the aqueous layer was extracted with three portions of ethyl acetate. The combined organics were dried over sodium sulfate and concentrated to give a yellow oil which was chromatographed on 80 g of 230-400 mesh silica gel (2: 1 hexane: ethyl acetate) to give 111 mg of the desired sulfide as a white foam.

The physical properties were as follows:

melting point 137-139 DEG C

Mass spectrum M/e 446 (M)⁺)，418，337，295，233，220，207，185，145，128，109，91，79，55，40。

Example 103- [ cyclopropyl [3- [ (phenylsulfonyl) methyl ] phenyl ] methyl ] -5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2H-cycloocta [ b ] pyran-2-one (formula C-7), see Table C.

To a solution of 119 mg of the title product of preparation 16 in 5 ml of tetrahydrofuran and 5 ml of methanol at 0 ℃ was added a solution of 279 mg of oxone in 5 ml of water. The solution was stirred for 2.5 hours, then warmed to room temperature and stirred for 2 hours. The solution was filtered and the solid was washed with chloroform. The filtrate was diluted with water, the layers were separated, and the aqueous layer was extracted with three portions of ethyl acetate. The combined organics were dried over sodium sulfate and concentrated to give a clear oil which was chromatographed on 80 g of 230-400 mesh silica gel (1: 1 hexane: ethyl acetate) to give 78 mg of the title product as a white foam.

The physical properties were as follows:

melting point of 80-85 deg.C

Mass spectrum M/e 479 (M)⁺+1)，463，450，391，337，309，207，161，149，127，115，71，57，41。

Accurate measured mass: 479.1885.

examples 11 to 39

The following compounds of the invention were prepared according to a synthetic route analogous to that described above:

11)3- [ cyclopropyl [3- [ (4-cyanophenylsulfonyl) methyl ] phenyl ] methyl ] -5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2H-cycloocta [ b ] pyran-2-one

The starting 4-cyanobenzenethiol is prepared from 4-cyanobenzenesulfonyl chloride according to the general literature procedure (Wagner, A.W. Ber Deutsch Chem Ges, 99: 375 (1996)).

The physical properties were as follows:

melting point 100-

Mass Spectrometry M/e 504 (M)⁺+1)，337，247，207，143。

Accurate measured mass: 504.1843.

12)3- [ cyclopropyl [3- [ (4-fluorophenylsulphonyl) methyl ] phenyl ] methyl ] -5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2H-cycloocta [ b ] pyran-2-one

The physical properties were as follows:

MP 95-100℃

¹H NMR(CDCl₃)δ7.61-7.57，7.40-7.37，7.27-7.20，7.13-7.07，7.02-6.99，6.42，4.30，3.88-3.85，2.64-2.61，2.51-2.47，1.83-1.40，1.40-1.27，0.69-0.58，0.48-0.43，0.19-0.14.

13)3- [ cyclopropyl [3- [ (4-methylphenylsulfonyl) methyl ] phenyl ] methyl ] -5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2H-cycloocta [ b ] pyran-2-one

The physical properties were as follows:

MP 100-105℃

¹H NMR(CDCl₃)δ7.37-7.34，7.25-7.22，7.17-7.05，6.86-6.84，4.15，3.60-3.58，2.52-2.42，2.42-2.30，2.28，1.70-1.14，0.57-0.32，0.32-0.20，0.06-(-)0.16.

14)3- [ cyclopropyl [3- [ (4-carboxyphenylsulfonyl) methyl ] phenyl ] methyl ] -5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2H-cycloocta [ b ] pyran-2-one

The physical properties were as follows:

melting point of 90-95 deg.C

Mass Spectrometry M/e 523 (M)⁺+1)，337，247，207，143。

Accurate measured mass: 523.1785.

15)3- [ cyclopropyl [3- [ (2- (1-methylimidazolyl) sulfonyl) methyl ] phenyl ] methyl ] -5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2H-cycloocta [ b ] pyran-2-one

The physical properties were as follows:

MP 95-103℃

¹H NMR(CDCl₃)δ7.36-7.34，7.29-7.27，7.14，7.06-7.03，6.98(8，1H)，6.86，4.30，3.73-3.70，3.20，2.67-2.54，1.90-1.36，0.71-0.50，0.46-0.33，0.18-0.03.

16)3- [ cyclopropyl [3- [ (2-pyrimidinylsulfonyl) methyl ] phenyl ] methyl ] -5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2H-cycloocta [ b ] pyran-2-one

17)3- [ cyclopropyl [3- [ (2-pyridylsulfonyl) methyl ] phenyl ] methyl ] -5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2H-cycloocta [ b ] pyran-2-one

18)3- [ cyclopropyl [3- [ (1-methyl-4-imidazolylsulfonyl) methyl ] phenyl ] methyl ] -5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2H-cycloocta [ b ] pyran-2-one

19)3- [ cyclopropyl [3- [ (5-cyano-2-pyridylsulfonyl) methyl ] phenyl ] methyl ] -5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2H-cycloocta [ b ] pyran-2-one

20)3- [ cyclopropyl [3- [ (2-benzimidazolylsulfonyl) methyl ] phenyl ] methyl ] -5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2H-cycloocta [ b ] pyran-2-one

21)3- [ cyclopropyl [3- [ (2-quinolinylsulfonyl) methyl ] phenyl ] methyl ] -5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2H-cycloocta [ b ] pyran-2-one

22)3- [ cyclopropyl [3- [ (4-cyanophenylsulfonyl) methyl ] phenyl ] methyl ] -4-hydroxy-coumarin

23)3- [ cyclopropyl [3- [ (2-pyridylsulfonyl) methyl ] phenyl ] methyl ] -4-hydroxy-coumarin

24)3- [ cyclopropyl [3- [ (1-methyl-4-imidazolylsulfonyl) methyl ] phenyl ] methyl ] -4-hydroxy-coumarin

25)3- [ cyclopropyl [3- [ (5-cyano-2-pyridylsulfonyl) methyl ] phenyl ] methyl ] -4-hydroxy-coumarin

26)3- [ cyclopropyl [3- [ (2-benzimidazolylsulfonyl) methyl ] phenyl ] methyl ] -4-hydroxy-coumarin

27)3- [ cyclopropyl [3- [ (2-quinolinylsulfonyl) methyl ] phenyl ] methyl ] -4-hydroxy-coumarin

28)3- [ cyclopropyl [3- [ (4-cyanophenylsulfonyl) methyl ] phenyl ] methyl ] -4-hydroxy-6- [1- (phenylmethyl) propyl ] -2H-pyran-2-one

29)3- [ cyclopropyl [3- [ (2-pyridylsulfonyl) methyl ] phenyl ] methyl ] -4-hydroxy-6- [1- (phenylmethyl) propyl ] -2H-pyran-2-one

30)3- [ cyclopropyl [3- [ (1-methyl-4-imidazolylsulfonyl) methyl ] phenyl ] methyl ] -4-hydroxy-6- [1- (benzyl) propyl ] -2H-pyran-2-one

31)3- [ cyclopropyl [3- [ (5-cyano-2-pyridylsulfonyl) methyl ] phenyl ] methyl ] -4-hydroxy-6- [1- (phenylmethyl) propyl ] -2H-pyran-2-one

32)3- [ cyclopropyl [3- [ (2-benzimidazolylsulfonyl) methyl ] phenyl ] methyl ] -4-hydroxy-6- [1- (phenylmethyl) propyl ] -2H-pyran-2-one

33)3- [ cyclopropyl [3- [ (2-quinolinylsulfonyl) methyl ] phenyl ] methyl ] -4-hydroxy-6- [1- (phenylmethyl) propyl ] -2H-pyran-2-one

34)3- [ cyclopropyl [3- [ (4-cyanophenylsulfonyl) methyl ] phenyl ] methyl ] -4-hydroxy-6- (2-phenylethyl) -6- (1-propyl) -5, 6-dihydro-2H-pyran-2-one

35)3- [ cyclopropyl [3- [ (2-pyridylsulfonyl) methyl ] phenyl ] methyl ] -4-hydroxy-6- (2-phenylethyl) -6- (1-propyl) -5, 6-dihydro-2H-pyran-2-one

36)3- [ cyclopropyl [3- [ (1-methyl-4-imidazolylsulfonyl) methyl ] phenyl ] methyl ] -4-hydroxy-6- (2-phenylethyl) -6- (1-propyl) -5, 6-dihydro-2H-pyran-2-one

37)3- [ cyclopropyl [3- [ (5-cyano-2-pyridylsulfonyl) methyl ] phenyl ] methyl ] -4-hydroxy-6- (2-phenylethyl) -6- (1-propyl) -5, 6-dihydro-2H-pyran-2-one

38)3- [ cyclopropyl [3- [ (2-benzimidazolylsulfonyl) methyl ] phenyl ] methyl ] -4-hydroxy-6- (2-phenylethyl) -6- (1-propyl) -5, 6-dihydro-2H-pyran-2-one

39)3- [ cyclopropyl [3- [ (2-quinolinylsulfonyl) methyl ] phenyl ] methyl ] -4-hydroxy-6- (2-phenylethyl) -6- (1-propyl) -5, 6-dihydro-2H-pyran-2-one

Preparation of 175, 6-dihydro-4-hydroxy-6-phenethyl-6-propyl-2H-pyran-2-one (formula D-1: R)₁Is phenethyl, R₂Is propyl) as shown in table D.

To a suspension of sodium hydride (567 mg, 60% dispersion in mineral oil) in THF (30 ml) was added methyl acetoacetate (1.47 ml) at 0 ℃. After 15 minutes, n-butyllithium (8.5 mL of a 1.6M solution in hexanes) was added dropwise and the reaction stirred for 15 minutes. 1-phenyl-3-hexanone (2.0 g) was then added to the reaction mixture in one portion using a syringe. The reaction was stirred for an additional 1 hour and then poured into a saturated ammonium chloride solution. Extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated in vacuo. The resulting material was dissolved in THF (25 ml) and 0.1N sodium hydroxide solution (113 ml) was added. After stirring for 3 hours, the mixture was extracted with ethyl acetate (1 ×). The aqueous layer was adjusted to pH3 with hydrochloric acid and then extracted with dichloromethane (3 × 25 ml), dried over anhydrous magnesium sulfate and evaporated to give the title compound as a white solid.

The physical properties were as follows:

¹H NMR(300MHz，CDCl₃)δ0.96，1.21，1.48，1.72，1.98，2.73，3.43，7.15-7.32。

elemental analysis, found: c, 73.77; h, 7.96.

Preparation of 184-hydroxy-3- [1- (3-nitrophenyl) propyl]-5, 6-dihydro-6-phenethyl-6-propyl-2H-pyran-2-one (formula D-4: R)₁Is phenethyl, R₂Is propyl, R₃Is ethyl) in table D.

To the title product of preparation 17 (formula D-1: R) at 0 deg.C₁Is phenethyl, R₂Is propyl) (1 g) and 3-nitrobenzaldehyde (formula D-2) (581 mg) in dry THF is added in one portion to solid aluminium trichloride (1.0 g). The cold bath was removed and the yellow solution was stirred at room temperature for 2 hours. By adding solid Na₂CO₃-10H₂The reaction was quenched with O (2.2 g) and stirred vigorously for 5 minutes. The mixture was filtered through celite with ether and the filtrate evaporated to dryness in vacuo. (ii) reacting the benzylidene intermediate of formula D-3 with CuBr-Me₂S (237 mg) was dissolved in anhydrous THF, and Et was added dropwise over 5 minutes at room temperature₃Al solution (4.23 ml, 1M solution in hexane). When the reaction was complete (monitored by thin layer chromatography), water was added to stop the reaction and the reaction mixture was transferred to a separatory funnel with diethyl ether. The aqueous layer was extracted with ether (3 × 15 ml) and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo to give an oil. Flash chromatography on silica gel with hexane/ethyl acetate (3: 1) gave 1.1 g of the title product as a pale yellow foam.

The physical properties were as follows:

¹h NMR is complicated by the presence of diastereomers.

¹H NMR(300MHz，CD₃OD)δ0.93，1.37，1.74，1.82-2.14，2.29，2.52-2.71，4.19，6.98-7.24，7.44，7.72，8.02，8.26。

Preparation 193- [ cyclopropyl- (3-nitrophenyl) methyl]-4-hydroxy-5, 6-dihydro-6-phenethyl-6-propyl-2H-pyran-2-one (formula D-4: R)₁Is phenethyl, R₂Is propyl, R₃Is cyclopropyl) as shown in table D.

To the title product of preparation 17 (formula D-1: R) at 0 deg.C₁Is phenethyl, R₂Is propyl) (1 g) and 3-nitrobenzaldehyde (formula D-2) (581 mg) in dry THF is added in one portion to solid aluminium trichloride (1.0 g). The cold bath was removed and the yellow solution was stirred at room temperature for 2 hours. By adding solid Na₂CO₃-10H₂The reaction was quenched with O (2.2 g) and stirred vigorously for 5 minutes. The mixture was filtered through celite with ether and the filtrate evaporated to dryness in vacuo. (ii) reacting the benzylidene intermediate of formula D-3 with CuBr-Me₂S (237 mg) was dissolved in anhydrous THF and cooled to-78 ℃. A solution of cyclopropylmagnesium bromide (15.6 ml of a 0.25M solution in THF) was added dropwise over 10 minutes and the reaction mixture was stirred for 30 minutes. Water was added to terminate the reaction, and 1N hydrochloric acid was added to neutralize it. The reaction mixture was transferred to a separatory funnel with ether, the aqueous layer was extracted with ether (3 × 15 ml), and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo to give an oil. Flash chromatography on silica gel with hexane/ethyl acetate (3: 1) gave 0.9 g of the title product as a pale yellow foam.

The physical properties were as follows:

¹h NMR is complicated by the presence of diastereomers.

¹H NMR(300MHz，CD₃OD)δ0.25，0.53，0.74，0.94，1.41，1.68-2.13，2.57-2.72，3.38，7.04-7.23，7.46，7.82，8.03，8.30。

Preparation of 203- [1- (3-aminophenyl) propyl]-4-hydroxy-5, 6-dihydro-6-phenethyl-6-propyl-2H-pyran-2-one (formula D-5: R)₁Is phenethyl, R₂Is propyl, R₃Is ethyl) in table D.

To the title product of preparation 18 (formula D-4: R) at room temperature₁Is phenethyl, R₂Is propyl, R₃Is ethyl) (350 mg) to a solution in methanol was added 10% Pd/C (35 mg) and ammonium formate (521 mg). The resulting mixture was stirred for 2 hours and then filtered through celite with dichloromethane. The filtrate was evaporated in vacuo and the resulting residue triturated with dichloromethane (3X 10 mL). The combined organic solutions were filtered and evaporated in vacuo to give 325 mg of the title product as a pale yellow foam.

The physical properties were as follows:

¹h NMR is complicated by the presence of diastereomers.

¹H NMR(300MHz，CDCl₃)δ0.89，1.40，1.64-2.07，2.20，2.62，3.94，6.54，6.72-7.25。

In a similar manner to prepare R₁Is propyl, R₂Is propyl and R₃A compound of formula D-5 which is ethyl or tert-butyl.

Wherein R is₁And R₂Is propyl and R₃The physical properties of the compound of formula D-5 which is ethyl are as follows:

¹H NMR：0.9，1.3，1.5-1.8，2.0，2.2，2.5，3.9，4.5，6.5，6.8，7.0ppm。

TLC R_f: 0.32 (10% ethyl acetate in dichloromethane).

EXAMPLE 404 cyano-N- [3- [1- (4-hydroxy-2-oxo-6-phenethyl-6-propyl-5, 6-dihydro-2H-pyran-3-yl) propyl ]Phenyl radical]Benzenesulfonamides (formula D-6: R)₁Is phenethyl, R₂Is propyl, R₃Is ethyl, R₄Is 4-cyanophenyl) as shown in table D.

Preparation 20 of the title product (formula D-5: R) was prepared at room temperature using syringe₁Is phenethyl, R₂Is propyl, R₃Is ethyl) (30 mg) and wherein R₄Is a cyanobenzeneTo a solution of 4-cyanobenzenesulfonyl chloride of formula D-7 (16.1 mg) in dichloromethane (1 ml) was added pyridine (13. mu.l). The resulting solution was stirred for 3 hours and the starting amine was consumed. The mixture was flash chromatographed on silica gel with 5% ethyl acetate in dichloromethane to give 21 mg of the title product as a white foam.

The physical properties were as follows:

¹h NMR is complicated by the presence of diastereomers.

¹H NMR(300MHz，CDCl₃)δ0.6-1.1，1.2-2.2，2.4-2.7，3.86-4.01，6.89-7.45，7.66-7.92。

HRMS found: 559.2267.

EXAMPLE 41N- [3- [1- (4-hydroxy-2-oxo-6-phenethyl-6-propyl-5, 6-dihydro-2H-pyran-3-yl) -propyl]Phenyl radical]-1-methyl-1H-imidazole-4-sulfonamide (formula D-6: R)₁Is phenethyl, R₂Is propyl, R₃Is ethyl, R₄Is 1-methylimidazol-4-yl) as shown in table D.

Using the general sulfonylation procedure of example 40, from the amine of preparation 20 (formula D-5: R)₁Is phenethyl, R₂Is propyl, R₃Is ethyl) and wherein R₄1-Methylimidazol-4-sulfonyl chloride of formula D-7, which is 1-methylimidazol-4-yl the title compound is prepared and flash chromatographed using 4% methanol in ethyl acetate to give the title compound as a beige amorphous solid.

The physical properties were as follows:

¹h NMR is complicated by the presence of diastereomers and tautomerism.

¹H NMR(300MHz，CDCl₃)δ0.75-0.96，1.17-1.43，1.45-2.11，2.43-2.68，3.24，3.64，3.94，6.72-7.51。

HRMS found: 538.2383.

EXAMPLE 42N- [3- [1- (4-hydroxy-2-oxo-6-phenethyl-6-propyl-5, 6-dihydro-2H-pyran-3-yl) -propyl]Phenyl radical]-8-quinolinesulfonamides (formula D-6: R)₁Is phenethyl, R₂Is propyl, R₃Is ethyl, R₄Is quinolin-8-yl) as shown in Table D.

Using the general sulfonylation procedure of example 40, from the amine of preparation 20 (formula D-5: R)₁Is phenethyl, R₂Is propyl, R₃Is ethyl) and wherein R₄8-quinolinesulfonyl chloride of formula D-7 being quinolin-8-yl the title compound was prepared and flash chromatographed using 5% ethyl acetate in dichloromethane to give the title compound as a white amorphous solid.

The physical properties were as follows:

¹h NMR is complicated by the presence of diastereomers and tautomerism.

¹H NMR(300MHz，CD₃OD)δ0.66，0.90，1.17-1.44，1.58-2.03，2.38-2.64，3.77，6.68-7.27，7.35-7.69，8.02，8.26，9.14。

HRMS found: 585.2402.

EXAMPLE 43N- [3- [1- (4-hydroxy-2-oxo-6, 6-dipropyl-5, 6-dihydro-2H-pyran-3-yl) -propyl]Phenyl radical]-8-quinolinesulfonamides (formula D-6: R)₁And R₂Is propyl, R₃Is ethyl, R₄Is quinolin-8-yl) as shown in Table D.

Using the general sulfonylation procedure of example 40, from the amine of preparation 20 (formula D-5: R)₁Is propyl, R ₂Is propyl, R₃Is ethyl) and wherein R₄8-quinolinesulfonyl chloride of formula D-7 being quinolin-8-yl the title compound was prepared and obtained after flash chromatography with 5% ethyl acetate in dichloromethane as a white amorphous solid.

The physical properties were as follows:

¹h NMR is complicated by the presence of diastereomers and tautomerism.

¹H NMR(300MHz，CD₃OD)δ0.67，0.85，1.27，1.54，2.01，3.73，6.78，6.90，7.04，7.57，8.12，8.29，8.38，9.13。

HRMS found: 523.2276.

elemental analysis, found: c, 66.09; h, 6.60; and N, 5.13.

EXAMPLE 44N- [3- [1- (4-hydroxy-2-oxo-6, 6-dipropyl-5, 6-dihydro-2H-pyran-3-yl) -propyl]Phenyl radical]-1-methyl-1H-imidazole sulfonamide (formula D-6: R)₁Is propyl, R₂Is propyl, R₃Is ethyl, R₄Is 1-methylimidazol-4-yl) as shown in table D.

Using the general sulfonylation procedure of example 40, from the amine of preparation 20 (formula D-5: R)₁Is propyl, R₂Is propyl, R₃Is ethyl) and wherein R₄1-Methylimidazol-4-sulfonyl chloride of formula D-7, which is 1-methylimidazol-4-yl the title compound is prepared and flash chromatographed using 4% methanol in ethyl acetate to give the title compound as a beige amorphous solid.

The physical properties were as follows:

¹H NMR(300MHz，CD₃OD)δ0.88，1.32，1.64，1.93，2.16，2.56，3.68，3.91，6.87，7.03，7.14，7.53，7.64。

HRMS found: 476.2223.

example 454-fluoro-N- [3- [1- (4-hydroxy-2-oxo-6, 6-dipropyl-5, 6-dihydro-2H-pyran-3-yl) -propyl ]Phenyl radical]Benzenesulfonamides (formula D-6: R)₁Is propyl, R₂Is propyl, R₃Is ethyl, R₄Is 4-fluorophenyl) as shown in table D.

Using the general sulfonylation procedure of example 40, from the amine of preparation 20 (formula D-5: R)₁Is propyl, R₂Is propyl, R₃Is ethyl) and wherein R₄4-fluorobenzenesulfonyl chloride of formula D-7, which is 4-fluorophenyl, the title compound is prepared and flash chromatographed on 5% ethyl acetate in dichloromethane to give the title compound as a white amorphous solid.

The physical properties were as follows:

¹h NMR is complicated by the presence of diastereomers and tautomerism.

¹H NMR(300MHz，CDCl₃)δ0.51-1.03，1.15-1.73，1.81-2.48，2.73，3.91，6.69，6.88，7.09，7.78。

HRMS found: 490.2085.

example 464-cyano-N- [3- [1- (4-hydroxy-2-oxo-6, 6-dipropyl-5, 6-dihydro-2H-pyran-3-yl) -propyl]Phenyl radical]Benzenesulfonamides (formula D-6: R)₁Is propyl, R₂Is propyl, R₃Is ethyl, R₄Is 4-cyanophenyl) as shown in table D.

Using the general sulfonylation procedure of example 40, from the amine of preparation 20 (formula D-5: R)₁Is propyl, R₂Is propyl, R₃Is ethyl) and wherein R₄4-Cyanobenzenesulfonyl chloride of formula D-7, which is 4-cyanophenyl the title compound was prepared and flash chromatographed using 5% ethyl acetate in dichloromethane to afford the title compound as a white amorphous solid.

The physical properties were as follows:

¹h NMR is complicated by the presence of diastereomers and tautomerism.

¹H NMR(300MHz，CDCl₃)δ0.68-0.96，1.15-1.42，1.44-1.76，1.83-2.12，3.18，3.88，6.69-7.18，7.71，7.85。

HRMS found: 497.2126.

example 47N- [3- [1- (4-hydroxy-6, 6-diisobutyl-2-oxo-5, 6-dihydro-2H-pyran-3-yl) propyl]Phenyl radical]-1-methyl-1H-imidazole-4-sulfonamide (formula D-6: R)₁Is isobutyl, R₂Is isobutyl, R₃Is ethyl, R₄Is 1-methylimidazol-4-yl) as shown in table D.

Using the general sulfonylation procedure of example 40, from the amine of preparation 20 (formula D-5: R)₁Is isobutyl, R₂Is isobutyl, R₃Is ethyl) and wherein R₄1-Methylimidazol-4-sulfonyl chloride of formula D-7, which is 1-methylimidazol-4-yl the title compound is prepared and flash chromatographed using 4% methanol in ethyl acetate to give the title compound as a beige amorphous solid.

The physical properties were as follows:

¹H NMR(300MHz，CD₃OD)δ0.82-0.94，1.52-1.83，1.86-2.03，2.06-2.22，2.60，3.68，3.92，6.87，7.03，7.16，7.56，7.65。

HRMS found: 504.2531.

elemental analysis, found: c, 62.03; h, 7.43; and N, 8.20.

EXAMPLE 48N- [3- [1- (4-hydroxy-2-oxo-6, 6-dipropyl-5, 6-dihydro-2H-pyran-3-yl) -cyclopropylmethyl]Phenyl radical]-1-methyl-1H-imidazole sulfonamide (formula D-6: R)₁Is propyl, R₂Is propyl, R₃Is cyclopropyl, R₄Is 1-methylimidazol-4-yl) as shown in table D.

Using the general sulfonylation procedure of example 40, from the amine of preparation 20 (formula D-5: R) ₁Is propyl, R₂Is propyl, R₃Is cyclopropyl) and wherein R₄1-Methylimidazol-4-sulfonyl chloride of formula D-7, which is 1-methylimidazol-4-yl the title compound is prepared and flash chromatographed using 4% methanol in ethyl acetate to give the title compound as a beige amorphous solid.

The physical properties were as follows:

¹H NMR(300MHz，CD₃OD)δ0.12，0.43，0.68，0.90-0.97，1.36，1.71，2.60，3.12，3.67，6.88，7.06，7.24，7.51，7.65。

HRMS found: 488.2225.

elemental analysis, found: c, 61.25; h, 6.94; and N, 8.42.

EXAMPLE 49N- [3- [1- (4-hydroxy-2-oxo-6, 6-dipropyl-5, 6-dihydro-2H-pyran-3-yl) -cyclopropylmethyl]Phenyl radical]-8-quinolinesulfonamides (formula D-6: R)₁Is propyl, R₂Is propyl, R₃Is cyclopropyl, R₄Is quinolin-8-yl) as shown in Table D.

Using the general sulfonylation procedure of example 40, from the amine of preparation 20 (formula D-5: R)₁Is propyl, R₂Is propyl, R₃Is cyclopropyl) and wherein R₄8-quinolinesulfonyl chloride of formula D-7 being quinolin-8-yl the title compound was prepared and flash chromatographed using 5% ethyl acetate in dichloromethane to give the title compound as a white amorphous solid.

The physical properties were as follows:

¹H NMR(300MHz，CD₃OD)δ-0.14，0.01，0.35，0.89，1.35，1.63，2.52，2.94，6.79，6.94，7.09，7.64，8.12，8.28，8.41，9.13。

HRMS found: 535.2256.

elemental analysis, found: c, 67.58; h, 6.53; n, 5.11.

EXAMPLE 504-cyano-N- [3- [1- (4-hydroxy-2-oxo-6, 6-dipropyl-5, 6-dihydro-2H-pyran-3-yl) -cyclopropylmethyl ]Phenyl radical]Benzenesulfonamides (formula D-6: R)₁Is propyl, R₂Is propyl, R₃Is cyclopropyl, R₄Is 4-cyanophenyl) as shown in table D.

Using the general sulfonylation procedure of example 40, from the amine of preparation 20 (formula D-5: R)₁Is propyl, R₂Is propyl, R₃Is cyclopropyl) and wherein R₄4-Cyanobenzenesulfonyl chloride of formula D-7, which is 4-cyanophenyl the title compound was prepared and flash chromatographed using 5% ethyl acetate in dichloromethane to afford the title compound as a white amorphous solid.

The physical properties were as follows:

¹H NMR(300MHz，CD₃OD)δ0.13，0.44，0.62，0.91，1.19，1.67，2.57，3.14，6.80，7.12，7.25，7.83。

HRMS found: 509.2096.

elemental analysis, found: c, 65.86; h, 6.39; and N, 5.48.

EXAMPLE 514-fluoro-N- [3- [1- (4-hydroxy-2-oxo-6, 6-dipropyl-5, 6-dihydro-2H-pyran-3-yl) -cyclopropylmethyl]Phenyl radical]Benzenesulfonamides (formula D-6: R)₁Is propyl, R₂Is propyl, R₃Is cyclopropyl, R₄Is 4-fluorophenyl) as shown in table D.

Using the general sulfonylation procedure of example 40, from the amine of preparation 20 (formula D-5: R)₁Is propyl, R₂Is propyl, R₃Is cyclopropyl) and wherein R₄4-fluorobenzenesulfonyl chloride of formula D-7, which is 4-fluorophenyl, the title compound is prepared and flash chromatographed on 5% ethyl acetate in dichloromethane to give the title compound as a white amorphous solid.

The physical properties were as follows:

¹H NMR(300MHz，CD₃OD)δ0.11，0.43，0.62，0.92，1.34，1.65，2.57，3.13，6.79，7.03-7.24，7.75。

HRMS found: 502.2063.

elemental analysis, found: c, 63.96; h, 6.29; n, 2.71.

Preparation 21: chiral HPLC resolution of 4-hydroxy-3- [1- (3-nitrophenyl)) Propyl radical]-5, 6-dihydro-6, 6-dipropyl-2H-pyran-2-one (formula D-4: R)₁Is propyl, R₂Is propyl, R₃Is ethyl) in table D.

The title product of preparation 18 (formula D-4: R) was purified by chromatography on a 2.0X 25cm (R, R) Whelk-O1 (regions technologies, Inc., Morton Grove, IL 60053) column using an automated chromatography system₁Is propyl, R₂Is propyl, R₃Is ethyl) (30 mg/ml) in 15% isopropanol in hexane was chromatographed 1 ml per injection. The eluate was monitored at 270nM and the appropriate fractions from multiple injections were pooled and concentrated in vacuo to give a brown oil. The fractions from multiple injections were analyzed on a 0.46X 25cm (S, S) Whelk-O1 column with the same solvent at a rate of 1.0 ml/min. The first peak of the 1.0cm column was > 99% ee (Rt in min) and the latter was 92% ee (Rt in min). The resolved material was flash chromatographed on silica gel with 3: 1 hexane/ethyl acetate before further use. The resolved material is converted to the amine of formula D-5 using the conditions described in preparation 20.

The physical properties were as follows:

the resolved substance and the racemic substance are detected¹H NMR and tlc characteristics were the same.

EXAMPLE 52(R or S) -N- [3- [1- (4-hydroxy-2-oxo-6, 6-dipropyl-5, 6-dihydro-2H-pyran-3-yl) -propyl]Phenyl radical]-8-quinolinesulfonamides (formula D-6: R)₁Is propyl, R₂Is propyl, R₃Is ethyl, R₄Is quinolin-8-yl) as shown in Table D.

Using the general sulfonylation procedure of example 40, from the amine of preparation 21 (formula D-5: R)₁Is propyl, R₂Is propyl, R₃Is ethyl) and wherein R₄8-quinolinesulfonyl chloride of formula D-7 being quinolin-8-yl the title compound was prepared and flash chromatographed using 5% ethyl acetate in dichloromethane to give the title compound as a white amorphous solid.

The physical properties were as follows:

with racemic mixtures¹H NMR and tlc characteristics were the same.

¹H NMR(300MHz，CD₃OD)δ0.67，0.85，1.27，1.54，2.01，3.73，6.78，6.90，7.04，7.57，8.12，8.29，8.38，9.13.

MSm/e(rel％)：523(100)，524(34)，129(11)，525(11)，522(10)，130(7)，139(5)，134(4).

Example 53(R or S) -N- [3- [1- (4-hydroxy-2-oxo-6, 6-dipropyl-5, 6-dihydro-2H-pyran-3-yl) -propyl]Phenyl radical]-1-methyl-1H-imidazole-4-sulfonamide (formula D-6: R)₁Is propyl, R₂Is propyl, R₃Is ethyl, R₄Is 1-methylimidazol-4-yl) as shown in table D.

Using the general sulfonylation procedure of example 40, from the amine of preparation 21 (formula D-5: R)₁Is propyl, R₂Is propyl, R₃Is ethyl) and wherein R ₄1-Methylimidazol-4-sulfonyl chloride of formula D-7, which is 1-methylimidazol-4-yl the title compound is prepared and flash chromatographed using 4% methanol in ethyl acetate to give the title compound as a beige amorphous solid.

The physical properties were as follows:

with racemic mixtures¹H NMR and tlc characteristics were the same.

¹H NMR(300MHz，CD₃OD)δ0.88，1.32，1.64，1.93，2.16，2.56，3.68，3.91，6.87，7.03，7.14，7.53，7.64.

MSm/e(rel％)：476(100)，477(28)，139(14)，492(12)，134(11)，278(10)，478(10)，83(9)，552(8)，145(7).

EXAMPLE 54(S or R) -N- [3- [1- (4-hydroxy-2-oxo-6, 6-dipropyl-5, 6-dihydro-2H-pyran-3-yl) -propyl]Phenyl radical]-8-quinolinesulfonamides (formula D-6: R)₁Is propyl, R₂Is propyl, R₃Is ethyl, R₄Is quinolin-8-yl) as shown in Table D.

Using the general sulfonylation procedure of example 40, from the amine of preparation 21 (formula D-5: R)₁Is propyl, R₂Is propyl, R₃Is ethyl) and wherein R₄8-quinolinesulfonyl chloride of formula D-7 being quinolin-8-yl the title compound was prepared and flash chromatographed using 5% ethyl acetate/chloroform to give the title compound as a white amorphous solid.

The physical properties were as follows:

with racemic mixtures¹H NMR and tlc characteristics were the same.

MSm/e(rel％)：523(100)，524(34)，522(24)，539(13)，525(10)，129(10)，130(5)，134(5)，128(5)，540(5).

Example 55(S or R) -N- [3- [1- (4-hydroxy-2-oxo-6, 6-dipropyl-5, 6-dihydro-2H-pyran-3-yl) -propyl]Phenyl radical]-1-methyl-1H-imidazole-4-sulfonamide (formula D-6: R)₁Is propyl, R₂Is propyl, R₃Is ethyl, R ₄Is 1-methylimidazol-4-yl) as shown in table D.

Using the general sulfonylation procedure of example 40, from the amine of preparation 21 (formula D-5: R)₁Is propyl, R₂Is propyl, R₃Is ethyl) and wherein R₄1-Methylimidazol-4-sulfonyl chloride of formula D-7, which is 1-methylimidazol-4-yl the title compound is prepared and flash chromatographed using 4% methanol in ethyl acetate to give the title compound as a beige amorphous solid.

The physical properties were as follows:

with racemic mixtures¹H NMR and tlc characteristics were the same.

MSm/e(rel％：476(100)，477(28)，139(19)，490(15)，498(14)，83(12)，478(9)，55(9)，145(9)，134(7).

EXAMPLE 56(R or S) -N- [3- [1- (4-hydroxy-2-oxo-6, 6-dipropyl-5, 6-dihydro-2H-pyran-3-yl) -cyclopropylmethyl]Phenyl radical]-1-methyl-1H-imidazole-4-sulfonamide (formula D-6: R)₁Is propyl, R₂Is propyl, R₃Is cyclopropyl, R₄Is 1-methylimidazol-4-yl) as shown in table D.

Using the general sulfonylation procedure of example 40, from the amine of preparation 21 (formula D-5: R)₁Is propyl, R₂Is propyl, R₃Is cyclopropyl) and wherein R₄1-Methylimidazol-4-sulfonyl chloride of formula D-7, which is 1-methylimidazol-4-yl the title compound is prepared and flash chromatographed using 4% methanol in ethyl acetate to give the title compound as a beige amorphous solid.

The physical properties were as follows:

with racemic mixtures ¹H NMR and tlc characteristics were the same.

¹H NMR(300MHz，CD₃OD)δ0.12，0.43，0.68，0.90-0.97，1.36，1.71，2.60，3.12，3.67，6.88，7.06，7.24，7.51，7.65.

MSm/e(rel％)：488(100)，489(30)，139(18)，145(14)，490(10)，55(10)，83(9)，564(7)，146(7)，510(7).

Example 57(S or R) -N- [3- [1- (4-hydroxy-2-oxo-6, 6-dipropyl-5, 6-dihydro-2H-pyran-3-yl) -cyclopropylmethyl]Phenyl radical]-1-methyl-1H-imidazole-4-sulfonamide (formula D-6: R)₁Is propyl, R₂Is propyl, R₃Is cyclopropyl, R₄Is 1-methylimidazol-4-yl) as shown in table D.

Using the general sulfonylation procedure of example 40, preparation 21 (formula D-5: R)₁Is propyl, R₂Is propyl, R₃Is cyclopropyl) and wherein R₄1-Methylimidazol-4-sulfonyl chloride of formula D-7, which is 1-methylimidazol-4-yl the title compound is prepared and flash chromatographed using 4% methanol in ethyl acetate to give the title compound as a beige amorphous solid.

The physical properties were as follows:

with racemic mixtures¹H NMR and tlc characteristics were the same.

¹H NMR(300 MHz，CD₃OD)δ0.12，0.43，0.68，0.90-0.97，1.36，1.71，2.60，3.12，3.67，6.88，7.06，7.24，7.51，7.65.

MSm/e(rel％)：488(100)，489(29)，139(18)，145(16)，83(10)，55(10)，490(10)，510(8)，146(8)，144(7).

Example 584-cyano-N- [3- [1- (4-hydroxy-2-oxo-6-phenethyl-6-propyl-5, 6-dihydro-2H-pyran-3-yl) cyclopropylmethyl]Phenyl radical]Benzenesulfonamides (formula D-6: R)₁Is phenethyl, R₂Is propyl, R₃Is cyclopropyl, R₄Is 4-cyanophenyl) as shown in table D.

Using the general sulfonylation procedure of example 40, from the amine of preparation 20 (formula D-5: R)₁Is phenethyl, R₂Is propyl, R₃Is cyclopropyl) and wherein R₄4-Cyanobenzenesulfonyl chloride of formula D-7, which is 4-cyanophenyl the title compound was prepared and flash chromatographed using 5% ethyl acetate in dichloromethane to afford the title compound as a white amorphous solid.

The physical properties were as follows:

¹H NMR(300MHz，CD₃OD)δ0.11，0.42，0.61，0.95，1.24，1.74-2.00，2.61-2.73，3.30，6.83-7.23，7.71-7.84。

HRMS found: 571.2267.

example 594-fluoro-N- [3- [1- (4-hydroxy-2-oxo-6-phenethyl-6-propyl-5, 6-dihydro-2H-pyran-3-yl) cyclopropylmethyl]Phenyl radical]Benzenesulfonamides (formula D-6: R)₁Is phenethyl, R₂Is propyl, R₃Is cyclopropyl, R₄Is 4-fluorophenyl) as shown in table D.

Using the general sulfonylation procedure of example 40, from the amine of preparation 20 (formula D-5: R)₁Is phenethyl, R₂Is propyl, R₃Is cyclopropyl) and wherein R₄4-fluorobenzenesulfonyl chloride of formula D-7, which is 4-fluorophenyl, the title compound is prepared and flash chromatographed on 5% ethyl acetate in dichloromethane to give the title compound as a white amorphous solid.

The physical properties were as follows:

¹h NMR is complicated by the presence of diastereomers.

¹H NMR(300MHz，CD₃OD)δ0.11，0.43，0.67，0.96，1.41，1.67-2.13，2.62，3.16，6.84，7.02-7.31，7.72。

HRMS found: 564.2211.

EXAMPLE 60N- [3- [1- (4-hydroxy-2-oxo-6-phenethyl-6-propyl-5, 6-dihydro-2H-pyran-3-yl) -cyclopropylmethyl]Phenyl radical]-8-quinolinesulfonamides (formula D-6: R)₁Is phenethyl, R₂Is propyl, R₃Is cyclopropyl, R₄Is quinolin-8-yl) as shown in Table D.

Using the general sulfonylation procedure of example 40, from the amine of preparation 20 (formula D-5: R)₁Is phenethyl, R₂Is propyl, R₃Is cyclopropyl) and wherein R₄8-quinolinesulfonyl chloride of formula D-7 being quinolin-8-yl the title compound was prepared and flash chromatographed using 5% ethyl acetate in dichloromethane to give the title compound as a white amorphous solid.

The physical properties were as follows:

¹H NMRare complicated by the presence of diastereomers.

¹H NMR(300MHz，CD₃OD)δ-0.13，0.01，0.35，0.93，1.46，1.54，1.58-2.06，2.56，2.96，6.81-7.23，7.50-7.68，8.08，8.24，8.37，9.12。

HRMS found: 597.2398.

EXAMPLE 61N- [3- [1- (4-hydroxy-2-oxo-6-phenethyl-6-propyl-5, 6-dihydro-2H-pyran-3-yl) -cyclopropylmethyl]Phenyl radical]-1-methyl-1H-imidazole-4-sulfonamide (formula D-6: R)₁Is phenethyl, R₂Is propyl, R₃Is cyclopropyl, R₄Is 1-methylimidazol-4-yl) as shown in table D.

Using the general sulfonylation procedure of example 40, from the amine of preparation 20 (formula D-5: R)₁Is phenethyl, R₂Is propyl, R₃Is cyclopropyl) and wherein R₄1-Methylimidazol-4-sulfonyl chloride of formula D-7, which is 1-methylimidazol-4-yl the title compound was prepared and flash chromatographed using 5% ethyl acetate in dichloromethane to give the title compound as a white amorphous solid.

The physical properties were as follows:

¹h NMR is complicated by the presence of diastereomers.

¹H NMR(300MHz，CD₃OD)δ0.13，0.42，0.67，0.95，1.44，1.68-2.13，2.56，3.17，6.91，7.01-7.33，7.52，7.63。

HRMS found: 550.2370.

EXAMPLE 62N- [3- [1- (4-hydroxy-2-oxo-6, 6-diphenylethyl-5, 6-dihydro-2H-pyran-3-yl) -cyclopropylmethyl]Phenyl radical]-1-methyl-1H-imidazole-4-sulfonamide (formula D-6: R)₁Is phenethyl, R₂Is phenethyl, R₃Is cyclopropyl, R₄Is 1-methylimidazol-4-yl) as shown in table D.

General procedure using example 40 Sulfonylation Process from the amine of preparation 20 (formula D-5: R)₁Is phenethyl, R₂Is phenethyl, R₃Is cyclopropyl) and wherein R₄1-Methylimidazol-4-sulfonyl chloride of formula D-7, which is 1-methylimidazol-4-yl the title compound was prepared and flash chromatographed using 5% ethyl acetate in dichloromethane to give the title compound as a white amorphous solid.

The physical properties were as follows:

¹H NMR(300MHz，CD₃OD)δ0.13，0.42，0.68，1.73，1.88-2.17，2.68，3.19，3.64，6.93，7.02-7.31，7.52，7.64。

HRMS found: 612.2530.

example 63N- [3- [1- (4-hydroxy-2-oxo-6, 6-diamyl-5, 6-dihydro-2H-pyran-3-yl) propyl]Phenyl radical]-1-methyl-1H-imidazole-4-sulfonamide (formula D-6: R)₁Is pentyl radical, R₂Is pentyl radical, R₃Is ethyl, R₄Is 1-methylimidazol-4-yl) as shown in table D.

Using the general sulfonylation procedure of example 40, from the amine of preparation 20 (formula D-5: R)₁Is pentyl radical, R₂Is pentyl radical, R₃Is ethyl) and wherein R₄1-Methylimidazol-4-sulfonyl chloride of formula D-7, which is 1-methylimidazol-4-yl the title compound was prepared and flash chromatographed using 5% ethyl acetate in dichloromethane to give the title compound as a white amorphous solid.

The physical properties were as follows:

¹H NMR(300MHz，CD₃OD)δ0.87，1.25，1.55-1.68，1.92，2.13，2.57，3.66，3.93，6.86，7.03，7.16，7.55，7.63。

example 644-cyano-N- [3- [1- (4-hydroxy-2-oxo-6, 6-diamyl-5, 6-dihydro-2H-pyran-3-yl) propyl]Phenyl radical]Benzenesulfonamides (formula D-6: R) ₁Is pentyl radical, R₂Is pentyl radical, R₃Is ethyl, R₄Is 4-cyanophenyl) as shown in table D.

Using the general sulfonylation procedure of example 40, from the amine of preparation 20 (formula D-5: R)₁Is pentyl radical, R₂Is pentyl radical, R₃Is ethyl) and wherein R₄4-Cyanobenzenesulfonyl chloride of formula D-7, which is 4-cyanophenyl the title compound was prepared and flash chromatographed using 5% ethyl acetate in dichloromethane to afford the title compound as a white amorphous solid.

The physical properties were as follows:

¹H NMR(300MHz，CD₃OD)δ0.86，1.23，1.52-1.67，1.93，2.14，2.56，3.93，6.80，7.05，7.18，7.80，7.86。

examples 65 to 93

Following the general procedure of example 40, but substituting the appropriate reactants, the following compounds of the invention were prepared:

example 65N- [3- [1(R or S) - (6(R or S) -4-hydroxy-2-oxo-6-phenethyl-6-propyl-5, 6-dihydro-2H-pyran-3-yl) propyl]Phenyl radical]-1-methyl-1H-imidazole-4-sulfonamide (formula D-6: R)₁Is phenethyl, R₂Is propyl, R₃Is ethyl, R₄Is 1-methylimidazol-4-yl) as shown in table D.

Example 66N- [3- [1(R or S) - (6(S or R) -4-hydroxy-2-oxo-6-phenethyl-6-propyl-5, 6-dihydro-2H-pyran-3-yl) propyl]Phenyl radical]-1-methyl-1H-imidazole-4-sulfonamide (formula D-6: R)₁Is phenethyl, R₂Is propyl, R₃Is ethyl, R₄Is 1-methylimidazol-4-yl) as shown in table D.

Example 67N- [3- [1(S or R) - (6(R or S) -4-hydroxy-2-oxo-6-phenethyl-6-propyl-5, 6-dihydro-2H-pyran-3-yl) propyl ]Phenyl radical]-1-methyl-1H-imidazole-4-sulfonamide (formula D-6: R)₁Is phenethyl, R₂Is propyl, R₃Is ethyl, R₄Is 1-methylimidazol-4-yl) as shown in table D.

Example 68N- [3- [1(S orR) - (6(S or R) -4-hydroxy-2-oxo-6-phenethyl-6-propyl-5, 6-dihydro-2H-pyran-3-yl) propyl]Phenyl radical]-1-methyl-1H-imidazole-4-sulfonamide (formula D-6: R)₁Is phenethyl, R₂Is propyl, R₃Is ethyl, R₄Is 1-methylimidazol-4-yl) as shown in table D.

EXAMPLE 69N- [3- [ tert-butyl- (4-hydroxy-2-oxo-6-phenethyl-6-propyl-5, 6-dihydro-2H-pyran-3-yl) -methyl]Phenyl radical]-1-methyl-1H-imidazole-4-sulfonamide (formula D-6: R)₁Is phenethyl, R₂Is propyl, R₃Is tert-butyl, R₄Is 1-methylimidazol-4-yl) as shown in table D.

Example 704-cyano-N- [3- [ tert-butyl- (4-hydroxy-2-oxo-6-phenethyl-6-propyl-5, 6-dihydro-2H-pyran-3-yl) methyl]Phenyl radical]Benzenesulfonamides (formula D-6: R)₁Is phenethyl, R₂Is propyl, R₃Is tert-butyl, R₄Is 4-cyanophenyl) as shown in table D.

Example 714-fluoro-N- [3- [ tert-butyl- (4-hydroxy-2-oxo-6-phenethyl-6-propyl-5, 6-dihydro-2H-pyran-3-yl) methyl]Phenyl radical]Benzenesulfonamides (formula D-6: R)₁Is phenethyl, R₂Is propyl, R₃Is tert-butyl, R ₄Is 4-fluorophenyl) as shown in table D.

Example 72N- [3- [ tert-butyl- (4-hydroxy-2-oxo-6-phenethyl-6-propyl-5, 6-dihydro-2H-pyran-3-yl) -methyl]Phenyl radical]-8-quinolinesulfonamides (formula D-6: R)₁Is phenethyl, R₂Is propyl, R₃Is tert-butyl, R₄Is quinolin-8-yl) as shown in Table D.

EXAMPLE 73N- [3- [1- (6- (2- (1-methyl-1H-imidazole-4-sulfonylamino) ethyl) -4-hydroxy-2-oxo-6-propyl-5, 6-dihydro-2H-pyran-3-yl) -propyl]Phenyl radical]-1-methyl-1H-imidazole-4-sulfonamide (formula D-6: R)₁Is 2- (1-methylimidazole-4-sulfonylamino) -ethyl, R₂Is propyl, R₃Is ethyl, R₄Is 1-methylimidazol-4-yl) as shown in table D.

Example 74N- [3- [1- (4-Hydroxyl)2-oxo-6, 6-diphenylethyl-5, 6-dihydro-2H-pyran-3-yl) propyl]Phenyl radical]-2-pyridinesulfonamide (formula D-6: R)₁Is phenethyl, R₂Is phenethyl, R₃Is ethyl, R₄Is 2-pyridyl) as shown in table D.

Example 754-cyano-N- [3- [1- (4-hydroxy-2-oxo-6, 6-diphenylethyl-5, 6-dihydro-2H-pyran-3-yl) -propyl]Phenyl radical]-2-pyridinesulfonamide (formula D-6: R)₁Is phenethyl, R₂Is phenethyl, R₃Is ethyl, R₄Is 4-cyano-2-pyridyl) as shown in table D.

EXAMPLE 76N- [3- [1- (4-hydroxy-2-oxo-6, 6-diphenylethyl-5, 6-dihydro-2H-pyran-3-yl) -propyl ]Phenyl radical]-2-quinolinesulfonamides (formula D-6: R)₁Is phenethyl, R₂Is phenethyl, R₃Is ethyl, R₄Is quinolin-2-yl) as shown in Table D.

Example 772-hydroxy-N- [3- [1- (4-hydroxy-2-oxo-6, 6-diphenylethyl-5, 6-dihydro-2H-pyran-3-yl) propyl]Phenyl radical]Benzenesulfonamides (formula D-6: R)₁Is phenethyl, R₂Is phenethyl, R₃Is ethyl, R₄Is 2-hydroxyphenyl) as shown in table D.

EXAMPLE 78N- [3- [1- (4-hydroxy-2-oxo-6, 6-diphenylethyl-5, 6-dihydro-2H-pyran-3-yl) -propyl]Phenyl radical]-2-pyrimidine-sulfonamides (formula D-6: R)₁Is phenethyl, R₂Is phenethyl, R₃Is ethyl, R₄Is 2-pyrimidinyl) is shown in table D.

EXAMPLE 79N- [3- [1- (4-hydroxy-2-oxo-6, 6-diphenylethyl-5, 6-dihydro-2H-pyran-3-yl) -propyl]Phenyl radical]-2-quinazolinesulfonamide (formula D-6: R)₁Is phenethyl, R₂Is phenethyl, R₃Is ethyl, R₄Is quinazolin-2-yl) as shown in table D.

EXAMPLE 80N- [3- [1- (4-hydroxy-2-oxo-6, 6-diphenylethyl-5, 6-dihydro-2H-pyran-3-yl) -propyl]Phenyl radical]-7H-purine-6-sulfonamide (formula D-6: R)₁Is phenethyl, R₂Is a radical of the phenethyl group,R₃is ethyl, R₄Is 7H-purin-6-yl) as shown in Table D.

Example 81N- [3- [1- (4-hydroxy-2-oxo-6, 6-diphenylethyl-5, 6-dihydro-2H-pyran-3-yl) -propyl ]Phenyl radical]-1H-imidazole-2-sulfonamide (formula D-6: R)₁Is phenethyl, R₂Is phenethyl, R₃Is ethyl, R₄Is 1H-imidazol-2-yl) as shown in table D.

Example 82N- [3- [1- (4-hydroxy-2-oxo-6, 6-diphenylethyl-5, 6-dihydro-2H-pyran-3-yl) -propyl]Phenyl radical]-1H-benzimidazole-2-sulfonamide (formula D-6: R)₁Is phenethyl, R₂Is phenethyl, R₃Is ethyl, R₄Is 1H-benzimidazol-2-yl) as shown in table D.

Example 83N- [3- [1- (4-hydroxy-2-oxo-6, 6-diphenylethyl-5, 6-dihydro-2H-pyran-3-yl) -propyl]Phenyl radical]Thiazole-4-sulfonamides (formula D-6: R)₁Is phenethyl, R₂Is phenethyl, R₃Is ethyl, R₄Is thiazol-2-yl) as shown in table D.

Example 84N- [3- [1- (4-hydroxy-2-oxo-6-phenethyl-6-propyl-5, 6-dihydro-2H-pyran-3-yl) -propyl]Phenyl radical]-2-pyridinesulfonamide (formula D-6: R)₁Is propyl, R₂Is phenethyl, R₃Is ethyl, R₄Is 2-pyridyl) as shown in table D.

EXAMPLE 854-cyano-N- [3- [1- (4-hydroxy-2-oxo-6-phenethyl-6-propyl-5, 6-dihydro-2H-pyran-3-yl) propyl]Phenyl radical]-2-pyridinesulfonamide (formula D-6: R)₁Is propyl, R₂Is phenethyl, R₃Is ethyl, R₄Is 4-cyano-2-pyridyl) as shown in table D.

EXAMPLE 86N- [3- [1- (4-hydroxy-2-oxo-6-phenethyl-6-propyl-5, 6-dihydro-2H-pyran-3-yl) -propyl ]Phenyl radical]-2-quinolinesulfonamides (formula D-6: R)₁Is propyl, R₂Is phenethyl, R₃Is ethyl, R₄Is quinolin-2-yl) as shown in Table D.

B example 872-hydroxy-N- [3- [1- (4-hydroxy-2-oxo-6-phenethyl-6-propyl-5, 6-dihydro-2H-pyran-3-yl) propyl ] group]Phenyl radical]Benzenesulfonamides (formula D-6: R)₁Is propyl, R₂Is phenethyl, R₃Is ethyl, R₄Is 2-hydroxyphenyl) as shown in table D.

EXAMPLE 88N- [3- [1- (4-hydroxy-2-oxo-6-phenethyl-6-propyl-5, 6-dihydro-2H-pyran-3-yl) -propyl]Phenyl radical]-2-pyrimidine-sulfonamides (formula D-6: R)₁Is propyl, R₂Is phenethyl, R₃Is ethyl, R₄Is 2-pyrimidinyl) is shown in table D.

EXAMPLE 89N- [3- [1- (4-hydroxy-2-oxo-6-phenethyl-6-propyl-5, 6-dihydro-2H-pyran-3-yl) -propyl]Phenyl radical]-2-quinazolinesulfonamide (formula D-6: R)₁Is propyl, R₂Is phenethyl, R₃Is ethyl, R₄Is quinazolin-2-yl) as shown in table D.

Example 90N- [3- [1- (4-hydroxy-2-oxo-6-phenethyl-6-propyl-5, 6-dihydro-2H-pyran-3-yl) -propyl]Phenyl radical]-7H-purine-6-sulfonamide (formula D-6: R)₁Is propyl, R₂Is phenethyl, R₃Is ethyl, R₄Is 7H-purin-6-yl) as shown in Table D.

Example 91N- [3- [1- (4-hydroxy-2-oxo-6-phenethyl-6-propyl-5, 6-dihydro-2H-pyran-3-yl) -propyl ]Phenyl radical]-1H-imidazole-2-sulfonamide (formula D-6: R)₁Is propyl, R₂Is phenethyl, R₃Is ethyl, R₄Is 1H-imidazol-2-yl) as shown in table D.

Example 92N- [3- [1- (4-hydroxy-2-oxo-6-phenethyl-6-propyl-5, 6-dihydro-2H-pyran-3-yl) -propyl]Phenyl radical]-1H-benzimidazole-2-sulfonamide (formula D-6: R)₁Is propyl, R₂Is phenethyl, R₃Is ethyl, R₄Is 1H-benzimidazol-2-yl) as shown in table D.

Example 93N- [3- [1- (4-hydroxy-2-oxo-6-phenethyl-6-propyl-5, 6-dihydro-2H-pyran-3-yl) -propyl]Phenyl radical]Thiazole-4-sulfonamides (formula D-6: R)₁Is propyl, R₂Is phenethyl, R₃Is ethyl, R₄Is thiazol-2-yl) as shown in table D.

Example 93A 4-fluoro-N- [3- [1- (4-hydroxy-2-oxo-6-phenethyl-6-propyl-5, 6-dihydro-2H-pyran-3-yl) propyl]Phenyl radical]Benzenesulfonamides (formula D-6: R)₁Is phenethyl, R₂Is propyl, R₃Is ethyl, R₄Is 4-fluorophenyl) as shown in table D.

Using the general sulfonylation procedure of example 40, from the amine of preparation 20 (formula D-5: R)₁Is phenethyl, R₂Is propyl, R₃Is ethyl) and 4-fluorobenzenesulfonyl chloride the title compound was prepared and flash chromatographed with 5% ethyl acetate in dichloromethane to yield the title compound as a beige amorphous solid.

The physical properties were as follows:

¹h NMR is complicated by the presence of diastereomers.

¹H NMR(300MHz，CD₃OD)δ0.75-0.96，1.31-1.48，1.57-2.01，2.09-2.22，2.48-2.71，3.92，3.94，6.86-7.24，7.72。

Preparation of 226- (2-cyclopropyl-1-cyclopropylmethylethyl) -4-hydroxy-2H-pyran-2-one (formula E-2), see Table E.

To a cooled (-78 ℃) and stirred solution of 1.5 ml of diisopropylamine in 9 ml of anhydrous tetrahydrofuran was added, under argon, 6.2 ml of a 1.6M solution of n-butyllithium in hexane. The solution was warmed to 0 ℃ and then treated with 378 mg of a commercially available solution of 4-hydroxy-6-methyl-2-pyrone of formula E-1 in 8 ml of hexamethylphosphoramide. After 30 minutes, 0.32 ml of bromomethylcyclopropane was added at 0 ℃; after a further 10 minutes, a second portion of bromomethylcyclopropane was added in the same amount. The reaction was stirred, allowed to warm to room temperature overnight, and then partitioned between ethyl acetate and excess dilute hydrochloric acid. The organic phase was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel 60(230-400 mesh) using a solution of 1% acetic acid in 25% ethyl acetate in dichloromethane to give 371 mg of the title compound and 206 mg of the monoalkylated material.

The physical properties were as follows:

¹H NMRδ0.0，0.4，0.6，1.5，1.6，2.2，5.6，6.1，7.2-7.3，11.5；

EI MSm/z＝234；

TLC R_f0.29 (1% acetic acid in 25% ethyl acetate in dichloromethane).

Preparation of 233- (. alpha. -cyclopropyl-m- (benzyloxycarbonylamino) benzyl) -6- (2-cyclopropyl-1-cyclopropylmethylethyl) -4-hydroxy-2H-pyran-2-one (formula E-3) is shown in Table E.

A mixture of 367 mg of the title compound of preparation 22, 470 mg of the title compound of preparation F-5, 60 mg of p-toluenesulfonic acid monohydrate and 1 g of 3A molecular sieve in 5 ml of benzene was heated overnight under argon with stirring. The mixture was diluted with dichloromethane and diethyl ether and filtered through a pad of sodium sulfate. The solvent was removed under reduced pressure and the residue was flash chromatographed on silica gel 60(230-400 mesh) using 5-20% ethyl acetate in dichloromethane to give 399 mg of the title compound.

The physical properties were as follows:

¹H NMRδ-0.06，0.3，0.5，1.4，1.5，2.5，3.5，5.1，7.2-7.4；

EI HRMS m/z＝513.2513；

TLC R_f0.28 (5% ethyl acetate in dichloromethane).

Preparation 243- (. alpha. -cyclopropyl-m-aminobenzyl) -6- (2-cyclopropyl-1-cyclopropylmethylethyl) -4-hydroxy-2H-pyran-2-one (formula E-4) is shown in Table E.

A mixture of 391 mg of the title compound of preparation 23 and 100 mg of 5% palladium on carbon in 10 ml of methanol was shaken overnight under a 40psi hydrogen atmosphere. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give 280 mg of the title compound.

The physical properties were as follows:

¹H NMRδ0.0，0.2-0.7，1.4，1.6，1.8，2.6，6.8，7.2-7.4；

TLC R_f0.38 (30% ethyl acetate in dichloromethane).

Example 94N- (3- { cyclopropyl- [6- (2-cyclopropyl-1-cyclopropylmethylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -4-fluorobenzenesulfonamide (formula E-6) is shown in Table E.

To a mixture of 57 mg of the title compound of preparation 24 and 24 μ L of pyridine in 0.5 ml of dichloromethane was added 29 mg of 4-fluorobenzenesulfonyl chloride. After stirring overnight, the solution was diluted with ethyl acetate and washed with dilute aqueous hydrochloric acid, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel 60(230-400 mesh) using 10% ethyl acetate in dichloromethane to give 56 mg of the title compound.

The physical properties were as follows:

¹H NMR(CDCl₃)δ-0.07，0.13，0.33，0.54，1.39，1.51，1.72，2.55，3.39，6.12，6.87，7.00，7.08，7.19，7.27，7.72，9.72；

EI-MS: [ M + ], 537.1977, found value.

Examples 95 to 97

Following the above procedures and using starting materials and reagents known and available to those of ordinary skill in the art of organic synthesis, the following compounds were prepared:

example 954-cyano-N- (3- { cyclopropyl- [6- (2-cyclopropyl-1-cyclopropylmethylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) benzenesulfonamide (formula E-7), see Table E.

The physical properties were as follows:

¹H NMR(CDCl₃)δ-0.03，0.13，0.23，0.36，0.44，0.57，1.41，1.58，1.75，2.57，3.32，5.98，6.89，7.11，7.21，7.68，7.82；

EI-MS: [ M + ], 544.2035, found value.

Example 96N- (3- { cyclopropyl- [6- (2-cyclopropyl-1-cyclopropylmethylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -8-quinolinesulfonamide (formula E-8) is shown in Table E.

The physical properties were as follows:

¹H NMR(CDCl₃)δ-0.07，0.18，0.37，0.54，1.37，1.51，2.53，3.31，5.96，6.87，7.00，7.13，7.48，7.54，7.92，8.23，9.07；

EI-MS: [ M + ], 570.2188, found value.

Example 97N- (3- { cyclopropyl- [6- (2-cyclopropyl-1-cyclopropylmethylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -1-methyl-1H-imidazole-4-sulfonamide (formula E-9) is shown in Table E.

The physical properties were as follows:

¹H NMR(CDCl₃-CD₃OD)δ-0.08，0.13，0.33，0.56，1.37，1.51，1.73，2.54，3.21，3.60，5.95，6.82，7.0，7.19，7.37，7.5；

EI-MS: [ M + ], 523.2142, found value.

EXAMPLE 98 chiral HPLC separation of N- (3- { cyclopropyl- [6- (2-cyclopropyl-1-cyclopropylmethylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -1-methyl-1H-imidazole-4-sulfonamide (formula E-9) to give (R or S) -N- (3- { cyclopropyl- [6- (2-cyclopropyl-1-cyclopropylmethylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -1-methyl-1H-imidazole-4-sulfonamide (formula E-10) and (R or S) -N- (3- { cyclopropyl-1-cyclopropylmethylethyl) -N- (3- { cyclopropyl-3-yl ] methyl } phenyl) Propyl- [6- (2-cyclopropyl-1-cyclopropylmethylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -1-methyl-1H-imidazole-4-sulfonamide (formula E-11) is shown in Table E.

Stock samples (3mg/ml) of the title compound of example 97 in 5.0 ml of each mobile phase (30% isopropanol, 0.1% acetic acid and 0.2% water in hexane) and isopropanol were prepared. The stock sample was filtered through a 0.45 micron syringe filter and washed with ethanol to give 14.0 ml of clear filtrate. The solution was chromatographed on a 2.0X 2.5cm (R, R) Whelk-O1 (Regis technologies, Inc., Morton Grove, II60053) column using an automated chromatography system, 3.50 ml per injection. The eluate was monitored, the fractions corresponding to the desired peak were combined for multiple injections, concentrated under reduced pressure and azeotroped with toluene. The residue was dissolved in methanol, filtered through a syringe filter, and the filtrate was concentrated under reduced pressure to give the title compound (> 95% purity):

(R or S) -N- (3- { cyclopropyl- [6- (2-cyclopropyl-1-cyclopropylmethylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -1-methyl-1H-imidazole-4-sulfonamide (formula E-10)

The physical properties were as follows:

¹H NMR(CDCl₃-CD₃OD)δ-0.07，0.14，0.34，0.57，1.32，1.55，1.75，2.51，3.24，3.60，5.87，6.85，7.03，7.15，7.27，7.37；

EI-MS: [ M + ], 523.2149, found value.

(R or S) -N- (3- { cyclopropyl- [6- (2-cyclopropyl-1-cyclopropylmethylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -1-methyl-1H-imidazole-4-sulfonamide (formula E-11)

The physical properties were as follows:

¹H NMR(CDCl₃-CD₃OD)δ-0.07，0.14，0.33，0.55，1.33，1.56，1.75，2.51，3.23，3.60，5.88，6.86，7.03，7.14，7.27，7.38；

EI-MS: [ M + ], 523.2137, found value.

Examples 99 to 103

example 99N- (3- { cyclopropyl- [6- (2-cyclopropyl-1-cyclopropylmethylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -2-pyridinesulfonamide (formula E-12).

The physical properties were as follows:

¹H NMR(CDCl₃-CD₃OD)δ-0.05，0.07，0.1 7，0.34，0.55，1.35，1.55，1.7，2.5，3.24，5.86，6.90，7.03，7.15，7.39，7.78，8.60；

EI-MS：[M+]＝520；

TLC R_f0.35 (25% ethyl acetate in dichloromethane).

Example 100N- (3- { cyclopropyl- [6- (2-cyclopropyl-1-cyclopropylmethylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -1-methyl-1H-imidazole-2-sulfonamide (formula E-13).

The physical properties were as follows:

¹H NMR(CDCl₃-CD₃OD)δ-0.05，0.1 5，0.35，0.56，1.35，1.55，1.75，2.53，3.23，3.39，5.89，6.81，6.90，6.97，7.09，7.25；

EI-MS：[M+]＝523；

TLC R_f0.31 (5% methanol in dichloromethane).

Example 101N- (3- { cyclopropyl- [6- (2-cyclopropyl-1-cyclopropylmethylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -1H-benzimidazole-2-sulfonamide (formula E-14).

The physical properties were as follows:

¹H NMR(CDCl₃-CD₃OD)δ-0.07，0.1，0.15，0.35，0.56，1.38，1.58，1.65，2.55，3.28，5.95，6.73，6.96，7.10，7.28，7.58；

FAB-MS: when M + H is 560.2220, found.

Example 102N- (3- { cyclopropyl- [6- (2-cyclopropyl-1-cyclopropylmethylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -1H-imidazole-2-sulfonamide (formula E-15).

The physical properties were as follows:

¹H NMR(CDCl₃-CD₃OD)δ0.0，0.25，0.4，0.6，1.4，1.6，1.65，2.6，3.35，6.0，6.8，7.0，7.2，7.4；

EI-MS：[M+]＝509；

TLC R_f0.25 (5% methanol in dichloromethane).

Example 103N- (3- { cyclopropyl- [6- (2-cyclopropyl-1-cyclopropylmethylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -2-quinolinesulfonamide (formula E-16).

The physical properties were as follows:

¹H NMR(CDCl₃)δ0.0，0.2，0.4，0.6，1.4，1.6，1.7，2.6，3.3，6.0，7.0-7.2，7.3，7.7，7.8-8.0，8.2，8.3；

EI-MS：[M+]＝570；

TLC R_f0.53 (5% methanol in dichloromethane).

Preparation of 25 cyclopropyl m-nitrophenyl ketone (formula F-2), see Table F.

To a 250 ml three-necked flask equipped with a thermometer and an addition funnel was added 130 ml of 90% fuming nitric acid, and cooled to-10 ℃. To the stirred liquid was added dropwise 21 ml of a commercially available cyclopropylphenylketone of formula F-1. The rate of addition was adjusted to maintain the reaction temperature at about-10 ℃. Once the addition was complete, the resulting clear yellow solution was stirred at-10 ℃ for a further 10 minutes and then poured into 1 liter of crushed ice. The precipitated solid was extracted with 700 ml of toluene, and the extract was washed twice with 5% sodium hydroxide solution, once with brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was recrystallized from methanol at-25 ℃ to give 14.6 g of the title compound as a thick pale yellow prism. The mother liquor contains a large amount of ortho-isomers.

The physical properties were as follows:

¹H NMRδ1.2，1.3，2.7，7.70，8.3，8.4，8.85；

IR 1664，1529，1352，1225，1082，1017，852，689cm^-1；

elemental analysis, found: c, 62.89; h, 4.73; n, 7.32;

EI MS m/z 191；

TLC R_f0.32 (25% ethyl acetate in hexane).

26 m-aminophenylcyclopropyl ketone (formula F-3) was prepared as shown in Table F.

A solution of 5.76 g of the title compound of preparation 25 was prepared by heating in 100 ml of methanol. To the solution was added 450 mg of 5% platinum on carbon catalyst, and the mixture was vigorously stirred under a hydrogen atmosphere of 1 atm. After 5 hours, the mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give 4.89 g of the title compound as a green oil.

The physical properties were as follows:

¹H NMRδ1.0，1.2，2.6，3.9，6.8，7.2，7.4；

TLC R_f0.50 (80% ethyl acetate in hexane).

Preparation of 27 m-benzyloxycarbonylaminophenyl cyclopropyl ketone (formula F-4) is shown in Table F.

To a cooled (0 ℃) and stirred solution of 4.89 g of the title compound of preparation 26 and 6.3 ml of diisopropylethylamine in 90 ml of dichloromethane, 4.7 ml of benzyl chloroformate are added dropwise. After the addition was complete, the solution was warmed to room temperature. After 4 hours, the mixture is washed with dilute hydrochloric acid and the aqueous phase is extracted with two portions of dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure to give a yellow solid. The solid was triturated with two 30 ml portions of hexane which were discarded and the remaining solid was dried under vacuum to give 8.74 g of the title compound.

The physical properties were as follows:

TLC R_f0.45 (5% ethyl acetate in dichloromethane).

Preparation of 28 m-benzyloxycarbonylaminophenyl cyclopropylmethanol (formula F-5), see Table F.

To a stirred solution of 8.74 g of Compound F-4 of preparation 27 in 100 ml of tetrahydrofuran and 100 ml of ethanol was added portionwise 4.5 g of sodium borohydride. After 3 hours at room temperature, the mixture was cooled on ice and 100 ml of 1N hydrochloric acid were added. The mixture was extracted three times with dichloromethane and the combined extracts were dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was flash chromatographed on silica gel 60(230-400 mesh) using 40% ethyl acetate in hexane to give 8.48 g of the title compound as a white crystalline solid. The solid was optionally recrystallized from ethyl acetate-hexane.

The physical properties were as follows:

¹H NMR δ0.3-0.6，1.1，2.35，3.92，5.17，7.1，7.2-7.4；

IR 1693，1599，1559，1449，1235，1054，697cm^-1；

elemental analysis, found: c, 72.57; h, 6.51; and N, 4.61.

Preparation of 294-hydroxy-6- [3- (2-methoxyethoxy) propyl ] pyran-2-one (formula G-1), see Table G.

To a flame-dried flask, under argon atmosphere, 2.80 ml of diisopropylamine and 20.0 ml of anhydrous tetrahydrofuran were added. The solution was cooled to-78 ℃ and treated with 12.5 ml (1.6M in hexane) of n-butyllithium. The solution was warmed to 0 ℃ for 30 minutes and then treated with 5.0 ml of anhydrous hexamethylphosphoramide. The lithium diisopropylamide solution was then treated with a solution of 1.20G of the commercially available 4-hydroxy-6-methyl-2-pyrone of formula G-0 in 16 ml of anhydrous tetrahydrofuran and 14 ml of anhydrous hexamethylphosphoramide. After 30 minutes, the mixture was treated with a solution of 2.30 g of 2- (2-methoxyethoxy) ethyl iodide in 12 ml of anhydrous tetrahydrofuran. The mixture was stirred at 0 ℃ for 1 hour and then warmed to room temperature. After 1 hour, the reaction was terminated with an excess of 1N aqueous hydrochloric acid solution. The mixture was concentrated under reduced pressure and partitioned between dichloromethane and water. The aqueous phase was extracted with a sufficient volume of dichloromethane to remove the title compound. The combined organic extracts were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to flash column chromatography on silica gel 60(230-400 mesh) eluting with 3% acetic acid in 30% ethyl acetate in dichloromethane to 5% acetic acid in 80% ethyl acetate in dichloromethane to give 1.34 g of the title compound.

The physical properties were as follows:

¹H NMR(CDCl₃)δ1.93，2.54，3.39，3.55，5.55，5.90；

TLC R_f0.26 (5% acetic acid in 50% ethyl acetate in dichloromethane).

Preparation of 303- (. alpha. -cyclopropyl m- (benzyloxycarbonylamino) benzyl) -4-hydroxy-6- [3- (2-methoxyethoxy) propyl ] pyran-2-one (formula G-2) is shown in Table G.

A mixture of 146 mg of the title compound of preparation 29, 340 mg of the title compound of preparation 28 (prepared as described in table F), 25 mg of p-toluenesulfonic acid monohydrate and 0.5 g of 3 angstrom molecular sieve in 5 ml of dichloromethane was heated overnight with stirring. The mixture was cooled and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel 60(230-400 mesh) using 5-10% methanol in ethyl acetate to give 129 mg of the title compound.

The physical properties were as follows:

¹H NMR(CDCl₃)δ0.25，0.45，0.67，1.77，2.39，3.38，3.51，5.13，5.84，7.17，7.32，7.42；

EI MS: (vi) [ M + ] -507.2257, found;

TLC R_f0.28 (50% ethyl acetate in dichloromethane).

Preparation of 313- (. alpha. -cyclopropylm-aminobenzyl) -4-hydroxy-6- [3- (2-methoxyethoxy) propyl ] pyran-2-one (formula G-3) is shown in Table G.

A mixture of 124 mg of the title compound of preparation 30 and 35 mg of 5% palladium on carbon in 5 ml of ethanol was shaken overnight under a 50psi hydrogen atmosphere. The mixture was filtered through celite and the filter cake was washed with ethanol. The filtrates were combined and the solvent was removed under reduced pressure to give 92 mg of the title compound.

The physical properties were as follows:

TLC R_f0.12 (ethyl acetate).

Example 104N- (3- { cyclopropyl- [ 4-hydroxy-6- (3- { 2-methoxyethoxy } propyl) -2-oxo-2H-pyran-3-yl ] methyl } phenyl) -1-methyl-1H-imidazole-4-sulfonamide (formula G-4) is shown in Table G.

To a mixture of 37 mg of the title compound of preparation 31 and 18 μ L of pyridine in 0.5 ml of dichloromethane was added 20 mg of 1-methylimidazole-4-sulfonyl chloride. After stirring overnight, the solvent was removed under reduced pressure. The residue was azeotroped with toluene and then purified by flash column chromatography on silica gel 60(230-400 mesh) with 2-8% methanol in dichloromethane to give 32 mg of the title compound.

The physical properties were as follows:

¹H NMR(CDCl₃)δ0.1，0.24，0.45，0.65，1.75，1.85，2.46，3.30，3.34，3.50，5.98，6.98，7.08，7.19，7.29，7.42；

EI-MS: (vi) [ M + ] -517.1874, found;

TLC R_f0.22 (5% methanol in dichloromethane).

Preparation of 323- (. alpha. -cyclopropyl m- (benzyloxycarbonylamino) benzyl) -4-hydroxy-6-methylpyran-2-one (formula H-1) is shown in Table H.

A mixture of 493 mg of the commercially available 4-hydroxy-6-methyl-2-pyrone of the formula H-0, 592 mg of the title compound of preparation 28 (prepared as described in Table F) and 56 mg of p-toluenesulfonic acid monohydrate in 20 ml of dichloromethane was heated to reflux for 6 hours via an addition funnel containing 3A molecular sieves. The mixture was cooled and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel 60(230-400 mesh) using 60-100% ethyl acetate in dichloromethane to give 470 mg of the title compound.

The physical properties were as follows:

¹H NMR(CDCl₃)δ0.23，0.43，0.66，1.78，3.41，5.09，5.89，7.00，7.14，7.29，7.37，10.1；

EI-MS：[M+]＝405；

TLC R_f0.52 (ethyl acetate).

Preparation of 333- (. alpha. -cyclopropyl m- (benzyloxycarbonylamino) benzyl) -4-hydroxy-6-propylpyran-2-one (formula H-2) is shown in Table H.

To a flame-dried flask, 0.45 ml of diisopropylamine and 3.0 ml of anhydrous tetrahydrofuran were added under an argon atmosphere. The solution was cooled to-78 ℃ and treated with 2.0 ml (1.6M in hexane) of n-butyllithium. The solution was warmed to 0 ℃ for 15 minutes and then cooled to-78 ℃. A solution of lithium diisopropylamide was treated with 405 mg of the title compound of preparation 32 in 4 ml of anhydrous tetrahydrofuran. After holding at-78 ℃ for 1 hour, the mixture was treated with 85. mu.L of bromoethane. The mixture was then stirred at-78 ℃ for 3 hours. The reaction was terminated with an excess of 1N aqueous hydrochloric acid solution. The mixture was warmed and partitioned between ethyl acetate and phosphate buffer. The aqueous phase was extracted twice with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to flash column chromatography on silica gel 60(230-400 mesh) eluting with 10-20% ethyl acetate in dichloromethane to give 277 mg of the title compound.

The physical properties were as follows:

¹H NMR(CDCl₃)δ0.24，0.45，0.65，0.88，1.55，1.79，2.28，3.42，5.10，5.95，6.89，7.15，7.3，10.0；

EI-MS：[M+]＝433；

TLC R_f0.33 (10% ethyl acetate in dichloromethane).

Preparation of 343- (. alpha. -cyclopropyl-m- (benzyloxycarbonylamino) benzyl) -6- [ 1-ethyl-3- (2-methoxyethoxy) propyl ] -4-hydroxypyran-2-one (formula H-3) is shown in Table H.

To a flame-dried flask, 0.30 ml of diisopropylamine and 2.0 ml of anhydrous tetrahydrofuran were added under an argon atmosphere. The solution was cooled to-78 ℃ and treated with 1.3 ml (1.6M in hexane) of n-butyllithium. The solution was warmed to 0 ℃ for 15 minutes and then cooled to-78 ℃. A solution of lithium diisopropylamide was treated with 277 mg of the title compound of preparation 33 in 3 ml of anhydrous tetrahydrofuran. After holding at-78 ℃ for 1 hour, the mixture was treated with a solution of 180 mg of 2- (2-methoxyethoxy) ethyl iodide in 3 ml of tetrahydrofuran. The mixture was then stirred at-78 ℃ for 3 hours. The reaction was terminated with an excess of 1N aqueous hydrochloric acid solution. The mixture was warmed and partitioned between ethyl acetate and phosphate buffer. The aqueous phase was extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel 60(230-400 mesh) eluting with 25-40% ethyl acetate in dichloromethane to give 198 mg of the title compound.

The physical properties were as follows:

¹H NMR(CDCl₃)δ0.25，0.46，0.66，0.75，1.5，1.76，2.36，3.4，5.15，5.96，7.2，7.3，7.42，10.0；

EI-MS：[M+]＝535；

TLC R_f0.29 (25% ethyl acetate in dichloromethane).

Preparation of 353- (. alpha. -cyclopropylm-aminobenzyl) -6- [ 1-ethyl-3- (2-methoxyethoxy) propyl ] -4-hydroxypyran-2-one (formula H-4) is shown in Table H.

A mixture of 180 mg of the title compound of preparation 34 and 50 mg of 5% palladium on carbon in 2 ml of ethanol was shaken overnight under a 50psi hydrogen atmosphere. The mixture was filtered through celite and the filter cake was washed with ethanol. The filtrates were combined and the solvent was removed under reduced pressure to give 127 mg of the title compound.

The physical properties were as follows:

TLC R_f0.19 (ethyl acetate).

Example 105N- (3- { cyclopropyl- [6- (1-ethyl-3- { 2-methoxyethoxy } propyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -1-methyl-1H-imidazole-4-sulfonamide (formula H-5), see Table H.

To a mixture of 32 mg of the title compound of preparation 35 and 13 μ L of pyridine in 0.8 ml of dichloromethane was added 14.5 mg of 1-methylimidazole-4-sulfonyl chloride. After stirring overnight, the solvent was removed under reduced pressure. The residue was azeotroped with toluene and then purified by flash column chromatography on silica gel 60(230-400 mesh) with 1-4% methanol in dichloromethane to give 38 mg of the title compound.

The physical properties were as follows:

¹H NMR(CDCl₃)δ0.05，0.25，0.45，0.65，0.83，1.5-2.0，2.45，3.3-3.5，3.62，6.00，6.99，7.1-7.3，7.48；

EI-MS: (vi) [ M + ] -545.2186, found;

TLC R_f0.24 (5% methanol in dichloromethane).

Example 1064-cyano-N- (3- { cyclopropyl- [ 6- (1-ethyl-3- {2- (methoxyethoxy } propyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) benzenesulfonamide

The title compound is prepared according to the methods described above using starting materials and reagents known and available to those of ordinary skill in the art of organic synthesis.

The physical properties were as follows:

¹H NMR(CDCl₃)δ0.15，0.25，0.45，0.65，0.78，1.2-1.8，2.4，3.3-3.6，3.54，5.89，6.95，7.1-7.3，7.6-7.9；

FAB-MS: (iv) [ M + H ] ═ 567.2176, found;

TLC R_f0.40 (50% ethyl acetate in dichloromethane).

Preparation of 363- (. alpha. -cyclopropyl-m- (benzyloxycarbonylamino) benzyl) -6- [ 1-ethyl-3-hydroxypropyl ] -4-hydroxypyran-2-one (formula I-1) is shown in Table I.

To a flame dried flask, 0.46 ml of diisopropylamine and 3.5 ml of anhydrous tetrahydrofuran were added under an argon atmosphere. The solution was cooled to-78 ℃ and treated with 2.0 ml (1.6M in hexane) of n-butyllithium. The solution was warmed to 0 ℃, held for 20 minutes, and then cooled to-78 ℃. A solution of lithium diisopropylamide was treated with 433 mg of the title compound of preparation 33 in 4 ml of anhydrous tetrahydrofuran. After holding at-78 ℃ for 1 hour, the mixture was treated with ethylene oxide gas for 5 minutes. The mixture was then stirred at-78 ℃ for 15 minutes. The reaction was terminated with an excess of 1N aqueous hydrochloric acid solution. The mixture was warmed and partitioned between ethyl acetate and phosphate buffer. The aqueous phase was extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to flash column chromatography on silica gel 60(230-400 mesh) eluting with 2-8% methanol in dichloromethane to give 144 mg of the title compound.

The physical properties were as follows:

¹H NMR(CDCl₃)δ0.22，0.45，0.65，0.7，1.3-1.7，1.8，2.25，3.4，5.1，5.91，7.1-7.4；

FAB-MS：[M+H]＝478；

TLC R_f0.29 (5% methanol in dichloromethane).

Preparation 376- (3-bromo-1-ethylpropyl ] -3- (. alpha. -cyclopropyl-m- (benzyloxycarbonylamino) benzyl) -4-hydroxypyran-2-one (formula I-2) is shown in Table I.

To a stirred solution of 114 mg of the title compound of preparation 36 in 3 ml of tetrahydrofuran were added 160 mg of triphenylphosphine and 200 mg of carbon tetrabromide. After 2 h, the solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel 60(230-400 mesh) eluting with 70-100% diethyl ether in hexane to give 113 mg of the title compound.

The physical properties were as follows:

¹H NMR(CDCl₃)δ0.25，0.35，0.55，0.65，0.84，1.5-2.2，3.2，3.35，3.52，5.16，5.95，6.79，7.1-7.4；

FAB-MS: (iv) [ M + H ] ═ 504.1404, found;

TLC R_f0.29 (75% diethyl ether in hexane).

Preparation of 386- (3-azido-1-ethylpropyl ] -3- (. alpha. -cyclopropyl-m- (benzyloxycarbonylamino) benzyl) -4-hydroxypyran-2-one (formula I-3) is shown in Table I.

To a stirred solution of 113 mg of the title compound of preparation 37 in 2.0 ml of ethanol was added 55 mg of sodium azide and 0.5 ml of water. The reaction mixture was heated overnight and then cooled. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel 60(230-400 mesh) eluting with ether to give 89 mg of the title compound.

The physical properties are as follows:

¹H NMR(CDCl₃)δ0.23，0.33，0.51，0.68，0.82，1.4-2.0，2.33，3.1-3.3，3.5，5.15，5.94，6.84，7.1-7.4；

EI-MS：[M+]＝502；

TLC R_f0.52 (10% ethyl acetate in dichloromethane).

Preparation 396- (3-amino-1-ethylpropyl ] -3- (. alpha. -cyclopropylm-aminobenzyl) -4-hydroxypyran-2-one (formula I-4) is shown in Table I.

A mixture of 87 mg of the title compound of preparation 38 and 35 mg of 5% palladium on carbon in 4 ml of ethanol is shaken under a 40psi hydrogen atmosphere for 4 hours. The mixture was filtered through celite and the filter cake was washed with ethanol. The filtrates were combined and the solvent was removed under reduced pressure to give 70 mg of a mixture of the title compound and 6- (3-amino-1-ethylpropyl ] -3- (. alpha. -cyclopropyl-m- (benzyloxycarbonylamino) benzyl) -4-hydroxypyran-2-one.

The physical properties were as follows:

TLC R_f0.05 (5% methanol in dichloromethane).

Preparation 403-cyclopropyl- [3- [ 1-methyl-1H-imidazole-4-sulfonylamino ] phenyl ] methyl ] -6- ({ 1-ethyl-3- [ 1-methyl-1H-imidazole-4-sulfonylamino ] } propyl) -2-oxo-2H-pyran-4-yl-1-methyl-1H-imidazole-4-sulfonate (formula I-5), see Table I.

To a mixture of 70 mg of the title compound of preparation 39 and 6- (3-amino-1-ethylpropyl ] -3- (. alpha. -cyclopropyl-m- (benzyloxycarbonylamino) benzyl) -4-hydroxypyran-2-one (also from preparation 39) in 1.5 ml of dichloromethane were added 120. mu.L of diisopropylethylamine and 92 mg of 1-methylimidazole-4-sulfonyl chloride, and after stirring overnight, the solvent was removed under reduced pressure, the residue was azeotroped with toluene, and then purified by flash column chromatography on silica gel 60(230-400 mesh) using a solution of 2-6% methanol in dichloromethane to give 49 mg of the title compound.

The physical properties were as follows:

¹H NMR(CDCl₃)δ0.2-0.5，0.75，0.90，1.4-2.0，2.55，3.0-3.4，3.6-3.7，6.63，7.0-7.7；

FAB-MS：[M+H]＝775；

TLC R_f0.14 (5% methanol in dichloromethane).

Example 107N- (3- { cyclopropyl- [6- (1-ethyl-3- { 1-methyl-1H-imidazole-4-sulfonylamino } propyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -1-methyl-1H-imidazole-4-sulfonamide (formula I-6) is shown in Table I.

A solution of 49 mg of the title compound of preparation 40 in 4 ml of methanol containing ammonia was cooled to 0 ℃ and treated with ammonia gas. After 5 minutes the introduction of ammonia was stopped and the flask was closed and warmed to room temperature. After standing overnight the solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel 60(230-400 mesh) using 3-9% methanol in dichloromethane to give 32 mg of the title compound.

The physical properties were as follows:

EI-MS：[M+]＝523；

TLC R_f0.33 (5% methanol in dichloromethane).

Preparation of 413- (. alpha. -cyclopropylm-aminobenzyl) -6- (1-ethyl-3-hydroxypropyl ] -4-hydroxypyran-2-one (formula J-1) is shown in Table J.

A mixture of 477 mg of the title compound of preparation 36 and 150 mg of 5% palladium on carbon in 10 ml of ethanol was shaken overnight under a 45psi hydrogen atmosphere. The mixture was filtered through celite and the filter cake was washed with ethanol. The filtrates were combined and the solvent was removed under reduced pressure to give 340 mg of the title compound.

The physical properties were as follows:

TLC R_f0.10 (5% methanol in dichloromethane).

Preparation 426- (3-bromo-1-ethylpropyl) -3- (. alpha. -cyclopropyl-m-aminobenzyl) -4-hydroxypyran-2-one (formula J-2), see Table J.

To a stirred solution of 340 mg of the title compound of preparation 41 in 7 ml of tetrahydrofuran was added 525 mg of triphenylphosphine and 663 mg of carbon tetrabromide. After 30 minutes, the solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel 60(230-400 mesh) using 30-50% ethyl acetate in dichloromethane to give 228 mg of the title compound.

The physical properties were as follows:

¹H NMR(CDCl₃)δ0.19，0.42，0.58，0.75，1.4-2.4，3.14，3.3，5.26，6.15，6.47，6.91，7.00；

TLC R_f0.45 (5% methanol in dichloromethane).

Example 108N- (3- { [6- (3-bromo-1-ethylpropyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] cyclopropylmethyl } phenyl) -1-methyl-1H-imidazole-4-sulfonamide (formula J-3) is shown in Table J.

To a mixture of 102 mg of the title compound of preparation 42 and 40 μ L of pyridine in 1.0 ml of dichloromethane was added 45 mg of 1-methylimidazole-4-sulfonyl chloride. After stirring overnight, the solvent was removed under reduced pressure. The residue was azeotroped with toluene and then purified by flash column chromatography on silica gel 60(230-400 mesh) with 2-5% methanol in dichloromethane to yield 86 mg of the title compound.

The physical properties were as follows:

¹H NMR(CDCl₃-CD₃OD)δ0.2，0.44，0.60，0.82，1.4-2.2，2.5，3.1-3.4，3.62，5.93，6.92，7.07，7.19，7.30，7.40；

FAB-MS: (iv) [ M + H ] ═ 505.1037, found;

TLC R_f0.36 (5% methanol in dichloromethane).

Example 109N- (3- { [6- (3-azido-1-ethylpropyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] cyclopropylmethyl } phenyl) -1-methyl-1H-imidazole-4-sulfonamide (formula J-4) is shown in Table J.

To a stirred solution of 113 mg of the title compound of example 108 in 1.2 ml of ethanol were added 50 mg of sodium azide and 0.4 ml of water. The reaction mixture was heated overnight and then cooled. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel 60(230-400 mesh) eluting with 3-6% methanol in dichloromethane to give 57 mg of the title compound.

The physical properties were as follows:

¹H NMR(CDCl₃-CD₃OD)δ0.25，0.48，0.66，0.90，1.3-1.8，2.42，2.9-3.2，3.68，5.94，6.93，7.12，7.1 9，7.23，7.35，7.46；

FAB-MS: (iv) [ M + H ] ═ 550.1037, found;

TLC R_f0.36 (5% methanol in dichloromethane).

Preparation of 43N- (3- { [6- (3-amino-1-ethylpropyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] cyclopropylmethyl } phenyl) -1-methyl-1H-imidazole-4-sulfonamide (formula J-5) is shown in Table J.

A mixture of 104 mg of the title compound of example 109 and 30 mg of 5% palladium on carbon in 2 ml of methanol and ethanol, respectively, was shaken overnight under a 45psi hydrogen atmosphere. The mixture was filtered through celite and the filter cake was washed with ethanol. The filtrates were combined and the solvent was removed under reduced pressure to give 69 mg of the title compound.

The physical properties were as follows:

TLC R_f0.05 (5% methanol in dichloromethane).

Example 1102- [ [8- [ [3- [3- [ cyclopropyl [3- [ [ (1-methyl-1H-imidazol-4-yl) sulfonyl ] amino ] phenyl ] methyl ] -4-hydroxy-2-oxo-2H-pyran-6-yl ] pentyl ] amino ] -1, 8-dioxooctyl ] methylamino ] ethanesulfonic acid monosodium salt (formula J-6), see Table J.

A suspension of 69 mg of the title compound of preparation 43 in 1.0 ml of dichloromethane was treated with 0.22 ml (0.65M acetonitrile solution) of triethylamine salt of sultanic acid and 25. mu.L of diisopropylcarbodiimide. After 1 hour, the mixture was treated with 0.5 ml of dimethylformamide. After stirring overnight, the solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel 60(230-400 mesh) eluting with 10-30% methanol in dichloromethane. The crude product was dissolved in water saturated n-butanol and partitioned with saturated aqueous sodium sulfate solution. The aqueous phase was extracted twice with another portion of water-saturated n-butanol. The combined n-butanol layers were filtered through a pad of sodium sulfate and concentrated under reduced pressure to give 94 mg of the title compound.

The physical properties were as follows:

¹H NMR(CDCl₃-CD₃OD)δ0.05-0.6，0.83，1.1-2.5，2.9-3.7，3.68，5.84，6.8-7.6；

FAB-MS: (iv) [ M + H ] ═ 768.2838, found;

TLC R_f0.21 (20% methanol in dichloromethane).

Example 111-

Using the above methods and using starting materials and reagents known and available to those of ordinary skill in the art of organic synthesis, the following compounds were prepared:

111) n- (3- { cyclopropyl- [ 4-hydroxy-6- (3- { [ (2-hydroxy-1, 1-bis { hydroxymethyl } ethyl) amino ] carbonyl } aminopropyl) -2-oxo-2H-pyran-3-yl ] methyl ] phenyl ] benzenesulfonamide

112) N- (3- { cyclopropyl- [ 4-hydroxy-6- (3- { [ (2-hydroxy-1, 1-bis { hydroxymethyl } ethyl) amino ] carbonyl } aminopropyl) -2-oxo-2H-pyran-3-yl ] methyl ] phenyl) -2-pyridinesulfonamide

113) N- (3- { cyclopropyl- [ 4-hydroxy-6- (3- { [ (2-hydroxy-1, 1-bis { hydroxymethyl } ethyl) amino ] carbonyl } aminopropyl) -2-oxo-2H-pyran-3-yl ] methyl ] phenyl) -1H-imidazole-2-sulfonamide

114) N- (3- { cyclopropyl- [ 4-hydroxy-6- (3- { [ (2-hydroxy-1, 1-bis { hydroxymethyl } ethyl) amino ] carbonyl } aminopropyl) -2-oxo-2H-pyran-3-yl ] methyl ] phenyl) -1H-benzimidazole-2-sulfonamide

115) N- (3- { cyclopropyl- [ 4-hydroxy-6- (3- { [ (2-hydroxy-1, 1-bis { hydroxymethyl } ethyl) amino ] carbonyl } aminopropyl) -2-oxo-2H-pyran-3-yl ] methyl ] phenyl) -1-methyl-1H-imidazole-4-sulfonamide

116) N- (3- { cyclopropyl- [ 4-hydroxy-6- (3- { [ (2-hydroxy-1, 1-bis { hydroxymethyl } ethyl) amino ] carbonyl } aminopropyl) -2-oxo-2H-pyran-3-yl ] methyl ] phenyl) -1-methyl-1H-imidazole-2-sulfonamide

117) N- (3- { cyclopropyl- [ 4-hydroxy-6- (3- { gamma-L-glutamyl } aminopropyl) -2-oxo-2H-pyran-3-yl ] methyl ] phenyl ] benzenesulfonamide

118) N- (3- { cyclopropyl- [ 4-hydroxy-6- (3- { gamma-L-glutamyl } aminopropyl) -2-oxo-2H-pyran-3-yl ] methyl ] phenyl) -2-pyridinesulfonamide

119) N- (3- { cyclopropyl- [ 4-hydroxy-6- (3- { γ -L-glutamyl } aminopropyl) -2-oxo-2H-pyran-3-yl ] methyl ] phenyl) -1H-imidazole-sulphonamide

120) N- (3- { cyclopropyl- [ 4-hydroxy-6- (3- { γ -L-glutamyl } aminopropyl) -2-oxo-2H-pyran-3-yl ] methyl ] phenyl) -1H-benzimidazole-sulfonamide

121) N- (3- { cyclopropyl- [ 4-hydroxy-6- (3- { γ -L-glutamyl } aminopropyl) -2-oxo-2H-pyran-3-yl ] methyl ] phenyl) -1-methyl-1H-imidazole-4-sulphonamide

122) N- (3- { cyclopropyl- [ 4-hydroxy-6- (3- { γ -L-glutamyl } aminopropyl) -2-oxo-2H-pyran-3-yl ] methyl ] phenyl) -1-methyl-1H-imidazole-2-sulphonamide

123) N- (3- { cyclopropyl- [ 4-hydroxy-6- (3- { [ piperazin-1-yl ] carbonyl } aminopropyl) -2-oxo-2H-pyran-3-yl ] methyl ] phenyl) benzenesulfonamide

124) N- (3- { cyclopropyl- [ 4-hydroxy-6- (3- { [ piperazin-1-yl ] carbonyl } aminopropyl) -2-oxo-2H-pyran-3-yl ] methyl ] phenyl) -2-pyridinesulfonamide

125) N- (3- { cyclopropyl- [ 4-hydroxy-6- (3- { [ piperazin-1-yl ] carbonyl } aminopropyl) -2-oxo-2H-pyran-3-yl ] methyl ] phenyl) -1H-imidazole-2-sulfonamide

126) N- (3- { cyclopropyl- [ 4-hydroxy-6- (3- { [ piperazin-1-yl ] carbonyl } aminopropyl) -2-oxo-2H-pyran-3-yl ] methyl ] phenyl) -1H-benzimidazole-2-sulfonamide

127) N- (3- { cyclopropyl- [ 4-hydroxy-6- (3- { [ piperazin-1-yl ] carbonyl } aminopropyl) -2-oxo-2H-pyran-3-yl ] methyl ] phenyl) -1-methyl-1H-imidazole-4-sulphonamide

128) N- (3- { cyclopropyl- [ 4-hydroxy-6- (3- { [ piperazin-1-yl ] carbonyl } aminopropyl) -2-oxo-2H-pyran-3-yl ] methyl ] phenyl) -1-methyl-1H-imidazole-2-sulphonamide

129)2- [ [8- [ [3- [3- [ cyclopropyl [3- [ [ phenylsulfonyl ] amino ] phenyl ] methyl ] -4-hydroxy-2-oxo-2H-pyran-6-yl ] propyl ] amino ] -1, 8-dioxooctyl ] methylamino ] ethanesulfonic acid monosodium salt

130)2- [ [8- [ [3- [3- [ cyclopropyl [3- [ [ (2-pyridinyl) sulfonyl ] amino ] phenyl ] methyl ] -4-hydroxy-2-oxo-2H-pyran-6-yl ] propyl ] amino ] -1, 8-dioxooctyl ] methylamino ] ethanesulfonic acid monosodium salt

131)2- [ [8- [ [3- [3- [ cyclopropyl [3- [ [ (1H-benzimidazol-2-yl) sulphonyl ] amino ] phenyl ] methyl ] -4-hydroxy-2-oxo-2H-pyran-6-yl ] propyl ] amino ] -1, 8-dioxooctyl ] methylamino ] ethanesulfonic acid monosodium salt

132)2- [ [8- [ [3- [3- [ cyclopropyl [3- [ [ (1H-imidazol-2-yl) sulfonyl ] amino ] phenyl ] methyl ] -4-hydroxy-2-oxo-2H-pyran-6-yl ] propyl ] amino ] -1, 8-dioxooctyl ] methylamino ] ethanesulfonic acid monosodium salt

133)2- [ [8- [ [3- [3- [ cyclopropyl [3- [ [ (1-methyl-1H-imidazol-4-yl) sulfonyl ] amino ] phenyl ] methyl ] -4-hydroxy-2-oxo-2H-pyran-6-yl ] propyl ] amino ] -1, 8-dioxooctyl ] methylamino ] ethanesulfonic acid monosodium salt

134)2- [ [8- [ [3- [3- [ cyclopropyl [3- [ [ (1-methyl-1H-imidazol-2-yl) sulfonyl ] amino ] phenyl ] methyl ] -4-hydroxy-2-oxo-2H-pyran-6-yl ] propyl ] amino ] -1, 8-dioxooctyl ] methylamino ] ethanesulfonic acid monosodium salt

Preparation of 44 (tetrahydropyran-4-yl) methanol (formula K-2), see Table K.

To a cooled (0 ℃) and stirred solution of 651 mg of tetrahydropyran-4-carboxylic acid in 2.5 ml of tetrahydrofuran, 10 ml of a 1.0M solution of borane in tetrahydrofuran are added dropwise under argon. After 18 hours at room temperature, the solution was cooled again to 0 ℃ and quenched with 1 ml of potassium hydroxide. The mixture was acidified with 1M aqueous hydrochloric acid and extracted 4 times with dichloromethane. The extract' was dried over magnesium sulfate and concentrated carefully under reduced pressure to give 0.72 g of colorless liquid alcohol.

The physical properties were as follows:

¹H NMRδ1.2-1.4，1.6，1.8，3.3-3.4，3.6，4.0ppm。

preparation of 45 p-toluenesulfonic acid (tetrahydropyran-4-yl) methyl ester (formula K-3), see Table K.

To a cooled (0 ℃) and stirred solution of 5 mmol of the title compound of preparation 44 and 0.81 ml of pyridine in 5 ml of dichloromethane was added 1.05 g of p-toluenesulfonyl chloride and the solution was warmed to room temperature. After 18 hours, the mixture was partitioned between ethyl acetate and dilute aqueous hydrochloric acid and the organic phase was washed with brine and dried over magnesium sulfate. After removal of the solvent under reduced pressure, the residue was subjected to flash chromatography on silica gel with 50% ethyl acetate in hexane to give 1.23 g of the title compound as a colorless liquid.

The physical properties were as follows:

¹H NMRδ1.2-1.4，1.6，1.9-2.0，2.46，3.34，3.85，3.95，7.3，7.8ppm。

MS：270。

preparation of 46 (tetrahydropyran-4-yl) methyl iodide (formula K-4), see Table K.

A solution of 800 mg of preparation 45 of tosylate and 887 mg of sodium iodide in 6 ml of acetone is refluxed for 6 hours under nitrogen and then partitioned between ether and dilute aqueous sodium thiosulfate. The organic phase was washed with brine, dried over magnesium sulfate and carefully concentrated at atmospheric pressure to give 648 mg of colorless liquid iodide.

The physical properties were as follows:

¹H NMRδ1.2-1.4，1.6-1.9，3.1，3.37，3.97。

preparation 476- (1- (tetrahydropyran-4-ylmethyl) propyl) -4-hydroxypyran-2-one (formula K-5) is shown in Table K.

To a cooled (-78 ℃ C.) and stirred solution of 0.90 ml of diisopropylamine in 5 ml of tetrahydrofuran, 3.7 ml of a 1.6M solution of n-butyllithium in hexane were added by syringe under argon. The solution was warmed to 0 ℃ for 10 minutes, and then a solution of 431 mg of the title compound of preparation 50 in 3 ml of hexamethylphosphoramide was added via cannula. After 20 minutes, the dark red solution was cooled to-50 ℃ and 605 mg of the preparation 46 iodide solution in 1 ml of tetrahydrofuran was added by cannula. The reaction was slowly warmed to 0 ℃ and then quenched with phosphate buffer at pH 7. After removal of tetrahydrofuran under reduced pressure, the residual liquid was acidified with dilute aqueous hydrochloric acid and the resulting precipitate was extracted with two portions of ethyl acetate. The organics were washed with dilute aqueous hydrochloric acid and brine, dried over magnesium sulfate, and concentrated under reduced pressure. Flash chromatography of the residue on silica gel with 5% acetic acid and 30-40% ethyl acetate in dichloromethane afforded 553 mg of the title compound as a thick yellow gum.

The physical properties were as follows:

TLC R_f0.36 (5% acetic acid, 65% ethyl acetate in dichloromethane)

¹H NMRδ0.85，1.2-1.8，2.45，3.34，3.9，5.56，5.94ppm。

MS：252。

Preparation of 483- [ (3-benzyloxycarbonylaminophenyl) cyclopropylmethyl ] -6- (1- (tetrahydropyran-4-ylmethyl) propyl-4-hydroxypyran-2-one (formula K-6) is shown in Table K.

A solution of 549 mg of the alkylation product of preparation 47, 970 mg of 3-benzyloxycarbonylaminophenyl cyclopropyl methanol and 60 mg of p-toluenesulfonic acid monohydrate in 5 ml of dichloromethane was refluxed over 10 ml of 3A molecular sieve for 18 hours. After removal of the solvent under reduced pressure. Flash chromatography of the residue on silica gel from 25-100% ethyl acetate in dichloromethane to 5% methanol in ethyl acetate afforded 511 mg of the title compound as a brown solid.

The physical properties were as follows:

TLC R_f0.32 (30% ethyl acetate in dichloromethane)

¹H NMRδ0.2，0.5，0.7，0.8，1.3-1.7，3.27，3.42，3.86，5.13，5.96，7.1-7.4ppm。

MS：531。

Preparation of 493- [ (3-aminophenyl) cyclopropylmethyl ] -6- (1- (tetrahydropyran-4-ylmethyl) propyl-4-hydroxypyran-2-one (formula K-7) is shown in Table K.

A mixture of 510 mg of the title compound of preparation 48, 605 mg of ammonium formate and 100 mg of 5% palladium on carbon in 8 ml of methanol is stirred for 3 hours under a hydrogen atmosphere and then filtered through celite. The filtrate was concentrated under reduced pressure and the residue was flash chromatographed on silica gel with 2-4% methanol in dichloromethane to give 280 mg of the title amine as a white solid.

The physical properties were as follows:

TLC R_f0.33 (5% methanol in methylene chloride)

¹H NMRδ0.24，0.42，0.53，0.68，0.84，1.1-1.7，2.35，3.33，3.6，3.9，5.82，6.5，6.83，6.9，7.11ppm。

Example 135N- (3- { cyclopropyl- [6- (1-tetrahydropyran-4-ylmethyl) propyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -1-methyl-1H-imidazole-4-sulfonamide (formula K-8) is shown in Table K.

To a stirred solution of 60 mg of the amine of preparation 49 and 24. mu.L of pyridine in 0.5 ml of dichloromethane was added 27 mg of 1-methylimidazole-4-sulfonyl chloride. After 18 hours, the reaction was chromatographed on silica gel with 3-6% methanol in dichloromethane to give 70 mg of the title compound as a white solid.

The physical properties were as follows:

TLC R_f0.24 (5% methanol in methylene chloride)

¹H NMRδ0.12，0.26，0.45，0.60，0.82，1.1-1.9，2.3，3.3，3.58，3.9，6.00，6.9-7.5ppm。

HRMS：541.2238。

Preparation of 504-hydroxy-6-propylpyran-2-one (formula K-9), see Table K.

To a cooled (-78 ℃) and stirred solution of 6.3 ml diisopropylamine in 40 ml dry tetrahydrofuran was added under argon 27.5 ml of a 1.6 molar solution of butyllithium in hexane. The solution is warmed to 0 ℃ and a solution of 2.52 g of 4-hydroxy-6-methyl-2-pyrone of the formula k-10 in 20 ml of hexamethylphosphoric triamide is added. The dark red solution was stirred at 0 ℃ for 30 minutes, then cooled to-45 ℃ and 1.5 ml of iodoethane was added. The solution was warmed to 0 ℃ and quenched with 60 ml of 1N aqueous hydrochloric acid. The tetrahydrofuran was removed under reduced pressure and the residue was extracted 5 times with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. Flash chromatography of the residue on silica gel with 4% acetic acid and 16% ethyl acetate in dichloromethane afforded 2.34 g of the title compound as a waxy yellow solid.

The physical properties were as follows:

TLC R_f0.29 (5% acetic acid and 15% ethyl acetate in dichloromethane)

¹H NMRδ0.98，1.6，2.4，5.63，6.05。

Preparation 514-hydroxy-6-phenethyl-2H-pyran-2-one (formula L-2), see Table L.

To a flame-dried flask containing a stirred solution of 0.90 ml of diisopropylamine in 6 ml of anhydrous tetrahydrofuran was added 4.0 ml of a 1.6M solution of n-butyllithium in hexane at-78 ℃ under an argon atmosphere. The resulting solution was warmed to 0 ℃ for 20 minutes and then treated by cannula with 378 mg of a commercially available solution of 4-hydroxy-6-methyl-2-pyrone of formula L-1 in 15 ml of tetrahydrofuran. The resulting red viscous slurry was treated slowly with 6.0 ml of distilled hexamethylphosphoramide and stirred for 30 minutes. The red cloudy solution was then treated with 0.36 ml of benzyl bromide. The reaction quickly turned into a dark orange solution and the reaction was stirred at 0 ℃ for 60 minutes. The mixture was quenched with an excess of 1N aqueous hydrochloric acid and the resulting yellow two-phase mixture was concentrated to remove tetrahydrofuran. The resulting mixture was partitioned between dichloromethane and water and the acidic aqueous phase was further extracted with another portion of dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. The resulting material was diluted with a large amount of ether and washed with dilute aqueous hydrochloric acid. The ether phase was washed with two more aqueous hydrochloric acid solutions, once with brine, dried over magnesium sulfate and finally concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel 60(230-400 mesh) eluting with 1% acetic acid and 20-40% ethyl acetate in dichloromethane to give 440 mg of the title compound as a brown solid.

The physical properties were as follows:

¹H NMRδ2.7，3.0，5.46，5.84，7.1-7.3。

TLC R_f0.38 (1% acetic acid and 25% ethyl acetate in dichloromethane).

Melting point 137-.

Preparation of 526- (. alpha. -ethylphenylethyl) -4-hydroxy-2H-pyran-2-one (formula L-3), see Table L.

To a cooled (-78 ℃ C.) and stirred solution of 0.29 ml of diisopropylamine in 4 ml of anhydrous tetrahydrofuran under argon was added 1.2 ml of a 1.6M solution of n-butyllithium in hexane. The solution was warmed to 0 ℃, held at that temperature for 10 minutes, and then cooled to-30 ℃. To this solution was added 189 mg of the title compound of preparation 51 in 4 ml of tetrahydrofuran using a cannula. The resulting heterogeneous mixture was warmed to 0 ℃ and enough hexamethylphosphoramide (about 1 ml) was added to make the mixture as homogeneous as possible. After stirring the mixture at 0 ℃ for 30 minutes, 77. mu.L of iodoethane was added dropwise. After stirring for a further 90 minutes, the reaction was quenched with an excess of 1N aqueous hydrochloric acid and the tetrahydrofuran was removed under reduced pressure. The residue was extracted with three portions of ethyl acetate and the combined organic extracts were washed with dilute aqueous hydrochloric acid, dried over magnesium sulfate and concentrated under reduced pressure. Flash chromatography of the residue on silica gel 60(230-400 mesh) using 1% acetic acid and 25% ethyl acetate in dichloromethane afforded 182 mg of the title compound.

The physical properties were as follows:

¹H NMRδ0.85，1.6，2.6，2.9，5.59，5.86，7.0-7.3。

FAB MS[m+H]＝245.1185。

TLC R_f0.33 (1% acetic acid and 25% ethyl acetate in dichloromethane).

Preparation of 533- (. alpha. -cyclopropyl-m- (benzyloxycarbonylamino) benzyl) -6- (. alpha. -ethylphenylethyl) -4-hydroxy-2H-pyran-2-one (formula L-4) is shown in Table L.

A mixture of 181 mg of the title compound of preparation 52, 220 mg of the compound of the formula F-5, 28 mg of p-toluenesulfonic acid monohydrate and 600 mg of 3 a molecular sieve in 2 ml of benzene was refluxed for 21 hours under argon atmosphere, then cooled and filtered through celite. The filtrate was concentrated under reduced pressure and the residue was subjected to flash chromatography on silica gel 60(230-400 mesh) using 50-100% ethyl acetate in hexane to give 250 mg of a mixture. The mixture was chromatographed over silica gel with 5-20% ethyl acetate in dichloromethane to give 154 mg (40%) of the title compound.

The physical properties were as follows:

¹H NMRδ0.26，0.48，0.67，0.81，1.6，1.8，2.5，2.7，2.9，3.48，5.14，5.86，6.81，7.0-7.5，9.46。

EI HRMS m/z＝523.2350。

TLC R_f0.27 (5% ethyl acetate in dichloromethane).

Preparation 543- (. alpha. -cyclopropylm-aminobenzyl) -6- (. alpha. -ethylphenylethyl) -4-hydroxy-2H-pyran-2-one (formula L-5), see Table L.

A mixture of 146 mg of the title compound of preparation 53 and 50 mg of 5% palladium on carbon in 2 ml of methanol was shaken under a 40psi hydrogen atmosphere for 2 hours and then filtered through celite. The filtrate was concentrated under reduced pressure to give 105 mg (96%) of the title compound.

The physical properties were as follows:

¹H NMRδ0.25，0.5，0.65，0.81，1.6，2.5，2.7，2.9，3.4，5.79，6.5，6.8-7.3。

TLC R_f0.38 (30% ethyl acetate in dichloromethane).

Example 136-

The following compounds of the present invention were prepared by reacting a compound of formula L-5 with the appropriate sulfonyl chloride in a manner analogous to that described above. The stereoisomers are prepared by chiral HPLC resolution of intermediates such as compounds of formulae L-3, L-4, L-5 and L-6. (see Table L).

136) N- (3- { cyclopropyl- [6- (1-ethylphenylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -1-methyl-1H-imidazole-4-sulfonamide

The physical properties were as follows:

TLC R_f0.29 (5% methanol in methylene chloride)

¹H NMRδ0.2，0.5，0.65，0.86，1.63，1.80，2.51，2.8，3.3，3.62，5.7，6.8-7.4ppm。

HRMS：533.1998。

137) N- (3- (R or S) - { cyclopropyl- [6- (1- (R) -ethylphenylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -1-methyl-1H-imidazole-4-sulfonamide

The physical properties were as follows:

TLC R_f0.32 (5% methanol in methylene chloride)

¹H NMRδ0.18，0.43，0.63，0.83，1.6，1.75，2.5，2.7-2.9，3.3，3.55，5.76，6.9-7.4ppm。

HRMS：533.1983。

138) N- (3- (R or S) - { cyclopropyl- [6- (1- (R) -ethylphenylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -1-methyl-1H-imidazole-4-sulfonamide

The physical properties were as follows:

TLC R_f0.30 (5% methanol in methylene chloride)

HRMS：533.1993。

139) N- (3- (R or S) - { cyclopropyl- [6- (1- (S) -ethylphenylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -1-methyl-1H-imidazole-4-sulfonamide

The physical properties were as follows:

TLC R_f0.30 (5% methanol in methylene chloride)

HRMS：533.1993。

140) N- (3- (R or S) - { cyclopropyl- [6- (1- (S) -ethylphenylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -1-methyl-1H-imidazole-4-sulfonamide

The physical properties were as follows:

TLC R_f0.30 (5% methanol in methylene chloride)

¹H NMRδ0.17，0.44，0.62，0.83，1.6，1.75，2.50，2.7-3.0，3.3，3.53，5.80，6.9-7.4ppm。

HRMS：533.1990。

141) N- (3- (R or S) - { cyclopropyl- [6- (1- (R) -ethylphenylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -2-pyridinesulfonamide

The physical properties were as follows:

TLC R_f0.34 (30% ethyl acetate in dichloromethane)

¹H NMRδ0.2，0.45，0.6，0.86，1.5-1.9，2.5，2.8-3.0，3.2，5.7，6.9-7.4，7.8，8.6ppm。

MS：530。

142) N- (3- (R or S) - { cyclopropyl- [6- (1- (R) -ethylphenylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -2-pyridinesulfonamide

The physical properties were as follows:

TLC R_f0.35 (30% ethyl acetate in dichloromethane)

¹H NMRδ0.11，0.20，0.43，0.58，0.85，1.5-1.8，2.5，2.7-3.0，3.3，5.69，6.9-7.4，7.8，8.6ppm。

MS：530。

143) N- (3- (R or S) - { cyclopropyl- [6- (1- (R) -ethylphenylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -1-methyl-1H-imidazole-2-sulfonamide

The physical properties were as follows:

TLC R_f0.34 (5% methanol in methylene chloride)

¹H NMRδ0.19，0.5，0.65，0.89，1.6-1.9，2.5，2.8-3.0，3.3，3.40，5.70，6.8-7.4ppm。

MS：533。

144) N- (3- (R or S) - { cyclopropyl- [6- (1- (R) -ethylphenylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -1-methyl-1H-imidazole-2-sulfonamide

The physical properties were as follows:

TLC R_f0.34 (5% methanol in methylene chloride)

¹H NMRδ0.20，0.44，0.65，0.88，1.6-1.8，2.5，2.8-3.0，3.3，3.42，5.73，6.8-7.4ppm。

MS：533。

145) N- (3- { cyclopropyl- [6- (1- (tetrahydropyran-4-ylmethyl) propyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -1-methyl-1H-imidazole-2-sulfonamide

The physical properties were as follows:

TLC R_f0.22 (5% methanol in methylene chloride)

¹H NMRδ0.16，0.24，0.47，0.64，0.86，1.2-1.9，3.2-3.4，3.47，3.7-4.0，5.89，6.9-7.4ppm。

MS：541。

145A) N- (3- [ cyclopropyl [ 4-hydroxy-2-oxo-6- (1- (tetrahydro-2H-pyran-3-yl) methyl ] propyl ] -2H-pyran-3-yl ] methyl ] phenyl ] -8-quinolinesulfonamide

The physical properties were as follows:

measured value of MW: m/z 588.

145B) N- (3- [ cyclopropyl [ 4-hydroxy-2-oxo-6- [1- [ (tetrahydro-2H-pyran-3-yl) methyl ] propyl ] -2H-pyran-3-yl ] methyl ] phenyl ] -1-methyl-1H-imidazole-4-sulfonamide

The physical properties were as follows:

measured value of MW: m/z 541.

146) N- (3- { cyclopropyl- [6- (1- (R) -ethylphenylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) benzimidazole-2-sulfonamide

The physical properties were as follows:

TLC R_f0.40 (50% ethyl acetate in dichloromethane)

¹H NMRδ0.1-0.6，0.85，1.5-1.7，2.5，2.7-3.0，3.3，5.74，6.7-7.3，7.5-7.7ppm。

HRMS：570.2054。

147) N- (3- { cyclopropyl- [6- (1- (R) -ethylphenyl-ethyl) -4-hydroxy-2-oxo-2H-pyran-3-ylmethyl } phenyl) -1H-imidazole-2-sulfonamide

The physical properties were as follows:

TLC R_f0.31 (5% methanol in dichloromethane)

¹H NMR δ 0.2，0.4，0.6，0.87，1.5-1.8，2.5，2.8-3.0，3.3，5.54，6.8，6.9-7.4ppm。

148) N- (3- (R or S) - { cyclopropyl- [6- (1- (R) -ethylphenylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -4-cyanobenzenesulfonamide

The physical properties were as follows:

TLC R_f0.47 (20% ethyl acetate in dichloromethane)

¹H NMRδ0.1，0.2，0.4，0.6，0.84，1.5-1.8，2.5，2.7-3.0，3.3，5.70，6.9，7.0-7.3，7.6，7.8ppm。

HRMS：554.1886。

149) N- (3- (R or S) - { cyclopropyl- [6- (1- (R) -ethylphenylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -4-cyanobenzenesulfonamide

The physical properties were as follows:

TLC R_f0.35 (15% ethyl acetate in dichloromethane)

¹H NMRδ0.1，0.2，0.4，0.6，0.85，1.5-1.9，2.5，2.7-3.0，3.3，5.7，6.9-7.3，7.6，7.8PPm。

HRMS：554.1876。

150) N- (3- { cyclopropyl- [6- (1-ethylphenylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -4-nitrobenzenesulfonamide

The physical properties were as follows:

TLC R_f0.28 (10% ethyl acetate in dichloromethane)

¹H NMRδ0.1，0.2，0.4，0.6，0.83，1.5-1.9，2.5，2.7-3.0，3.3，5.70，6.9-7.3，7.9，8.2ppm。

HRMS：574.1773。

Preparation of 55 (2- (2- (2-methoxyethoxy) ethoxy) p-toluenesulfonate (formula M-2), see Table M.

To a stirred suspension of 19.1 g of p-toluenesulfonyl chloride in 100 ml of dichloromethane was added a mixture of 16 ml of triethylene glycol monomethyl ether and 10 ml of pyridine, followed by 200 mg of dimethylaminopyridine. After 3 days, the mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and dilute aqueous hydrochloric acid. The organic phase was washed with water, saturated aqueous sodium bicarbonate and brine and dried over magnesium sulfate. After removal of the solvent under reduced pressure, the residue was subjected to flash chromatography on silica gel with 25% ethyl acetate in dichloromethane to give 18.25 g of the title compound as a colorless liquid.

The physical properties were as follows:

TLC R_f0.27 (20% ethyl acetate in dichloromethane)

¹H NMRδ2.45，3.38，3.5-3.8，4.15，7.35，7.8ppm。

IR 2879，1357，1190，1177，1108，1099，924，665cm^-1

MS：318。

Preparation 562-hydroxy-4- (2- (2- (2-methoxyethoxy) ethoxy) acetophenone (formula M-3), see table M.

A mixture of 1.52 g of 2, 4-dihydroxyacetophenone, 3.82 g of the tosylate of preparation 55, 3.26 g of cesium carbonate and 0.2 g of potassium iodide in 20 ml of dioxane was heated at 100 ℃ overnight, then cooled and partitioned between dichloromethane and dilute aqueous hydrochloric acid. The aqueous phase was extracted with two more portions of dichloromethane and the combined organic phases were dried over magnesium sulfate and then concentrated under reduced pressure. Flash chromatography of the residue on silica gel with 80-100% ethyl acetate in hexane afforded 2.91 g of the title compound as an almost colorless liquid.

The physical properties were as follows:

TLC R_f0.35 (80% ethyl acetate in hexane)

¹H NMRδ2.56，3.38，3.5-3.9，4.2，6.4-6.5，7.6ppm。

IR 1635，1372，1257，1133cm^-1

MS：298。

Preparation 573 ethyl- (2-hydroxy-4- (2- (2- (2-methoxyethoxy) ethoxy) phenyl-3-oxopropanoate (formula M-4) is shown in Table M.

To a stirred solution of 1.49 g of the title compound of preparation 56 in 10 ml of diethyl carbonate 600 mg of a 60% sodium hydride dispersion in mineral oil are added in portions. The resulting mixture was heated at 80 ℃ for 2 hours, then cooled and partitioned between dichloromethane and dilute aqueous hydrochloric acid. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure, and the residue is purified by flash chromatography on silica gel with 20-30% ethyl acetate in dichloromethane to give 0.91 g of the title compound as a yellow oil.

The physical properties were as follows:

TLC R_f0.44 (3% acetic acid and 30% ethyl acetate in dichloromethane)

¹H NMRδ1.3，3.38，3.5-4.0，4.2，6.4-6.5，7.6ppm。

MS：370。

Preparation 584-hydroxy- (2- (2- (2-methoxyethoxy) ethoxy) coumarin (formula M-5) is shown in Table M.

A solution of 789 mg of the title compound of preparation 57 in 10 ml of acetic acid is refluxed for 2 hours and then concentrated under reduced pressure. Flash chromatography of the residue on silica gel with 5-1O% acetic acid in ethyl acetate afforded 634 mg of the title compound as a pale yellow solid.

The physical properties were as follows:

TLC R_f0.31 (10% acetic acid in ethyl acetate)

¹H NMRδ3.37，3.5-3.9，4.1，5.67，6.6，6.7，7.6ppm。

MS：324。

Preparation 593- [ (3-benzyloxycarbonylaminophenyl) cyclopropylmethyl ] -4-hydroxy-7- {2- [2- (2-methoxyethoxy) ethoxy ] coumarin (formula M-6) is shown in Table M.

A mixture of 704 mg of the title compound of preparation 58, 775 mg of m-benzyloxycarbonylaminophenyl cyclopropyl methanol of formula F-5, and 62 mg of p-toluenesulfonic acid monohydrate in 8 ml of dichloromethane was refluxed over about 10 ml of 3A molecular sieves for 18 hours. The solution was then concentrated under reduced pressure and the residue was flash chromatographed on silica gel using 10-20% (10% acetic acid in ethyl acetate) in dichloromethane to give 760 mg of the title compound.

The physical properties were as follows:

TLC R_f0.33 (2% acetic acid and 20% ethyl acetate in dichloromethane)

¹H NMRδ0.27，0.46，0.71，1.61，3.33，3.5-3.9，4.1，5.13，6.6，6.7，7.1-7.6ppm。

Preparation 603- [ (3-aminophenyl) cyclopropylmethyl ] -4-hydroxy-7- {2- [2- (2-methoxyethoxy) ethoxy ] coumarin (formula M-7) is shown in Table M.

A solution of 760 mg of the title compound of preparation 59, 800 mg of ammonium formate and 200 mg of 5% palladium on carbon catalyst in 8 ml of methanol was stirred for 1 hour under argon and then filtered through a pad of celite. The filtrate was concentrated under reduced pressure and the residue was triturated with dichloromethane. The solvent was removed under reduced pressure to give 591 mg of the title amine.

The physical properties were as follows:

TLC R_f0.29 (5% methanol in methylene chloride)

Example 151N- (3- { cyclopropyl- [7- (2- (2- (2-methoxyethoxy) ethoxy) -4-hydroxycoumarin-3-yl ] methyl } phenyl) -1-methyl-1H-imidazole-4-sulfonamide (formula M-8) is shown in Table M.

To a stirred solution of 70 mg of the title compound of preparation 60 and 24 μ L of pyridine in 0.5 ml of dichloromethane was added 27 mg of 1-methylimidazole-4-sulfonyl chloride. After 18 hours, the solution was flash chromatographed on silica gel with 5-15% methanol in dichloromethane to give 76 mg of the title sulfonamide as a pink amorphous foam.

The physical properties were as follows:

TLC R_f0.21 (5% methanol in methylene chloride)

¹H NMR δ 0.16，0.29，0.45，0.61，1.71，3.34，3.4-3.9，4.1，6.6-6.8，7.0-7.4，7.7ppm。

HRMS：614.2179

Example 152-

The following compounds of the present invention were prepared in a similar manner to that described above.

152) N- (3- { cyclopropyl- [ 7-methoxy-4-hydroxycoumarin-3-yl ] methyl } phenyl) -1-methyl-1H-imidazole-4-sulfonamide

The physical properties were as follows:

TLC R_f0.29 (5% methanol in methylene chloride)

¹H NMR δ 0.18，0.35，0.50，0.63，1.61，3.51，3.7，3.84，6.7-6.8，7.1-7.4，7.7ppm。

HRMS：481.1301

153) N- (3- { cyclopropyl- [7- (2- (2- (2-methoxyethoxy) ethoxy) -4-hydroxycoumarin-3-yl ] methyl } phenyl) -8-quinolinesulfonamide

The physical properties were as follows:

TLC R_f0.41 (5% methanol in methylene chloride)

¹H NMR δ -0.03，0.31，0.47，1.30，3.36，3.5-3.8，3.9，4.2，6.6-7.6，7.8，8.0，8.2ppm。

HRMS：661.2219

154) N- (3- { cyclopropyl- [7- (2- (2- (2-methoxyethoxy) ethoxy) -4-hydroxycoumarin-3-yl ] methyl } phenyl) -2-pyridinesulfonamide

The physical properties were as follows:

TLC R_f0.31 (5% methanol in dichloromethane)

¹H NMR δ 0.13，0.34，0.49，0.63，1.6，3.36，3.5-3.9，4.1，6.68，6.8，7.1-7.4，7.6-7.8，8.5ppm。

HRMS：611.2051

Example 155-

Using a similar procedure to that described above, the following compounds of the invention were prepared:

155) n- (3- { cyclopropyl- [6- (1- (tetrahydropyran-4-ylmethyl) propyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -2-pyridinesulfonamide

156) N- (3- { cyclopropyl- [6- (1- (tetrahydropyran-4-ylmethyl) propyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -4-cyano-2-pyridinesulfonamide

157) N- (3- { cyclopropyl- [6- (1- (tetrahydropyran-4-ylmethyl) propyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -2-quinolinesulfonamide

158) N- (3- { cyclopropyl- [6- (1- (tetrahydropyran-4-ylmethyl) propyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -2-hydroxybenzenesulfonamide

159) N- (3- { cyclopropyl- [6- (1- (tetrahydropyran-4-ylmethyl) propyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -2-pyrazole sulfonamide

160) N- (3- { cyclopropyl- [6- (1- (tetrahydropyran-4-ylmethyl) propyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -2-quinazolinesulfonamide

161) N- (3- { cyclopropyl- [6- (1- (tetrahydropyran-4-ylmethyl) propyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -7H-purine-6-sulfonamide

162) N- (3- { cyclopropyl- [6- (1- (tetrahydropyran-4-ylmethyl) propyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -1H-imidazole-2-sulfonamide

163) N- (3- { cyclopropyl- [6- (1- (tetrahydropyran-4-ylmethyl) propyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) benzimidazole-2-sulfonamide

164) N- (3- { cyclopropyl- [6- (1- (tetrahydropyran-4-ylmethyl) propyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) thiazole-4-sulfonamide

165) N- (3- { cyclopropyl- [6- (1- (tetrahydropyran-4-ylmethyl) propyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -4-ethoxycarbonyl-1H-imidazole-2-sulfonamide

166) N- (3- { cyclopropyl- [6- (1- (tetrahydropyran-4-ylmethyl) propyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -3-hydroxy-2-pyridinesulfonamide

167) N- (3- { cyclopropyl- [6- (1-ethylphenylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -2-pyridinesulfonamide

168) N- (3- { cyclopropyl- [6- (1-ethylphenylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -4-cyano-2-pyridinesulfonamide

169) N- (3- { cyclopropyl- [6- (1-ethylphenylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -2-quinolinesulfonamide

170) N- (3- { cyclopropyl- [6- (1-ethylphenylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -2-hydroxybenzenesulfonamide

171) N- (3- { cyclopropyl- [6- (1-ethylphenylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -2-pyrazole sulfonamide

172) N- (3- { cyclopropyl- [6- (1-ethylphenylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -2-quinazolinesulfonamide

173) N- (3- { cyclopropyl- [6- (1-ethylphenylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -7H-purine-6-sulfonamide

174) N- (3- { cyclopropyl- [6- (1-ethylphenylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -1H-imidazole-2-sulfonamide

175) N- (3- { cyclopropyl- [6- (1-ethylphenylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) benzimidazole-2-sulfonamide

176) N- (3- { cyclopropyl- [6- (1-ethylphenylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) thiazole-4-sulfonamide

177) N- (3- { cyclopropyl- [6- (1-ethylphenylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -4-ethoxycarbonyl-1H-imidazole-2-sulfonamide

178) N- (3- { cyclopropyl- [6- (1-ethylphenylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl ] methyl } phenyl) -3-hydroxy-2-pyridinesulfonamide

179) N- (3- { cyclopropyl- [ 4-hydroxycoumarin-3-yl ] methyl } phenyl) -2-pyridinesulfonamide

180) N- (3- { cyclopropyl- [ 4-hydroxycoumarin-3-yl ] methyl } phenyl) -4-cyano-2-pyridinesulfonamide

181) N- (3- { cyclopropyl- [ 4-hydroxycoumarin-3-yl ] methyl } phenyl) -2-quinolinesulfonamide

182) N- (3- { cyclopropyl- [ 4-hydroxycoumarin-3-yl ] methyl } phenyl) -2-hydroxybenzenesulfonamide

183) N- (3- { cyclopropyl- [ 4-hydroxycoumarin-3-yl ] methyl } phenyl) -2-pyrazole sulfonamide

184) N- (3- { cyclopropyl- [ 4-hydroxycoumarin-3-yl ] methyl } phenyl) -2-quinazolinesulfonamide

185) N- (3- { cyclopropyl- [ 4-hydroxycoumarin-3-yl ] methyl } phenyl) -7H-purine-6-sulfonamide

186) N- (3- { cyclopropyl- [ 4-hydroxycoumarin-3-yl ] methyl } phenyl) -1H-imidazole-2-sulfonamide

187) N- (3- { cyclopropyl- [ 4-hydroxycoumarin-3-yl ] methyl } phenyl) benzimidazole-2-sulfonamide

188) N- (3- { cyclopropyl- [ 4-hydroxycoumarin-3-yl ] methyl } phenyl) thiazole-4-sulfonamide

189) N- (3- { cyclopropyl- [ 4-hydroxycoumarin-3-yl ] methyl } phenyl) -4-ethoxycarbonyl-1H-imidazole-2-sulfonamide

190) N- (3- { cyclopropyl- [ 4-hydroxycoumarin-3-yl ] methyl } phenyl) -3-hydroxy-2-pyridinesulfonamide

Preparation of 61 cyclopropyl- (3-nitrophenyl) methanone (formula N-2), see Table N.

To a 1 liter three-neck round bottom flask equipped with a stirrer and addition funnel was added 580 ml of fuming nitric acid under nitrogen and cooled to-40 ℃. The reaction mixture was used as 1.Cyclopropylphenyl ketone of formula N-1 (100 g) was added slowly over 5 hours, maintaining the temperature below-35 ℃. Stir for 3 hours and monitor by TLC. The reaction mixture was poured into 3 kg of ice/water. Extraction was carried out with 3X 500 ml of ethyl acetate. The combined organic phases were washed with 2 × 1.5 l of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated to give 138 g of residue. The residue was dissolved in 270 ml of methanol, cooled to-20 ℃, held for 18 hours, filtered and the filter cake washed with cold methanol. The product was dried under reduced pressure for 72 hours to give 63.86 g. GC analysis (15m. DB-1, T) ₀100 ℃, 10 ℃/min, RT-6.0 min) indicated that the material was greater than 98% pure.

The physical properties were as follows:

¹H NMR(CDCl₃)δ8.86，8.43，8.34，7.70，2.72，1.33，1.17ppm。

IR (liquid paraffin) 2954, 2925, 1664, 1614, 1529, 1442, 1386, 1352, 1225, 1082, 1047, 852, 720, 689cm^-1。

Elemental analysis, found: c, 62.89; h, 4.73; and N, 7.32.

MS(EI)：191，150，104，69m/z。

Preparation of 62 cyclopropyl- (3-aminophenyl) methanone (formula N-3), see Table N.

Platinum-carrying carbon (8.7 g) was added to the Paar bottle. To a flask was added cyclopropyl- (3-nitrophenyl) methanone preparation 61 (86.7 g) and methanol (1.56 l), warmed to dissolution, and then cooled to 9 ℃ with an ice bath. Hydrogenation for 50 min, maintaining temperature below 35 ℃ and monitoring the reaction by TLC. The reaction mixture was filtered through solka flocs (floc) and concentrated under reduced pressure to give 70 g.

The physical properties were as follows:

¹H NMR(CDCl₃)δ7.99，7.47-7.19，6.84，3.84，2.60，1.23-1.15，1.03-0.96ppm。

¹³C NMR(CDCl₃)δ200.9，146.8，139.1，129.4，119.3，118.4，113.9，17.2，11.6ppm。

preparation of 63 cyclopropyl- (3-aminobenzyloxycarbonylphenyl) methanone (formula N-4) see Table N.

To a 3-liter round bottom flask equipped with a mechanical stirrer and an addition funnel was added cyclopropyl- (3-aminophenyl) methanone of preparation 62 (70.0 g), diisopropylethylamine (DIPEA, 90.2 ml) and dichloromethane (1.3 l) under a nitrogen atmosphere. The reaction mixture was cooled to 0 ℃. Benzyl chloroformate (67.5 ml) was diluted with dichloromethane (186 ml) and added to the substrate solution over 1 hour, maintaining the temperature at 0-5 ℃. A large amount of precipitate formed. Warm for 1.5 hours with stirring and monitor the reaction by TLC. The reaction mixture was poured into 600 ml of 1N hydrochloric acid/600 g of ice/4.2 l of dichloromethane and stirred until dissolved. The phases were separated and the organic phase was dried over magnesium sulfate, filtered and concentrated to dryness. A solid slurry of 3 ml/g hexane was made, filtered, and dried under vacuum to give 125 g.

The physical properties were as follows:

¹H NMR(CDCl₃) δ 8.01，7.76-7.69，7.43-7.33，7.18，5.21，2.64，1.25-1.20，1.03-0.97ppm.

¹³C NMR(CDCl₃) δ 200.6，153.4，138.7，138.5，135.9，129.3，128.6，128.4，123.1，122.8，118.1，67.2，17.3，12.0ppm.

preparation of 64 cyclopropyl- (3-aminobenzyloxycarbonylphenyl) methanol (formula N-5) is shown in Table N.

To a 2 l three neck round bottom flask equipped with an overhead stirrer was added under nitrogen atmosphere cyclopropyl- (3-aminobenzyloxycarbonylphenyl) methanone of preparation 63 (25 g), Tetrahydrofuran (THF) (450 ml) and ethanol (90 ml). The reaction mixture was cooled to 0-5 ℃ and sodium borohydride tablets (12.4 g) were added in three equal portions over 30 minutes. Warm to 23 ℃ and stir for 20 h, monitor the reaction by TLC. The reaction mixture was cooled to 0-5 ℃ again and quenched by the slow addition of 90 ml of 1N hydrochloric acid, maintaining the temperature below 10 ℃. Dichloromethane (600 ml) and 1N hydrochloric acid (400 ml) were poured with stirring. The phases were separated and the organic phase was washed with saturated sodium chloride solution (1 l). Dried over magnesium sulfate, filtered and concentrated to give 23.7 g.

The physical properties were as follows:

¹H NMR(CDCl₃) δ 7.41-7.35，7.33，7.17，7.10，5.17，3.93，2.36，1.16-1.12，0.60-0.32ppm.

¹³C NMR(CDCl₃) δ 153.5，145.0，137.9，136.1，129.0，128.6，128.3，121.2，117.9，116.5，67.9，67.0，19.1，3.6，2.8ppm.

preparation of phenylmethyl 65[3- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ] pyran-3-yl) methyl ] phenyl ] carbamate (formula N-6), see Table N.

To a 12 liter three neck round bottom flask equipped with a Soxhlet extractor containing 3 angstrom molecular sieve (180 grams) and nitrogen inlet was added cyclooctene-1-propenoic acid beta, 2-dihydroxy-delta-lactone (59.6 grams), p-toluene sulphonic acid (14.9 grams) and dichloromethane (7.2 liters). The title compound of preparation 64 (90.0 g) was added and the reaction mixture was warmed to reflux for 1 hour. The reaction mixture was cooled to 20 ℃ and washed with 1: 1 saturated sodium chloride/saturated sodium bicarbonate (3 liters), water (3 liters) and saturated sodium chloride (3 liters). The water was filtered off and washed with dichloromethane (2X 1.5L). The organic layers were then combined, dried over magnesium sulfate, filtered and concentrated to about 1.5 liters. The reaction mixture was cooled to-20 ℃, held for 72 hours, filtered, and dried under reduced pressure to give 103.5 g of crude product. The crude product was then slurried into 12.5 ml/g hexane, filtered, and dried to yield 102.4 g of the title compound. By concentrating the crystallization mother liquor and recrystallizing the residue from ethyl acetate, another 10.9 g of the title compound were obtained.

The physical properties were as follows:

melting point 113 ℃ and 115 ℃ were used.

¹H NMR(CDCl₃) δ 7.48，7.38-7.26，7.17，6.70，6.29，5.20，3.95，2.64-2.60.2.47-2.43，1.76-1.72，1.61-1.42，0.88，0.73-0.72，0.63-0.55，0.29-0.26ppm.

¹³C NMR(CDCl₃) δ 165.6，164.0，161.3，142.2，138.5，129.9，128.5，128.3，128.2，122.9，118.0，117.9，117.6，110.7，106.0，67.0，43.7，30.7，29.1，28.8，26.2，25.8，22.1，13.0，4.9，3.8ppm.

IR(Nujol)3304，2995，2953，2923，2855，1734，1698，1665，1666，1633，1610，1595，1553，1491，1463，1455，1445，1406，1377，1313，1222，1175，1085，1068，740，696cm^-1.

MS(EI)m/z473，445，382，338，91.

High resolution mass spectrometry, found: 473.2202.

preparation 663- [ (3-aminophenyl) cyclopropylmethyl ] -5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2H-cycloocta [ b ] pyran-2-one (formula N-7), see Table N.

To a mixture of the title product of formula N-6 prepared in preparation 65 (1.95 g) in cyclohexene (50 mL) in a 100 mL three-neck round-bottom flask equipped with a reflux condenser and a nitrogen inlet was added 10% palladium on carbon (1.0 g) and the mixture was refluxed for 4 hours. The mixture was filtered through celite, washed with dichloromethane and concentrated to give 1.25 g of the title compound as a white solid.

The physical properties were as follows:

MP75-79℃

IR(Nujol)2995，2951，2921，2868，1660，1619，1605，1590，1551，1491，1460，1447，1428，1404，1247，1226，1202，1191，1172，1126cm^-1.

MS(EI)m/z339，310，213，187，159.

¹H NMR(CDCl₃) δ 7.16，6.96，6.84，6.63，5.67，3.87，2.61，2.48-2.37，1.98，1.75，1.63-1.26，0.74-0.65，0.61-0.53，0.28-0.22ppm.

¹³C NMR(CDCl₃) δ 164.2，161.1，142.8，130.2，117.7，117.6，114.7，114.6，114.5，110.9，106.2，43.5，30.6，29.1，28.8，26.2，25.8，22.0，12.8，4.7，3.7ppm.

high resolution mass spectrometry, found: 339.1845.

preparation of 674-cyano-N- [3- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ]]Pyran-3-yl) methyl]Phenyl radical]Benzenesulfonamides (formula O-3, wherein R₆₁Is 4-cyanophenyl) see table O.

A solution of the title compound of preparation 66 (660 mg), pyridine (320 μ L) and 4-cyanobenzenesulfonyl chloride (440 mg) in dichloromethane (40 mL) was stirred at room temperature for 18 h. The crude reaction mixture was evaporated to a volume of 5 ml and chromatographed on silica gel using 50% ethyl acetate in hexane as eluent to give the title compound as a white amorphous solid (641 mg). The amorphous solid was prepared from acetone: crystallization from hexane gave 499 mg.

The physical properties were as follows:

melting point of white solid: 183-183.5 deg.C

Elemental analysis: found, C, 66.76; h, 5.68; n, 5.38; s, 6.30.

MS(EI)：504，476，463，338，309，233，220，207，195，186，153，144，130，117，102.

HRMS：504.1710.

TLC (silica gel GF): r_f0.4 in 50% ethyl acetate in hexane.

Example 1914-cyano-N- [3- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ] pyran-3-yl) methyl ] phenyl ] benzenesulfonamide disodium salt

To 12.6 g of the title product of preparation 67 were added 500 ml of methanol and 50 ml of 1N aqueous sodium hydroxide solution with rapid stirring. The reaction solution was stirred at room temperature for 1 hour. The yellow solution was evaporated to dryness at 35 ℃ and the resulting amorphous residue was dissolved in anhydrous ethanol and evaporated to dryness again. The yellow residue was kept under high vacuum at room temperature for 18 hours to give 14 g of a yellow amorphous solid.

The physical properties were as follows:

TLC (silica gel GF): r_f0.8 stripes of starting material (20% ethyl acetate in hexane).

K.f. water: 6.16 percent

Molten solvate: 4.2% ethanol

Weight loss at room temperature: 4.99 percent

Gray matter: measured value: 7.83 percent; calculated values: 7.50% (corrected for 6.16% water and 4.2% ethanol)

Preparation of 68N-methyl-3 [ (3-aminophenyl) cyclopropylmethyl ] -5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2H-cycloocta [ b ] pyran-2-one

To 678 mg of the title product of preparation 66 was added 100 mL of absolute ethanol and 330 mg of 10% Pd/C. Adding 183 microliter 35% CH₂O/H₂O solution, and the mixture was shaken in a Paar apparatus at room temperature under a 50lbs hydrogen atmosphere for 2 hours. The reaction was filtered through celite and the filter cake was washed with ethanol. The resulting amber solution was evaporated to dryness. The residue was chromatographed using 10% ethyl acetate in dichloromethane to give 110 mg of the title product. This material was used without further purification for the subsequent sulfonamide synthesis.

The physical properties were as follows:

TLC (silica gel GF): r_f0.5, 10% ethyl acetate in dichloromethane.

¹H NMR(CDCl₃) δ 7.19，6.90，6.71，6.54-6.52，3.90，2.80，2.63-2.59，2.43-2.39，1.75-1.26，.70-.53，.28-.22PPm.

Example 1924-cyano-N-methyl-N- [3- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ] pyran-3-yl) methyl ] phenyl ] benzenesulfonamide

A solution of the title compound of preparation 68 (35 mg), pyridine (16 μ L) and 4-cyanobenzenesulfonyl chloride (20.1 mg) in dichloromethane (2 ml) was stirred at room temperature for 18 h. The crude reaction mixture was chromatographed on silica gel using 10% ethyl acetate in dichloromethane as eluent to give 27 mg of the title compound as a white amorphous solid.

The physical properties were as follows:

MS(EI)：518，490，352，233，207，172，158，143，129，115，102，81，54，43。

TLC (silica gel GF): r_f0.7, 10% ethyl acetate in dichloromethane.

¹H NMR(CDCl₃) δ 7.75-7.72，7.63-7.60，7.38-7.19，6.97-6.94，6.62，3.86，3.19，2.66-2.62，2.54-2.50，1.76-1.20，.70-.59，.47-42，.24-.19ppm.

Example 1934-fluoro-N-methyl-N- [3- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ] pyran-3-yl) methyl ] phenyl ] benzenesulfonamide

A solution of the title compound of preparation 68 (20 mg), pyridine (11 μ L) and 4-fluorobenzenesulfonyl chloride (10.7 mg) in dichloromethane (2 ml) was stirred at room temperature for 18 h. The crude reaction mixture was chromatographed on silica gel using 10% ethyl acetate in dichloromethane as eluent to give 19 mg of the title compound as a white amorphous solid.

The physical properties were as follows:

MS(EI)：512，483，470，366，352，324，247，227，207，172，158，147，118，55。

HRMS: measured value: 512.1915

TLC (silica gel GF): r_f0.7, 10% ethyl acetate in dichloromethane.

¹H NMR(CDCl₃) δ 7.53-7.48，7.33-7.23，7.13-7.07，6.99-6.97，6.38，3.93，3.16，2.63-2.61，2.49-2.46，1.76-1.25，.78-.61，.51-.45，.30-.17 ppm.

Example 194N-methyl-N- [3- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ] pyran-3-yl) methyl ] phenyl ] benzenesulfonamide

A solution of the title compound of preparation 68 (33.4 mg), pyridine (16 μ L) and benzenesulfonyl chloride (16.6 mg) in dichloromethane (2 ml) was stirred at room temperature for 18 hours. The crude reaction mixture was chromatographed on silica gel using 10% ethyl acetate in dichloromethane as eluent to give 20 mg of the title compound as a white amorphous solid.

The physical properties were as follows:

TLC (silica gel GF): r_f0.7, 10% ethyl acetate in dichloromethane.

¹H NMR(CDCl₃) δ 7.59-7.41，7.33-7.23，6.98-6.96，6.44，3.90，3.16，2.64-2.60，2.50-2.48，1.75-1.20，.67-.40，.23-.20ppm.

Example 195N-methyl-N- [3- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ] pyran-3-yl) methyl ] phenyl ] -1H-imidazole-1-methanesulfonamide

A solution of the title compound of preparation 68 (33.4 mg), pyridine (16 μ L) and N-methylimidazole-3-sulfonyl chloride (16 mg) in dichloromethane (2 ml) was stirred at room temperature for 18 hours. The crude reaction mixture was chromatographed on silica gel with 50% ethyl acetate in dichloromethane as eluent to give 28 mg of the title compound as a white amorphous solid.

The physical properties were as follows:

TLC (silica gel GF): r_f0.5, 50% ethyl acetate in dichloromethane.

¹H NMR(CDCl₃) δ 7.43，7.33，7.27-7.15，3.84-3.81，3.69，3.35，2.63-2.59，2.50-2.46，1.75-1.26，.68，.55，.47-.42，.24-.20ppm.

196) 5-cyano-N- [3- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ] pyran-3-yl) methyl ] phenyl ] -2-pyridinesulfonamide

197) N- [3- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ] pyran-3-yl) methyl ] phenyl ] -2-quinolinesulfonamide

198) N- [3- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ] pyran-3-yl) methyl ] phenyl ] -2-imidazole sulfonamide

199) N- [3- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ] pyran-3-yl) methyl ] phenyl ] -2-pyrimidine sulfonamide

200) N- [3- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ] pyran-3-yl) methyl ] phenyl ] -2-benzimidazole sulfonamide

201) N- [3- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ] pyran-3-yl) methyl ] phenyl ] -2-quinazolinesulfonamide

202) N- [3- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ] pyran-3-yl) methyl ] phenyl ] -6-purinesulfonamide

203) 5-cyano-N- [3- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ] pyran-3-yl) methyl ] phenyl ] -N-methyl-2-pyridinesulfonamide

204) N- [3- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ] pyran-3-yl) methyl ] phenyl ] -N-methyl-2-quinolinesulfonamide

205) N- [3- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ] pyran-3-yl) methyl ] phenyl ] -N-methyl-2-imidazole sulfonamide

206) N- [3- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ] pyran-3-yl) methyl ] phenyl ] -N-methyl-2-pyrimidine sulfonamide

207) N- [3- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ] pyran-3-yl) methyl ] phenyl ] -2-benzimidazole sulfonamide

208) N- [3- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ] pyran-3-yl) methyl ] phenyl ] -2-quinazolinesulfonamide

209) N- [3- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ] pyran-3-yl) methyl ] phenyl ] -N-methyl-6-purinesulfonamide

210) N- [3- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ] pyran-3-yl) methyl ] phenyl ] -N-methyl-4-thiazolesulfonamide

211) N- [3- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ] pyran-3-yl) methyl ] phenyl ] -N-methyl-2-pyridinesulfonamide

212) 5-cyano-N- [6- (1 '-benzylpropyl) -4-hydroxy-3- (1' -cyclopropylmethylphenyl) -2-pyrone ] -N-methyl-2-pyridinesulfonamide

213) N- [6- (1 '-benzylpropyl) -4-hydroxy-3- (1' -cyclopropylmethylphenyl) -2-pyrone ] -N-methyl-2-quinolinesulfonamide

214) N- [6- (1 '-benzylpropyl) -4-hydroxy-3- (1' -cyclopropylmethylphenyl) -2-pyrone ] -N-methyl-2-imidazole sulfonamide

215) N- [6- (1 '-benzylpropyl) -4-hydroxy-3- (1' -cyclopropylmethylphenyl) -2-pyrone ] -N-methyl-2-pyrimidine sulphonamide

216) N- [6- (1 '-benzylpropyl) -4-hydroxy-3- (1' -cyclopropylmethylphenyl) -2-pyrone ] -N-methyl-2-benzimidazolesulfonamide

217) N- [6- (1 '-benzylpropyl) -4-hydroxy-3- (1' -cyclopropylmethylphenyl) -2-pyrone ] -N-methyl-2-quinazolinesulfonamide

218) N- [6- (1 '-benzylpropyl) -4-hydroxy-3- (1' -cyclopropylmethylphenyl) -2-pyrone ] -N-methyl-6-purinesulfonamide

219) N- [6- (1 '-benzylpropyl) -4-hydroxy-3- (1' -cyclopropylmethylphenyl) -2-pyrone ] -N-methyl-4-thiazolesulfonamide

220) N- [6- (1 '-benzylpropyl) -4-hydroxy-3- (1' -cyclopropylmethylphenyl) -2-pyrone ] -N-methyl-2-pyridinesulfonamide

221) 5-cyano-N- [3- (1' -cyclopropylmethylphenyl) -4-hydroxycoumarin ] -N-methyl-2-pyridinesulfonamide

222) N- [3- (1' -cyclopropylmethylphenyl) -4-hydroxycoumarin ] -N-methyl-2-quinolinesulfonamide

223) N- [3- (1' -cyclopropylmethylphenyl) -4-hydroxycoumarin ] -N-methyl-2-imidazole sulfonamide

224) N- [3- (1' -cyclopropylmethylphenyl) -4-hydroxycoumarin ] -N-methyl-2-pyrimidine sulfonamide

225) N- [3- (1' -cyclopropylmethylphenyl) -4-hydroxycoumarin ] -N-methyl-2-benzimidazolesulfonamide

226) N- [3- (1' -cyclopropylmethylphenyl) -4-hydroxycoumarin ] -N-methyl-2-quinazolinesulfonamide

227) N- [3- (1' -cyclopropylmethylphenyl) -4-hydroxycoumarin ] -N-methyl-6-purinesulfonamide

228) N- [3- (1' -cyclopropylmethylphenyl) -4-hydroxycoumarin ] -N-methyl-4-thiazolesulfonamide

229) N- [3- (1' -cyclopropylmethylphenyl) -4-hydroxycoumarin ] -N-methyl-2-pyridinesulfonamide

230) 5-cyano-N- [3- [1- (4-hydroxy-2-oxo-6, 6-diphenylethyl-5, 6-dihydro-2H-pyran-3-yl) propyl ] phenyl ] -N-methyl-2-pyridinesulfonamide

231) N- [3- [1- (4-hydroxy-2-oxo-6, 6-diphenylethyl-5, 6-dihydro-2H-pyran-3-yl) propyl ] phenyl ] -N-methyl-2-quinolinesulfonamide

232) N- [3- [1- (4-hydroxy-2-oxo-6, 6-diphenylethyl-5, 6-dihydro-2H-pyran-3-yl) propyl ] phenyl ] -N-methyl-2-imidazole-sulfonamide

233) N- [3- [1- (4-hydroxy-2-oxo-6, 6-diphenylethyl-5, 6-dihydro-2H-pyran-3-yl) propyl ] phenyl ] -N-methyl-2-pyrimidine sulfonamide

234) N- [3- [1- (4-hydroxy-2-oxo-6, 6-diphenylethyl-5, 6-dihydro-2H-pyran-3-yl) propyl ] phenyl ] -N-methyl-2-benzimidazolesulfonamide

235) N- [3- [1- (4-hydroxy-2-oxo-6, 6-diphenylethyl-5, 6-dihydro-2H-pyran-3-yl) propyl ] phenyl ] -N-methyl-2-quinazolinesulfonamide

236) N- [3- [1- (4-hydroxy-2-oxo-6, 6-diphenylethyl-5, 6-dihydro-2H-pyran-3-yl) propyl ] phenyl ] -N-methyl-6-purinesulfonamide

237) N- [3- [1- (4-hydroxy-2-oxo-6, 6-diphenylethyl-5, 6-dihydro-2H-pyran-3-yl) propyl ] phenyl ] -N-methyl-4-thiazolesulfonamide

238) N- [3- [1- (4-hydroxy-2-oxo-6, 6-diphenylethyl-5, 6-dihydro-2H-pyran-3-yl) propyl ] phenyl ] -N-methyl-2-pyridinesulfonamide

Example 239N- [4- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ] pyran-3-yl) methyl ] phenyl ] -2-pyridinesulfonamide (formula P-2, R is 2-pyridyl) see Table P.

3- [ (3-aminophenyl) cyclopropylmethyl ] -5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2H-cycloocta [ b ] pyran-2-one (100 mg) of preparation 66 was dissolved in dichloromethane (3 ml), and pyridine (70. mu.L) was added. 2-pyridine sulfonyl chloride (52 mg) was added to stir the solution at 25 ℃ for 2 hours. Chloroform (25 ml) was added, and the combined extracts were washed with 1N hydrochloric acid (20 ml) and dried over sodium sulfate. The solvent was removed to give a pink gum which was chromatographed on silica gel using flash column techniques, eluting with 60% ethyl acetate-hexanes. The title compound was obtained as a white solid (80 mg).

The physical properties were as follows:

MS m/z480，339，338，186，145，144，132，130，78，55。

example 240N- [4- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ] pyran-3-yl) methyl ] phenyl ] -4-pyridinesulfonamide (formula P-2, R is 4-pyridyl) see Table P.

The title compound was obtained as a white solid by the method described in example 239.

The physical properties were as follows:

MS m/z480，338，207，186，145，144，117，79，78，55。

example 241N- [4- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ] pyran-3-yl) methyl ] phenyl ] -5-cyanopyridin-2-yl sulfonamide (formula P-2, R is 5-cyanopyridin-2-yl) see Table P.

The title compound was prepared by the method described for example 239.

Example 242N- [4- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ] pyran-3-yl) methyl ] phenyl ] -2-pyrazinylsulfonamide (formula P-2, R is 2-pyrazinyl) is shown in Table P.

The title compound was prepared by the method described for example 239.

Example 243N- [4- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ] pyran-3-yl) methyl ] phenyl ] -2-pyrimidinylsulfonamide (formula P-2, R is 2-pyrimidyl) see Table P.

The title compound was prepared by the method described for example 239.

Example 244N- [4- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ] pyran-3-yl) methyl ] phenyl ] -4, 6-dimethylpyrimidin-2-ylsulfonamide (formula P-2, R is 4, 6-dimethylpyrimidin-2-yl) see Table P.

The title compound was prepared by the method described for example 239.

Example 245N- [4- [ cyclopropyl (5, 6, 7, 8, 9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta [ b ] pyran-3-yl) methyl ] phenyl ] -4-methylpyrimidin-2-yl-sulfonamide (formula P-2, R is 4-methylpyrimidin-2-yl) see Table P.

The title compound was prepared by the method described for example 239.

Preparation 696, 6-bis- (2-cyclopropylethyl) dihydropyran-2, 4-dione (formula Q-2), see Table Q.

To a suspension of 150 mg of sodium hydride (60% dispersion in mineral oil) in 4 ml of anhydrous THF at 0 ℃ under argon atmosphere, 0.38 ml of methyl acetoacetate are added dropwise. After 10 minutes, 2.3 ml of butyllithium (1.6M solution in hexane) were added dropwise. After 10 minutes, a solution of 0.48 g of the compound of formula Q-1 (formula S-4, see Table S, prepared as described in preparation 79) in 3 ml of tetrahydrofuran was added. The reaction mixture was stirred at room temperature for 1 hour and then partitioned between ethyl acetate and dilute aqueous hydrochloric acid. The aqueous phase was extracted with two more portions of ethyl acetate. The organic phases were combined, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was diluted with 5 ml of methanol and the resulting solution was treated with 12 ml of water and then with 3.0 ml of 1M aqueous sodium hydroxide solution. After vigorous stirring for 2 hours, the methanol was removed under reduced pressure. The aqueous phase was washed once with ether and the ether phase was discarded. The aqueous phase was cooled to 0 ℃ and then acidified with dilute aqueous hydrochloric acid. The resulting precipitate was extracted with four portions of dichloromethane. The combined dichloromethane extracts were dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ether-hexane, and the solution was cooled to give 0.42 g of the title compound as a pale yellow solid.

The physical properties were as follows:

¹H NMR δ 0.0，0.4，0.6，1.2，1.7，2.6，3.4。

preparation 706, 6-bis- (2-cyclopropylethyl) -5, 6-dihydro-4-hydroxy-3- [1- (3-nitrophenyl) propyl ] pyran-2-one (formula Q-3), see Table Q.

To a stirred solution of 0.41 g of the title compound of preparation 69 (formula Q-2) and 0.25 g of 3-nitrobenzaldehyde in 5 ml of anhydrous tetrahydrofuran was added a solution of 0.44 g of aluminum trichloride in 4.5 ml of tetrahydrofuran. After 2 hours, the reaction mixture was treated with 1.0 g of sodium carbonate decahydrate, stirred for 10 minutes, diluted with ether and finally magnesium sulfate was added carefully. The resulting mixture was filtered through a pad of celite, rinsing with ether. The filtrates were combined and concentrated under reduced pressure. To the resulting residue were added 103 mg of copper (I) bromide-dimethylsulfide complex and 5 ml of anhydrous tetrahydrofuran under an argon atmosphere. To the reaction mixture was added dropwise 2.5 ml of triethylaluminum (1.0M solution in hexane) over 1.5 hours. The reaction was then treated slowly with ice and partitioned between ether and dilute aqueous hydrochloric acid. The aqueous phase was extracted with three additional portions of ether. The combined ether extracts were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel with 20% -40% ethyl acetate in hexane to give 0.44 g of the title compound as a brown foam.

The physical properties were as follows:

¹H NMR δ 0.0，0.4，0.6，1.0，1.2，1.7-1.9，2.0-2.4，2.6，4.2，7.5，7.8，8.1，8.3。

preparation 713- [1- (3-aminophenyl) propyl ] -6, 6-bis- (2-cyclopropylethyl) -5, 6-dihydro-4-hydroxypyran-2-one (formula Q-4), see Table Q.

To a solution of 0.44 g of the title compound of preparation 70 (formula Q-3) in 6 ml of methanol was added 0.65 g of ammonium formate and 50 mg of 10% palladium on carbon. The black slurry was stirred under argon for 3 hours, then filtered through a pad of celite, washing with methanol. The filtrates were combined and the solvent was removed under reduced pressure. The residue was triturated with four portions of dichloromethane. The combined dichloromethane washes were concentrated under reduced pressure to give 0.37 g of the title compound as a white foam.

The physical properties were as follows:

R_f0.08 (50% Ether in hexane)

Example 246N- [3- (1- [6, 6-bis- (2-cyclopropylethyl) -5, 6-dihydro-4-hydroxy-2-oxo-2H-pyran-3-yl)]Propyl) phenyl]-1-methyl-1H-imidazole-4-sulfonamide (formula Q-5, R)₁Is 1-methylimidazol-4-yl) as shown in table Q.

To a flask containing 57 mg of the title compound of preparation 71 (formula Q-4) and 24. mu.L of pyridine in 1.0 mL of dichloromethane was added 27 mg of 1-methylimidazole-4-sulfonyl chloride. After 6 hours, the reaction mixture was concentrated under reduced pressure. Pyridine was azeotroped three times with toluene. The resulting residue was subjected to flash column chromatography on silica gel with 2% -6% methanol in dichloromethane to give 51 mg of the title compound as a white foam.

The physical properties were as follows:

¹H NMR δ 0.0，0.4，0.6，0.9，1.1-1.4，1.7-2.2，2.5，3.7，3.95，6.9，7.1，7.4，7.5。

HRMS：528.2537(FAB)

EXAMPLE 247N- [3- (1- [6, 6-bis- (2-cyclopropylethyl) -5, 6-dihydro-4-hydroxy-2-oxo-2H-pyran-3-yl)]Propyl) phenyl]-5-cyano-2-pyridinesulfonamide (formula Q-5, R)₁Is 5-cyano-2-pyridyl) as shown in table Q.

Using the general sulfonylation procedure described in example 246, 57 mg of the amine of preparation 71 (formula Q-4) was reacted with 30 mg of 5-cyanopyridine-2-sulfonyl chloride. Flash column chromatography on silica gel with 1% -3% methanol in dichloromethane afforded 62 mg of the title compound as a brown foam.

The physical properties were as follows:

¹H NMR δ 0.0，0.4，0.6，0.9，1.1-1.4，1.6-2.2，2.5，3.95，6.9-7.2，8.0，8.2.9.0。

HRMS：550.2370(FAB)

723-Aminophenylethyl ketone (formula R-2) was prepared, see Table R.

To a solution of 3-nitrophenylethyl ketone (formula R-1) (1.79 g) in diethyl ether was added 5% Pt/C catalyst (0.20 g). The resulting suspension was placed under a hydrogen atmosphere and stirred for 6 hours. The reaction mixture was filtered through a pad of celite, and the pad was washed with another portion of ether. The combined filtrates were concentrated under reduced pressure to give 1.49 g of the title compound as a pale yellow low melting solid.

The physical properties were as follows:

¹H NMR δ 1.2，3.0，6.9，7.2-7.4。

R_f0.45 (33% ethyl acetate in hexane).

Preparation of 731- [3- (dibenzylamino) phenyl ] propan-1-one (formula R-3), see Table R.

To a solution of the title compound of preparation 72 (formula R-2) (1.5 g) in dichloromethane (50 ml) was added diisopropylethylamine (6.0 ml) followed by benzyl bromide (3.6 ml). After stirring for 6 hours, the reaction mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature, diluted with ether (50 ml) and washed successively with dilute aqueous potassium hydrogensulfate, water, saturated aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with 5% -20% ethyl acetate in hexanes to give 2.38 g of the title compound as a light yellow solid.

The physical properties were as follows:

¹H NMR δ 1.1，2.9，4.7，6.9，7.2-7.4。

elemental analysis, found: c, 83.88; h, 7.03; n, 4.20

MS：329(EI)

Preparation of 746- [3- (dibenzylamino) phenyl ] dihydropyran-2, 4-dione (formula R-4), see Table R.

Using the general procedure for the formation of a dihydropyrone ring described in preparation 69, a compound of formula R-3 of preparation 73 (1.96 g) was reacted with the dianion of methyl acetoacetate and cyclized to give 0.76 g of the title compound.

The physical properties were as follows:

¹H NMR δ 0.8，1.9，2.6-2.9，3.1-3.2，4.7，6.5-6.7，7.1-7.4。

MS：413(EI)

preparation 756- [3- (dibenzylamino) phenyl ] -5, 6-dihydro-6-ethyl-4-hydroxy-3- [1- (3-nitrophenyl) propyl ] pyran-2-one (formula R-5), see Table R.

Using the general procedure described for preparation 70, the condensation of 3-nitrobenzaldehyde with the compound of formula R-4 of preparation 74 (727 mg) was catalyzed by aluminum trichloride followed by copper catalyzed conjugate addition to triethylaluminum to give 800 mg of the title compound.

The physical properties were as follows:

¹H NMR δ 0.6，1.6-2.1，2.8，3.4，3.8，4.4，6.4-6.6，6.8-7.4，7.7-8.0。

MS：576(EI)

preparation 766- (3-aminophenyl) -3- [1- (3-aminophenyl) propyl ] -6-ethyl-5, 6-dihydro-4-hydroxypyran-2-one (formula R-6), see Table R.

Using the general procedure described for preparation 71, a compound of formula R-5 (114 mg) of 75 was prepared using ammonium formate and Pd/C catalytic hydrogenation to give 61 mg of the title compound. Alternatively, preparation 75 of a compound of formula R-5 (114 mg) was reduced with Pd/C and hydrogen to give 72 mg of the title compound.

The physical properties were as follows:

¹H NMR δ 0.6-0.9，1.8-2.1，3.0，3.8，6.4-6.6，6.95，7.1。

R_f0.40 (10% methanol in methylene chloride)

EXAMPLE 248N- (3- [1- (6-Ethyl-5, 6-dihydro-4-hydroxy-6- [3- ([ (1-methyl-1H-imidazol-4-yl) sulfonyl) N]Amino) phenyl]-2-2H-pyran-3-yl) propyl]Phenyl) -1-methyl-1H-imidazole-4-sulfonamide (formula R-7: r₁Is 1-methylimidazol-4-yl) as shown in table R.

Using the general sulfonylation procedure described in example 246, preparation 76 of a compound of formula R-6 (61 mg) was reacted with 1-methylimidazole-4-sulfonyl chloride to give 59 mg of the title compound.

The physical properties were as follows:

¹H NMR δ 0.3-0.7，1.6-2.0，3.0，3.4-3.7，6.7-7.5。

HRMS：655.1995(FAB)

example 2495-cyano-N- (3- [1- (6- [3- ([ (5-cyano-2-pyridyl) sulfonyl ] amino) phenyl ] -6-ethyl-5, 6-dihydro-4-hydroxy-2-oxo-2H-pyran-3-yl) propyl ] phenyl) -2-pyridinesulfonamide (formula R-7: R is 5-cyano-2-pyridyl) see Table R.

Using the general sulfonylation procedure described in example 246, preparation 76 of a compound of formula R-6 (66 mg) was reacted with 5-cyano-2-pyridinesulfonyl chloride to give 40 mg of the title compound.

The physical properties were as follows:

¹H NMR δ 0.3-0.9，1.3，1.6-1.9，3.0，3.7，6.6-7.2，7.9-8.2，8.8-9.0。

HRMS：699.1679(FAB)

preparation of 77M-methoxy-N-methyl-4-pentenamide (formula S-2), see Table S.

To a suspension of 4-pentenoic acid (formula S-1) (2.00 g) and N, O-dimethylhydroxylamine hydrochloride (2.15 g) in dichloromethane (50 ml) was added diisopropylethylamine (11.5 ml) at 0 deg.C followed by bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride (5.60 g). After stirring overnight, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between dilute aqueous potassium hydrogen sulfate and diethyl ether. The aqueous phase was extracted with two more portions of ether. The organic extracts were combined, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Flash column chromatography of the residue on silica gel eluting with 50% to 80% diethyl ether in hexane afforded 2.58 g of the title compound as a brown oil.

The physical properties were as follows:

¹H NMR δ 2.3-2.6，3.20，3.70，4.9-5.1，5.75-5.95。

R_f0.17 (25% Ether in hexane)

Preparation of 78 nona-1, 8-dien-5-one (formula S-3), see Table S.

To a flame-dried flask containing a solution of the title compound of preparation 77 (formula S-2) (1.45 g) in anhydrous tetrahydrofuran (10 ml) was added 3-butenyl-1-magnesium bromide (20 ml, 1M solution in tetrahydrofuran) at 0 ℃ under argon. (the Grignard reagent is prepared from magnesium metal and 4-bromo-1-butene as described in J.org.chem.43: 4247 (1978)). After 1 hour at 0 ℃, the reaction mixture was warmed to room temperature; after 1 hour at room temperature, the reaction mixture was poured into dilute aqueous potassium hydrogen sulfate and partitioned with ether. The aqueous phase was extracted with three additional portions of ether. The organic extracts were combined, washed with brine, dried over sodium sulfate, and concentrated carefully under reduced pressure. The resulting liquid was purified by distillation to give 1.32 g of the title compound as a brown oil.

The physical properties were as follows:

¹H NMR δ 2.3，2.5，5.0，5.7-5.9；

R_f0.66 (25% diethyl ether in hexane).

Preparation 791, 5-Dicyclopropylpentan-3-one (formula S-4), see Table S.

To a flame-dried flask equipped with a reflux condenser, containing metallic zinc (8.0 g) and cuprous chloride (1.25 g), was added a solution of the title compound of preparation 78 (formula S-3) (1.32 g) in anhydrous ether (10 ml) under argon atmosphere. To the resulting suspension was added diiodomethane (5.0 ml) and the reaction flask was sonicated in an ultrasonic bath (Branson 2200) at 40 ℃. After 2 hours the heating was stopped and sonication was continued overnight. The reaction mixture was then diluted with ether (50 ml), cooled to 0 ℃ and treated with an excess of saturated aqueous ammonium chloride solution. After vigorous stirring for 0.25 h, the mixture was filtered and the layers were separated. The aqueous phase was extracted with two more portions of ether. Combining the organic extracts, washing with dilute aqueous sodium thiosulfate solution, saturated aqueous sodium bicarbonate solution and brine in sequence; dried over magnesium sulfate and then carefully concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with 5% to 20% diethyl ether in hexane to give 0.48 g of the title compound as an oil.

The physical properties were as follows:

¹H NMR δ 0.0，0.4，0.65，1.45，2.50

R_f0.44 (15% diethyl ether in hexane).

Preparation 803- [2, 2-dimethyl-1- (3-nitro-phenyl) -propyl ] -5, 6-dihydro-4-hydroxy-6-phenethyl-6-propyl-pyran-2-one (formula T-3), see Table T.

To a flame-dried flask containing a slurry of 977mg active zinc in 1.0mL dry tetrahydrofuran, under an argon atmosphere, was added 40 μ L of 1, 2-dibromoethane. The mixture was placed in a 45 ℃ ultrasonic water bath (Branson 2200) and sonicated with stirring. After 10 minutes the mixture was treated with 0.25mL of trimethylchlorosilane (1.0M, tetrahydrofuran). After 10 minutes, the mixture was diluted with 4mL of tetrahydrofuran and treated dropwise with 1.50mL of 2-iodo-2-methylpropane. The mixture was stirred and sonicated at 45 ℃ for an additional 3 hours, then stirring was stopped and cooled to room temperature. 954mg of anhydrous LiCl was heated in another flask in an oil bath at 110 ℃ under vacuum for 1 hour. The LiCl flask was cooled to room temperature, placed under an argon atmosphere and 1.01g of copper (I) cyanide and 10mL of tetrahydrofuran were added in that order. After stirring for 15 minutes at room temperature, the LiCl-CuCN mixture was cooled to-30 ℃ and treated by a cannula with the organozinc mixture prepared in the first flask as described above. The reaction flask was warmed from-30 ℃ to 0 ℃, stirred for 10 minutes and then cooled to-78 ℃. The preparation of the organometallic reagent is similar to the literature methods described for related reagents [ org.syn.70: 195-203(1991)].

In a separate flask a solution of 1.56g of 6-phenethyl-6-propyl-dihydro-pyran-2, 4-dione of formula T-2 (prepared from a compound of formula T-1 as described in preparation 17 above) and 915mg of 3-nitrobenzaldehyde in 22mL of dry tetrahydrofuran was treated with a solution of 1.60g of aluminum trichloride in 14mL of tetrahydrofuran with stirring. After 2 hours, the reaction mixture was treated with 3.6g of sodium carbonate decahydrate, stirred for 5 minutes, diluted with ether and magnesium sulfate was added. The resulting mixture was filtered through a pad of celite and washed with ether. The filtrates were combined and concentrated under reduced pressure. The resulting residue was added to 9mL of dry tetrahydrofuran under argon and added via cannula to a cooled (-78 deg.C) solution of the organometallic reagent prepared above. After 0.5 h the reaction mixture was warmed to 0 ℃. After 0.5 h at 0 ℃ the reaction was poured into a cooled dilute ammonium chloride solution and the aqueous phase was acidified with dilute hydrochloric acid. The mixture was treated with ethyl acetate and filtered through a pad of celite, washing with ethyl acetate. The layers were separated and the aqueous phase was extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed with sodium thiosulfate solution, brine; dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to flash column chromatography on silica gel eluting with 30% to 50% ethyl acetate/hexane to give 1.73g of the title compound as a brown foam.

The physical properties were as follows:

¹H NMR δ 0.9，1.1，1.3，1.6-2.0，2.5-2.8，4.3，6.9-7.3，7.8，8.0，8.5

HRMS：452.2449(FAB)

preparation 813- [1- (3-amino-phenyl) -2, 2-dimethyl-propyl ] -5, 6-dihydro-4-hydroxy-6-phenethyl-6-propyl-pyran-2-one (formula T-4), see Table T.

To a solution of 1.72g of the title compound of preparation 80 (formula T-3) in 25mL of methanol was added 3.0g of ammonium formate and 400mg of 10% palladium on charcoal. The black slurry was stirred under nitrogen for 3 hours, then filtered through a pad of celite, washing with methanol. The filtrates were combined and the solvent was evaporated off under reduced pressure. The residue was triturated repeatedly with portions of dichloromethane and the combined dichloromethane washes were concentrated under reduced pressure. The residue was subjected to flash column chromatography on silica eluting with 10% ethyl acetate in dichloromethane to give 1.48g of the title compound as a white foam.

The physical properties were as follows:

¹H NMR δ 0.7-0.9，1.1，1.3-2.6，4.2，6.55，6.9-7.3

HRMS：422.2686(FAB)

EXAMPLE 250N- [3- (1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6-propyl-2H-pyran-3-yl)]-2, 2-dimethylpropyl) phenyl]-1-methyl-1H-imidazole-4-sulfonamide (formula T-5: R)₁Is 1-methylimidazol-4-yl), see table T.

To a solution of 1.48g of the title compound of preparation 81 (formula T-4) in 25mL of dichloromethane at 0 deg.C were added 0.57mL of pyridine followed by 632mg 1-methylimidazole-4-sulfonyl chloride. After 3 hours the reaction mixture was warmed to room temperature and concentrated under reduced pressure. Pyridine was azeotroped three times with toluene. The resulting residue was subjected to flash silica gel column chromatography eluting with 2% to 6% methanol in dichloromethane to give 1.7g of the title compound as a white solid.

The physical properties were as follows:

¹H NMR δ 0.8-1.0，0.97，1.35，1.6-2.0，2.5-2.7，3.6，4.1，6.9-7.5

HRMS：566.2684

the individual stereoisomers of this compound are as follows:

n- [3- (1(S) - [5, 6-dihydro-4-hydroxy-2-oxo-6 (R) - (2-phenylethyl) -6-propyl-2H-pyran-3-yl]-2, 2-dimethylpropyl) phenyl]-1-methyl-1H-imidazole-4-sulfonamide (formula KK-8, wherein R is₄Is 1-methylimidazol-4-yl), see table KK;

n- [3- (1(R) - [5, 6-dihydro-4-hydroxy-2-oxo-6 (R) - (2-phenylethyl) -6-propyl-2H-pyran-3-yl]-2, 2-dimethylpropyl) phenyl]-1-methyl-1H-imidazole-4-sulfonamide (formula LL-8, wherein R is₄Is 1-methylimidazol-4-yl), see table LL;

n- [3- (1(S) - [5, 6-dihydro-4-hydroxy-2-oxo-6 (S) - (2-phenylethyl) -6-propyl-2H-pyran-3-yl]-2, 2-dimethylpropyl) phenyl]-1-methyl-1H-imidazole-4-sulfonamide (formula MM-8, wherein R is₄Is 1-methylimidazol-4-yl), see table MM;

n- [3- (1(R) - [5, 6-dihydro-4-hydroxy-2-)Oxo-6 (S) - (2-phenylethyl) -6-propyl-2H-pyran-3-yl]-2, 2-dimethylpropyl) phenyl]-1-methyl-1H-imidazole-4-sulfonamide (formula NN-8 wherein R is₄Is 1-methylimidazol-4-yl), see table NN.

Example 2515-cyano-N- [3- (1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6-propyl-2H-pyran-3-yl)]-2, 2-dimethylpropyl) phenyl ]-2-pyridinesulfonamide (formula T-5: R)₁Is 5-cyano-2-pyridyl) see table T.

Using the general sulfonylation procedure described in example 250, 42mg of the amine of preparation 81 (formula T-4) was reacted with 20mg 5-cyanopyridine-2-sulfonyl chloride. Flash column chromatography on silica gel eluting with 1% to 3% methanol in dichloromethane afforded 56mg of the title compound as a white foam.

The physical properties were as follows:

¹H NMR δ 0.8-1.0，0.92，1.35，1.6-2.0，2.5-2.7，4.0，6.9-7.4，8.0，8.9

HRMS：588.2532

preparation of 82N-methoxy, N-methyl 3- (4-fluorophenyl) propionamide (formula U-2), see Table U.

A solution of 5.0ml of diethyl cyanophosphonate in 10ml of dichloromethane is added with stirring to a cold (0 ℃ C.), 5.0g of 3- (4-fluorophenyl) propionic acid of the formula U-1, 3.2g of (N, O) -dimethylhydroxylamine hydrochloride and 11.4ml of diisopropylethylamine in 40ml of dichloromethane. After 18 hours the solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, the solution was washed with dilute hydrochloric acid, water, aqueous sodium bicarbonate and brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 6.94g of the title compound.

The physical properties were as follows:

¹H NMR δ 2.7，2.9，3.17，3.61，7.0，7.2ppm

IR 1665，1511，1222，1033，990cm^-1

TLC R_f0.34 (5% ethyl acetate/dichloromethane)

Preparation 831- (4-fluorophenyl) -3-hexanone (formula U-3) is referred to Table U.

Preparation 82 of the title compound (formula U-2)4.68g in 25ml dry THF stirring solution under argon cooling to-15 ℃, to the solution was added 17ml1M propyl magnesium chloride in ether solution. The resulting solid was warmed to 0 ℃ for 90 minutes and then partitioned between ether and cold dilute HCl. The aqueous phase was extracted once with ether and the combined organic phases were washed with brine and dried over magnesium sulfate. The solvent was then distilled off at atmospheric pressure, and the residue was purified by evaporative distillation (about 160 ℃ C. and 13mmHg) to give 3.51g of the title compound as a colorless liquid.

The physical properties were as follows:

¹H NMR δ 0.89，1.6，2.36，2.7，2.9，6.9，7.1ppm

IR 2965，1714，1511，1222cm^-1

preparation 845, 6-dihydro-4-hydroxy-6- (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-2-one (formula U-4) is referenced in Table U.

To a cold (0 ℃ C.), stirred slurry of 950mg of sodium hydride (60% dispersion in mineral oil) in 30ml of dry THF is added dropwise, under argon, 2.3ml of methyl acetoacetate. After 5 minutes, 13.5ml of butyllithium (1.6M, hexane) were added and the mixture was stirred for a further 5 minutes and then 3.51g were added

Preparation 83 of a solution of the title compound (formula U-3) in 4ml of THF. The solution was stirred for 1 hour and then partitioned between ethyl acetate and cold dilute HCl. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give the ester of intermediate having the following physical properties: TLC R_f0.45 (50% ethyl acetate/hexanes).

The ester was stirred in 20ml of 1M sodium hydroxide, 80ml of water, and 40ml of methanol for 90 minutes, and then the methanol was distilled off under reduced pressure. The aqueous phase was washed once with ether, the ether phase was discarded and then acidified with dilute HCl. The resulting precipitate was extracted four times with dichloromethane, and the extracts were dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in 1: 1 ether-hexane and the solution was cooled to give crystals, which were filtered, washed with ether-hexane and dried under vacuum to give 3.24g of the title compound.

The physical properties were as follows:

¹H NMR δ 0.96，1.4，1.8，2.0，2.5，2.7，7.0，7.1ppm

IR 2962，1655，1604，1510，1221cm^-1

M.P.113-114.5°

elemental analysis found: c, 68.85; h, 6.99

MS：M+278

R_f0.44 (5% methanol/dichloromethane)

Preparation 853- (1- (3-benzyloxycarbonylaminophenyl) -2, 2-dimethylpropyl) -5, 6-dihydro-4-hydroxy-6- (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-2-one (formula U-6: R)₁Is t-butyl) with reference to table U.

To a solution of 3.06g of the title compound of preparation 84 (formula U-4) and 2.81g of the title compound of preparation 6 (formula B-2) above in 30ml of dry THF was added 2.93g of AlCl with stirring₃Solution in 20ml THF. After two hours, 6.4g of sodium carbonate decahydrate were added and after 5 minutes the mixture was filtered through celite and rinsed with ether. The solvent was distilled off under reduced pressure to give a benzylidene intermediate compound of the formula U-5.

To the intermediate was added 1.13g of copper (I) bromide-dimethylsulfide complex and 30ml of THF under argon, the mixture was cooled to 0 ℃ and 18.1ml of t-butylmagnesium chloride (1.0M, THF) was added dropwise. After 10 min, the reaction was partitioned between ether and cold dilute HCl. The organic phase was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to flash silica gel column chromatography, eluting with 30-35% ethyl acetate/hexane to give 1.83g of the title compound as a foam.

The physical properties were as follows:

¹H NMR δ 0.87，1.1，1.3，1.6-2.2，2.5，5.12，6.8-7.6ppm

HRMS：574.2955

R_f0.29 (35% ethyl acetate/hexane)

Preparation 863- (1- (3-aminophenyl) -2, 2-dimethylpropyl) -5, 6-dihydro-4-hydroxy-6- (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-2-one (formula U-7: R)₁Is t-butyl) with reference to table U.

A mixture of 1.83g of the title compound of preparation 85 (formula U-6), 2.0g of ammonium formate, and 400mg of 10% palladium on charcoal in 25ml of methanol was stirred under argon for 90 minutes and then filtered through celite. The solvent was distilled off under reduced pressure and the residue was subjected to flash silica gel column chromatography using 10% ethyl acetate/dichloromethane to give 1.24g of the title compound as a white foam.

The physical properties were as follows:

R_f0.28 (10% ethyl acetate/dichloromethane)

R₁Use of a compound of formula U-7 which is ethyl for the preparation of R₁U-7 which is t-butyl (preparations 85 and 86) was prepared analogously to U-4.

Example 252N- [3- {1- (4-hydroxy-5, 6-dihydro-2-oxo-6- (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl]-1-methyl-1H-imidazole-4-sulfonamide (formula U-8: R)₁Is tert-butyl, R₂Is 1-methylimidazol-4-yl), see table U.

To a solution of 88mg of the title compound of preparation 86 (formula U-7) and 32. mu.L of pyridine in 0.5ml of dichloromethane, cold (0 ℃ C.) with stirring, was added 36mg of 1-methylimidazole-4-sulfonyl chloride. After 90 minutes the reaction mixture was subjected to flash column chromatography on silica eluting with 3% to 4% methanol in dichloromethane to give 112mg of the title compound as a white foam.

The physical properties were as follows:

¹H NMR δ 0.8-1.0，0.96，1.3，1.7，2.35，2.5，3.6，3.7，6.8-7.5ppm

HRMS：583.2525

R_f0.31 (5% methanol/dichloromethane)

Example 253N- [3- {1- (4-hydroxy-5, 6-dihydro-2-oxo-6- (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl]-5-cyanopyridine-2-sulfonamide (formula U-8: R)₁Is tert-butyl, R₂Is 5-cyanopyridin-2-yl) with reference to table U.

Using the general sulfonylation procedure of example 252, 88mg of the amine of formula U-7, where R is prepared 86₁Is t-butyl) with 5-cyanopyridine-2-sulfonyl chloride. Flash column chromatography on silica gel eluting with 10-15% ethyl acetate in dichloromethane afforded 107mg of the title compound as an amorphous white solid.

The physical properties were as follows:

¹H NMR δ 0.92，1.3，1.7，2.5，6.8-7.5，8.0，8.9ppm

HRMS：606.2423

EXAMPLE 254N- [3- {1- (4-hydroxy-5, 6-dihydro-2-oxo-6- (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) propyl } phenyl]-1-methyl-1H-imidazole-4-sulfonamide (formula U-8: R)₁Is ethyl, R₂Is 1-methylimidazol-4-yl), see table U.

Using the general sulfonylation procedure of example 252, 82mg of an amine of the formula U-7, wherein R₁Is ethyl and is reacted with 1-methylimidazole-4-sulfonyl chloride. Flash column chromatography on silica gel eluting with 3% methanol in dichloromethane afforded 101mg of the title compound as an amorphous white solid.

The physical properties were as follows:

¹H NMR δ 0.8，1.3，1.6-2.2，2.5，3.5，3.6，3.9，6.8-7.4ppm

HRMS：555.2192

R_f0.29 (5% methanol/dichloromethane)

EXAMPLE 255N- [3- {1- (4-hydroxy-5, 6-dihydro-2-oxo-6- (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) propyl } phenyl]-5-cyanopyridine-2-sulfonamide (formula U-8: R)₁Is ethyl, R₂Is 5-cyanopyridin-2-yl) with reference to table U.

Using the general sulfonylation procedure of example 252, 82mg are prepared of an amine of the formula U-7, wherein R₁Is ethyl, and is reacted with 5-cyanopyridine-2-sulfonyl chloride. Flash column chromatography on silica gel eluting with 10-15% ethyl acetate in dichloromethane afforded 101mg of the title compound as an amorphous white solid.

The physical properties were as follows:

¹H NMR δ 0.9，1.3，1.6-2.2，2.5，3.9，6.9-7.3，8.0，8.1，8.9ppm

HRMS：557.2059

R_f0.44 (20% ethyl acetate/dichloromethane)

Preparation 871, 5-bis- (4-fluorophenyl) -penta-1, 4-dien-3-one (formula V-2) with reference to Table V.

To a rapidly stirred solution of 10g of sodium hydroxide in 100ml of water and 80ml of ethanol at room temperature is added a mixture of 12.4g of 4-fluorobenzaldehyde of the formula V-1 and 2.9g of acetone. After 45 minutes, the resulting precipitate was filtered, washed thoroughly with water and dried in vacuo. Recrystallization from ethyl acetate-hexane gave 10.7g of the title compound as pale yellow flakes.

The physical properties were as follows:

¹H NMR δ 6.9-7.2，7.6-7.7ppm

IR 1653，1587，1508，984，835cm^-1

MS：M+270

elemental analysis found: c, 75.40; h, 4.41

R_f0.35 (methylene chloride)

M.P.152-154℃

Preparation 881, 5-bis- (4-fluorophenyl) -pentan-3-one (formula V-3), reference is made to Table V.

To a solution of 5.41g of preparation 87 of dienone (formula V-2) in 10ml of THF and 50ml of methanol was added 2.0g of magnesium turnings. The reaction temperature was maintained close to ambient with a water bath. After magnesium depletion the reaction mixture was partitioned between dichloromethane and dilute HCl and the aqueous phase was extracted two additional times with dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to flash silica gel column chromatography using 50% dichloromethane/hexane to give 3.66g of the title compound as a yellow oil.

The physical properties were as follows:

¹H NMR δ 2.67，2.85，6.9，7.1ppm

IR 2932，1716，1603，1511，1223，1159，828cm^-1

MS：M+274

R_f0.28 (50% dichloromethane/hexane)

Preparation 894-hydroxy-5, 6-dihydro-6, 6-bis (2- (4-fluorophenyl) ethyl) -2H-pyran-2-one (formula V-4) is shown in Table V.

Using the usual acetoacetate condensation and ring closure procedure of preparation 84 (formula U-4), 3.9g of the ketone of preparation 88 (formula V-3) were converted to 2.86g of the title compound which was recrystallized from dichloromethane-hexane.

The physical properties were as follows:

¹H NMR δ 2.1，2.57，2.7，7.0，7.1ppm

IR 2924，1659，1578，1508，1241，1216cm^-1

MS：M+358

elemental analysis found: c, 70.17; h, 5.50

M.P.140-141℃

Preparation 903- [1- (3-benzyloxycarbonylaminophenyl) -2, 2-dimethylpropyl]-6, 6-bis [2- (4-fluorophenyl) ethyl]-4-hydroxy-5, 6-dihydro-2H-pyran-2-one (formula V-6, wherein R is ₁Is t-butyl) with reference to table V.

1.075g of the dihydropyrone of preparation 89 (formula V-4) was converted into 707mg of the title compound (via the intermediate compound of formula V-5) by the usual benzylidene condensation and cuprate addition method of preparation 85 (formula U-6), which was purified by flash column chromatography on silica gel using 40% ethyl acetate/hexane.

The physical properties were as follows:

¹H NMR δ 1.07，2.0，2.6，3.9，5.16，6.8-7.5ppm

HRMS：654.3023

R_f0.25 (40% ethyl acetate/hexane)

Preparation 913- [1- (3-aminophenyl) -2, 2-dimethylpropyl]-6, 6-bis [2- (4-fluorophenyl) ethyl]-4-hydroxy-5, 6-dihydro-2H-pyran-2-one (formula V-7, wherein R is₁Is t-butyl) with reference to table V.

684mg of the carbamate of preparation 90 (formula V-6, R) are prepared by the usual transfer hydrogenation procedure for preparation 86 (formula U-7)₁Is t-butyl) to 497mg of the title compound, which is purified by flash column chromatography on silica gel using 5-10% ethyl acetate in dichloromethane.

The physical properties were as follows:

¹H NMR δ 1.09，2.0，2.6，6.8-7.1ppm

R_f0.34 (10% ethyl acetate/dichloromethane)

R₁Use of a compound of formula V-7 which is ethyl for the preparation of R₁V-7 (preparations 90 and 91) which is tert-butyl was prepared analogously from V-4.

EXAMPLE 256N- [3- {1- (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-bis (2- (4-fluorophenyl) ethyl) -2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl ]-1-methyl-1H-imidazole-4-sulfonamide (formula V-8: R)₁Is tert-butyl, R₂Is 1-methylimidazol-4-yl), see table V.

Using the general sulfonylation procedure of example 252, 78mg of the amine of formula V-7, R of preparation 91₁Is t-butyl) with 1-methylimidazole-4-sulfonyl chloride. Flash column chromatography on silica gel using 3-4% methanol in dichloromethane afforded 92mg of the title compound as an amorphous white solid.

The physical properties were as follows:

¹H NMR δ 0.94，1.7-2.1，2.5，3.50，6.8-7.4ppm

HRMS：664.2647

R_f0.34 (5% methanol/dichloromethane)

EXAMPLE 257N- [3- {1- (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-bis (2- (4-fluorophenyl) ethyl) -2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl]-5-cyanopyridine-2-sulfonamide (formula V-8: R)₁Is tert-butyl, R₂Is 5-cyanopyridin-2-yl) with reference to table V.

Using the general sulfonylation procedure of example 252, 78mg of the amine of formula V-7, R of preparation 91₁Is t-butyl) with 5-cyanopyridine-2-sulfonyl chloride. Flash column chromatography on silica gel using 10-15% ethyl acetate/dichloromethane afforded 91.5mg of the title compound as an amorphous white solid.

The physical properties were as follows:

¹H NMR δ 0.92，1.9，2.6，3.2，6.8-7.5，8.0，8.9ppm

HRMS：686.2488

R_f0.28 (10% ethyl acetate/dichloromethane)

EXAMPLE 258N- [3- {1- (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-bis (2- (4-fluorophenyl) ethyl) -2H-pyran-3-yl) propyl } phenyl ]-1-methyl-1H-imidazole-4-sulfonamide (formula V-8: R)₁Is ethyl, R₂Is 1-methylimidazol-4-yl), see table V.

Using the general sulfonylation procedure of example 252, 74mg of the amine of formula V-7, wherein R₁Is ethyl and is reacted with 1-methylimidazole-4-sulfonyl chloride. Flash column chromatography on silica gel using 3-4% methanol in dichloromethane afforded 77mg of the title compound as an amorphous white solid.

The physical properties were as follows:

¹H NMR δ 0.87，2.0，2.6，3.62，4.0，4.05，6.9-7.5ppm

HRMS：636.2350

R_f0.31 (5% methanol/dichloromethane)

Example 259N- [3- {1- (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-bis (2- (4-fluorophenyl) ethyl) -2H-pyran-3-yl) propyl } phenyl]-5-cyanopyridine-2-sulfonamide (formula V-8: R)₁Is ethyl, R₂Is 5-cyanopyridin-2-yl) with reference to table V.

Using the general sulfonylation procedure of example 252, 74mg of the amine of formula V-7, wherein R₁Is ethyl, and is reacted with 5-cyanopyridine-2-sulfonyl chloride. Flash column chromatography on silica gel using 10% ethyl acetate/dichloromethane afforded 83mg of the title compound as an amorphous white solid.

The physical properties were as follows:

¹H NMR δ 0.83，2.0，2.6，3.96，6.8-7.2，8.0，8.8ppm

HRMS：658.2200

R_f0.49 (10% ethyl acetate/dichloromethane)

EXAMPLE 260N- [3- {1- (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-dipropyl-2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl]-5-cyanopyridine-2-sulfonamide (formula D-6: R) ₁Is propyl, R₂Is propyl, R₃Is tert-butyl, R₄Is 5-cyanopyridin-2-yl) with reference to table D.

Using the general sulfonylation procedure of example 252, 54mg of the amine (R) of the formula D-5₁And R₂Is propyl, R₃Is t-butyl) by reaction with preparation D-5 (R) as described in preparation 20₁Is phenethyl, R₂Is propyl, R₃Is ethyl) analogously to 5-cyanopyridine-2-sulfonyl chloride (R) of the formula D-7₄Is 5-cyanopyridin-2-yl) and flash column chromatography on silica gel using 10% to 15% ethyl acetate in dichloromethane afforded the title compound as an amorphous solid, 62 mg.

The physical properties were as follows:

¹H NMR δ 0.90，1.2-1.8，2.5，7.0-7.4，8.1，8.2，8.9ppm

HRMS：525.2305

R_f0.44 (20% ethyl acetate/dichloromethane)

EXAMPLE 261N- [3- {1- (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-dipropyl-2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl]-1-methyl-1H-imidazole-4-sulfonamide (formula D-6: R)₁Is propyl, R₂Is propyl, R₃Is tert-butyl, R₄Is 1-methylimidazol-4-yl), see table D.

Using the general sulfonylation procedure of example 252, 54mg of the amine (R) of the formula D-5₁And R₂Is propyl, R₃Is tert-butyl) with 1-methylimidazole-4-sulfonyl chloride of the formula D-7 (R)₄Is 1-methylimidazol-4-yl) conjugate, and flash column chromatography on silica gel using 3% to 5% methanol in dichloromethane afforded 53mg of the title compound as an amorphous solid.

The physical properties were as follows:

¹H NMR δ 0.9，0.96，1.2-1.8，2.5，3.6，3.7，6.9-7.5ppm

MS：503.2422

R_f0.26 (5% methanol/dichloromethane)

Example 262N- [3- {1- (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-dipropyl-2H-pyran-3-yl) propyl } phenyl]-5-cyanopyridine-2-sulfonamide (formula D-6: R)₁Is propyl, R₂Is propyl, R₃Is ethyl, R₄Is 5-cyanopyridin-2-yl) with reference to table D.

67mg of the amine (R) of formula D-5 of preparation 20 were prepared by the general sulfonylation method of example 252₁And R₂Is propyl, R₃Is ethyl) with 5-cyanopyridine-2-sulfonyl chloride (R) of formula D-7₄Is 5-cyanopyridin-2-yl) and flash column chromatography on silica gel using 10% ethyl acetate in dichloromethane afforded 78mg of the title compound as an amorphous solid.

The physical properties were as follows:

¹H NMR δ 0.6-1.0，1.2-1.8，3.4，3.5，6.9-7.4，8.0-8.2，8.9ppm

HRMS：498.2072

R_f0.38 (15% ethyl acetate/dichloromethane)

Example 263N- [3- {1- (4-hydroxy-5, 6-dihydro-2-oxo-6-phenethyl-6-propyl-2H-pyran-3-yl) propyl } phenyl]-5-cyanopyridine-2-sulfonamide (formula D-6: R)₁Is phenethyl, R₂Is propyl, R₃Is ethyl, R₄Is 5-cyanopyridin-2-yl), ginsengSee table D.

Using the general sulfonylation procedure of example 252, 79mg of the amine (R) of the formula D-5 of preparation 20₁Is phenethyl, R₂Is propyl, R₃Is ethyl) with 5-cyanopyridine-2-sulfonyl chloride (R) of formula D-7₄Is 5-cyanopyridin-2-yl) and flash column chromatography on silica gel using 10% ethyl acetate in dichloromethane afforded 102mg of the title compound as an amorphous solid.

The physical properties were as follows:

¹H NMR δ 0.7-1.0，1.2-2.6，3.4，3.5，6.9-7.3，7.9-8.2，8.9ppm

HRMS：560.2231

R_f0.37 (15% ethyl acetate/dichloromethane)

Example 264-

The following compounds were prepared using the general sulfonylation procedure of example 246. The desired amine was prepared from the compound of formula Q-1 (preparation 69) in analogy to preparations 80 and 81.

264) N- [3- (1- [6, 6-bis- (2-cyclopropyl-ethyl) -5, 6-dihydro-4-hydroxy-2-oxo-2H-pyran-3-yl ] -2, 2-dimethyl-propyl) phenyl ] -1-methyl-1H-imidazole-4-sulfonamide

The physical properties were as follows:

¹H NMR δ 0.0，0.4，0.6，1.0，1.2，1.7，2.5，3.7，4.1，6.9-7.6

HRMS：556.2833(FAB)

265) n- [3- (1- [6, 6-bis- (2-cyclopropyl-ethyl) -5, 6-dihydro-4-hydroxy-2-oxo-2H-pyran-3-yl ] -2, 2-dimethyl-propyl) phenyl ] -5-cyano-2-pyridinesulfonamide

The physical properties were as follows:

¹H NMR δ 0.0，0.4，0.6，1.0，1.2，1.7，2.5，4.1，7.0-7.5，8.0，8.1，9.0

HRMS：578.2689(FAB)

preparation of 92 (3(2E), 4S) -3- (2-pentenyl) -4-phenyl-2-oxazolidinone (formula W-4), see Table W.

A1L round bottom flask equipped with a nitrogen inlet and an addition funnel was charged with 6.92g of (S) - (+) -4-phenyl-2-oxazolidinone and 250mL of tetrahydrofuran and cooled to-78 ℃. 25.6mL of n-butyllithium were added to the previous solution, during which time a white solid, W-3, was separated from the reaction solution. To this suspension was added 4.88g of trans-2-pentenoyl chloride of formula W-2 (prepared by treating commercially available trans-2-pentenoic acid of formula W-1 with oxalyl chloride) dissolved in a small amount of THF. The resulting pale yellow homogeneous solution was allowed to warm to room temperature and stirring was continued for 20 minutes. The reaction was quenched by addition of saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was separated, washed with brine and water, dried over magnesium sulfate, filtered and concentrated to give a white solid. Recrystallization from hot hexane gave 9.13g of the title compound.

The physical properties were as follows:

MP 86-88℃

¹H NMR(CDCl₃)δ7.42-7.23，7.18-7.09，5.49，4.70，4.28，2.28，1.08ppm.

[α]_D(CHCl₃)＝+109

elemental analysis found: c, 68.59; h, 6.25; n, 5.70

Preparation of 93 (3(3R), 4S) -3- [3- (3-aminophenyl) -1-oxopentyl ] -4-phenyl-2-oxazolidinone (formula W-5), see Table W.

A1L round bottom three necked flask equipped with a nitrogen inlet and addition funnel was charged with 8.90g of copper (I) bromide-dimethyl sulfide complex and 125mL of THF and cooled to-40 deg.C. To this suspension 43mL of 1M (in THF) of 3- [ bis (trimethylsilyl) amino chloride were added dropwise over 15 min]Phenyl magnesium solution. The reaction mixture was warmed over 30 minutesTo 0 deg.C, 25mL of a THF solution containing 8.85g of preparation 92 of (3(2E), 4S) -3- (2-pentenoyl) -4-phenyl-2-oxazolidinone (formula W-4) was then added. The reaction mixture was stirred at 0 ℃ for 30 minutes, quenched by the addition of 1N HCl, and then adjusted to pH 8 with 1N NaOH. The reaction solution was washed with water, brine and the organic phase was dried (Na)₂SO₄). The organic solvent was evaporated in vacuo and the resulting oil was chromatographed on 600g silica gel, eluting with ethyl acetate/hexane to give 7.91g of the title compound.

The physical properties were as follows:

MP 94-95℃

¹H NMR(CDCl₃) δ 7.28-7.25，7.07-6.99，6.60-6.51，5.38，4.63，4.16，3.52-3.44，3.10-2.92，1.65-1.53，0.76ppm.

IR (mineral oil) 3437, 3355, 1773, 1696, 1605, 1337, 1322, 1299, 1263, 1212, 1096, 1070, 791, 762, 704cm ^-1.

Elemental analysis found: c, 71.00; h, 6.67; n, 8.17

EI-MS：[M+]＝338.

[α]_D(19.87mg/2mL CHCl₃)＝+60°

Preparation of 943- [3- (3- [ bis (phenylmethyl) amino ] phenyl) -1-oxopentyl ] -4-phenyl-2-oxazolidinone, (3R) (4S) (formula W-6) is referred to Table W.

To 25ml Na₂CO₃And 80ml of methylene chloride were added successively 7.90g of (3(3R), 4S) -3- [3- (3-aminophenyl) -1-oxopentyl ] preparation 93]4-phenyl-2-oxazolidinone (formula W-5) and 15.94g of benzyl bromide. The mixture was heated at 65 ℃ for 18 hours, the dichloromethane layer separated and dried (Na)₂SO₄) And the solvent was evaporated to give the crude product as a black viscous oil. The oil was chromatographed on 700g silica gel, eluting with 25% ethyl acetate/hexane to give 8.55g of the title compound.

The physical properties were as follows:

MP 92-3℃

¹H NMR(CDCl₃)δ7.24，7.02，6.53，5.34，4.59，4.14，3.44，3.07，2.89，1.50，0.64 ppm

elemental analysis found: c, 78.47; h, 6.68; n, 5.26

[α]_D(19.602mg/2mL CHCl₃)＝+32°

Preparation of 95 (3R) (4S)3- [3- (3- [ bis (phenylmethyl) amino ] phenyl) -2- (2-methyl-1, 3-dioxolan-2-yl) -1-oxopentyl ] -4-phenyl-2-oxazolidinone (formula W-8), see Table W.

2.1g of the amide of formula W-6 of preparation 94 are added to 25mL of dichloromethane and the resulting solution is cooled to-78 ℃ under a nitrogen atmosphere. 872. mu.L of pure TiCl were added to the solution in sequence₄And 732. mu.L of diisopropylethylamine. The resulting mixture was warmed to 0 ℃ for 30 minutes, then cooled to-78 ℃ and 1.3g of 2-methoxy-2-methyl-1, 3-dioxolane of the formula W-7 was added, and the resulting reaction liquid was warmed to 0 ℃ and stirred for 1 hour, then quenched with saturated ammonium chloride and extracted with dichloromethane. The organic phase was dried (Na) ₂SO₄) And the organic solvent is distilled off in vacuum to obtain a crude product. Chromatography on 100g silica gel eluting with 10% hexane/dichloromethane afforded 1.76g of the title compound.

The physical properties were as follows:

¹H NMR(CDCl₃)δ7.36，7.08，5.99，5.42，4.80，4.68，4.60，4.25，3.68，3.57，3.48，3.07，2.90，1.5，0.86，0.54ppm

elemental analysis found: c, 75.34; h, 6.99; n, 4.87

[α]_D(18.086mg/2mL CHCl₃)＝+25°

Preparation of 96 (3R) (4S)3- [ 2-acetyl-3- [3- (bis (phenylmethyl) amino) phenyl ] -1-oxopentyl ] -4-phenyl-2-oxazolidinone (formula W-9), see Table W.

In 25mL of tetrahydrofuran and 10mL of 30% HClO₄To this was added 5.0g of the title compound of preparation 95 (formula W-8) and the resulting solution was stirred at 40 ℃ for 3 hours. Saturated NaHCO is used for reaction liquid₃Neutralized to pH 8 and extracted with 400mL of diethyl ether. The ether layer was washed with water, brine and dried (Na)₂SO₄) The solvent was evaporated in vacuo to give an oil. Chromatography on 300g silica gel eluting with 15% acetone/hexane afforded 4.12g of the title compound.

The physical properties were as follows:

¹H NMR(CDCl₃) δ 7.31，7.08，6.59，6.55，5.42，4.67，4.61，4.22，3.09，1.63，1.56，0.61ppm

elemental analysis found: c, 77.11; h, 6.76; n, 4.98

[α]_D(20.172mg/2mL CHCl₃)＝-10°

Preparation of 97 (3R) (4S)3- [2- [1- (3- [ bis (phenylmethyl) amino ] phenyl) propyl ] -5-hydroxy-1, 3-dioxo-5-propyloctyl ] -4-phenyl-2-oxazolidone (formula W-10) see Table W.

To 25mL of dichloromethane was added 1.32g of the compound of preparation 96 (formula W-9) and the resulting solution was cooled to-78 ℃ under a nitrogen atmosphere. To this solution was added 279 μ L of TiCl in sequence ₄And 450. mu.L of diisopropylethylamine and stirring was continued for 1 hour. To this solution 689. mu.L of heptanone was added and the reaction temperature was raised to 0 ℃ for 1.5 hours. The reaction was terminated by adding saturated ammonium chloride solution and the mixture was extracted with dichloromethane. The organic phase was extracted with saturated NaHCO₃Washed and dried (Na)₂SO₄) And evaporated in vacuo to give the crude product. Chromatography on 100g silica gel eluting with 5% hexane/dichloromethane afforded 1.16g of the title compound as a beige foam.

The physical properties were as follows:

¹H NMR(CDCl₃)7.36，7.07，6.58，6.54，5.44，5.24，4.69，4.61，4.27，3.21，3.01，2.48，1.90，1.54，1.15，0.81，0.76，0.58ppm

elemental analysis found: c, 76.62; h, 7.63; n, 4.17

[α]_D(15.380mg/2mL CHCl₃)＝+16°

Preparation of 98 (3S) -3- [1- (3- (bis (phenylmethyl) amino) phenyl) propyl ] -6, 6-dipropyl-5, 6-dihydro-4-hydroxy-2H-pyran-2-one (formula W-11) see Table W.

770mg of the title compound of preparation 97 (formula W-10) was added to 10mL of dry tetrahydrofuran and the resulting solution was cooled to 0 ℃ under a nitrogen atmosphere. To this solution was added 150mg of an oil dispersion of 60% sodium hydride and the reaction temperature was raised to 20 ℃ and stirring was continued for 16 hours. The reaction was quenched by addition of saturated ammonium chloride and extracted with ethyl acetate. The extract was dried and evaporated in vacuo to give a crude product. Chromatography on 100g silica eluting with 15% EtOAc in hexanes provided 560mg of the title compound.

The physical properties were as follows:

¹H NMR(CDCl₃)7.34，6.69，5.87，4.69，4.60，4.09，2.28，2.17，1.89，1.73，1.55，1.32，0.88ppm

[ measured values of elemental analysis: c, 79.71; h, 8.07; n, 2.61]

[[α]_D(15.998mg/2mL CHCl₃)＝-56°]

Preparation of 99 (3S) -3- [1- (3-aminophenyl) propyl ] -6, 6-dipropyl-5, 6-dihydro-4-hydroxy-2H-pyran-2-one (formula W-12) is shown in Table W.

110mg of the title compound of preparation 98 (formula W-11) ((3R) -3- [1- (3-di-benzylaminophenyl) propyl ] -6, 6-dipropyl-5, 6-dihydro-4-hydroxypyran-2-one) was added to 20mL of ethyl acetate. To this solution was added 50mg of 10% Pd/C and the resulting mixture was hydrogenated at 50psi for 6 hours. The reaction solution was filtered through celite to obtain 83mg of the title compound.

The physical properties were as follows:

IR 2957，2922，2855，2871，2854，1378，1605，1459，1617，1262，1319，1251，1282，1107cm^-1.

[α]_D(6.526mg/2mL CH₃OH)＝-34°

preparation of 100 (4R)3- (1-oxo-2-pentenyl) -4-phenyl-2-oxazolidinone (formula X-4), see Table X.

A2L round bottom three necked flask equipped with a nitrogen inlet tube and addition funnel was charged with (R) - (-) -4-phenyl-2-oxazolidinone (31.2g) and tetrahydrofuran (1.2L) and cooled to-78 ℃. N-butyllithium (1.6M in hexanes, 117mL) was added to the addition funnel and added dropwise to the reaction mixture over 20 minutes. A white precipitate of X-3 was formed. The reaction mixture was stirred at-78 ℃ for a further 30 minutes. Trans-2-pentenoyl chloride of formula X-2 was then added to the addition funnel, prepared from the acid of formula X-1, (24.4g) and tetrahydrofuran (50mL) and the solution was added dropwise to the reaction mixture over 10 minutes. The resulting pale yellow homogeneous solution was allowed to warm to room temperature and stirring was continued for 30 minutes. The reaction was quenched by the addition of saturated ammonium chloride solution and extracted with ethyl acetate (2500 mL). The organic layer was separated, washed with brine and water, dried over magnesium sulfate, filtered and concentrated to give 48g of a white solid. The solid was recrystallized from ethyl acetate (100mL) and hexane (200mL) to give 38.0g of the title compound as a white solid.

The physical properties were as follows:

MP 86-88℃

¹H NMR(CDCl₃) δ 7.42-7.23，7.18-7.09，5.49，4.70，4.28，2.28，1.08ppm.

IR (mineral oil) 1785, 1764, 1686, 1638, 1349, 1336, 1329, 1257, 1234, 1214, 1087, 1076, 756, 716, 699cm^-1

EI-MS：[M+]＝245.

Preparation of 101 (3(3S), 4R) -3- [3- (3-aminophenyl) -1-oxopentyl ] -4-phenyl-2-oxazolidinone (formula X-5), see Table X.

Copper (I) bromide-dimethyl sulfide complex (25.1g) and THF (250mL) were added to a 2L round bottom three necked flask equipped with a nitrogen inlet and addition funnel and cooled to-40 ℃. 3- [ bis (trimethylsilyl) amino ] phenylmagnesium chloride (1.0M in THF, 122mL) was added to the addition funnel and added dropwise to the reaction mixture over 20 minutes. The reaction mixture was warmed from-40 ℃ to-20 ℃ over 20 minutes. 25g of the title compound of preparation 100 (formula X-4) and tetrahydrofuran (100mL) were added to the addition funnel and the solution was added dropwise to the reaction mixture over 30 minutes at 0 ℃. The reaction mixture was stirred at 0 ℃ for 15 minutes and quenched by the addition of saturated ammonium chloride solution (adjusted to pH8 by the addition of ammonium hydroxide). The reaction mixture was poured into ether (2L) and washed with ammonium chloride solution until the aqueous layer no longer appeared blue. The organic layer was separated, washed with water, dried over magnesium sulfate, filtered and concentrated to give 58g of a yellow oil. The crude product of the reaction mixture was stirred at room temperature in a slurry of silica gel (75g) and dichloromethane (100mL) for 1 hour. The mixture was filtered, washed with methanol and concentrated to give 49g of oil. Chromatography on 300g of silica gel (10-75% ethyl acetate-hexane, 100% ethyl acetate) afforded 30.9g of a yellow oil. The oil was recrystallized from ethyl acetate (75mL) and hexane (150mL) to give 21.4g of the title compound as a white solid.

The physical properties were as follows:

MP 94-97℃

IR (mineral oil) 3437, 3355, 1773, 1696, 1605, 1337, 1322, 1299, 1263, 1212, 1096, 1070, 791, 762, 704 cm^-1.

EI-MS：[M+]＝338.

Preparation of 102 (3(3S), 4R) -3- [3- (3- (phenylmethyl) amino) phenyl) -1-oxopentyl ] -4-phenyl-2-oxazolidinone (formula X-6), see Table X.

To 80ml Na₂CO₃And 280ml of methylene chloride were successively added 21.0g of (3(3S), 4R) -3- [3- (3-aminophenyl) -1-oxopentyl ] preparation 101]-4-phenyl-2-oxazolidinone (formula X-5) and 23.4g benzyl bromide. The mixture was heated at 65 ℃ for 18 hours, the dichloromethane layer separated and dried (Na)₂SO₄) And the solvent was evaporated to give the crude product as a black viscous oil. The oil was chromatographed on 700g of silica gel, eluting with 25% ethyl acetate/hexane to give 31.42g of the title compound.

The physical properties were as follows:

MP 91.8-93.5℃

¹H NMR(CDCl₃) δ 7.32，7.08，6.60，5.34，4.67，4.15，3.43，3.02，2.91，1.56，0.65ppm

preparation of 103 (3R) (4S) -3- [3- [3- (bis (phenylmethyl) amino ] phenyl ] -2- (2-methyl-1, 3-dioxolan-2-yl) -1-oxopentyl ] -4-phenyl-2-oxazolidinone (formula X-8), see Table X.

To 12mL of dichloromethane was added 1.55 g of (3(3S), 4R) -3- [3- (3-dibenzylaminophenyl) valeryl of preparation 102 under nitrogen]-4-phenyl-2-oxazolidinone (formula X-6) and cooling the resulting solution to-78 ℃. 646 mu LTiCl was added to the above solution in sequence ₄And 525. mu.L of diisopropylethylamine. After stirring at 0 ℃ for 30 minutes, the reaction was cooled to-78 ℃ and 886. mu.L of 2-methoxy-2-methyl-1, 3-dioxolane (formula X-7) (also W-7) was added. The reaction was stirred for 1 hour, then saturated NH was added₄The reaction was stopped with Cl and then saturated NaHCO was added₃(pH8) and finally the aqueous phase is extracted with dichloromethane and diethyl ether. The solvent was evaporated to give a viscous oil which was chromatographed on 150g silica gel, eluting with 7% hexane/dichloromethane to give 1.14g of the title compound.

The physical properties were as follows:

IR (mineral oil) 2920, 2954, 2854, 2870, 1776, 1376, 1453, 1196, 699 cm^-1.

Elemental analysis found: c, 75.27; h, 6.68; n, 4.55

Preparation of 104 (3S) (4R)3- [ 2-acetyl-3- [3- [ bis (phenylmethyl) amino ] phenyl ] -1-oxopentyl ] -4-phenyl-2-oxazolidinone (formula X-9), see Table X.

To 15ml of THF was added 960mg of (3(3S), 4R) -3- [2- (2-methyl-1, 3-dioxan-2-yl) -3- (3-dibenzylaminophenyl) valeryl of preparation 103]-4-phenyl-2-oxazolidinone (formula X-8). To this solution was added 4mL of 30% perchloric acid and the resulting mixture was stirred at 40 ℃ for 2 hours. The reaction was cooled to room temperature and excess saturated NaHCO was added ₃The reaction was terminated. The reaction mixture was extracted with 200mL of diethyl ether and dried (Na)₂SO₄) And the solvent was distilled off in vacuo to give 981mg of crude product. Chromatography on 100g silica gel eluting with 10% pentane/dichloromethane afforded 854mg of the title compound.

The physical properties were as follows:

¹H NMR(CDCl₃) δ 7.40，7.08，6.61，6.56，5.41，4.96，4.66，4.61，4.21，3.09，1.63，1.65，0.61

IR (mineral oil) 1778, 1718, 1600, 1695, 1452, 1335, 1385, 1200 cm^-1.

EI-MS：[M+]＝560.

Elemental analysis found: c, 76.81; h, 6.59; n, 4.84

Preparation of 105 (3S) (4R)3- [2- [1- [3- [ bis (phenylmethyl) amino ] phenyl ] propyl ] -5-hydroxy-1, 3-dioxo-5-propyloctyl ] -4-phenyl-2-oxazolidinone (formula X-10), see Table X.

To 8mL of dichloromethane was added 440mg of preparation 104 (3) under nitrogen(3S), 4R) -3- [2- (acetyl) -3- (3-dibenzylaminophenyl) pentanoyl]-4-phenyl-2-oxazolidinone (formula X-9) and cooling the solution to-78 ℃. To this solution was added sequentially 90. mu. LTiCl₄And 143. mu.L of diisopropylethylamine. The solution was warmed to 0 ℃ for 40 minutes and then cooled to-78 ℃, at which point 126 μ L4-heptanone was added and the reaction temperature was raised to 0 ℃ and stirring was continued for 1.5 hours. Adding saturated NH₄The reaction was stopped with Cl and then saturated NaHCO was added₃. The reaction mixture was extracted with dichloromethane (3X 60mL) and dried (Na)₂SO₄) And evaporated in vacuo to give a crude oil. Chromatography on silica gel (100g) eluting with 10% hexane/dichloromethane afforded 293mg of the title compound.

The physical properties were as follows:

¹H NMR(CDCl₃) δ 7.28，7.07，6.56，5.44，5.24，4.68，4.61，4.26，3.21，3.10，2.48，1.90，1.55，1.21，0.81，0.74，0.58

IR (mineral oil) 2959, 293.1, 1779, 1720, 1690, 1600, 1494, 1452, 1385, 1359, 1334, 1238, 698 cm^-1.

Preparation of 106 (3R)3- [1- [3- [ bis (phenylmethyl) amino ] phenyl ] propyl ] -5, 6-dihydro-4-hydroxy-6, 6-dipropyl-2H-pyran-2-one (formula X-11), see Table X.

To 3mL THF under nitrogen was added 28mg NaH. To this suspension was added 418mg of (3(3S), 4R) -3- [2- ((3-hydroxy-3-propyl) hexanoyl) -3- (3-dibenzylaminophenyl) pentanoyl preparation 105 dissolved in 3mL THF at 20 deg.C]-4-phenyl-2-oxazolidinone (formula X-10). The reaction was stirred for 16 hours, cooled to 0 ℃ and quenched by addition of 1N HCl. Adding saturated NaHCO₃The reaction solution was made alkaline. The aqueous phase is extracted several times with ethyl acetate and the organic extracts are dried (Na)₂SO₄) And the solvent was distilled off in vacuo to give 518mg of crude product. Chromatography on silica eluting with 15% EtOAc in hexanes afforded 128mg of the title compound.

The physical properties were as follows:

IR (mineral oil) 2959, 2931, 2873, 1636, 1599, 1451, 1465, 1386, 1363, 1328, 1249, 1260, 696cm^-1.

EI-MS：[M+]＝511.

Preparation of 107 (3R)3- [1- [ 3-amino ] phenyl ] propyl ] -5, 6-dihydro-4-hydroxy-6, 6-dipropyl-2H-pyran-2-one (formula X-12), see Table X.

110mg of the dihydropyrone of the formula X-11 of preparation 106 ((3R) -3- [1- (3-dibenzylaminophenyl) propyl ] -6, 6-dipropyl-5, 6-dihydro-4-hydroxypyran-2-one) was added to 20mL of ethyl acetate. To this solution was added 50mg of 10% Pd/C and the resulting mixture was hydrogenated at 50psi for 6 hours. The reaction solution was filtered through celite to obtain 83mg of the title compound.

The physical properties were as follows:

IR (mineral oil) 2961, 2932, 2873, 1682, 1623, 1604, 1458, 1384, 1369, 1319, 1282, 1259, 1150, 1108cm^-1.

EI-MS：[M+]＝331

Preparation of 1082-phenethyl-2-propen-1-ol (formula BB-2), see Table BB.

To a cold (-10 ℃ C.) solution of N, N, N, N, -tetramethyl-1, 2-ethylenediamine (24.1mL) in hexane (50mL) was slowly added butyllithium (100mL1.6M in hexane). After stirring at-10 ℃ for 45 minutes, the mixture was cooled (-78 ℃) and 2-methyl-2-propen-1-ol (BB-1, 6.41mL) was added dropwise. The reaction was allowed to warm to room temperature and stirring was continued for 72 hours. The mixture was cooled to-78 ℃ and a solution of benzyl bromide (8.6mL) in anhydrous tetrahydrofuran (10mL) was added slowly. The mixture was stirred at-78 ℃ for 1 hour and then gradually warmed to room temperature. Stirring was continued for 2 hours and then saturated NH was used₄The reaction was terminated with an aqueous solution of Cl. The organic layer was diluted with ether and washed with brine, dried (MgSO) ₄) Filtered and concentrated in vacuo. Purification by flash column chromatography using dichloromethane/ethyl acetate/hexane (1: 6) as the eluent gave the title compound as an oil (3.5 g).

The physical properties were as follows:

¹H NMR(CDCl₃) δ 7.3 1-7.16，5.07，4.93，4.09，2.82-2.76，2.41-2.36ppm.

¹³C NMR(CDCl₃) δ 148.30，141.69，128.24，125.80，109.76，65.90，34.52，34.16ppm.

preparation of 109 (2S) -2-phenethyloxirane methanol (formula BB-8), see Table BB.

To a cold (-20 ℃ C.) slurry of molecular sieve (4. ANG., crushed and freshly activated, 150mg) in dichloromethane (1.5mL) was added diethyl L-tartrate (22mg) and titanium (IV) isopropoxide (25 mg). The mixture was stirred at-20 ℃ for 30 minutes and t-butyl hydroperoxide (0.84mL5-6M in nonane) was added. After stirring at-20 ℃ for an additional 25 minutes, a solution of the allylic alcohol of formula BB-2 of preparation 108 (300mg) in dichloromethane (0.5mL) was added slowly. The mixture was stirred at-20 ℃ overnight and then warmed to-10 ℃. After keeping for 4 hours, the reaction mixture was warmed to 0 to 5 ℃ and water (1mL) was added to terminate the reaction. After warming to room temperature, stirring was continued for 1 hour, and then tartrate was hydrolyzed by adding 30% aqueous NaOH solution (0.1mL) saturated with NaCl. After 30 minutes, the mixture was filtered through celite and the aqueous phase was extracted several times with dichloromethane. The combined organic layers were dried (MgSO) ₄) Filtration and concentration in vacuo gave a residue which was purified by flash column chromatography using hexanes and a gradient of increasing ethyl acetate (10-20%) as eluent to give the title compound of formula BB-3 as an oil (223 mg). Mosher esters formed by reaction of p-BB-3 with (S) - (+) -alpha-methoxy-alpha- (trifluoromethyl) phenylacetyl chloride¹HNMR(C₆D₆) The enantiomeric excess of the reaction was determined to be 86% [ j.a.dale, d.l.dull, h.s.mosher, j.org.chem. (1969) 34: 2543]。

The physical properties were as follows:

¹H NMR(CDCl₃) δ 7.34-7.16，3.83-3.61，2.89-2.87，2.72-2.64，2.17-2.04，1.89-1.79ppm

¹³C NMR(CDCl₃) δ 141.17，137.58，128.49，128.21，126.11，63.00 59.57，49.92，33.58，30.82ppm.

preparation of 110 (2S) -2-phenethyl-2-phenylmethoxymethyloxirane (formula BB-9), see Table BB.

To a cold (0-5 deg.C) slurry of sodium hydride (124mg 60% suspension in mineral oil) in THF (10mL) was added the alcohol of formula BB-3 preparation 109 (460 mg). The mixture was stirred at 0-5 ℃ for 5 minutes, warmed to room temperature and stirred for an additional 30 minutes. Benzyl bromide (441mg) was added to the solution, and the mixture was stirred at room temperature overnight. The mixture was quenched with brine (10mL) and diluted with ether. The organic layer was washed with brine and dried (MgSO)₄) Filtration and concentration in vacuo gave a residue which was purified by flash column chromatography using hexanes and a gradient of increasing ethyl acetate (2-5%) as eluent to give the title product as an oil (510 mg).

The physical properties were as follows:

¹H NMR(CDCl₃) δ 7.34-7.13，4.59-4.49，3.64-3.45，2.75-2.59，2.19-2.09，1.94-1.84

¹³C NMR(CDCl₃) δ 141.42，137.93，128.58，128.38，127.88，125.94，73.23，71.98，58.21，50.37，33.65，30.83ppm.

preparation of 110a (3S) -1-phenyl-3- (phenylmethoxymethyl) hex-3-ol (formula BB-10), see Table BB.

Cold (-45 ℃) Li₂CuCl₄(0.28mL of a 0.1M solution in THF) to a solution of THF (2mL) was added ethylmagnesium bromide (0.203mL of a 3M solution in ether). The brown solution was stirred at-45 ℃ for 45 minutes and the epoxide of formula BB-4 of preparation 110 (150mg) was added dropwise over about 10 minutes. After one hour saturated NH was added₄The reaction was stopped with aqueous Cl solution and the aqueous layer was washed with acetic acidAnd (5) extracting with ethyl ester. The combined organic layers were washed with brine and dried (MgSO)₄) Filtration and concentration in vacuo gave a residue which was purified by flash column chromatography using hexane/ethyl acetate (5%) as eluent to give the title product as an oil (150 mg).

The physical properties were as follows:

¹H NMR(CDCl₃) δ 7.38-7.14，4.54，3.37，2.66-2.58，2.20，1.88-1.76，1.58-1.52，1.39-1.25，0.92

¹³C NMR(CDCl₃) δ 142.61，138.10，128.41，128.33，127.71，127.63，125.68.75.45，73.79，73.44，38.95，38.52，29.86，16.79，14.37ppm.

preparation of 110b (2R) -2-phenylethyl-2- (p-toluenesulfonyloxymethyl) oxirane (formula BB-13) is shown in Table BB.

To a cold (ca. -10 ℃) solution of the compound of formula BB-8 of preparation 109 (245mg) in dichloromethane (4mL) was added 4-toluenesulfonyl chloride (302g), triethylamine (160mg), and 4-dimethylaminopyridine (8 mg). The mixture was stirred at about-10 ℃ overnight and then warmed to 0-5 ℃ for 1 hour. The mixture was diluted with dichloromethane and saturated NaHCO ₃The aqueous solution and brine were washed and dried (MgSO)₄) Filtration and concentration in vacuo gave a residue which was purified by flash column chromatography using hexane/ethyl acetate (5%) as eluent to give the title compound (448 mg).

The physical properties were as follows:

¹H NMR(CDCl₃) δ 7.79，7.33，7.28-7.08，4.13-3.98，2.64-2.58，2.44，2.11-2.00，1.92-1.82

¹³C NMR(CDCl₃) δ 145.17，140.67，132.53，129.96，128.48，128.19，127.95，126.15，71.98，56.49，50.63，32.89，30.37，21.64ppm.

preparation of 110c (2S) -2-phenylethyl-2-propyloxirane (formula BB-12) is shown in Table BB.

Cold (-45 ℃) Li₂CuCl₄(0.3mL of a 0.1M solution in THF) to a solution of THF (2mL) was added ethylmagnesium bromide (0.22mL of a 3M solution in ether). The brown solution was stirred at-45 ℃ for 45 minutes, cooled to-65 ℃ and then the tosylate of formula BB-13 of preparation 110b (200mg) was added dropwise over about 10 minutes. The mixture was stirred for 2.5 hours, warmed to-50 ℃ for 2 hours, and then saturated NH was added₄The reaction was stopped with Cl solution. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried (MgSO)₄) Filtration and concentration in vacuo gave a residue which was purified by flash column chromatography using hexane/ethyl acetate (5%) as the eluent to give the title product (60mg) and hydroxytoluene sulfonate ester of formula BB-14 (47 mg).

The conversion of a hydroxy tosylate of formula BB-14 to an epoxide of formula BB-12 is as follows: to a cold (0-5 deg.C) solution of the compound of formula BB-14 (43mg) in methanol (2mL) was added anhydrous K ₂CO₃(20 mg). After 1 hour at 0-5 deg.C, the mixture was allowed to warm to room temperature, stirring was continued for 90 minutes, and then saturated NH was added₄The reaction was terminated with an aqueous solution of Cl. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried (MgSO)₄) Filtration and concentration in vacuo gave a residue which was purified by flash column chromatography using hexane/ethyl acetate (5%) as the eluent to give the epoxide of formula BB-12 (20 mg).

The physical properties of BB-12 were as follows:

¹H NMR(CDCl₃) δ 7.31-7.16，2.68，2.59，1.98-1.82，1.73-1.37，0.94

¹³C NMR(CDCl₃) δ 141.71，128.41，128.24，125.92，59.11，52.57，36.42，36.02，31.03，18.19，14.22ppm.

the physical properties of BB-14 were as follows:

¹H NMR(CDCl₃) δ 7.79，7.34，7.29-7.11，3.90，2.58-2.53，2.44，1.87，1.77-1.72，1.54-1.48，1.31-1.21.0.89

¹³C NMR(CDCl₃) δ 145.10，141.66，132.50，129.97，128.45，128.25，127.97，125.96，74.33，73.07，38.37，37.87，29.37，21.66，16.47，14.48ppm.

preparation of 111 (4S) -3-acetyl-4-phenyl-2-oxazolidinone (formula FF-3) is referred to Table FF.

To a solution of (S) - (+) -4-phenyl-2-oxazolidinone of formula FF-2 (20g) in anhydrous tetrahydrofuran (600mL) cooled to-78 deg.C was added 1.6M n-butyllithium in hexane (77.8mL) and the resulting suspension was stirred at-78 deg.C for 30 minutes. The suspension was treated with acetyl chloride of formula FF-1 (10.23mL) and then gradually warmed to room temperature. The reaction mixture was quenched with 1L saturated ammonium chloride and partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude solid was recrystallized from ethyl acetate/hexane to give the title compound as a white solid (21.27 g).

The physical properties were as follows:

Mp 86-87℃

¹H NMR(CDCl₃) δ 7.42-7.26，5.44-5.40，4.68，4.30-4.26，2.52ppm

¹³C NMR(CDCl₃) δ 169.50，153.71，138.81，128.97，128.53，125.73，69.73，57.20，23.59ppm

preparation of 112 (3(2E), 4S) -3- [4, 4-dimethyl (2-pentanoyl) ] -4-phenyl-2-oxazolidinone (formula FF-4), see Table FF.

To a solution of the compound of formula FF-3 of preparation 111 (21.27g) in anhydrous dichloromethane (500mL) cooled to-78 deg.C was added dropwise titanium tetrachloride (12.0 mL). The suspension was treated with diisopropylethylamine (19.9mL) and stirred at-78 ℃ for 30 min. The suspension was then treated successively with trimethylacetaldehyde (11.4mL) and diisopropylethylamine (19.9mL) and gradually warmed to room temperature. After 1 hour the reaction mixture was quenched with water (200mL) and stirred vigorously for 15 minutes. The organic layer was separated and the aqueous layer was re-extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude solid was recrystallized from ethyl acetate/hexane to give 21.6 g of the title compound as an off-white solid.

The physical properties were as follows:

Mp 148-149℃

¹H NMR(CDCl₃) δ 7.42-7.05，5.5 1-5.46，4.69，4.30-4.25，1.09ppm

¹³C NMR(CDCl₃) δ 165.17，161.61，153.70，139.16，129.12，128.61，125.97，115.71，69.88，57.74，34.31，28.56ppm；

preparation of 113 (3(3S), 4S) -3- [3- (3-aminophenyl) -4, 4-dimethylvaleryl ] -4-phenyl-2-oxazolidinone (formula FF-5), see Table FF.

To a slurry of copper (I) bromide dimethyl sulfide complex (18.76g) cooled to-78 deg.C in anhydrous tetrahydrofuran (60mL) was added a 1.0M solution of 3- [ bis (trimethylsilyl) amino ] phenylmagnesium chloride in tetrahydrofuran (182.2mL) and the resulting slurry was stirred at-78 deg.C for 5 minutes. The slurry was warmed to-15 ℃ for 15 minutes and then cooled to-78 ℃. The slurry was then treated with a compound of formula FF-4 of preparation 112 (16.6g) added via a solid addition funnel and stirred at-78 ℃ for 3 hours. The reaction mixture was poured into saturated ammonium chloride (200mL) and partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer (pH8) was basified with concentrated ammonium hydroxide to pH 9.5. The aqueous layer was extracted three more times with ethyl acetate and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude residue was slurried in chloroform (400mL) and 200g of silica gel (230-400 mesh) at room temperature for 2 hours. The slurry was filtered and the solid was washed several times with chloroform and methanol in sequence. The filtrate was concentrated in vacuo. Purification by flash column chromatography eluting with hexane/ethyl acetate (15-40%) afforded 17.52 g of the title compound as a pale yellow solid.

The physical properties were as follows:

¹H NMR(CDCl₃) δ 7.26-7.12，7.01，6.74-6.70，6.61-6.50，5.32-5.28，4.56，4.11-3.95，3.48，2.97-2.91，0.91ppm

¹³C NMR(CDCl₃) δ 172.34，153.51，145.37，142.24，138.12，128.67，128.23，127.68，124.71，119.80，116.49，113.02，69.39，57.39，52.30，34.75，33.49，27.83ppm

preparation of 114 (3(3S), 4S) -3- [3- (3-dibenzylaminophenyl) -4, 4-dimethylpentanoyl ] -4-phenyl-2-oxazolidinone (formula FF-6), see Table FF.

To a solution of preparation 113 of compound of formula FF-5 (15.0g) in dichloromethane (190mL) was added saturated sodium carbonate (48.7mL) and benzyl bromide (14.3mL) sequentially at room temperature and the resulting mixture was refluxed for 24 hours. The reaction mixture was cooled to room temperature and partitioned between water (300 mL) and dichloromethane, the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo, purified by flash column chromatography, eluting with hexane/ethyl acetate (10-25%) to give 15.1 g of the title compound as a white solid.

The physical properties were as follows:

¹H NMR(CDCl₃) δ 7.29-6.99，6.69-6.49，5.32-5.26，4.71-4.50，4.06-3.94，2.90-2.81，0.73ppm

¹³C NMR(CDCl₃) δ 172.79，153.78，148.32，142.08，139.04，138.48，129.07，128.59，128.37，127.89，126.83，124.92，118.44，114.64，110.87，69.70，57.68，54.77，52.97，34.84，33.79，27.97ppm

preparation of 115 [ S, [ R ]^*，S^*(E)]]-N- (2-hydroxy-1-methyl-2-phenylethyl) -methyl-N-pentenamide (formula NNN-3) see table NNN.

A250 mL round-bottom three-necked flask equipped with a nitrogen inlet and an addition funnel was charged with the compound of formula NNN-1 (6.6g) (prepared from commercially available trans-2-pentenoic acid treated with oxalyl chloride) and tetrahydrofuran (80 mL). A solution of (1R, 2S) -ephedrine of formula NNN-2 (7.2g) and triethylamine (6.0mL) in tetrahydrofuran (15mL) was added to the addition funnel and added dropwise to the reaction mixture. After stirring for an additional 1 hour, the reaction mixture was poured into 200mL ethyl acetate, washed with 3X 25mL water and concentrated in vacuo to give 13.5g of an oil. Column chromatography on 100g silica gel (10-100% ethyl acetate-hexanes elution) afforded 10.75g of the title compound as a colorless oil.

The physical properties were as follows:

HRMS found: 248.1652.

preparation of 116 [1R- [1R ]^*(R^*)2S^*]]-3-amino- β -ethyl-N- (2-hydroxy-1-methyl-2-phenylethyl) -N-methyl-phenylacrylamide (formula NNN-4) is shown in table NNN.

A50 mL round bottom three necked flask equipped with a nitrogen inlet was charged with the title compound of preparation 115 (0.247g) and 5mL t-butyl methyl ether and cooled to 0 ℃. Propylmagnesium chloride (0.55ml of a 2.0M solution in ether) was added dropwise and the reaction mixture was stirred for a further 15 minutes. 3- [ bis (trimethylsilyl) amino ] phenylmagnesium chloride (2.0mL of 1.0M in tetrahydrofuran, 2.0mmol) was added dropwise and the resulting mixture was stirred for an additional 2 hours at 0 ℃ and 1 hour at room temperature. The reaction mixture was then quenched with saturated aqueous ammonium chloride (pH adjusted to 8 with ammonium hydroxide) and partitioned between 100mL ethyl acetate and 5mL water. The organic layer was separated, washed with additional ammonium chloride solution and water and concentrated in vacuo to give 0.72g of a yellow oil. The crude oil was dissolved in chloroform and silica gel was added to the solution. The resulting mixture was stirred at room temperature for 1.5 hours, then filtered through celite, rinsed with methanol, and concentrated in vacuo to give 0.38g of a yellow oil. Column chromatography on 50g silica gel (eluting with 20-100% ethyl acetate-hexanes) afforded 0.174g of the title compound as an oil.

The physical properties were as follows:

HRMS found: 340.2162.

preparation 117 [1R- [1R ]^*(R^*)2S^*]]-3- [ bis (phenylmethyl) amino]-b-ethyl-N- (2-hydroxy-1-methyl-2-phenylethyl) -N-methyl-phenylacrylamide (formula NNN-5) is shown in table NNN.

A50 mL round-bottom three-necked flask with a condenser equipped with a nitrogen inlet was charged with a solution of the title compound of preparation 116 (0.548g) in 8mL acetonitrile. Sodium carbonate (0.375g) and benzyl bromide (0.42mL) were added and the reaction mixture was heated at reflux for 4 hours. The reaction mixture was then concentrated in vacuo and partitioned between 100mL ethyl acetate and 10mL water. The organic layer was separated, washed with another 10mL of water, and concentrated in vacuo to give 1.0g of a yellow oil. Column chromatography on 65g silica gel (eluting with 20-100% ethyl acetate-hexanes and 5% methanol-dichloromethane) afforded 0.447g of the title compound as a pale yellow oil.

The physical properties were as follows:

HRMS found: 520.3102.

preparation 1181-phenyl-6, 6, 6-trifluoro-3-hexanol (formula PPP-2), reference Table PPP.

To a stirred solution of 4.0g of ethyl 4, 4, 4-trifluorobutyrate of the formula PPP-1 in 25mL of tetrahydrofuran, 24mL of DiBAL-H (1M solution in toluene) were added dropwise at-70 ℃ and the solution was stirred for 90 minutes. 1-phenyl-2-bromoethane dissolved in 20mL of tetrahydrofuran was added to a separate flask containing 680mg of magnesium turnings and 5mL of tetrahydrofuran at a rate to maintain reflux. The mixture was heated for an additional 1 hour, then cooled to room temperature and added to the above DiBAL-H reaction via cannula. The resulting white suspension was stirred at-70 ℃ for 30 minutes and then warmed to room temperature. The reaction was quenched with saturated aqueous ammonium chloride solution, diluted with 1N hydrochloric acid to dissolve the precipitated salt and extracted with ethyl acetate. The organic layers were combined, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was subjected to flash column chromatography on silica gel eluting with 20% ethyl acetate/hexane to give 2.0g of the title compound as a colorless oil.

The physical properties were as follows:

HRMS：232.1088

IR (pure liquid): 3385, 2950, 1455, 1255, 1140, 700cm^-1。

Preparation 1191-phenyl-6, 6, 6-trifluoro-3-hexanone (formula PPP-3), reference Table PPP.

To a solution of 0.48mL of oxalyl chloride in 10mL of dichloromethane was added dropwise 0.81mL of dimethyl sulfoxide at-60 ℃. The solution was stirred for 5 minutes and then treated with 860mg of a solution of the 1-phenyl-6, 6, 6-trifluoro-3-hexanol of the formula PPP-2 of preparation 118 in 5mL of dichloromethane and stirred for 15 minutes. Triethylamine (1.5ml) was added, the mixture was warmed to room temperature, diluted with water and the organic layer was separated. The aqueous layer was extracted with dichloromethane, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The oil obtained is chromatographed on silica gel on a flash column to give 600mg of the title compound as an oil. The physical properties were as follows:

¹H NMR(CDCl₃)：δ 7.2-7.3，2.9，2.7，2.6，2.4.

¹³C NMR(CDCl₃)：δ 206，140，129，128，126，125，44，35，30，28.

preparation 1205, 6-dihydro-4-hydroxy-6-phenethyl-6- (3 ', 3 ', 3 ' -trifluoropropyl) -2H-pyran-2-one (formula PPP-4), see PPP, Table.

A suspension of 350mg of 50% sodium hydride in 10mL of tetrahydrofuran is treated with 0.78mL of methyl acetoacetate dropwise at 0 ℃. After stirring for 30 minutes, 4.5ml of a 1.6M solution of n-butyllithium in hexane were added and stirring was continued for 15 minutes. 840mg of a solution of 1-phenyl-6, 6, 6-trifluoro-3-hexanone of formula PPP-3 of preparation 119 in 5mL of tetrahydrofuran are added, stirred at 0 ℃ for 15 minutes and then warmed to room temperature and stirred for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water and brine, concentrated in vacuo, and then dissolved in 20mL of tetrahydrofuran. The solution was diluted with 60mL of water and treated with 20mL of 1N sodium hydroxide, stirred at room temperature for 3 hours, concentrated in vacuo to remove tetrahydrofuran, cooled to 5 ℃ and acidified with concentrated HCl. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was subjected to flash column chromatography on silica gel eluting with 30% ethyl acetate/hexane to give 870mg of the title compound.

The physical properties were as follows:

elemental analysis: c, 61.14; h, 5.45.

Preparation of 121- [3- [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6- (3, 3, 3-trifluoropropyl) -2H-pyran-3-yl ] -2]-2, 2-dimethylpropyl radical]Phenyl-carbamic acid benzyl ester (formula QQQ-3 wherein R₁t-Bu), refer to table QQQ.

Preparation 120A solution of the title compound (850mg) in 25mL of tetrahydrofuran was treated with 750mg of aluminum trichloride at 0 deg.C, stirred for 15 minutes, and then 700mg of 3-benzyloxycarbonylaminobenzaldehyde was added. The mixture was allowed to warm to room temperature for 2 hours, then treated with 2g of sodium carbonate monohydrate and 0.1mL of water, stirred for 30 minutes, filtered through celite and the filter cake was washed with tetrahydrofuran. The filtrate was concentrated in vacuo. The resulting material was dissolved in 25mL of tetrahydrofuran and 285mg of cuprous bromide-dimethyl sulfide complex was added, and after stirring the mixture for 15 minutes, 11mL of 1M solution of t-butyl magnesium chloride in tetrahydrofuran was added over 15-20 minutes. The resulting brown mixture was stirred for a further 15 minutes and then quenched with 50mL of water at 0 ℃. The organic layer was separated and the aqueous layer was acidified with concentrated hydrochloric acid to dissolve inorganic salts, followed by extraction with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash column chromatography on silica gel eluting with ethyl acetate-hexanes afforded 1.19g of the title compound as a white to beige foam.

The physical properties were as follows:

¹H NMR(CDCl₃)：δ 7.1-7.7，6.7，6.5，4.4，1.8-2.8，1.16.

HRMS：609.2711.

preparation 122 preparative resolution of [3- [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6- (3, 3, 3-trifluoropropyl) -2H-pyran-3-yl]-2, 2-dimethylpropyl radical]Phenyl carbamic acid benzyl ester (formula QQQ-3 wherein R₁Is 4 isomers, 3(R or S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (R or S) - (2-phenylethyl) -6- (R or S) - (3, 3, 3-trifluoropropyl) -2H-pyran-3-yl]-2, 2-dimethylpropyl radical]Phenyl-carbamic acid benzyl ester (formula QQQ-4-7 wherein R₁t-Bu), refer to table QQQ.

The first stage of resolution was accomplished using a 5.1X 25cm (R, R) Whelk-O1 column, eluting with 15% (V/V) isopropanol/hexane at 99mL/min [ (R, R) Whelk-O1 is a registered trademark, Regis technologies, Inc., Morton Grove, IL 60053). The peaks eluted at approximately 54 and 87 minutes were judged to be pure isomer 3 and isomer 2, respectively, using system a described below. The mixture of undisresolved isomer 1 and isomer 4 elutes at about 64 minutes and is further processed as described below.

The second stage of resolution, the above mixture eluting at about 64 minutes was injected onto a 2.1 × 25cm Chiralcel OD column (Chiral Technologies, Inc.) and eluted with 35% (V/V) isopropanol/hexane at 8 mL/min. The peaks eluted at approximately 8.7 and 23.9 minutes were pure isomer 1 and isomer 4, respectively.

In both stages of the enantiomeric resolution, the fractions were collected after the determination with System A and the collected liquid was concentrated to dryness at 30mm with a rotary evaporator, setting a water bath of up to 50 ℃.

The four enantiomers (in order of elution from system a) were labeled (Peak #1), (Peak2), (Peak #3), (Peak # 4). System A consisted of a 0.46X 25cmChiralcel OD-H column eluting with 20% isopropanol/hexane (V/V) at 1.0 mL/min. (Chiralcel OD-H is a registered trademark, Chiral Technologies, Inc., Exton PA 19341.)

Preparation of 1233 (R or S) - [1- (3-chlorophenyl) -2, 2-dimethylpropyl]-4-hydroxy-5, 6-dihydro-6- (R or S) -phenethyl-6- (3, 3, 3-trifluoropropyl) -2H-pyran-2-one (formula QQ-8 wherein R is₁t-Bu), refer to table QQQ.

A solution of 210mg of preparation 122, identified as peak 1, in 10mL of methanol was treated with 400mg of ammonium formate and 40mg of 10% palladium on charcoal, stirred for 2 hours, filtered through celite, and the filter cake was washed with methanol. The filtrate was diluted with ethyl acetate and washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 160mg of the title compound as a white foam.

The physical properties were as follows:

¹H NMR(CD₃OD)：δ 6.9-7.3，6.6，4.1，2.6-2.7，1.9-2.4，1.0.

TLC (silica gel GF): r_f0.24 (40% ethyl acetate/hexane).

Example 2665-cyano-N- [3- (R or S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6- (R or S) - (3, 3, 3-trifluoropropyl) -2H-pyran-3-yl]-2, 2-dimethylpropyl radical]Phenyl radical]-2-pyridinesulfonamide (formula QQQ-13, R)₁Is t-Bu, R₂Is [ 5-cyano-2-pyridyl]) Refer to table QQQ.

Preparation 123A solution of the title product (50mg), pyridine (30mL), and 5-cyano-pyridine-2-sulfonyl chloride (30mg) in dichloromethane was stirred at 0 ℃ for 2 hours. The crude reaction mixture was subjected to silica gel column chromatography to give the title compound as a white amorphous solid.

The physical properties were as follows:

FAB HRMS：642.2267。

example 267N- [3- (R or S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (R or S) - (2-phenylethyl) -6- (3, 3, 3-trifluoropropyl) -2H-pyran-3-yl]-2, 2-dimethylPropyl radical]Phenyl radical]-1-methyl-1H-imidazole-4-sulfonamide (formula QQQ-13, R)₁Is t-Bu, R₂Is [ 1-methyl-4-imidazolyl ]]) Refer to table QQQ.

The title compound was prepared according to the procedure described for example 266, substituting 1-methylimidazole-4-sulfonyl chloride for 5-cyano-pyridine-2-sulfonyl chloride.

The physical properties were as follows:

HRMS：619.2298。

example 2685-amino-N- [3- (R or S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6- (R or S) - (3, 3, 3-trifluoropropyl) -2H-pyran-3-yl ]-2, 2-dimethylpropyl radical]Phenyl radical]-2-pyridinesulfonamide (formula QQQ-13, R)₁Is t-Bu, R₂Is [ 5-amino-2-pyridyl]) Refer to table QQQ.

Preparation 123A solution of the title product (50mg), pyridine (30. mu.L), and 5-nitro-pyridine-2-sulfonyl chloride (30mg) in dichloromethane was stirred at 0 ℃ for 2 hours. The crude reaction mixture was subjected to silica gel column chromatography to give the sulfonamide as a white amorphous solid. The white solid was dissolved in 4mL of methanol and treated with 25mg of ammonium formate and 5mg of 10% palladium on charcoal, stirred at room temperature for 1 hour, diluted with water and extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound as an off-white solid.

The physical properties were as follows:

FAB HRMS：632.2393。

preparation 1243 (R or S) - [1- (3-aminophenyl) -2, 2-dimethyl-propyl]-4-hydroxy-5, 6-dihydro-6- (S or R) -phenethyl-6- (3 ', 3 ', 3 ' -trifluoropropyl) -2H-pyran-2-one (formula QQQ-9, [ R ]₁＝t-Bu]) Refer to table QQQ.

The title compound is prepared according to the procedure described for preparation 123, starting from the compound isolated from peak 2 of preparation 122 and using starting materials and reagents known and available to those of ordinary skill in the art of organic synthesis.

The physical properties were as follows:

1H NMR(CD₃OD)：δ 6.9-7.3，6.6，4.1，2.6-2.7，1.9-2.4，1.0.

TLC (silica gel GF): r _f0.24 (40% ethyl acetate/hexane).

Example 2695-cyano-N- [3- (R or S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6- (R or S) - (3, 3, 3-trifluoropropyl) -2H-pyran-3-yl]-2, 2-dimethylpropyl radical]Phenyl radical]-2-pyridinesulfonamide (formula QQQ-14, R)₁Is t-Bu, [ R ]₂Is 5-cyano-2-pyridyl]) Refer to table QQQ.

A solution of the title product of preparation 124 (50mg), pyridine (30 μ L), and 5-cyano-pyridine-2-sulfonyl chloride (30mg) in dichloromethane was stirred at 0 ℃ for 2 hours. The crude reaction mixture was subjected to silica gel column chromatography to give the title compound as a white amorphous solid.

The physical properties were as follows:

FAB HRMS：642.2260。

example 270N- [3- (R or S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (R or S) - (2-phenylethyl) -6- (3, 3, 3-trifluoropropyl) -2H-pyran-3-yl]-2, 2-dimethylpropyl radical]Phenyl radical]-1-methyl-1H-imidazole-4-sulfonamide (formula QQQ-14, R)₁Is t-Bu, [ R ]₂Is 1-methyl-4-imidazolyl]) Refer to table QQQ.

The physical properties were as follows:

HRMS：619.2362。

example 2715-amino-N- [3- (R or S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6- (R or S) - (3, 3, 3-trifluoropropyl) -2H-pyran-3-yl ]-2, 2-dimethylpropyl radical]Phenyl radical]-2-pyridinesulfonamide (formula QQQ-14, R)₁Is t-Bu, [ R ]₂Is 5-amino-2-pyridineBase of]) Refer to table QQQ.

The title compound was prepared according to the procedure described for the preparation of example 268.

The physical properties were as follows:

FAB HRMS：632.2387。

preparation of 1253- (S or R) - [1- (3-aminophenyl) -2, 2-dimethyl-propyl]-4-hydroxy-5, 6-dihydro-6- (R or S) -phenethyl-6- (R or S) - (3 ', 3 ', 3 ' -trifluoropropyl) -2H-pyran-2-one (formula QQQ-10, [ R ] C₁Is t-Bu]) Refer to table QQQ.

The title compound is prepared according to the procedure described for preparation 123, starting from the compound isolated from peak 3 of preparation 122 and using starting materials and reagents known and available to those of ordinary skill in the art of organic synthesis.

The physical properties were as follows:

¹H NMR(CD₃OD)：δ 6.9-7.3，6.6，4.1，2.6-2.7，1.9-2.4，1.0.

TLC (silica gel GF): r_f0.24 (40% ethyl acetate/hexane).

Example 2725-cyano-N- [3- (R or S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6- (R or S) - (3, 3, 3-trifluoropropyl) -2H-pyran-3-yl]-2, 2-dimethylpropyl radical]Phenyl radical]-2-pyridinesulfonamide (formula QQQ-15, R)₁Is t-Bu, [ R ]₂Is 5-cyano-2-pyridyl]) Refer to table QQQ.

Preparation 125A solution of the title product (50mg), pyridine (30mL), and 5-cyano-pyridine-2-sulfonyl chloride (30mg) in dichloromethane was stirred at 0 ℃ for 2 hours. The crude reaction mixture was subjected to silica gel column chromatography to give the title compound as a white amorphous solid.

The physical properties were as follows:

FAB HRMS：642.2254。

example 273N- [3- (R or S) - [1 ]- [5, 6-dihydro-4-hydroxy-2-oxo-6- (R or S) - (2-phenylethyl) -6- (3, 3, 3-trifluoropropyl) -2H-pyran-3-yl]-2, 2-dimethylpropyl radical]Phenyl radical]-1-methyl-1H-imidazole-4-sulfonamide (formula QQQ-15, R)₁Is t-Bu, [ R ]₂Is 1-methyl-4-imidazolyl]) Refer to table QQQ.

The physical properties were as follows:

FAB HRMS：642.2397。

example 2745-amino-N- [3- (R or S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6- (R or S) - (3, 3, 3-trifluoropropyl) -2H-pyran-3-yl]-2, 2-dimethylpropyl radical]Phenyl radical]-2-pyridinesulfonamide (formula QQQ-15, R)₁Is t-Bu, [ R ]₂Is 5-amino-2-pyridyl]) Refer to table QQQ.

The physical properties were as follows:

FAB HRMS：632.2393。

preparation 1263- (S or R) - [1- (3-aminophenyl) -2, 2-dimethyl-propyl]-4-hydroxy-5, 6-dihydro-6 (S or R) -phenethyl-6- (3 ', 3 ', 3 ' -trifluoropropyl) -2H-pyran-2-one (formula QQQ-11, [ R ]₁Is t-Bu]) Refer to table QQQ.

The title compound is prepared according to the procedure described for preparation 123, starting from the compound isolated from peak 4 of preparation 122 and using starting materials and reagents known and available to those of ordinary skill in the art of organic synthesis.

The physical properties were as follows:

¹H NMR(CD₃OD)：δ 6.9-7.3，6.6，4.1，2.6-2.7，1.9-2.4，1.0.

TLC (silica gel GF): r_f＝0.24 (40% ethyl acetate/hexane).

Example 2755-cyano-N- [3- (R or S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6- (R or S) - (3, 3, 3-trifluoropropyl) -2H-pyran-3-yl]-2, 2-dimethylpropyl radical]Phenyl radical]-2-pyridinesulfonamide (formula QQQ-16, R)₁Is t-Bu, [ R ]₂Is 5-cyano-2-pyridyl]) Refer to table QQQ.

A solution of the title product of preparation 126 (50mg), pyridine (30mL), and 5-cyano-pyridine-2-sulfonyl chloride (30mg) in dichloromethane was stirred at 0 ℃ for 2 hours. The crude reaction mixture was subjected to silica gel column chromatography to give the title compound as a white amorphous solid.

The physical properties were as follows:

FAB HRMS：642.2248。

example 276N- [3- (R or S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (R or S) - (2-phenylethyl) -6- (3, 3, 3-trifluoropropyl) -2H-pyran-3-yl]-2, 2-dimethylpropyl radical]Phenyl radical]-1-methyl-1H-imidazole-4-sulfonamide (formula QQQ-16, R)₁Is t-Bu, [ R ]₂Is 1-methyl-4-imidazolyl]) Refer to table QQQ.

The physical properties were as follows:

FAB HRMS：620.2403。

example 2775-amino-N- [3- (R or S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6- (R or S) - (3, 3, 3-trifluoropropyl) -2H-pyran-3-yl ]-2, 2-dimethylpropyl radical]Phenyl radical]-2-pyridinesulfonamide (formula QQQ-16, R)₁Is t-Bu, [ R ]₂Is 5-amino-2-pyridyl]) Refer to table QQQ.

The physical properties were as follows:

FAB HRMS：632.2406。

EXAMPLE 278N- [3- (R or S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) - [6- (R or S) -propyl ] -2H-pyran-3-yl ] -2, 2-dimethylpropyl ] phenyl ] -2-pyridinesulfonamide

The title compound was obtained according to a similar method to that described above using isomer 2 of preparation 143.

The physical properties were as follows:

FAB HRMS：562.2527。

EXAMPLE 279N- [3- (R or S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6- (R or S) -propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl ] phenyl ] -2-pyridinesulfonamide

The title compound was obtained according to a similar method to that described above using isomer 1 of preparation 143.

The physical properties were as follows:

FAB HRMS：562.2528。

preparation of 1272-mercapto-4-trifluoromethylpyridine

To 1.0g of 2-chloro-4-trifluoromethylpyridine (Lancaster Chemical Co) were added 10ml of anhydrous ethanol and 417mg of thiourea. The reaction mixture was heated to reflux for 4 hours and 1.25ml of a solution of 7.44g KOH in 20ml water was added. The solution was heated to reflux for an additional 1 hour. The reaction was cooled and poured into 100ml of 0.1N NaOH solution. The resulting solution was extracted three times with 100ml dichloromethane and the resulting aqueous solution was acidified to pH4 by addition of glacial acetic acid. The aqueous solution was extracted three times with 100ml of dichloromethane and the organic solution was dried over anhydrous sodium sulfate. After filtration, it was evaporated to dryness to give 501mg of a yellow crystalline solid.

The physical properties were as follows:

found value C: 40.22; h: 2.33; n: 8.07; s: 17.59

HRMS：179.0019。

Preparation of 1282-chlorosulfonyl-4-trifluoromethylpyridine

To 425mg of 2-mercapto-4-trifluoromethylpyridine prepared as 127 was added 10ml of 1N aqueous HCl solution. The reaction mixture was cooled to 0 ℃ and Cl was added to the cooled reaction mixture₂Gas for 15 minutes. The reaction mixture was filtered and the resulting solid was washed well with water. The white solid was dissolved in dichloromethane and saturated NaHCO₃The aqueous solution was washed twice and then once more with water. The organic solution was dried over sodium sulfate (anhydrous) and the solution was filtered and evaporated to dryness to give 300mg of 2-chlorosulfonyl-4-trifluoromethylpyridine, which was used without further purification and stored at-78 ℃ until ready for use.

Preparation of 1292-chlorosulfonyl-5-trifluoromethylpyridine

Substituting 2-mercapto-5-trifluoromethylpyridine for 2-mercapto-4-trifluoromethylpyridine in the above reaction to prepare 128 gave 2-chlorosulfonyl-5-trifluoromethylpyridine as a colorless oil and crystallized slowly. The starting material was used directly without further purification and stored at-78 ℃ until ready for use.

Preparation of 1303- [1- [5, 6-dihydro-4-hydroxy-2-oxo-6, 6-di-n-propyl-2H-pyran-3-yl ]-propyl radical]Phenyl-carbamic acid (formula SSS-1; R)₁Is an ethyl group; reference table SSS).

To 7.2gAlCl₃At-70 ℃ N₂Next, 180ml of THF were added. The mixture was stirred at 0 ℃ for 15 minutes, then 5.38g of the compound of formulA SSS-A was added; with reference to table SSS, prepared according to a similar method to that described in preparation 17. The reaction mixture was stirred for 15 minutes, and 6.88g 3-amino Cbz-benzaldehyde (formula SSS-B; see Table SSS) was added. The reaction mixture was stirred at 0 ℃ for 15 minutes and then at room temperature for 3 hours. The reaction was cooled to 0 ℃ and 35g of sodium carbonate monohydrate was added, stirred vigorously and then 1.6ml of water were added. After stirring at 0 ℃ for a further 15 minutes, 120ml of THF were added and the mixture was filtered through celite. The celite was washed well with THF and the THF solution was evaporated to dryness in vacuo to give an amber foam. Disabled personThe residue was dissolved in 180ml THF, the solution was cooled to-5 ℃ and 3.2g CuBr₂And S. The mixture was stirred for 15 minutes and 65ml of a solution of 2M of ethylmagnesium chloride in THF were added dropwise, the reaction temperature not exceeding 0 ℃. The reaction was stirred for a further 15 minutes, 9ml of water were slowly added and then 45ml of 1N HCl were added. The addition was carried out at 0 ℃. The reaction mixture was poured into 2L of diethyl ether and 200ml of water were added. The aqueous layer was separated and the organic layer was extracted three times with 10% aqueous ammonium carbonate solution and then once with water. The organic solution was dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give 10.2g of crude amorphous foam. The crude product is chromatographed on silica gel using 2% ethyl acetate/dichloromethane as eluent to give 4.74g3- [1- [5, 6-dihydro-4-hydroxy-2-oxo-6, 6-di-n-propyl-2H-pyran-3-yl ] -2 ]-propyl radical]Phenyl-carbamic acid.

Preparation of 130A 3- [1- [5, 6-dihydro-4-hydroxy-2-oxo-6-phenethyl-6-propyl-2H-pyran-3-yl]-propyl radical]-phenyl-carbamic acid (formula RRR-1; R)₁Is an ethyl group; refer to table RRR).

The title compound was prepared following the procedure of preparation 130 starting from the compound of preparation 17.

The physical properties were as follows:

¹H NMR(CD₃OD)：δ 6.9-7.5，5.1，4.0，1.4-2.7，0.9.

TLC (silica gel GF): r_f0.28 (30% ethyl acetate/hexane).

Preparation 131 preparative chiral resolution of 3- [1- [5, 6-dihydro-4-hydroxy-2-oxo-6, 6-di-n-propyl-2H-pyran-3-yl]-propyl radical]Phenyl-carbamic acid (formula SSS-1; R)₁Is an ethyl group; reference table SSS) to give the two isomers 3(R or S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6, 6-di-n-propyl-2H-pyran-3-yl]-propyl radical]Phenyl-carbamic acid (formula SSS-3 and SSS-4; R)₁Is an ethyl group; reference table SSS).

A sample of the title compound of preparation 130 was injected onto a 2.1X 25cm Chiralcel OD-H column and washed with 20% isopropanol/hexane (V/V) toElution was carried out at 10 mL/min. The material eluting at about 19.1 minutes was 3(R or S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6, 6-di-n-propyl-2H-pyran-3-yl]-propyl radical]Phenyl-carbamic acid (alpha)²⁵ _D+26 ° (methanol), (formula SSS-3; see Table SSS) (Peak 1), eluting at about 37.7 minutes is 3(R or S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6, 6-di-n-propyl-2H-pyran-3-yl ]-propyl radical]Phenyl-carbamic acid (alpha)²⁵ _D27 ° (methanol), (formula SSS-4; reference Table SSS) (peak 2). The pools were individually concentrated on a rotary evaporator (approximately 30mm, water bath up to 50 ℃) to give a white amorphous solid.

Preparation 1323 (R or S) - [1- (3-aminophenyl) -propyl]-4-hydroxy-5, 6-dihydro-6, 6-dipropyl-2H-pyran-2-one (formula SSS-5; R)₁Is an ethyl group; reference table SSS).

To 1.04g of 3(R or S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6, 6-di-n-propyl-2H-pyran-3-yl ] -propyl ] phenyl-carbamic acid of preparation 131 (formula SSS-3; see Table SSS), which compound is identified as peak 1 of the chiral resolution of the product of preparation 131, 20mL of methanol and 1.29g of ammonium formate were added. After complete dissolution 275mg 10% Pd/C were added and the reaction mixture was stirred at room temperature for 60 minutes. The reaction mixture was filtered (celite) and the methanol solution was evaporated to dryness to give crude solid. The crude solid was partitioned between dichloromethane and water. The organic layer was washed twice with water and dried over anhydrous sodium sulfate. The dichloromethane solution was filtered and evaporated to dryness to give 625mg amorphous foam of 3(R or S) - [1- (3-aminophenyl) -propyl ] -4-hydroxy-5, 6-dihydro-6, 6-dipropyl-2H-pyran-2-one.

The physical properties were as follows:

MS(EI)：331

(α)²⁵ _D+38 ° (c ═ 3715, methanol).

Preparation 1333 (R or S) - [1- (3-aminophenyl) -propyl]-4-hydroxy-5, 6-dihydro-6, 6-di-n-propyl-2H-pyran-2-one (formula SSS-5; R)₁Is an ethyl group; reference table SSS).

To 825mg of 3(R or S) - [1- (3-aminophenyl) propyl ] - -4-hydroxy-5, 6-dihydro-6, 6-dipropyl-2H-pyran-2-one (formula SSS-4; see Table SSS) of preparation 131, which compound was identified as peak 2 of the chiral resolution of the product of preparation 131, 20mL of methanol and 1.02g of ammonium formate were added. After complete dissolution 210mg 10% Pd/C were added and the reaction mixture was stirred at room temperature for 60 minutes. The reaction mixture was filtered (celite) and the methanol solution was evaporated to dryness to give crude solid. The crude solid was partitioned between dichloromethane and water. The organic layer was washed twice with water and dried over anhydrous sodium sulfate. The dichloromethane solution was filtered and evaporated to dryness to give 483mg of the title compound as an amorphous foam.

The physical properties were as follows:

MS(EI)：331

(α)²⁵ _D-39 ° (c ═ 2680, methanol).

Example 2805-trifluoromethyl-N- [3- [1- [ 4-hydroxy-2-oxo-6, 6-di-N-propyl-5, 6-dihydro-2H-pyran-3-yl]-propyl radical]-phenyl radical]-2-pyridinesulfonamide (formula SSS-9, R) ₁Is ethyl, R₂Is 5-trifluoromethylpyridine; reference table SSS).

Deprotection of the title compound of preparation 130 as in preparation 132 affords a compound of formula SSS-2. To 132mg of a compound of formula SSS-2 were added 15ml of dichloromethane and 66. mu.l of pyridine. The reaction solution was cooled to-5 ℃ and 98mg of 2-chlorosulfonyl-5-trifluoromethylpyridine (product of preparation 129) was added. After stirring for 60 min at 0 ℃ the solution was applied to a silica gel column and eluted with 10% ethyl acetate/dichloromethane until 5-trifluoromethyl-N- [3- [1- [ 4-hydroxy-2-oxo-6, 6-di-N-propyl-5, 6-dihydro-2H-pyran-3-yl ] -propyl ] -phenyl ] -2-pyridinesulfonamide was collected. Rf 0.6 in 10% ethyl acetate/dichloromethane. The organic solution was evaporated to dryness to give 177mg of 5-trifluoromethyl-N- [3- [1- [ 4-hydroxy-2-oxo-6, 6-di-N-propyl-5, 6-dihydro-2H-pyran-3-yl ] -propyl ] -phenyl ] -2-pyridinesulfonamide.

The physical properties were as follows:

MS(EI)：540，497，411，401，383，342，331，197，174，146，133

HRMS：540.1938

rf 0.6, 10% ethyl acetate/dichloromethane

¹H NMR(MeOD)：δ8.91，8.21-8.19，7.12，6.98-6.96，6.86-6.83，3.85-3.79，2.46，2.10-1.98，1.84-1.75，1.58-1.47，1.27-1.15，.82-.72ppm

Example 2815-trifluoromethyl-N- [3- (R or S) - [1- [ 4-hydroxy-2-oxo-6, 6-di-N-propyl-5, 6-dihydro-2H-pyran-3-yl]-propyl radical]-phenyl radical]-2-pyridinesulfonamide (formula SSS-7, R)₁Is ethyl, R₂Is 5-trifluoromethylpyridine; reference table SSS).

To 66mg of the title product of preparation 132 (formula SSS-5; Table SSS) were added 8ml of dichloromethane and 33. mu.l of pyridine. The reaction solution was cooled to-5 ℃ and 49mg of 2-chlorosulfonyl-5-trifluoromethylpyridine (product of preparation 129) was added. After stirring for 60 min at 0 ℃ the solution was applied to a silica gel column and eluted with 10% ethyl acetate/dichloromethane until 5-trifluoromethyl-N- [3(R or S) - [1- [ 4-hydroxy-2-oxo-6, 6-di-N-propyl-5, 6-dihydro-2H-pyran-3-yl ] -propyl ] -phenyl ] -2-pyridinesulfonamide was collected. Rf 0.6 in 10% ethyl acetate/dichloromethane. The organic solution was evaporated to dryness to yield 69mg of the title compound.

The physical properties were as follows:

MS(EI)：540，497，411，401，383，342，331，197，174，146，133

rf 0.6, 10% ethyl acetate/dichloromethane

Example 2825-trifluoromethyl-N-, [3- (R or S) - [1- [ 4-hydroxy-2-oxo-6, 6-di-n-propyl-5, 6-dihydro-2H-pyran-3-yl]-propyl radical]-phenyl radical]-2-pyridinesulfonamide (formula SSS-8, R)₁Is ethyl, R₂Is 5-trifluoromethylpyridine; reference table SSS).

The procedure is as in example 281, but the product from preparation 133 (formula SSS-6) is used instead of the prepared amorphous foam of 5-trifluoromethyl-N- [3(R or S) - [1- [ 4-hydroxy-2-oxo-6, 6-di-N-propyl-5, 6-dihydro-2H-pyran-3-yl ] -propyl ] -phenyl ] -2-pyridinesulfonamide.

The physical properties were as follows:

MS(EI)：540，497，411，401，383，342，331，197，174，146，133

rf 0.6, 10% ethyl acetate/dichloromethane

Example 2834-trifluoromethyl-N- [3- (R or S) - [1- [ 4-hydroxy-2-oxo-6, 6-di-N-propyl-5, 6-dihydro-2H-pyran-3-yl]-propyl radical]-phenyl radical]-2-pyridinesulfonamide (formula SSS-7, R)₁Is ethyl, R₂Is 4-trifluoromethylpyridine; reference table SSS).

Following the procedure of example 281, but substituting the pyridine sulfonyl chloride with the product of preparation 128, amorphous foam 4-trifluoromethyl-N- [3(R or S) - [1- [ 4-hydroxy-2-oxo-6, 6-di-N-propyl-5, 6-dihydro-2H-pyran-3-yl ] -propyl ] -phenyl ] -2-pyridinesulfonamide was prepared.

The physical properties were as follows:

MS(EI)：146，145，139，133，71，57，55，43，41

HRMS：540.1902

example 2844-trifluoromethyl-N- [3- (R or S) - [1- [ 4-hydroxy-2-oxo-6, 6-di-N-propyl-5, 6-dihydro-2H-pyran-3-yl]-CBase of]-phenyl radical]-2-pyridinesulfonamide (formula SSS-8, R)₁Is ethyl, R₂Is 4-trifluoromethylpyridine; reference table SSS).

Following the procedure of example 282, but substituting the pyridine sulfonyl chloride with the product of preparation 128, amorphous foam of 4-trifluoromethyl-N- [3- (R or S) - [1- [ 4-hydroxy-2-oxo-6, 6-di-N-propyl-5, 6-dihydro-2H-pyran-3-yl ] -propyl ] -phenyl ] -2-pyridinesulfonamide was prepared.

The physical properties were as follows:

MS(EI)：146，145，139，133，71，57，55，43，41

HRMS：540.1896

example 2855-trifluoromethyl-N- [3- (R or S) - [1- [ 4-hydroxy-2-oxo-6, 6-di-N-propyl-5, 6-dihydro-2H-pyran-3-yl ]-2, 2-dimethylpropyl radical]-phenyl radical]-2-pyridinesulfonamide (formula TTT-6; R)₁Is a tert-butyl group; r₂Is n-propyl; r₃Is 5-trifluoromethyl-2-pyridyl; refer to table TTT).

The procedure is as in example 281, but using isomer 1 from preparation 144 (formula TTT-4; Table TTT; R)₁Is a tert-butyl group; r₂Is N-propyl) to obtain amorphous solid 5-trifluoromethyl-N- [3- (R or S) - [1- [ 4-hydroxy-2-oxo-6, 6-di-N-propyl-5, 6-dihydro-2H-pyran-3-yl]-2, 2-dimethylpropyl radical]-phenyl radical]-2-pyridinesulfonamide.

The physical properties were as follows:

MS(EI)：163，162，147，146，69，57，56，43，41

HRMS：568.2213

example 2865-trifluoromethyl-N- [3- (R or S) - [1- [ 4-hydroxy-2-oxo-6, 6-di-N-propyl-5, 6-dihydro-2H-pyran-3-yl]-2, 2-dimethylpropyl radical]-phenyl radical]-2-pyridinesulfonamide (formula TTT-7; R)₁Is a tert-butyl group; r₂Is n-propyl; r₃Is 5-trifluoromethylpyridine; refer to table TTT).

The procedure is as in example 281, but using isomer 2 from preparation 144 (formula TTT-5; Table TTT; R)₁Is a tert-butyl group; r₂Is N-propyl) to give amorphous solid 5-trifluoromethyl-N- [3- [1(R or S) -4-hydroxy-2-oxo-6, 6-di-N-propyl-5, 6-dihydro-2H-pyran-3-yl]-2, 2-dimethylpropyl radical]-phenyl radical]-2-pyridinesulfonamide.

The physical properties were as follows:

HRMS：568.2237

example 2875-trifluoromethyl-N- [3- (R or S) - [1- [ 4-hydroxy-2-oxo-6, 6-diphenylethyl-5, 6-dihydro-2H-pyran-3-yl ]-propyl radical]-phenyl radical]-2-pyridinesulfonamide (formula TTT-6; R)₁Is an ethyl group; r₂Is phenyl; r₃Is 5-trifluoromethylpyridine; refer to table TTT).

The procedure is as in example 281, but using isomer 1 from preparation 145 (formula TTT-4; Table TTT; R₁Is an ethyl group; r₂Is phenyl) to give amorphous solid 5-trifluoromethyl-N- [3(R or S) - [1- [ 4-hydroxy-2-oxo-6, 6-di-N-propyl-5, 6-dihydro-2H-pyran-3-yl]-propyl radical]-phenyl radical]-2-pyridinesulfonamide.

The physical properties were as follows:

MS(EI)：665，647，456，455，333，134，133，117，105，91

example 2885-trifluoromethyl-N- [3- (R or S) - [1- [ 4-hydroxy-2-oxo-6, 6-diphenylethyl-5, 6-dihydro-2H-pyran-3-yl]-propyl radical]-phenyl radical]-2-pyridinesulfonamide (formula TTT-7; R)₁Is an ethyl group; r₂Is phenyl; r₃Is 5-trifluoromethylpyridine; refer to table TTT).

The procedure is as in example 281, but using isomer 2 from preparation 145 (formula TTT-5; Table TTT; R₁Is an ethyl group; r₂Is phenyl) to give amorphous solid 5-trifluoromethyl-N- [3- (R or S) - [1- [ 4-hydroxy-2-oxo-6, 6-di-N-propyl-5, 6-dihydro-2H-pyran-3-yl]-propyl radical]-phenyl radical]-2-pyridinesulfonamide.

The physical properties were as follows:

HRMS：665.2300

MS(EI)：665，647，456，455，333，134，133，117，105，91

example 2894-trifluoromethyl-N- [3- (R or S) - [1- [ 4-hydroxy-2-oxo-6, 6-diphenylethyl-5, 6-dihydro-2H-pyran-3-yl ]-propyl radical]-phenyl radical]-2-pyridinesulfonamide (formula TTT-6; R)₁Is an ethyl group; r₂Is phenyl; r₃Is 4-trifluoromethylpyridine; refer to table TTT).

The procedure is as in example 281, but using isomer 1 from preparation 145 (formula TTT-4; Table TTT; R₁Is an ethyl group; r₂Is phenyl) to give amorphous solid 5-trifluoromethyl-N- [3- (R or S) - [1- [ 4-hydroxy-2-oxo-6, 6-di-N-propyl-5, 6-dihydro-2H-pyran-3-yl]-propyl radical]-phenyl radical]-2-pyridinesulfonamide.

The physical properties were as follows:

MS(EI)：666，665，647，134，133，117，105，91

HRMS：665.2306

example 2904-trifluoromethyl-N- [3- (R or S) - [1- [ 4-hydroxy-2-oxo-6, 6-diphenylethyl-5, 6-dihydro-2H-pyran-3-yl]-propyl radical]-phenyl radical]-2-pyridinesulfonamide (formula TTT-7; R)₁Is an ethyl group; r₂Is phenyl; r₃Is 4-trifluoromethylpyridine; refer to table TTT).

The procedure is as in example 281, but using isomer 2 from preparation 145 (formula TTT-5; Table TTT; R₁Is an ethyl group; r₂Is phenyl) to give amorphous solid 4-trifluoromethyl-N- [3- (R or S) - [1- [ 4-hydroxy-2-oxo-6, 6-di-N-propyl-5, 6-dihydro-2H-pyran-3-yl]-propyl radical]-phenyl radical]-2-pyridinesulfonamide.

The physical properties were as follows:

HRMS：665.2306

MS(EI)：666，665，647，134，133，117，105，91

example 2914-trifluoromethyl-N- [3- (R or S) - [1- [ 4-hydroxy-2-oxo-6, 6-di-N-propyl-5, 6-dihydro-2H-pyran-3-yl ]-2, 2-dimethylpropyl radical]-phenyl radical]-2-pyridinesulfonamide (formula TTT-6; R)₁Is a tert-butyl group; r₂Is methyl; r₃Is 4-trifluoromethylpyridine; refer to table TTT).

The procedure is as in example 283, but using isomer 1 of preparation 144 (formula TTT-4; Table TTT; R)₁Is a tert-butyl group; r₂Is methyl) to give amorphous solid 4-trifluoromethyl-N- [3- (R or S) - [1- [ 4-hydroxy-2-oxo-6, 6-di-N-propyl-5, 6-dihydro-2H-pyran-3-yl]-2, 2-dimethylpropyl radical]-phenyl radical]-2-pyridinesulfonamide.

The physical properties were as follows:

MS(EI)：525，512，428，411，302，284，258，146，57

HRMS：568.2209

example 2924-trifluoromethyl-N- [3- (R or S) - [1- [ 4-hydroxy-2-oxo-6, 6-di-N-propyl-5, 6-dihydro-2H-pyran-3-yl]-2, 2-dimethylpropyl radical]-phenyl radical]-2-pyridinesulfonamide (formula TTT-7; R)₁Is a tert-butyl group; r₂Is methyl; r₃Is 4-trifluoromethylpyridine; refer to table TTT).

The procedure is as in example 283, but using isomer 2 of preparation 144 (formula TTT-5; Table TTT; R)₁Is a tert-butyl group; r₂Is methyl) to give amorphous solid 4-trifluoromethyl-N- [3- (R or S) - [1- [ 4-hydroxy-2-oxo-6, 6-di-N-propyl-5, 6-dihydro-2H-pyran-3-yl]-2, 2-dimethylpropyl radical]-phenyl radical]-2-pyridinesulfonamide.

The physical properties were as follows:

MS(EI)：569，551，511，493，439，371，360，303，284，161，139

HRMS(MI+H⁺)：569.2297

preparation of 134N- [3- [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6-N-propyl-2H-pyran-3-yl ]-2, 2-dimethylpropyl radical]Phenyl-carbamic acid phenylmethyl ester (formula RRR-1; R)₁Is a tert-butyl group; refer to table RRR).

To 4.8gAlCl₃At-70 ℃ N₂Next, 120ml of THF was added. The mixture was stirred at 0 ℃ for 15 minutes and 4.68g of preparation 17 (formulA RRR-A) was added. The reaction mixture was stirred for 15 minutes and 4.59g 3-amino Cbz-benzaldehyde (formula RRR-B) was added. The reaction mixture was stirred at 0 ℃ for 15 minutes and then at room temperature for 3 hours. The reaction was cooled to 0 deg.C, 26g of sodium carbonate monohydrate (0.21M) was added, stirred vigorously, and then 1.08ml of water was added. After stirring at 0 ℃ for a further 15 minutes, the mixture was treated with 120ml of THF and filtered through celite. The celite was washed well with THF and the THF solution was evaporated to dryness in vacuo to give an amber foam. The residue was dissolved in 120ml THF, the solution was cooled to-5 ℃ and 2.1g CuBr₂And S. The mixture was stirred for 15 minutes and 65ml of a solution of 1M tert-butylmagnesium chloride in THF were added dropwise, the reaction temperature not exceeding 0 ℃. The reaction mixture was stirred for a further 15 minutes at 0 ℃ and 6ml of water were added slowly, followed by 30ml of 1N HCl. The reaction mixture was poured into 1.3L of diethyl ether. The aqueous layer was separated and the organic layer was extracted three times with 10% aqueous ammonium carbonate solution and then once with water. The organic solution was dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give amorphous foam. The crude product was chromatographed on silica gel using 30% ethyl acetate/dichloromethane as eluent to give 6.15g of the title compound.

Preparation 135 preparative resolution of N- [3- [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6-N-propyl-2H-pyran-3-yl]-2, 2-dimethylpropyl radical]Phenyl-carbamic acid phenylmethyl ester (formula RRR-1; R)₁Is tert-butyl) is 4 isomers, 3(R or S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (R or S) - (2-phenylethyl) -6- (R or S) -n-propyl-2H-pyran-3-yl]-2, 2-dimethyl-propyl]Phenyl-carbamic acid benzyl ester (formula RRR-3-6; R1 is tert-butyl; see Table RRR).

The four enantiomers are (in order of elution from System A) isomer 1 (formula RRR-4; reference Table RRR), isomer 2 (formula RRR-3; reference Table RRR), isomer 3 (formula RRR-5; reference Table RRR), and isomer 4 (formula RRR-6; reference Table RRR). System A consisted of a 0.46X 25cm Chiralcel OD-H column eluting with 20% isopropanol and 0.1% trifluoroacetic acid in hexane (V/V) at 0.5 mL/min. (Chiralcel OD-H is a registered trademark, Chiral Technologies, Inc., Exton PA 19341.)

The first stage of resolution was accomplished using a 2.1X 25cm (R, R) Whelk-O1 column, eluting with 20% (V/V) isopropanol/hexane at 12mL/min [ (R, R) Whelk-O1 is a registered trademark, Regis technologies, Inc., Morton Grove, IL 60053. ). The peaks eluting at approximately 35 and 41 minutes were determined to be a mixture of isomers 3 and 4 and a mixture of isomers 1 and 2, respectively, as described above for system a. Both mixtures were further processed as described below.

The second stage of resolution, the mixture eluting at approximately 41 minutes above was injected onto a 2.1 × 25cm Chiralcel OD column (Chiral Technologies, Inc.) and eluted with 15% isopropanol and 0.05% trifluoroacetic acid/hexane (V/V) at 9.0 mL/min. Peaks eluting at approximately 11.0 and 22.0 minutes were labeled as peak 1 and peak 2, respectively, as judged by system a.

At the final stage of the resolution, the mixture eluted at about 35 minutes from the Whelk-O column was injected onto a 2.2X 25cm Chiralcel OD column and eluted with 35% isopropanol and 0.1% trifluoroacetic acid/hexane (V/V) at 9.0 mL/min. The isomer eluting at approximately 9.7 minutes was labeled as peak 3 and the isomer eluting at approximately 16.6 minutes was labeled as peak 4.

Preparation 1363- [1- (3-aminophenyl) -2, 2-dimethyl-propyl ] -5, 6-dihydro-4-hydroxy-6-phenethyl-6-n-propyl-pyran-2-one (formula RRR-2, see Table RRR).

To 590mg of preparation 134 of 3- [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6-n-propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl ] phenyl-carbamic acid was added 10ml of methanol and 660mg of ammonium formate. When all reactants dissolved 140mg 10% Pd/C was added and the reaction was stirred at room temperature for 60 min. The reaction was filtered (celite) and the filter cake was washed thoroughly with methanol, and the methanol solution was evaporated under vacuum to give a crude solid. The solid was partitioned between water and dichloromethane and the dichloromethane layer was washed twice with water, dried over anhydrous sodium sulphate and evaporated to dryness to give 372mg of 3- [1- (3-amino-phenyl) -2, 2-dimethyl-propyl ] -5, 6-dihydro-4-hydroxy-6-phenethyl-6-n-propyl-pyran-2-one. The substance was the same as the aforementioned substance (formula T-4; see Table T).

Preparation 1373 (R or S) - [1- (3-amino-phenyl) -2, 2-dimethyl-propyl]-5, 6-dihydro-4-hydroxy-6 (R or S) -phenethyl-6 (R or S) -propyl-pyran-2-one (formula RRR-7; R)₁Is a tert-butyl group; refer to table RRR).

Following the procedure of preparation 136, but replacing the compound of preparation 134 with the compound of preparation 135 labeled as peak 2, amorphous foam 3(R or S) - [1- (3-amino-phenyl) -2, 2-dimethyl-propyl ] -5, 6-dihydro-4-hydroxy-6 (R or S) -phenethyl-6 (R or S) -propyl-pyran-2-one was prepared.

The physical properties were as follows:

MS(EI)：421，365，164，163，147，146，118，107，91，57.

HRMS：421.2617

preparation 1383 (R or S) - [1- (3-amino-phenyl) -2, 2-dimethyl-propyl]-5, 6-dihydro-4-hydroxy-6 (R or S) -phenethyl-6 (R or S) -propyl-pyran-2-one (formula RRR-8; R)₁Is a tert-butyl group; refer to table RRR).

Following the procedure of preparation 136, but replacing the compound of preparation 134 with the compound labeled peak 1 of preparation 135, amorphous foam 3(R or S) - [1- (3-amino-phenyl) -2, 2-dimethyl-propyl ] -5, 6-dihydro-4-hydroxy-6 (R or S) -phenethyl-6 (R or S) -propyl-pyran-2-one was prepared.

The physical properties were as follows:

MS(EI)：421，365，164，163，147，146，118，107，91，57.

example 2935-trifluoromethyl-N- [3- [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6-N-propyl-2H-pyran-3-yl ]-2, 2-dimethylpropyl radical]-phenyl radical]-2-pyridinesulfonamide (formula RRR-15, R)₁Is a tert-butyl group; r₂Is 5-trifluoromethyl; refer to table RRR).

The procedure of example 281 is followed, except that the product of preparation 136 is used in place of the product of preparation 132 to prepare 5-trifluoromethyl-N- [3- [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6-N-propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl ] -phenyl ] -2-pyridinesulfonamide as amorphous foam.

The physical properties were as follows:

MS(EI)：497，411，401，383，343，331，197，174，146，133

HRMS：540.1938

example 2945-trifluoromethyl-N- [3(R or S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (R or S) - (2-phenylethyl) -6(R or S) -N-propyl-2H-pyran-3-yl]-2, 2-dimethylpropyl radical]-phenyl radical]-2-pyridinesulfonamide (formula RRR-11, R)₁Is a tert-butyl group; r₂Is 5-trifluoromethyl; refer to table RRR).

The procedure of example 281 is followed, but using the product of preparation 137 instead of the product of preparation 132, to prepare 5-trifluoromethyl-N- [3(R or S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (R or S) - (2-phenylethyl) -6(R or S) -N-propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl ] -phenyl ] -2-pyridinesulfonamide as an amorphous foam.

The physical properties were as follows:

MS(EI)：373，355，201，146，145，118，117，91，57。

HRMS：630.2394

example 2955-trifluoromethyl-N- [3(R or S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (R or S) - (2-phenylethyl) -6(R or S) -N-propyl-2H-pyran-3-yl ]-2, 2-dimethylpropyl radical]-phenyl radical]-2-pyridinesulfonamide (formula)RRR-12，R₁Is a tert-butyl group; r₂Is 5-trifluoromethyl; refer to table RRR).

Following the procedure of example 281, but substituting the product of preparation 138 for the product of preparation 132, amorphous foam 5-trifluoromethyl-N- [3(R or S) - (1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (R or S) - (2-phenylethyl) -6(R or S) -N-propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl) -phenyl ] -2-pyridinesulfonamide was prepared.

The physical properties were as follows:

MS(EI)：373，355，201，146，145，118，117，91，57.

HRMS：630.2379

example 2964-trifluoromethyl-N- [3(R or S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (R or S) - (2-phenylethyl) -6(R or S) -N-propyl-2H-pyran-3-yl } -2, 2-dimethylpropyl]-phenyl radical]-2-pyridinesulfonamide (formula RRR-11, R)₁Is a tert-butyl group; r₂Is 4-trifluoromethyl; refer to table RRR).

The procedure of example 294 was followed, except that the product of preparation 128 was used in place of the product of preparation 129, to prepare 4-trifluoromethyl-N- [3(R or S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (R or S) - (2-phenylethyl) -6(R or S) -N-propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl ] -phenyl ] -2-pyridinesulfonamide as an amorphous foam.

The physical properties were as follows:

MS(EI)：633，632，631，614，613，346，201，146，91，57.

HRMS：631.2444

example 2974-trifluoromethyl-N- [3(R or S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (R or S) - (2-phenylethyl) -6(R or S) -N-propyl-2H-pyran-3-yl ]-2, 2-dimethylpropyl radical]-phenyl radical]-2-pyridinesulfonamide (formula RRR-12, R)₁Is a tert-butyl group; r₂Is 4-trifluoromethyl; refer to table RRR).

Following the procedure of example 295, but substituting the product of preparation 128 for the product of preparation 129, 4-trifluoromethyl-N- [3(R or S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (R or S) - (2-phenylethyl) -6(R or S) -N-propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl ] -phenyl ] -2-pyridinesulfonamide was prepared as amorphous foam.

The physical properties were as follows:

MS(EI)：633，632，631，614，613，346，201，146，91，57.

HRMS：631.2450

example 2985-trifluoromethyl-N- [3(R or S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (R or S) - (2-phenylethyl) -6(R or S) -N-propyl-2H-pyran-3-yl]-propyl radical]-phenyl radical]-2-pyridinesulfonamide (formula RRR-11, R)₁Is an ethyl group; r₂Is 5-trifluoromethyl; refer to table RRR).

The procedure of example 294 is followed, but instead of using the product of preparation 147A, to obtain 5-trifluoromethyl-N- [3(R or S) - (1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (R or S) - (2-phenylethyl) -6(R or S) -N-propyl-2H-pyran-3-yl ] -propyl) -phenyl ] -2-pyridinesulfonamide as an amorphous foam.

The physical properties were as follows:

MS(EI)：605，604，603，602，586，585，393，201，133，91

HRMS：603.2153

EXAMPLE 298A 5-trifluoromethyl-N- [3(R or S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (R or S) - (2-phenylethyl) -6(R or S) -N-propyl-2H-pyran-3-yl ]Propyl radical]-phenyl radical]-2-pyridinesulfonamide (formula RRR-12, R)₁Is an ethyl group; r₂Is 5-trifluoromethyl; refer to table RRR).

The title compound was obtained as amorphous foam by the method of example 294 but replacing the amine obtained from isomer 1 of preparation 147 (obtained according to the method of preparation 147A).

The physical properties were as follows:

¹H NMR(CD₃OD)：δ8.9，8.2，8.0，7.0-7.3，3.9，2.4-2.7，1.2-2.2，0.8-1.0.

TLC (silica gel GF): rf 0.19, 40% ethyl acetate/hexane

Preparation of 139 (5-nitro-pyridin-2-yl) -isothiourea hydrochloride (formula UUU-2), see Table UU.

A solution of 3.81g of thiourea in 75mL of hot absolute ethanol was treated with 7.61g of 2-chloro-5-nitropyridine (formula UUUU-1) and heated at reflux for 6 hours. The mixture was then cooled to 0 ℃ and the precipitated solid was collected. The solid was washed successively with cold absolute ethanol and chloroform. The solid was dried in vacuo to give 6.91g of the title compound as a pale brown solid.

The physical properties were as follows:

MP 175 deg.C (decomposition)

¹H NMR(CD₃OD) δ 7.9，8.6，9.4ppm

Preparation of 1405-nitro-2-thiopyridine (formula UUU-3), cf. the table UU.

A solution of 1.65g of sodium carbonate in 50mL of water was treated with 2.35g of the title compound of preparation 139. To the mixture was added a solution of 2.75g of sodium hydroxide in 50mL of water and the resulting mixture was warmed to room temperature. After stirring for 1 hour, the mixture was heated to 95 ℃ for 1 hour and finally cooled to room temperature. The aqueous mixture was extracted twice with ether and carefully acidified with 6N aqueous hydrochloric acid. The orange solid precipitate was collected and washed successively with cold dilute aqueous hydrochloric acid and water. The solid was dried in vacuo to give 1.27g of the title compound as an orange solid.

The physical properties were as follows:

MP 167-170℃

¹H NMR(CDCl₃-CD₃OD) δ 7.4，7.9，8.5ppm

preparation 1415-Nitro-2-pyridinesulfonyl chloride (formula UUU-4) see Table UU.

To a suspension of 1.27g of the title compound of preparation 140 in 25mL of 1N aqueous hydrochloric acid and 5mL of acetic acid at 0 ℃ was vigorously bubbled chlorine gas. After 15 minutes, the addition of chlorine was stopped and replaced with nitrogen. The resulting solid was collected and washed successively with cold dilute hydrochloric acid and water. The solid was dried in vacuo to give 1.60g of the title compound as a brown solid.

The physical properties were as follows:

MP 77-80℃

¹H NMR(CDCl₃) δ 8.3，8.8，9.6ppm

preparation of 142N- [3- (1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6-propyl-2H-pyran-3-yl)]-2, 2-dimethylpropyl) phenyl]-5-nitro-2-pyridinesulfonamide (formula UUUU-5: R)₁Is 2-phenylethyl, R₂Is propyl, R₃Is t-butyl), see table UUU.

To a solution of 210mg of the title compound of preparation 81 (formula T-4) in 2mL of dichloromethane at 0 deg.C were added 80. mu.L of pyridine followed by 111mg of the title compound of preparation 141 (formula UUU-4). The temperature was allowed to rise to room temperature overnight, and the reaction mixture was subjected to flash silica gel column chromatography, eluting with 3% to 9% ethyl acetate in dichloromethane, to give 303mg of the title compound as a yellow foam.

The physical properties were as follows:

¹H NMR(CDCl₃-CD₃OD)δ 0.8-1.0，1.2-1.4，1.6-1.9，2.4-2.7，4.0，6.9-7.4，8.0，8.5，9.4ppm

HRMS 608.24 12(EI)

example 2995-amino-N- [3- (1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6-propyl-2H-pyran-3-yl ]-2, 2-dimethylpropyl) phenyl]-2-pyridinesulfonamide (formula UUUU-6: R)₁Is 2-phenylethyl, R₂Is propyl, R₃Is t-butyl), see table UUU.

To a solution of 300mg of the title compound of preparation 142 (formula UUUU-5) in 5mL of methanol under argon was added, in that order, 500mg of ammonium formate and 100mg of 10% palladium on charcoal. After 1 hour, the reaction mixture was filtered through a pad of celite and washed with methanol. The combined filtrates were concentrated under reduced pressure and the residue was triturated repeatedly with several portions of dichloromethane. The combined dichloromethane washes were concentrated under reduced pressure and the residue was subjected to flash silica gel column chromatography, eluting with 50% ethyl acetate in dichloromethane, to give 246mg of the title compound as a white solid.

The physical properties were as follows:

¹H NMR(CDCl₃-CD₃OD) δ 0.8-1.0，1.2-1.4，1.5-2.0，2.4-2.6，4.0，6.7，6.8-7.3，7.4，7.9ppm

HRMS 577.2617(EI)

example 300-

The following other compounds of the invention in table 3 were prepared from the compounds prepared in the following preparations according to the methods described previously and using starting materials known and available to those of ordinary skill in the art of organic synthesis.

Preparation 143 preparative separations of benzyl N- [3- [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6-N-propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl ] phenyl ] -carbamate gave 4 isomers.

The title compound of preparation 134 was isolated as four stereoisomers, which were (in order of elution from system a) 4 isomers: isomer 1, isomer 2, isomer 3, and isomer 4, each having an observed residence time approximated as follows: 10.5, 14.9, 21.4 and 65.2 minutes. System A consisted of a 0.46X 25cm Chiralcel OD-H column eluting with 20% isopropanol and 0.1% trifluoroacetic acid in hexane (V/V) at 0.5 mL/min. (Chiralcel OD-H is a registered trademark, Chiral Technologies, Inc., Exton PA 19341.)

The first stage of separation was accomplished using a 2.1X 25cm (R, R) Whelk-O1 column eluting with 20% (V/V) isopropanol/hexane at 12mL/min [ (R, R) Whelk-O1 is a registered trademark of Regis Technologies, Inc., Morton Grove, IL 60053. ). The peaks eluting at approximately 35 and 41 minutes were determined to be a mixture of isomers 3 and 4 and a mixture of isomers 1 and 2, respectively, as described above for system a. Both mixtures were further processed as described below.

In the second stage of separation, the above mixture eluting at about 41 minutes was injected onto a 2.1X 25cm Chiralcel OD column (Chiral Technologies, Inc.) and eluted with 15% isopropanol and 0.05% trifluoroacetic acid/hexane (V/V) at 9.0 mL/min. The peaks eluting at approximately 11.0 and 22.0 minutes were identified as isomer 1 and isomer 2, respectively, as determined by system a.

At the end of the separation, the mixture eluted at about 35 minutes from the (R, R) Whelk-O1 column was injected onto a 2.2X 25cm Chiralcel OD column and eluted with 35% isopropanol and 0.1% trifluoroacetic acid (V/V)/hexane at 9.0 mL/min. The isomer eluting at about 9.7 minutes was isomer 3 and the isomer eluting at about 16.6 minutes was isomer 4.

At each stage of isomer separation, fractions were collected after analysis with system a and the collection was evaporated to dryness on a rotary evaporator.

Preparation 144 resolution of benzyl N- [3- (1- [5, 6-dihydro-6, 6-dipropyl-4-hydroxy-2-oxo-2H-pyran-3-yl ] -2, 2-dimethylpropyl) phenyl ] carbamate gives 2 isomers.

Samples of the starting compound (up to 1.0 g per resolution) were injected onto a 5.1X 50cm Chiralcel OD column (Chiral Technologies, Inc.). Enantiomer at about 23 min [ corresponding to analogue of benzyloxycarbonyl protected amine (isomer 1) (EI-MS: 359[ M ]⁺]；¹HNMR(CDCl₃-CD₃OD)：7.1-6.9，6.5，4.2，2.6-2.3，1.8-1.2，1.1，0.9；TLC：R_f0.42 (10% ethyl acetate/dichloromethane), and about 33 minutes [ corresponding to the benzyloxycarbonyl protected amine ]Analog of (isomer 2) (EI-MS: 359[ M ]⁺]；¹HNMR(CDCl₃-CD₃OD)：7.1-6.9，6.5，4.2，2.6-2.3，1.8-1.2，1.1，0.9；TLC：R_f0.42 (10% ethyl acetate/dichloromethane)]And (4) eluting. The mobile phase was 20% isopropanol and 0.1% acetic acid/hexane (V/V) at a flow rate of 60 mL/min. Purity was checked on a 0.46X 25cm Chiralcel OD column (Chiral Technologies, Inc.). The mobile phase was 20% isopropanol/hexane (V/V) and 0.1% trifluoroacetic acid at a flow rate of 0.5 mL/min. The observed residence times for isomer 1 and isomer 2 were 8.9 and 16.7 minutes, respectively (monitor set at 238 nm).

Preparation of 145N- [3- (1- [6, 6-bis (2-phenylethyl) -5, 6-dihydro-4-hydroxy-2-oxo-2H-pyran-3-yl ] propyl) phenyl ] carbamic acid phenylmethyl ester resolution gave 2 isomers.

Samples of the starting compound (up to 1.3 g per resolution) were injected onto a 5.1X 50cm Chiralcel OD column (Chiral Technologies, Inc.). The enantiomers were eluted with 20% isopropanol and 0.025 acetic acid/hexane (V/V) at 60mL/min until the first enantiomer eluted. At this point (approximately 120 minutes) the flow rate was increased to 90mL/min to accelerate elution of the second enantiomer. The enantiomer eluted at about 91.2 minutes (benzyloxycarbonyl analog corresponding to the amine of isomer 1), and about 132 minutes (benzyloxycarbonyl analog corresponding to the amine of isomer 2). Purity was checked on a 0.46X 25cm Chiralcel OD column. The mobile phase was 30% isopropanol/hexane (V/V) at a flow rate of 0.5mL/min.

Preparation of 1465-carbamoylpyridine-2-sulfonyl chloride (formula VVV-2), see Table VVV. To a cold (0 ℃ C.) stirred suspension of 400mg of 2-mercapto-5-carbamoylpyridine of the formula VVV-1 in 7.5ml of 1N HCl is passed vigorously chlorine. After 10 minutes, the suspension was filtered, and the solid was washed well with water and dried in vacuo. 517mg of the title compound are obtained as an off-white solid.

Example 328N- [3- {1- (4-hydroxy-5, 6-dihydro-2-oxo-6- (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl]-4-cyanobenzenesulfonamide (C)Formula U-8: r₁Is tert-butyl, R₂Is 4-cyanophenyl) see table U.

Using the general sulfonylation procedure of example 252, 88mg of the amine of preparation 86 (formula U-7, wherein R is₁Is t-butyl) with 4-cyanobenzenesulfonyl chloride. Flash column chromatography on silica gel eluting with 10% ethyl acetate in dichloromethane afforded 117mg of the title compound as an amorphous white solid.

The physical properties were as follows:

¹H NMR δ 0.90，1.3，1.7，2.5，3.6，6.8-7.4，7.6，7.8ppm

HRMS：605.2478

R_f0.36 (10% ethyl acetate/dichloromethane)

Example 329N- [3- {1- (4-hydroxy-5, 6-dihydro-2-oxo-6- (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl]-8-quinolinesulfonamides (formula U-8: R)₁Tert-butyl radical, R₂Is 8-quinolinyl), see table U.

Using the general sulfonylation procedure of example 252, 88mg of the amine of formula U-7, R of preparation 86₁Is t-butyl) with 8-quinolinesulfonyl chloride. Flash column chromatography on silica gel eluting with 5-10% ethyl acetate in dichloromethane afforded 101mg of the title compound as an amorphous white solid.

The physical properties were as follows:

¹H NMR δ 0.63，0.9，1.1，1.3，1.6-1.9，2.4-2.6，6.7-7.6，8.0，8.2，9.1ppm

HRMS：631.2638

R_f0.30 (5% ethyl acetate/dichloromethane)

Example 330N- [3- {1- (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-bis (2-phenylethyl) -2H-pyran-3-yl) propyl } phenyl]-1-methyl-1H-imidazole-4-sulfonamide (formula D-6: R)₁Is phenethyl，R₂Is phenethyl, R₃Is ethyl, R₄Is 1-methylimidazol-4-yl), see table D.

Using the general sulfonylation procedure of example 252, 77mg of an amine of the formula D-5, wherein R₁And R₂Is phenethyl, R₃Is ethyl and is reacted with 1-methylimidazole-4-sulfonyl chloride. Flash column chromatography on silica gel eluting with 3% methanol in dichloromethane afforded 97.0mg of the title compound as a crystalline white solid.

The physical properties were as follows:

¹H NMR δ 0.88，1.9-2.2，2.6，3.6-3.8，3.97，6.9-7.5ppm

HRMS：600.2521

R_f0.31 (5% methanol/dichloromethane)

EXAMPLE 331N- [3- {1- (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-bis (2-phenylethyl) -2H-pyran-3-yl) propyl } phenyl]-5-cyanopyridine-2-sulfonamide (formula D-6: R)₁Is phenethyl, R₂Is phenethyl, R₃Is ethyl, R₄Is 5-cyanopyridin-2-yl) with reference to table D.

Using the general sulfonylation procedure of example 252, 77mg of an amine of the formula D-5, wherein R₁And R₂Is phenethyl, R₃Is ethyl, and is reacted with 5-cyanopyridine-2-sulfonyl chloride. Flash column chromatography on silica gel eluting with 10% ethyl acetate in dichloromethane afforded 88.3mg of the title compound as a crystalline white solid.

The physical properties were as follows:

¹H NMR δ 0.85，1.8-2.2，2.5-2.7，3.97，6.9-7.4，7.9，8.8ppm.

HRMS：622.2355

R_f0.28 (10% ethyl acetate/dichloromethane)

Example 332N- [3- {1- (4-hydroxy-5, 6-dihydro-2)-oxo-6- (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) propyl } phenyl]-5-carbamoylpyridine-2-sulfonamide (formula U-8: R)₁Is ethyl, R₂Is 5-carbamoylpyridin-2-yl), see table U.

Using the general sulfonylation procedure of example 252, 82mg of an amine of the formula U-7, wherein R₁Ethyl, with 5-carbamoylpyridine-2-sulfonyl chloride prepared at 146. Flash column chromatography on silica gel eluting with 3-6% methanol in dichloromethane afforded 55.4mg of the title compound as an amorphous solid.

The physical properties were as follows:

¹H NMR δ 0.7-0.9，1.3，1.6-2.1，2.5，3.9，6.8-7.3，7.8，8.2ppm.

HRMS：596.2216

R_f0.16 (5% methanol/dichloromethane)

Example 333N- [3- {1- (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-bis (2- (4-fluorophenyl) ethyl) -2H-pyran-3-yl) propyl } phenyl]-5-carbamoylpyridine-2-sulfonamide (formula V-8: R)₁Is ethyl, R₂Is 5-carbamoylpyridin-2-yl), see table V.

Using the general sulfonylation procedure of example 252, 98mg of an amine of the formula V-7, wherein R₁Ethyl, with 5-carbamoylpyridine-2-sulfonyl chloride prepared at 146. Flash column chromatography on silica gel eluting with 3-6% methanol in dichloromethane afforded 58.3mg of the title compound as an amorphous solid.

The physical properties were as follows:

¹H NMR δ 0.83，1.8-2.2，2.5-2.6，6.8-7.2，7.8，8.1，9.0ppm.

HRMS：676.2297

R_f0.17 (5% methanol/dichloromethane)

Example 334N- [3- {1- (4-hydroxy-5,6-dihydro-2-oxo-6, 6-dipropyl-2H-pyran-3-yl) propyl } phenyl]-5-carbamoylpyridine-2-sulfonamide (formula D-6: R)₁Is propyl, R₂Is propyl, R₃Is ethyl, R₄Is 5-carbamoylpyridin-2-yl), see table D.

Using the general sulfonylation procedure of example 252, 66mg of the amine (R) of the formula D-5₁And R₂Is propyl, R₃Is ethyl) was coupled to 5-carbamoylpyridine-2-sulfonyl chloride preparation 146 and chromatographed on flash silica gel eluting with 3-6% methanol in dichloromethane to give 83.8mg of the title compound as an amorphous white solid.

The physical properties were as follows:

¹H NMR δ 0.7-0.9，1.2-2.1，3.87，7.0-7.3，7.8，8.2ppm.

HRMS：516.2156

R_f0.22 (5% methanol/dichloromethane)

Preparation 147N- [3- [1- (4-hydroxy-5, 6-dihydro-2-oxo-6-phenethyl-6-propyl-2H-pyran-3-yl) -propyl]Phenyl radical]Resolution of benzyl carbamate to give 4 isomers (formula WWW-2: R)₁Is phenethyl, R₂Is propyl, R₃Is ethyl), see tables WWW and RRR.

Preparation of 130A product (formula RRR-1: R)₁Is ethyl) are (in order of increasing residence time in system B): (about 16.9 min) (isomer 1), (about 28.0 min) (isomer 2), (about 38.2 min) (isomer 3), and (about 49.8 min) (isomer 4). System B consisted of a 0.46X 25cm Chiralcel OD-H column (Chiral Technologies, Inc.) eluting with 25% isopropanol/hexane (V/V) at 0.5 mL/min.

In the first stage of total resolution, 55mg of the product sample of preparation 130A was repeatedly injected onto a 2.1X 25cm (R, R) Whelk-O1 column (regions Technologies, Inc.). The isomers were eluted with 35% isopropanol and 0.5% acetic acid/hexane (V/V) at 10 mL/min. The first of the three peaks eluted (about 12 minutes) was confirmed by injecting a portion thereof into system B as a mixture of isomer 1 (formula RRR-4 of Table RRR) and isomer 2 (formula RRR-3 of Table RRR). The mixture was resolved in stage 2 described below.

The second stage consisted of a 2.1X 25cm Chiralcel OD column maintained at 30 ℃. A set of 60mg of the mixture obtained in the first stage was injected and the enantiomers were eluted with 25% isopropanol and 0.05% trifluoroacetic acid (V/V) at 9.0 mL/min. Fractions eluting at approximately 14.5 and 23.9 minutes were collected and concentrated to give isomer 1 (formula RRR-4 of Table RRR where R is₁Is ethyl) and isomer 2 (formula RRR-3 of Table RRR wherein R₁Is ethyl).

Preparation 147A 3- (R or S) - [1- (3-aminophenyl) -propyl]-4-hydroxy-5, 6-dihydro-6 (R or S) -phenethyl-6- (R or S) -propyl-2H-pyran-2-one (formula RRR-7; R)₁Is an ethyl group; refer to table RRR).

Following the procedure of preparation 132, the peak labeled Peak 2 in the chiral resolution of the product of preparation 147 was used (formula RRR-3 of Table RRR; R ₁Is ethyl) to yield the title compound.

The physical properties were as follows:

¹H NMR(CD₃OD)：δ 6.5-7.3，3.9-4.0，2.5-2.7，1.2-2.3，0.8-1.0.

TLC (silica gel GF) Rf 0.31, 40% ethyl acetate/hexane.

Example 335N- [3- {1(R or S) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (R or S) -phenethyl-6-propyl-2H-pyran-3-yl) propyl } phenyl]-5-cyanopyridine-2-sulfonamide (formula WWW-4: R)₁Is phenethyl, R₂Is propyl, R₃Is ethyl, R₄Is 5-cyanopyridin-2-yl) [ isomer 1]Refer to table WWW.

The title compound was synthesized using the general sulfonylation procedure of example 252 using an amine of the formula WWW-3 (wherein R is₁Is phenethyl, R₂Is aRadical, R₃Is ethyl). The amine was prepared from the first stereoisomer of preparation 147 (formula WWW-2) eluting from a Chiralcel OD chiral HPLC column. Flash chromatography on silica eluting with 10% ethyl acetate in dichloromethane afforded the title compound as an amorphous solid.

The physical properties were as follows:

¹H NMR δ 0.7-1.0，1.2-2.6，3.3-3.6，6.9-7.3，7.7-8.2，8.8-9.0ppm.

HRMS：560.2210

R_f0.41 (15% ethyl acetate/dichloromethane)

Example 336N- [3- {1(R or S) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (S or R) -phenethyl-6-propyl-2H-pyran-3-yl) -propyl } phenyl]-5-cyanopyridine-2-sulfonamide (formula WWW-4: R)₁Is phenethyl, R₂Is propyl, R₃Is ethyl, R₄Is 5-cyanopyridin-2-yl [ isomer 2 ] ]Refer to table WWW.

The title compound was synthesized using the general sulfonylation procedure of example 252 using the title product amine of preparation 147A (formula WWW-3, where R is₁Is phenethyl, R₂Is propyl, R₃Is ethyl). The amine was prepared from the second stereoisomer of preparation 147 (formula WWW-2) eluting from a Chiralcel OD chiral HPLC column. Flash chromatography on silica eluting with 10% ethyl acetate in dichloromethane afforded the title compound as an amorphous solid.

The physical properties were as follows:

¹H NMR δ 0.6-2.6，3.3-3.6，6.9-7.3，7.7-8.2，8.8-9.0ppm.

HRMS：560.2215

R_f0.41 (15% ethyl acetate/dichloromethane)

EXAMPLE 337N- [3- {1(S or R) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (R or S) -phenethyl-6-propyl-2H-pyran-3-yl) propylPhenyl radical]-5-cyanopyridine-2-sulfonamide (formula WWW-4: R)₁Is phenethyl, R₂Is propyl, R₃Is ethyl, R₄Is 5-cyanopyridin-2-yl [ isomer 3]Refer to table WWW.

The title compound was synthesized using the general sulfonylation procedure of example 252 using an amine of the formula WWW-3 (wherein R is₁Is phenethyl, R₂Is propyl, R₃Is ethyl). The amine was prepared from the third stereoisomer of preparation 147 (formula WWW-2) eluting from a Chiralcel OD chiral HPLC column. Flash chromatography on silica eluting with 10% ethyl acetate in dichloromethane afforded the title compound as an amorphous solid.

The physical properties were as follows:

¹H NMR δ 0.6-2.6，3.3-3.6，6.9-7.3，7.7-8.2，8.8-9.0ppm.

HRMS：560.2210

R_f0.41 (15% ethyl acetate/dichloromethane)

Example 338N- [3- {1(S or R) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (S or R) -phenethyl-6-propyl-2H-pyran-3-yl) propyl } phenyl]-5-cyanopyridine-2-sulfonamide (formula WWW-4: R)₁Is phenethyl, R₂Is propyl, R₃Is ethyl, R₄Is 5-cyanopyridin-2-yl [ isomer 4]Refer to table WWW.

The title compound was synthesized using the general sulfonylation procedure of example 252 using an amine of the formula WWW-3 (wherein R is₁Is phenethyl, R₂Is propyl, R₃Is ethyl). The amine was prepared from the fourth stereoisomer of preparation 147 (formula WWW-2) eluting from a Chiralcel OD chiral HPLC column. Flash chromatography on silica eluting with 10% ethyl acetate in dichloromethane afforded the title compound as an amorphous solid.

The physical properties were as follows:

¹H NMR δ 0.7-1.0，1.2-2.6，3.3-3.6，6.9-7.3，7.7-8.2，8.8-9.0ppm.

HRMS：560.2210

R_f0.41 (15% ethyl acetate/dichloromethane)

Example 339N- [3- {1(R or S) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (R or S) -phenethyl-6-propyl-2H-pyran-3-yl) -propyl } phenyl]-1-methyl-1H-imidazole-4-sulfonamide (formula WWW-4: R)₁Is phenethyl, R₂Is propyl, R₃Is ethyl, R₄Is 1-methylimidazol-4-yl [ isomer 1 ]]Refer to table WWW.

The title compound was synthesized using the general sulfonylation procedure of example 252 using an amine of the formula WWW-3 (wherein R is ₁Is phenethyl, R₂Is propyl, R₃Is ethyl). The amine was prepared from the first stereoisomer of preparation 147 (formula WWW-2) eluting from a Chiralcel OD chiral HPLC column. Flash chromatography on silica eluting with 3% methanol in dichloromethane afforded the title compound as an amorphous solid.

The physical properties were as follows:

¹H NMR δ 0.7-2.8，3.2-3.7，3.9，7.0-7.6ppm.

HRMS：537.2317

R_f0.36 (5% methanol/dichloromethane)

Example 340N- [3- {1(R or S) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (S or R) -phenethyl-6-propyl-2H-pyran-3-yl) propyl } phenyl]-1-methyl-1H-imidazole-4-sulfonamide (formula WWW-4: R)₁Is phenethyl, R₂Is propyl, R₃Is ethyl, R₄Is 1-methylimidazol-4-yl [ isomer 2 ]]Refer to table WWW.

The title compound was synthesized using the general sulfonylation procedure of example 252 using an amine of the formula WWW-3 (wherein R is₁Is phenethyl, R₂Is propyl, R₃Is ethyl). The amine was prepared from the second stereoisomer of preparation 147 (formula WWW-2) eluting from a Chiralcel OD chiral HPLC column. Flash chromatography on silica eluting with 3-4% methanol in dichloromethane afforded the title compound as an amorphous solid.

The physical properties were as follows:

¹H NMRδ 0.7-2.7，3.3-3.7，4.0，7.0-7.5ppm.

HRMS：537.2275

R_f0.36 (5% methanol/dichloromethane)

Example 341N- [3- {1(S or R) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (R or S) -phenethyl-6-propyl-2H-pyran-3-yl) -propyl } phenyl ]-1-methyl-1H-imidazole-4-sulfonamide (formula WWW-4: R)₁Is phenethyl, R₂Is propyl, R₃Is ethyl, R₄Is 1-methylimidazol-4-yl [ isomer 3 ]]Refer to table WWW.

The title compound was synthesized using the general sulfonylation procedure of example 252 using an amine of the formula WWW-3 (wherein R is₁Is phenethyl, R₂Is propyl, R₃Is ethyl). The amine was prepared from the third stereoisomer of preparation 147 (formula WWW-2) eluting from a Chiralcel OD chiral HPLC column. Flash chromatography on silica eluting with 3% methanol in dichloromethane afforded the title compound as an amorphous solid.

The physical properties were as follows:

¹H NMR δ 0.7-2.7，3.3-3.7，4.0，7.0-7.5ppm.

HRMS：537.2329

R_f0.36 (5% methanol/dichloromethane)

Example 342N- [3- {1(S or R) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (S or R) -phenethyl-6-propyl-2H-pyran-3-yl) -propyl } phenyl]-1-methyl-1H-imidazole-4-sulfonamide (formula WWW-4: R)₁Is phenethyl, R₂Is propyl, R₃Is ethyl, R₄Is 1-methylimidazol-4-yl [ isomer 4 ]]Refer to table WWW.

The title compound was synthesized using the general sulfonylation procedure of example 252 using an amine of the formula WWW-3 (wherein R is₁Is phenethyl, R₂Is propyl, R₃Is ethyl). The amine was prepared from the fourth stereoisomer of preparation 147 (formula WWW-2) eluting from a Chiralcel OD chiral HPLC column. Flash chromatography on silica eluting with 3% methanol in dichloromethane afforded the title compound as an amorphous solid.

The physical properties were as follows:

¹H NMR δ 0.7-2.8，3.2-3.7，3.9，7.0-7.6ppm.

HRMS：537.2312

R_f0.36 (5% methanol/dichloromethane)

Preparation of 1483- [ (3-nitrophenyl) methyl ] -6, 6-diphenylethyl-4-hydroxy-5, 6-dihydro-2H-pyran-2-one (formula XXX-3), see Table XXX.

To a solution of 172mg of 6, 6-diphenylethyl-4-hydroxy-5, 6-dihydro-2H-pyran-2-one of formula XXX-1 and 81mg of m-nitrobenzaldehyde in 2ml of dry THF under argon was added 142mg of AlCl₃Solution in 1ml THF. The solution was stirred at room temperature for 2 hours, then quenched with 310mg of sodium carbonate decahydrate, diluted with ether, filtered through celite and rinsed with ether. The solvent was then distilled off under reduced pressure to give 264mg of crude benzylidene of formula XXX-2. The starting material was dissolved in 5ml of methanol, and the solution was cooled to 0 ℃ to add 44mg of sodium cyanoborohydride. After one hour, another portion of 20mg sodium cyanoborohydride was added. After a further 30 minutes, the mixture was acidified to pH1 with dilute HCl and extracted three times with dichloromethane. The extract was dried (MgSO)₄) Then concentrated under reduced pressure. The residue was subjected to flash column chromatography on silica eluting with 5-20% ethyl acetate in dichloromethane to give 211mg of the title compound as an amorphous white solid.

The physical properties were as follows:

¹H NMR δ 2.0，2.7，3.8，7.0-7.4，7.6，8.0，8.2ppm.

MS：M+457

R_f0.25 (5% ethyl acetate/dichloromethane)

Preparation of 1493- [ (3-aminophenyl) methyl ] -6, 6-diphenylethyl-4-hydroxy-5, 6-dihydro-2H-pyran-2-one (formula XXX-4), see Table XXX.

A mixture of 211mg of preparation 148 (formula XXX-3) and 50mg of 10% palladium on charcoal in 5ml of methanol was stirred at room temperature under 1 atm of hydrogen. After two hours, the mixture was filtered through celite and concentrated under reduced pressure. The residue was subjected to flash column chromatography on silica gel eluting with 25% ethyl acetate in dichloromethane to give 133.6mg of the title compound.

The physical properties were as follows:

¹H MR δ 2.0，2.6，3.6，4.1，6.5，6.6，6.7，6.9-7.3ppm.

MS：M+427

R_f0.33 (25% ethyl acetate/dichloromethane)

Example 343N- [3- {1- (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-bis (2-phenylethyl) -2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl]-1-methyl-1H-imidazole-4-sulfonamide (formula YYY-5: R)₁And R₂Is phenethyl, R₃Is 1-methylimidazol-4-yl), see table YYY.

Using the general sulfonylation procedure of example 252, 77mg of the amine (R) of the formula YYY-4₁And R₂Is phenethyl) with 1-methylimidazole-4-sulfonyl chloride. Flash chromatography on silica gel with 3% methanol in dichloromethane afforded 90.7mg of the title compound as an amorphous white solid.

The physical properties were as follows:

¹H NMR δ 0.96，1.0，1.6-2.7，3.45，6.8-7.5ppm.

HRMS：628.2832

R_f0.38 (3% methanol/dichloromethane)

Example 344N- [3- {1- (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-bis (2-phenylethyl) -2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl ]-5-cyanopyridine-2-sulfonamide (formula YYYY-5: R)₁And R₂Is phenethyl, R₃Is 5-cyanopyridin-2-yl) with reference to table YYY.

Using the general sulfonylation procedure of example 252, 77mg of the amine (R) of the formula YYY-4₁And R₂Is phenethyl) with 5-cyanopyridine-2-sulfonyl chloride. Flash chromatography on silica gel with 10% ethyl acetate/dichloromethane afforded 86.1mg of the title compound as an amorphous white solid.

The physical properties were as follows:

¹H NMR δ 0.96，1.8-2.2，2.5-2.8，4.1，4.3，6.9-7.4，7.9-8.0，8.9ppm.

HRMS：650.2681

R_f0.27 (10% ethyl acetate/dichloromethane)

Preparation of 150N- [3- [1- (4-hydroxy-5, 6-dihydro-2-oxo-6- (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) -2, 2-dimethylpropyl]Phenyl radical]Resolving methyl carbamate to obtain 4 isomers (formula WWW-2: R)₁Is 4-fluorophenethyl, R₂Is propyl, R₃Is t-butyl), see table WWW.

System C was used to track the enantiomers and monitor the preparative column. System C consisted of a 0.46X 25cm Chiralcel OD-H column (Chiral Technologies, Inc.) eluting with 15% isopropanol/hexane (V/V) at 0.5 mL/min. Peaks eluting at approximately 13.5, 18.8, 37.1, and 79.7 minutes were isomer 1, isomer 2, isomer 3, and isomer 4, respectively.

Isomers 3 and 4 were separated from the mixture on a 2.1X 25cm (R, R) Whelk-O1 column (regions Technologies, Inc.). When the column was developed with 20% isopropanol/hexane (V/V) at 10mL/min at 30 ℃, the two isomers eluted at approximately 23.9 and 26.8 minutes. The desired isomer elutes as an undissociated isomer mixture at about 28.9 minutes and is separated in the second stage of resolution.

In the second stage, the unresolved mixture was injected onto a 2.1X 25cm Chiralcel OD column (regions Technologies, Inc.) maintained at 30 ℃. Eluting with 12% isopropanol/hexane (V/V) at 12mL/min, isomer 1 appeared at about 14.5 minutes and isomer 2 appeared at about 20.8 minutes.

Example 345N- [3- {1(R or S) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (R or S) - (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl]-5-cyanopyridine-2-sulfonamide (formula WWW-4: R)₁Is 4-fluorophenethyl, R₂Is propyl, R₃Is tert-butyl, R₄Is 5-cyanopyridin-2-yl) [ isomer 1]Refer to table WWW.

The title compound was synthesized using the general sulfonylation procedure of example 252 using an amine of the formula WWW-3 (wherein R is₁Is 4-fluorophenethyl, R₂Is propyl, R₃Is ethyl). The amine was prepared from the first stereoisomer of preparation 150 (formula WWW-2) eluting from a Chiralcel OD chiral HPLC column. The title compound was obtained as an amorphous solid after flash chromatography on silica gel with 10% ethyl acetate/dichloromethane.

The physical properties were as follows:

¹H NMR δ 0.7-2.7，3.2，3.5，3.6，3.7，4.1，6.8-7.4，7.5，7.8-8.2，8.8ppm.

HRMS：606.2429

R_f0.40 (15% ethyl acetate/dichloromethane)

EXAMPLE 346N- [3- {1(R or S) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (S or R) - (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl ]-5-cyanopyridine-2-sulfonamide (formula WWW-4: R)₁Is 4-fluorophenethyl, R₂Is propyl, R₃Is tert-butyl, R₄Is 5-cyanopyridin-2-yl [ isomer 2 ]]Refer to table WWW.

The title compound was synthesized using the general sulfonylation procedure of example 252 using an amine of the formula WWW-3 (wherein R is₁Is 4-fluorophenethyl, R₂Is propyl, R₃Is ethyl). The amine was prepared from the second stereoisomer of preparation 150 (formula WWW-2) eluting from a Chiralcel OD chiral HPLC column. The title compound was obtained as an amorphous solid after flash chromatography on silica gel with 10% ethyl acetate/dichloromethane.

The physical properties were as follows:

¹H NMR δ 0.6，0.7-2.6，3.4，3.5，3.7，4.2，6.8-7.3，7.5，7.8-8.2，8.8-9.0ppm.

MS：606.2434

R_f0.40 (15% ethyl acetate/dichloromethane)

Example 347N- [3- {1(S or R) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (R or S) - (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl]-5-cyanopyridine-2-sulfonamide (formula WWW-4: R)₁Is 4-fluorophenethyl, R₂Is propyl, R₃Is tert-butyl, R₄Is 5-cyanopyridin-2-yl [ isomer 3]Refer to table WWW.

The title compound was synthesized using the general sulfonylation procedure of example 252 using an amine of the formula WWW-3 (wherein R is₁Is 4-fluorophenethyl, R₂Is propyl, R₃Is ethyl). The amine was prepared from the third stereoisomer of preparation 150 (formula WWW-2) eluting from a Chiralcel OD chiral HPLC column. The title compound was obtained as an amorphous solid after flash chromatography on silica gel with 10% ethyl acetate/dichloromethane.

The physical properties were as follows:

¹H NMR δ 0.6，0.7-2.6，3.4， 3.5，3.7，4.2，6.8-7.3，7.5，7.8-8.2，8.8-9.0ppm.

MS：606.2423

R_f0.40 (15% ethyl acetate/dichloromethane)

EXAMPLE 348N- [3- {1(S or R) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (S or R) - (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl]-5-cyanopyridine-2-sulfonamide (formula WWW-4: R)₁Is 4-fluorophenethyl, R₂Is propyl, R₃Is tert-butyl, R₄Is 5-cyanopyridin-2-yl [ isomer 4]Refer to table WWW.

The title compound was synthesized using the general sulfonylation procedure of example 252 using an amine of the formula WWW-3 (wherein R is₁Is 4-fluorophenethyl, R₂Is propyl, R₃Is ethyl). The amine was prepared from the fourth stereoisomer of preparation 150 (formula WWW-2) eluting from a Chiralcel OD chiral HPLC column. The title compound was obtained as an amorphous solid after flash chromatography on silica gel with 10% ethyl acetate/dichloromethane.

The physical properties were as follows:

HRMS：606.2429

R_f0.40 (15% ethyl acetate/dichloromethane)

Example 349N- [3- {1(R or S) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (R or S) - (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl]-1-methyl-1H-imidazole-4-sulfonamide (formula WWW-4: R)₁Is 4-fluorophenethyl, R₂Is propyl, R₃Is tert-butyl, R₄Is 1-methylimidazol-4-yl [ isomer 1 ] ]Refer to table WWW.

The title compound was synthesized using the general sulfonylation procedure of example 252 using an amine of the formula WWW-3 (wherein R is₁Is 4-fluorobenzeneEthyl radical, R₂Is propyl, R₃Is ethyl). The amine was prepared from the first stereoisomer of preparation 150 (formula WWW-2) eluting from a Chiralcel OD chiral HPLC column. The title compound was obtained as an amorphous solid after flash chromatography on silica gel with 3% methanol/dichloromethane.

The physical properties were as follows:

¹H NMR δ 0.8-1.0，1.4，1.7，2.3-2.7，3.6，3.9，4.1，6.8-7.5ppm.

HRMS：584.2585

R_f0.34 (5% methanol/dichloromethane)

EXAMPLE 350N- [3- {1(R or S) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (S or R) - (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl]-1-methyl-1H-imidazole-4-sulfonamide (formula WWW-4: R)₁Is 4-fluorophenethyl, R₂Is propyl, R₃Is tert-butyl, R₄Is 1-methylimidazol-4-yl [ isomer 2 ]]Refer to table WWW.

The title compound was synthesized using the general sulfonylation procedure of example 252 using an amine of the formula WWW-3 (wherein R is₁Is 4-fluorophenethyl, R₂Is propyl, R₃Is ethyl). The amine was prepared from the second stereoisomer of preparation 150 (formula WWW-2) eluting from a Chiralcel OD chiral HPLC column. The title compound was obtained as an amorphous solid after flash chromatography on silica gel with 3% methanol/dichloromethane.

The physical properties were as follows:

¹H NMR δ 0.7-1.1，1.3，1.7，2.3-2.7，3.6，3.9，4.1，6.8-7.5ppm.

HRMS：584.2585

R_f0.34 (5% methanol/dichloromethane)

Example 351N- [3- {1(S or R) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (R or S) - (2- (4-fluorophenyl) ethyl)) -6-propyl-2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl]-1-methyl-1H-imidazole-4-sulfonamide (formula WWW-4: R)₁Is 4-fluorophenethyl, R₂Is propyl, R₃Is tert-butyl, R₄Is 1-methylimidazol-4-yl [ isomer 3 ]]Refer to table WWW.

The title compound was synthesized using the general sulfonylation procedure of example 252 using an amine of the formula WWW-3 (wherein R is₁Is 4-fluorophenethyl, R₂Is propyl, R₃Is ethyl). The amine was prepared from the third stereoisomer of preparation 150 (formula WWW-2) eluting from a Chiralcel OD chiral HPLC column. The title compound was obtained as an amorphous solid after flash chromatography on silica gel with 3% methanol/dichloromethane.

The physical properties were as follows:

¹H NMR δ0.7-1.1，1.3，1.7，2.3-2.7，3.6，3.9，4.1，6.8-7.5ppm.

HRMS：584.2591

R_f0.34 (5% methanol/dichloromethane)

Example 352N- [3- {1(S or R) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (S or R) - (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl]-1-methyl-1H-imidazole-4-sulfonamide (formula WWW-4: R)₁Is 4-fluorophenethyl, R₂Is propyl, R₃Is tert-butyl, R₄Is 1-methylimidazol-4-yl [ isomer 4 ] ]Refer to table WWW.

The title compound was synthesized using the general sulfonylation procedure of example 252 using an amine of the formula WWW-3 (wherein R is₁Is 4-fluorophenethyl, R₂Is propyl, R₃Is ethyl). The amine was prepared from the fourth stereoisomer of preparation 150 (formula WWW-2) eluting from a Chiralcel OD chiral HPLC column. The title compound was obtained as an amorphous solid after flash chromatography on silica gel with 3% methanol/dichloromethane.

The physical properties were as follows:

¹H NMR δ 0.8-1.0，1.4，1.7，2.3-2.7，3.6，3.9，4.1，6.8-7.5ppm.

HRMS：584.2580

R_f0.34 (5% methanol/dichloromethane)

Example 353N- [3- {1- (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-bis (2-phenylethyl) -2H-pyran-3-yl) methyl } phenyl]-5-cyanopyridine-2-sulfonamide (formula XXX-5; R)₁Is 5-cyanopyridin-2-yl) with reference to table XXX.

Using the general sulfonylation procedure of example 252, 64mg of an amine of formula XXX-4 was reacted with 5-cyanopyridine-2-sulfonyl chloride. Flash chromatography on silica gel with 2-3% methanol in dichloromethane afforded 73.2mg of the title compound as an amorphous white solid.

The physical properties were as follows:

¹H NMR δ 1.8-2.1，2.6，6.9-7.3，7.9，8.8ppm.

HRMS：594.2068

R_f0.40 (3% methanol/dichloromethane)

Example 354N- [3- {1- (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-bis (2-phenylethyl) -2H-pyran-3-yl) methyl } phenyl]-5-aminopyridine-2-sulfonamide (formula UUUU-6; R)₁And R ₂Is phenethyl, R₃Is H), refer to table UUU.

Using the general sulfonylation procedure of example 252, 69mg of an amine of formula XXX-4 was reacted with 5-nitropyridine-2-sulfonyl chloride. Flash chromatography on silica gel with 2-3% methanol in dichloromethane afforded 107mg of the nitro compound intermediate (R) of formula UUUU-5₁And R₂Is phenethyl, R₃Is H). Reduction to the amine is accomplished by using hydrogen and a catalyst of palladium on charcoal. Flash chromatography on silica gel with 4-6% methanol in dichloromethane afforded 65.0mg of the title compound as an amorphous white solid.

The physical properties were as follows:

¹H NMR δ 1.9-2.1，2.6，3.5-4.0，6.7，6.9-7.3，7.5，7.9ppm.

HRMS：584.2215

R_f0.24 (5% methanol/dichloromethane)

Preparation 151N- [3- [1- (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-bis (2-phenylethyl) -2H-pyran-3-yl) -2, 2-dimethylpropyl ] -amide]Phenyl radical]Resolving methyl chlorobenzoate to obtain 2 enantiomers (formula WWW-2: R)₁And R₂Is phenethyl, R₃Is t-butyl), see table WWW.

Each batch of 40mg of starting compound was injected onto a 2.1X 25cm (R, R) Whelk-O1 column maintained at 30 ℃ (regions Technologies, Inc.). Both enantiomers were eluted at approximately 37 minutes (enantiomer 1) and 43 minutes (enantiomer 2) with 25% isopropanol and 0.05% acetic acid at 12 mL/min. Fractions were collected according to the analysis on a 0.46X 25cm (R, R) Whelk-O1 column eluting with 30% isopropanol and 0.1% acetic acid (V/V) at 1.0 mL/min. Isomers eluted at (isomer 1)19.1 and (isomer 2)23.0 minutes, respectively.

EXAMPLE 355N- [3- {1(R or S) - (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-bis (2-phenylethyl) -2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl]-5-aminopyridine-2-sulfonamide (formula WWW-4, R)₁And R₂Is phenethyl, R₃Is tert-butyl, R₄Is 5-aminopyridin-2-yl) [ enantiomer 1]Refer to table WWW.

Using the general sulfonylation procedure of example 252, 73mg of the amine (R) of the formula WWW-3₁And R₂Is phenethyl, R₃Is tert-butyl) with 5-nitropyridine-2-sulfonyl chloride. The amine used was prepared from the first enantiomer of preparation 151 (formula WWW-2) eluting from an (R, R) Whelk-O chiral HPLC column. Flash chromatography on silica gel with 5-10% ethyl acetate/dichloromethane afforded 94.0mg of the nitro compound intermediate of formula UUUU-5 (R)₁And R₂Is phenethyl, R₃Is a tert-butyl group). Is reduced toThe amine is accomplished by using hydrogen and a catalyst of palladium on carbon. Flash chromatography on silica gel with 4% methanol in dichloromethane afforded 74.8mg of the title compound as an amorphous white solid.

The physical properties were as follows:

¹H NMR δ 0.95，2.0，2.6，6.8，6.9-7.4，7.5，7.9ppm.

HRMS：640.2828

R_f0.27 (5% methanol/dichloromethane)

EXAMPLE 356N- [3- {1(S or R) - (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-bis (2-phenylethyl) -2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl]-5-aminopyridine-2-sulfonamide (formula WWW-4, R) ₁And R₂Is phenethyl, R₃Is tert-butyl, R₄Is 5-aminopyridin-2-yl) [ enantiomer 2]Refer to table WWW.

Using the general sulfonylation procedure of example 252, 73mg of the amine (R) of the formula WWW-3₁And R₂Is phenethyl, R₃Is tert-butyl) with 5-nitropyridine-2-sulfonyl chloride. The amine used was prepared from the second enantiomer of preparation 151 (formula WWW-2) eluting from a (R, R) Whelk-O chiral HPLC column. Flash chromatography on silica gel with 5-10% ethyl acetate/dichloromethane afforded 91.3mg of the nitro compound intermediate of formula UUUU-5 (R)₁And R₂Is phenethyl, R₃Is a tert-butyl group). Reduction to the amine is accomplished by using hydrogen and a catalyst of palladium on charcoal. Flash chromatography on silica gel with 4% methanol in dichloromethane afforded 54.3mg of the title compound as an amorphous white solid.

The physical properties were as follows:

¹H NMR δ 0.95，2.0，2.6，6.8，6.9-7.4，7.5，7.9ppm.

HRMS：640.2828

R_f0.27 (5% methanol/dichloromethane)

EXAMPLE 357N- [3- {1(R or S) - (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-bis (2-phenylethyl) -2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl]-1-methyl-1H-imidazole-4-sulfonamide (formula WWW-4, R)₁And R₂Is phenethyl, R₃Is tert-butyl, R₄Is 1-methylimidazol-4-yl [ enantiomer 1]Refer to table WWW.

The title compound was synthesized using the general sulfonylation procedure of example 252 using an amine of the formula WWW-3 (wherein R is ₁And R₂Is phenethyl, R₃Is t-butyl). The amine was prepared from the first enantiomer of preparation 151 (formula WWW-2) eluting from a (R, R) Whelk-O chiral HPLC column. The title compound was obtained as an amorphous solid after flash chromatography on silica gel with 3% methanol/dichloromethane.

The physical properties were as follows:

¹H NMR δ 0.98，2.0，2.6，3.6，3.8，6.9-7.5ppm.

HRMS：628.2832

R_f0.38 (5% methanol/dichloromethane)

Example 358N- [3- {1(S or R) - (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-bis (2-phenylethyl) -2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl]-1-methyl-1H-imidazole-4-sulfonamide (formula WWW-4, R)₁And R₂Is phenethyl, R₃Is tert-butyl, R₄Is 1-methylimidazol-4-yl [ enantiomer 2 ]]Refer to table WWW.

The title compound was synthesized using the general sulfonylation procedure of example 252 using an amine of the formula WWW-3 (wherein R is₁And R₂Is phenethyl, R₃Is t-butyl). The amine was prepared from the second enantiomer of preparation 151 (formula WWW-2) eluting from a (R, R) Whelk-O chiral HPLC column. The title compound was obtained as an amorphous solid after flash chromatography on silica gel with 3% methanol/dichloromethane.

The physical properties were as follows:

¹H NMR δ 0.98，2.0，2.6，3.6，3.8，6.9-7.5ppm.

HRMS：628.2838

R_f0.38 (5% methanol/dichloromethane)

Example 359N- [3- {1(R or S) - (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-bis (2-phenylethyl) -2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl ]-5-cyanopyridine-2-sulfonamide (formula WWW-4, R)₁And R₂Is phenethyl, R₃Is tert-butyl, R₄Is 5-cyanopyridin-2-yl) [ enantiomer 1]Refer to table WWW.

The title compound was synthesized using the general sulfonylation procedure of example 252 using an amine of the formula WWW-3 (wherein R is₁And R₂Is phenethyl, R₃Is t-butyl). The amine was prepared from the first enantiomer of preparation 151 (formula WWW-2) eluting from a (R, R) Whelk-O chiral HPLC column. The title compound was obtained as an amorphous solid after flash chromatography on silica gel with 10% ethyl acetate/dichloromethane.

The physical properties were as follows:

¹H NMR δ 0.87，1.9，2.6，6.8-7.4，7.9，8.8ppm.

HRMS：650.2681

R_f0.46 (15% ethyl acetate/dichloromethane)

EXAMPLE 360N- [3- {1(S or R) - (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-bis (2-phenylethyl) -2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl]-5-cyanopyridine-2-sulfonamide (formula WWW-4, R)₁And R₂Is phenethyl, R₃Is tert-butyl, R₄Is 5-cyanopyridin-2-yl) [ enantiomer 2]Refer to table WWW.

The title compound was synthesized using the general sulfonylation procedure of example 252 using an amine of the formula WWW-3 (wherein R is₁And R₂Is phenethyl, R₃Is t-butyl). The amine is eluted from a (R, R) Whelk-O chiral HPLC columnPreparation 151 of the second enantiomer (formula WWW-2). The title compound was obtained as an amorphous solid after flash chromatography on silica gel with 10% ethyl acetate/dichloromethane.

The physical properties were as follows:

¹H NMR δ 0.87，1.9，2.6，6.8-7.4，7.9，8.8ppm.

HRMS：650.2681

R_f0.46 (15% ethyl acetate/dichloromethane)

Preparation of 152N- [3- [1- (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-dipropyl-2H-pyran-3-yl) -propyl]Phenyl radical]Resolving methyl carbamate to obtain 2 isomers (formula WWW-2: R)₁And R₂Is propyl, R₃Is ethyl) refer to table WWW.

A sample of the starting compound was injected onto a 2.1X 25cm Chiralcel OD column and eluted with 20% isopropanol (V/V)/hexane at 10 mL/min. The material eluted at about 19.1 minutes was one isomer (enantiomer 1) and the other isomer (enantiomer 2) eluted at about 37.7 minutes. The pools were each concentrated on a rotary evaporator (approximately 300mm, water bath up to 50 ℃) to give a white solid.

Example 361N- [3- {1(R or S) - (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-dipropyl-2H-pyran-3-yl) -propyl } phenyl]-5-cyanopyridine-2-sulfonamide (formula WWW-4: R)₁And R₂Is propyl, R₃Is ethyl, R₄Is 5-cyanopyridin-2-yl) [ enantiomer 1]Refer to table WWW.

The title compound was prepared in a similar manner as described above but using enantiomer 1 of preparation 152.

The physical properties were as follows:

¹H NMR δ 0.8-1.0，1.2-2.2，3.90，6.9-7.2，8.0，8.15，8.9ppm.

HRMS：497.1984

R_f0.38 (15% ethyl acetate/dichloromethane)

Example 362N- [3- {1(S or R) - (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-dipropyl-2H-pyran-3-yl) -propyl } phenyl ]-5-cyanopyridine-2-sulfonamide (formula WWW-4: R)₁And R₂Is propyl, R₃Is ethyl, R₄Is 5-cyanopyridin-2-yl) [ enantiomer 2]Refer to table WWW.

The title compound was prepared in a similar manner as described above but using enantiomer 2 of preparation 152.

The physical properties were as follows:

¹H NMR δ 0.8-1.0，1.2-2.2，3.90，6.9-7.2，8.O，8.15，8.9ppm.

HRMS：497.1980

R_f0.38 (15% ethyl acetate/dichloromethane)

Example 363N- [3- {1(R or S) - (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-dipropyl-2H-pyran-3-yl) -propyl } phenyl]-5-aminopyridine-2-sulfonamide (formula WWW-4: R)₁And R₂Is propyl, R₃Is ethyl, R₄Is 5-aminopyridin-2-yl) [ enantiomer 1]Refer to table wwwwww.

The physical properties were as follows:

¹H NMR δ 0.7-0.9，1.2-2.2，3.8，6.8-7.2，7.5，7.9ppm.

HRMS：487.2122

R_f0.28 (5% methanol/dichloromethane)

Example 364N- [3- {1(S or R) - (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-dipropyl-2H-pyran-3-yl) -propyl } phenyl]-5-aminopyridine-2-sulfonamide (formula WWW-4: R)₁And R₂Is propyl, R₃Is ethyl, R₄Is 5-aminopyridin-2-yl) [ enantiomer 2]Refer to table WWW.

The physical properties were as follows:

¹H NMR δ 0.7-0.9，1.2-2.2，3.8，6.8-7.2，7.5，7.9ppm.

HRMS：487.2140

R_f0.28 (5% methanol/dichloromethane)

Preparation 153N- [3- [1- (4-hydroxy-5, 6-dihydro-2-oxo- (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) -propyl]Phenyl radical]Resolving methyl carbamate to obtain 4 isomers (formula WWW-2: R)₁Is 4-fluorophenethyl, R₂Is propyl, R₃Is ethyl) refer to table WWW.

Enantiomers are defined in the order of elution from system D. HPLC System D consisted of a 0.46X 25cm Chiralcel OD-H column (Chiral Technologies, Inc.) eluting with 20% isopropanol and 0.05% trifluoroacetic acid/hexane (V/V) at 0.5 mL/min. The residence time in the system was (isomer 1)21.6, (isomer 2)34.5, (isomer 3)55.2 and (isomer 4)66.6 minutes.

The enantiomers were separated on a 2.1X 25cm Chiralcel OD column (Chiral Technologies, Inc.). Each aliquot was injected and the enantiomer was eluted with 17.5% isopropanol/hexane (V/V) at 10 mL/min. After analysis with system D, fractions eluting at around 24.6, 42.9, 66.3 and 77.4 minutes were collected appropriately. The four isomers were labeled as isomers 1-4, respectively, in the order of elution.

In all cases, the following protocol was used at any time to remove the solvent from the collection: the solvent was removed from each fraction of the pool under normal vacuum (approximately 30mmHg) on a rotary evaporator set at 45 + -5 deg.C in a water bath. If acetic acid is present in the solvent, approximately 10mL of toluene per L of pool is added before the flask is evaporated to dryness. The residue was then washed into a tared flask with dichloromethane and the solvent removed as above. Before weighing, the solvent is finally removed at room temperature under a pressure of 1mmHg for 2-24 hours.

Example 365N- [3- {1(R or S) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (R or S) - (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) propyl } phenyl]-5-cyanopyridine-2-sulfonamide (formula WWW-4: R)₁Is 4-fluorophenethyl, R₂Is propyl, R₃Is ethyl, R₄Is 5-cyanopyridin-2-yl) [ isomer 1]Refer to table WWW.

Following a similar procedure to that described above, but using isomer 1 of preparation 153, the title compound was obtained.

The physical properties were as follows:

¹H NMR δ 0.8.-1.0，1.3，1.6-2.2，2.5，3.9，6.8-7.3，7.9-8.1，8.9ppm.

HRMS：578.2120

R_f0.35 (15% ethyl acetate/dichloromethane)

EXAMPLE 366N- [3- {1(R or S) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (S or R) - (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) propyl } phenyl]-5-cyanopyridine-2-sulfonamide (formula WWW-4: R)₁Is 4-fluorophenethyl, R₂Is propyl, R₃Is ethyl, R₄Is 5-cyanopyridin-2-yl [ isomer 2 ]]Refer to table WWW.

Following a similar procedure to that described above, but using isomer 2 of preparation 153, the title compound was obtained.

The physical properties were as follows:

¹H NMR δ 0.8-1.0，1.3，1.6-2.2，2.5，3.9，6.8-7.3，7.9-8.1，8.9ppm.

HRMS：578.2120

R_f0.35 (15% ethyl acetate/dichloromethane)

Example 367N- [3- {1(S or R) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (R or S) - (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) propyl } phenyl]-5-cyanopyridine-2-sulfonamide (formula WWW-4: R) ₁Is 4-fluorophenethyl, R₂Is propyl, R₃Is ethyl, R₄Is 5-cyanopyridin-2-yl [ isomer 3]Refer to table WWW.

Following a similar procedure to that described above, but using isomer 3 of preparation 153, the title compound was obtained.

The physical properties were as follows:

¹H NMR δ 0.8-1.0，1.3，1.6-2.2，2.5，3.9，6.8-7.3，7.9-8.1，8.9ppm.

HRMS：578.2126

R_f0.35 (15% ethyl acetate/dichloromethane)

Example 367A N- [3- {1(S or R) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (S or R) - (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) propyl } phenyl]-5-cyanopyridine-2-sulfonamide (formula WWW-4: R)₁Is 4-fluorophenethyl, R₂Is propyl, R₃Is ethyl, R₄Is 5-cyanopyridin-2-yl [ isomer 4]Refer to table WWW.

Following a similar procedure to that described above, but using isomer 4 of preparation 153, the title compound was obtained.

The physical properties were as follows:

¹H NMR δ 0.8-1.0，1.3，1.6-2.2，2.5，3.9，6.8-7.3，7.9-8.1，8.9ppm.

HRMS：578.2126

R_f0.35 (15% ethyl acetate/dichloromethane)Alkane)

Example 368N- [3- {1(R or S) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (R or S) - (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) propyl } phenyl]-1-methyl-1H-imidazole-4-sulfonamide (formula WWW-4: R)₁Is 4-fluorophenethyl, R₂Is propyl, R₃Is ethyl, R₄Is 1-methylimidazol-4-yl [ isomer 1 ]]Refer to table WWW.

The physical properties were as follows:

¹H NMR δ 0.8-1.0，1.3，1.6-2.2，2.6，3.63，4.0，6.9-7.5ppm.

HRMS：556.2265

R_f0.29 (5% methanol/dichloromethane)

Example 369N- [3- {1(R or S) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (R or S) - (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) propyl } phenyl]-5-aminopyridine-2-sulfonamide (formula WWW-4: R)₁Is 4-fluorophenethyl, R₂Is propyl, R₃Is ethyl, R₄Is 5-aminopyridin-2-yl) [ isomer 1]Refer to table WWW.

The physical properties were as follows:

¹H NMR δ 0.8-1.0，1.3，1.6-2.2，2.5，3.9，6.8-7.2，7.5，7.9ppm.

HRMS：568.2271

R_f0.27 (5% methanol/dichloromethane)

Preparation 154 hexahydro-2H-1-benzopyran-2, 4(3H) -dione (formula DDDD-2, where n is 1), see Table DDDD.

A solution of 0.42g of platinum oxide and 1.66g of the compound of formula DDDD-1 (where n is 1) in 100mL of acetic acid was placed in a Parr hydrogenator at an initial hydrogen pressure of 50psi for 1.5 hours. The reaction mixture was then filtered through celite and concentrated in vacuo to give a beige solid. Flash column chromatography on silica gel 60(230-400 mesh) purified the crude product with 0.94g of the title compound as a white solid eluting with 0-5% methanol/chloroform.

The physical properties were as follows:

¹H NMR(CDCl₃) δ 4.84-4.80，3.54，3.40，2.60-2.53，2.08-2.02，1.79-1.65，1.62-1.54，1.44-1.40ppm.

¹³C NMR(CDCl₃) δ 203.0，167.4，74.3，47.7，45.6，29.1，23.5，23.2，19.7ppm.

IR (mineral oil) 3092, 2768, 2714, 2695, 2662, 1657, 1614, 1577, 1444, 1352, 1345, 1340, 1323, 1308, 1295, 1287, 1260, 1244, 1211, 1188, 1057, 1004, 938, 909, 890, 843, 832, 600cm ^-1.

EI-MS：[M+]＝168.

Elemental analysis found: c, 64.16; h, 7.16

Preparation of 1554 a, 5, 6, 7, 8, 8 a-hexahydro-4-hydroxy-3- [1- (3-nitrophenyl) propyl]-2H-1-benzopyran-2-one (formula DDDD-4, wherein n is 1 and R₁Is ethyl) see table DDDD.

A solution of 3.17g of aluminum trichloride in 30mL of tetrahydrofuran was added to a solution of 2.00g of the title compound of preparation 154 and 1.82g of 3-nitrobenzaldehyde in 20mL of tetrahydrofuran. The resulting mixture was stirred at room temperature for 2.5 hours, at which point 7.28g of sodium carbonate decahydrate were added and the reaction mixture was stirred for an additional 20 minutes. The mixture was then dried over magnesium sulfate, filtered through celite and concentrated in vacuo to give 6.05g of a yellow gum. The crude product was immediately dissolved in 50mL of tetrahydrofuran containing 0.73g of cuprous bromide-dimethyl sulfide complex, and 13.1mL of 1.0M solution of triethylaluminum in hexane was added to the mixture. After stirring at room temperature for 1 hour, the reaction was terminated by adding water, and the resulting mixture was partitioned between ether and water. The organic layer was separated, washed with brine and concentrated in vacuo to give 4.0g of a yellow oil. The crude product was purified by flash column chromatography eluting with 10-50% ethyl acetate/hexane to give 0.63g of the title compound as a yellow foam.

The physical properties were as follows:

MP86-91℃

IR (mineral oil) 3085, 1635, 1569, 1528, 1448, 1394, 1365, 1349, 1325, 1307, 1288, 1270, 1251, 1244cm^-1.

Example 3705-cyano-N- [3-1- (4a, 5, 6, 7, 8, 8 a-hexahydro-4-hydroxy-2-oxo-2H-1-benzopyran-3-yl) propyl]Phenyl radical]-2-pyridinesulfonamide (formula DDDD-7, wherein n is 1, R)₁Is ethyl, R₂Is 5-cyano-2-pyridyl), see table DDDD.

A solution of 0.63g of the title compound of preparation 155 and 0.3g of 10% palladium on charcoal in 50mL of ethanol was placed in a Parr hydrogenator at an initial hydrogen pressure of 50psi for 3 hours. The reaction mixture was then filtered through celite and concentrated in vacuo to give 0.519g of crude intermediate. 0.25g of the intermediate is immediately dissolved in 5mL of dichloromethane and 0.168g 5-cyano-2-pyridinesulfonyl chloride and 0.134mL pyridine are added to the solution. The resulting mixture was stirred at room temperature for 18 hours. Flash column chromatography on silica gel 60(230-400 mesh) was carried out and the reaction mixture was purified by eluting with 0-2.5% methanol/chloroform to give 0.164g of the title compound as a white foam.

The physical properties were as follows:

MP 122-125℃

HRMS found: 468.1611

Example 3714-cyano-N- [3-1- (4a, 5, 6, 7, 8, 8 a-hexahydro-4-hydroxy-2-oxo-2H-1-benzopyran-3-yl) propyl ]Phenyl radical]Benzenesulfonamides (of the formula DDDD-7, where n is 1, R₁Is ethyl, R₂Is 4-cyanophenyl) see table DDDD.

Following the general method of example 370, with non-critical changes, substituting only 4-cyanobenzene sulfonyl chloride for 5-cyano-2-pyridine sulfonyl chloride, 0.236g of the title compound is obtained as a white foam.

The physical properties were as follows:

MP 127-130℃

HRMS found: 466.1583

Preparation 1564-hexahydrocyclohepta [ b ] pyran-2, 4(3H, 4aH) -dione (formula DDDD-2, where n is 2), see Table DDDD.

Following the general procedure for preparation 154, and making non-critical changes, only the cycloheptylpyrone of formula DDDD-1 (where n is 2) was used in place of the cyclohexylpyrone of formula DDDD-1 (where n is 1) to give 0.337g of the title compound as a white solid.

The physical properties were as follows:

¹H NMR CDCl₃) δ 4.97-4.91，3.52，3.42，2.64-2.58，2.22-2.11，2.01-1.72，1.59-1.36ppm.

¹³C NMR(CDCl₃) δ 203.0，167.2，78.0，52.1，46.5，32.1，28.6，27.1，25.7，21.3ppm.

IR (mineral oil) 3074, 2791, 2755, 2736, 2687, 2637, 2608, 2585, 1655, 1625, 1586, 1500, 1480, 1443, 1333, 1324, 1293(s), 1265, 1254, 1240, 1222, 1196, 1173, 1082, 1053, 1016, 909, 889, 832, 611cm^-1.

EI-MS：[M+]＝182.

Elemental analysis found: c, 66.16; h, 7.90

Preparation of 1575, 6, 7, 8, 9, 9 a-hexahydro-4-hydroxy-3- [1- (3-nitrophenyl) propyl group]-cyclohepta [ b ]]Pyran-2 (4aH) -one (formula DDDD-4, wherein n is 2 and R₁Is ethyl) see table DDDD.

Following the general procedure of preparation 155 with non-critical changes, substituting only the title compound of preparation 156 for the title compound of preparation 154, 2.5g of the title compound were obtained as a yellow foam.

The physical properties were as follows:

MP75-78℃

IR (mineral oil) 3071, 2667, 1638, 1528, 1395, 1350, 1305, 1276, 1250, 1143, 1130, 1120, 1100, 1066, 782, 764, 741, 697, 685cm^-1.

HRMS found: 345.1590

Elemental analysis found: c, 58.74; h, 5.63; and N, 3.48.

Example 3725-cyano-N- [3- [1- (2, 4a, 5, 6, 7, 8, 9, 9 a-octahydro-4-hydroxy-2-oxocyclohepta [ b ]]Pyran-3-yl) propyl]Phenyl radical]-2-pyridinesulfonamide (formula DDDD-7, wherein n is 2, R)₁Is ethyl, R₂Is 5-cyano-2-pyridyl), see table DDDD.

Following the general method of example 370, with non-critical changes, substituting only the title compound of preparation 157 for the title compound of preparation 155, 0.206g of the title compound was obtained as a white foam.

The physical properties were as follows:

MP163-166℃

IR (mineral oil) 3352, 3128, 3100, 3073, 3029, 1760, 1726, 1641, 1608, 1593.1584, 1411, 1397, 1355, 1295, 1282, 1242, 1207, 1173, 1125, 1106, 1086, 1074, 1028, 974, 967, 721, 701, 645, 638cm ^-1

HRMS found: 481.1693

Preparation of 158 octahydro-2H-cycloocta [ b ] pyran-2, 4(3H) -dione (formula DDDD-2, where n is 3), see Table DDDD.

Following the general procedure for preparation 154, and making non-critical changes, only cyclooctylpyranone of formula DDDD-1 (where n ═ 3) was used in place of cycloheptylpyranone of formula DDDD-1 (where n ═ 2) to afford 1.72g of the title compound as a white solid.

The physical properties were as follows:

¹H NMR(CDCl₃) δ 4.84-4.78，3.61，3.40，2.75-2.70，2.14-1.97，1.90-1.72，1.68-1.44ppm.

¹³C NMR(CDCl₃) δ 204.2，167.2，78.2，49.5，46.1，28.5，27.3，26.2，24.7，23.9，22.1ppm.

IR (mineral oil) 2659, 2617, 1650, 1612, 1579, 1444, 1356, 1332, 1307, 1287, 1265, 1244, 1227, 1209, 1041, 1035, 1003, 962, 946, 860, 832, 824cm^-1.

HRMS found: 196.1100

Elemental analysis found: c, 67.06; h, 8.23.

Preparation 1593- [2, 2-dimethyl-1- (3-nitrophenyl) propyl]-4a, 5, 6, 7, 8, 9, 10, 10 a-octahydro-4-hydroxy-2H-cycloocta [ b]Pyran-2-one (formula DDDD-4, wherein n is 3 and R₁Is t-butyl), see table DDDD.

A solution of 1.36g of aluminum trichloride in 30mL of tetrahydrofuran was added to a solution of 1.0g of the title compound of preparation 158 and 0.77g of 3-nitrobenzaldehyde in 20mL of tetrahydrofuran. The resulting mixture was stirred at room temperature for 2.3 hours, at which point 3.06g of sodium carbonate decahydrate were added and the reaction mixture was stirred for a further 15 minutes. The mixture was then dried over magnesium sulfate, filtered through celite and concentrated in vacuo to give a yellow foam. The crude product was immediately dissolved in 5mL tetrahydrofuran for the second step.

A dry flask was charged with a solution of 0.82g of activated zinc, 3mL of tetrahydrofuran, 0.035mL of dibromomethane and 0.21mL of 1M of trimethylchlorosilane in tetrahydrofuran. After the addition of the various reagents was complete, the mixture was sonicated at 45 ℃ for 15 minutes. The mixture was further diluted by the addition of 2mL of tetrahydrofuran and 1.32mL of tert-butyl iodide was added dropwise. The resulting mixture was sonicated at 45 ℃ for 3 hours. A mixture of 0.85g of copper (I) cyanide and 0.80g of lithium chloride in 4mL of tetrahydrofuran was stirred at room temperature for 1 hour until near homogeneous phase and then cooled to-30 ℃. The organozinc solution was then added to the cuprous cyanide solution via cannula and the resulting mixture was warmed to 0 ℃ and stirred for 15 minutes. The reaction mixture was then cooled to-78 ℃ and a solution of the crude intermediate prepared above was added. After stirring at-78 ℃ for 20 minutes and 0 ℃ for 30 minutes, the reaction was quenched with saturated aqueous ammonium chloride and diluted with a further 60mL of tetrahydrofuran. The organic layer was separated, washed with water and concentrated in vacuo to give 2.17g of an orange foam. The crude product was then purified by flash column chromatography eluting with 10-30% ethyl acetate/hexane followed by recrystallization from dichloromethane/hexane to yield 0.60g of the title compound as a yellow solid.

The physical properties were as follows:

MP158-161℃

IR (mineral oil) 3077, 2646, 1632, 1599, 1529, 1477, 1450, 1396, 1357, 1349, 1334, 1317, 1283, 1273, 1252, 1232, 1217, 1205, 1181cm^-1.

Example 3735-cyano-N- [3- [2, 2-dimethyl-1- (4a, 5, 6, 7, 8, 9, 10, 10 a-octahydro-4-hydroxy-2-oxo-2H-cycloocta [ b)]Pyran-3-yl) propyl]Phenyl radical]-2-pyridinesulfonamide (formula DDDD-7, wherein n is 2, R)₁Is tert-butyl, R₂Is 5-cyano-2-pyridyl), see table DDDD.

Following the general method of example 370, with non-critical changes, substituting only the title compound of preparation 159 for the title compound of preparation 157, 0.034g of the title compound was prepared as white crystals.

The physical properties were as follows:

MP182-185℃

IR (mineral oil)

3246，3121，3098，2615，1655，1633，1607，1585，1575，1491，1411，1395，1354，1335，1322，1311，1298，1281，1275，1262，1255，1233，1206，1178，1121，1109，1028，977，702，657，646，635，605cm^-1.

HRMS found: 524.2216

Elemental analysis found: c, 63.86; h, 6.41; and N, 7.82.

Preparation of 160 (3(3R), 4S) -3- [2- [1- [3- [ bis (phenylmethyl) amino]Phenyl radical]Propyl radical]-5-hydroxy-]3-dioxo-5- (2-phenylethyl) octyl]-4-phenyl-2-oxazolidinone (formula W-10 wherein R₁Is 2-phenylethyl) with reference to table W.

5.0g of the title compound of preparation 95 (W-8) was added to 100mL of dichloromethane and the resulting solution was cooled to-78 ℃ under a nitrogen atmosphere. To this solution was added 1.0ml of TiCl ₄And 1.63mL of diisopropylethylamine, and the resulting solution was stirred for 1 hour. Then, 3.30 gl-phenyl-3-hexanone was added and the reaction temperature was raised to 0 ℃ for 2.5 hours. The reaction was terminated by adding a saturated ammonium chloride solution, and the mixture was extracted with dichloromethane. The organic extracts were washed with saturated sodium bicarbonate solution and evaporated in vacuo to give 9.7g of a yellow oil. Column chromatography on 900g silica gel (10% hexane-dichloromethane, 100% dichloromethane elution) afforded 3.30g of the title compound as a yellow foam.

The physical properties were as follows:

¹H NMR(CDCl₃) δ 7.33-7.23，7.14，7.04，6.61-6.50，5.45，5.22，4.71，4.60，4.48，4.26，3.33，3.15-3.03，2.58，2.47-2.31，1.93，1.40-1.28，1.24-1.13，1.11-0.96，0.88-0.77，0.62-0.57ppm.

MP121-126℃.

¹³C NMR(CDCl₃) δ 167.2，167.1，153.7，142.6，141.0，138.2，138.1，129.6，129.5，129.2，128.9，128.8，128.6，128.4，128.3，127.0，125.8，125.6，125.6，73.1，70.0，69.9，63.9，57.9，54.8，54.7，51.5，51.4，48.3，41.3，41.0，40.8，40.5，29.8，29.6，27.1，26.9，16.8，16.6，14.6，11.7，11.6ppm.

IR (mineral oil) 3525, 3061, 3026, 1777, 1720, 1690, 1601, 1495, 1361, 1335, 1238, 1199, 1104, 735, 698cm^-1.

EI-MS：[M+]＝736.

Elemental analysis found: c, 78.03; h, 7.11; n, 3.79

Preparation of 161 (3S) -3- [1- [ 3-bis (phenylmethyl) amino]Phenyl radical]Propyl radical]-5, 6-dihydro-4-hydroxy-6- (2-phenylethyl) -6-propyl-pyran-2-one (formula W-11 wherein R is₁Is 2-phenylethyl) with reference to table W.

2.7g of the title compound of preparation 160 were added to 5mL of dry tetrahydrofuran and the resulting solution was cooled to 0 ℃ under a nitrogen atmosphere. To this solution was added 0.45mL of 1M solution of potassium tert-butoxide in tetrahydrofuran. The reaction mixture was then warmed to 20 ℃ and stirred for 2 hours. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with water, dried and evaporated in vacuo to give 0.28g of a yellow oil. Column chromatography on 80g silica gel (10-30% acetone/hexanes elution) gave 0.195g of yellow foam. Recrystallization from ethyl acetate/hexane gave 0.146g of the title compound.

The physical properties were as follows:

MP 128-131℃

¹H NMR(CDCl₃) δ 7.35-7.12，6.73-6.64，5.84，4.73-4.57，4.12，2.69-2.61，2.38-2.20，1.95-1.65，1.41-1.32，0.98-0.87ppm.

¹³C NMR(CDCl₃) δ 204.1，204.0，171.7，171.4，169.6，140.9，140.8，140.6，140.5，140.4，139.9，139.8，138.3，129.7，129.6，129.5，128.9，128.6，128.5，128.4，128.2，128.1，127.1，126.9，126.8，126.7，126.5，126.4，126.3，126.2，126.0，125.9，116.8，112.6，112.5，112.4，112.3，112.2，112.1.112.0，.82.0，81.9，81.8，80.4，80.3，58.6，58.5，54.5，51.4，50.4，50.1，49.9，47.8，47.4，47.0，46.6，43.0，42.9，42.2，41.9，40.2，40.1，40.0，39.2，29.8，29.7，29.6，29.1，29.0，26.8，26.7，24.7，24.6，24.3，16.9，16.5，14.0，12.3ppm.

IR (mineral oil) 3023, 1637, 1599, 1584, 1575, 1494, 1347, 1300, 1257, 1243, 1234, 920, 731, 704, 695cm^-1.

EI-MS：[M+]＝573.

[a]_D(CHCl₃)＝-83°

Elemental analysis found: c, 81.53; h, 7.82; and N, 2.34.

Preparation 162 (3S) -3- [1- (3-aminophenyl) propyl]-5, 6-dihydro-4-hydroxy-6- (2-phenylethyl) -6-propyl-pyran-2-one (formula W-12, wherein R is₁Is 2-phenylethyl) with reference to table W.

0.63g of the title compound of preparation 161 was dissolved in 45mL of ethyl acetate and 15mL of methanol. To this solution was added 0.47g of 10% Pd/C and the resulting mixture was hydrogenated at 50psi for 2.5 hours. The reaction mixture was then filtered through celite and concentrated in vacuo to give 0.466g of a beige foam. Column chromatography on 80g silica gel (20-50% ethyl acetate-hexanes elution) afforded 0.389g of the title compound as a beige solid.

The physical properties were as follows:

MP 155-159℃.

¹H NMR(CD₃OD) δ 7.26-7.20，7.15-7.04，6.95，6.81，6.74，6.54-6.51，3.98-3.91，2.68-2.54，2.25-2.17，2.02-1.67，1.43-1.28，0.99-0.87ppm.

¹³C NMR(CD₃OD)δ 171.2，171.0，148.5，148.2，143.9，130.4，130.2，127.8，120.8，117.8，115.3，107.4，82.7，44.6，44.4，41.8，41.7，41.5，38.4，3 1.8，26.8，26.7，18.8，15.6，14.3ppm.

IR (mineral oil) 3085, 3061, 3026, 1617, 1605, 1495, 1314, 1258, 1168, 1119, 1065, 1030, 923, 776, 699cm^-1.

EI-MS：[M+]＝393.

Elemental analysis found: c, 76.13; h, 8.16; n, 3.37

[α]_D(MeOH)＝-41 °

Example 374N- [3- [1- (S) - [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6-propyl-2H-pyran-3-yl]Propyl radical]Phenyl radical]-5- (trifluoromethyl) -2-pyridinesulfonamide (formula W-13, wherein R is ₁Is 2-phenylethyl) with reference to table W.

To a solution of 0.200g of the title compound of preparation 162 in 5mL of dichloromethane was added 0.12mL of pyridine. The resulting mixture was cooled to 0 ℃ and 0.132g 5-trifluoromethylpyridine-2-sulfonyl chloride was added. The reaction mixture was then stirred at room temperature for 1.5 hours, concentrated in vacuo and partitioned between ethyl acetate and water. The organic layer was concentrated in vacuo to give 0.39g of a pink oil. Column chromatography on 50g silica gel (20-50% ethyl acetate in hexanes) afforded 0.252g of the title compound as a white foam.

The physical properties were as follows:

MP 170-173℃.

¹H NMR(CD₃OD) δ 8.95-8.92，8.23-8.16，8.04-8.00，7.25-6.90，4.86，3.98-3.90，3.31，3.30，2.69-2.46，2.18-2.09，1.96-1.65，1.41-1.28，0.99-0.81ppm.

¹³C NMR(CD₃OD) δ 167.3，147.7，147.5，142.9，142.8，137.7，137.0，129.5，129.2，126.9，126.2，126.1，124.1，122.6，122.5，120.3，120.2，81.8，81.7，43.6，43.2，40.9，40.5，37.5，30.9，25.8，25.6，17.9，14.7，13.3，13.2ppm.

IR (mineral oil) 3087, 3027, 1642, 1606, 1595, 1327, 1260, 1173, 1142, 1110, 1074, 1016, 720, 700, 613cm^-1.

FAB-MS：[M+H]＝603.

Elemental analysis found: c, 61.79; h, 5.86; n, 4.48; s, 5.16

[α]_D(MeOH)＝-31 °

Preparation of 163 (3S, 6R) -3- [1- [ 3-bis (phenylmethyl) amino ] phenyl ] propyl ] -5, 6-dihydro-4-hydroxy-6- (2-phenylethyl) -6-propyl-pyran-2-one (formula FFF-2) see Table FFF.

The title compound of preparation 161 was chromatographed on a 5.1X 30cm Cyclobond I2000 column in ice bath, 90mg per injection, using an automatic chromatographic system, with the mobile phase being acetonitrile containing 0.1% diethylamine and 0.05 glacial acetic acid (V/V). The eluate was monitored at 260nm at a flow rate of 45mL/min, and the appropriate fractions from multiple injections were combined and concentrated in vacuo to give 0.300g of a black oil. The oil was partitioned between ethyl acetate, saturated aqueous sodium bicarbonate and water. The organic layer was separated and concentrated in vacuo. Column chromatography on 50g silica gel (10-20% acetone in hexanes) afforded 0.22g of the title compound as a colorless oil.

The physical properties were as follows:

the residence time of the title compound was 57 minutes.

Preparation of 164 (3S, 6S) -3- [1- [ 3-bis (phenylmethyl) amino ] phenyl ] propyl ] -5, 6-dihydro-4-hydroxy-6- (2-phenylethyl) -6-propyl-pyran-2-one (formula FFF-3), see Table FFF.

The title compound of preparation 161 was isolated as described above for preparation 163. Further purification as described in preparation 163 gave 0.117g of the title compound as a colorless oil.

The physical properties were as follows:

the residence time of the title compound was 66 minutes.

Preparation 165 (3S, 6R) -3- [1- (3-aminophenyl) propyl ] -5, 6-dihydro-4-hydroxy-6- (2-phenylethyl) -6-propyl-pyran-2-one (formula FFF-4), see Table FFF.

Following the general procedure of preparation 162 with non-critical changes, substituting only the title compound of preparation 163 for the title compound of preparation 161, 0.022g of the title compound was prepared.

The physical properties were as follows:

¹H NMR(CD₃OD) δ 7.25-7.18，7.15-7.12，7.07-7.05，6.97，6.82-，6.76-6.71，6.53，4.00-3.92，2.67-2.54，2.29-2.15，2.06-1.92，1.90-1.62，1.46-1.28，0.97-0.88 ppm.

example 375 (3S, 6R) -N- [3- [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6-propyl-2H-pyran-3-yl ] propyl ] phenyl ] -5- (trifluoromethyl) -2-pyridinesulfonamide (formula FFF-5), cf.

Following the general method of example 374, with non-critical changes, substituting only the title compound of preparation 165 for the title compound of preparation 162, 0.024g of the title compound was obtained as a white foam.

The physical properties were as follows:

¹H NMR(CD₃OD) δ 8.90，8.20-8.17，8.02-7.99，7.28-6.88，4.00-3.90，2.71-2.46.2.20-2.10，1.98-1.67，1.41-1.28，0.98-0.81ppm.

example 376 (3S) -N- [3- [1- (5, 6-dihydro-4-hydroxy-2-oxo-6, 6-dipropyl-2H-pyran-3-yl) propyl ] phenyl ] -5- (trifluoromethyl) -2-pyridinesulfonamide (formula W-13) reference Table W.

182mg of the title compound of preparation 99 (formula W-12) was dissolved in 5mL of dichloromethane and 133. mu.L of pyridine was added. The reaction was cooled to 0 ℃ and 142mg of 5-trifluoromethyl-2-pyridinesulfonyl chloride was added. The reaction solution was stirred for 30 minutes, methylene chloride was distilled off, and the resulting substance was diluted with ethyl acetate. The organic solution was washed with water, brine and then dried over sodium sulfate. The solvent was distilled off to leave 580mg of a crude product. Chromatography on silica gel (50g) eluting with 50% ethyl acetate/hexanes provided 211mg of the desired compound as a white foam.

The physical properties were as follows:

elemental analysis found: c, 57.80; h, 5.95; n, 5.01; s, 5.64

[α]_D(18.094mg/2mL CHCl₃)＝-30°

Example 377 (3R) -N- [3- [1- (5, 6-dihydro-4-hydroxy-2-oxo-6, 6-dipropyl-2H-pyran-3-yl) propyl ] phenyl ] -5- (trifluoromethyl) -2-pyridinesulfonamide (formula X-13), see Table X.

170mg of the title compound of preparation 107 (formula X-12) was dissolved in 5mL of dichloromethane and 136. mu.L of pyridine was added. The reaction was cooled to 0 ℃ and 132mg of 5-trifluoromethyl-2-pyridinesulfonyl chloride was added. The reaction solution was stirred for 30 minutes, methylene chloride was distilled off, and the resulting substance was diluted with ethyl acetate. The organic solution was washed with water, brine and then dried over sodium sulfate. Evaporation of the solvent gave a crude product which was chromatographed on 50g silica gel, eluting with 50% ethyl acetate/hexane to give 225mg of the desired compound as a white foam.

The physical properties were as follows:

[α]_D(mg/2mL CHCl₃)＝+29°

preparation 166 (3S) (4R)3- [2- [1- [3- [ bis (phenylmethyl) amino ] phenyl ] propyl ] -5-hydroxy-1, 3-dioxo-5-phenethyloctyl ] -4-phenyl-2-oxazolidinone (formula X-10), see Table X.

To 1.12g of the title compound of preparation 104 was added 20mL of dichloromethane and the resulting solution was cooled to-78 ℃. To this solution was added 237. mu. LTiCl in sequence₄And 400. mu.L of ErisoPropyl ethylamine and the resulting solution was stirred at-78 ℃ for 1 hour. To the foregoing solution, 776 μ L of 1-phenyl-3-hexanone was added and stirring was continued at-40 ℃ for 40 minutes, after which the temperature was raised to-10 ℃ for 1.5 hours. The reaction was quenched by addition of saturated ammonium chloride solution, then extracted with dichloromethane and the organic extracts evaporated. The crude product was chromatographed on 200g of silica gel, eluting with 10% hexane/dichloromethane to give 870mg of the title compound.

The physical properties were as follows:

IR (mineral oil) 2956, 2926, 2854, 1777, 1600, 1494, 1452, 698cm^-1

[α]_D(16.578mg，CHCl₃)＝+4°

Mass spectrum: molecular ion peak 736

Elemental analysis found: c, 78.00; h, 7.14; and N, 3.61.

Preparation of 167 (3R)3- [1- [3- [ bis (phenylmethyl) amino]Phenyl radical]Propyl radical]-5, 6-dihydro-4-hydroxy-6-phenethyl-6-propyl-2H-pyran-2-one (formula X-11, wherein R is ₁Is phenethyl), see table X.

The title compound of preparation 166 (750mg) was added to 5mL dry THF and potassium tert-butoxide (1.0M in THF; 1.2mL) was added. The reaction mixture was stirred at 20 ℃ for 30 minutes and then saturated ammonium chloride solution was added to terminate the reaction. The reaction solution was extracted with ethyl acetate, the organic extracts were washed with water and brine and finally evaporated to give the crude product. Chromatography on 100g silica eluting with 15% ethyl acetate/hexanes provided 511mg of the title compound.

The physical properties were as follows:

IR (mineral oil) 2956, 2855, 1628, 1599, 1577, 1494, 1385, 1364 and 697cm^-1

Elemental analysis found: c, 81.30; h, 7.68; and N, 2.30.

Mass spectrum: molecular ion Peak 573

[α]_D(18.116mg/2mLCH₃OH)＝+38°

Preparation of 168 (3R)3- [1- [ 3-aminophenyl]Propyl radical]-5, 6-dihydro-4-hydroxy-6-phenethyl-6-propyl-2H-pyran-2-one (formula X-12, wherein R is₁Is phenethyl), see table X.

Dissolve preparation 167 of the title compound (370mg) in 35mL ethyl acetate and 6mL methanol. To this solution was added 200mg of 10% palladium on charcoal catalyst and the reaction was hydrogenated under 50psi of hydrogen for 2 hours. The reaction was evaporated and chromatographed on 60g of silica gel to give 244mg of the title compound.

The physical properties were as follows:

IR (mineral oil) 3025, 2954, 2871, 2854, 1635, 1619, 1604, 1494, 1456, 1383, 1378, 1256cm^-1

[α]_D(16.764mg/mL，CH₃OH)＝+39°

Mass spectrum: molecular ion peak 393

Elemental analysis found: c, 75.95; h, 8.05; and N, 3.27.

Example 378 (3R) -N- [3- [1- (5, 6-dihydro-4-hydroxy-2-oxo-6-propyl-6-phenethyl-2H-pyran-3-yl) propyl]Phenyl radical]-5- (trifluoromethyl) -2-pyridinesulfonamide (formula X-13, wherein R is₁Is phenethyl), see table X.

Prepare 168 (156mg) was added to 5mL of dichloromethane. To the solution was added 96. mu.L of pyridine and then the reaction was cooled to 0 ℃. To the foregoing solution was added 102mg 5-trifluoromethyl-2-pyridinesulfonyl chloride. The reaction was stirred for 1 hour and then poured into ethyl acetate, washed with water, brine and MgSO₄And (5) drying. The solvent was evaporated in vacuo and the resulting material was chromatographed on 100g silica gel, eluting with 50% ethyl acetate/hexane to give 200mg of the title compound.

The physical properties were as follows:

mass spectrum: molecular ion peak 602

IR (mineral oil)

2953，2922，2870，2853，1642，1605，1459，1457，1326，1259.1180，1171，1141cm^-1.

UV(EtOH)λ_max(ε)216(22300)，264 sh(10700)，270(11500)，279(12100)

Elemental analysis found: c, 57.53; h, 5.98; n, 4.84.

Example 379 (3R, 6S) -N- [3- [1- (5, 6-dihydro-4-hydroxy-2-oxo-6-propyl-6-phenethyl-2H-pyran-3-yl) propyl]Phenyl radical ]-5- (trifluoromethyl) -2-pyridinesulfonamide (formula X-13, wherein R is₁Is phenethyl), see table X.

The product of example 378 was added to isopropanol and injected onto a 0.46X 25cm Cyclobond I2000 column (Advanced separations technologies, Inc., Whippany, NJ). The column was located in an ice-water bath. The sample was eluted with acetonitrile containing 0.1% diethylamine and 0.6% glacial acetic acid (V/V) at 1.0 mL/min. The monitor was set at 250 nm. The first eluting diastereomer was identical to the compound of example 298. The second eluting diastereomer was purified on 60g silica gel eluting with 40% ethyl acetate/hexanes to give 13mg of the title compound.

The physical properties were as follows:

contrary to the stereochemistry at C-6 of the compound of example 298.

¹H-NMR(CD₃OD，δ)8.91，8.19，8.16，8.02，7.99，7.25，7.18，7.15，7.13，7.11，7.04，6.97，6.89，6.75，3.95，2.69，2.64，2.53，2.48，2.13，1.91，1.71，1.68，1.37，119，1.17，1.14，0.94，0.92.0.89，0.85.0.83.0.80.0.93.

Preparation 169 (3S) -3- [ (3-bis (phenylmethyl) amino) phenyl ] -4, 4-dimethylpentanoic acid methyl ester (formula LLL-9), see Table LLL.

Titanium tetrachloride (IV) (0.07mL) was added to anhydrous methanol (2mL) at room temperature. The resulting pale green solution was stirred for 2 hours, treated with a compound of formula LLL-2 (wherein R is phenyl, prepared by a similar method as described in Table FF) (100mg) and refluxed for 18 hours. The reaction mixture was cooled and partitioned between 1N HCl and ether. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification was by flash chromatography, eluting with hexane/ethyl acetate (95: 5) to give the title compound as a pale amber oil (58 mg).

The physical properties were as follows:

¹H NMR(CDCl₃) δ 7.32-7.20，7.04，6.61-6.48，4.61，3.48，2.85-2.80，2.72-2.55，0.75ppm

¹³C NMR(CDCl₃) δ 173.69，148.45，142.51，138.91，128.53，126.78，117.98，114.49，110.89，54.54，52.24，51.40，35.56，33.65，27.87ppm

MS(EI)m/z 415.

preparation of 170 (3S) -3- [ (3-bis (phenylmethyl) amino) phenyl ] -4, 4-dimethylpentanoic acid (formula LLL-10), see Table LLL.

A slurry of preparation 169 of the compound of formula LLL-9 (406mg) was formed in glacial acetic acid (2.6mL) and 6N sulfuric acid. The reaction mixture was refluxed for 5 hours. Cooled and partitioned between water and diethyl ether. The aqueous layer was separated and extracted twice with ether. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting light brown residue was dissolved in diethyl ether and treated with dicyclohexylamine (0.16mL) at 0 ℃. The solid was isolated, washed with diethyl ether and dried in vacuo. The light brown solid was suspended in diethyl ether and washed with 0.25N HCl. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a light brown amorphous solid (54 mg).

The physical properties were as follows:

¹H NMR(CDCl₃) δ 7.31-7.19，7.04，6.61-6.48，4.61，2.81-2.56，0.74ppm

¹³C NMR(CDCl₃) δ 179.15，148.56，142.28，138.83，128.55，128.23，126.76，117.90，114.49，110.98，54.51，51.83，35.45，33.67，27.84ppm

MS(EI)m/z 401.

preparation of 171N- [ (S) -4-benzyl-2-oxazolidinone ] 3-aminocinnamamide (formula HHH-4), see Table HHH.

In a 1L round bottom flask equipped with a nitrogen inlet and a loading funnel was charged 10.02g of commercially available (S) -4-benzyl-2-oxazolidone and 260mL of tetrahydrofuran, which was then cooled to-78 ℃. To the previous solution was added 37mL of n-butyllithium, during which time a white solid separated from the reaction solution. To this suspension was added 11.46g of trans-3-nitrocinnamoyl chloride (prepared by treating commercially available 3-nitrocinnamic acid with oxalyl chloride) dissolved in a small amount of THF. The resulting pale yellow homogeneous solution was warmed to room temperature, quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was separated, washed with brine and water, dried over magnesium sulfate, filtered and concentrated to give a reddish brown syrup (formula HHH-3, Table HHH) which was used without purification. The crude reaction mixture was added to a solution containing 64.18 g SnCl ₂.2H₂O in ethanol and the mixture was heated to reflux for 20 minutes. The reaction was cooled to room temperature and poured into ice. With saturated Na₂CO₃The mixture was adjusted to pH9-10 with aqueous solution. The mixture was filtered and the filter cake was washed thoroughly with ethyl acetate. The filtrate was washed with brine and the organic phase was dried (Na)₂SO₄) Filtered and concentrated in vacuo to give a yellow solid. Recrystallization from ethanol gave 11.56g of the title compound.

The physical properties were as follows:

IR (mineral oil) 3450, 3369, 2924, 1771, 1678, 1620, 1462, 1392, 1357, 1347, 1214cm^-1

[α]_D(14.418mg/mLCHCl₃)＝+51°

Preparation of 172N- [ (S) -4-benzyl-2-oxazolidinone ]3- (bis (benzyl) amino) cinnamamide (formula HHH-5), see Table HHH.

An amine of formula HHH-4 of preparation 172 (10.13g), 10.48g potassium carbonate, 8.3mL benzyl bromide and 100mL acetonitrile were heated to reflux for 3 hours. The reaction was cooled to room temperature and partitioned between water and ethyl acetate. The aqueous phase was extracted several more times with ethyl acetate. The combined ethyl acetate extracts were dried (Na)₂SO₄) Filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 25% ethyl acetate/hexane to give 8.87g of the title compound.

The physical properties were as follows:

¹³C-NMR(CDCl₃，ppm)165，153，149，147，138，135，129.6，129.3 128.8，128.6，127，126.9，126.5，116.54，116.50，114，113，65，55，54，37

IR (mineral oil):

2954，2870，2854，1776，1677，1616，1595，1493，1454，1353，1029，988cm^-1

preparation 173 (3S) (4S)3- [3- (3- (bis (phenylmethyl) aminophenyl) pentanoyl ] -4-phenyl-2-oxazolidinone (formula HHH-6), reference is made to Table W.

Copper (I) bromide dimethyl sulfide complex (1.69g), 20mL tetrahydrofuran and 10mL dimethyl sulfide were added to a 100mL three-necked flask equipped with a stir bar, a 25mL constant pressure addition funnel and a nitrogen inlet tube. The title compound of preparation 172 (2.747g) and 10mL of tetrahydrofuran were added to the addition funnel. The reaction mixture was cooled to-40 ℃ and ethyl magnesium bromide (5.5ml3.0M in ether) was added dropwise over 5 minutes. The resulting black mixture was stirred at-40 ℃ for a further 10 minutes and then warmed to-10 ℃. A solution of the title compound of preparation 172 in tetrahydrofuran was added dropwise to the reaction mixture over 17 minutes. The addition funnel was then rinsed with another 3mL of tetrahydrofuran and the reaction mixture was stirred at about-40 to-60 ℃ for 2.5 hours. The reaction was terminated by pouring the mixture into 50mL of a saturated aqueous ammonium chloride solution, and the organic solvent was distilled off by vacuum concentration. The resulting residue was partitioned between 75mL ethyl acetate and 50mL water and filtered through glass wool. The organic layer was separated, washed with 2X 100mL 10% ammonium hydroxide solution and 50mL brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give 3.59g of a yellow oil. Column chromatography on 150g silica gel (5-15% ethyl acetate in hexanes) afforded the two diastereomeric products. The title compound was isolated as a pale yellow oil (less polar diastereomer) 1.602 g.

The physical properties were as follows:

¹H NMR(CDCl₃) δ 7.32-7.17，7.06，6.60，6.55，4.63，4.43-4.37，4.00，3.85，3.37，3.20，3.08，3.02-2.92，2.62，1.7 1-1.48，0.73ppm]

0.310g of the more polar diastereomer was also isolated from the column as a pale yellow oil.

The physical properties were as follows:

¹H NMR(CDCl₃) δ 7.32-7.18，7.12，7.05，6.64-6.56，4.63，4.60-4.52，4.08-4.04.3.48-3.38，3.07-2.96，2.48，1.69-1.48，0.73ppm.

in addition, a fraction containing 0.708g of a mixture of less polar and more polar diastereomers in a ratio of about 1: 4 was collected from the column.

Preparation 174 (3S, 6S) -3- [1- (3-aminophenyl) propyl ] -5, 6-dihydro-4-hydroxy-6- (2-phenylethyl) -6-propyl-2H-pyran-2-one (formula FFF-6) is referenced in Table FFF.

Following the general procedure for preparation 162 with non-critical changes, only the title product of preparation [ U-141164] was used in place of the title compound of preparation 161 to give 0.040g of crude title compound. This compound was used directly in the next step without further purification.

Example 380 (3S, 6S) -N- [3- [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6-propyl-2H-pyran-3-yl ] propyl ] phenyl ] -5- (trifluoromethyl) -2-pyridinesulfonamide (formula FFF-7), see Table FFF.

Following the general method of example 374 with non-critical changes, substituting only the title product of preparation 174 for the title product of preparation 162, 0.015g of the title compound was obtained as a white foam.

The physical properties were as follows:

¹H NMR(CD₃OD) δ 8.95，8.25-8.21，8.07-8.02，7.25-6.93，3.94-3.88，2.70-2.51，2.20-2.18，1.97-1.66，1.40-1.30，0.92-0.81ppm.

thus, for example, the compounds of the present invention include the following stereoisomers:

5-cyano-N- [3- (R) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6- (R) - (3, 3, 3-trifluoropropyl) -2H-pyran-3-yl ] -2, 2-dimethylpropyl ] phenyl ] -2-pyridinesulfonamide,

5-cyano-N- [3- (S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6- (S) - (3, 3, 3-trifluoropropyl) -2H-pyran-3-yl ] -2, 2-dimethylpropyl ] phenyl ] -2-pyridinesulfonamide,

5-cyano-N- [3- (R) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6- (S) - (3, 3, 3-trifluoropropyl) -2H-pyran-3-yl ] -2, 2-dimethylpropyl ] phenyl ] -2-pyridinesulfonamide,

5-cyano-N- [3- (S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6- (R) - (3, 3, 3-trifluoropropyl) -2H-pyran-3-yl ] -2, 2-dimethylpropyl ] phenyl ] -2-pyridinesulfonamide,

n- [3- (R) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (R) - (2-phenylethyl) -6- (3, 3, 3-trifluoropropyl) -2H-pyran-3-yl ] -2, 2-dimethylpropyl ] phenyl ] -1-methyl-1H-imidazole-4-sulfonamide,

n- [3- (S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (S) - (2-phenylethyl) -6- (3, 3, 3-trifluoropropyl) -2H-pyran-3-yl ] -2, 2-dimethylpropyl ] phenyl ] -1-methyl-1H-imidazole-4-sulfonamide,

n- [3- (R) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (S) - (2-phenylethyl) -6- (3, 3, 3-trifluoropropyl) -2H-pyran-3-yl ] -2, 2-dimethylpropyl ] phenyl ] -1-methyl-1H-imidazole-4-sulfonamide,

N- [3- (S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (R) - (2-phenylethyl) -6- (3, 3, 3-trifluoropropyl) -2H-pyran-3-yl ] -2, 2-dimethylpropyl ] phenyl ] -1-methyl-1H-imidazole-4-sulfonamide,

5-amino-N- [3- (R) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6- (R) - (3, 3, 3-trifluoropropyl) -2H-pyran-3-yl ] -2, 2-dimethylpropyl ] phenyl ] -2-pyridinesulfonamide,

5-amino-N- [3- (R) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6- (S) - (3, 3, 3-trifluoropropyl) -2H-pyran-3-yl ] -2, 2-dimethylpropyl ] phenyl ] -2-pyridinesulfonamide,

5-amino-N- [3- (S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6- (R) - (3, 3, 3-trifluoropropyl) -2H-pyran-3-yl ] -2, 2-dimethylpropyl ] phenyl ] -2-pyridinesulfonamide,

5-amino-N- [3- (S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6- (S) - (3, 3, 3-trifluoropropyl) -2H-pyran-3-yl ] -2, 2-dimethylpropyl ] phenyl ] -2-pyridinesulfonamide,

n- [3- (R) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) - [6- (R) -propyl) -2H-pyran-3-yl ] -2, 2-dimethylpropyl ] phenyl ] -2-pyridinesulfonamide,

n- [3- (R) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) - [6- (S) -propyl) -2H-pyran-3-yl ] -2, 2-dimethylpropyl ] phenyl ] -2-pyridinesulfonamide,

N- [3- (S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) - [6- (R) -propyl) -2H-pyran-3-yl ] -2, 2-dimethylpropyl ] phenyl ] -2-pyridinesulfonamide,

n- [3- (S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) - [6- (S) -propyl) -2H-pyran-3-yl ] -2, 2-dimethylpropyl ] phenyl ] -2-pyridinesulfonamide,

5-trifluoromethyl-N- [3- (R) - [1- [ 4-hydroxy-2-oxo-6, 6-di-N-propyl-5, 6-dihydro-2H-pyran-3-yl ] -propyl ] phenyl ] -2-pyridinesulfonamide,

5-trifluoromethyl-N- [3- (S) - [1- [ 4-hydroxy-2-oxo-6, 6-di-N-propyl-5, 6-dihydro-2H-pyran-3-yl ] -propyl ] phenyl ] -2-pyridinesulfonamide,

4-trifluoromethyl-N- [3- (R) - [1- [ 4-hydroxy-2-oxo-6, 6-di-N-propyl-5, 6-dihydro-2H-pyran-3-yl ] -propyl ] phenyl ] -2-pyridinesulfonamide,

4-trifluoromethyl-N- [3- (S) - [1- [ 4-hydroxy-2-oxo-6, 6-di-N-propyl-5, 6-dihydro-2H-pyran-3-yl ] -propyl ] phenyl ] -2-pyridinesulfonamide,

5-trifluoromethyl-N- [3- (R) - [1- [ 4-hydroxy-2-oxo-6, 6-di-N-propyl-5, 6-dihydro-2H-pyran-3-yl ] -2, 2-dimethylpropyl ] phenyl ] -2-pyridinesulfonamide,

5-trifluoromethyl-N- [3- (S) - [1- [ 4-hydroxy-2-oxo-6, 6-di-N-propyl-5, 6-dihydro-2H-pyran-3-yl ] -2, 2-dimethylpropyl ] phenyl ] -2-pyridinesulfonamide,

5-trifluoromethyl-N- [3- (R) - [1- [ 4-hydroxy-2-oxo-6, 6-di-phenethyl-5, 6-dihydro-2H-pyran-3-yl ] -propyl ] phenyl ] -2-pyridinesulfonamide,

5-trifluoromethyl-N- [3- (S) - [1- [ 4-hydroxy-2-oxo-6, 6-di-phenethyl-5, 6-dihydro-2H-pyran-3-yl ] -propyl ] phenyl ] -2-pyridinesulfonamide,

4-trifluoromethyl-N- [3- (R) - [1- [ 4-hydroxy-2-oxo-6, 6-di-phenethyl-5, 6-dihydro-2H-pyran-3-yl ] -propyl ] phenyl ] -2-pyridinesulfonamide,

4-trifluoromethyl-N- [3- (S) - [1- [ 4-hydroxy-2-oxo-6, 6-di-phenethyl-5, 6-dihydro-2H-pyran-3-yl ] -propyl ] phenyl ] -2-pyridinesulfonamide,

4-trifluoromethyl-N- [3- (R) - [1- [ 4-hydroxy-2-oxo-6, 6-di-N-propyl-5, 6-dihydro-2H-pyran-3-yl ] -2, 2-dimethylpropyl ] phenyl ] -2-pyridinesulfonamide,

4-trifluoromethyl-N- [3- (S) - [1- [ 4-hydroxy-2-oxo-6, 6-di-N-propyl-5, 6-dihydro-2H-pyran-3-yl ] -2, 2-dimethylpropyl ] phenyl ] -2-pyridinesulfonamide,

5-trifluoromethyl-N- [3(R) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (R) - (2-phenylethyl) -6(R) -N-propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl ] -phenyl ] -2-pyridinesulfonamide,

5-trifluoromethyl-N- [3(R) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (S) - (2-phenylethyl) -6(S) -N-propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl ] -phenyl ] -2-pyridinesulfonamide,

5-trifluoromethyl-N- [3(S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (R) - (2-phenylethyl) -6(R) -N-propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl ] -phenyl ] -2-pyridinesulfonamide,

5-trifluoromethyl-N- [3(S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (S) - (2-phenylethyl) -6(S) -N-propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl ] -phenyl ] -2-pyridinesulfonamide,

4-trifluoromethyl-N- [3(R) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (R) - (2-phenylethyl) -6(R) -N-propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl ] -phenyl ] -2-pyridinesulfonamide,

4-trifluoromethyl-N- [3(R) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (S) - (2-phenylethyl) -6(S) -N-propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl ] -phenyl ] -2-pyridinesulfonamide,

4-trifluoromethyl-N- [3(S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (R) - (2-phenylethyl) -6(R) -N-propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl ] -phenyl ] -2-pyridinesulfonamide,

4-trifluoromethyl-N- [3(S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (S) - (2-phenylethyl) -6(S) -N-propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl ] -phenyl ] -2-pyridinesulfonamide,

5-trifluoromethyl-N- [3(R) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (R) - (2-phenylethyl) -6(R) -N-propyl-2H-pyran-3-yl ] -propyl ] -phenyl ] -2-pyridinesulfonamide,

5-trifluoromethyl-N- [3(R) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (S) - (2-phenylethyl) -6(S) -N-propyl-2H-pyran-3-yl ] -propyl ] -phenyl ] -2-pyridinesulfonamide,

5-trifluoromethyl-N- [3(S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (R) - (2-phenylethyl) -6(R) -N-propyl-2H-pyran-3-yl ] -propyl ] -phenyl ] -2-pyridinesulfonamide,

5-trifluoromethyl-N- [3(S) - [1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (S) - (2-phenylethyl) -6(S) -N-propyl-2H-pyran-3-yl ] -propyl ] -phenyl ] -2-pyridinesulfonamide,

5-cyano-N- [3(R) - (1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (R) - (2-phenylethyl) -6-propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl) -phenyl ] -2-pyridinesulfonamide,

5-cyano-N- [3(R) - (1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (S) - (2-phenylethyl) -6-propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl) -phenyl ] -2-pyridinesulfonamide,

5-cyano-N- [3(S) - (1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (R) - (2-phenylethyl) -6-propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl) -phenyl ] -2-pyridinesulfonamide,

5-cyano-N- [3(S) - (1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (S) - (2-phenylethyl) -6-propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl) -phenyl ] -2-pyridinesulfonamide,

N- [3(R) - [1- (5, 6-dihydro-4-hydroxy-2-oxo-6 (R) - [ 2-phenylethyl ] -6-propyl-2H-pyran-3-yl) -2, 2-dimethylpropyl ] -phenyl ] -1-methyl-1H-imidazole-4-sulfonamide,

n- [3(R) - [1- (5, 6-dihydro-4-hydroxy-2-oxo-6 (S) - [ 2-phenylethyl ] -6-propyl-2H-pyran-3-yl) -2, 2-dimethylpropyl ] -phenyl ] -1-methyl-1H-imidazole-4-sulfonamide,

n- [3(S) - [1- (5, 6-dihydro-4-hydroxy-2-oxo-6 (R) - [ 2-phenylethyl ] -6-propyl-2H-pyran-3-yl) -2, 2-dimethylpropyl ] -phenyl ] -1-methyl-1H-imidazole-4-sulfonamide,

n- [3(S) - [1- (5, 6-dihydro-4-hydroxy-2-oxo-6 (S) - [ 2-phenylethyl ] -6-propyl-2H-pyran-3-yl) -2, 2-dimethylpropyl ] -phenyl ] -1-methyl-1H-imidazole-4-sulfonamide,

5-amino-N- [3(R) - (1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (S) - (2-phenylethyl) -6-propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl) phenyl ] -2-pyridinesulfonamide,

5-amino-N- [3(S) - (1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (R) - (2-phenylethyl) -6-propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl) phenyl ] -2-pyridinesulfonamide,

5-amino-N- [3(S) - (1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (S) - (2-phenylethyl) -6-propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl) phenyl ] -2-pyridinesulfonamide,

5-amino-N- [3(R) - (1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (R) - (2-phenylethyl) -6-propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl) phenyl ] -2-pyridinesulfonamide,

5-amino-N- [3(R) - (1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (R) - (2-phenylethyl) -6-propyl-2H-pyran-3-yl ] propyl) phenyl ] -2-pyridinesulfonamide,

5-amino-N- [3(R) - (1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (S) - (2-phenylethyl) -6-propyl-2H-pyran-3-yl ] propyl) phenyl ] -2-pyridinesulfonamide,

5-amino-N- [3(S) - (1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (R) - (2-phenylethyl) -6-propyl-2H-pyran-3-yl ] propyl) phenyl ] -2-pyridinesulfonamide,

5-amino-N- [3(S) - (1- [5, 6-dihydro-4-hydroxy-2-oxo-6 (S) - (2-phenylethyl) -6-propyl-2H-pyran-3-yl ] propyl) phenyl ] -2-pyridinesulfonamide,

5-amino-N- [3(R) - (1- [6(R) - (2- [ 4-fluorophenyl ] ethyl) -5, 6-dihydro-4-hydroxy-2-oxo-6-propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl) phenyl ] -2-pyridinesulfonamide,

5-amino-N- [3(R) - (1- [6(S) - (2- [ 4-fluorophenyl ] ethyl) -5, 6-dihydro-4-hydroxy-2-oxo-6-propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl) phenyl ] -2-pyridinesulfonamide,

5-amino-N- [3(S) - (1- [6(R) - (2- [ 4-fluorophenyl ] ethyl) -5, 6-dihydro-4-hydroxy-2-oxo-6-propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl) phenyl ] -2-pyridinesulfonamide,

5-amino-N- [3(S) - (1- [6(S) - (2- [ 4-fluorophenyl ] ethyl) -5, 6-dihydro-4-hydroxy-2-oxo-6-propyl-2H-pyran-3-yl ] -2, 2-dimethylpropyl) phenyl ] -2-pyridinesulfonamide,

n- [3(R) - (1- [5, 6-dihydro-6, 6-dipropyl-4-hydroxy-2-oxo-2H-pyran-3-yl ] -2, 2-dimethylpropyl) phenyl ] -1-methyl-1H-imidazole-4-sulfonamide,

n- [3(S) - (1- [5, 6-dihydro-6, 6-dipropyl-4-hydroxy-2-oxo-2H-pyran-3-yl ] -2, 2-dimethylpropyl) phenyl ] -1-methyl-1H-imidazole-4-sulfonamide,

5-amino-N- [3(R) - (1- [5, 6-dihydro-6, 6-dipropyl-4-hydroxy-2-oxo-2H-pyran-3-yl ] -2, 2-dimethylpropyl) phenyl ] -2-pyridinesulfonamide,

5-amino-N- [3(S) - (1- [5, 6-dihydro-6, 6-dipropyl-4-hydroxy-2-oxo-2H-pyran-3-yl ] -2, 2-dimethylpropyl) phenyl ] -2-pyridinesulfonamide,

5-cyano-N- [3(R) - (1- [5, 6-dihydro-6, 6-dipropyl-4-hydroxy-2-oxo-2H-pyran-3-yl ] -2, 2-dimethylpropyl) phenyl ] -2-pyridinesulfonamide,

5-cyano-N- [3(S) - (1- [5, 6-dihydro-6, 6-dipropyl-4-hydroxy-2-oxo-2H-pyran-3-yl ] -2, 2-dimethylpropyl) phenyl ] -2-pyridinesulfonamide,

n- [3(R) - (1- [6, 6-bis (2-phenylethyl) -5, 6-dihydro-4-hydroxy-2-oxo-2H-pyran-3-yl ] propyl) phenyl ] -1-methyl-1H-imidazole-4-sulfonamide,

N- [3(S) - (1- [6, 6-bis (2-phenylethyl) -5, 6-dihydro-4-hydroxy-2-oxo-2H-pyran-3-yl ] propyl) phenyl ] -1-methyl-1H-imidazole-4-sulfonamide,

n- [3(R) - (1- [6, 6-bis (2-phenyl-ethyl) -5, 6-dihydro-4-hydroxy-2-oxo-2H-pyran-3-yl ] propyl) phenyl ] -5-cyano-2-pyridinesulfonamide,

n- [3(S) - (1- [6, 6-bis (2-phenyl-ethyl) -5, 6-dihydro-4-hydroxy-2-oxo-2H-pyran-3-yl ] propyl) phenyl ] -5-cyano-2-pyridinesulfonamide,

n- [3- {1(R) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (R) -phenethyl-6-propyl-2H-pyran-3-yl) propyl } phenyl ] -5-cyanopyridine-2-sulfonamide,

n- [3- {1(R) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (S) -phenethyl-6-propyl-2H-pyran-3-yl) propyl } phenyl ] -5-cyanopyridine-2-sulfonamide,

n- [3- {1(S) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (R) -phenethyl-6-propyl-2H-pyran-3-yl) propyl } phenyl ] -5-cyanopyridine-2-sulfonamide,

n- [3- {1(S) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (S) -phenethyl-6-propyl-2H-pyran-3-yl) propyl } phenyl ] -5-cyanopyridine-2-sulfonamide,

n- [3- {1(R) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (R) -phenethyl-6-propyl-2H-pyran-3-yl) propyl } phenyl ] -1-methyl-1H-imidazole-4-sulfonamide,

N- [3- {1(R) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (S) -phenethyl-6-propyl-2H-pyran-3-yl) propyl } phenyl ] -1-methyl-1H-imidazole-4-sulfonamide,

n- [3- {1(S) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (R) -phenethyl-6-propyl-2H-pyran-3-yl) propyl } phenyl ] -1-methyl-1H-imidazole-4-sulfonamide,

n- [3- {1(S) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (S) -phenethyl-6-propyl-2H-pyran-3-yl) propyl } phenyl ] -1-methyl-1H-imidazole-4-sulfonamide,

n- [3- {1(R) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (R) - (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl ] -5-cyanopyridine-2-sulfonamide,

n- [3- {1(R) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (S) - (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl ] -5-cyanopyridine-2-sulfonamide,

n- [3- {1(S) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (R) - (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl ] -5-cyanopyridine-2-sulfonamide,

n- [3- {1(S) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (S) - (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl ] -5-cyanopyridine-2-sulfonamide,

N- [3- {1(R) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (R) - (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl ] -1-methyl-1H-imidazole-4-sulfonamide,

n- [3- {1(R) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (S) - (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl ] -1-methyl-1H-imidazole-4-sulfonamide,

n- [3- {1(S) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (R) - (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl ] -1-methyl-1H-imidazole-4-sulfonamide,

n- [3- {1(S) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (S) - (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl ] -1-methyl-1H-imidazole-4-sulfonamide,

n- [3- {1(R) - (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-bis (2-phenylethyl) -2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl ] -5-aminopyridine-2-sulfonamide,

n- [3- {1(S) - (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-bis (2-phenylethyl) -2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl ] -5-aminopyridine-2-sulfonamide,

n- [3- {1(R) - (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-bis (2-phenylethyl) -2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl ] -1-methyl-1H-imidazole-4-sulfonamide,

N- [3- {1(S) - (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-bis (2-phenylethyl) -2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl ] -1-methyl-1H-imidazole-4-sulfonamide,

n- [3- {1(R) - (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-bis (2-phenylethyl) -2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl ] -5-cyanopyridine-2-sulfonamide,

n- [3- {1(S) - (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-bis (2-phenylethyl) -2H-pyran-3-yl) -2, 2-dimethylpropyl } phenyl ] -5-cyanopyridine-2-sulfonamide,

n- [3- {1(R) - (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-dipropyl-2H-pyran-3-yl) -propyl } phenyl ] -5-cyanopyridine-2-sulfonamide

N- [3- {1(S) - (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-dipropyl-2H-pyran-3-yl) -propyl } phenyl ] -5-cyanopyridine-2-sulfonamide

N- [3- {1(R) - (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-dipropyl-2H-pyran-3-yl) -propyl } phenyl ] -5-aminopyridine-2-sulfonamide

N- [3- {1(S) - (4-hydroxy-5, 6-dihydro-2-oxo-6, 6-dipropyl-2H-pyran-3-yl) -propyl } phenyl ] -5-aminopyridine-2-sulfonamide

N- [3- {1(R) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (R) - (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) propyl } phenyl ] -5-cyanopyridine-2-sulfonamide,

N- [3- {1(S) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (R) - (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) propyl } phenyl ] -5-cyanopyridine-2-sulfonamide,

n- [3- {1(R) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (S) - (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) propyl } phenyl ] -5-cyanopyridine-2-sulfonamide,

n- [3- {1(S) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (S) - (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) propyl } phenyl ] -5-cyanopyridine-2-sulfonamide,

n- [3- {1(R) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (R) - (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) propyl } phenyl ] -1-methyl-1H-imidazole-4-sulfonamide,

n- [3- {1(S) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (S) - (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) propyl } phenyl ] -1-methyl-1H-imidazole-4-sulfonamide,

n- [3- {1(R) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (S) - (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) propyl } phenyl ] -1-methyl-1H-imidazole-4-sulfonamide,

n- [3- {1(S) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (R) - (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) propyl } phenyl ] -1-methyl-1H-imidazole-4-sulfonamide,

n- [3- {1(R) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (R) - (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) propyl } phenyl ] -5-aminopyridine-2-sulfonamide,

N- [3- {1(S) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (S) - (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) propyl } phenyl ] -5-aminopyridine-2-sulfonamide,

n- [3- {1(R) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (S) - (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) propyl } phenyl ] -5-aminopyridine-2-sulfonamide,

n- [3- {1(S) - (4-hydroxy-5, 6-dihydro-2-oxo-6 (R) - (2- (4-fluorophenyl) ethyl) -6-propyl-2H-pyran-3-yl) propyl } phenyl ] -5-aminopyridine-2-sulfonamide,

structural formula table

Structural formula watch (continue)

TABLE A

TABLE B

Watch C

Table D

TABLE E

TABLE E (continuation)

TABLE F

Watch G

Watch H

TABLE I

TABLE J

Watch K

Watch L

Watch M

TABLE N

Watch O

Watch P

Watch Q

TABLE R

Watch S

Watch T

Watch U

TABLE V

Watch W

Watch W (continuation)

Table X

Watch X (continue)

Watch Y

Watch Z

TABLE AA

Table AA (continue)

Table BB

Watch BB (continuation)

Watch CC

Watch CC (continuation)

Table DD

Watch DD (continuation)

TABLE EE

Table EE (continue)

Watch FF

Watch FF (continuation)

Table GG

Watch GG (continue)

Table HH

Watch HH (continuation)

TABLE II

TABLE JJ

Watch JJ (continue)

Watch KK

Watch LL

Watch LL (continue)

Watch MM

Table NN

Watch NN (continuation)

Watch OO

Watch PP

Watch QQ

TABLE RR

Watch SS

Table TT

Table UU

Watch VV

Watch WW

Table XX

Watch YY

Watch ZZ

Watch AAA

Watch BBB

Watch CCC

TABLE DDD

TABLE EEE

Table FFF

Watch GGG

Watch GGG (continue)

Watch HHH

Watch HHH (continuation)

TABLE III

TABLE III (continuation)

TABLE JJJ

Watch JJJ (continue)

Watch KKK

Watch KKK (Su)

TABLE LLL

TABLE LLL (continuation)

Table MMM

TABLE NNN

Watch NNN (continue)

Table OOO

Table PPP

Watch QQQ

Watch QQ (continue)

TABLE RRR

Watch RRR (continue)

Watch SSS

Watch TTT

Watch UUU

Watch VVV

Table WWW

Watch XXX

Watch YYY

TABLE ZZZ

TABLE AAAA

Table BBBB

TABLE CCCC

Watch CCCC (continuation)

Table DDDD

Table EEEE

TABLE I

Compounds of example No	HIV protease FITC assay
	HIV protease FITC assay			Dosage (uM)	Protease inhibition%	K_i(nM)
	136	0.123	71.65	Dosage (uM)	Protease inhibition%	K_i(nM)
	136	0.123	71.65	0.370	85.67
		1.100	99.02	0.370	85.67
		1.100	99.02	3.300	100.99
		10.000	102.37	3.300	100.99
		10.000	102.37	30.000	101.94
				30.000	101.94		1.320
145A				0.123	108.66		1.320
145A		0.370	111.34	0.123	108.66
		0.370	111.34	1.100	118.54
		3.300	115.43	1.100	118.54
		3.300	115.43	10.000	113.05
		30.000	114.19	10.000	113.05
		30.000	114.19			1.100
	137	0.123	98.83			1.100
	137	0.123	98.83	0.370	91.54
		1.100	100.7	0.370	91.54
		1.100	100.7	3.300	109.9
		10.000	98.17	3.300	109.9
		10.000	98.17	30.000	93.82
				30.000	93.82		0.520
						0.700	0.520
	138	0.123	100.88			0.700
	138	0.123	100.88	0.370	95.51
		1.100	101.11	0.370	95.51
		1.100	101.11	3.300	99.64
		10.000	94.75	3.300	99.64
		10.000	94.75	30.000	104.68
				30.000	104.68		0.730

Compounds of example No	HIV protease FITC assay
	HIV protease FITC assay			Dosage (uM)	Protease inhibition%	K_i(nM)
				Dosage (uM)	Protease inhibition%	K_i(nM)	1.400
97				0.123	104.87		1.400
97		0.370	106.06	0.123	104.87
		0.370	106.06	1.100	110.44
		3.300	106.67	1.100	110.44
		3.300	106.67	10.000	115.76
		30.000	115.47	10.000	115.76
		30.000	115.47			1.000
	98 first Compound					1.000	0.740
	98 first Compound					0.800	0.740
	98 second Compound					0.800	0.840
	98 second Compound					0.800	0.840
	139	0.123	98.33			0.800
	139	0.123	98.33	0.370	101.22
		1.100	104.71	0.370	101.22
		1.100	104.71	3.300	99.3
		10.000	99.28	3.300	99.3
		10.000	99.28	30.000	102.85
				30.000	102.85		1.890
140				0.123	103.22		1.890
140		0.370	96.01	0.123	103.22
		0.370	96.01	1.100	107.37
		3.300	112.51	1.100	107.37
		3.300	112.51	10.000	112.53
		30.000	119.14	10.000	112.53
		30.000	119.14			1.440
	40	0.123	59.6			1.440
	40	0.123	59.6	0.370	101.71

Compounds of example No	HIV protease FITC assay
	HIV protease FITC assay			Dosage (uM)	Protease inhibition%	K_i(nM)
		1.100	98.73	Dosage (uM)	Protease inhibition%	K_i(nM)
		1.100	98.73	3.300	105.16
		10.000	88.7	3.300	105.16
		10.000	88.7	30.000	72.74
				30.000	72.74		10.800
41				0.123	103		10.800
41		0.370	102.38	0.123	103
		0.370	102.38	1.100	103.92
		3.300	100.93	1.100	103.92
		3.300	100.93	10.000	85.88
		30.000	72.79	10.000	85.88
		30.000	72.79			3.170
	44	0.123	98.43			3.170
	44	0.123	98.43	0.370	114.5
		1.100	119.79	0.370	114.5
		1.100	119.79	3.300	112.7
		10.000	101.66	3.300	112.7
		10.000	101.66	30.000	80.02
				30.000	80.02		1.800
145B				0.123	81.81		1.800
145B		0.370	88.38	0.123	81.81
		0.370	88.38	1.100	96.54
		3.300	87.85	1.100	96.54
		3.300	87.85	10.000	102.12
		30.000	84.52	10.000	102.12
		30.000	84.52			1.240
	135	0.123	33.21			1.240
	135	0.123	33.21	0.370	84.5
		1.100	99.09	0.370	84.5

Compounds of example No	HIV protease FITC assay
	HIV protease FITC assay			Dosage (uM)	Protease inhibition%	K_i(nM)
		3.300	96.86	Dosage (uM)	Protease inhibition%	K_i(nM)
		3.300	96.86	10.000	101.49
		30.000	102.4	10.000	101.49
		30.000	102.4			0.480
	104	0.123	＜10			0.480
	104	0.123	＜10	0.370	61.68
		1.100	81.78	0.370	61.68
		1.100	81.78	3.300	93.28
		10.000	96.4	3.300	93.28
		10.000	96.4	30.000	109.22
				30.000	109.22		1.600
48				0.123	111.37		1.600
48		0.370	103.64	0.123	111.37
		0.370	103.64	1.100	110.44
		3.300	89.27	1.100	110.44
		3.300	89.27	10.000	110.97
		30.000	105.44	10.000	110.97
		30.000	105.44			0.520
	49	0.123	111.16			0.520
	49	0.123	111.16	0.370	119.71
		1.100	120.17	0.370	119.71
		1.100	120.17	3.300	106.02
		10.000	108.34	3.300	106.02
		10.000	108.34	30.000	112.5
				30.000	112.5		0.960
50				0.123	100.54		0.960
50		0.370	108.31	0.123	100.54
		0.370	108.31	1.100	112.66
		3.300	112.42	1.100	112.66

Compounds of example No	HIV protease FITC assay
	HIV protease FITC assay			Dosage (uM)	Protease inhibition%	K_i(nM)
		10.000	101.02	Dosage (uM)	Protease inhibition%	K_i(nM)
		10.000	101.02	30.000	84.79
				30.000	84.79		1.780
105				0.123	101.26		1.780
105		0.370	114.56	0.123	101.26
		0.370	114.56	1.100	107.19
		3.300	110.88	1.100	107.19
		3.300	110.88	10.000	111.16
		30.000	110.6	10.000	111.16
		30.000	110.6			0.880
	52	0.123	85.08			0.880
	52	0.123	85.08	0.370	87.32
		1.100	92.64	0.370	87.32
		1.100	92.64	3.300	97.38
		10.000	97.15	3.300	97.38
		10.000	97.15	30.000	88.89
				30.000	88.89		1.400
53				0.123	88.61		1.400
53		0.370	97.74	0.123	88.61
		0.370	97.74	1.100	97.95
		3.300	99.62	1.100	97.95
		3.300	99.62	10.000	90.16
		30.000	84.37	10.000	90.16
		30.000	84.37			0.900
	55	0.123	＜10			0.900
	55	0.123	＜10	0.370	18.77
		1.100	58.27	0.370	18.77
		1.100	58.27	3.300	86.98
		10.000	98.33	3.300	86.98

Compounds of example No	HIV protease FITC assay
	HIV protease FITC assay			Dosage (uM)	Protease inhibition%	K_i(nM)
		30.000	85.88	Dosage (uM)	Protease inhibition%	K_i(nM)
		30.000	85.88			1.700
	107	0.123	92.69			1.700
	107	0.123	92.69	0.370	99.24
		1.100	105.15	0.370	99.24
		1.100	105.15	3.300	103.44
		10.000	110.33	3.300	103.44
		10.000	110.33	30.000	103.47
				30.000	103.47		0.890
						0.700	0.890
	99	0.123	85.69			0.700
	99	0.123	85.69	0.370	101.55
		1.100	108.05	0.370	101.55
		1.100	108.05	3.300	100.05
		10.000	106.61	3.300	100.05
		10.000	106.61	30.000	103.12
				30.000	103.12		0.660
141				0.123	78.72		0.660
141		0.370	88.65	0.123	78.72
		0.370	88.65	1.100	92.04
		3.300	88.26	1.100	92.04
		3.300	88.26	10.000	97.8
		30.000	98.48	10.000	97.8
		30.000	98.48			1.400
	142	0.123	78.01			1.400
	142	0.123	78.01	0.370	92.52
		1.100	106.64	0.370	92.52
		1.100	106.64	3.300	105.15
		10.000	110.58	3.300	105.15

Compounds of example No	HIV protease FITC assay
	HIV protease FITC assay			Dosage (uM)	Protease inhibition%	K_i(nM)
		30.000	106.77	Dosage (uM)	Protease inhibition%	K_i(nM)
		30.000	106.77			1.600
	56	0.123	104.11			1.600
	56	0.123	104.11	0.370	108.31
		1.100	105.31	0.370	108.31
		1.100	105.31	3.300	105.47
		10.000	114.94	3.300	105.47
		10.000	114.94	30.000	111.25
				30.000	111.25		0.230
57				0.123	99.07		0.230
57		0.370	105.17	0.123	99.07
		0.370	105.17	1.100	110.68
		3.300	97.8	1.100	110.68
		3.300	97.8	10.000	104.74
		30.000	115.02	10.000	104.74
		30.000	115.02			0.360
	58	0.123	64.87			0.360
	58	0.123	64.87	0.370	83.71
		1.100	94.24	0.370	83.71
		1.100	94.24	3.300	95.88
		10.000	100.27	3.300	95.88
		10.000	100.27	30.000	89.81
				30.000	89.81		3.800
59				0.123	76.69		3.800
59		0.370	90.54	0.123	76.69
		0.370	90.54	1.100	101.9
		3.300	99.87	1.100	101.9
		3.300	99.87	10.000	105.16
		30.000	102.02	10.000	105.16

Compounds of example No	HIV protease FITC assay
	HIV protease FITC assay			Dosage (uM)	Protease inhibition%	K_i(nM)
				Dosage (uM)	Protease inhibition%	K_i(nM)	3.500
60				0.123	73.03		3.500
60		0.370	94.3	0.123	73.03
		0.370	94.3	1.100	101.28
		3.300	100.84	1.100	101.28
		3.300	100.84	10.000	105.68
		30.000	107.38	10.000	105.68
		30.000	107.38			0.950
	61	0.123	86.83			0.950
	61	0.123	86.83	0.370	95.51
		1.100	103.35	0.370	95.51
		1.100	103.35	3.300	102.54
		10.000	105.61	3.300	102.54
		10.000	105.61	30.000	103.53
				30.000	103.53		0.710
93A				0.123	59.48		0.710
93A		0.370	90.42	0.123	59.48
		0.370	90.42	1.100	103.54
		3.300	108.54	1.100	103.54
		3.300	108.54	10.000	109.19
		30.000	96.57	10.000	109.19
		30.000	96.57			6.060
	143	0.123	80.78			6.060
	143	0.123	80.78	0.370	97.65
		1.100	104.91	0.370	97.65
		1.100	104.91	3.300	102.39
		10.000	101.25	3.300	102.39
		10.000	101.25	30.000	103.08
				30.000	103.08		0.800

Compounds of example No	HIV protease FITC assay
	HIV protease FITC assay			Dosage (uM)	Protease inhibition%	K_i(nM)
	144	0.123	80.58	Dosage (uM)	Protease inhibition%	K_i(nM)
	144	0.123	80.58	0.370	87.39
		1.100	93.82	0.370	87.39
		1.100	93.82	3.300	100.01
		10.000	98.12	3.300	100.01
		10.000	98.12	30.000	95.88
				30.000	95.88		1.200
145				0.123	73.63		1.200
145		0.370	89.78	0.123	73.63
		0.370	89.78	1.100	99.69
		3.300	94.8	1.100	99.69
		3.300	94.8	10.000	96.85
		30.000	87.97	10.000	96.85
		30.000	87.97			0.490
	100	0.123	102.53			0.490
	100	0.123	102.53	0.370	100.67
		1.100	91.01	0.370	100.67
		1.100	91.01	3.300	96.54
		100.000	100.86	3.300	96.54
		100.000	100.86	30.000	100.62
				30.000	100.62		0.730
62				0.123	76.18		0.730
62		0.370	85.15	0.123	76.18
		0.370	85.15	1.100	85.28
		3.300	78.67	1.100	85.28
		3.300	78.67	10.000	79.69
		30.000	79.39	10.000	79.69
		30.000	79.39			0.800
	108	0.123	103.43			0.800

Compounds of example No	HIV protease FITC assay
	HIV protease FITC assay			Dosage (uM)	Protease inhibition%	K_i(nM)
		0.370	102.13	Dosage (uM)	Protease inhibition%	K_i(nM)
		0.370	102.13	1.100	101.87
		3.300	102.41	1.100	101.87
		3.300	102.41	10.000	107.73
		30.000	106.39	10.000	107.73
		30.000	106.39			0.160
	109	0.123	105.42			0.160
	109	0.123	105.42	0.370	99.35
		1.100	103.75	0.370	99.35
		1.100	103.75	3.300	100.96
		10.000	108.56	3.300	100.96
		10.000	108.56	30.000	109.31
	239	0.123	83.64	30.000	109.31
	239	0.123	83.64	0.370	96.63
		1.100	98.41	0.370	96.63
		1.100	98.41	3.300	99.53
		10.000	103.21	3.300	99.53
		10.000	103.21	30.000	108.02
				30.000	108.02		1.440
						0.860	1.440
	152	0.123	11.52			0.860
	152	0.123	11.52	0.370	80.2
		1.100	95.79	0.370	80.2
		1.100	95.79	3.300	94.43
		10.000	95.45	3.300	94.43
		10.000	95.45	30.000	96.47
				30.000	96.47		0.710
8				0.123	99.23		0.710
8		0.370	110.11	0.123	99.23

Compounds of example No	HIV protease FITC assay
	HIV protease FITC assay			Dosage (uM)	Protease inhibition%	K_i(nM)
		1.100	102.93	Dosage (uM)	Protease inhibition%	K_i(nM)
		1.100	102.93	3.300	110.02
		10.000	105.11	3.300	110.02
		10.000	105.11	30.000	101.91
				30.000	101.91		0.350
9				0.123	99.09		0.350
9		0.370	103.78	0.123	99.09
		0.370	103.78	1.100	104.9
		3.300	104.69	1.100	104.9
		3.300	104.69	10.000	107.08
		30.000	107.87	10.000	107.08
		30.000	107.87			0.420
	10	0.123	102.17			0.420
	10	0.123	102.17	0.370	111.74
		1.100	115.65	0.370	111.74
		1.100	115.65	3.300	119.47
		10.000	128.59	3.300	119.47
		10.000	128.59	30.000	130.05
				30.000	130.05		5.710
151				0.123	111.03		5.710
151		0.370	114.59	0.123	111.03
		0.370	114.59	1.100	117.62
		3.300	118.9	1.100	117.62
		3.300	118.9	10.000	116.34
		30.000	114.87	10.000	116.34
		30.000	114.87			0.360
	153	0.123	81.27			0.360
	153	0.123	81.27	0.370	91.11
		1.100	100.49	0.370	91.11

Compounds of example No	HIV protease FITC assay
	HIV protease FITC assay			Dosage (uM)	Protease inhibition%	K_i(nM)
		3.300	104.09	Dosage (uM)	Protease inhibition%	K_i(nM)
		3.300	104.09	10.000	102.76
		30.000	100.71	10.000	102.76
		30.000	100.71			1.850
	154	0.123	99.8			1.850
	154	0.123	99.8	0.370	98.17
		1.100	99.52	0.370	98.17
		1.100	99.52	3.300	97.59
		10.000	103.54	3.300	97.59
		10.000	103.54	30.000	99.18
				30.000	99.18		0.220
240				0.123	96.32		0.220
240		0.370	100.98	0.123	96.32
		0.370	100.98	1.100	102.71
		3.300	101.88	1.100	102.71
		3.300	101.88	10.000	104.28
		30.000	107.17	10.000	104.28
		30.000	107.17			1.300
	1	0.123	75.4			1.300
	1	0.123	75.4	0.370	87.3
		1.100	97.1	0.370	87.3
		1.100	97.1	3.300	96.76
		10.000	99.68	3.300	96.76
		10.000	99.68	30.000	97.43
				30.000	97.43		15.000
101				0.123	70.24		15.000
101		0.370	83.98	0.123	70.24
		0.370	83.98	1.100	93.35
		3.300	97.01	1.100	93.35

Compounds of example No	HIV protease FITC assay
	HIV protease FITC assay			Dosage (uM)	Protease inhibition%	K_i(nM)
		10.000	102.48	Dosage (uM)	Protease inhibition%	K_i(nM)
		10.000	102.48	30.000	97.35
				30.000	97.35		0.660
146				0.123	68.12		0.660
146		0.370	87.38	0.123	68.12
		0.370	87.38	1.100	103.18
		3.300	103.26	1.100	103.18
		3.300	103.26	10.000	102.54
		30.000	101.95	10.000	102.54
		30.000	101.95			0.690
	147	0.123	77.45			0.690
	147	0.123	77.45	0.370	102.86
		1.100	111.6	0.370	102.86
		1.100	111.6	3.300	110.34
		10.000	114.04	3.300	110.34
		10.000	114.04	30.000	108.28
				30.000	108.28		1.000
110				0.123	77.89		1.000
110		0.370	82.72	0.123	77.89
		0.370	82.72	1.100	95.11
		3.300	99.1	1.100	95.11
		3.300	99.1	10.000	99.22
		30.000	101.27	10.000	99.22
		30.000	101.27			3.260
						3.260	3.630
102				0.123	87.11		3.630
102		0.370	92.73	0.123	87.11
		0.370	92.73	1.100	102.21
		3.300	110.44	1.100	102.21

Compounds of example No	HIV protease FITC assay
	HIV protease FITC assay			Dosage (uM)	Protease inhibition%	K_i(nM)
		10.000	116.72	Dosage (uM)	Protease inhibition%	K_i(nM)
		10.000	116.72	30.000	107.83
				30.000	107.83		0.700
103				0.123	65.51		0.700
103		0.370	82.58	0.123	65.51
		0.370	82.58	1.100	96.86
		3.300	100.29	1.100	96.86
		3.300	100.29	10.000	104.76
		30.000	96.05	10.000	104.76
		30.000	96.05			1.720
	194	0.123	＜10			1.720
	194	0.123	＜10	0.370	20.03
		1.100	53.89	0.370	20.03
		1.100	53.89	3.300	75.23
		10.000	85.48	3.300	75.23
		10.000	85.48	30.000	85.18
	195	0.123	60.89	30.000	85.18
	195	0.123	60.89	0.370	85.08
		1.100	90.79	0.370	85.08
		1.100	90.79	3.300	90.83
		10.000	93.14	3.300	90.83
		10.000	93.14	30.000	92.69
				30.000	92.69		3.700
150				0.123	78.42		3.700
150		0.370	96.45	0.123	78.42
		0.370	96.45	1.100	100.07
		3.300	102.81	1.100	100.07
		3.300	102.81	10.000	106.88
		30.000	109.34	10.000	106.88

Compounds of example No	HIV protease FITC assay
	HIV protease FITC assay			Dosage (uM)	Protease inhibition%	K_i(nM)
				Dosage (uM)	Protease inhibition%	K_i(nM)	5.900
148				0.123	81.35		5.900
148		0.370	91.68	0.123	81.35
		0.370	91.68	1.100	95.57
		3.300	90.04	1.100	95.57
		3.300	90.04	10.000	99.17
		30.000	93.52	10.000	99.17
		30.000	93.52			4.770
						4.770	18.100
149				0.123	80.51		18.100
149		0.370	87.52	0.123	80.51
		0.370	87.52	1.100	96.32
		3.300	92.86	1.100	96.32
		3.300	92.86	10.000	97.12
		30.000	95.99	10.000	97.12
		30.000	95.99			3.410
						3.410	62.700
94				0.123	75.76		62.700
94		0.370	106.6	0.123	75.76
		0.370	106.6	1.100	107.3
		3.300	104.91	1.100	107.3
		3.300	104.91	10.000	109.2
		30.000	111.29	10.000	109.2
		30.000	111.29			16.370
	95	0.123	91.2			16.370
	95	0.123	91.2	0.370	102.33
		1.100	105.86	0.370	102.33
		1.100	105.86	3.300	112.79
		10.000	110.04	3.300	112.79

Compounds of example No	HIV protease FITC assay
	HIV protease FITC assay			Dosage (uM)	Protease inhibition%	K_i(nM)
		30.000	112.69	Dosage (uM)	Protease inhibition%	K_i(nM)
		30.000	112.69			5.350
	96	0.123	94.17			5.350
	96	0.123	94.17	0.370	119.36
		1.100	122.12	0.370	119.36
		1.100	122.12	3.300	111
		10.000	111.32	3.300	111
		10.000	111.32	30.000	109.23
				30.000	109.23		5.300
42				0.123	86.15		5.300
42		0.370	102.71	0.123	86.15
		0.370	102.71	1.100	98.26
		3.300	102.4	1.100	98.26
		3.300	102.4	10.000	91.43
		30.000	76.12	10.000	91.43
		30.000	76.12			3.100
	43	0.123	85.63			3.100
	43	0.123	85.63	0.370	99.01
		1.100	95.68	0.370	99.01
		1.100	95.68	3.300	96.68
		10.000	101.58	3.300	96.68
		10.000	101.58	30.000	85.57
				30.000	85.57		3.650
45				0.123	82.22		3.650
45		0.370	94.37	0.123	82.22
		0.370	94.37	1.100	101.04
		3.300	103.16	1.100	101.04
		3.300	103.16	10.000	89.76
		30.000	67.5	10.000	89.76

Compounds of example No	HIV protease FITC assay
	HIV protease FITC assay			Dosage (uM)	Protease inhibition%	K_i(nM)
				Dosage (uM)	Protease inhibition%	K_i(nM)	4.780
46				0.123	85.86		4.780
46		0.370	99.19	0.123	85.86
		0.370	99.19	1.100	103.31
		3.300	97.62	1.100	103.31
		3.300	97.62	10.000	91.45
		30.000	74.13	10.000	91.45
		30.000	74.13			2.920
	47	0.123	66.3			2.920
	47	0.123	66.3	0.370	86.79
		1.100	94.7	0.370	86.79
		1.100	94.7	3.300	100.95
		10.000	98.68	3.300	100.95
		10.000	98.68	30.000	84.45
				30.000	84.45		3.000
						2.980	3.000
	51	0.123	98.71			2.980
	51	0.123	98.71	0.370	103.68
		1.100	104.78	0.370	103.68
		1.100	104.78	3.300	101.27
		10.000	95.07	3.300	101.27
		10.000	95.07	30.000	79.72
				30.000	79.72		2.660
106				0.123	60.94		2.660
106		0.370	86.56	0.123	60.94
		0.370	86.56	1.100	93.7
		3.300	98.88	1.100	93.7
		3.300	98.88	10.000	99.03
		30.000	106.06	10.000	99.03

Compounds of example No	HIV protease FITC assay
	HIV protease FITC assay			Dosage (uM)	Protease inhibition%	K_i(nM)
				Dosage (uM)	Protease inhibition%	K_i(nM)	3.290
54				0.123	46.64		3.290
54		0.370	72.41	0.123	46.64
		0.370	72.41	1.100	87.91
		3.300	89.11	1.100	87.91
		3.300	89.11	10.000	87.77
		30.000	91.99	10.000	87.77
		30.000	91.99			13.300
	146	10.000	102.54			13.300
	146	10.000	102.54	30.000	101.95
				30.000	101.95		0.690
192				0.123	44.04		0.690
192		0.370	76.28	0.123	44.04
		0.370	76.28	1.100	93.96
		3.300	96.93	1.100	93.96
		3.300	96.93	10.000	103.33
		30.000	94.38	10.000	103.33
		30.000	94.38			7.200
	193	0.123	18.42			7.200
	193	0.123	18.42	0.370	40.3
		1.100	77.74	0.370	40.3
		1.100	77.74	3.300	98.1
		10.000	108.41	3.300	98.1
		10.000	108.41	30.000	103.17
				30.000	103.17		35.000
11				0.123	78.93		35.000
11		0.370	95.26	0.123	78.93
		0.370	95.26	1.100	100.26
		3.300	95.12	1.100	100.26

Compounds of example No	HIV protease FITC assay
	HIV protease FITC assay			Dosage (uM)	Protease inhibition%	K_i(nM)
		10.000	99.66	Dosage (uM)	Protease inhibition%	K_i(nM)
		10.000	99.66	30.000	104.39
				30.000	104.39		1.900
12				0.123	75.65		1.900
12		0.370	87.16	0.123	75.65
		0.370	87.16	1.100	91.79
		3.300	91.11	1.100	91.79
		3.300	91.11	10.000	94.74
		30.000	95.69	10.000	94.74
		30.000	95.69			2.150
	13	0.123	68.94			2.150
	13	0.123	68.94	0.370	88.07
		1.100	93.98	0.370	88.07
		1.100	93.98	3.300	95.51
		10.000	98.61	3.300	95.51
		10.000	98.61	30.000	104.2
				30.000	104.2		4.150
14				0.123	65.67		4.150
14		0.370	87.96	0.123	65.67
		0.370	87.96	1.100	96.79
		3.300	96.56	1.100	96.79
		3.300	96.56	10.000	101.77
		30.000	106.39	10.000	101.77
		30.000	106.39			6.880
	15	0.123	77.63			6.880
	15	0.123	77.63	0.370	88.45
		1.100	92.44	0.370	88.45
		1.100	92.44	3.300	94.03
		10.000	95.84	3.300	94.03

Compounds of example No	HIV protease FITC assay
	HIV protease FITC assay			Dosage (uM)	Protease inhibition%	K_i(nM)
		30.000	99.23	Dosage (uM)	Protease inhibition%	K_i(nM)
		30.000	99.23			2.800
	63	0.123	68.88			2.800
	63	0.123	68.88	0.370	79.56
		1.100	88.58	0.370	79.56
		1.100	88.58	3.300	87.44
		10.000	83.58	3.300	87.44
		10.000	83.58	30.000	78.84
	64	0.123	27.95	30.000	78.84
	64	0.123	27.95	0.370	50.83
		1.100	75.60	0.370	50.83
		1.100	75.60	3.300	80.88
		10.000	82.03	3.300	80.88
		10.000	82.03	30.000	84.39
	250			30.000	84.39		1.2
261	250					0.87	1.2
261	260					0.87	2.0
258	260					4.3	2.0
258	259					4.3	2.2
256	259					8.3	2.2
256	257					8.3	9.0
246	257					1.7	9.0
246	247					1.7	1.2
254	247					3.0	1.2
254	255					3.0	1.6
248	255					4.7	1.6
248	249					4.7	0.75
251	249			0.123	70.84		0.75
251		0.370	90.56	0.123	70.84

Compounds of example No	HIV protease FITC assay
	HIV protease FITC assay			Dosage (uM)	Protease inhibition%	K_i(nM)
		1.100	97.68	Dosage (uM)	Protease inhibition%	K_i(nM)
		1.100	97.68	3.300	94.5
		10.000	94.16	3.300	94.5
		10.000	94.16	30.000	93.24
				30.000	93.24		1.9
253				0.123	94.03		1.9
253		0.370	96.84	0.123	94.03
		0.370	96.84	1.100	97.64
		3.300	95.93	1.100	97.64
		3.300	95.93	10.000	96.95
		30.000	98.52	10.000	96.95
252		30.000	98.52	0.123	69.96
252		0.370	85.05	0.123	69.96
		0.370	85.05	1.100	89.69
		3.300	100.57	1.100	89.69
		3.300	100.57	10.000	96.21
		30.000	91.38	10.000	96.21
		30.000	91.38			1.6
	262	0.123	91.8			1.6
	262	0.123	91.8	0.370	96.6
		1.100	97.13	0.370	96.6
		1.100	97.13	3.300	95.4
		10.000	94.17	3.300	95.4
		10.000	94.17	30.000	89.18
	263	0.123	98.08	30.000	89.18
	263	0.123	98.08	0.370	98.99
		1.100	99.1	0.370	98.99
		1.100	99.1	3.300	98.08
		10.000	96.21	3.300	98.08

Compounds of example No	HIV protease FITC assay
	HIV protease FITC assay			Dosage (uM)	Protease inhibition%	K_i(nM)
		30.000	88.19	Dosage (uM)	Protease inhibition%	K_i(nM)
264		30.000	88.19	0.123	67.18
264		0.370	75.01	0.123	67.18
		0.370	75.01	1.100	67.71
		3.300	57.62	1.100	67.71
		3.300	57.62	10.000	53.69
		30.000	64.58	10.000	53.69
		30.000	64.58			3.7
	265	0.123	33.23			3.7
	265	0.123	33.23	0.370	56.33
		1.100	57.78	0.370	56.33
		1.100	57.78	3.300	63.69
		10.000	80.29	3.300	63.69
		10.000	80.29	30.000	85.64
				30.000	85.64		1.0

TABLE II

Example No. 2	Enzyme	Dosage form	Protease inhibition%	FITCKI(NM)
Example No. 2	Enzyme	Dosage form	Protease inhibition%	FITCKI(NM)	280293295281285286287283296291289290298266272270273	HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV1TANDEMHIV1TANDEMHIV1TANDEMHIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV1TANDEMHIV1TANDEMHIV1TANDEMHIV1TANDEMHIV1TANDEMHIV1TANDEMHIV1TANDEMHIV1TANDEMHIV1TANDEMHIV1TANDEMHIV1TANDEMHIV1TANDEMHIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV-1HIV-1HIV-1HIV-1HIV-1HIV-1	0.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.000	95.2894.9893.0186.6978.6476.8553.4577.5194.18103.0397.4192.0181.895.899.11109.33104.6186.8434.7668.7489.2993.11108.1795.3175.2685.6293.4596.6294.5782.67＜1023.2475.3894.6395.9391	0.1004.3000.0710.0020.0040.01513.3000.0380.0040.0420.0120.0260.1331.8800.0040.0030.0070.0333.6000.0242.300

276278268271299300302304305306307

HIV1TANDEMHIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV1TANDEMHIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIVTANDEMHIVTANDEMHIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIVTANDEMHIVTANDEMHIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV1TANDEMHIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV-1

0.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.123

16.4938.9566.190.0190.9787.676.7686.9995.696.9193.3286.1883.51104.76117.95115.61128.03102.8990.6199.05111.45109.19105.56104.913865.5789.51118.39104.4992.1692.0193.2896.47100.47107.6179.6899.99110.76114.35110.88102.0157.8371.7982.7189.397.2982.5953.4377.39

33.0000.0400.8350.0510.2000.1000.1001.8703.6000.1000.0500.4000.040

308310311312314315316317318

HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV1TANDEMHIV1TANDEMHIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV-1HIV-1HIV-1HIV-1HIV-1

0.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.000

99.85107.8793.3483.4969.7475.06108.1495.01108.43110.7596.2816.8150.1178.69100.22124.77110.9186.5191.49101.896.593.7777.6382.9296.14114.86100.7688.7573.4279.9587.2588.0897.03100.2106.475.4985.02100.3295.4699.7187.9187.3894.1498.4595.97101.26108.5998.06106.35101.8888.7394.49

0.0720.0741.5000.0070.2550.7000.0290.3570.0400.019

319320322324326328329330331332333334

HIV-1HIV1TANDEMHIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV1TANDEMHIV1TANDEMHIV1TANDEMHIV1TANDEMHIV1TANDEMHIV1TANDEMHIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV-1HIV-1HIV-1

30.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.100

82.8310.7532.6560.1475.8693.4674.4827.8179.4795.4596.7796.7892.1746.488.1996.63100.3297.0796.3593.7494.3293.6685.6387.969.8299.76104.06108.5199.3103.2893.381.8785.6586.2393.2891.6895.0866.7385.0785.1293.6989.3877.9193.4990.2594.57

29.5000.0710.0500.0751.0701.2900.1560.02922.00012.0000.5240.2720.4001.6007.7000.450

335336338339340342343344345

HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV-1HIV-1HIV-1HIV-1

3.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.300

102.4797.6196.360.0799.7597.0592.0689.7776.2565.6411289.5488.0677.1262.2861.7485.3280.4689.6283.5362.3483.49100.6101.42104.7191.3872.8680.5890.4990.1691.5789.4971.9981.0693.1896.9485.5573.5573.9557.576.8381.0286.4360.564647.3772.8481.1783.0868.4746.2469.1994.37101.6799.08

0.0400.0320.1000.1200.0600.3092.9005.9000.032

347348349351352353354355356

HIV-1HIV-1HIV1TANDEMHIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV-1HIV-1

10.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.370

97.4384.5620.9950.8271.48390.9787.1853.4778.3289.8492.9696.2884.6774.588.2199.92104.99103.4998.24＜10＜1025.455.1178.5390.55＜1025.3147.7874.9985.8687.8251.8368.4970.7163.9651.843.93＜1010.3726.7946.154.9754.5＜10＜10＜1020.7246.6667.8254.9671.75

13.6001.9600.111558.000168.00010.4005.300665.000700.0001.100

357359363365368370371372373374

HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV1TANDEMHIV1TANDEMHIV1TANDEMHIV1TANDEMHIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV-2HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV-1HIV1TANDEMHIV1TANDEM0.3701.1003.30010.00030.000

1.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.1230.3701.1003.30010.00030.0000.12382.1484.9887.7095.2580.11

90.1992.28100.2295.1692.8187.87102.89109.33113.7998.1439.8472.9491.61104.12102.7107.2143.5286.68101.5299.5697.81106.1890.7190.35103.8388.7285.7589.5378.970.031

48.50016.4000.0830.0230.2320.5900.0500.05015.4004.0000.200

TABLE 3

U-No.	MS data	Name (R)	Source
U-No.	MS data	Name (R)	Source	300	587.2453(EI)	5-cyano-N- [3(R or S) - (1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (R or S) - (2-phenylethyl) -6-propyl-2H-pyran-3-yl ]-2, 2-dimethylpropyl) phenyl]-2-pyridinesulfonamides	A single stereoisomer; from isomer 1 of preparation 143
301	587.2458(EI)	5-cyano-N- [3(R or S) - (1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (R or S) - (2-phenylethyl) -6-propyl-2H-pyran-3-yl]-2, 2-dimethylpropyl) phenyl]-2-pyridinesulfonamides	A single stereoisomer; from isomer 2 of preparation 143	300	587.2453(EI)		A single stereoisomer; from isomer 1 of preparation 143
301	587.2458(EI)		A single stereoisomer; from isomer 2 of preparation 143	302	587.2444(EI)	5-cyano-N- [3(R or S) - (1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (R or S) - (2-phenylethyl) -6-propyl-2H-pyran-3-yl]-2, 2-dimethylpropyl) phenyl]-2-pyridinesulfonamides	A single stereoisomer; from isomer 3 of preparation 143
303	587.2446(EI)	5-cyano-N- [3(R or S) - (1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (R or S) - (2-phenylethyl) -6-propyl-2H-pyran-3-yl]-2, 2-dimethylpropyl) phenyl]-2-pyridinesulfonamides	A single stereoisomer; from isomer 4 of preparation 143	302	587.2444(EI)		A single stereoisomer; from isomer 3 of preparation 143
303	587.2446(EI)		A single stereoisomer; from isomer 4 of preparation 143	304	525.2311(EI)	5-cyano-N- [3- (1- [5, 6-dihydro-6, 6-diisobutyl-4-hydroxy-2-oxo-2H-pyran-3-yl)]Propyl) -phenyl]-2-pyridinesulfonamides	Racemic mixture
305	532.2856(FAB)	N- [3- (1- [5, 6-dihydro-6, 6-diisobutyl-4-hydroxy-2-oxo-2H-)	Racemic mixture	304	525.2311(EI)		Racemic mixture

		Pyran-3-yl]-2, 2-dimethylpropyl) -phenyl]-1-methyl-1H-imidazole-4-sulfonamide
				306	554.2688(FAB)	5-cyano-N- [3- (1- [5, 6-dihydro-6, 6-diisobutyl-4-hydroxy-2-oxo-2H-pyran-3-yl)]-2, 2-dimethylpropyl) -phenyl]-2-pyridinesulfonamides	Racemic mixture
307	565.2607(EI)	N- [3(R or S) - [1- (5, 6-dihydro-4-hydroxy-2-oxo-6 (R or S) - [ 2-phenylethyl)]-6-propyl-2H-pyran-3-yl) -2, 2-dimethylpropyl radical]-phenyl radical]-1-methyl-1H-imidazole-4-sulfonamide	A single stereoisomer; from isomer 1 of preparation 143	306	554.2688(FAB)		Racemic mixture
307	565.2607(EI)		A single stereoisomer; from isomer 1 of preparation 143	308	565.2629(EI)	N- [3(R or S) - [1- (5, 6-dihydro-4-hydroxy-2-oxo-6 (R or S) - [ 2-phenylethyl)]-6-propyl-2H-pyran-3-yl) -2, 2-dimethylpropyl radical]-phenyl radical]-1-methyl-1H-imidazole-4-sulfonamide	A single stereoisomer; from isomer 2 of preparation 143
309	565.2605(EI)	N- [3(R or S) - [1- (5, 6-dihydro-4-hydroxy-2-oxo-6 (R or S) - [ 2-phenylethyl)]-6-propyl-2H-pyran-3-yl) -2, 2-dimethylpropyl radical]-phenyl radical]-1-methyl-1H-imidazole-4-sulfonamide	A single stereoisomer; from isomer 3 of preparation 143	308	565.2629(EI)		A single stereoisomer; from isomer 2 of preparation 143
309	565.2605(EI)		A single stereoisomer; from isomer 3 of preparation 143	310	565.2626(EI)	N- [3(R or S) - [1- (5, 6-dihydro-4-hydroxy-2-oxo-6 (R or S) - [ 2-phenylethyl)]-6-propyl-2H-pyran-3-yl) -2, 2-dimethylpropyl radical]-phenyl radical]-1-methyl-1H-imidazole-4-sulfonamide	A single stereoisomer; from isomer 4 of preparation 143

311	571.2113(EI)	5-cyano-N- [3- (1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl) -6-propyl-2H-pyran-3-yl ]-cyclopropylmethyl) phenyl]-2-pyridinesulfonamides	Diastereomer mixtures
311	571.2113(EI)		Diastereomer mixtures	312	577.2630(EI)	5-amino-N- [3(R or S) - (1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (R or S) - (2-phenylethyl) -6-propyl-2H-pyran-3-yl]-2, 2-dimethylpropyl) phenyl]-2-pyridinesulfonamides	A single stereoisomer; preparation from preparation 138 amine (prepared from isomer 1 of preparation 143)
313	577.2585(EI)	5-amino-N- [3(R or S) - (1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (R or S) - (2-phenylethyl) -6-propyl-2H-pyran-3-yl]-2, 2-dimethylpropyl) phenyl]-2-pyridinesulfonamides	A single stereoisomer; from the amine of preparation 137 (prepared from isomer 2 of preparation 143)	312	577.2630(EI)
313	577.2585(EI)			314	550.2380(FAB)	5-amino-N- [3(R or S) - (1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (R or S) - (2-phenylethyl) -6-propyl-2H-pyran-3-yl]Propyl) phenyl]-2-pyridinesulfonamides	A single stereoisomer; from isomer 1 of preparation 147
315	550.2365(FAB)	5-amino-N- [3(R or S) - (1- [5, 6-dihydro-4-hydroxy-2-oxo-6- (R or S) - (2-phenylethyl) -6-propyl-2H-pyran-3-yl]Propyl) phenyl]-2-pyridinesulfonamides	A single stereoisomer; from isomer 2 of preparation 147	314	550.2380(FAB)		A single stereoisomer; from isomer 1 of preparation 147

316	596.2583(FAB)	5-amino-N- [3(R or S) - (1- [6(R or S) - (2- [ 4-fluorophenyl)]Ethyl) -5, 6-dihydro-4-hydroxy-2-oxo-6-propyl-2H-pyran-3-yl ]-2, 2-dimethylpropyl) phenyl]-2-pyridinesulfonamides	A single stereoisomer; from isomer 1 of preparation 150
316	596.2583(FAB)		A single stereoisomer; from isomer 1 of preparation 150	317	596.2583(FAB)	5-amino-N- [3(R or S) - (1- [6(R or S) - (2- [ 4-fluorophenyl)]Ethyl) -5, 6-dihydro-4-hydroxy-2-oxo-6-propyl-2H-pyran-3-yl]-2, 2-dimethylpropyl) phenyl]-2-pyridinesulfonamides	A single stereoisomer; from isomer 2 of preparation 150
318	503.2445(EI)	N- [3(R or S) - (1- [5, 6-dihydro-6, 6-dipropyl-4-hydroxy-2-oxo-2H-pyran-3-yl)]-2, 2-dimethylpropyl) -phenyl]-1-methyl-1H-imidazole-4-sulfonamide	A single enantiomer; preparation from amine prepared from isomer 1 of preparation 144	317	596.2583(FAB)		A single stereoisomer; from isomer 2 of preparation 150
318	503.2445(EI)			319	503.2454(EI)	N- [3(R or S) - (1- [5, 6-dihydro-6, 6-dipropyl-4-hydroxy-2-oxo-2H-pyran-3-yl)]-2, 2-dimethylpropyl) -phenyl]-1-methyl-1H-imidazole-4-sulfonamide	A single enantiomer; preparation from amine prepared from isomer 2 of preparation 144
320	515.2453(EI)	5-amino-N- [3(R or S) - (1- [5, 6-dihydro-6, 6-dipropyl-4-hydroxy-2-oxo-2H-pyran-3-yl)]-2, 2-dimethylpropyl) phenyl]-2-	A single enantiomer; preparation from amine prepared from isomer 1 of preparation 144	319	503.2454(EI)

		Pyridine sulfonamides
		Pyridine sulfonamides		321	515.2463(EI)	5-amino-N- [3(R or S) - (1- [5, 6-dihydro-6, 6-dipropyl-4-hydroxy-2-oxo-2H-pyran-3-yl) ]-2, 2-dimethylpropyl) phenyl]-2-pyridinesulfonamides	A single enantiomer; preparation from amine prepared from isomer 2 of preparation 144
322	525.2287(EI)	5-cyano-N- [3(R or S) - (1- [5, 6-dihydro-6, 6-dipropyl-4-hydroxy-2-oxo-2H-pyran-3-yl)]-2, 2-dimethylpropyl) phenyl]-2-pyridinesulfonamides	A single enantiomer; preparation from amine prepared from isomer 2 of preparation 144	321	515.2463(EI)
322	525.2287(EI)			323	525.2288(EI)	5-cyano-N- [3(R or S) - (1- [5, 6-dihydro-6, 6-dipropyl-4-hydroxy-2-oxo-2H-pyran-3-yl]-2, 2-dimethylpropyl) phenyl]-2-pyridinesulfonamides	A single enantiomer; preparation from amine prepared from isomer 1 of preparation 144
324	600.2537(FAB)	N- [3(R or S) - (1- [6, 6-bis (2-phenylethyl) -5, 6-dihydro-4-hydroxy-2-oxo-2H-pyran-3-yl)]Propyl) phenyl]-1-methyl-1H-imidazole-4-sulfonamide	A single enantiomer; preparation from amine prepared from isomer 1 of preparation 145	323	525.2288(EI)
324	600.2537(FAB)			325	600.2537(FAB)	N- [3(R or S) - (1- [6, 6-bis (2-phenylethyl) -5, 6-dihydro-4-hydroxy-2-oxo-2H-pyran-3-yl)]Propyl) phenyl]-1-methyl-1H-imidazole-4-sulfonamide	A single enantiomer; preparation from amine prepared from isomer 2 of preparation 145

326	622.2378(FAB)	N- [3(R or S) - (1- [6, 6-bis (2-phenylethyl) -5, 6-dihydro-4-hydroxy-2-oxo-2H-pyran-3-yl)]Propyl) phenyl]-5-cyano-2-pyridinesulfonamide	A single enantiomer; preparation from amine prepared from isomer 1 of preparation 145
326	622.2378(FAB)			327	622.2367(FAB)	N- [3(R or S) - (1- [6, 6-bis (2-phenylethyl) -5, 6-dihydro-4-hydroxy-2-oxo-2H-pyran-3-yl)]Propyl) phenyl]-5-cyano-2-pyridinesulfonamide	A single enantiomer; preparation from amine prepared from isomer 2 of preparation 145

Claims

1. Preparation method of compound of formula W-10

Wherein R is₁Is that

a) N-propyl, or

b) A phenethyl group;

the method comprises the following steps:

a) reacting a compound of formula W-9

Wherein X_AAs defined above, with TiCl₄Processing;

b) treating the product of step a) with an amine base; and is

c) Reacting the product of step b) with 4-heptanone or 1-phenyl-3-hexanone to produce a compound of formula W-10.

2. A process for preparing a compound of formula W-13A, comprising the steps of:

d) treating a compound of formula W-10 prepared by the process of claim 1 with sodium hydride or potassium tert-butoxide to give a compound of formula W-11

Wherein R is₁Is that

a) N-propyl, or

b) A phenethyl group;

e) hydrogenation of a compound of formula W-11 to give a compound of formula W-12

Wherein R is₁As defined above;

Wherein R is₄Is that

a) 5-trifluoromethyl-2-pyridyl, or

b) 5-cyano-2-pyridinyl to give compounds of the formula W-13A

Wherein R is₁As defined above.

3. A process for preparing a compound of formula X-10

Wherein R is₁Is that

a) N-propyl, or

b) A phenethyl group;

the method comprises the following steps:

a) reacting a compound of formula X-9

Wherein X _AAs defined above, with TiCl₄Processing;

b) treating the product of step a) with an amine base; and is

c) Reacting the product of step b) with 4-heptanone or 1-phenyl-3-hexanone to produce a compound of formula X-10.

4. A process for preparing a compound of formula X-13A, comprising the steps of:

d) treating the compound of formula X-10 prepared by the process of claim 3 with sodium hydride or potassium tert-butoxide to give a compound of formula X-11

Wherein R is₁Is that

a) N-propyl, or

b) A phenethyl group;

Wherein R is₁As defined above;

Wherein R is₄Is that

a) 5-trifluoromethyl-2-pyridyl, or

b) 5-cyano-2-pyridinyl to give compounds of the formula X-13A

Wherein R is₁As defined above.

5. Process for preparing compounds of formula GGG-10

Wherein R is₁Is that

a) N-propyl, or

b) A phenethyl group;

the method comprises the following steps:

a) reacting a compound of formula GGG-9

Wherein X_AAs defined above, with TiCl₄Processing;

b) treating the product of step a) with an amine base; and is

c) Reacting the product of step b) with 4-heptanone or 1-phenyl-3-hexanone to produce a compound of formula GGG-10.

6. A process for preparing a compound of formula GGG-13A, the process comprising the steps of:

d) treating a compound of formula GGG-10 prepared by the process of claim 5 with sodium hydride or potassium tert-butoxide to give a compound of formula GGG-11

Wherein R is₁Is that

a) N-propyl, or

b) A phenethyl group;

Wherein R is₁As defined above;

Wherein R is₄Is that

a) 5-trifluoromethyl-2-pyridyl, or

b) 5-cyano-2-pyridinyl to give compounds of formula GGG-13A

Wherein R is₁As defined above.

7. A process for the preparation of a compound of formula HHH-10

Wherein R is₁Is that

a) N-propyl, or

b) A phenethyl group;

the method comprises the following steps:

a) reacting a compound of formula HHH-9

Wherein X is_AAs defined above, with TiCl₄Processing;

b) treating the product of step a) with an amine base; and is

c) Reacting the product of step b) with 4-heptanone or 1-phenyl-3-hexanone to produce a compound of formula HHH-10.

8. A process for preparing a compound of formula HHH-13A, comprising the steps of:

d) treating a compound of formula HHH-10 prepared by the process of claim 7 with sodium hydride or potassium tert-butoxide to give a compound of formula HHH-11

Wherein R is₁Is that

a) N-propyl, or

b) A phenethyl group;

Wherein R is₁As defined above;

Wherein R is₄Is that

a) 5-trifluoromethyl-2-pyridyl, or

b) 5-cyano-2-pyridinyl to give compounds of formula HHH-13A

Wherein R is₁As defined above.

9. A process for preparing a compound of formula III-10

Wherein R is₁Is that

a) N-propyl, or

b) A phenethyl group;

the method comprises the following steps:

a) reacting a compound of formula III-9

Wherein X_AAs defined above, with TiCl₄Processing;

b) treating the product of step a) with an amine base; and is

c) Reacting the product of step b) with 4-heptanone or 1-phenyl-3-hexanone to produce a compound of formula III-10.

10. A process for preparing a compound of formula III-13A, comprising the steps of:

d) treating a compound of formula III-10 prepared by the process of claim 9 with sodium hydride or potassium tert-butoxide to give a compound of formula III-11

Wherein R is₁Is that

a) N-propyl, or

b) A phenethyl group;

Wherein R is₁As defined above;

Wherein R is₄Is that

a) 5-trifluoromethyl-2-pyridyl, or

b) 5-cyano-2-pyridinyl to give compounds of formula III-13A

Wherein R is₁As defined above.

11. Method for preparing compound of formula JJJ-10

Wherein R is₁Is that

a) N-propyl, or

b) A phenethyl group;

the method comprises the following steps:

a) reacting a compound of formula JJJ-9

Wherein X_AAs defined above, with TiCl₄Processing;

b) treating the product of step a) with an amine base; and is

c) Reacting the product of step b) with 4-heptanone or 1-phenyl-3-hexanone to produce a compound of formula JJJ-10.

12. A process for preparing a compound of formula JJJ-13A, comprising the steps of:

d) treating a compound of formula JJJ-10 prepared by the process of claim 11 with sodium hydride or potassium tert-butoxide to give a compound of formula JJJ-11

Wherein R is₁Is that

a) N-propyl, or

b) A phenethyl group;

Wherein R is₁As defined above;

Wherein R is₄Is that

a) 5-trifluoromethyl-2-pyridyl; or

b) 5-cyano-2-pyridinyl to give compounds of formula JJJ-13A

Wherein R is₁As defined above.