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AU703962B2 - Substituted cyclic carbonyls and derivatives - Google Patents

Substituted cyclic carbonyls and derivatives Download PDF

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Publication number
AU703962B2
AU703962B2 AU32895/95A AU3289595A AU703962B2 AU 703962 B2 AU703962 B2 AU 703962B2 AU 32895/95 A AU32895/95 A AU 32895/95A AU 3289595 A AU3289595 A AU 3289595A AU 703962 B2 AU703962 B2 AU 703962B2
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AU
Australia
Prior art keywords
substituted
benzyl
alkyl
compound
formula
Prior art date
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Ceased
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AU32895/95A
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AU3289595A (en
Inventor
George Vincent Delucca
Charles Joseph Eyermann
Carl Nicholas Hodge
Prabhakar Kondaji Jadhav
Patrick Yuk-Sun Lam
James David Rodgers
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bristol Myers Squibb Pharma Co
Original Assignee
DuPont Merck Pharmaceutical Co
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Priority claimed from US08/197,630 external-priority patent/US5610294A/en
Application filed by DuPont Merck Pharmaceutical Co filed Critical DuPont Merck Pharmaceutical Co
Priority to AU32895/95A priority Critical patent/AU703962B2/en
Publication of AU3289595A publication Critical patent/AU3289595A/en
Application granted granted Critical
Publication of AU703962B2 publication Critical patent/AU703962B2/en
Assigned to DU PONT PHARMACEUTICALS COMPANY reassignment DU PONT PHARMACEUTICALS COMPANY Alteration of Name(s) of Applicant(s) under S113 Assignors: DU PONT MERCK PHARMACEUTICAL COMPANY, THE
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
    • C07D239/10—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
    • C07C49/723—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups polycyclic
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    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
    • C07C49/747—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups containing six-membered aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • C07D211/76—Oxygen atoms attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
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    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D223/08—Oxygen atoms
    • C07D223/10—Oxygen atoms attached in position 2
    • C—CHEMISTRY; METALLURGY
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    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D223/12—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/04—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D245/00—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms
    • C07D245/02—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
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    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/06—Seven-membered rings having the hetero atoms in positions 1 and 3
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/02—1,2-Thiazines; Hydrogenated 1,2-thiazines
    • C—CHEMISTRY; METALLURGY
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    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/15—Six-membered rings
    • C07D285/16—Thiadiazines; Hydrogenated thiadiazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/36—Seven-membered rings
    • C—CHEMISTRY; METALLURGY
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    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C07D313/02—Seven-membered rings
    • C07D313/04—Seven-membered rings not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
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    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
    • C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
    • C07F9/65848—Cyclic amide derivatives of acids of phosphorus, in which two nitrogen atoms belong to the ring

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

P/00/011 Regulation 3 2
AUSTRALIA
PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT
ORIGINAL
ft f ft ft .c a f ft ft *r Nf a f -'ft.
U
*4 ft ft...
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ft *9 ft t f TO BE COMPLETED BY APPLICANT Name of Applicant: Actual Inventors: Address for Service: Invention Title: THE DU PONT MERCK PHARMACEUTICAL COMPANY Patrick Yuk-Sun Lam; Prabhakar Kondaji Jadhav; Charles Joseph Eyermann; Carl Nicholas Hodge; George Vincent De Lucca; James David Rodgers.
CALLINAN LAWRIE, 278 High Street, Kew, 3101, Victoria, Australia "SUBSTITUTED CYCLIC CARBONYLS AND DERIVATIVES" The following statement is a full description of this invention, including the best method of p..rforming it known to me:- The present application is a divisional application of Australian Patent Application No 65493/94 (International Application No PCT/US94/01609) FIELD OF THE INVENTION This invention relates to substituted cyclic carbonyls and derivatives thereof useful as retroviral protease inhibitors, to pharmaceutical compositions comprising such compounds, and to methods of using these compounds for treating viral infection.
BACKGROUND OF THE INVENTION S" •Current treatments for viral diseases usually involve administration of compounds that inhibit viral DNA synthesis. Current treatments fo. AIDS (Dagani, Chem. Eng. News, November 23, 1987 pp. 41-49) involve administration of compounds such as diceoxycyt-. ine, tr'sodium phosphonoformate, ammonium e 21-tungsto-9-antimoniate, 1-b-D-ribofuranoxyl-1, 2,4triazole-3-carboxamiae, 3'-azido-3'-deoxythymidine (AZT), and adriamycin that inhibit viral DNA synthesis; compounds such as AL-721 and polymannoacetate which may prevent HIV from penetrating the host cell; and compounds which treat the opportunistic infections caused by the immunosuppression resulting from HIV infection. None of the current AIDS treatments have proven to be totally effective in treating and/or reversing the disease, In addition, many of the compounds currently used to treat AIDS cause adverse side effects including low platelet count, renal toxicity, and none marrow cytopenia.
The genomes of retroviruses encode a protease that is responsible for the proteolytic processing of one or more polyprotein precursors such as the pol and gag gene products. See Wellink, Arch. Virol. .9 1 (1988).
Retroviral proteases most commonly process the gag precursor into the core proteins, and also process the pol precursor into reverse transcriptase and retroviral protease.
The correct processing of the precursor polyproteins by the retroviral protease is necessary for the assembly of the infectious v'-i i. It has been shown that in vitro mutagenesis it produces proteasedefective virus leads to the production of immature core forms which lack infectivity. See Crawford et al., J.
Virol. a 899 (1985); Katoh et al., Virology 1J5. 28J (1985). Therefore, retroviral protease inhibition 15 provides an attractive target for antiviral therapy.
9. See Mitsuya, Nature 125 775 (1987) Moore, Biochem. Biophys. Res. Commun., 159 420 S. (1989) discloses peptidyl inhibitors of HIV protease.
Erickson, European Patent Application No. WO 89/10752 discloses derivatives of peptides which are inhibitorof HIV crrcease.
U.S. Patent 4,652,552 discloses methyl ketone derivatives of tetrapeptides as inhibitors of viral proteases. U.S. Patent No. 4,644,055 discloses I 25 halomethyl derivatives of peptides as inhibitors of viral proteases. European Patent Application No. WO 87/07836 discloses L-clutamic acid gamma-monohydroxamate as an antiviral agent. PCT Patent Application Publication No. WO 93/07128, the disclosure of which is hereby incorporated herein by reference, discloses synthetic proceduxes for preparing HIV protease inhibitors.
The ability to inhibit a viral protease provides a method for blocking viral replication and therefore a treatment for viral diseases, such as AIDS, that may have fewer side effects, be more efficacious, and be c -r r -3less prone to drug resistance when compared to current treatments.
The present invention concerns novel substituted cyclic carbonyls and derivatives thereof, which compounds are capable of inhibiting viral protease and which compounds are believed to serve as a means of combating viral diseases, such as AIDS. The substituted cyclic carbonyls and derivatives thereof of this invention provide significant improvements over protease inhibitors that are known in the art. The substituted cyclic carbonyls and derivatives of the invention are particularly useful as inhibitors of HIV protease and similar retroviral proteases.
The compounds of the invention are of low molecular weight and may, therefore, have good oral absorption properties in mammals.
carbonyl compounds and derivatives thereof, of formula S(1) (described below) which are useful as inhibitors of Human Immunodeficiency Virus (HIV)E The compounds of the present inventiun inhibit the HIV protease and thereby inibit HIV replication. The present invention also includes pharmaceutical compositions containing such compounds of formula I, and methods of using such compounds for the inhibition of HIV in a sample containing HIV, and methods of using such compounds for the treatment of HIV infection in a patient.
The present invention also includes methods of inhibiting HIV or treating HIV infection by administering a compound of formula in combination with one or more second therapeutic agents selected from -4other inhibitors of HIV and/or therapeutic agents for the treatment of HIV-mediated disease conditions.
Also included in the present invention are pharmaceutical kits comprising one or more containers containing pharmaceutical dosage units comprising a compound of formula I, for the treatment of HIV infection.
DETAILED DESCRIPTION OF THE TNVENTTON This invention provides novel substituted cyclic carbonyl compounds and derivatives thereof, of formula (described below) which are useful as inhibitors of Huma. Im,-munodeficiency Virus (HIV). The compounds of 1. the present invention inhibit the HIV protease and thereby inhibit HIV replication. The present invention also includes pharmaceuticai compositions containing such compounds of formula I, and methods of using such .co..-cunds fo- the inhibition of HIV in a sample 2 containing and methods of using such compounds for the treatment or HIV infection in a patient.
;1 There is provided by this invention a compound of the fcrrrua
R
4 A R 7
A
R
4
R
7
R
5 R R 6 Sn
(I)
or a pharmraceutically acceptable salt forr.. thereof wherein: R4~ and R7 are independently selected from the following groups: hydrogen; Cl-CS alkyl substituted with 0-3 R1- 1 C2-C8 alkenyl substituted with 0-3 R11; C2-CB alkynyl substituted with 0-3 R 1 1 a C3-C 1 4 carbocyclic ring system substituted with 0-3 R 1 1 or 0-3 R 1 2 a heterocyclic ring system selected independently from indolyl, furanyl, pyridyl, thienyl, pyrrolyl, benzolbthienyl, pyrazolyl, thiazolyl, benzofuranyl, teteadhydroisoquinolinyl, benzotriazolyl, benzimidazolyl, or imidazolyl said heterocyclic ring system being substituted with 0-2 R 12 11 7CO2RI 3
R
4 A and R 7 A are independently selected from the following groups: hydrogen; CI-C4 alkyl substituted with 0-6 halogen or 0-3 Cl-C2 alkoxy; benzyl substituted with 0-6 halogen or 0-3 Ci-C2 *~.alkoxy; C02R, 1 3 :R'4 and R 4 A can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R 12 S R 7 and R 7 A can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R2 n is 1
R
5 is selected from H; halogen; Cl-C6 alkyl substituted with 0-3 RI 1
-N(R
20
-SR
20
-OR
20 or -N 3 -6- R6 is independently selected from: hydrogen, halogen, Cl-C6 alkyl substituted with 0-3 R" -N(R 2 0 )2,
-SR
2 0
-OR
2 1 or -N 3
R
5 and R 6 can alternatively join to form an epoxide or aziridine ring; -OCH2SCH2O-; OCH2O-; -OC(CH3)20-; -OC (CH2) 3NH2) (CH 3 -OC (OCH3) (CH 2
CH
2
CH
3 0-; -OS -NHC NH-; -OC NH4-; -NHC 0-; -NHCH2O-; -OCH2NH-; -NHC -Os NH-; -NI-C -OC NH-; -NHC NH-; -NHC (CH 3 20-; -OC (CH 3 2NH- R~a is selected from hydrogen, halogen, C1-C6 alkyl, -14(R 2
-SR
20 or -OR 20 R~a is selected from: hydrogen, halogen, Cl-C6 alkyl, *-N(p 2 0
-SR
2 0 or -OR 2 1 R6 and R~a can alternatively join to form or a :ketal ring; R20 and R2a cane altentively joinctd fom:=~=,o
R
20 andR 2 are ainependenl selecited from: 0- -7benzoyl substituted with 0-3 R 1 2 phenoxycarbonyl substituted with 0-3 R1 2 phenylaminoc-arbonyl substituted with 0-3 R1 2 or phosphate ester"; Rll is selected from one or more' of the following: keto, halogen, cyano, -CH 2
NR
13
R
1 4
-NR
13
R
14 -C02RI 3 00C(=O)R 1 3
I-OR
1 3 -S(O)mRl 3 -NHC(=NH-)N11R 1 3 -C(=Nli)NHR 1 3
-C(=O)NR
1 3
R
1 4
-NR
1 4
C(=O)R]
3
=NOR
1 4
-NR
1 4 0(=O)0R 1 4 -00 NR 13 Rl 4
-NR
13 C (=O)NR1 3
R
1 4 -NR1 4 S02NR 13
RI
4
-NR
14 SO2R 1 3 -SO2NR 13 Rl 4 -OP (OR 13 2 Cl-C4 alkyl, 02-04 alkenyl, C3-C6 cycloalkylmethyl, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C7-ClO arylalkyl, hydroxamic acid, hydrazide, boronic acid, sulfonamide, formyl, C 3
-C
6 cycloalkoxy, CI-C4 alkyl substituted with -NR 13 Rl 4 01-04 hydroxyalkyl, methylenedioxy, ethylenedioxy, 0-04 haloalkyl, 01-04 haloalkoxy, 01-04 alkoxycarbonyl, pyridylcarbonyloxy, 01-04 alkylcarbonyl, 01.-04 alkylcarbonylamino, -00H2C02H, 2-(l-morpholino)ethoxy, azido, or C0(R 1 4 =N (0R 14 1-3 amino acids linked together via amide bonds, .9:9 said amino acid being linked via the amine or carboxyJ-ate terminus; :30 03-010 cycloalkyl substituted with 0-2 R 1 2 0-04 alkyl substitued. with 0-2 R 1 2 (01-03 al~kyl) substituted with 0-2 R 1 2 02-06 alkoxyalkyl, substituted with 0-2 R 12 01-04 alkylcarbonyloxy substituted with 0-2 R1 2 06-010 arylcarbonyloxy substituted with 0-2 R 12 C5-C14 carbocyclic residue substituted with 0-3
R
1 2 1.
a 5- to J.0-membered heterocyclic ring system containing~ 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-3 R 12 R117' is selected from one or more of the following: IC keto, halogen, cyano, -CH-2N CR13B) (Rl4B) -N (Rl 3 B) (Rl4B) -C02H, -00 (01-03 alkyl) -OH, 02-06 alkoxyalkyl, -C(=O)NH 2 -OC-(=0)NH 2 -NHCi(=O)NH- 2 -SO2NH-2, Cl-C4 alkyl, 02-04 alkenyl, C3-COQ cycloalkyl, 03-CS 15cycloalkylmethyl, benzy.1, phenethyl, phenoxy, benzyloxy, nitro, 07-010 arylalkyl, hyciroxamic acid, hydrazide, boronic acid, C3-C6 cycloalkoxy, 01-04 alkyl substituted with -N:H2, 01-0C4 hyldroxyalkyl, methylenedioxy, ezhylenedioxy, 01-04 haloalkyl, 01-04 nalcalkoxy, 01-04 alkoxycarbonyl, 01-04' a 1ky 1ca rbonyloxy, 01-04 alkylcarbonyl, C1-04 vylcarbonylaino, -O0H2C02H, 2- (1-morpholino) ethoxy, azido, aryl (01-03 aky) ,a 05-014 carbocyclic residue; E :c 1O-mernbered heterocyclic ring system containing 1 to 4 heteroatoms independently se'.ected from oxygen, nitrogen or sulfur, said heterocyclic ring system substituted with 0.3 p,12AI; .L wher. a substituent on carbon, is selected from one or more of the following: ph-en:,K', benzyl1, phenethyl, phenoxy, bentyl,,oxy, halogen, hydroxy, nitro, cyano, 01-04 alkyl, cycloalkyl, C3-C6 cycloalk-ylrethyl, C7- -9arylalkyl, Cl-C 4 alkoxy, -C02H-, hydroxamic acid, hydrazide, boronic acid, sulfonamide, formyl, C3-C6 cycloalkoxy, -OR 13 C1-04 alkyl substituted with -NR 13
R
14
-NR
13 R!4, C2-C6 alkoxyalkyl optionally substituted with -Si(CH- 3 3 Cl-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, Cl-C4 haloalkyl, Cl-C4 haloalkoxy, Cl--C4 alkoxycarbonyl, Cl-C4 alkylcarbonyloxy, Cl-C 4 alkylcarbonyl, Cl-C4 alkylcarbonylamino, -S(O)mRl 3 -S02NR 13 Rl 4 NHSO2R 1 4 -OCH-2CO2R1 3 2- (2-morpholino) ethoxy, -C (R 1 4 =N (0R 1 4 or a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur; or R 12 may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-membered ring, said 5- or 6- membered ring being optionally substituted on aliphatic caibons with halogen, Cl-CK., 0-04 alko>:y, hydroxy, -NR 1 3 Rl 4 or, when R 1 2 is attached to a saturated carbon atom, it may be =0 or or when p, 12 is attached to *sulfur it may be =0; p1 2 when a substituent on nitrogen, is selected from .one or more of the following: phenyl, benzyl, phenethyl, hydroxy, 01-04 hydroxyalkyl, Cl-C4 alkoxy, C1-C4 alkyl, 03-06 cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR 13
R'
4 -NRl 3
R
14 C2-C6 alkoxyalkyl, Cl- C4 haloalkyl, Cl-C4 alkoxycarbonyl, -CO2H, Ca- 04 alkylcarbonyloxy, Cl-C4 alkylcarbonyl, -C (R 14 =1 (OR 4 Rl 2 A, when a substituent on carbon, is selected from one or more of the following: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, Cl-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, 07- Clo arylalkyl, Cl-C4 alkoxy, -C02H, hydroxamic acid, hydrazide, boronic acid, sulfonamide, formyl, C 3
-C
6 cycloalkoxy, -OR 1 3
CI-C
4 alkyl substituted with -NH 2 -14H 2 -NHMe, C2-CG alkoxyalkyl optionally substituted with -Si(CH 3 3 CI-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, Cl-C4 haloalkoxy, Cl-C 4 alkoxycarbonyl, 01--4 alkylcarbonyloxy, Cl-C4 alkylcarbonyl, Ci-C4 15 alkylcarbonvlamino, -S(O)mMe, -SO2NH 2 -NHSO2Me, -OCH2C02R1 3 2-(l-morpholino)ethoxy,
C(=NOH)-')H
2 or *a c: 6-membered heterocyclic ring containing V. from I. to 4 heteroatoms independently selected frolm oxygen, nitrogen or sulfur; 8 may be a 3- or 4- carbon chain attached to 4 adjacent carbons on the ring to form a fused cr 6-membered ring, said 5- or 6- membered ri-ng being optionally substituted on the aliphatic carbons with halogen, Cl-C4 alkyl, C4 alkoxy, hydroxy, -NH 2 or, w.nR* 2 A is attached to a saturated carbon atom, imay be =0 or or when R 1 2 is attached to nut.f r it may be =0; pJ.2A, when a substituent on nitrogren, is selected from one or more of the following: phenyl, benzyl, phenethyl, hydroxy, Cl-C4 hydroxyalkyl, Cl-C4 alkoxy, Cl-C4 alkyl, C3-C6 loalkyl, C3-C6 cycloaIKYlmethyl, -CF .NH2, -11-
-NH
2 C2-C6 alkoxyalkyl, CI-C4 haloalkyl, Ci- C4 alkoxycarbonyl, -CO2H, Cl-C4 alkylcarbonyloxy, CI-C4 alkylcarbonyl, -C (=NOH) NH2; R1 3 is selected from:
H;
phenyl substituted with 0-3 R11A; benzyl substituted with 0-3 R11A; C,-CG alkyl substituted with 0-3 R11A;
C
2
-C
4 alkeny substituted with 0-3 R11A; Cl-C6 alkylcarbonyl substituted with 0-3 R11A; Cl-CG alkoxycarbonyl substituted with 0-3 RlA; CI-C6 alkylaminocarbonyl substituted with 0-3 R11A; C3-C6 alkoxyalkyl substituted with 0-3 R11A;
R
1 4 is hydrogen, hydroxy, CF3, Ci-C 6 alkyl substituted with 0-3 groups s-lected from Oi, CI-C 4 alkoxy, 0 halogen, NH2, -NH(C1-C4 alkyl), CI-C 6 alkoxy, C2-C6 alkenyl, phenyl, benzylj 00 *66,25 0 R 1 3 and ?14 can alternatively join to form -(CH2)4-, -CH2CH2N(R 1 5 )CH2CH2-, or -CH2CH2CH2CH2-; R1 3 B and R1 4 B are independently selected from H or C 1
-C
6 0 30 alkyl, or R1 3 B and R14B can alteratively join to fo-.n -CH2CH2N(R 15 )CH2CH2-, or -CR2CH20CH2CH2-;
R
1 5 is H or CH3; 0 m is 0, 1 or 2; 12 W is selected from:
-N(R
22 )2N(R 23 -ppR 2 2
(R
2 4a)N (pR 23 wherein: Z' is 0 or R4
R
22 and R 23 are independently selected from the following: hydrogen; Cl-GB alkyl substituted with 0-3 R 31 C2-C8 alkenyl substituted with 0-3 R 31 C2-C8 alkynyl substituted with 0-3 R 31 a C3-C14 carbocyclic ring system substituted with 0-5 R 3 1- or 0-5 R 3 2 a heterocyclic ring system selected independently from pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, tetrazoyl, triazinyl, pyrazinyl, pyridazinyl, oxazolidinyl and thiazolyl said I: heterocyclic ring system being substituted with 0-2 R 32 :OR22r; -N (R 2 2 a) (R2 2 bs, Go**: 13
R
22 a and R 2 2 b are independen~tly selected from the following: hydrogen; Cl-C8 alkyl. substituted with 0-3 R 3 1 C2-C8 alkenyl substituted with 0-3 R 3 1 C2-C8 alkynyl substituted with 0-3 R 3 1 a C3-C14 carbocyclic ring system substituted with
R
31 or 0-5 R 32 a heterocyclic ring system selected independently from pyridinyl, furanyl, thienyl, pyrrolyl, thiazolyl, pyrazolyK imidazolvi, indolyl, benzimidazolyl, 1 H-indazolyl, oxaxolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl said heterocyclic ring system being substituted with 0-2 R 3 2
R
2 4 is selected from; hydrogen; hydroxy; amino; Cl-C4 alkyl; Cl-C4 alkoxy; mono- or di- (CI-C6 alkyl)amino; cyanc; nitro; benzyloxy; -NHS2aryl, aryl being optionally substituted with (Cl-CE) alkyl; 14 R2 4 a is selected from: hydroxy; amino; CI-C4 alkyl; Cl-C 4 alkoxy; mono- or di-(Cl-C6 alkyl)amino; cyano; nitro; benzyloxy; or phenoxy; alternatively, R 2 2 p 25, or R 2 6 independently, can join with R 4 or R 4 A to form a 5- or 6-membered fused heterocyclic rinq selected from pyrrolidine, miorpholine, thiomorpholine, p i peridine, or piperazine or alternatively, R 23 can Join with R7 or R741to form a 5- or 6-membered fused heterocyclic ring or carbocyclic ring substituted with 0-2 R 1 2 said heterocyclic ring selected from pyrrolidine, mrorpholine, thiomorpholine, piperidine, or piperazine or ***alternatively, or R 23 :e can join with R 5 or R 6 to form a 0- to 7-membered 00 bridge to form a carbocyclic or heterocyclic ring, 9 said bridge being substituted with 0-2 R 1 2 and said heterocyclic ring being selected from pyrrolidine, morpholine, thiomorpholine, *piperidlne, or piperazine) 15 alternatively direct bond; alternatively direct bond;
R
23 can j~~~Inwt 7 tofra R3can join with R7A to form a
R
3 1 is selected from one or more of the following: keto, halogen, cyano, -CH 2
NR
13
R
14
-NR
13
R
14
I
-C02R 13 -C(=O)Rll, -OC(=O)RI 3 -0R 13 C2-C6 alkoxyalkyl, -S (0)MR 13 -NHC (NH) NHR 13 p p 0 *0 0 0 p.
00 0 0 0 @0 0* 0 00~ 0 0 4e 0 0* 0 90 0 000~~0 0 0 000* 0* 0 ('7 -16- -C(=NH)NHR-, -C NPI"R!4, -NR 14 C-(=O)Rl 3 =N0R 14
-NR
14
C(=O)OR
14 -0C NR 1 3
R
1 4
-NR
13 C NR 13
RI
4
-NR
13 0 NR1 3
R
1 4
-NR
14 S02NR1 3 RI4, -NR' 4 S02R1 3 -S02NR1 3 R14, Cj- C4 alkyl, C2-04 alkenyl, 03-ClO cycloalkyl, C3-C6 cycloalkylmethyl, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C7-ClO arylalkyl, hydroxamic acid, hydrazide, oxime, boronic acid, sulfonamide, formyl, C 3
-C
6 cycloalkoxy,
C
1
-C
4 alkyl substituted with -NR 1 3Rl 4 C1-04 hydroxyalkyl, inethylenedioxy, ethylenedioxy, 01-04 haloalkyl, Clj-C4 haloalkoxy, Cl-C4 alkoxycarbonyl, 01-04 alkylcarbonyloxy, 01-04 alkylcarbonyl, Cl-C 4 alkylcarbonylamino, ~-00H2002RI 3 2-(I-mo,.pholI'no)et.oxy, azido, -C (pt' 4 1 4 nr -3amino acids, lini.,,d together via amide bonds, **said amino .icid be~ng linked via the amine or carboxylate terminus; 2C a C05-C14 :arbocyclic residue substituted with to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently fee~* selected from ox:ygen, nitrogen or sulfur, said 2 heterocyclic ring system being substituted with 0-2 FR 32 0 *$of p.
3 when a substituent on carbon, is selected from one or more of the following 3 r. phenethyl, phenoxy, 03-010 cycloalkyl, 03-06 cycloalkylinethyl, 07-010 arylalkyl, hydrazide, oxime, borecnic acid, 02-06 alkoxyalkyl, methylenediox:y, etiiylenedioxy, 01-04 alkylcarbonyloxy, -NH-S02R 14 benzyloxy, halogen, 2-(V-morpholino)ethoxy, -CQ2P13, 17 hydroxamic acid, -0ONR13NR1 3 Rl 4 cyaflo, sulfonamide, -CHO0, C3-C6 cycloalkoxy, -NR1 3 Rl 4 _(R14)=N(0R 1 4 -N02,
-OR,
1 3
-NR
4 0
R
4 1
_SOMR
13 -SOmNR1 3 R1 4 0C(0)NR1 3 Rl 4 -OC( =O)NR1 3 Rl 4 -C(=O)Rll,
-OC(=O)R
1 1 -0002R1 3 phenyl, -C
NR-
3 (Cl-C4 alky') NR1 3 Rl 4 -C(=O)NR4 0
R
4 1 Cl-C 4 haloalkyl, 01-04 haloalkoxy, 02-04 haloalkelYl, C1-C4 haloalkyflyl, NR13C 2Nhl 3 R1 4 -C
NR
1 3 C (B 11 2 NR1 3 C2R3 -C (-0)NR 1 3 (0-04 alkyl)hNR13CO2R1 3 -C
CR
13 (Cl-C4 alkyl)-R11; C C 2
NRI
3
R
1 4 15 -C 0R 1 1 2 NR13C02R 1 3 -C -(01-04 alkyl)
R
13
R
4 -C '01-04 alkyl) NR13CO2R; or *O CI-C4 alkoxy substituted with 0-4 groups selected from:
R
11 03-06 cycloalkyl,
CO
2
R
13 -C(0O)NR13R~I, -,NR1 3 Rl 4 or OH; alkyl substituted with 0-4 groups selected frcm:
R
1 1 =Iqpl 4 =NNR13C(0O)NR1 3 RI4, =1Np 1NR 3 C OR', or -NR1 3 R1 4 C 2-04 alkenyl substituted with 0-4 R1U; C 2-1-04 alkynyl substituted with 0-4 R 1 a 5- or 6-meimbered heterocyclic ring containinlg from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur substituted with 0-2 R 12 or R32 may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused or 6-membered rinj, said 5- or 6- membered ring bcing optionally substituted on the aliphatic carbons with halogen, 01-04 alkyl, 01-0C4 alkoxy, hydrcxY,
-NR
1 3
R
1 or, -18when *32 is attached to a saturated carbon it may be =N0I-; or when JR 32 attached to sulfur it may be =0;
R
32 when a substituent on nitrogen, is selected from one or more of the following: phenyl, benzy., phenethyl, hydroxy, Cl-C4 hydroxyalkyl, Cl-C4 alkoxy, Cl-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR 13
R
1 4
-NR
13
R
1 4 C2-C6 alkoxyalkyl, Cj-- C4 haloalkyl, C1-C4 alkoxycarbonyl, -CO2H, Cl-
C
4 alkylcarbonyloxy, Cl-C4 alkylcarbonyl, -C (R 14
(OR
14
R
40 is selected from: H, Ci-C 3 alkyl;
JR
41 is selected from: -C (=0)NR 1 3
RI
4
NR
13
NR
1 3
R
1 4 U:-C (R" 1 2NR 1 3
R
1 4 -C C (RI 1 I) 2
NR
1 3
NR
13 Rl 4 9. -C C(R" 1 2NR 13 C02R 1 3 -C vG.oV 19- -C R 1 1; -C -(CI-C 4 alky]-.NR13C2R 3 1-3 amino acids linked together via amide bonds, and linked to the N atom via the carboxyl2.te terminus.
wherein said aryl group is phenyl or naphthyl; provided that:
R.
4 pR 4 A, R 7 and R 7 A are not all hydrogen; when R 4 and R 4 A are hydrogen, R 22 is not hydrogen.
6* I p ft.. ft ft.. ft ft. ft ft.
ft. ft ft ft ft.
ftft ft.
ft. ft ft ft ft ft ft ft 0
N
20 111al Preferred compounds include those compounds described above wherein: -C
(R
2 4 a); -S and n is I. or 2.
Preferred compounds of this invention are those compounds described above with the proviso that when: W is -C (p 2 5) (p 2 6 C(R27) (R2 8 and 0; and Z, is 0; 9 then R2 5 p, 2 6
R.
27 and
R
2 8 are not all
H.
Ic] Preferred compounds of this invention are those 99 compounds described above with the proviso that when: :W is -C 5 (p2 6) S (Z,2C(' 2 7) (p 28 and n 0; and -21- Z' is C or NH; then R 2 5
R
2 6
R
27 arnd R 28 are not all H.
[Id] Preferred compounds of this invention are those compounds described above with the proviso that when: W is or and n 1; then R 6 and R 6a are not both H.
[le] Preferred compounds of this invention are those compounds described above with the proviso that when: W is -C(R 25
(R
26
)C(R
34
(R
35
)C(R
27
(R
28 and n 0; and 15 R 34 or R 3 5 are N(R 38
(R
3 9 then R 25 26
R
27 and R 28 are not all H.
Further preferred compounds of the invention of S: formula are compounds of formula (II): w
R
4 R7
R
5
R
6
(II)
S* S O 25 or a pharmaceutically acceptable salt form thereof wherein:
R
4 and R 7 are independently selected from the following groups: hydrogen; C1-C4 alkyl substituted with 0-3 R 1 1 C3-C4 alkenyl substituted with 0-3 R11;
-II
-22-
R
5 is -OR 2 0
R
6 is hydrogen or -OR 21
R
2 0 and R 2 1 are hydrogen; RUI is selected from one or more of the following: 11, keto, halogen, -CH 2
NR
13 Rl 4
-NR
13
RI
4
-OR
13 C2-C 4 alkoxyalkyl, C2-C 4 alkenyl,; cycloalkyl substituted with 0-2 R 12
C
1
-C
4 alkyl substituted with 0-2 R-1 2 ary'L(Ca-C 3 alkyl) substituted with 0-2-R 1 2 aryl substituted with 0-3 Ri 2 or a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently se'lected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 12 12 when a substituent on carbon, is selected from one or Pnore of the following: pheniyl, benzyl, phenethyl, phenoxy, benzyloxy, 25 alogenC1-C4 alkyl, C7-ClO arylalkyl,C-C alkoxy, 2- (1-morpholino) ethoxy, -CO2H, hydroxamic acid, hydrazide, -C(Rl 4 )=N(0R 14 cyano, boronic acid, sulfonamide, formyl, C 3 C6 cycloalkoxy, -OR 1 3
C
1
-C
4 alkyl substituted with -NR 1 3
R,
1 4
-NR
1 3 Rl 4 rnethylenedioxy, C1-C4 haloalkyl, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, hydroxy, hydroxymethyl; or aa 5- or 6-membered heterocyclic ring containing from I to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur; -23-
R
12 when a substituent on nitrogen, is selected from benzyl or methyl;
R
1 3 is H, Ca-C 4 alkyl, C3-CG alkoxyalkyl, 02-04 alkenyl, or benzyl; R1 4 is OH, H, CE 3 C1-04 alkyl, 01-04 alkoxy, NH 2 02-04 alkenyl, or benzyl;
R
13 and R14~ can alternatively join to form -(CH2)4-, -CH2CH2N(R 1 5 )CH2CH2-, or -CH2CH20CH2CH2-;
R
15 is H or CH3; W is selected from: -N(R 22 2 N (R 23 -N(R 22 (R 24 (N(R 23 wherein: Z is 0, S, or N-CN; 2/ is 0;
R
22 and R 2 are independently selected from the following: hydrogen; Cj-CB alkyl substituted with 0-2 R 31 C2-C6 alkenyl substituted with 0-1 R 31 alkynyl substituted with 0-1 R 31
R
24 a is selected from -OH, Cl-C 4 alkoxy, mono- or di- (Ci-C6 alkyl) amino; R3 isslce rmoeo mr ftefloig keo haogn -C2R31,-R1R4 9
C
a 5s seet 0med feroe li of n thefolowng seohlogten, fromoxygen, nrogen 4 -or ufu, sa-id hetercyclaiyc -Cring(R 1 syte0binRsbsitte ar wiustt ed with 0-p32o p3,we slec tdfro onygen, nirog e sufrm said or mnore of the following: phenethyl, phenc,-xy, 03-06 cycloalkyl, C 3 -C6 cycloalkylmethyl, C7-Cl0 arylalkyl, hydrazide, oxime, boronic acid, 02-06 alko)xyalkyl, methylenedioxy, ethylenedioxy, 01-04 alkylcarbonyloxy, -NHS02R1 4 f benzy~oxy, halogen, 2- (1-morpholino) ethoxy, -CO2RI 3 hydroxamic acid, -C0NR1 3 lqRl 3 Rl 4 cyano, boronic acid, sulfonamide, -CHO, 03-06 cycloalkoxy, -NR1 3 Rl 4 -C(R14)=N(OR1 4 N02,
-OR
1 3
-NR
4 0
R
4 1 -SOmR1', -SOmNR 1 3
R
1 4 -C(=0)NR 13 Rl 4 -O0(=O)NR1 3
RI
4 -0(=0)RII, -00 Rll, -O002RI 3 phenyl, -C NR 13 (01-04 alkyl)_NRl 3 R3 4, -c NR4 0
R
4 01-04 haloalkyl, 01-04 haloalkoxy, 02-04 is :1 haloa±lkenyl, 02-04 haloalkynyl, or -C (=0)0C(R 1 2 1qR 1 3
R
1 4 -C 1 2 NR1 3 002R 1 (01-04 alkyl)-NR 1 3
R
1 4 -(01-C4 alkyl)-IRl 3 C02R! 3 or 01j-0_ alko.v substituted with 0-3 groups selected 0 ~from: F11, 03-06 cycloalkyl, -CO 2
R
1 3, (=0)I'R 13
R
1 4 -IpR' 3 Rl 4 or OH; 01-04 alkyl substituted with 0-3 groups selected from: =NR 1 4 =qNpR1 3 C(=O)NR1 3 Rl 4 or 02-04 alker~.1 substituted with 0-3 Ri 1 02-04 alkyny.. substituted with 0-3 Ri 1 a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, substituted 0 with 0-3 Ri 2 1;
R
32 when a substituent on nitrogen, is selected from benzyl or methyl; mn is 0, 2, or 2; 26 PA4 0 is selected from: CI-C3 alkyl-; R41- is seliected from: -C NR1:3R1 4 -C jj13NR' 4 -C C 2 NR1 3 p, 4 0, -27- -C C 2 NR1 3 C0 2
R
1 -C H-; -C R 1 -1; -C -(C 2
-C
4 alkyl) -NR 13
R
1 4 -C -(CI-C 4 alkyl) -NR1 3 C0 2
R
1 3 1-3 amino acids linked together via amY.de bonds, and linked to the N atom via the carboxylate terminus; provided that:
R
4 and R7 are not both hydrogen; when R 4 is hydrogen, R2 is not hydrogen a 20 Preferred compounds of the present invention are compounds of formula (II) described above, wherein:
R
4 and R7 are selected from benzyl, fluorobenzyl, pyrrolylmethyl, methoxybenzyl, isobutyl, 25 nitrobenzy. or aminobenzyl, thienyirnethyl, hydroxybenzyl, pyridylmeth.'1, naphthylmethyl;
R
5 is -OH;
R
6 is hydrogen or -OH; R13 is H, C 1
-C
4 alkyl, C 2
-C
4 alkenyl, or benzyl; R14~ is OH, H, CF3, C 1
-C
4 alkyl, C 1
-C
4 alkoxy, NH2, C 2 -C4 alkenyl, or benzyl; -28-
R
13 and R 14 can alternatively join to form -(CH2)4-, -CH2CH2N(R' 5 )CH2CH2-, or -CH2CH20CH2CH2-; W is selected from:
-N(R
22 S 2N (R 23 1C R 22 and R 23 are independently selected from the following.
hydrogen; Cl-CB alkyl substituted with 0-2 R 3 1 i C2-C6 alkenyl substituted with 0-2 R 31 C2-C4 alkynyl substituted with 0-2 R 31 9.
20 9999 99 *9 S 9.
9 99 09 9 96 9 99 .9 9* 25 is selected from one or more of the following: halogen, -OR 13 Cl-C4 alkyl, C3-C10 cycloalkyl, -C (RI 4
(OR
1 4 -C02RI 3 _S (0)mR 1 3; aryl substituted with 0-5 R 3 2 or a heterocyclic ring system chosen from pyridyl, pyri-midinyl, triazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, iLnidazolyl, tetrazolyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl, oxazolidinyl, benzimidazolyl, benzotriazolyl, indazolyl, benzoxazolinyl, benzoxazolyl, said heterocyclic ring being substAtuted with 0-2 R 3 2 30 p 32 when a substituent on carbon, is selected from one 9 or more of the following: -CONH2, -C02H, -CH-O, -CH 2 NHOH, -CH 2 Np 1 3
RI
4
-NR
13
R
1 4 hydroxy, hydroxymethyl, -C(Rl 4 )=N(0R 1 4 halogen, methoxy, methyl, 9.:e 35 n~itro, cyano, allyloxy, -CO2CH3, -NHCHO, -11HCOCH23, -OCO2CH3, -CH=NCH2CH2OHb -29- -OCONHCH2C 6H5, -OCONHCH3, oxazolidinyl, -C=c- CH2OR, -COCR3, hydroxyethyl, C1-3 alkyl (said alkyl substituted with 0-4~ halogen, or OH), tetrazolyl, -OCH2CONR2, -CONRNH2, -CH=NNHCONH2, -CONHOCH3, -CH2CH(OH)CH2OR, adarnantamido, hydroxyethoxy, dihydroxyethyl, -C (NH2) =NH, -CONH-CH3, -B (OH) 2, benzyloxy, -CONHCH2CHJ, -CON (CH2CH3) 2, rethylthio, -SO2CH3, -IHCONH2, -NHCONHCHJ, -NHCOCH2N (CH3) 2, -NHCOCH2NHCH3, -NHCOCH2NHCO2CH2C6H5, -NH :H2NH2, -NHCOCR (CH3)NHCO2CR2C6H5, -NRC -OCH (CR206-I CO2CH2C6H5, -NHCOCH (CR3) NH2, -NRHCOCRH(CH2C6HS)NH2, -CO2CH2CH3, 15 -CONRHCH2CR2CH3, -CONRCH(CH3) 2, -CH2-iinidazole, -COC(CH3)3, -CH(OH)CF3, -CO-imidazole, -C0p\'razolyl, oxadiazolidinony]., -COCF3, -COCE2CH3, -COCH2CH2CH3, pyrazolyl, -SO2NH2, =N(OH) or C(CF3)=N (OH) phenyl, 2 C acetox:y, hydroxyamino, -N (CR3) (CR0) cy.1 -propyi me-.hoxy, -COIR 3 P1, -CO)NOR, 4 (diethylaminoethyl) aminocarbonyl, N-ethyl, N-methylaminoethyl) aminocarbonyl, ****(4-rethylpiperazinylethy.) aminocarbonyl, (pyrrolidiriylethyl) aminocarbony-, (piperidinylethy2.) aminocarnonyl, -NHCCH-NHC,13, N- (4morpholino) ethyl) aminocarbonyJ., or N- dimethylarnino) ethyl) aminocarboinyl;
R
3 2 when a substitueit on nitrogen, is methyl.
Alsc preferred are compounds of formula (IIdc) or a pharmaceutically acceptable salt form thereof, wherein: p 4 an~d F7 are independer~t .y selected from: benzyl, fl,,.3rcbenzyl, pyrrolylmethyl, methoxybenzyl, iS, .bu nitrobenzyl or aminobenzyl, thin-zKttthyl, hydrc;;ybenzyl, pyridvlriet',yl, naphthylmethyl; *Z 2 p2and are i.ndepender, selected fromr the group h rog 0 ly-, mp et hy~ propy I cy-ocropy lmethyl, n-butyl, i-butyl, C:9:Hi&C (CH3) 2tpyridinylmethyl, methallyl, n p, r-tyl, i4-pentyl, he>;yl, benzyl, isoprenyl., propargy.2, pic linyl, rethoxyethyl, -y oh:.:lr~z~h..,dimethyl-1--tyl, ethoxyet-hyl, Methyl-oxazolinylmethyl, n...phthylmethyl, netylcazoinymetylvinyloxyethyl, r -e talucrobenzyl, cjuinolinylmettyl, carbo:xybenzyl, chloro-':hienyl, tenzyloxybenzyl, phenylbenzyl, adamantylethyl, cy t--!opropylmethoxyberizyl, methoxybenzyl, mez-hylbenzyl, ethoxybenzyl, hydroxybelzyl, i rxynety~enzlaminobenzyl', rryllbenzyl, cyanohenzyl', cinnamyl, allyloxybenzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl, chloromethylbenzyl, fluoromethylbenzyl, iodobenzyl, brornobenzyl, cyclobutylmethyl, formaldoximebenzyl, cyclopentylmethyl, nitrobenzyl, (H 2 benzyl, carbomethoxybenzyl, carboethoxybenzyl, tetrazolylbenzyl, and dimethylallyl, aminornethylbenzyl, (O-benzylformaldoxime) benzyl, (O-methylformaldoxime)benzyl, (CH3O200)-benzyl, (HOCH2CH2N=CH) -benzyl, N-benzylaminocarbonylbenzyl, Nmethylaminobenzyl, N-ethylaminobenzyl, N-ethylarninomethylbenzyl, acetylbenzyl, acetoxybenzyl, N-hydroxylaminobenzyl, phenyirnethyl-boronic acid, Nhydroxy2.aminomethylbenzyl, a. (hydro:yl) ethylbenzyl, (CH3C (=NOH) )-benzyl, (H2NNI-C(=O) )-benzyl, (H2NC(=O)NHN=CH)-benzyl, 20 (CH3ONH-C(=O) )-benzyl, (HONHC(=O) )-benzyl, N, N-dimethylaminocarbonylbenzyj., (.HOCH2C-i(OH) CH20) -benzyl, hydroxyetho:~ybenzyl (oxazolidinyl) -benzyl, Chydroxyl) hexyl, hexenyl, (hydroxy)octyl, (hydroxyl)pentyl, (carboxy) pentyl, (carbornethoxy) pentyl, *:(metLhylthio)benzyl, (methylsulfonyl)benzyl, N, N-dimethylaminomet hylbenzyl, N-methylaminomethylbenzyl, glycylarninobenzyl, N, N-ditnethylglycylaminobenzyl, alanylaminobenzyl, (Nphenyirnethoxycarbonyl) alanylaminobenzyl, phenylalanyJlaminobenzyl, (Nphenylmethoxycarbony.) phenylalanylaminoib'nzyl, (CH3CH2NHC benzyl, N, N-diethylaniinocarbonylbenzyl, -32- N-ethylaminocarbonylbenzyl, N-propylaminocarbonylbenzyl, N, N-diisopropylaminocarbonylbenzyl, N, N-di-npropylaminocarbonylbenzyl, (hycroxypropynyl)benzyl, (idcazOlyl-C(=0) benzyl, (pyrazolyI--C(=0) )-benzyl, (pyridylmethylaminocarbonyl) benzyl, (oxaciazolidinonyl) benzy'i, trifluoroacetylbenzyl, (pyrazolyl) benzyl, (H2NSO2) -ben zyl, cihydroxyethylbenzyl, (MeHNC(=)NH)-benzyl, (II2NC(=)NH)-benzyl, (HC NI-)-benzyl, methanesulfonylpentyl, methoxypentyl, N-formyl-N-methylaminobenzyl, acetylarninobenzyl, pronionylbenzyl, buty,,rylberizyl, (CH3C-I2C(mNCH-) )-benzyl, (t-rifluorohydroxyethyl)benzyl, (CF3C(=NOH) benzyl, (N-rethylglycyl)aminobenzyl, (4-morpholino) ethyl) arinocarbonylbenzyl, N-dirnethyJlarinoethyl) amiriocarbonylbenzyl, '20 N-diethylaminoethyl) aminocarbonylbenzyl, .(-methylpiperazin-lylethyl) aminocarbonylbenzyl, (benzyl- NHC benzyl, (CH3NHC 0)benzyl, (N2C.C2)bny,(HC(N~ezl '25 ((N-phenylmethoxycarbonyl) glycylamino) benzyl, (iridazolylrnethyl)benzyl, ((CH 3 3
C-
)benzyl, (N-methyl-Nethylamirioethyl) aminocarbonylbenzyl, (pyrroliclinylethyl) aiminocarbonylbenzyl, C)3 (piper idin yl ethyl) aminocarbonylbenzyl,
(H
2 NC(=NOH) )benzyl, (H 2 NC(=NOH) )fluorobenzyl, benzirnidazolylmethyl, benzotriazolylnethyl, indazolylmethyl, benzoxazolinylmethyl, benzisoxazolylmethyl, thienylmethyl, 3E furylmethyl) (aminoindazolyl)methyl, (methylaminoindazolyl)methyl, (ethytaminoindazolyl)methyl, (isopropylaminoindazolyl)nlethyl, (chloroindazolyl~methyl.
-33- Specifically preferred are compounds of formula (Id) R22N~ NR 23 Ph __Ph HO (lId) or a pharmaceutically acceptable salt form thereof, selected from the group consisting of: the compound of formula (Id) wherein p 22 is 4hydroxymethylbenzyl and R 23 is 4hydroxymethylbenzyl; the compound of f,'ormula (IId) wherein p 2 is 3hdroxybenzyl and R 2 3 is 3-hydroxybenzyl; the corn~ound of formula (Id) wherein p 22 is cyclopropylmethyl and R 23 is 4 cyclopropylmethyl; the compound of formula (Id) wherein R 22 is 2na-phthylmethyl and B 23 is 2-naphthylmethyl; the compound of formula (Id) wherein R 22 is 4hydroxybenzyl and R 23 is 4-hyvdroxybenzyl; the compound of formula (Id) where'in R 22 is 3aminobenzyl and R 2 3 is 3-aminobenzyl; the comr-ound of formula (Id) wherein R 22 is 3hydroxymethylbenzyl and R 2 3 is 3hydroxymethylbenzyl; the compound of formula (id) wherein R 22 is 3- (Me2NCH2C(=O)NH)-nenzyl and R 23 is 3- (He2NCH2C NH) -benzyl; -34 the compound of formula (Id) wherein R 22 is 3-formaldoximebenzyl and R 23 is 3formaldoximebenzyl; the compound of formula wherein R 2 2 is 3-(CH3C(=N-OH))-benzyl and R 2 3 is 3-(CH3C(=N- 01-) )-benzyl; the compound of formula (Ild) wherein R 2 2 is 3-(2arino-4-thienyl)benzyl and R 2 3 is 3- (2-amino- 4-thienyl) benzyl; the compound of formula (Id) wherein R 2 2 is hydroxypenty]. and R 23 is the compound of formula (id) wherein R 22 is 6hydroxypentyl and R.
23 is 6-hydroxypentyl; the compound of formula (Id) wherein R 2 2 is hydroxypentyl and R 23 is 2-naphthylmethyl; the compound of formula (id) wherein R 22 is hyvdroxypentyl and R 2 3 is 4hydroxymethylbenzyl; ~the compound of formula (id) wherein R 22 is *20 hydroxypentyl and R 23 is 3hydroxymethylbenzyl.
Specifically preferred are compounds of 34a forrula (IId)
S
R
22 N NR 23 HO OH (I1d) or a pharmaceutically acceptable salt form -thereof, wherein:
R
1 3 is H, CI-C 4 alkyl, C3-C6 alkoxyalkyl, C 2
-C
4 alkenyl, or benzyl;
R
1 4 is OH, H, CF 3
C
1
-C
4 alkyl, C 1
-C
4 alkoxy, NH 2
C
2
-C
4 alkenyl, or benzyl;
R
1 3 and R 1 4 can alternatively join to form -(CH2)4-, -CH2CH2N(RI 5 )CH2CH2-, or -CH2CH2OCH2CI2-;
R
22 is selected from the following: Cl-C8 alkyl substituted with 0-2 R 3 1 940-C6 alkenyl substituted with 0-2 R31;
C
2 -C6 alkenyl substituted with 0-2 R 31 .s 25 R2 3 is irdazolylmethyl optionally substituted with halogen or -R13R14;
R
3 1. is selected from one or more of the following: halogen, -OR1 3 Cl-C 4 alkyl, C3-C10 cycloalkyl, -C(R4) =N(ORl 4 -C0 2
R
1 3 -S(O)mR 3 34b aryl substituted with 0-5 R 32 or a heterocyclic ring system chosen from pyridyl, pyrirnidinyl, triazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, etetrazolyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl, oxazolidinyl, benzimidazolyl, benzotriazolyl, indazolyl, benzoxazolilyl, benzoxazolyl, said heterocyclic ring being substituted w~ith 0-2 R 3 2
R
32 when a substituent on carbon, is selected from one or more of the following: -CONH-2, -CO2H, -CHO, -CH 2 NHOH, -CH 2
NR
1 3
R
1 4
-NR
1 3 Rl 4 hydroxy, hydroxymethyl, -C (R 14 =N(0R 1 4 halogen, is methoxy, methyl, nitro, cyano, allyloxy, -C02CH13, -NHCHO, -NHCOCH-3, -OCO2CH3, -CH=NCHi2CI{2OH, -OCONHiCH2C6i5, -OCONHCHi3, oxazolidinyl, -C=C-CH2OH, -COCH3, hydroxyethyl, 20 Cl-C 3 alkyl (said alkyl substituted with 0-4 rp 20halogen, or OH), tetrazolyl, -OCH2CONH2, Sb -CONHNH-2, -Cli=NNHCONH2, -CONHOCH3, -CH2CH (QH) CH2OH, adamantaxnido, hydroxyethoxy, dihydroxyethyl, =NH, -CONHCH3, -B (011) 2 benzyloxy, -CONHC912CH3, -CON (CH2CH3) 2, methylthio, -'S02CH13, -NHCQNH2, -NHCONHCH3, -NHCOCH2N (CH3) 2, -NHCOCH2NHCH3, S ~-NI{COCH2NHCO2 CH-2C GM5, -NHCOCH2NII2, -NHCOCH (CH3 )NHCO2CHi2C6H5, -NHCOCHi CCU2C6II)NHCO2CH2C6HS, -NHCOCHI(CH3 )NH2, -NIICOCH(C2CH)NH2, -CO2CH2CH3, -CONIICH2CH2CH3, -CONI{CH(C113)2, -CH2-imidazole, -COC(C-3) 3, -C CF3, -CO-irnidazole, -CQ-pyrazolyl, sea.' oxadliazolidinonyl, -COCF3, -COCH2CH-3, -COCi*2CfI2CH3, pyrazolyl, -SO2NH2, -C(CH2C-13)N(OH) or -C(CF3)=N(OH), phenyl, 34c axcetoxy, hydrocyamino, -N(CH 3
(CHO),
cyclopropylmethoxy, -C0NR 2 3
R
14 -CONHiOH, (diethylaxninoethyl) aminocarbonyl, CN-ethylN-methylaminoethyl) axinocarbonyl, (4-rethylpiperazinylethyl) aminocar bonyl, (pyrrolidinylethyl) aminocarboiyl, (piperidinylethyl) amtinocarbonyl, -NHCOCH- 2
NHCH
3 N-(2-(4-morpholinoQ)ethyl)aninocarbonyl, or N-(2- N-dimethylanino) ethyl) arinocarbonyl;
R
32 when a substituent on nitrogen, is methyi.
7- second ernhodiment of this invention is a compound of the formula
S
B
5 4* 3 *6
'I
*6 9
U
B.
0* SO B B or a pharmaceutically acceptable salt form thereof whereini:
N,
F 1 and R 7 are independently selected from the following groups: Cl-C8 alkyl substituted with 1-3 R113; C2-C8 alkenyl substituted with 1-3 R11B; 02-C8 alkynyl substituted with 1-3 RIIB;
-OR
1 3
-SR
1 3 C0 2
R
1 3 R47' and R 7 A" are independently selected from the following groups: hydrogen;
C
1 -C4 alkyl substituted with 0-6 halogen or 0-3 Ci- C2 alko.XY; benzvl substituted with 0-6 halogen or 0-3 Cl-C2 15 alkoxy; -ORI3; -SR- 3 C0 2
R
1 3 pA and R 4 A can. alternatively join to form a 5-7 rnembered carbocyclic ring substituted with 0-2 R 1 2;.
S. R7 and VAI can alternatively join to form a 5-7 membered carcocxcl c ring substituted with 0-2 p, 1 2; r. i C, or 2; R'5 is selected from H; halogen; C1-C6 alkyl substituted S.S with 0-3 R11, -N(R 2 02 S 2
,-R
0 or -N 3
R
6 is independently selected from: hydrogen, halogen, 01-0C6 alkyl substituted with 0-3 R 11
-N,(RP
20 )2,
-SR
20
-O)R
21 Or -N3;
R
5 and R 6 can alternatively join to form an epoxide or aziridi4ne ring; -OCH 2 SCH2O-; -OCH2O-; -OC(CH3)20-; -0CC( (C.H2) 3NI-2) (Cii 3 -0C (OCH 3
(CH
2
CH
2 -36- -Os -NHC -00 -NHC -IqHCH 2 -OCH-2NH-; -NHC -Os NI-; -NHC(0O)C(=O)O-; -NhC(CH3) 2 -OC(CH3) 2 NH- or any group that, when administered to a mammalian subject, cleaves to form a free dihydroxyl or diamino or hydroxyl and amino; p~a is selected from hydrogen, halogen, 01-06 alkyl, -lq(R 2 0%2, -SR 2 0 or -OR 2 0 p6a 4s selected from: hydrogen, halogen, C'--C6 alkyl,
-INI(R
20
-SR
20 or -OR 21 Rt ar.d P -acar. alt-ernatively join to form or a ring; an ae ineednl eetc rm *l a SSb -it z d C 3 R 1 sub Ute ih0SR1 2* r cn 1 sbs i u e i h 0 3 R 1 3C~ phnya~inderondel l suseleted from:3 12 o q- amin ory su5';tutd wih -3R i 3se1c.: do: from one or more 'of .he f ollow,,ing: -37- Hi, keto, nalogen, cyano, -CH 2
NR
1 3
RI
4
-NR
1 3
R
1 4, C02RI 3
-OC(=O)R
1 3 -O3 -S(O)mRl 3 -NHC(=Nli)NHR 1 3
-C(=NH-)NHR
1 3 -C(=O)NR1 3 Rl 4
-NR
1 4 C(=O)Rl 3 =N0R 1 4
-NR
1 4
C(=O)OR
1 4,,
-OC(=O)NR
13
R'
1
-NR
13
C(=O)NR
13
RI
4 -14R1 4 S2NR1 3
R
1 4
-NR
1 4 S02R 1 3 -SO2NR 1 3
R!
4 -OP (OR 1 3 2, Cl-'C4 alkyl, C2-C 4 alkenyl, C3- C6 cycloalkylmethyl, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C7-ClO arylalkyl, hydroxamic acid, hydrazide, boronic acid, sulfonamide, formyl, C 3
-C
6 cycloalkoxy, Cl-C 4 alkyl substituted with -NR 1 3
RJ-
4 Cl-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, 15 Cl-C 4 haloalhyl, Cl-C4 haloalkox:y, CI-C4 alkoxycarbonyl, pyridylcarbonyloxy, CI-C4 alkylcarbonyl, Cl-C4 alkylcarbonylamino, -OCH2CO2H, 2-(l-morpholino)etho:y, azido, 0-C (R 1 4
(ORI
4 1-3 amino acids linked together via amide bonds, 2 C said amino acid beino linked v-a the amine or carboxylate terminus; C"3-Cln cycloalkyl substituted with 0-2 R 1 2
C
1 -C4 alkyvI substitued with 0-2 R 12 aryl (C1-03i alkyl) substituted with 0-2 R' 2 C2-C6 alkoxyalkyl, substituted n~ 0-2 R 12 :Cl-C- alkylcarbonyloxy substituted with 0-2 R1 2
C
6 -CIO arylcarbonyloxy substituted with 0-2 R 12 1; a C5-CI4 carbocyclic residue substituted with 0-3 1:1 or a 5- to J0-membered heterocyclic ring system containing I to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-3 R1 2 -38- R11A is selected from crie or more of the following: H, keto, halogen, cyano, .CH 2
NR)
3 BRl 4 B, -NRl 3 BRl 4
B,
-CO2H, (Cl-C 3 alkyl), -OHI, C2-C6 alkoxyalkyl, -C (=O)NH2, -OC (=O)NH2, -NHC (=O)NH2, -SO2NH2, Cl-C4 alkyl, C2-C4~ alkenyl, C3-ClO cycloalkyl, C3-C6 cycloalkylmethyl, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C7-CjO arylalkyl, hydroxamic acid, hydrazide, boronic acid, C 3
-C
6 cycloalkoxy, Cj-C 4 alkyl substituted with -14H 2 Cl-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, Cl-C4 haloalkyl, CI-C4 haloalkoxy, CJ.-C4 alkoxycarbonyl, Cj-C4 alkylcarbonyloxy, 01-04 alkylcarbonYl, Cl-C4 1lkylcarbonylamino, -OCH2C02H, 2-(1-morpholiJno)ethox~y, azido, aryl(CI-C3 9*alky') a C5-C14 carbocyclic residue; a 5- to :L-membered heterocyclic ring system, containing 1 to 4 heteroatoms independently 2C selecied from oxygen, nitrogen or sulfur, said n.e~eroocyclic ring system substituted with 0-3 Ii 2 I'S~ -Q selected f--rom one or more of the following: NRl3ApIl4,
-C
0 2 pI3A, -QC(=()p,13A, -O :S (O)mF~l A, NHC NH)NH p, 3
A,
-C(=NH)NHPl3A, -C(=O)Np.13AR1 4 NR14C(=O)Rl3A, ,-O(=O)NR1 3 AR1 4 -NR13ACV=O)NRl 3 ARl 4 -INR14SO2140 3 AR4, NRlAS0 2 pl 3 A, -SO 2
NR'.
3 AR1 4
CH
2 NRl 3 R1 4 A, _NR1 3 Rl 4 A, -C(=O)NR1 3 Rl 4
A,
-NRl4AC(=O)Rl1 3 =NORl 4 A, -NR14C(=O)ORl 4
A,
-COC(=O)Np,1 3 Rl 4 A, -NRl3CV=O)Np'± 3 Rl 4
A,
-N.Rl4ASO 2 NqRlJpl 4 A, -NR' 4
A
30 2 l3 -S0 2 NR1 3 Rl 4
A,
itro, hydrazide, boronic 3cid, forny2, C3-CC 3$ cvcloalkO-XY,
C
2
-C
4 alky-' subst tut ed with -39-
-NR
1 3 RI4, Cl-Cl hydroxyalkyl, methylenedioxy, ethylenedioxy, C0104 ha2oalkyl, Ci-CI haloalkoxy, pyridylcarbonyioxy, 01-04 alkylcarbonyl, -OCH2CO2H, 2-(1-morpholino)ethoxy, azido, -C (R 1 4 =N (OR! 4 -OP (OR 13 2; cycloalkyl substituted with 0-2 R1 2
CI-C
4 alkyl substitued with 1-2 R1 2 aryl (CI-C3 alkyl) substituted with 1-2 R12; 02-0-6 alkoxyalkyl, substituted with 1-2 R1 2 01-04 alkylca-bonyloxy substituted with 1-2 R 12
C
6
-C
10 arylcarbonyloxy substituted with 1-2 R 1 2
R
1 2 wher. a substituent on carbon, is selected frcm one or more of the following: phanyl, benzyl, phenethyl, phenoxy, benzyloxy, :9.,.halogen, hydroxy, nitro, cyano, Cl-C4 alkyl, 03-06 cycloalkyl, 03-06 cycloalkyirnethyl, C7- 0:0 arylalkyl, Cl-C 4 alkoxy, -CO2H, hydroxamic 20 acji, hydrazicie, boronic acid, sulfonamide, formyl, 03-06 cycloalkoxy, -OR 13 01-04 alkyl substituted NR 1 3 p) 4
-NR
1 3 RI'4, 02-06 alkoxyalkyl optionally substituted with -Si(CH- 3 3 01-04 hydroxyalkyl, methylenedio:y, :925 ethylenedioxy, 01-0C4 haloalkyl, 01-04 .*.:haloalkoxy, 01-04 alkoxycarbonyl, 01-04 alkylcarbonyloxy, 01-04 alkylcarbonyl, 01-04 alkylcarbonylamino, -SCO)mR 1 3 5S02NR 13
RI
4 -NHSO2R 14 -OOH2002 R1 3 2- (1-morpholino) ethoxy, -C (R 1 4 =N (0R 1 4 a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur; or p12 may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused or 6-memberei ring, said 5- or 6- membered ring being optionally substituted on the aliphatic carbons with halogen, 01-04 aikyl, C1-C4 alkoxy, hydroxy, -NR13R1 4 or, whenR1 is attached to a saturated carbon atom, it may be =0 or or when R 12 is attached to sulfur it may be =0; R1 2 when a substituent on nitrogen, is selected from one or more of the following: phenyl, benzyl, phenethyl, hydroxy, Cl-C4 hydroxyalkyl, Cl-C4 alkoxy, 01-04 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, ~:.-OH2NR,.
3 Rl 4
-NR
1 3 Rl 4 C2-C6 alkoxyalkyl, Cl- 15 C4 haloalkyl, C1-C4 alkoxycarbonyl, -C02H, Cl- C4 alkylcarbonyloxy, CI-C4 alkylcarbonyl, wer. a substituent on carnon, is selected from one 2 o: r rz r 4- f i tr. fo 1lwi ng: pnenyl, terizyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, naitro, cyano, 01-04 alkyl, 0-26 cycloalkyl, 03-CE cycloalkylmethyl, C7- 210 arylalkyl, 01-0-4 alkoxy, -C02H, hydroxamic 2r acid, hydrazide, boronic acid, sulfonamide, fcr" y, 3-C6 cycloalkoxy, -Cp,13, C 1
-C
4 alky! substituted with -NH 2 -NH2, NHMe, 02-CE alko:yalkyl optionally substituted with -Si (CH3)3, C1-C~j hydroxyalkyl, methylenedioxy, 3C, ethylenedioxy, 01-04 haloalkyl, 01-04 haloalkoxy, 01-04 alkoxycarbonyl, 01-04 alkylcarbonyloxy, 01-04 alkylcarbonyl, 01-04 alkylcarbonylamino, -S (0)nMe, -SQ2NH2, -"FS02Me, -OCH2C02RFI, 2- (1--mrphclino)etbhox-,, C =IOH NH 2 -4 1a 5- or 6-membered heterocyclic ring containing from I to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur; or R1 2 A may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused or 6-members-i ring, said 5- or 6- membered ring being optionally substituted on the aliphatic carbons with halogen, Cl-C4 alkyl, Cl-C4 alkoxy, hydroxy, or -NH 2 or, when RlI 'A is attached to a se -rated. carbon atom, it may be =0 or or when R 12 isattached to sulfur it may be =0; p2Awhen a substituent on nitrogen, is selected from one or more of the following: phenyl, benzyl, phenethyl, hydroxy, C 1
-C
4 hydroxyalkylk, Cl-C4 alkoxy, Cl-C4 alkyl, C3-6 cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NH 2 -11,H 2 C2-C6 alkoxyalkyl, CI-C4 haloalk:'1, Cl- C4 alkoxycarbonyl, -C0211, C 1-C4 alkylcarbonylox:y, Cl-C 4 alkylcarbonyl, -C 'H12;
R
13 is selected from:
H;
phna...s.t te ih0- 1A penyl substituted with 0-3 R1lA; benz'6ayl substituted with 0-3 R 11A; Cl-C4 alkeyl substituted with 0-3 RlA; ~CI-CC alkecbnyl substituted with 0-3 R IIA; CI-CC alkycarbonyl substitute with 0-3 RlA; Cl-CG alkoymcarbonyl subs-itute with 0-3 RulA; C3-C6 alkoxyalkyl substituted with 0-3 RilA; an 4mine protecting group when R1 is bonded to N; a hydroxy protecting group when R13 is bonded to 0; R13A is selected from: phenyl substituted with 1-3 R1 1 benzyJ. substituted with 1-3 RU1; C1-C6 alkyl substituted with 1-3 R11; 02-04 alkenyl substituted with 1-3 R1 1 CI-C6 alkyJlcarbonyl substituted with 1-3 R 1 11 alkoxycarbonyl substituted with 1-3 Ri1 1 I~-~C6 alkylaminocarbonyl substituted with 1-3 R 11 03-05 alkoxyalkyl substituted with 1-3 R 1 1 an amine protecting group when R 13 is bonded to N; a hydroxy protecting group when R 1 3 is bonded to 0; FP13 is hydrogen, hydroxy, CF 3 01-06 alkyl substituted with 0-3 groups selected from OH, Cl-C 4 alkoxy, ha2t ,en, NH 2 -NH (01-04 alkyl) 01-06 alkoxy, 02-C6 alIk eIny I, phenyl, benzylI, an amine protecting group :when PI4 is bonded to N, a hydroxy protecting group *whnr.R 1 4 is bonded to 0; al)y- sbiutdwh1-3 groups selected f rC7 C*i, OI-C 4 a 1ko0XY, halogern, NI- 2 -NH (01-04 a C--C6 al.koxy, C 2
-C
6 alkenyl, phenyl, benzyl,
OV.
an amin:re protezt'_iri group when R1 4 is bonded to N, a rytr~'protectng group when R 14 is bonded to 0; F-an: can ali-errnazively jci4n to form -(CH2)4-, -CH20H211(R' 5 )CH2CH2-, or -CH2CH20CH2CH2-; Pi-!h and ~1~are independently selected from H or 0C alkyl, or Rl1 3 B and R1 4 B can alternatively join to for-m -CH2CH2N(R 1 5 )CH2CH2-, Or -0H2CH20CH-2CH2-;
P
15 is H or CH3; m is 0, 1 or 2; W is selected from: -N (p 2 2 C Nq (R 2 3
-(R
2 2 C 0-, -C (R 2 5
(R
2 6 C C (R 2 1) (R 2 8 -N (R 2 2 )C (=Z)C(R 2 7
(R
2 8 -C (R 2 5
(R
2 6 C(=Z)O0-, R2 R3
-(R
2 5
CR
2 6) C (F2)0 C R 2 7
(R
2 8 -C(p, 2 5
(R
2 6 N(CH3) C(R 2 7
(R
2 8 -C (p 2 5
(R
2 6 N (0R, 2 9) C0(R 2 7
(R
2 8
-OCR
2 5
(R
2 6
)C(=ZNS-,
_N (R 2 2 S(=0)NIq(R 2 3 wherein: Z is 0, S, NR2 4
B
2 2 and p'23 are independently selected from,. the ~f fc lowing: hydrogien; Ci-C& alkyl substituted with 0-3 R 3 1 -2C alkenx. subst ituted with 0-3 R 3 1; 02-CE alkynyl substituted with 0-3 R 3 1 a C---C 1 74 carbocyclic ring system substituted with C'
R
3 1 or 0-5 p 3 2 a 5- to lO-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from ox<ygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 3 2 _0R 2 2 a, _rjp.22a) (R 2 2 b); R22a and R 2 2 t are independently selected from the following: -44hydrogen; CI-C8 alkyl substituted with 0-3 R 3 1; C2-C8 alkenyl substituted with 0-3 R 3 1 C2-C8 alkynyl substituted with 0-3 R 3 1 a C3-C14 carbocyclic ring system substituted with
R
3 1 or 0-5 R32; a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 32
R
2 4 is selected from: hydrogen; hydroxy; amino; Cl-C4 alkyl; CI-C4 alkoxy; mono- or di-(Cl-C6 15 alkyl)amino; cyano; nitro; benzyloxy; -NHSO2aryl, aryl being optionally substituted with alky a.n R2 are independently selected from the 2C f. llw'ng: S-C alkyv substitutea with 0-3 R 3 1 alkenyl substituted with 0-3 R 3 1 C3-C alkyny substituted with 0-3 R31; C3-1 4 carbocyclic ring system substituted with p3 or 0-5 R 3 2 a tc 10-merr~ered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur. said heterocyclic ring system being substituted with 0-2 R 3 2
-C
1 -SR1 3
F
2 p ant pR2 are independently selected from: h'drogen; P-PP--Y I Ci-C4 alkyl substituted with 0-3 halogen or 0-3 C1- C2 alkoxy; benzyl substituted with 0-3 halogen or 0-3 Cl-C2 alkoxy;
-OR
13
-SR
13
R
29 is selected from: hydrogen; C1-C4 alkyl substituted with 0-3 halogen or 0-3 Ci-C2 alkoxy; benzyl substituted with 0-j halogen or 0-3 Cl-C2 alkoxy; alternatively, R 2 2
R
25 or R 26 independently, can join 15 with R 4 or R 4A to form a 5- or 6-membered fused heterocyclic ring or carbocyclic ring substituted with 0-2 R 1 2 said hezerocyclic ring containing 1-3 Sheteroatoms independently selected from N, S, or O; or alternatively, R 23
R
27 or R 28 independently, can join with R 7 or R 7 A to form a 5- or 6-membered fused heterocyclic ring or carbocyclic ring substituted with 0-2 R 12 said heterocyclic ring containing 1-3 heteroatoms independently selected from N, S, or O; or or alternatively, R 22
R
25
R
2 6
R
23
R
27
R
28
R
34 or R 3 can join with R 5 or R6 to form a 0- to 7-membered bridge to form a carbocyclic or heterocyclic ring, said bridge being substituted with 0-2 R 12 and said bridge containing 0-3 heteroatoms independently selected from N, S, or 0 a 0-membered bridge is formed when R 22
R
2 5
R
26
R
23
R
27
R
28
R
3 4 or R 3 5 are taken together with R 5 or R 6 to form a direct bond); -4 6alternatively R28 or R23 can Join v:hR7A to form a direct bond; alternatively R26 or R22 can join with R4A to form a direct bond; p.
3 1 is selected from one or more of the following: keto, halogen, cyano, -0H 2
NR
1 3
R
14
-NR
1 3 Rl 4 -CO2R1 3
-OC(=O)R
13 C2-C6 alkoxyalkyl, -S(O)mRI 3 -NHC(=NH)NHRl 3
-C(=NH)NHR
1 3, -C(=O)NRl 3 p.
1 4 -NPl4C(=O)Rl 3 =N0R 1 4 -NRl 4
C(=O)ORI
4
-OC(=O)NR
1 3 Rl 4
:-NR
1 3C(=O)NqRl 3 Rl 4 -NRl 3 C(=S)NR1 3 Rl 4 15 NR' 4 SO2NR- 3 RI4', -NRI 4 S02R1 3 -SO2NR' 3 R1' C1_ C4 alkyl C2-C4 alkenyl, C3-C10 cycloalkyl, 3-C26 cycloalkylmethyl, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C7-CJ0 arylalkyl, hydrcx.amic acid, hydrazide, oxime, boronic 2 -cii, l'Ifonarmide, f OfMY I, C 3
-C
6 cyc loalkoxy, substituted wit:. -IR-3R'4, Cl-C4 hyciro>:yalkyl, methylenedioxy, ethylenedioxy, 21I-C4 haloalkyi, C1-C4 haloalkoxy, Cl1C4 a koxycarbonyl, CJ-C4 alkylcarbonyloxy, C1-C4 k.-lcarbonyl, a~C Ilkylcarbonyl amino, 2- (1-mzrcholino~ethoxy, azidr,, 14R)I or ami~no acids, linked together via amide bonds, at.amino .cid being linked via ti~e amine or carooxylate terminus; a CI- carbocyclic residue substituted with p32; or a- 0-membered heterocyclic ring system cz::n-ainino 1 to 4 heteroatoms .n -4 endent I se 7 zed f r o r oxyvg en n.i tro g en -,zs ulf'r, s aidr.
I heterocyclic ring system being substituted with 0-2 R 3 2
R~
3 2 when a substituent on carbon, is selected from one or more of the following: phenethyJ-, phenoxy, C3-C10 cycloalkyl, C3-C6 cycloalkylmethyl, C7-Clo arylalkyl, hydrazide, oxime, boronic acid, C2-C6 alkoxyalky-, methylenedioxy, ethylenedioxy, Cl-C4 alkylcarbonyloxy, -NHSO2R 1 4 benzyloxy, halogen, 2- (l-morphoJlino)ethoxy, -CO2R1 3 hydroxamic acid, -C0NR1 3 NR1 3 Rl 4 cyano, sulfonamide, -CHO, 0 3 -C6 cycloalkoxy, NR1 3 p,1 4 _C(p1 4 )=j,(OR14) -N02, -OR 13
-NR
4 0
R
4 1 -SCrnR3 -SOmNR 13 Rl 4 -C(0)NR 1 3 Rl 4
-OC(=O)NR
3 RI4, -C(=O)Rll, -OC(=O)Rll, -OOO2RI3, phenyl, -C NP.
1 3
(C
1
-C
4 alkyl)-
*'NR
1 3
R
1 4 -C (=O)NR 4 0
R
4 1
C-C
4 haloalkyl,
C
1 -C4 haloalkoxy,
C
2
-C
4 haloalkenyl, Cl-C4 ?0 haloalkynyl; ~C(=0N?13(R11 )2NRl 3 Rl 4 -c =0 N 1 3C (R 1 1 INR1 3 C02R 1 3 C4 aly NR3CO2PRl 3 N 3 (C1C4 alkyl) -P' 1 or C 2NR'1 3 p, 4 (R1 1) 2 14R1 3 00 2
R
1 3
-(C
1 -C4 alkyl) -NR 1 3
R
1 4 -C -(Cl-C 4 alkyl) -NR1 3 CO2Rl 3 Ca-C4 alkoxy substituted with 0-4 groups selected 0 from: R 1 1
C
3 -C6 cycloalkyl, -C0 2
_R
1 3 -C(=O)NR1 3 Rl 4
-NR
1 3 Rl 4 or OH;
C
1 -C4 alkyl substituted with 0-4 groups selected from:
R
1 1
=NR
1 4
=NNR
1 3 C NR 1 3
R
1 =NNR13C(=O)OR1 3 or -NR1 3 Rl 4
C
2
-C
4 alkenyl substituted with 0-4 R 1 1;
C
2
-C
4 alkynyl substituted with 0-4 R 1 1 -48a 5- or 6-mernbered heterocyclic ring containing from 1 to 4 heteroators independently selected from oxygen, nitrogen or sulfur, substituted with 0-2 R 1 2 or R 3 2 may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused or 6-membered ring, said 5- or 6- membered ring being optionally substituted on the aliphatic carbons with halogen, C1-C4 alkyl, Cl-C 4 alkoxy, hydroxy, -NR1 3
R
1 4 or, when R 3 2 is attached to a saturated carbon it may be =NOH; or when R 3 2 attached to sulfur it may be =0; 15 R 3 2 w*en a subsituent on nitrogen, is selected from one cr more of the following: phen,, benzvl, phenethyl, hydroxy, C1-C4 V *hdroxyalkyl, C 1
-C
4 alkoxy, Cl-C4 alkyl, C 3 -C6 cycloalkyl, C3-C6 cycloalkylmethyl, CH2?,' 3 R' -NR1 3
R
1 4 C2-C6 alkoxyalkyl, CIhaloalkyl, C 1 -C4 alkoxycarbonyl, -CO2H, C- C4 alkylcarbonyloxy, Cl-C 4 alkyylcarbonyl, 1 4
(OR
1 4 H, CI-C 3 alkvl; s s e I ed fro (=Cl NR 13 4Rp14; -C C (R 11 2
NR
13
R
1 4
C(R-
1 2
NR
1 3 NRl 4 -C C CR" 1 2
NR
1 3 C0 2
R
1 3 -C(=01HR; C 2: C, -C('1-04 alkyl -NR- 3 R4 1 4 (C-C4 alkyl) -NR 1 3 C0 2 p'I3; -49- 1-3 amino acids linked together via amide bonds, and linked to the N atom via the carboxylate terminus.
Preferred compounds of this second embodiment are compounds of formula (II):
W
R
4
R
7
R
5
R
6
(II)
oio or a pharmaceutically acceptable salt form thereof wherein: *9 15 R 4 and P 7 are independently selected from the following groups: *i hydrogen; C-C4 alkyl substituted with 1-3 R 1 1 C3-C4 alkenyl substituted with 1-3 R 1 1
R
5 is selected from -OR 2 0
R
6 is hydrogen or -OR 21
R
20 and R 21 are independently hydrogen or any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl;
R
11 is selected from one or more of the following: H, keto, halogen, cyano, -CH 2
NR
1 3
R
14
-NR
1 3
R
14 -C02R 13
-OC(=O)R
1 3
-OR
13 -S(O)mR 1 3 C2-C4 alkenyl, C3-C6 cycloalkylmethyl, nitro, hydrazide, boronic acid, formyl, C3-C6 I~II L -sl -1 cycloalkoxy, methylenedioxy, ethylenedioxy, Cl-C4 haloalkyl, Cl-C4 haloalkoxy, Cl-C4 alkoxycarbonyl, C 1
-C
4 alkylcarbonyl, Cl-C4 alky2.carbonylamino, -OCH-2C02H, -C (RI 4 =N (ORI 4 C3-ClO cycloalkyl substituted with 0-2 R 12 Cl-C4 alkyl substitued with 0-2 R 1 2 ;r aryl (Cl-C3 alkyl) substituted with 0-2 Ri 2 C2-C6 alkoxyalkyl, substituted with 0-2 R1 2 Cl-C4 alkylcarbonyloxy substituted with 0-2 R 1 2
C
6 -Cj 0 ary~lcarbonyloxy substituted with 0-2 R 1 2 aryl substituted with 0-3 R 1 2 or a 5- to 10-membered heterocyclic -ing system containing 1 to 4 heteroatons independently 15 selected from oxygen, nitrogen or sulfur, said .**heterocvclic ring system be-inl substituted w.h 0 -2 p1 2 F2EI'S selected fr-om one or more of the following: '2 3Ap14, -NPl 3 ARl4, -CO 2
RI
3 A, -O-(=0)R1 3
A,
-c (0)rrRl---A, -CH 2
NR
1 3
F
1 4 A, N.RlA a V .tro, hvdrazide, boronic acid, formyl, C3-C6 cycloalkoxy, Cl-C4 hydroxyalkyl, rrethylenedioxy, ethylenedioxy, CI-C4 .loaikyl, CI-C4 haloalkoxy, C1-C4 0. :a2lk'y~rarbonyI, C 1
-C
4 alkylcarbonylamino, S3C H2C02 H, C(R '1 4 =I(OR 1 4 cycloalkyJ. substituted with 0-2 Ri 2 CI-C"4 alkyl substitued wit ,1-2 Ri 2 ary. (Cl-C3 alkyl) substituted with 1-2 R 12 C2-C6 alkoxyalkyl, substituted with 1-2 R 1 2 CI-C4 alkylcarbonyloxy substituted with 1-2 R 1 C-CIC, arylcarbonyloxy substituted with 1-2 R 12 -51p1 2 when a substituent on ::arbon, is selected from one or more of the following: phenyl, benzyl, phenethyl, phenoxy, benzy1oxy, halogen, Cl-C 4 alkyl, C7-ClO arylE-lkyl, Cl-C4 alkoxy, 2-(l-morpholino)ethoxy, -CO2H, hydroxamic acid, hydrazide, -C(R 14 )=N(0R 14 )1 cyano, boronic acid, sulfonamide, formyl, C3-
C
6 cycloalkoxy, -OR 1 3 c 2 -c 4 alkyl substituted with -NR 13
RI
4
-NR
13
R
14 methylenedioxy, CI-C4 haloalkyl, Cl-C4 alkylcarbonyl, Cl-C4 alkylcarbonylamino, hydroxy, hydroxymethyl; or a 5- or 6-mernbered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur; S' *R1 2 when a substituent on nitrogen, is selected from benzyl or methyl; 0 S o. P'3 iS H, 4 alkyl, C3-C6 alkoxyalkyl, C 2
-C
4 alkenyl, or benzyl; p:J i37-s selected from: 6obstituted with 1-3 P11; benzxv. substituted with 1-3 R 1 1; Cl-CE alkyl substituted with 1-3 R111 0-04 alkeny.2 substituted with 1-3 RII; C3-'C- alkoxyalkyl substituted with 1-3 R 1 1 an amine protecting group when R 13 is bonded to N; a hydroxy protecting group when R1 3 is bonded to 0;
R
1 4 is OH, H, CF3, C 1
-C
4 alkyl, Cl-C 4 alkoxy, NH 2 C2-C 4 alkenyl, or benzyl; p14A is CI,-C6 alkyl substituted with 1-3 groups selected from OH, Cl-C 4 alkoxy, halogen, NH 2 -NH(Cl-C4 0 -52alkyl), C:-C 6 alkoxy, C 2
-C
6 alkenyl, phenyl, benzyl, an amine protecting group when R 1 4 is bonded to N, a hydroxy protecting group when R 14 is bonded to 0;
R
13 and R 14 can alternatively join to form -(CH2)4-, -CH2CH2N(R' 5 )C2CH2-, or -CH2CH20CH2CH2-; R1 5 is H or CH3; W is selected from: -N R 2 2 C NC(R 2 3
-NCR
2 2 C 0-; -N 2 2) C (R 2 7
(R
2 8 -Nr (,2 2 C N (R 2 3 wherein: I* I Z S S 1 C 3~ 2 P and, are -rndEpend. ntly selected fro- the *C:p-0 alkxK substituted with 0-2 R 3 1 C- alkenyl substituted with 0-1 R 3 1; C2-74 alky' l substituted with 0-1 R 3 1
I..
1 .s s e--ctea from the fc.Jowing: hydrogen; C:-CE alky1' substitut !d with 0-3 R 1 02-06 alkenyl substituted with C-3 R 3 1 C0--C alkynyl substituted with C-3 R 3 1 p28 is hydroger or halogen; 5s se~.ectea fror one or more of the followina: -53keto, halogen, cyano, -CH 2
IR
1 3 R1 4
-NR
1 3 Rl 4 -CO2pR1 3 -C RU, -00 Rl 3 -OR1 3 C2-C6 alkoxyalkyl, -S(O)mRl 3 -NHC(=NH)NqHR 13
-C(=NH)NHR
13 -C(=0)NR 13 Rl 4
-NR
14
C(=O)RI
3 =140R 14
-NR
14 C(=O)0R, 14
-OC(=O)NR
13 Rl 4
-NR
13 /0(=O)NR 13 Rl4, -NR 13
C(=S)NR
13 Rl 4 -NR1 4 SO2NR1 3
R
14 -NR1 4 S02Rl 3 -SO2NR1 3 Rl 4 Cp- C4 alkyl, C2-C4 alkenyl, C3-ClO cyclo;:lkyl, 03-C6 cycloalkylmethyl, benzyl, phenethyl, phenox.y, benzyloxy, nitro, C7-ClQ arylalkyl, hydroxamic acid, hydrazide, oxime, boronic acid, sulfonamide, formyl, C 3 -C6 cycloalkoxy, CI-04 alkyli substituted with -NR 13 Rl 4 Cl-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, 15 01-04 haloalky1, Cp--C4 haloalkoxy, Cl-C4
V
alkoxycarbonyl, Cl-C4 alkylcarbonyloxy, Cl-C4 9. alkylcarbonyl, CI-0 4 alkylcarbonylamino, -OH2O2', 2- (1-morpholino) ethoxy, azido,
(P.
4 or 1-3~ amiuno acids, linked together via amide bonds, said amino acid being linked via the amine or carboxylate terminus; a CS-C14 rbocyclic residue substituted with R2or a 5- to lO-membered heterocyclic ring system containing to 4 heteroatoms ndependently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 32
R
3 2 when a substituent on carbon, is selected from one or more of the following: phenethyl, phenoxy, 03-010 cycloalkYl, 03-06 cycloalkylmethyl, C7-ClO arylalkyl, hydrazide, oxime, boronic acid, C2-CE alkoxyalkyl, -541methylenedioxy, ethyleneclioxy, Cl-C4 alkylcarbonyloxy, -NHSO2R 1 4, benzyloxy, halogen, 2- (1-morpholino) ethoxy. -C02R1 3 nydroxamic acid, -CONR1 3
NR
13 Rl4, cyano, sulfonamide, -CHO, C3-C 6 cycloalkoxy,
-NR
1 3
R
1 4 -C (R 1 4 =N (OR1 4
-NO
2
-OR
1 3
-NR
4 0
R
4 1, _S~mR1 3 -SOmNR 1 3
R
1 4 -C(0)NR 1 3 Rl 4 -00 NR 1 3 Rl 4 -C Rll, -00 Rl 1 -OCO2p.13, phenyl, -C(=O)NRp 1 3 (Cl-C 4 alkyl)- NR1 3
RI
4
-C(=O)NR
40
R'
1 01-C4 haloalkyl, Cj-04 haloalkoxy,
C
2
-C
4 haloalkenyl, 01-04 haloalkynyl, -C(O NF-.C (R1 1 2NR1 3 Rl 4 off, -C NP-1 3 (R1 1 2NF<' 3
CO
2
RA
3 (01-04 alkyl )-NR 13 0R 3 11 cc'1 (R 13 (C0-C 4 alkyl) -R1; or C C (P41) 2r .R13RI1; -c 0) (C-C4aikYl)-NR1 3 p14; =0;-14 alkyl) CNl0 2 R1 3 7:4a2.u: ~'bzituted with 0-4 groups selete 3
-C
6 cycloalkyl, -C02P.1,
-C(CNP'-R
1 4
-NR
1 3
R
1 4 or OH; -C~4a) su bstituted with 0-4 groups selectec I- 4 subst:ituted with 0-4 R11;
C
2 -C4 a.'kyny! substituted with 0-4 R 1 ;r or 6-memb-ed heterocyclic ring containing 1rr 11 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, substituted i; 12 1 or P32 may be a 3- or 4- carbon chair, attached to ad~acent carbons on the ring tc form a fuse.or 6-r~rmbered rin~g, sciid 5- or 6- memrb'erE -i beinq. op~tionallv sul- t ttuted on th aliphatic carbons with halogen, 01-C4 alkyl, 01-04 alkoxy, ,ydroxy, -NR 1 3 Rl 4 or, when R 32 is ttached to a saturated carbon it may be =NOH; or when R 3 2 attached to sulfur it may be =0; R3,when a substituent on nitrogen, is selected from one or more of the following: phenyl, benzyl, phenethyl, hyciroxy, Cl-C 4 hydroxyalkyl, Cl-C 4 alkoxy, Cl-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR 13
R
14 I -NRl 3
R
14 C2-C6 alkoxyalkyl, Cl- C4 haloalkyl, Cl-C4 alkoxycarbonyl, -C02H, Cj- 04 alkylcarbonyloxy, Cl-C 4 alkylcarbonyl, -C (R 1 4 =N (OR 14 rr, is 0, 1, or 2; 9 p 43 is selected from: E, C 1 -C3 alkyl; F is selected from: -C NR 1 3
R
1 4 -C NR i 3 NR 14 -C C (R 1 1 2NR1 3
R''
1 -C 2NR1 3 NR1 4 C 11 2NR 1 3 CD2R 1 3 -C H; -C R 21
I;
-C (01-04 alkyl) -NR 1 3
RI
4 alkyl)-NR 13 00 2
R
1 3 1-3 amino acids linked together via amide bonds, and linked to the N atom via the carboxylate terminus.
-56- A third embodiment of this invention is a compound of the formula R 4 A W R 7
A
R
R
7
R
5
R
6 (i) or a pharmaceutically acceptable salt form thereof wherein: :9p 4 and are indeperlaently selected from the following groups: P. yrogen; :Ce alkyl subst-ituted with 0-3 R11; V. 5 C2-CS alkenyl su ituted with 0-3 R11; C2-CE alkyrnyl subs.ituted with 0-3 RI 1 zarbo:'zli: ring syster substitutei it C-3 ~or ~3p'2 a 10-mer-aoered; heterocyclic ring system 20 ccntai.inn 1 to 4 heteroatoms independently sele 'cted from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted *with CG-2 R 2 ?4A1 and P'71 are independently selected from the .,llowing groups: hydrogen; CI- 04 alkyl. substituted with 0-6 halogen or 0-3 C01-C2 alkoxy; benzy! substituted witth 0>-0 haiogen or G--3 C1-02 a1k ox y; -57-
-OR
13
-SR<
13 C0 2
R
13 R4 and R 4 A can c-Oternatively joir, to form a 5-7 memnbered carbocyclic ring substituted with 0-2 R 1 2
R
7 and R 7 A can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R 1 2 n is 0, 1, or 2;
R
5 is selected from H; halogen; Cl-C6 alkyl substituted with 0-3 RII, -N(R 2 0
-SR
2 0
-OR
20 or -N 3
R
6 is independently selected from: hydrogen, halogen, Cl-C6 alkyl substituted with 0-3 R 1 1 -N (R 2 0 2,
-SR
2 0
-OR
2 or -N 3
R
5 and R6 can alternatively join to form an epoxide or aziridine ring; -OCH 2
SCH
2
-OCH
2
O-;
-OCCCH
3 2O-; (02)31qH2) (CH 3 -OC (OCH 3
(CH
2
CH
2 CH)0-;' -OS -NHC(=0) -OC NH-; -NHC(=O) 0-; OV. -NHCH 2
-OCH
2 NHq-; NHC -05 NH-;
-NHC(CH
3 2 -OC(CH3)2NH- or any group that, when administered to a mammalian subject, cleaves to :form a free dihydroxyl or diamino or hydroxyl and amino; R~a is selected from hydrogen, halogen, Ci-C6 alkyl,
-N(R'
0
-SR
2 0 or -O 2 0
R
6 a is selected from: hydrogen, halogen, Cl-C6 alkyl,
-N(R
2 0
-SR
2 0 or -OR 2 1 -58-
R
5 and R5a can alternatively join to form or a ketal ring;
R
6 and R 6 a can alternatively join to form or a ketal ring;
R
20 and R 21 are independently selected from: hydrogen; Cl-CG alkyl. substituted with 0-3 Rll; C3-CG alkoxyalkyl substituted with 0-3 Rllf; CI-C6 alkylcarbonyl substituted with 0-3 R1- 1 Cl-Ce alkox-ycarbonyl substituted with 0-3 R 1 1 C1-C -6 alkylanrocarbonyl substituted with 0-3 R 1 1 ~:benzoyl substituted with 0-3 R 1 2 peo:croy usiue ih03P phenoxamycarbonyl substituted with 0-3 P1;2o .any group that, when administered to a mammalian subject, cleaves to for-m a free hydroxyl, amino or sulfhydryl; :Se.e~te-- from one ujr more of the following: Hketo, halogen, cyano, -CH 2 NRl 3
R-
4
-NR
1 3 Rl 4 R13 -0=ON -N-4(3R3 =C(0 R 1
-R
3 (0)rnR 1 4, -0:C 1 4, -CNHC()NR 13
R(=)R
1
R
4 3 4 -NF(;C(-1)NR 3
R
14 IR4SG2I.'RlJp1 4 -14R 1 4 S02 R 13
-ON
1
F
4 -Op (O0R 3 2, Cl-C4 alkyl, C2-C4 alkenyl, C- C6 cy.zcoalkylmethyl, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C7-ClO arylalkyl, hydroxamic acid, hydrazide, boronic acid, sulfonamide, formyl, C 3
-C
6 cycloalkoxy, Cl-C4 alkyl substituted with -IjR 1 3 Rl 4 Cl-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, haloalkyl, CI-C4 haloalkoxy, Cl-C4 -59alkoxycarbonyl, pyridyicarbonyloxy, Cl-C4 alkylcarbonyl, Cl-C4 alkylcarbonylamino, -00H2C02H, 2- (1-morpholino) ethoxy, azido, -C (RI 4 =N (OR 1 4 1-3 amino acids linked together via amide bonds, said amino acid being linked via the amine or carboxylate terminus; 03-ClO cycloalkyl substituted with 0-2 R1 2
C
1
-C
4 alkyl substitued with 0-2 R1 2 aryl(CC1-C3 alkyl) substituted with 0-2 R 1 2 02-06 alkoxyalkyl, substituted with 0-2 R1 2 01-04 alkylcarbonyloxy substituted with 0-2 R 12 C6-Cj10 arylcarbonyloxy substituted with 0-2 R 12 a 05-014 carbocyclic residue substituted with 0-3 p1 R 2 or a 5- to lO-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic rIno system being substituted with 0-3 p, 1 2 Ril1A is selected from one or more of the following: F, ke,:o, halogen, cyano, -0H 2 NRI3BRl 4 B, -NRl 3 Bp,1 4
B,
-C02H, -00 (01-03 alkyl) -OH, 02-06 alkoxyalkyl, -C NH 2 -OC NH 2
*.-NHC(=O)NH
2 -SO2NH 2 C1-C4 alkyl, 02-04 alkenyl, 03-010 cycloalkyl, 03-06 cycloalkylmethyl, benzyl, phenethyl, phenoxy, benzyloxy, nitro, 07-010 arylalkyl, hydroxamic acid, hydrazide, boronic acid, 03-06 cycloalkoxy, 01-04 alkyl substituted with
-NH
2 01-04 hydroxyalkyl, methylenedioxy, ethylenedioxy, r:I-04 haloalkyl, 01-04 haloalkoxy, 01-04 aDhoxycarbonyl, 01-04 alkylcarbonyloxy, 01-04 alkylcarbonyl, 01-04 alkylcarbonylamino, -OCH2CO2H, 2- (1-morpholino) ethoxy, azido, aryl (Ca-C 3 alkyl), a C 5 -C1 4 carbocyclic residue; a 5- to 10-mernbered heterocyclic ring system containing 1. to 4 heteroatoms independently selected from oxygen.. nitrogen or sulfur, said heterocyclic ring system substituteo with 0-3 R12A;
R
1 2 when a substituent on carbon, is selected from one or more of the following: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, Cl-C4 alkyl, C3-C 6 cycloalkyl, C3-C6 cycloalkylmethyl, 07- 15 010 arylalkyl, CJ.-C4 alkoxy, -CO2H, hydroxamic acid, hydrazide, boronic acid, sulfonamide, .9...fcrmyl, C 3
-C
6 cycloalkoxy, -OR 1 3 Cl-C 4 alkyl substituted with -NR 1 3
R
1 4, -NR 1 3
R
1 4, -2-C6 9 alkoxyalkyl optionally substituted with
(CH
3 3 Cl-C 4 hydroxyalkyl, methylenedioxy, e:-'.Kenedi oxy, Cl-C4 haloalkyl, C1-C4 9 haloalkoxy, 01-04 alkoxycarbonyl, Cl-C4 o :.alkylcarbonyloxy, Cl-Co alkylcarbonyl, 01-04 alkylcarbonylamino, -S(O)mR 1 3 -SO2NR-1 3
R
1 4 -IHS02RI 4 -OCH2C02R1 3 a 2- (1-morph olino) ethoxy, -C (R 1 4 =N (0R 1 4 V or 6-mernbered heterocyclic ring containing from 1 to 4 heteroatoms independently selected froxygen, nitrogen or sulfur; or i 1 may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused or 6-membered ring, said 5- or 6- membered ri~ng being optionally substituted on the aliaphatic carbons with halogen, Cl-C4 alkyl, 3 5 CI-C4 alkoxy, hydroxy, or -NF 1 3
R
1 4 or, -61when R 12 is attached to a saturated carbon atom, it may be =0 or or when R 12 is attached to sulfur it may be =0;
R
12 when a substituent on nitrogen, is selected from one or more of the following: phenyl, benzyl, phenethyl, hydroxy, CI-C4 hydroxyalkyl, Cl-C4 alkoxy, Cl-C4 alkyl, C3-C6 cycloalkyl, C3-C 6 cycloalkylmethyl, -CH2NR 13
R
1 4
-NR
13
R
1 4 C2-C6 alkoxyalkyl, Ci- 04 haloalkyl, Cl-C4 alkoxycarbonyl, -CO2H, Cl- C4 alkylcarbonyloxy, Cl-C4 alkylcarbonyl, -C9 (R )=N9R is 1 Rl 2 A, when a substituent on carbon, is selected from one or more of the following: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, Cl-C4 alkyl, 03-05 cycloalkyl, C3-C6 cycloalkylmethyl, C7- .20 010 arylalkvl, Cl-C4 alkoxy, -C02H, hydroxamic 499 acid, hydrazide, boronic acid, sulfonamide, formyl, 03-06 cycloalkoxy, -OR 1 3
C
1
-C
4 alkyl substituted with -NH 2
-NH
2 -NHMe, C2-C6 alkoxyalkvl optionally substituted with -Si (CH 3 3 Cl-C4 hydroxyalkyl, methylenedioxy, .:..ethylenedioxy, Cl-C4 haloalkyl, 01-04 haloalkoxy, 01-04 alkoxycarbonyl, Cl-C4 dilkylcarbonyloxy, 01-04 alkylcarbonyl, Cl-C4 alkylcarbonylamino, -S (0)mMe, -SO2NH 2 -NHSO2Me, -OCH2CO2R1 3 2- (l-morpholino) ethoxy, -C (NOH) NH 2 or a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur; or -62- R1 2 A may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused or 6-rnembered ring, said 5- or 6- membered ring being optionally substituted Dn the aliphatic carbons with halogen, Cl-C4 alkyl,
C
1
-C
4 alkoxy, hydroxy, or -NE 2 or, when R1 2 A is attached to a saturated carbon atom, it may be =0 or or when R 12 is attached to sulfur it may be =0; R1 2 A, when a substituent on nitrogen, is selected from one or more of the foliowing: phenyl, benzyl, phenethyl, hydroxy, CI-C4 h vdrox\'alkyl, Cj-C 4 alkox.-', Cl-C4 alkyl, 03-CC cy-Cloalkyl, 03-06 cycloalkylmethyl, -CH-2NH-2,
-NIH
2 C2-'6 alkoxyalkyl, 01-04 haloalkyl, C1- 04 alkoxycarbonyl, -C02H, Cl-C4 ::alI kylcarbon yl oxy, 01-04 alkylcarbonyl, 0 -C NH- 2 1 A :22 lxenyl substituted with 0-3 R 11A; Cl-CC alkycoyl substituted with 03 AA;; C 1* -C alIoycbnyl substituted with 0-3 R 1lA; CI-C6 alkylmcarbonyl substituted with 0-3 p,.
C3-C6 alkoxyalkyl substituted wit+h 0-3 RilA; an an.ne protecting group when R 13 is bonded to N; a hydroxy protecting group when R 1 3 is bonded to 0; p2.3A I's selected fr-om: -usItuted with. -63benzyl substituted with 1-3 R 1 1 C1-C6 alkyl substituted with 1-3 R 1 1
C
2
-C
4 alkenyl substituted with 1-3 R 11 CI-C6 alkylcarbonyl tubstituted with 1-3 R 11
CI-C
6 alkoxycarbonyl substituted with 1-3 R 11 C1-C 6 alkylaminocarbonyl substituted with 1-3 R 11 C3-C6 alkoxyalkyl substituted with 1-3 R 11 an amine protecting group when R 13 is bonded to N; a hydroxy protecting group when R 1 3 is bonded to O;
R
14 is hydrogen, hydrjxy, C 1
-C
6 alkyl substituted with 0-3 groups selected from OH, CI-C4 alkoxy, halogen,
NH
2 -NH(C1-C4 alkyl), CI-C6 alkoxy, C 2
-C
6 alkenyl, phenyl, benzyl, an amine protecting group when R 14 15 is bonded to N, a hydroxy protecting group when R 14 is bonded to O; 4 4" R 14 A is CI-C 6 alkyl substituted with 1-3 groups selected from OH, C1-C4 alkoxy, halogen, NH 2 -NH(C1-C4 20 alkyl), C1-Cg alkoxy, C 2
-C
6 alkenyl, phenyl, benzyl, an amine protecting group when R 14 is bonded to N, a hydroxy protecting group when R 14 is bonded to 0;
F
1 and can alternatively join to form -(CH2)4-, -CH2CH2N(R 5 )CH2CH2-, or -CH2CH20CH2CH2-;
R
1 3 B and R 14 B are independently selected from H or CI-C 6 alkyl, or R 13B and R 14 B can alternatively join to form -CH 2 CH2N(R 15 )CH2CH2-, or -CH2CH20CH2CH2-;
R
15 is H or CH3; m is 0, 1 or 2; W is selected from: -64-, -N (p, 2 2
N(R
2 3 -OC 0-, -N (R 2 2 C 0-, -N (R 2 2 C (R 2 7
(R
2 8 -N (R 2 2
N(R
2 3 -N (R 2 2 S NC(R 2 3 wherein: Z is 0, S, NR 2 4
R
2 2 and F.
23 are independently selected from the fc o c: Ca-Ca alky2. substituted with 1-3 R 3 1 asC2-C8 alkenyJ. substituted with 1-3 R 3 1 '02-CE alk yny! substituted with 1-3 R3; 02"-014 carbocyclic ring system substituted with A -5 R7,1 or 1-5 R 32 a E- to l0-mernbered heterocyclic ring system 2C containing 1 to 4 heteroatoms independently r'ror-r oxyg'cen, niroqr r or sulfur, s-z he:-erocyclic ring system being substituted w-th 1-2 R 32 -*p2-a -N p 2 )(2b p22'"- are independently selected from the hy drogen; C~-.alky], substituted with R3 1 C2-05 alkenyl substituted with 0-3 R 3 1 0; 02-CS alkynyl substituted with 0-3 R 3 1 a 03 -C 21 carbocyclic ring system substituted with
P.
31 or 0-5 R 32 a o lO-membered heterocyclic ring system ccntaining I to 4 heteroatoms independentY selected from oxygen, nitrogen or sulfur, said heterocyclic ring system neing substituted with 0-2 R 32
R
2 4 is selected from: hydrogen; hydroxy; amino; C1-C4 alkyl; Cl-C4 alkoxy; mono- or di- (C1-C6 alkyl)amino; cyano; nitro; benzyloxy; -NHSO2aryl, aryl being optionally substituted with (Ca-CE) alkyl;
F,
31 is selected from one or more of the following;
-CH
2 NR13ARl 4 -NR1 3 AR1 4 -C0 2 R13A, -OC(=O)Rl3A, 0KR1 3 A, -S(O))mR1 3 A, -NHC(=NH)NHR1 3
A,
C(=NH)NHRl.
3 A, -C(=O)NRl 3 AR1 4 -NR14C(=O)Rl 3
A,
15 -OC(=O)NR1 3 AR1 4 -NR13AC(=O)Npj 3 AR1 4 -NR14SO2NR1 3 AR1 4 -NR1 4 S0 2 Rl3A, -SO 2 NR1 3 AF,1 4
CH
2 .NR 1 3
R
4 A, -NR1 3 R1 4 A, -C(=0)NR1 3 Rl 4
A,
-NR14AC(=0)Rl 3 =NOR1 4 A, -NR1 4 C(=0)OR1 4
A,
-0C(=O))NR± 3 Rl 4 A, -14Rl 3 C(=0)Npl 3 R1 4
A,
20 -NR14AS0 2 NRl 3 Rl 4 A, -NR14ASO2Rl 3
-SO
2 NR1 3 R1 4
A,
ni~tro, hydrazide, borornic acid, formyl, C3-C6 cycloalkoxy, C 2
-C
4 a lkyl substituted with -NRp 1 3
R
14 Cl-C4 hydroxyaJlkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, CI-C4 :25 haloalkoxy, Cl-C4 alkylcarbonyl, -0OCH2CO2H, 2-(1-morpholino)ethoxy, azido, or -C (R 1 4 =I (0RI 4
A);
aryl substituted with 1-5 R 32 or a 5- to 10-membered heterocyclic ring system containino 1 to 4 heteroatoms independently selected from oxygen, nitzogen or sulfur, said heterocyclic ring system being substituted with 1-2 R 3 2
R
32 when a substituent on carbon, is selected from one or more of the following: -66- C7-CIO cycloalkyl. NHRS 2 RI4A, -C0 2 R1 3 A, NRjplARl'4, NR13R1 4 A, -C =N 0 pI4A), -C0N1R1 3 -NR4~ 0
R
4 1 -SOMR1 3 A, -C(=0)MRl 3 Rl 4 -OC(-O)NR<1 3 Rl 4 -0C(=0)Rll, -OCO2R1 3 -C (=0)NR 1 3
-(C
1
-C
4 alkyl)-NRl 3 Pl 4 0R,13A -C (=O)Np.4 0
R
4 1 C2-C4 haloalkenl,
C
1 C4 haloalkyflyl, or -C
NR
1 3 C (R 1 1) 2
NR<
1 3
R'
4 -C
NR
1 3 C (P.
1 1 2 NR3C02RI 3 -C(=0)NRI 3 -(C1-C4 alkyl)NR13C2R 1 3 C N(Rl 3
-(G
1 -C4 alkyl)
-P
1 1 or -C C (R11) 2 NpR 1 3 R] 4; *9 C(=O)C(R1) 2 NR13C02Pl 3 alkyl)V
NR
1
R
1 4 -O -(CI-C4 alkyl) -NP1C2l or 9 5 C-4alkoxy substituted with 1-4 groups selected 99 9 from:
R
1 1
C
3 -C6 cycloalkYlt -C02R' 3 9, 99 -C
-NPR
1 or OH; 1-'4 alky!. substituted with 1-4 groups selected to 0. from:
P
1 1, -11R 1 4 =NNR13C(=O)tjR1 3
RI
4 to 0- al ey substituted with 0-4 P 1 1 4T.
C
2
-C
4 alkynyl substituted with 0-4 F 1 1 or 5- or 6-mernbered heterocyclic ring containing fro~r 1 to 4 heteroatomns independently selected 99 2E [-rom oxvgen, nitrogen or sulfur, substituted w- th 1-2 when p 3 2 is attached to a sato~rated carbon, it. may be =NOH; or when F3 at-ached to sulfur it may be =0; 3 C/1432, wter. a substituent on nitrogen, is selected from e or more of the following: CH2NIR 1 3Apl 4, 1 pp3ARl 4
-CH
2 VRl3h)l 4
A,
3~ eleced from: H, Ca-C3 alky'l; -6 1- R4 1 is selected from; -c NR 1 3
R
1 4 -C NP1 3 NR1 3 Rl"4; -C C(R11) 2NR1 3 Rl 4 -C C CRI 1 2
NR
1 3 NR1 3
R
1 4 -C (=0)0C(R 1 1 2 NR1 3 0C02R 13 -C -C
R
1 1 -C -(CI-C4 alkyl) -NR 1 3
P
1 4 -C (Cl-C 4 al kyl) -NR1 3 C0 2R 13; 1-3 amino acids linked together via amide bonds, 4* and linked to the N atom via the carboxylate terminus; provided that- 4p4, R4h R" and R7 h are not all hydrogen, Preferred compounds of this third embodiment are compounds of the formula wherein: ::4.R 4 and RI are independent.ly selected from the following g roup s: hydrogen; 4444aky usittdwth03R1 3-CC alkeny substituted with 0-3 R 1 1 03-04 alkenyl substituted with 0-3 R 11 R4A and R7A are hydrogen; n is 0, 1, or 2;
R
5 is selected fromr fluoro or -OR 20 -68- R6 is independently selected from: hydrogen, fluoro or
R
5 and p6, can alternatively join to form an epoxide or aziridine ring; -OCI- 2
SCH
2 -OC(0O)O-;
-OCH-
2 -OC(CH3)20-; -00 (OCR 3 (CH2CH 2
CH
3 or any group that, when administered to a mammalian subject, cleaves to form a free dihydroxyl; Ra is selected from hydrogen or fluoro; p6a IS Selected from: hydrogen or fluoro; S. R 5 1 5 and 1k 5a Can alternatively join to form or a 'S *ketal r-inQ;- F and P- can alternatively join to form or a 2Cketal ring; arE- irdeenden,.Iy selected from: hydrogen; a2.kylcarbonyl; 2E 2:-C6 a2lcxcarbonyl; Sben:,yl or any group that, when administered to a mammalian sub~ict, cleaves to form a free hydroxyl; R11 is selected from one or more of the following: H, keto, halogen, cyano, -CH2NP. 3
R
14
-NR
13
R
14 -C02RI 3 0OC(=O)RI 3 .0R 1 3 -S(0)mRl 3 C2-C 4 alkenyl, C3-C6 cycloalkylmethyl, nitro, hydrazide, boronic acid, formyl, C 3 -C6 cy-l oalkoxy, methylenedioxy, ethylenedioxy,
I
-69- Ci-C4 haloalkyl, Ci-C4 haloalkoxy, C10C4 alkoxycarbonyl, 01-04 alkylcarbonyl, Ci-C4 alkylcarbonylamino, -0CH2C02-, -C (R 14
(OR
1 4 03-GbO cycloalkyl substituted with 0-2 R1 2
C
1
-C
4 alkyl substitued with 0-2 Ri 2 aryl (Cl-C3 alkyl) substituted with 0-2 R 12 6 alkoxyalkyl, substituted with 0-2 Ri 2 Ci-C4 alkylcarbonyloxy substituted with 0-2 R 12
C
6 -CIO arylcarbonyloxy substituted with 0-2 Rl?, aryl substituted with 0-3 R1 2 or a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently :selected from oxygen, nitrogen or sulfur, said 15 heterocyclic ring system being substituted s with 0-2 R1 2
*R
12 when a substituent on carbon, is selected from one or more of- the following: phenyl, benzyl1, phenethyl, phenoxy, benzyloxy, halog en, 01-04 alkYl, 07-010 arylalkyl, 01-04 a lkox.y, 2- (1-morpholino) ethoxy, -C02H, hydroxamic acid, hydrazide, -C(R1 4 )=N(0R 1 4 a...'.cyano, boronic acid, sul-fonamide, formy1, 03- 06 cycloalkoxy, -OR 1 3 01-04 alkyl substituted with -NR 13
R
1 4
-NR
1
-'RI
4 methylenedioxy, 01-C4 haloalkyl, 01-04 alkylcarbonyl, 01-04 alkylcarbonylamino, hydroxy, hydroxymethyl; or a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur;
R
12 when a substituent on nitrogen, is selected from benzyl or methyl;
R
1 3 is H, C1-C4 alkyl, C3-C6 alkoxyalkyl, C 2
-C
4 alkenyl, or benzyi; R 1 3 A is selected from: phenyl substituted with 1-3 R 11 benzyl substituted with 1-3 R 1 1 Ci-OG alkyl substituted with 1-3 R 1 1
C
2
-C
4 alkenyl substituted with 1-3 R1 1 C3-C6 alkoxyalkyl substituted with 1-3 R 11 an amine protecting group when R 1 3 is bonded to N; a hydroxy protecting group when R 13 is bonded to 0;
R
1 4 is OH, H, CI-C 4 alyl, CI-C 4 alkoxy, NH 2 C2-C 4 alkenyl, or benzyl; *P :4 is 01-06 alkyl substituted with 1-3 groups selected from OH', C:.-C 4 alkoxy, halogen, NH 2 -NH(C1-C4 alkyl), 01-C6 alkoxy, C 2
-C
6 alkenyl, phenyl, benzyl, an amine protect ing group when R 1 4 is bonded to N, 2 C a hvydroxy Iprozecting group when R 1 4 is bonded to 0; R13 and p14 can alternatively join to form -(CH2)4-, -CH2CH2N(Rl 5 )CH2CI12-, or -CH2CH20CH2CH2-; 2 5 p 1 5 is H cr CH3; W is selected from; -N (2)C(Z R3 -N (p2 2)0C C N CR 2 3 wherein: Z is 0, S, N-Nii$ -OCH 3
I=
R
22 and R 23 are independently selected from the following: hydrogen; Cl-CS alkyl substituted with 1-2 R1 C2-C6 alkenyl substituted with one R1 C2-C4 alkynyl substituted with one R 31
R
27 is selected from the following: hydrogen; Cl-GB alkyl substituted with 0-3 R 31 C2-C8 alkenyl substituted with 0-3 R1 C3-C8 alkynyl substituted with 0-3 R 3 1 15 R 28 is hydrogen or halogen;
.:R
31 is selected from one or more of the following: 2 NRl 3 Rl 4 -NR1 3 ARl 4 -Co 2 PRl 3 A, ~C~)lA ORl 3 A, -S mR 3 A, -NHC (NH) NHRl 3
A,
20 -C(=NH)NHR1 3 A, -C(=0)NR1 3 ARl 4 -NP,14C(=O)Rl3A, OCV=O)NR1 3 AR'-I, -IqRl3AC(=0)NR1 3 AR1 4 NR14S0 2 NR1 3 Ap.l 4 -NRl4S0 2 R1 3 A, -SO 2 NRl 3 ARl 4 OV CH 2 NR,13Rl 4 A, NR1 3 Rl 4 A, C(=0)NR1 3 Rl1 4
A,
-Iqp 4 AC(=O) Rl =NORl 4 A, -NR14C(=0)0Rl 4
A,
25 -OC(=O)NR1 3 Rl 4 A, -NR13C(=0)NR1 3 Rl 4
A,
2 NR1 3 Rl 4 A, -NR14ASO2Rl 3 -S0 2 NR1 3 Rl 4
A,
*C nitro, hydrazide, boronic acid, formyl, C 3
-CE
cycloalkoxy,
C
2
-C
4 alkyl substituted with -NRl 3 RI4 Cl-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, Cl1C4 haloalkoxy, C1-C4 alkylcarbonyl, -OCH2CO2H, 2- (1-morpholino)ethoxy, azido, or aryl substituted with 1-5 R 32 or a 5- to lO-membered heterocyclic ring system containingi 1 to 4 heteroatoms independently -72selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 1-2 R 32
R
32 when a substituent on carbon, is selected from one or more of the following: C7-Cio cycloalkyl, NHRS0 2 Rl 4 A, -CO 2 R1 3 A, NR13AR1 4 NR1 3 R1 4 A, -C (R 1 4 (R1 4 -CONR1 3 NR1 3 Rl 4
-NR
4 0
R
4 1 I -SOmR13A, -C (=0)NR1 3
R
1 4 -OC(=0)NR 1 3 Rl 4 -C(=O)Rll, -OC(=0)Rll, -OCO2R1 3 -C NRl 3 -(Ca-C 4 alkyl) -NR 1 3
R.
1 4 OR1 3 A, -C (=0)NR 4 0
R
4 1, C 2
-C
4 haloalkenyl, Cl-C 4 haloalkynyl, or -C =0 NP 1 'C(RJ) 2
NR
13
R
1 4
NP
3
(C
1
-C
4 alkyl) -NR1 3 C02R' 3 -C(=C)N(Rl 3 )-(Cl-C 4 alkyl)-R 1 1 or -C (=jC (R 2 N 2
N
1 4 -(CC(RI 2 2
NR
2 3 C0 2 R 13 4 alkyl)- 20, NF.13T,14; 4 alkyl)-NPR 1 3 C02R'3; Of a I2 o2:D: su hstituted with 1-4 groups selectec
P
11 C3-C6 cycloalkyl, -CO 2 R1 3 (=0)NR' 3 R1 4
-NR
1 -'Rl 4 or OH; -0-4 alkyl substituted with 1-4 groups selected fom: =NR 1 4
=NNR
1 3 C(-O)NR1 3 Rl 4 1 3 C OR 1 3 or -IqR 1 3
R
1 4 C2--4 alkenyJ. substituted with 0-4 R 1 1
C
2
-C
4 alk~ynyl! substituted with 0-4 R 1 or a or 6-membered heterocyclic ring containing fromn 1 to 4 heteroatoms independently selected ronoxygen, nitrogen or sulfur, substituted with 1-2 R 12 when R 32 is attached to a saturated carbon, it may be =NOH; or when R 3 2 atzached to sulfur it may be =0; rr. is 0 I or 2 -73-
R
4 0 i s selected from: H, 02-03 alkyl;
R
4 1 is selected from: -C (=)NRI 3 R 4 -C NR 1 3 NRI 4 -C C (R 1 1 2NR1 3
R'
4 -C (=0D)0C (R11) 2NR' 3
NR
1 4 -C C(R 1 1 21qRI 3 0 2
R
13 -c H; -C RI I; -C -(Cl-0 4 alkyl)-NR1 3
R
1 4 -C (01-04 alkl -NR 13 0 0 2
R
1 3 :1-3 amino acids linked together via amide bonds, :15 and linked to the N atom via the carboxylate terminus; provided that: p4 and R 7 are not both hydrogen; when R 4 is hydrogen, at least one of the following is not hydrogen: R 2 2 and R 2 8 ~25 [10) Further preferred compounds of this third embodiment of formula ()are compounds of formula (II) w
R
5
R
6 or a pharmaceutically acceptable salt form thereof wherein: -74-
R
4 and R 7 are indepDendently selected from the following groups: hydrogen,- CI-C4 alkyl substituted with 0-3 R 1 1; C3-C 4 alkenyl substituted with 0-3 R11;
R
5 is se3J-cted from -OR 20
R
6 is hydrogen or -OR 21 R0and p 21 are independently hydrogen or any group that-, when administered to a mammalian subject, cleaves to form a free hydroxyl;
P.
11 is selected from one or more of the following: H, keto, halogen, cyano, -CH- 2
NR
1 R, -N 1
R
14 -C02 R13 2 -O -S(O)mRl 3 2C V. 0 alkenyl, C3-C6 cycloalkylmethyl, nitro, hx'dr azide, boronic acid, formyl, C3-C6 2 cycl calkoxy, methylenedioxy, ethylenedioxv, haloalkyl, haloalkoxy, 01-C4 a 2.koxycarbonyl, 01-04 alkylcarbonyl, C1-C4 al}:-ylcarbonylamino, -001-2C02H-, -Cocycloalkyl substituted with 0-2 R1 2 C~-~alkv2. substitued with 0-2 Ri 2 9.a ryl(C1--3 alkyl) substituteo with 0-2 R±Z C2-C6 alkoxyalkyl, substituted with 0-2 R1 2 alkylcarbonyloxy substituted with 0-2 R 12 C6-C-Io arylcarbonyloxy substituted with 0-2 R 1 2 ary: substituted with 0-3 R1 2 or a 5- to lO-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said rneterocyclic ring system being substituted wih0-2 pR 1 2
R
12 when a substituent on carbon, is selected from one or more of the following: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, Cl-C 4 alkyl, C7-CjO arylalkyl, Cl-C4 alkoxy, 2- (I-morpholino)ethoxy, -CO2H, hydroxamric acid, hydrazide, -C(R 1 4 )=N(C0-P 1 4 cyano, boronic acid, sulfonamide, formyl, C 3
C
6 cycloalkoxy, -OR13, Cl-C 4 alkyl substituted with -NR1 3 Rl 4
-NR
1 3
R
1 4 methylenedioxy, Cl-C4 haloalkyl, Cl-C 4 alkylcarbonyl, Cl-C4 alkylcarbonylamino, hydroxy, hydroxymethyl; or a 5- or 6-mernbered heterocyclic ring containing f-romr 1 to 4 heteroator-s independently selected from oxygen, nitrogen or sulfur;
R
12 when a substituent on nitrogen, is selected from *ben-z,,,l or methyl; 2, H, C:-C 4 alkyl, C-3-C6 alkoxyalkyl, C 2
-C
4 alkenyl, cr benzyl;pl3A is selected from: phlen.-.- substituted with 1-3 R11; 25 benz-;' substit-uted with 1-3 R 1 1 CI- CE alkylI substituted with 1-3 R 1 1
*C
2
-%C
4 alkernyl substituted with 1-3 R 1 1 C3-C6 alkoxyalkyl substituted with 1-3 R 11 an amine protecting group when p, 13 is bonded to N; a hydroxy protecting group when R 13 is bonded to 0; R14 is OH, H, CI-C4 alkyl, CI-C 4 alkoxy, NH 2
C
2
-C
4 alkenyl, or benzyl; pl4A is CI-CE alkyl substituted with 1-3 groups selected from OH, Cj-C 4 alkoxy, halogen, NH 2 -NH(C1-C4 -76alkyl) C 1
I-C
6 alkoxy, C 2
-C
6 alkenyl, phenyl, benzyl, an amine protecting group when R 14 is bonded to Nq, a hydroxy protecting group when R 14 is bonded to 0; R1 3 and R 1 4 can alternatively join to form -(CH2)4-, -CH2CH-2N(Rl 5 )CH2CH2-, or -CH2CH2OCH2CH2-;
R
1 5 is H or CR3; W is selected -N (R 2 2 C (R 23 -N (R 22 0-;
-N(P
2 C (p 2 7
(R
2 8 -N (R 22
N(R
23 wherein: Z I's 0, S, NI ON ~~22are :neednJ;selected from the O. hyrgn Ci C8 al'yl substituted with 1-2 R 31 02-C6 alker.yl substituted with one R 3 1 l.yny! substituted with one R 3 1 R2-i selected from the following: hydro':en; C:-CE, alky! substituted with 0-3 R 31 C2-CS alkenyl substituted with 0-3 R 31 23-05 alkynyl substituted with 0-3 R 31 R2E I's hydro--gen or halogen; ~selected from one c- more of the following: -77-
-CH
2 NRiJARl 4 -NRl 3 ARl 4 -C0 2 1R1 3 A, -0RlJA, S(0)mR1 3 A, -OH 2 NRl 3 Rl 4 A, -NR1 3 R1 4 A, or -C (R 1 4 =N (0RI 4 aryl substituted with 1-5 R 3 2 or a 5- to lO-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 1-2 R3 2
R
3 2 when a substituent on carbun, is selected from one or more of the following: 7-CI) cycloalkyl, NHRS0 2 R1 4 A, -C0 2 R1 3 A, Npl 3 AR1 4 N1RIJRA, -C (R 1 4 =N (OR 1 4
-CONR
1 3
NR
1 3
R
1 4 \Np 4
OR
4 1 -SOmR1 3 A, -0(=0)NR 1 3
R
1 4 -00(=D)jqR 1 3
R
1 4 -C(=0)R 1 1 -00(=0)R 1 1 *:~-OC02R13, -C NR 13 (Cl-C 4 alkyl) -NR 1 3 R1 4 ORl3A, -C(=L)NR 4 0
R
4 1 02-04 haloalkenyl, Cl-C 4 ~*:haloalkynyl, or IR 1 3
(R
2 2 NR1 3 R14; -C NR1 3 C (R2 1) 2NR1 3 C0 2
R
1 3 -C(-0)NR' 3 -(01-04 alkyl)-NR 1 3 C0 2
R
1 3 -C N(R 1 3
(C
1 4 alkyl)-R 1 1 or -C 1 21qR1 3 RI 4 25 -C C=0)(R 1 1 2
NR
1 3 0C0 2
R
13 -C (01I-04 alkyl)
*.:NR
13
R,
14 4 alkyl)-NR 1 3 C0 2 Rl 3 or 01-04 alkoxy substituted with 1-4 groups selected from: R 11 03-06 cycicalkyl, -C0 2
R
1 3 -C(=0)Np 1 3
R
1 4
-NR
1 3
R
1 4 or 01H; 01-04 alkyl substituted with 1-4 groups selected from: R 1 1 =NR\1 4 =NNR1 3 C(=0)NR 1 3
RI
4
=NNR
1 3 C(=0)0R 1 3 or -NR 1 3 R1 4 02-04 alkenyl substituted with 0-4 Ri 1 02-04 alkynyl substituted with 0-4 R1 1 or -78a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, substituted with 1-2 R 12 when R 32 is attached to a saturated carbon, it may be =NOH; or when R 3 2 attached to sulfur it may be =0; m is 0, 1, or 2;
R
4 0 is selected from: H, CI-C 3 alkyl;
R
4 1 is selected from: -C NR 1 3
R
1 4 -C R13NR 1 15 -C C (R
I
2NF13R14 -C C()R
I
2 N 13N4; 13; 2 S.
R
1 1 2 -C (-C4 alkyl) -NR1 3 0 2
R
1 3 S- alky )-NRl 3CO2 R 3 am.i:n acids linked together via amide bonds, asnd inked to the N atom via the carboxylate rob* P4 and R7 are not both hyarogen; when R is hydrogen, at least one of the following is not hydrogen: R 2 2 and R 2 8 Preferred compounds of this third embodiment are compoun ds of formula (II) described above, wherein: -79- 4 and R 7 are selected from benzyl, fluorobenzyl, pyrrolylmethyl, methoxybenzyl, isobutyl, nitrobenzyl or aminobenzyl, thienylmethyl, hydroxybenzyl, pyridylmethyl, naphthylmethyl;
R
5 is -OH; .9 0 9*i* 9.
*9 9 4. 9 9 9* 9 *9*9
O
9. 9 99e9o 99
R
6 is hydrogen or -OH; p 1 3 is H, Cl-C4 alkyl, C 2
-G
4 alkenyl, or benzyl; pj4 is OH, H, CF 3
C
1
-C
4 alkyl, C 1
-C
4 alkoxy, NH2, C 2 -C4 alkenyl, or benzyl; 15 P! and pJ4 car alternatively join to form -(CH2)4-, -CH2CH2N (R 1 5 )CH2CH2-, or -CH2CH200H2Ch2-; V; is selected from: (p 2 2 (p 2 3 23 (p 2 2) (C-21' N (R 2 3 -N (p 2 2) R23) p 22 and p23 are independently selected from the :ollov.inc: hydrogen; Ci-CE alky substituted with 1-2 R 3 1; C2-CG alkenyl substituted with 1-2 R31; C2-C4 alkynyl substituted with 1-2 R 3 1 R31 is selected from one or more of the following: halogen, -OR13A, -C(RII)=N(OR 1 4 -C0 2 R13A, p131; aryl substituted with 1-5 R32; or a heterocyclic ring system chosen from pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, pyrrolyl, pyrazoly,, imidazolyl, tetrazolyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl, oxazolidinyl, said heterocyclic ring being substituted with 1-2 312, or benzimidazolyl, benzotriazolyl, indaz,>:-.l, benzoxazolinyl, benzoxazolyl, optionally substituted with 0-2 R 32
R
3 2 when a substituent on carbon, is selected from one or more of the following: -Ch~ 2 NF..1AR1 4 _jqRl 3 AR1 4
-CH
2 IR1 3 R1 4 A, _NR1 3 R1 4
A,
_C(p,1 4 )=N(OR1 4 allyloxy, -CO2CH3, -NHCHO, -00-02CH3, -CH=NCH2CH2OH, -OCONHCH2C6H5, -OCONHCH3, -C=C-CH2OH, -OCH2CONH2, -CH=NNHC10NH2, -CONHOCH3, -CH2CH (OH) CH2OH, adamantamido, hydroxyethoxy, dihydroxyethyl, -C(NF2)=NIH, -COIIHCH3, -CONHCH2CH3, (0H2CH3) 2, -NHO-ONH2, -NHCONIHCH3, -IHZO-_H2N (CH3) 2, -NHCOCH2NHCH3, -NEC0CH21NHCO2CH2C6H5, ThHCOCH2Nfl2, HC0CH (CH3)IIH?02CH2 -":oC2H(cii")6H5)NHO-iO2CH2C6H5,
-NHCOC'H(CH')NH-,,
-NHCO-H'(TH2C6H5)NH2, -CO2CH2CH3, -CON!HCH2C-H2CH3, -CONHCH (CH3) 2, -CH2-imidazole, -COCH -CH(OH)CF3, -CD-imidazole, -CO- :Ya2CIlvl -COC-F3, acetoxy, -(CH3) (CH0), -CO0NR 1 3
R
14
-CONHOH,
.:(iet +-hlaminoethy1) ami nocarbonyl, (N-ethyl,1N-methylaminoethyl) aminocarbony, 14 -mrethylpiperaz inylethyl) aminocarLbonyl, (piperidinylethyl) aminocarbonyl,
-NHCCH
2 111CF3, N- (4- :.:rrholino)ethyl)amiinocarbonyl, or N(-NN methylamino) ethyl1) aminocarboflyl.
-81- (12) Also preferred in the present in~vention are compounds, or a pharmaceutically acceptable salt form thereof, of the formula: w R3 4 R7 SHO OH wherein: W IS -jN(p 2 2 .4R 2 3
CR
22 C N (R 23 -N (p 2 2 C Nq (p 2 3
**R
4 and R 7 are independently selected from: benzy'L, 15 fluorobenzy'l, pyrrolylmethyl, methoxybenzyl, isobutyl, nitrobenzyl c~r arinobenzyl, thienylmethyl, hydroxybenzyl, pyridylmethyi, 4:4naph, 1hyTet.hyl; *23 R 22 and R 2 3 are independently selected from the group consisting of;
(F
2 )-benzyl, carboethoxybenzyl, (O-benzylformaldox'ime)benzyl, (0-methylformaldoxime) ben zyl, (CH302C0) -benzyl, (HOCH2CH2N=CH-) -benzyl, N-benzylaminocarbonylbenzyl, (H2NNHC(=O) benzyl, (CH3ONHC )-benzyl, (HONEC -benzyl, (CH3NHC -benzyl, N4,N-dimethylaminocarbonylbenzyl, rH (OH) CR20) -benz-y., hydroxyethoxybenzyl, (carbornethoxy)pentyl, glycylaminobenzyl, N, N-dimethylcilycylaminobenzyl, -82alanylarninobenzyl, (N-phenylmethoxyca-bonyl) alanylaminobenzyl, phenylalanylaminobenzyl, (14-phenylmethoxycarbonyJ.) phenylaianylaminobenzyl, (CH3CH2NPC benzyl, N, N-diethylaminocarbonylbenzyl, N-ethyJlarinocarbonylbenzyl, N-propylaminocarbonyl~henzy'l, N, N-diisopropylaminoc nylbenzyl, N, N-cu-npropylaminocarbonylbenzyl, (hydroxypropyny'~benzyl, (iridazoly1- C benzyl, (pyrazolyl-C )-benzyl, (pv ridylmethylaninocarbonyl) benzyl, triflucr-oacetylbenzyl, dihydroxyethylbenzy-, (MeFNC(=O)NH)-benzyl, (H2NC(=O)NH)-beflzyl, is1 (hC(=O)NH)-benzy1, methanesulfonylpentyl, N- 4 -rN.l-qmethylaminobenzyl, acetyaminobenzyl, ;::prcpionylbenzyl, butyrylbenzyl, (trifluorohydroxyethyl)benzy1, (CF3C(=NOiH) a berzyl, (N-,-methylglycy.1}aminobenzyl, 4 4-rmzrph. ino) ethyl) arinocarbonylbenzyl, N-diethyJlarrinoethyl aminocarbonylbenzyl, 444* C ~4 -me thylIpipe ra zin-i- ,,ethyljarr.inocarbony.Lbenzyl, (benzyll,'C(='O)O)benzyl, (CH3NHC(=O))benzyl, CIRZO) benzyl. (NI-1 2 C benzy., IN-phenybmethovycarbonyl) glycylamino) benzyl, (lricLazoylmethyl)benzyl, ((CH3) 3
C-
et hylaminoethyl) aminocarbonylbenzyl, (pyrrolidinylethyl) ,aminocarbonylbenzyl, (pi-periclinylethyl) aminocarbonylbenzyl,
(H'
2 NC benzyl, (H 2 N! (=NOH) )fluorobenzy>' 12 p eferrecl are compaundL of ftrrnula (11,R) R22N NR 23 Ph HO *,OH (Iha) or a pharmaceutically acceptable salt ,-orm thereof, wherein: R22 and R 23 are independently selected from the group consisting of:
:(H
2 NC(=O))-benzyl, carboethoxybenzyl, (O-benzyl- 10 formaldoxime)benzyl, (0-methylformaldoxime)benzyl, ChOO)-benzyl, (HOCH2CH2N=CH) -benzyl, N-benzylamrinocarbonylbenzyl, (H2NNHC benzyl, (H2NC(=O)NHN=CH)-benzyl, (CH3ONqHC(=O))-benzyl, (HONHC(=Ofl-benzyl, :(CH3NIC -benzyl, N, ,N-dimethylaminocarbonylbenzyl, (HUCH2CH (OH) CH2O) -benzyl, hydroxyethoxybenzyl, (carbomethox.y)pentyl, glycylaminobenzyl, N,N-dimethylglycylaminobenzyl, alanylaminobenzyl, (N-phenylmethoxycarbonyl)alanylaminobenzyl, phenylalanylaminobenzyl, (N-phenylmethoxyca rbonyl) phenylalanylaminobenzyl, (CH.3CH2NHC benzyl, N,N-diethylaminocarbonylbenzyl, N-ethylaminocarbonylbenzyl., N-propylaminocarbonylbenzyl, N, N-diisopropylamin-ocarbonylbenzyl, N, N-di-npropylaminocarbonylben zyl, (hydroxypro.Dynyl)benzyl, (i;midazolyl-C benzyl, (pyrazolyl-C(=O) )-benzyl, -84- (pyridylmechylartunocarbonyl) benzyl, trifluoroacetylbenzyl, dihydroxyethylbenzyl, (MeHNC(=)NH-)-benzyl, (HC (=0)NH)-benzyl, methanesulfonylpenty-, Nformyl-N-rnethylarninobenzyl, acetylaminobenzyl, propionylbenzyl, butyrylbenzy., (trifluorohydroxyethyl) benz.v', (CF3C benzy!; (N-methylglycyl)arninobenzyl, (4-morpholino) ethyl) aminocarbonylbenzyl, (N,N-dimethylaminoethyl)aminocarbonylbenzyl, N-ciiethylaminoethyl) aminocarbonylbenzyl, (4-methylpiperaz in-iyiethyl) ami4nocarbonylbenzyl, (benzyl- NHC 0)benzyl, (CH3NHC benzyl, -5 CH0)benzyl, (NH 2 C benzyl, (-phenylrethoxycarbonyl)glycylami1o)benzyl, (I'midazoJlyJmethyl)oenzyl, ((CH-i) 3
C-
)benzyl, (N-methyl-Netlhylaminoethyl) aminocarbonylbenzyl, 20(z, 'rolidinrylethyl) aminocarhonylbenzyl, -oeridinylIethylaminocarbonlbelzyl, 2 IC(=NOH) )benzyl, (H 2 NC(=N0OH) )fluorobenzy-.
.:ificly preferred are copus of formula R2"N
NR
23
P
HO OH (Iha) or z5 p!,_rraceutically acceptable salt form thereof, selece fro:-. the group consisting of: the compound cf formula (IIa) wherein R 2 2 is 1cinnamyl and R 23 is l-cinnamyl; the compound of formula (IIa) wherein R 22 is vinylbenzyl and R 23 is vinylbenzyl; the compound of formula (IIa) wherein R 22 is 3- (NHCHO)benzyl and R 23 is 3-(NHCHO)benzyl; the compound of formula (IIa) wherein R 22 is 3- (NHCOCH3)benzyl and R 23 is 3-(NHCOCH3)benzyl; the compound of formula (IIa) wherein R 22 is 3formaldoximebenzyl and R 23 is 3-(Nhydroxy)aminomethylbenzyl; the compound of formula (IIa) wherein R 22 is 3- (CH30C(=0)O-)benzyl and R 23 is 3-(CH30C(=O)O- )benzyl; 15 the compound of formula (IIa) wherein R 2 2 is 3- (HOCH2CH2N=CH)benzyl and R 23 is 3- (HOCH2CH2N=CH)benzyl; the compound of formula (IIa) wherein R 22 is 3- (HOCH2CH2N=CH)benzyl and R 2 3 is 3-(2- 20 oxazolidinyl)benzyl; the compound of formula (IIa) wherein R 22 is 3- (C6H5CH2NHC(=0)O)benzyl ard R 23 is 3- (C6H5CH2HC(=0)O)benzyl; ,the compound of formula (IIa) wherein R 22 is 3- (CH3NHC(=0)0)benzyl and R 23 is 3the compound of formula (IIa) wherein R 22 is 3- (HOCH2CC)benzyl and R 23 is 3-bromobenzyl; the compound of formula (IIa) wherein R 22 is 3- 3C aminocarbonylbenzyl and R 23 is 3aminocarbonylbenzyl; the compound of formula (IIa) wherein R 22 is 3- (H2NCOCH20)benzyl and R 23 is 3- (H2NCOCH20)benzyl; I c~ -86the compound of formula (Iha) wherein Rk 22 is 3- (H2NNHC )-benzyl and R 2 3 is 3- (H2{NNIIC benzyl; the compound of formula (Iha) wherein R 22 is 4- (H2NNHC(=0))-benzyl and R 2 3 is 4- (H2NNHC benzyl; the compound of formula (Iha) wherein R22 is 3and R23 is 3- (H2qC NHN=CH) -benzyl; the compound of formula (Iha) wherein R2 2 is 3- methoxy) aminocarbonyl )-ben zyl and R23 is 3ethoxy) aminocarbonyl] -benzyl; the compound of formula (ha) wherein R22 is 4-[(Iq- *.met hoxy) aminocarbonyl) -ben zyl and R 2 3 is 4- E (Nq-rehoxy)aminocarbony2]-benzyl; compound of formula (ha) wherein R22 is 3- (HOCH-2CH (OH)CH9O)benzyl and R 23 is 3- (1-IOCH-2CE CH20) benzyl; he compound of formula (ha) wherein R 2 2 is 3-(2- 20 hvd roxyethoxy)ben zyl and P23 is 3-(2hyciroxyetho-x-y) benzy]l; the comoound of formula (IIa) wherein R 22 is 3- 2-dihydroxyethyl) benzy'l and p 2 3 is 4- 2di-h,.'dro>:yethyl) benzyl; I.e :comioulnd of formula (ha) wherein R22 is amrr-.carbonylbenzyl and R23 is 3- (H2NO benzyl; the compound of formula (ha) wherein R22 is 3carbomethoxvbenzil and R 23 is 3-(Nmetnylaminocarbonyl) benzyl; the comoound of formula (Iha) wherein R 2 2 is 3- (1,2-dihydroxyethyl)benzyl and R 2 3 is 3-(1,2d-ihydro>:yethvl) benzy'L; -87the compound of formula (Iha) wherein R 22 is 4- 2-dihydroxyethyl)benzyl and R 23 is 4- (1,2dihydroxyethyl) benzyl; the compound of formula (ha) wherein R 22 is 3hydroxymethylbenzyl and R 2 3 is 3- (Nmethylaminocarbonyl) benzyl; the compound of formula (Ila) wherein R 2 2 is 3-(Nethylaminocarbonyl)benzyl and R 23 is 3-(Nethylaminocarbonyl) benzyl; the compound of formula (ha) wherein R 2 2 is 3carbomethoxybenzyl and R 23 is 3-(N,Ndiet hylaminocarbonyl) benzyl; the compound of formula (ha) wherein R 2 2 is 3carbomethoxybenzyl and R 23 is 3-(N- 15 ethylaminocarbonyljbenzyl; (H2NC(=0)NH)benzyl and R 23 is 3-(FI2NC(=0)NH)benzyl; compound of formula (ha) wherein R 2 2 is 3aminobenzyl and R 23 is 3-(CH3NHC(=)NH-)benzyl; the compound of formula (ha) wherein R 2 2 is 3- 20 (CH3NHC(=0)NH)benzyl and R 2 3 is 3- (CHJNqHC benzyl;, the compound of formula (ha) wherein R 2 2 is 3- N-dimethvlaminoglycyl) amino) ben zyl and R 23 's N-imehylaminoglycyl) amino) benzyl, 2 5 the com-,pound of formula (ha) wherein R 2 2 is 3- methylaminoglycyl)amino)benzy. and R 23 is 3- (N-methylaminoglycyl)ami-no)benzyl; the compound of formula (ha) wherein R 2 2 is 3- N-dimethylaminoglycy±) amino) benzyl and
R
23 is 4-hydroxymethylbenzyl; the. ompound of formula (ha) wherein R 2 2 is 3- phenylmethoxycarboniylaminoglycyl) amino) benzyl and R 23 is 3-((Iqphenylmethoxycarbonylaminoglycyl) amino) benzj-1; -88the compound of formula (Iha) wherein R 22 is 3-(glycylamlino)benzyl and R 2 3 is 3- (glycylamino) lenzyl; the compound of formula (Iha) wherein R 2 2 is 3- (glycylamino) benzyl and R 23 is 4-hydroxymethylbenzyl; the compound of formula (ha) wherein R 2 2 is 3-(CNpheny lmethoxycarbonylamino-Lalanyl) amino) ben zy 1 and R 2 3 is phenylmethoxycarbonylamino-Lalanyl) amino) benzyl; the compound of formula (Mia) wherein R 2 2 is phenylmethoxycarbonylamino-Lphenylalanyl) amino) benzyl and P 23 is 3- (N- C phenylmethoxycarbonylamino-Lphenylalanyl) amino) benzyl; *.:the compound of formula (Iha) wherein p 2 2 is 3- Lalanyl) amino) ben zyl and R 2 3 is 3-(Lalanyl) amino) benzyl; 20 th:e cornoound of formula (ha) wherein R 2 2 is 3-(Lphenylalar'yl) amino) benzyl and R 2 3 is 3- pr. e nylalanyl) amino) benzyl; the compound of formula (Ma) wherein R 22 is hydroxy-l-pentyl and R 2 3 is 3cazboethoxybenzyl; the ccTmcound c11 formula (Ma) wherein p 22 is 4o:'..me-1-hexyl and R 2 3 is 4-oxime-l-hexyl; the comp.-ound of formula (ha) wherein R 2 2 is 3- 0; N-dieth~ilaminocarbony)benzyl. and R~ 2 3 is 3- 1-diethylaminocarbonyl) benzyl; the compound of formula (ha) wherein R 22 is 3carbomethoxybenzyl and R 2 3 is 3-(N,N- .I ethylaninocarbonyl) ben zyl; -89the compound of formula (Ila) wherein R 2 2 is 3carbomethoxybenzyl and R 2 3 is 3-(Nethylaminocarbonyl)benzyl; the compound of formula (Ila) wherein R 22 is 3hydroxymethylbenzyl and R 23 is 3-(N,Ndiethylaminocarbonyl)benzyl; the compound of formula (IIa) wherein R2 2 is 3hydroxymethylbenzyl and R 23 is 3-(Nethylarinocarbonyl)benzyl; the compound of formula (Ila) wherein R 22 is 3-(Npropylaminocarbonyl)benzyl and R 23 is 3-(Npropylaminocar-,nyl)benzyl; the compound of formula (Iha) wherein R 22 is 3- (HO2C)benzy and R 23 is 3-(N- 15 isopropylaminocarbon yl)benzyl; the compound of formula (Ila) wherein R 22 is 3- S. (HO2C)benzyl and p 23 is 3-(Npropylam.inocarbonyl) benzyl; hydroxymethylbenzyl and R 23 is 3aminocarbonylbenzyl; the compound of formula (Ila) wherein R 22 is cyclopropylmethyl and R 23 is 3arminocarbonylbenzyl; the compound of formula (Ila) wherein R 22 is 3aminocarbonylbenzyl and R 23 is hydrogen; the compound of- formula (Iha) wherein R 22 is 3hydroxymethylbenzyl and R 23 is 3-(Nethylaminocarbonyl)benzyl; the compound of formula (Iha) wherein R 22 is 3-(Nimidazolylmethyl)benzyl and R2 3 is 3-(Nimidazolylmethyl)benzyl; the compound of formula (Ila) wherein R 22 is 3- (2,2-dimethyl-l-propionyl)benzyl and R 23 is 3- (2,2-dimethyJ-l-propionyl)benzyl; the compound of formula (Ma) wherein R 22 is 3- 2-trifluoro-l-hydroxyethyl)benzyl and R 23 is 3- 2-trifluoro--i-hydroxyethyl)benzyl; the comrpound of formula (ha) wherein R.
22 is 3-(2imidazolyl-C(=0))benzyl and R.
23 is 3-(2imidazolyl-C )benzyl; the compound of formula (Ma) wherein R.
22 is 3-(3hydroxy-l-propyn-.-yl)benzyl and R 23 is 3-13hydroxy-1-propyn-i-yl) benzyl; the compound of formula (Iha) wherein P.
22 is 3- (2,2,2-trifluoroacetyl)benzyl and R.
23 is 3- 2, 2-trifluoroacetyi)benzyl; the compound of formula (Iea) wherein P.
22 is 3propionylbenzyl and R.
23 is 3-propionylbenzyl; the compound of formula (Iha) wherein P.
22 is 3- (CH3G2C(=-0H))benzyl and R 23 is 3- (CH-3CH2C )benzyl; he czrncound of formula (Ma) wherein P.
22 is 3- (CF'3C:H2C(=Iq-0I) )benzyl and P.
23 is 3- 20 (CF2CR92C )benzyl; O iormula (lIe.) where~in p.
2 2 is 3- ~r.etnyl,-,,3-oxadiazolyl)benzyI and R.
23 is 3- (5-methyl- l,2,3-ox:adiazolyl)benzyl; the compound'of, formula (Iea) wherein p.
22 is 3 (Hz2N(=N0H)benzyl and P.
23 is 3- (HN(=NOH) benzyl the z-mound formula (Iha) wherein P.
22 is 3- (H,2NV,-(=N0,IH)-4-fluorobenzyl and R.
2 3 is 3- (=NDH) -4--fluorobenzyl; the compound of formula (lIe.) wherein P.
22 is 3and R.
23 is 3-chlorothe compound of formula (lIe.) wherein P.
22 is 3and P.
2 3 i 3- -91the compound of formula (Iha) wherein R2 2 is 3and R 23 is 3the compound of formula (IHa) wherein R 22 is 3amino-5--benzisoxazolylmethyl and R 23 is 3- Also preferred are compounds of formula (IIaa): R22N
NR
23 HO OH (I Iaa) or a pharmaccu'Jcally acceptable salt form thereof wherein: p 4 ani R7 are independently selected from: benzyl, flucrobenz-yl, pyrrolylmethyl, methoxybenzyl, isobutyl-, nitrobenzyl aminobenzyl, hydrox.,ybenzyl 4-ovridvlmezhy, or thienylmethyl; p 2 2 and p,13 are independently selected from:
(H
2 NIC(=0)) -benzyl, carboethoxybenzyl, (O-benzylformaldoxime)benzyl, (0-methylformaldoxime)benzyl, (CH3O2CO)-benzyl, (HOCH2CH2N=CH) -benzyl, Nq-benzylaminocarbonylbenzyl, (112NNHC benzyl, (H2NC NHN=CH) -benzyl, (CH3ONHC(O) )-benzyl, (HONHC(=0) )-benzyl, (CH3NHC(O) )-benzyl, N,N-'dimethylaminocarbonylbelzyl, (H-OCH2C-!(OH) CH-20) -benzyl, hydroxyethoxybelzyl, -92- (carbomethoxy) mnty., glycylaminobenzyl, N, N-dimethylglycylaminobeizy-', alanylamniobenzy2., (N-phenylrnethoxycarbonyl) alanylaminobenzyl, phenylalany.Iaminobenzyl, (N-phenylmethoxycarbonyl) phenylalanylarninobenzyl, (CH3CH2NHC benzyl, N, N-diethylaminocarbonyl"benzyJ., N-ethylaminocarbonylbenzyl, N-propylarninocarbonylbenzyl, N,N-diisopropylarninocarbonylbenzyl, N, N-di-flpropylaminocarbonylbenzyl, (hyciroxypropynyl) benzyl, (imiciazolyl-C ben zyl, (pyrazoly.-C )-benzyl, (pyridylmethylaminocb-fbonyl) benzyl, trifluoroacetylbenz dihyciroxyethylbenzyl, NH) -benzyl, (HgNC NH) -benzyl, (HK(=0)NH)-benzyl, methanesulfonylpentyl, Nformyl-N-methylaminobenzyl, acetylaminobenzy2., propionvlbenzyl, butyrylbenzyl, 1, riluorchydroxyechiy2)benzyl, (CF'jC(=NOH))nenz2 C-rnetiylglycyl) aminobenzyl, (4-rnorphiolino) ethyl) aminocarbonylbenzyl, 1-dmethylaminoethyl)aminocarbonylbenzy N-diethylaminoethyl ~arr4nocarbonylbenzyl, 2-1 ~4 r.e*-h ylp ip er a z in- Iye,'hyl) aminocarbonylbenzyl, (benzyl- I? U 0) benzyl, (CH3NHC benzyl,
(NH
2 C'l(=0)CH20) benzyl, (NH 2 C(=NH) )benzyl, M-phenylmethoxycarbonyl) glycylar-nino) ben zyl, (I'midazolylrnethyl) benzyl, CH3) 3C- C (=0C))benzyl, (N-methyl-N-.
eth-Iylarninoethiyl) aminocarbonylbenzyl, (pyrr-olidinylethiyl) aminocarbonylbenzyl-, (riperidiflylethyl) arinocarbonylbefizyl, Ui 2 NC (=109) benzyl, (H 2 N =NH) fluorobenzyl.
-93- (161 Specifically preferred are compounds of formula (TIaa): 0 R22N NR 23 HO 'O (IIaa) or a pharmaceutically acceptable salt form thereof, cted from the group consisting of: the compound of formula (TIaa) wherein R 4 and R7 10are isobutvl, R 22 and R 23 are *.:cyclopropylmethyl; the compound of formula (IIaa) wherein R 4 and R 7 are isobutyl, R 22 and p 2 3 are allyl;, the compound of formula (IIaa) wherein R 4 is ~4-nitrobenzyl, P 7 is 2-nitrobenzyl,P 2 an a p.
2 3 are cyclopropylmethyl; the compound of formula (Ijaa) wherein R 4 and R 7 0 OV. are 4-nitrobenzyl, R 22 and p,23 are acyclopropylmethyl; the compound of formula (,Iaa) wherein R 4 is 4 roer s2-irbez and
P
23 are n-butyl; the compound of formula (IIaa) wherein PR 4 is 4-aminobenzyl, R 7 is 2-aminobenzyl, R 22 and
P.
23 are cyclopropylmethyl; the compound of formula (IIaa) wherein R 4 and R 7 are 4-fluorobenzyl, R 22 and p, 2 3 are 3hydroxybenzyl; the compound of formula (IIaa) wherein R4 and R7 are 4-1fluorobenzyl, R 22 and R23 are cyclopropylrnethyl; :4 the compound of formiIa (IIaa) wherein 0 4 and R 7 are 4-fluorobenzyl, R 22 and P 23 are 4 -hydroxymethylbenzyl; the compound of formula (IIaa) wherein R4 and R 7 are 4-fluorobenzyl, R 22 and R 23 are 3-aminocarbonylbenzyl; the compound of formula (IIaa) wnerein R 4 and R7 are 4-fluorobenzyl, R 22 and R 23 are 3acetvlbenzyl; the compound of formula (IIaa) wherein P 4 and R 7 are 4-fluorobenzyl, R 22 and R 23 are 3but yr ylben zyl; the conmoound of formula (IIaa) wherein P 4 and RI are 4-fluorobenzyl, R 22 and R 23 are 3l hydroxymer-hylbenzyl; compound of formula (IIaa) wherein R 4 and R 7 :are 4-fluorobenzyl, P 22 and R 23 are 3- (C2H20(=N-CH) benzyl; tne zom)Dund cf formula wherein R 4 ano R 7 C'C'are 3-methoxybenzyI, p2and p3are benzyl; cC fcormula (IIaa) where~, P12 ann PI arc- 4-fluocrobenzyl, p 22 and p 2 3 are 3tne:mzound cf formula (IIaa) wherein F~and p7 aze 4-fluorobenzyl, p 22 and R 23 are 3lucrobenzyl; tv formula (Ilaa) wherein P 4 and R' ar 3-me--hoxybenzyl, p 22 and p 23 are zpropy Imethyl; ;:com;)nd of formula (Ilaa) wherein R 4 and 1(' are 3-mathoxybenzyl, R22 and R3are 4hyd oxymethylbenzyl; tnc co:mpound of formula (IIaa) wherei.n R4 and P" a-rc 3-methoxybenzyl, p 22 and R~ 2 3 are 3 as the compound of formula (Ilaa) wk. in R 4 and R 7 are 3-hydroxybcnzyl,
R
2 2 an- p 2 3 are 3hydroxybenzyl.
the compound of formula (IIaa) wherein
R
4 and R7 are 4-methoxybenzyl,
R
22 and R 23 are cyclopropylmethyl; the compound of formula (IIad) wherein
R
4 and R7 are 4-methoxybenzyl,
R
2 2 and K 23 are benzyl; the compouna of formula (IIaa) wherein
R
4 anC R 7 are 4-niethoxybenzyl,
R
22 and R 23 are 2naphthylmethyl; the compound of formula (IIaa) wherein F4 and R7 are 4-methoxybenzyl, R2 2 and R 23 are 4hydro:ymethylbenz 1 is tne compound of formula (IIaa) wherein
R
4 and R7 .are 4-hydroxybenzYl,
R
22 and B 23 are benzyl; :the compound of formula (IIaa) wherein
R
4 and R 7 S. are 4-methoxybenzyl,
R
22 and R 23 are allyl; the compound of formula (IIaa) wherein
R
4 and K 7 are 4 (2-h-roxyethoxy) benzYIr 2 2 and R 2 3 are benzyl; the compound of formula (Ilaa) wherein R4 and R7 are 4 (2-iorpnolinylethoy)benzyi, p 2 2 and ,23 44** are benzyl; the compound of formula (IIaa) wherein
R
4 and R7 are 3- 1422=O) Chi20) benzyl,
P
2 2 and R23 are n- 4* 4 4, .~butyl the compound of formula (IIaa) wherein
R
4 and R 7 are 3,4-difluorobenzyl,
R
22 and p 23 are 3hydroxymethylbenzyl; the cc-npound of formula (IIaa) wherein
R
4 and R7 are 3,4-difluorobenzl, 2 and p2 3 are 4hydroymethylbenzyl; i,.,-~sT~sRo l~ -96thp, compound of formula (IIaa) wherein R 4 and R 7 are 3,4-difluorobenzyl,
R
22 and R 23 are 3-
(H-
2 NC )ben zyl; the compound of formula (IIaa) wherein R4 and R 7 are 3,4-difluorobenzyl,
R
22 and R.
23 are 3-
(H
2 NC (=NOH) benzyl; the compound of formula (Ilaa) wherein
R
4 and R 7 are 2-naphthylmethyl,
R
22 and R 23 are benzyl; the compound of formula fllaa) wherein R4 and R.
7 are 2-naphthylmethyl,
R.
22 and R.
23 are cyclopropylmethyl; the compound of formula (IIaa) wherein
R
4 and R.
7 are 2-thienylmethyl, p 22 and R.
2 3 are cyclopropylmethyl; 1E the compound of iormuia j(IIaa) wherein R.
4 and P 7 are 2-thienylmet.
R.
22 and R 23 are 3- 9*.(H 2 1,C .enzyl; A. ne compound of formula (IJda) wflerein R 4 and R7 are j-mrethylthiobenzyl,
R
22 and R3are 2C benzyl; o formula (I1aa) wherein
R.
4 and F.
7 are Isopropyl, p, 22 and R.
23 are n-hexyl; ti 6, '0706 -lsz prf''e n the present embodiment are 2 cOm-Pounids formula 1Ib) Ph W Ph HO
OH
(Ila, V. I 4 -97- -N (R 2 2 C N (R 2 3 -N (R 2 2 C N (R 2 3
R
2 2 and R 23 are independently select d from: (H-2NC(=O) )-benzyl, carboethoxybenzyl, (0-benzy2.formaldoxime~benzyl, (0-methylformaldoxime) benzyl, (CHt302C0) -benzyl, 'HOiCH-2CH2N=CH-) -benzyl, N-benzyla,,ninocarbonylbenzyl, (H2NNHC benzyl, (CH3ONH )-benzyl, (HONHC )-benzyl, (CH3NHC )-benzyl, N il-dimethylaminocarbonylbenzyl, (HCCH2CH(OH)CH20)-benzyl, hydroxyethoxybenzyl, (carbomethoxy)perty., glycylaminobenzyl, N-dimethylglycylaminobenzvl, alanylaminobenzyl, (Iq-phenylmetI.oxycarbonyl) alanylaminobenzy1, phenylalanylaminobenzyl, (N'l-phenylmethoxycarbonyl) phenylalanylaminobenzyl, (CH3CP,2NHC(0))benzyl, IN, N-d~ethylaminocarbonylbenzyl, N-ethylaminocarbonylbenzyl, o N-propylaminocarbonylbenzyl, N, N-diisopropyllaminocarbonylbenzyl, N, N-di-nprcpylaminocarbonylbenzyl, (hydroxypropynyl)benzyl, (imidazolyl-C(=0) benzyl, (pyrazolyl-C(=0) )-benzyl, (pyridylmet.hylaminocarbonyl) benzyl, trifluoroacetylbenzyi, dihydroxyethylbenzyl, (NjeHNC(=C)NH)-beflzyl, (H2NC(=)NH)-benzyl, (HC(=0)NH-)-b!enzyl, met.ianesulfonylpentyl, Nformyl-N-methylarninobenzyl, acetylaminobenzyl, prcpionylbenzyl, butyrylbenzyl, ,trifluorohydroxyethyl)benzyl, benz-yl, (N-methylglycyliaminobenzyl, ((4-morpholino) ethyl)aminocarbonyl'-nzyl, -98- N-dimethylaminoethyl) aminocarbonylbenzy, N-diethylaminoethyl) aminocarbonylbenzyl, (4-methylpiperazinylethyl) aminocarbonylbenzyl, (benzyl- NHC(=0)0)benzyl, (CH 3 NHC(=0)O)benzyl,
,NH
2 C (=0)CR20) benzyl, (NH- 2 C )benzyl, ((N-phenylmethoxycarbonyl) glycylzmino) benzyl, (imidazolylmethyl)benzyl, ((CH3)3C- C benzyl, (N-methyl-Nethylaminoethy.) aminocarbonylbenzyl, (pyrrolidinylethyl) aminocarbonylbenzyl, (piperidin;'lethyl) aminocarbonylbenzyl,
(H-
2 NC(=N0:-))benzyJ., (H 2 NC(=NOH) )fluorobenzyl.
1v [10, Specifically preferred are compounds of formula *1 (lb):
CN
N
R22N NR 23 Pn ""-Ph S'HO "0H (Iib) p. or ap.. ar-m.-utically, acceptable salt form thereof, selected from. the group consisting of: the compound of formula (IMb) wherein R 22 is 4hydroxybenzyl and R 23 is 4-hydroxybenzyl; the compound of formula Cub) wherein R 22 is cy clopentylmethy. and R 2 3 is cyclopentylmethyl; the com~po~und of formula (Ilb) wherein R 2 2 is nbu~yl and R 2 3 is n-butyl; -99the compound of formula (IIb) wherein R 2 2 is 3-hydroxybenzyl and R 2 3 is 3-hydroxybenzyl; the compound of formula (Ilb) wherein R 22 is 3-aminobenzyl and R 2 3 is 3-aminoben::vl; the compound of formula (Ib) wherein R 22 is cyclohexylmethyl and R 23 is cyclohexylmethyl; the compound of formula (Ib) wherein R 22 is cyclobutylmethyl and R 23 is cyclobutylmethyl; the compound of formula (Ib) wherein R 22 is 3hydroxymethylbenzyl and R 23 is 3hydroxymethylben zyl; the compound of formula wherein p, 22 is 3formvlbenzvl and R 2 3 is 3-formylbenzyl; the compound cf formula (Ib) wherein p 2 2 is 15 3-forrnaldoximebenzyl and R 2 3' is 3ibormaldOximebenzyl.
:001 [19) Specifically preferred are compounds of formula (Ibb): (S
R
22 N ~NR 23 L* SPn HO "0H (Ibb) or a pharmaceutically salt form thereof, selected from the group consisting of: the compound of formula (Ibb) wherein R 2 2 is benzyl and R 2 3 is hydrogen; the compound of formula (Ibb) wherein R 2 2 is cyclopropylmethyl and R 2 3 is cyclopropylmethyl; -100the compound of formula (Ibb) wherein R 22 is benzyl and R 23 is benzyl; the compound of formula (Ibb) wherein R 22 is 3-hydroxybenzyl and R 2 3 is 3-hydroxybenzyl; the compound of formula (Ibb) wherein R 22 is 3hydroxymethylbenzyl and R 23 is 3hydroxymethylbenzyl; the compound of formula (Ibb) wherein R 22 is 4hydroxybenzyl and R 2 3 is 4-hydroxybenzyl; the compound of formula (Ibb) wherein R 22 is 3methoxybenzyl and R 2 3 is 3-methoxybenzyl; the compound of formula (Ibb) wherein R 22 is 3- (H2NC (=NOE) )benzyl and R 2 3' is 4- *hydroxymethylbenzyl; 15the compound of formula (Ibb) wherein R 22 is 3- (11i21 (NO) )benzyl and R 23 is 3- *the orcund of formula (Ibb) wherein R 2 2 is 3- 2 1 (=INO'I -4-fluorobenzy! and K 2 s3- 2 2r (H-2tN2(=NOH) )-4-fluorobenzyl.
K- :cur ~.embodiment of this invention is a compound
:R
4 A ,W RA R 7 R4 R7
R
5
R
5 a 3r 6
(I)
or a pharmraceutically acceptable salt form thereof wherein: -101-
R
4 and R 7 are independently selected from the following groups: hydrogen; C1-C8 alkyl substituted with 0-3 R 1 1 C2-C 8 alkenyl substituted with 0-3 R 1 1 C2-CS alkynyl substituted with 0-3 R 1 1 a C3-C14 carbocyclic ring system substituted with 0-3 R 1 1 or 0-3 R 1 2 a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 1 2 -O -S C0 2
R
13 C23 S
RP
4 A and R 7 A are independently selected from the following groups: 4 9 S• hydrogen;
C
1
-C
4 alkyl substituted with 0-6 halogen or 0-3 Cl- 20 C2 alkoxy; benzyl substituted with 0-6 halogen or 0-3 C1-C2 a k o o:y -OR; 1; CO2R 1 25 R 4 and R 4 A can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R12;
,R
7 and R 7 A can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R 12 n is 0, 1, or 2;
R
5 is selected from hydrogen; bromine, chlorine, Ci-C6 alkyl substituted with 1-3 R 1 1
-N(R
2 0 2
-SR
2 0 or
-N
3 -102-
R
6 is selected from bromine, chlorine, Cl-C6 alkyl substituted with 1-3 R11, -N (K 2 0 2, -SR 2 0 or -N3;
R
5 and R 6 can alternatively join to form an aziridine ring; -OC ((CH2) 3NH2) (CH 3 -NHC NH-; -OC -NHC -NHCH 2
-OCH
2
NI--;
-NH-C(CH
3
-OC(CH
3 2 NH-; or any group that, when administered to a mammalian subject, cleaves to form a diamino or hydroxyl and amino; is selected from hydrogen, halogen, Cl-CS alkyl, -1U(R2C)2, -SR 2 0 or -OR 2 0 1R6a is selected from: hydrogen, halogen, Cl-C6 alkyl, -l4 20 j 2
-SR.
20 or -OR 2 1 Rt ad ~-an alternatively join to form or a *ring; ant, F-8 can alt:ernatively join to form =D ',or a 2- an:F are independently selected from: n\'Zrogen; -CC al ky! substituted with 0-3 R 1 1 0- alkoxyalkyl substituted with 0-3 R 1 1 01-CC alkylcarbonyl substituted with 0-3 R 11 C-5alkoxycarbonyl substituted with 0-3 K 11 Cl-CE alkylaminocarbonyl substituted with 0-3 R 11 henzoy. substituted with 0-7 Rl2; phenoxycarbonyl substituted with 0-3 R 1 2 pnenylaminocarbony.l substit tt d with 0-3 F, 12 c: -103any group that., when administered to a mammalian subject, cleaves to form a free hydroxyl, amino or sulf'hydryl; Rl 1 is selected from one or more of the following: keto, halogen, cyano, -Ch 2 NRl 3
R
1 4
-NR
1 3
R
1 4 -C02R1 3 -00 R' 3
-OR
1 3 -S mnR 1 3 f
-NHC(=NH-)NHR
1 3
-C(=NH)NHR
2 3 -C =O)NR1 3
R
1 4
-NR
1 4
R
1 3 =N0R 1 4
-NR
1 4 0 OR 1 4
-OC(=O)NR
1 3
RI
4
-NR
1 3
C(=O)NR
1 3
R
1 4
-NR
1 4 S02NR 1 3
R
1 4
-NR'
4 S02RI 3 -SO2NR1 3 Rl 4 -OP (0)(OR 13 2 C 1
-C
4 alkyl, 02-04 alkenyl, 03- 06 cycloalkylmethy'l, benzyl, phenethyl, P phenoxy, benzyloxy, nitro, 07-Cia arylalkyl, hydroxamic acid, hydrazide, boronic acid, sulfonarm.,ie, formyl, 03-CE cycloalkoxy, C 1
-C
4 alkyl subszituted with -NR 1 3 Rl 4 01-04 hydroxyalkyl, methylenedioxy, ethylenedioxy, 01-04 haloalkyl, 01-04 haloalkoxy, 01-04 alkoxycarbonyl, pyridylcarbonyloxy, 01-04 alkylcarbonyl, 01-C4 alkylcarbonylamino, I- IC~, 2-(2-morpholino)ethoxy, azido, or -C (p1 4
(OR
14 'ncr~ acids linked together via am-de bonds, 2 5 sai'd ami4no acid being lii.zed via the amine or :carboxylate terminus; 03-010 cycloalkyl substituted with 0-2 R 12 01-04 alkyl substitued with 0-2 R 12 aryl(01'-02- alkyl) substituted with 0-2 R 1 2 02-06 alkoxyalkyl, substituted with 0-2 Ri 2 01-04 alkylcarbonyloxy qubstituted with 0-2 RI 2 06-010 arylcarbonyloxy substituted with 0-2 R1 2 a 05-C14 carbocyclic residue substituted with 0-3 a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently
R
1 1 A is
H,
-104selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-3 R 12 selected from one or more of the following: keto, halogen, cyano, -CH 2 NRlJBRl 4 B, -NR1 3 BRl 4
BI
-CO2H, (Cl-C 3 alkyl), -OH, C2-C6 alkoxyalkyl, -C NH 2 -OC NH2, I'4HC (=O)NPH 2 -SO2NH2, Cl-C4 alkyl, C2-C4 alkenyl, C3-ClO cycloalkyl, C3-C6 cycloalkylmethyl, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C7-Cl0 arylalkyl, hydroxamic acid, hydrazide, boronic acid, C 3
-C
6 cycloalkoxy, C 1
-C
4 alkyl substituted with
-NH
2 C1-C-4 hydroxyalkyl, methylenedioxy, ethylenedioxx', CI-C4 haloalkyl, Cl-C4 'hAl-oalko>:y, Cl-C 4 alkoxycarbonyl, CI-C4 'lkv. carbonyloxy, Cl-C4 alkylcarbonyl, Cl-C4 al'ky I carbonyl amino, -OCH2CO2)H, 2- (1-mcrpho!lino) ethoxy, azido, aryl (CI-C 3 y a C_-C,1 carbocyclic residue; a -t !C-memrberej heterocyclic ring system c::nta-'.ncn 1 to 4 heteroatons independently selezted -Fr-or- oxygen, nitrogen or sulfur, sal," e terocyclic ring system substituted with 0-3 99 9* .9 a *9 9 *4 9 a 1' wh'>r s,.;stituernt on carbon, is selected from one cr morg, of the followino: pneny., benzyl, phenethyl, phenoxy, benzyloxy, -alogen, hvdroyxy, nitro, cyano, Cl-C4 alkyl, -C cycloalkyl, 03-06 cycloalkylmethyl, 07- Z-C, arylalkyl, Cl-C4 alkoxy, -CO2H, hydroxamic acid, hydrazide, boronic acid, sulfonamide, :crmvl, C-,-C 6 cycloalkoxy, -0P4", 071-C4 aJlk', su .stituted with -1jk3rl4, -jqR 1 3 02-CC -105alkoxyalkyl optionally substituted with -Si (CH 3 3, Cl-C 4 hydroxyalkyl, !ethylenedioxy, ethylenedioxy, 01-04 haloalky., CIj-C4 haloalkoxy, Cl-C 4 alkoxycarbonyl, Cl-C4 alky-Lcarbonyloxy, Cp-C4 alkylcarbonyl, C1-C4 alkylcaz'bonylamino, -S C0)mR 1 3 -SO2NR 1 3
RI
4 -NH-S02R 14 -0CH2C02R 1 3 2- (1-morphol ino) ethoxy, -C (RI 4 (0R 14 or a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur; or R2may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused or 6-membered ring, said or 6- membered 15 ring being optionally substituted on, the aliphatic carbons with halogen, C1-04 alkyvl, '**CI11C4 alkoxy, hydroxy, or -NR 1 3
R-
4 or, when R 12 is attached to a saturated carbon atom, it may be =0 or or when R 1 2 is attached to 20. sulfur it may be =0; 2wher. a substituent or, nitrogen, is selected from one or more of the following: phenyl, benzy.1, phenetLhyl, hydroyy, 01-04 25 hydroxyalkyl, C' 1
-C
4 alkoxy, CI-04 alkyl, C3-06 .:cycloalkyl, 03-06 cycloalkylmethyl, -CH2NR1 3
R-
4
-NR
1 3
R
1 4 02-06 alkoxyalkyl, 01- 04 haloalkyl, 01-04 alkoxycarbonyl, -C02H, Cl- 04 alkylcarbonyloxy, C1-C 4 alkylcarbonyl, 3C R O 14 R1 2 A, when a substituent on carbon, is selected from one or more of the following: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, 01-04 alkyl, C3-CG cycloalkyl, 03-06 cycloalkylmethyl, 07- -106arylalkyl, 0 1
-C
4 alkox.y, -C02H-, nydroxanic acid, hydrazide, boronic acid, sulfonamide, formyl, C3-C6 cycloalkoxy, -OR 1 3 01-04 alkyl substituted with -NH 2 -NH2, -NHMe, 02-06 alkoxyalkyl optionally substituted with -Si(CH- 3 3 01-04 hydroxyalkyl, methylenedioxy, ethylenedioxy, Cl-C 4 haloalkylI C1-C4 haloalkoxy, 01-04 alkoxycarbonyl, Cl-C4 alkylcarbonyloxy, Cj-C4 alkylcarbonyl, 01-04 alkylcarbonylamino, -S(O)mMe, -SO2NH 2 -NH-SO2Me, -OCH-2C02R' 3 2- (l-morpholino)ethoxy, -C (NOH) NH 2 or a 5- or 6-memberei heterocyclic ring containing from 1 to 4 heteroatoms independently selected frzr7 oxygen, nitrogen or sulfur; o r ~~1Amay be a 3- or 4- carbon chain attached to at-acen-t carbons or, the ring to form a fused Cr 6-membered ring, said 5- or 6- membered g-*n being optionally substituted on the ojC-,ha--ic carbons with halogen, 01-04 alkyl, er i s at".acned tc a saturated carbon atom, 4 -ay be =0 or or when R12 is attached to) r I't m ay b e C
R
2 W a sosiu~ton rj'lrocier, is selec:,.ed f ror o-e r mo-re of the followina: phen~yl, benz-yl, phenethy"., hydroxy, 01-04 h yd roxyalkyl., 01-04 alkoxy, (21-04 alyl 3-Ce cy-:...oalkyl', 0:3-06 cycloakyl.-methyl, -CH2NH-2, 2-0-6 alkoxycilkyl, 01-04 haloalkyl1, 01- C4 alkoxycarbonyl, 01-04 aky !carbony loxy, 0:Calkyicarbonyl', C (=NOM) NH 4; P sle,:te frov: -107- H phenyl. substituted with 0-3 R 1 benzyl substituted with 0-3 R11A; Ci-C6 alkyl substituted with 0-3 RIIA;
C
2
-C
4 alkenyl substituted with 0-3 R 11
A;
C1-C6 alkylcarbonyl substituted with 0-3 RilAI.
Cl-C6 alkoxycarbonyl substituted with 0-3 R11A; Cl-C6 alkylaminocarbonyl substituted with 0-3 R1lA; C3-C6 alkoxyalkyl substituted with 0-3 R11A; an amine protecting group when R1 3 is bonded to N; a hydroxy protecting group when R 13 is bonded to 0;
F'
14 is hydrogen, hycroxy, CI-C 6 alkyl substituted with 0-3 groups selected from OH, Cl-C 4 alkoxy, halogen, NH, -N4H(Cl-C4 alkyl) C 1
-C
6 alkoxy, C 2
-C
6 alkenyl, phenyl, benzyl, an amine protecting group when R 14 is bonded to N, a hydroxy protecting group when R 14 9 is bonded to 0; 2 P13 and RI4can alternatively joir to f ormr (CH2) 4-' -(CH2) -CH2:ThJ2N 5 C-H2CH2-, Gr 2CH20CI42CH2-;
R
1 3" and R1 4 B are independently selected from H or C 1
-C
6 alyor R1 3 2 and P14B can alternatively join to forr7 (CH2)5-, -CH2CH 2 N(FlS)2"H 2 CH2-, Or
R
15 is H or CH3; m is 0, 1 or 2; W is selected from: -N (R22) C N (R 2 3 N 24)Ctz -108-
-N(R
22
)C(=Z)C(R
2 7
)(R
2 8
-C(R
2 5
(R
2 6 )C(=Z)0-1
-NCR
2 2 23
-C(R
25
)(R
26 )C(F2)C(R 2 7
(R
2 8 S -C CR 2 5
)CR
2 6 N (3 (O)CR 2 7
R
2 8
-C(R
2 5
(R
2 6 )N R 2 9
)C(R
2 7
(R
2 8
-C(R
2 5
(R
2 6 -N (R 2 2 S N (R 2 3 wherein: Z is 0, S, NR 24 F 7 and F23 are independently selected from the Sfollowing: hvcirogen; CI-CS alky substituted with 0-3 R 3 1; r2-Cd alkenyl substituted with 0-3 R 3 1 a r a .%yr.2 substituted with 0-3 R31i a C!4 carbocyclic ring system substituted with 2. F3-1 cr C-5 R32; h 3 <Iz-m;~em heterocyclic ring systemT zsr.:ainina ts 4 heteroatzom indepencently selected from oxygen, nitrogen or sulfur, said nrteerocyclic rina system being substituted Swith C-2 R2; or (p22t' ana are independently selected from the fC nr Ce.: Z2-CE alkyl substituted with 0-3 R 3 l; 22-c& alkenyl substituted with 0-3 R 3 1 alkynyl substituted with 0-3 R 3 C2-2:4 carbocyclic ring system substituted with or -5 R 2 or I -109a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 3 2
R
24 is selected from: hydrogen; hydroxy; amino; Ci-C4 alkyl.; CI-C4 alkoxy; mono- or di- (Cl-C6 alkyl)amino; cyano; nitro; benzyloxy; -NHSO2ary1, aryl being optionally substi-tUted with (Cl-C 6 alkyl; p 2 5 and p 2 are in-dependently selected from. the following: S 5hdrogen; .9 4Cl-CS alky" substituted with 0-3 R 3 1; 02-CS alkenyl7 substituted with 0-3 R 3 1 02- CS-' alkyny2. substitU..ed with 0-3 R 3 1 20a C2--C14 carbocyclic ring system substituted with a tc -ebered he~erccyclic ring systerr ccr.:aininQ 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said he-terocy'cl.ic ring systemr being substituted 25 with, 0-2 R 3 2 -0 -SR 13
R
6 and R 28 are independently selected from: hydr:ogen; halocien; 01-04 alky. substituted with 0-3 halogen of 0-3 02 alkoxy; benzyl substituted with 0-3 halogen or 0-3 01-02 al1k~ox y; -110-
R
29 is selected from: hydrogen; C1-C4 alkyl substituted with 0-3 halogen or 0-3 C1- C2 alkoxy; benzyl substituted with 0-3 halogen or 0-3 Cl-C2 alkoxy; alternatively, R 22
R
25 or R26, independently, can join with R 4 or R 4 A to form a 5- or 6-membered fused heterocyclic ring or carbocyclic ring substituted with 0-2 R 12 said heterocyclic ring containing 1-3 heteroatoms independently selected from N, S, or O; 15 alterna :vely, R 23
R
27 or R 26 independently, can join *with R 7 or R 7A to form a 5- or 6-membered fused heterocyclic ring or carbocyclic ring substituted with 0-2 m 12 said heterocyclic ring containing 1-3 heteroatoms indcipe-f tly selected from N, S, or 0; c: S•al tenately, P22, R 2 5, RB 6 y 2 3
R
2 7
R
2 8
R
3 4 or car. -cin with R 5 or p 6 to form a 0- to 7-membered bridge to form a rarbocyclic or heterocyclic ring, 21 said bridge being substituted with 0-2 R 12 and said bridge containing 0-3 heteroatoms independently selected from NI, S, or O a 0-membered bridge is formed when R 22 p 2 5
R
26
R
23 g 27
R
28
R
3 4 or P3 E are taken together with R 5 or R 6 to form a direct bond); alt:rnatively R 2A or R23 can join with R7A to form a direct bond; 112alternatively R 26 or R 22 caii join with RIA to form a ect bond; R31- is selected from one or more of the following: keto, halogen, cyano, -CH 2
NR
13
R
1 4, -NR 13 Rl 4 -C02R 13 -C(=O)Rll, -OC(=O)Rl 3
-OR
13 C2-C6 alkoxyalkyl, -S(O)mR 1 3
-NHC(=NH)NHR
13
-C(=NH)NHR
1 3
-C(=O)NR
1 3 Rl 4
-NR,
1 4 C(=O)Rl 3
=NOR
1 4, -NR 14 C(=O)0R 14
-OC(=O)NR
13 Rl 4 -NRlJC(=O)NR1 3 Rl4, -NR 13
C(=S)NR
13 Rl 4 -,qRl 4 S02NR 13 Rl 4
-NR
1 4 SO2R 13 -SO2NR1 3 R'4, C1- C4 alkyl, C2-C 4 alkenyl, 03-ClO cycloalkyl, 03-C6 cycloalkylmethyl, benzyl, phenethyl, ;phenoxy, benzyloxy, nitro, 07-010 ary'.alkyl, 15hydroxamic acid, hydrazide, oxime, boronic a aCi4d, sulfonamide, fOrniyl, C 3
-C
6 cycloalkoxy, :CI-C4 alkyl substituted with -NqRl 3
R
1 4 01-04 hydroxyalkyl, methyleriedioxy, ethylenedioxy, 01-04 haloalkyl, CI-C4 haloalkoxy, C1-C4 al!koxycarbonyl, C 1 -C4 alkylcarbonyloxy, CI-C4~ a1hk'lcarbonyl, C1-C4 alkylcarbonylamino, -CH?2CO02F,:, 2-(l-morpholino)ethoxy, azido, -C (R 1 4 1 4 or 1-3 ai-.--no acids, linked together via amide bonds, said amino acid being linked via the amine or carboxylate terminus; a CS-C14 carbocyclic residue substituted with p.
3 2 or a 5- to lO-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen,. nitrogen or sulfur, said -112heterocyclic ring system being substituted with 0-2 R 32 R3,when a substituent on carbon, is selected from one or more of the following: phenethyl, phenoxy, C3-C 1 0 cycloalkyl, C3-C6 cycloalkylmethyl, C7-Clo arylalkyl, hydrazide, oxime, boronic acid, C2-C6 alkoxyalkyl, methylenedioxy, ethylenedioxy, CJ.-C4 alkylcarbonyloxy, -NH-SO2R1 4 benzyloxy, halogen, 2- (1-morpholino) ethoxy, CO2R! 3 hydroxamic acid, -CONR1 3
NR
13 Rl4/ :cyano, sulfonamide, CHOI, C 3
-C
6 cycloalkoxy,
-NR
4 04 4, -SOmR1', -SOmNR 1 3 Rl 4 -C(=0),NR 13 R1 4
,I
-O)NR-*RI, -C(0)Rll, -OC(0C)Rll, -0C02R1 3 phenyl, -C(=O)NR1 3 -(Ca-C 4 alkyl)- NR1 3
R
1 4
-C(=O)NR
40 R4 1
C
1
-C
4 haloalkyl, Ca-C 4 20 haloalkoxy, C 2
-C
4 haloalkenyl, CI-C 4 h=2 oa Ik vn yl; or p,'-N 3 C (RI1) 2 1qR1 3
RI
4 -C IR 1 3C (R1 1 1 2 tIR1 3 C0 2
R
1 3 -Z NR 1 (Ca- C 4 alkyl)-NR 1 3CO 2
R
1 3 Z N (R 1 3
(C
1
-C
4 alkyl) or -C C (R 1 1 2
NR
1 3
R'.
4 .N 1 3 R1 4 -C -(Cj-C 4 alkyl) -NR 3 C0 2
R
1 3 or a: I0 k o xy substituted with 0-4 groups selected 2C f rom: C 3
-C
6 cycloalkyl, -C0 2
R
1 3
-C(=O)N~R
1 3 Rl 4
-NIR
1 3
RI
4 or OH; Ca-C 4 alkyl substituted with 0-4 groups selected from: R 1 1
=NR
1 4
=NNR
1 3
C(=O)NR
1 3
R
1 4
=NNR
1 3 C(=0)0R 1 3 or -NR 1 3 Rl 4 32 C-4 a- eny substituted with 0-4 R1u; 02-04 alkvYny2 substituted with 0-4 RII; -113a 5- or 6-rnerbered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, substituted with 0-2 R 12 or R 3 2 may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused or 6-membered ring, said 5- or 6- membered ring being optionally substituted on the aliphatic carbons with halogen, C 1
-C
4 alkyl, cl-c 4 alkoxy, hydroxy, or -NR 1 3 Rl 4 or, when R 3 2 is attached to a saturated carbon it may be =-NOH; or when R3 2 attached to sulfur it may be =0;
R-
2 when a substituent on nitrogen, is selected from one or more of' the following: phenyl, benzyl, phenethyl, hydroxy, 0I-C4 5 hydroxyalkyl, Cl-0 4 alkoxy, 01-04 alky.L, 03-06 cycl oalkyl, 03-C 6 cycloalkylmechyl, -CH2N 1 p 3
R
1 4
-NR
1 3
R
1 4 02-06 a2.koxyalkyl, 01- -4 Caolkl 1-C4 alkoxycarbonyl, -C02H, 01- C4, alkylcarbonyloxy, 01-04 alkvl'carbonyl, -(F'1 4
(OR'
1 4 p40 is se-ec--ed from: CI-C 3 alkyl; p 4 l is selected from: -0 NR 1 1 2R3; (=0)0C(R 1 1 2
NR
1 3
NR
1 3R;4 -C C (PR) 2
NR
1 3
NOR
1 3 1 -C H; -C R 1 1 alky.)-NR 1 3 p1 4 -C 4 alky.) -NR 1 3 00 2
R
2 3 -114- 1-3 amino acids linked together via amide bonds, and linked to the N atom via the carboxylate terminus; provided that:
R.
4
R
4 A, R7 and R 7 A are not all hydrogen; when W is
(R
24 or R 4 and
R
7 are not hydrogen.
'21" Al.sc included in the present invention are compounds, cr a pharmaceutically acceptable salt form ±:thereo-- selected from compounds having the following f or.-u 1ae 0 0 a a. a a a a a. a a a baa.
a a *0 H 0 Ph
N
H
0 Ph RA GOOH R R6 R- C 0 \N- 4 R23 R R'
OH
R
0 N
P
7 Ph OH R .N
N
NO ON H 0 H 9 H 9 0
C.,
C.
C. C
C*.
C*
S
9
*CC
C C
C
C, CC C. C
CC
C. C
C.
C. C C
S..
Lid N 0 9\ Lu su
"U
4H CZUN fN -22 0 La vU 0 N -ZU -116- R 22
R
2 2 N R 23
R
4
R
R 5
R
6 44 .4
H
RN
R
4 J R 7
R
5
R
6 0, ,OPh R2-N P NR 2 R5 R6 4*4 4 P~ c ar- in~dependently selected from the following all,,- .ub-titutea with 0-1 R 1 1 I S -Por -OR 2 1 p 2 0 an- 7,21 are independently hydrogen or any group tho=t, wh~en administercd to a mammalian subject, cleaves o form a free hydroxyl; t f-r one or more o.1 the following: H; halogen; -OR 13 -1- C3-C10 cycloalkyl substituted with 0-2 R 12 Cl-C4 alkyl substituted with 0-2 Ri 2 aryl. (Cl-C 3 alkyl) substituted with 0-2 R1 2 aryl substituted with 0-2 R1 2 or a heterocyclic ring system selected from pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl, oxazolidinyl, said heterocyclic ring system being substituted with 0-2 R 12
R
1 2 when a substituent on carbon, is selected from one cr more of the following: benzyloxv, halogen, methyl, CI-C4 alkoxy, CF3, 2- (1-morpholino)ethoxy, -CO2H, hydroxamic acid, hycrazide, -C (R 1 4 (0R 1 4 cyano, borornic acid, sulfonamide, tormyl, C 3 -C6 *.cycloalkoxy, C1--C 4 alkyl subst ituted with .2C -INR 1 3 pl4, -NqRl 3 Rl4, hydroxy, hydro>:ymethyl; or p P2, w e r. a sutstituenlt or. nitrogen, is methyl; is 14, C 2
I-C
4 alkyl1, C 2
-C
4 alkenyl, or benzyl; p 1 4 is H, C7 3
C
2
-C
4 alkyl, C 1
I-C
4 alkoxy, NH 2
C
2
-C
4 alkenyl, or benzyl; p.l 3 and Rl 4 can alternat ively join to f orm (CH2) 4- -(2)-,-CH2CH2N (R 1 5 )CH2CH2-, or -CH2CH2OCH2CH2-;
R
15 is H or CH3; W is selected from: 35-N(2)C(ZN R3 -N (R 2 2 C 0-; -C (p 2 5
(R
2 6
C(R
2 7
(R
2 8 -N (R 2 2
N(R
2 3 -N (R 2 2 2N(R 2 3 -C (R 2 5
(R
2 6
C(R
3 4)(R 3 5
C(R
2 7
(R
2 8 -N=C (R3 6 N (R 2 3 -C Z is 0, S, or N-CN; Z' is 0; R22 and R 23 are independently selected from the *.~...hvydrogen; -CE a!)kvl' substituted with 0-3 R 3 1; al ernyl substituted with 0-3 R 3 1 C2-C4 a1ivynyl1 substituted with 0-3 R 3 1 *-and",2 are i-ndevendently s elected from the ~-4alk, substituted with 03 R 3 1 a.enyl Substituted with 0-3 R 3 1; P~are hydrogen or halogen; .2 in elected from one or more of the following: haicoqen, -OP-O3, C1-C4 alkyl, C3-C10 cycloalkyl,
-C(R!
4 )=N(0R 14 -C0 2
RI
3 -S(0)mRl 3 ary! substituted with 0-5 p, 3 2 or a h.eterocyclic ring system chosen from pyridyl, pyrimridinyl, triazinyl, furanyl, thienyl, pyr rolyl, p-yrazolyl, imiciazolyl, tetrazoly>" henzofurany-., indolyl, quinolinyl, -119isoquinolinyl, oxazoliclinyl, said heterocyclic ring being substituted with 0-2 R 3 2
R
3 2 when a substituent on carbon, is selected from one or more of the following: benzyloxy, halogen, 2- (1-morpholino) ethoxy, -CO2R1 3 hydroxamic acid, -CONR 1 3 NR1 3
R
1 4 cyano, boronic acid, sulfonamide, -CHO, C 3 -C6 cycloa ikoxy, -NR 13
RI
4 -C (R 14 =N (OR 14 N02, 0OR 1 3
-NR
4
OR
4 1 -SOmR 13 -SOmNR 1 3 Rl 4
-C(=O)NR
1 3 Rl 4 -OC(=O)N1 3
RI
4 -C(=O)Rll,
-OC(=O)R
1 1 -OCO2RI 3 phenyl, -C(=O)NR1 3 -(C1--C4 alkyl)-NR 13
R,
14 0
R
4 1 Ca-C 4 haloalkyl, C2-04 haloalkoxy, C 2
-C
4 aolenl 2 C haloalkynyl, -C (0O)NR 1 3 Rl 4 1 1 2
N'P.
1 4 -C(=0)C(R 1 2
NR
1 3 NR1 4 V. -C C(R 1 2 1qP1 3 CO._p.
3 -C -(C1-04 alkyl)
NRF,
3
R
1 4 4 alkyl)-?qRl 3 002Rl 3 or Cj -04 alkoxy subst ituted with 0-3 groups selected 2p fro: P 1 1
C
3 -C6 cycloalkyl, -C(=O)NR 1 3
RI
4 -1C alkYl subs-:.tuted with 0-3 groups selected ~*from: =NR 1 4
=NNP.
1 3
C(=O)NR
1 3 p.
1 4 or
C
2 -C4 alkenmy. substituted with 0-3 R1 1 C2- C 4 alkynya substituted with 0-3 R 1 1 1 a 5- or 6-mernbered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, substituted with 0-2 Ri 2
R
3 2 when a substituent on nitrogen, is methyl; m is 0, 1, or 2; p 3 4 is selected from: -120hydrogen; 01-02 alkyl; C1-C2 alkoxy; R35 is selected from: hydrogen; C1-C2 alkyl; 01-02 alkoxy;
P
3 6 is selected from: Cl-C2 alkyl; C0R 3 7
NR
3 8
R
3 9
CN;
CC13; 9z-s selected from: hydrogen; Ca-C2 alkYl substituted with 0-1 R'; alkxy substituted with Rll; -z 3 C' 2- an' are -rdependently sele' ed from: al'.y. suosttl.ited withI L-3 R- or a: amre proe c- ing group; e s e 1xtet arok:y !.:.R13R)?3n 4; C=02 (P 1) 2
N
1 3 p.
14 =Ci (P 1 2
N
1 N I R 13
R
14 -C 2 (P 11) 2NP 3 C0R1 3 'ZrC: akv> 1-NR 1 3
P
1 4 -C R: -Q a-.kyl) 7Rl 3
CR
3
I
-12 1- 1-3 amino acids linked together via amide bonds, and linked to the N atom via the carboxylate terminus.
[22) Another aspect of the invention is a process for preparing cyclic compounds of formula R 4 A W R 7
A
R4- R 7 R 5
HR)
wherein: :W is selected from: :(n22) C 1: (p, 2 3 1 (p 2 3 (p22) S 21,( 2 2 Ce P22F R Fa and R~a are as defined above; rvdd hta .eas on o 2; rP 3 ms eh p20pA p' A and R"a are as defined above;admyinadto an comoun anf the ar sdfinedlaov andma i adiio
R
22 HN R6a) with a suitable cyclizing reagent in a suitable solvent, said solvent optionally comprising a base, thereby to form a compound of formula F'or compournds of. formula wherein W is suitable cyclizing reagent may V. i be selected from, but is not limited to, phenyl :*ch.'r,.or7zaze, pheny! tetrazoylformate, urea, phosgene, trip~-osgene, oxalyl chloride, N,N'-disuccinimidyl carbonate, ','-carbony1diimidazole, trlchloromethyl c; r .3f rm-a an d 2 3 -py r idli ned iyl1 t h ioc a rbona te. A pree~r-~r.o reorz sll-carbony! c:rrud f formula wherein W is ~2 -,the soitable cyclizing reagent may 2' be Eelected from, but is not limited to, trccarTor. cdm-iid zc'e or carbon disul 'ide.
?re~eabL';,the cyclizing. reagent is 1, 1a:i aroor yltdi~mi a zc Ie.
F-o: cornpo-ur~cs Of formula wherein W is -jN(p 2 2e(O, V( 2 3 the suitable cyclizinq reagent may be selecte-. from, but is- not limited to, sulfamide.
A base may. opt;.onally be included in the ec m o 4 i crd t-r toc a cc ou nt r th e Sand P. hydroxyl prote:t'.na qtroz;p-s -123to the cyclization conditions. The base may be selected from organic bases which include, but are not limited to, pyridine, diisopropylethylamine, and triethylamine.
The base may alternatively be selected from inorganic bases which include but are not limited to sodium hydroxide.
The above-described reaction is arrjed out in a suitable solvent, for example, in a.i orgar.ic solvent or in a biphasic suspension of water and an organic solvent. Suitable solvents include chlorinated organic solvents which include, but are not limited to, cr-lorofcrn., methylene chloride, tetrachloroethane, butyl chloride and dichloroethane. A preferrable chlorinated 15 organic solvent is chloroform. The non-chlorinated organic solvents useful in the method of the invention include, but are not limited to tetrahydrofuran, N,Ndimetnylrormamide and toluene, A preferrable nonrtlorinated organic solvent is toluene, Tre reaction can be conducted at a temperature of fror. about CC to about the boiling point of the solvent selected, 1 5 3 °C in the case of N,N-dimethylformamide.
.Freferably, the temperature of the reaction is about 0 C to about roor temperature.
The time required for completion of the reaction can range from about 1 houi to about 5 days, depending on the combination of cyclizing reagent, solvent, base and stereoisomer of compound (III) selected. The reaction can be run under nitrogen or other inert atmosphere, provided that any changes in concentration and integrity of the reagents due to decomposition are compensated for.
As used herein, the term "hydroxyl protecting group" means an group known in the art of organic -124synthesis for the protection of hydroxyl. grouaps. Such protecting groups include those listed in Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley Sons, New York (1991) the disclosure of which is hereby incorporated oy reference. The hydroxyl protecting groups are base-stable and can include, but are riot limited to acyl types, aromatic carbamate types and alkyl types. Exemplary are methyl, methoxymethyl, methylthiomethyl, benzyloxymethy.
t-butoxymethyl, ?-methoxyethoxyniethyl, 2,2,2trichioroethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, tetrahydrofuranyl, t-butyl, triohenylmethyl, trimethylsi.yl, triethylsilyl, t-butvld.~mezh, lsilyl, t-butyldjiphenylsilyl, pivaloate or N-phenv.carbarnate, :in the present invention it has been discovered t hat the compoundis of formula above are us:eful as in:;ib4zzrs cf HIV protease and similar retroviral 2C _rz:zeaseZ, and f..r the inhibition of H-IV and the .re~m~n irfectlor. anJ similar retrovirus infect ior'S 9. 0The present invention also provides methods for the 0 "rearser. infection by administering to a host :rnfe:c..ez FIV a pharmaceutically or therapeutically go effective or acceptable amount of a compound of formula as described above. By therapeutically effective amount, zft is meant an amount of a compound of the p~resent irent. *n effective to inhibit HIV infect ion c., the sympctoms of HIVy infection in a host.
Tne compounds of formula of the present inventisrn are also useful for the inhibition of HI1V in an ex vivo sample containing HIV or expected to be exnzsea to H~v Thus, the compounds of the presenn ven t cn r a% be used to inhibit HIV present in a budy -125fluid sample (for example, a serum or semen sample) which contains or is suspected to contain or be exposed to HIV, The compounds provided by this invention are also useful as standard or reference compounds for use in tests or !.ays for determining the ability of an agent to inhibit viral replication and/or HIV prctease, for example in a pharmaceutical research program. Thus, the compounds of the present invention may be used as a control or reference compound in such assays and as a quality control standard. The compounds of the present invention may be provided in a commercial kit or container for use as such standard or reference compound.
15 Since the compounds of the present invention exhibit specificity for HIV protease, the compounds of the present invention may also be useful as diagnostic reagents in diagnostic assays for the detection of HIV protease. Thus, inhibition of the protease activity in an assay (such as the assays described herein) by a compound of the present invention would be indicative of tne presence of HIV protease and HIV virus.
The compounds herein described may have asymmetric centers. All chiral, diastereomeric, and racemic forms are included in the present invention. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. It will be appreciated that certain compounds of the present invention contain an asymmetrically substituted carbon atom, and may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials.
-126- Also, it is realized that cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.
When any variable (for example, R 1 through
R
4 1
R
4 A and R 7 A, m, n, W, Z, etc.) occurs more than one time in any constituent or in formula or or any other formula herein, its definition on each occurrence is independent of its definition at every 1 other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R 1 1, then said group S:rr may optionally be substituted with up to three R 11 and Fl- at each occurrence is selected independent'. from the defined list of possible R 1 1 Also, for example, in 2C -N'Rp2) 2 each cf the R 2 0 substituents may be ie.-cepn-cr.oe:-.: selected from the list of possible R 2 0 r::ups defined. Also, combinations of substituents ar.ancr variables are permissible only if such ccrninazions result in stable compounds. Similarly, by way cf example, for the group -C(R 1 1 2 each of the two P12" r substituents .nr C is independently selected from the defined list of pssible R 1 1 As u ;ed herein, "alkyl" is intended to include both branched an. straight-chain saturated aliphatic hydrccarocn groups having the specified number of carbon atomrz; "haloalky!" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen; "alkoxy" represents ar. alkyl group of indicated number of carbon atoms L I I -127attached through an oxygen bridge; "cycloalkyl" is intended to include saturated ring groups, including mono-,bi- or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl and cyclooctyl; and "biycloalkyl" is intended to include saturated bicyclic ring groups such as [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2)bicyclooctane, and so forth. "Alkenyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like; and "alkynyl" is intended to include hydrocarbon chains of 15 either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like.
The terms "-(alkyenyl)-", and the like, refer to alkyl, alkenyl, and phenyl groups, respectively, which are connected by two bonds to the rest of the structure of Formula I. Such S" groups may alternatively and equivalently be denoted as "alkylene", "alkenylene", "phenylene", and the like, respectively.
"Alkylcarbonyl" is intended to include an alkyl .group of an indicated number of carbon atoms attached through a carbonyl group to the residue of the compound at the designated location. "Alkylcarbonylamino" is intended to include an alkyl group of an indicated number of carbon atoms attached through a carbonyl group to an amino bridge, where the bridge is attached to the residue of the compound at the designated location.
"Alkylcarbonyloxy" is intended to include an alkyl group of an indicated number of carbon atoms attached to a carbonyl group, where the carbonyl group is attached -128through an oxygen atom to the residue of the compound at the designated location. "Halo" or "halogen" as used herein refers to fluoro, chloro, bromo, and iodo; and "counterion" is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
As used herein, "aryl" or "aromatic residue" is intended to mean phenyl or naphthyl. As used herein, "carbocycle" or "carbocyclic residue" is intended to mean any stable 3- to 7- memlered monocyclic or bicyclic or 7- to 14-membered bicyclic or tricyclic or an up to 2.6-membered polycyclic carbon ring, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocyles include, but are not limited to, 15 cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin) "C7-C1C arylalkyl" is intended to refer to aryl group attached through a C1-C4 alkyl bridge to the residue of the indicated compound. "(C1-C3 2? alkyi)aryl" is intended to refer to a Cl-C3 alkyl group .whc.: _s attached through an aryl ring to the residue of the in-icated compound. "Aryl(C1-C3 alkyl)" is intended refer to an aryl group attached through a Cl-C3 alkyi cr-oup tc the residue of the indicated compound.
2F .s used herein, the term "heterocycle" is intended to mear, a stable 5- to 7- membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which con :ists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, C and S and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached to its pendant group at any heteroatom -12 9or carbon atom which results in a stah,-e structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. Examples of such heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, btenzofuranyl, benzothiophenyl, indolyl, indolenyl, qu.-nolinyl, i soquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl or octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1, 2, 5-thiadiazinyl, 2H, 6H-1, 5, 2dithiazinyl, thiophenyl, thianthrenyl, pyranyl, 15 isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, S L:o lyl, isothiazolyl1, isoxazolyl, pyrazinyl, *:pyridazinyl, indolizinyl, isoindolyl, 3H-iridolyl, lHindazolyl, purinyl, 4H-quinoliz-inyl, phthalazinyl, naphthyridinyl, guinoxalinyl, quinazolinyl, cinnolinyl, 20 pteridinyl, 4aH-carbaz-oly'L, carbazolyl, 13-carbolinyl, pheranthridinyl, acridinyl1, perimidinyl, phenanthrolinyl, phenazinyl, phenarsazinyl, phenothiazi4nyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imiJdazo2.idinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriaz-olyl, benzisoxazolyl, ox:indolyl, benzoxazolinyl, or is- ~inoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinvil, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl.
-130- The term "substituted", as used herein, means that an one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto then 2 hydrogens on the atom are replaced.
By "stable compound" or "stable structure" is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
As used herein, the term "any group that, when 15 administered to a mammalian subject, cleaves to form a free hydroxyl, amino or sulfhydryl" means any group bonded to an 0, N, or S atom, respectively, which is cleaved fror, tne 0, N, or S atom when the compound is administered to a mammalian subject to provide a 20 compound having a remaining free hydroxyl, amino, or s'I.fhydry: grc:, respectively. Examples of groups that, when administered to a mammalian subject, are cleaved to form a free hydroxyl, amino or sulfhydryl, include but are not limited to, phosphate esters, CI-C6 alkyi substitu:ed with 0-3 R 1 1 C3-C6 alkoxyalkyl substituted with 0-3 R 1 1
C
1
-C
6 alkylcarbonyl 'substitu:ed with 0-3 R 1 1 C1-C6 alkoxycarbonyl substituted with 0-3 R 11 C1-C6 alkylaminocarbonyl substituted with 0-3 R 11 benzoyl substituted with 0-3 R1 2 phenoxycarbonyl substituted with 0-3 R 12 phenylaminocarbonyl substituted with 0-3 R 12 or heteroarylcarbonyl. Examples of groups that, when administered tc a mammalian subject, are cleaved to form a free hydroxyl, amino or sulfhydryl, include hydroxy, amine or sulfhydryl protecting groups, respectively.
Ln rrcaas ~BL~R~ -131- As used herein, the term "amine protecting group" means any group known in the art of organic synthesis for the protection of amine groups. Such amine protecting groups include those listed in Greene and Wuts, "Protective Groups in Organic Synthesis" John Wiley Sons, New York (1991) and "The Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), the disclosure of which is hereby incorporated by reference. Any amine protecting group known in the art can be used. Examples of amine protecting groups include, but are not limited to, the following: 1) acyl types such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; 2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) 15 and substituted benzyloxycarbonyls, 1-(p-biphenyl)-1methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate types such as tertbutyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4) 2 cyclic alkyl carbamate types such as cyciopen:yl.:xycarbonyl and adamantyloxycarbonyl; alkyl types such as triphenylmethyl and benzyl; 6) trialkylsilane such as trimethylsilane; and 7) thiol containing types such as phenylthiocarbonyl and dithiasuccinoyl.
By a "ketal ring" or "ketal" group is meant any ketal protecting group which can be hydroyzed to form a carbonyl. Such ketal rings or ketal protecting groups are well known in the art of organic synthesis and typically include, for example, substituted or unsubstituted carbocyclic diethers, dithioethers, or mixed ethers. Such ketal protecting groups include those listed in Greene and Wuts, "Protective Groups in Organic Synthesis" John Wiley Sons, New York (1991) The term "amino acid" as used herein means an organic compound containing both a basic amino group and U I an acidic carboxyl group. Included within this term are natural amino acids, modified and unusual amino acids, as well as amino acids which are known to occur biologically in free or combined form but usually do not occur in proteins. Included within this term are modified and unusual amino acids, such as those disclosed in, for example, Roberts and Velikaccio (1983) Ilia PZcip 5: 342-429, the teaching of which is hereby incorporated by reference. Modified or unusual amino acids which can be used to practice the invention include, but are not limited to, D-amino acids, hydrox~yysine, 4-hydroxyproline, an N-Cbz-protected amino acid, ornithine, 2,4-diaminobutyric acid, homoarginine, norleucine, N-methylaminobutyric acid, naphzn ylalanine, phenylglycine, 1-phenylproline, terz-leucine, 4-am.inocyclohexylalanine, N-methylnorleucine, 3,4-dehydroproline, N,Niz~ehf.ai~. noz~ycneN-methylaminoglycine, 4-ar:nccirnerid-ine-4-carboxyiic acid, 6-aminocaproic 2 d: re:- (ar.-riomechyl) -cyclohexanecarboxylic acid, 4 -(ar.inome:hyl) -benzci'c acid, 1-amrr.:rczclopentanecarboxyl ic acid, I-ami'nocyclo-ropanecarbo:xylic acid, and ::~.arrnoper.:ar.&,-c acidi.
e term "lamino acid residue" as used herein means Lh* -J of an aminc acid (as defined herein) that *is or-esen- in a pe-tide.
76e :em"peptide" as used herein means a compound Lhax: consist:s of two or more amino acids as defined herein) that are linked by means of a peptide bond. The tern "peptide" also includes compounds containing both pe-rcide and non-peptide components, such as pseuciopeptide or peptide mimetic residues or other non-amino acid components. Such a compound containirn: 2~both oectioe and non-peptide components may also be refrre to~sa "peptide analog".
-133- The term "peptide bond" means a covalent amide linkage formed by loss of a molecule of water between the carboxyl group of one amino acid and the amino group of a second amino acid.
As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound of formula is modified by making acid or base salts of the compound of formula (I) Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic ac ds; and the like.
"Prodrugs" are considered to be any covalently 15 bonded carriers which release the active parent drug according to formula in vivo when such prodrug is .administered to a mammalian subject. Prodrugs of the compounds of formula are prepared by modifying :'functional groups present ir. the compounds in such a way tha: the modifications are cleaved, either in routine manipulation cr in vivo, to the parent compounds.
Prodrucs include compounds of formula wherein hydroxy, amine, or sulfhydryl groups are bonded to any croup that, when administered to a mammalian subject, 25 cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, or benzoate derivatives of alcohol and amine functional groups in the compounds cf formula phosphate esters, dimethylglycine esters, aminoalkylbenzyl esters, aminoalkyl esters and carboxyalkyl esters of alcohol and phenol functional groups in the compounds of formula and the like.
The pharmaceutically acceptable salts of the compounds of formula include the conventional nontoxic salts or the cuaternary ammonium salts of the
-I
-134compounds of formula formed, for example, from nontoxic inorganic or organic acids. For c>:ample, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized fror the compounds a of formula which contain a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms S" of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic 2: s=lvent, cr in a mixture of the two; generally, ncr.ac2eecu- r~edia like ether, ethyl acetate, ethanol, iscpropanc1o or acetonitrile are preferred. Lists of suitable salts are found in Reminton's Pharmaceutical n 17th ed., Mack Publishing Company, Easton, PA, 2 1985, p. 1416, the disclosure of which is hereby Si.nczrpoa:ed by reference.
*o Ar used herein, is not intended to be a symbol for tungsten.
Tne disclosures of all of the references cited herein are hereby incorporated herein by reference in their entirety.
The description may include matter which exceeds the scope of the claims but is retained herein for the sake of clarity. The disclosure of PCT International Applicatic. Publication Number WO 53/07128 is inccrp::ated herein by reference. Specific reference ir
,-I
-135made herein to the disclosure of PCT International Application Publication Number WO 93/07128, including the Schemes and Examples Synthesis The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synth,;is. The compounds of the 1C present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art.
Preferred methods include but are not limited to those 15 methods described below.
The compounds of the present invention may be synthesized using the general synthetic procedures described below. Each of the references cited below are hereby incorporated herein by reference.
2C SCcmr.psun.s sf the invention wherein: is (P 2 2)C(=Z)N(R23)- or -N(222)C(=0)C(=0)N(p23)- or N(R 2 3 or 25 or -N(R22)P(=0)(P 2 4 a)NR 2 3 or -N(R22)C(F2)C(=0)N(P 2 3 or 2 (R 2 2 C(F2) S N (R 2 3
R
5 is -OR 20 or H; Rb is -OR 2 1 or H; and n is 1; can be formed from diamines of formula (III)
I
-136-
R
22
HN
NHR
23 The diarrnines of formula (III) can be synthesized as described in copending commonly assigned patent application Jadhav et USSN 07/714,042, filed 5,'21/91 Alternat~ve methods which can be used to synthesize the compounds of structure (JII) above are 32des,:ribea4 ir. Eropean Patent Application Publication Nuber -646-1, U.S. Patent 4,837,204, and Canadian Patent Applocation 2,026,832 *Tne campz'jnds of formula (III) can be cyclized to A fr; o fz~2. (P'~under cond--or r nzrma~iv 4 r~ rea, asis known to one skilled 1t.E art. eet s where J and il are le av4-a roupF, are employed, preferably under AV. ~relat1ive.- d.Iu:c conditions (for example, less than, about,; C. M) t effect rino closure tc provide :rru.~a Many examples of J and are kr~:;preferre-z are carbonyl diimidazole, thcrnya~lir~daolephosgene, thiophosgene, obnhenv'l carbzate, or diphenyl thiocarbonate, 2t, Acditionally, for compounds wherein W is 1:(2 2 2 J~,compounds of formula (III) can ne r-eacted with. activated derivatives of oxalic acid, preferably oxalyl chloride, under the above conditions -137- For compounds of the invention where R 20 or R2 1 is -OH, it is Advantageous to protect the free hydroxyl before cyclization. Protecting groups used can include any of those listed in Greene and Wuts, Protecti'ae Grouns in O.tganic Svnthesi, Chapter 2, Wiley, NY (1991). The preferred protecting groups are trimethylsilylethoxymethyl (SEM), methoxyethoxymethyl (UIEM) or metho>:ymethyl (MOM).
Cyclization of compounds of formula (III) results in structure (IV) structure wherein W is
-N(R
22 23 and r is 1).
z
*R
22 N N R 23 .R4A
R
7 R ~R 6
V)
kncther, preferred method tc forr compounds of frm~a(IV), in cases wherein R' and p 23 are linked tc tne r esectvenitrogens by aCH2 residue, isto cyclize a compound of structure (III) where p 22 and B 23 are hydrogen, and to alKylate the iitrogens using a base, a phase transfer catalyst, and an alkylating agen~t, using methods well known in the art. The preferred base is sodium hydride, and the preferred alkylating aqentL. -re P.
2 2 y and p 2 3 y, wherein Y is a halogen, triflate, or mesylate, preferably a bromide or iodide. Preferred conditions are in polar aprotic solvents between 0 and 100 CC.
-138- Cleavage of protecting groups, if employed, yields structures of f ,rmula wherein R 5 and R 6 are hydroxyl,
R
5 an 6 are other than OR 2 0 and 0R 2 1, some chemiical manipulation of functional groups may need to be performed in the preparation of the compounds of formula (III) or as is appreciated by one of skill in the art of organic synthesis. Described below are examoles of such procedures.
Met)-ods for obtaining compounds wherein R 5 is OH and P is OR 2 1 include protection cnf nitrogen, if necessary, followed by reaction of the diol with l one eq'..i valertt cf base and one equivalent of acyl halzde, al :yl halide, alkoxyalkyl halide, ~zxyarbnvlhalide, benzoyl halide, diphenyl carbona:e cr pheny2.isocyanate, and puri'fication by co *um. cliromatocraphy of the unwanted bis-alkylated 'Aan J i'r ea ct ed m- t er ia I fr obtaining compoun~ds wherein P 5 is OH.1 a. F- is H. include protection of nitrogen, if recezsary, and red-uction of the di.ol to the monool' :enn~czesknown in the art (see, for ex a F c, Chie: Cozrn, 1971, L097; J. Qrmg. Chemn.
.a 923/1 he preferred method is formation of Scy-hc diol estez, and reduction using hydride.
Dez~e:i~nof nitrogen, if necessary, results .n t.he desired compound.
Xe~~i for cbtaining compounds wherein R 5 is OH and F~ Is r' .'ncude protection of nitrogen, if n~c~ssary, folowed by formation of mono-prt.'tected above. Reactior. with a .gr t, preferably,, -139diethylaminosulfurtrifluoride (DAST) (Reaqnt_ for Organic Synthesis, Vol. 13, p. 110, Wiley Interscience, NY, 1988), provides the alkyl fluoride. Deprotection of nitrogen, if necessary, and hydroxyl results in the desired compound.
Methods for obtaining compounds wherein R 5 is OH and R 6 is =0 include protection of nitrogen, if necessary, and standard conditions for oxidizing glycols to pinacols. The preferred oxidant is one equivalent of pyridinium dichromate in dichloromethane, or one equivalent of NaOC1 in HOAc. Deprotection of nitrogen, if necessary, results in the desired compound. Alternatively, a 15 monohydroxy compound described above can be oxidized to the ketone under standard conditions, S. preferably Swern dation using oxalyl chloride, DMSO and Et3N, owed by alpha-hydroxylation of the ketone (see Tet. Lett. 1981, 607; Tet. Lett.
1982, 2917) Methods for obtaining compounds wherein R 5 is OH and FP is difluoro include protection of nitrogen, if necessary, and hydroxyl of the above obtained 25 pinacol, followed by reaction of the carbonyl with a fluorinating reagent, such as DAST. Deprotection of hydroxyl and nitrogen, if necessary, results in the desired compound.
Metnods for obtaining compounds wherein R 5 and R 6 join to form an epoxide include protection of nitrogen, if necessary, followed by standard conditions for the formation of an epoxide from a glycol (see, for example, J. Org. Chem. 1981, 3361). Preferred is the reaction of the glycol -140with more than 2 equivalents of base and one equi'valent of an activating group, such as methanesulfonyl chloride, Deprotection if necessary results in the desired compound.
Methods for obtaining compounds wherein R 5 is OHi and R 6 is Cl-C 3 alkyl include protection of nitrogen, if necessary, and reaction of the epoxide prepared above with Cl-C3 alkylmetal reagents.
Preferred is the reaction of lithium dialkyl cuprates in aprotic solvents at low temperatures 78 to -40 0 C) (see Carruthers, Some Modern Method I!--Clca' S'r rhaeL1,a p. 64, Cambridge University Press, 1978), a j-;dicic-js selection of reagents, as .is wel' pz:e ;ate toone sk-illed in the art, these r-'Z rn c can beperformed in a straightforward le I.ne tox d t ne cla imed combinat ions of R 5 and R 6 .e r'un wl e r ein.
.s 4)C(=Z)N(p 2 or or, -(R 2 2 N (R 2 3 o or, -N (R2 2
(R
2 4 a) q(R 2 3 t )C 2N(R 2 1) or 1,(E23 or R 2 )1 R a Z 0 I ,Ie zyvnthesi zed from diamines of formula() -141-
R
22
HN,
R 4A' N HR 23
(V)
which can in turn be synthesized as described in European Patent Application Publication Number 402 646
AM.
Protection, if necessary, cyclization, and ICfunctional group manipulation if desired is performed as described above to obtain compounds of structure (VI): S S 4. ~5 S
(VI)
Cor;-,pounds of the invention wherein: Wis 0- or -C or -OC R 2 5
(R
2 6
(R
2 4 a) C CR4 27
(R
28 or -P (R 2 4 a) and n is 1; can be formed from diols of structure (VII): 142-
R
5 R 7 HO
O
R
4 A R46
(VII)
which can in turn be synthesized as described in copending, commonly assigned U.S. patent application Jadhav et al. USSN4 07/714,042, filed 5/'31/91.
Functional group manipulation, if desired, may be 10 performed as described above, followed by cyclization to the carbcnate using standard conditions, preferably phosgene or thiophosgene in the presence of 2 ecuivalents of a base such as potassium hydride, to *obzair. compc-inc of st-ruct.ure (I) ~f th lrverntion wherein: V or (RL k (p 2 4 a) C(R 2 (pR 28 or -C1p2) (p 24 an d n i~ E.; C r e fcorned fror., aminoaicoh3l structure R7 7A
R
22 HN R 4
A'
-143-
(VIII)
which can in turn be synthesized as described in a copending, commonly assigned U.S. patent application Jadhav et al. USSN 07/714,042, filed 5/31/91, by employing a single equivalent of azide in the reaction of the diol of formula (VII) to obtain the azidoalcohol, followed by reduction as described in USSN 07/714,042, to form the aminoalcohol.
Protection, if necessary, and functional group manipulation, if desired, is performed as described above, followed by cyclization to the carbamate using 15 standard conditions, preferably phosgene or thiophosgene in the presence of 2 equivalents of a base, such as potassium hydride, to obtain compounds of structure (I) Compounds cf the inven=ion wherein: S- W is and n is 0; ca.- be formed from the diol of structure (IX):
R
6 HO OH
R
4 A
R
7
A
(IX)
which can in turn be synthesized by the reaction of
R
4 CHO with the lithium anion of 1,3 dithiane, followed -144by the reaction of R 7 CHO with the anion of the product (see Carruthers, Some Mociern Methods~ inOrLganijc .qynt-hesis, p. 45, Cambridge University Press, 19,78).
Cleavage of the dithiane with mercuric ion yields the acyclic alpha, alpha' dihydroxyketone.
Functional group manipulation, if desired, is performed as described above, followed by cyclization to the carbonate using standard conditions, preferably phosgene or thiophosgene, in the presence of 2 equivalents of a base such as potassium hydride, to obtain compounds of structure 15om~ounds of the invention wherein: W C(=Z)C r- and n is 0; *car. be forme i 4rc,- aminoalcohol of structure
R
22 HN
OH
RO4A
-R
7
A
R 4
R
7 9M 2- ca ntr5esnhsie ytetcnqe 646~z A]r for tunb the snzei by techonques structure above; however, in place of azide, in oper.:nc the oxirane (shown below) an oxygen C uclectchile, such as acetate or hydroxide ion, I., -145reacted in the presence of a polar aprotic solvent, such as DMSO.
0 BOC-NH R7
R
4 Alternatively, the oxirane is treated with a catalytic amount of a strung acid in water and a cosolvent, if necessary, which technique also removes the BOC protecting group.
Protection, if necessary, and functional group manipulation, if desired, is performed as described above, followed by cyclization to the carbamate using standard conditions, preferably phosgene or thiophosgene 15 in the presence of 2 equivalents of a base such as potassium hydride, to obtain compounds of structure (I) s Compounds of the present invention wherein: W is -C(R 2 5 (R26)N(CH3) (0)C(R2 7 (R2 8 can be synthesized from aminoalcohols (VIII) and by the following steps: protection of nitrogen, if necessary, preferably with a btnzyloxycarbonyl group; activation of the alcohol to displacement, preferably with a sulfonate derivative, such as mesyl chloride; removal of the nitrogen protecting group, preferably with hydrogen in the presence of a catalyst, such as palladium on carbon; and heating under dilute conditions in the presence of a base such as triethylamine to effect cyclization.
I I -I The secondary cyclic amine is then methylated, preferably with formic icid/formaldehyde, and oxidized, preferably with a peracid, such as MCPBA, to form compounds of formula wherein W is
-C(R
25
(R
26 )N(CH3) (O)C(R 27
CR
28 The secondary cyclic amine can alternatively be directly oxidized to form structure where W is -C (R 2 5
(R
2 6
N(OR
2 9 r(R27) (R 2 8 Comrounds wherein: N s-C(R 2 5) pR 2 6
)C(=Z)C(R
2 7
CR
2 8 and n is 0; ~*can be prepared by the alkylation of protected *1 0.
cyclohexanedione with the required R 4 -LG and R 7 -LI-3, and optionally R41*-LG and R 7 A-LG groups, wherein LG :0 represents a leaving: group such as halogen or sulfonate a..
*fee* S..66 0000 a a 6 (X IL) 147- Reduction of the ketone to the alcohol, preferably with LiAlH4, or manipulation to other values of R 5 as described above, is followed by cleavage of the ketal (see Greene and Wuts, Protective Groups in Organic Synthesis, Chapter 2, Wiley, NY, 1991) Protection of the alcohol or other reactive groups, followed by alkylation ketone and deprotection, provides compounds of structure wherein W is
-C(R
2 5
(R
2 6
)C(=Z)C(R
2 7
(R
2 8 and n is 0.
1C Compounds wherein: W is -C(R 2 5 (R26)C(=-Z)C(R27) (R 2 8 and n is 1; S' car, be prepared frorm the protected hydroxyketones described immediately above by ring expansion, for example via the Tiffeneau-Demyanov reaction (March, Advanced Organic Chemistry, p. 965, Wiley, NY, 1985), or S 2C by treatment with dimethylsulfonium ylide to form the sp-iro-epoxide, followed by acid-catalyzed ring expansion tc the cycloheptanone pp. 871, 966) Tne above routes have the advantage of producing a number of stereoiomers which, upon purification, can be evaluated for the best combination of potency, safety and in vivo availability.
Compounds wherein: W is -C(R 2 5
(R
2 6 )C(F2)C(R 2 7 (R28)- and n is 0 or 1; 11 llsll II -14~8can be obtained from the above-described protected hydroxyketong by treatment with a fluorinating reagent, preferably DAST, as described above.
Compounds wherein: w is -NCR 2 2
)C(=Z)C(R
2 7
(R
2 8 and n is 0; can be obtained by cyclization of compound (XlI) to the lactam using techniques known in the art (March, Advancp~d Crganc Chemistry, p. 371, Wiley, NY, 1985) 0 0 S. 0 0* C
H
2
N
(X 1 C~ndsof structure can, in turn be chiE-incci aE derstribed inl European Patent Application 2~ Uuer 4 34 365 A2, European- Patent z~za~::.~u~icatcm urnber 386 Ell A2, European Fat:.:A lostc~nE-.. bication Number 389 127 Al, and CA '105233, each cf which are hereby incorporated by referenc C" in structure (XII) designates protected oxygern. Hyaroxy'l can be protected by the use of any of a number of groups as described in Greene and Wuts, Ora i e- Ai, Chapter 2, o':rcthe resulting lacta,- (XIU): -149-
R
2 7
HN
(XIII)
can be further functionalized, for example by the following techniques: the lactam nitrogen can be alkylated with an R2 2 -LG group, preferably employing *sodium hydride in DME; an p4A, R 7 or RAgroup can be added by deprotection and oxidation of the alcohol, 10 followed by alkylation of the enolate using R 4 A-LG, R 7 LG or R 7 A-LG; and reduction of the ketone to hydroxyl or otherwise functionalizing to obtain the R 5 group of choice as described above.
Compounds wherein: W is -N(?z 2 2 )C(=Z)C(tp 2 7
(R
28 and n is 1, can be obtained through techniques known in the art from ketones of structure wherein W is
-C(R
25
(R
26
)C(=Z)C(R
27 (R28). and n is 0, preferably via the Beckmann rearrangement (March, Advanced.Organic -Chemistry, p. 987, Wiley, NY, 1985),. Manipulation of the R 5 group, if desired, as described above provides R and R 6 -substituted examples of wherein W
-N(R
22
)C(-Z)C(R
27
)(R
28 and n -1.
-150- Compounds wherein: W is -C (R 2 5
(R
2 6 )C 0- and n is 0 or 1; can be obtained from compounds of structure wherein W =-N(R 22
)C(=Z)C(R
27
(R
28 n 0 or 1, and R 22
=H,
for example, by hydrolysis of the lactam, followed by displacement of the primary amine by hydroxyl, and closure to the lactone (March, Adyanced Organic p. 348, Wiley, NY, 1985).
Sir~ilarly, compounds wherein: W is -C R (p, 2 6 C S- and n is 0 or 1; a a aa*ca te zbtained fror. compounds of structure wherein 2 2)C- C 7
(R
2 8 n 0 or 1, and R 2 2
H
fr examp-e, by hydrolysi s oil the lactarr., followed by c~nvers:or. of t~he primary amine to the diazonium salt, ~em~tby NaS'i, and closure to the th~olactone 61,1, Wiley, NY, a. zznaz cf structure ()described above wherein -carn -e converted to the thio dor~vatives, Z =S is., vtar.rzc~nzin (March,, Adya~nCed O'-aniz a~ ~~32 ~J NY, 1985) preferred is the use of the als~lfide described in Bull Son. rhim.
19, 223, 3C Str-uc:-,res described above wherein Z =0 can be converted to the imino derivatives, Z -NR 2 4 using stanaard conditions. When R 2 4 is OH or O-alkyl, the oximes car. te formed and alkylated if desired as d, rrd Mn''arch, i1~droj hmtyp.3, ~-rrsa~-auaua~- -151- 805, Wiley, NY, 1985. The hydrazcnes and imines can be formed similarly (ibid, pp. 533, 797).
The compounds of the formula I where in W
-N(R
2 2
(R
2 4 a)N(R 2 3 and n 1, and R 2 4 a is ethyl, can be synthesized by cyclization of diamine III under conditions normally used to form cyclic phosphoric amides, as exemplfied by Patois et al. in Heteroatom.
Chem. 369-374, (1990), wherein ethyl phosphorodichloridate in presence of trialkylamine, such as triethylamine, was used to cyclize a diimino derivative. Similarly, other diimines could be cyclized to form cyclic phosphoric amide derivatives.
It is expected that the compounds of the invention can also be prepared as snown in Scheme 1 (shown below) The intra-molecular coupling of the N-substituted or unsubstituted dialaehydes may be achieved by organometal 2 reagents derived from vanadium, titanium, samarium etc.
The dialdehyde precursors can be prepared from the commrcially available materials by the methods known to those skilled in the art of organic synthesis, preferably by the techniques disclosed in copending commmonly assigned U.S. Patent Application, Hodge, USSN 07/659,442, filed 2/21/91.
Compounds wherein W is -N(R 2 2 )C(=0)N(R 2 3 and n is 2 can be synthesized as shown in Scheme 2 (below). The eight-membered cyclic urea in Scheme 2 can be protected, if necessary, and manipulated as described above to yield the desired compounds.
Compounds wherein W is -N(R 2 2
)C(=O)N(R
2 3 and n is 1 can likewise be synthesized as shown in Schemes 3, 4, 6, 7 (below) If necessary, intermediates described Id -152herein can be manipulated by methods known to those skilled in the art of organic synthesis to provide compounds within the scope of the invention.
Compounds wherein W is -N(R 2 2
)C(=N-OR)N(R
2 3 or
-N(R
2 2
)C(=S)N(R
2 3 and n is 1 can be synthesized as shown in Scheme 5 (below). If necessary, intermediates described herein can be manipulated by methods known to those skilled in the art of organic synthesis to provide compounds within the scope of the invention.
Compounds wherein W is -N(R 2 2
)C(=O)N(R
2 3 and n is C can likewise be synthesized as shown in Scheme 8 S. (below). If necessary, intermediates described herein can be manipu'ated by methods known to those skilled in the art of organic synthesis to provide compounds within the scope cf the invention.
oo Compounds wherein W is -N(R 2 2
)C(=O)N(R
2 3 n is 0 2' and p 2 3 and are combined to be a direct bond, can be h syn.--hesized as shown in Scheme 9. Compounds of (XXXIIa; were treated under strongly ionizing conditions to produce compounds where W is -N(R 2 2
)C(=O)N(R
2 3 n is C, and p 2 3 is H, R 3 3 is -02C-alkyl. Treatment of 2- comrpound (XXXIIa) with hydrogen and palladium catalyst provided R" is H, whereas treatment with gaseous hydrogen bromide provided R 3 3 is Br, Another route to these compounds was developed (Scheme 10). If necessary, intermediates described nerein can be 3 manipulated by methods known to those skilled in the art of organic synthesis to provide compounds within the scope of the invention.
Compounds wherein W is -N(R 2 2 )S(=O)2N(R 2 3 n is could be synthesized as shown in Scheme 11. Diamines
I_
-153structure (III) were treated with sulfamide to give the cyclic sulfamides. Alkylation using a metal hydride base gave the bisalkylated products. The monoalkylated products could be obtained by selective alkylation using techniques known to one skilled in the art of orgainc synthesis and further described in this invention.
Compounds wherein W is -C(R 2 5
(R
2
E)SC(R
2 7
(R
28
-C(R
2 5
(R
2 6 2 7
(R
2 8 and
-C(R
25
(R
26 )S(=Z')2C(R 27
(R
2 8 n is 1, and Z' is defined above can be synthesized as shown in Scheme 12.
Asymmetric epoxidation of muconic acid (Sharpless et al., J. Or.a Chem. 57, 2768 (1992)); followed by benzylation (Seebach, D. and Wasmuth, D. Helv. Chim.
15 Acta 63, 197 (1980)) provides a secondary diol, which can be converted to primary diol (XXXVIIa) by protection and reduction with lithium aluminum hydride. Further elaboration by the methods of Dugger et al. (Tetrahedron Letters 33, 6763 (1992)) and Trost et al, (Tetrahedron S 2C Letters, 22, 128" (1981)) provide the sulfoxide shown.
S' Further oxidation using a stronger oxidizing agent such as m-chloroperbenzoic acid would provide the ft corresponding sulfone (W is
-C(R
2 5
(R
2 6 )S 2C (R 2 7
(R
2 8 The intermediates described therein can be manipulated by methods known to those skilled in the art of organic synthesis to provide compounds within the scope of the invention.
Compounds wherein W is
-C(R
25
(R
2 6
)C(=Z)C(R
2 7 n is 1, and Z is defined above can be synthesized as shown in Scheme 13.
Compound XXXVIIa could be converted to the corresponding dibromide using carbon tetrabromide/ triphenylphosphine.
Dithiane anion, formed according to the method of Seebach, as reported in Org. Syn., Coll. Vol. 6, 316 -154- (1988), could be alkylated with this dibromide. The seven-membered ring ketone (Z is upon liberation with aqueous mercuric ion, could be alkylated according to methods reported in the literature. Imines (Z is
NR
24 and thiocarbonyls (Z is S) can be prepared by one skilled in the art of organic synthesis using methods described in the literature.
Compounds wherein W is n is 1, and Z is defined above can be synthesized as shown in Scheme 14.
Secondary diol (VII) could be converted to the dibromide using such as described previously. Dithiane alkylation followed by deprotection with mercury ion would produce the five-mermbered ring ketone. Alkylation of the alpha- .o 15 carbons would provide for substitution at R 4A and R 7
A
Thiocarbcnyls and imines of the carbonyl could be prepared using methods described in the literature.
Compounds wherein W is
-C(R
2 (pR26;?) (R 2 4 a)N(R 2 2 or -C(Rn 2 (R2E*) (R2 4 6)O- and n is I, could be preparec as shown in Scheme 15. Aminoalcohol (VIII) could be converted to the corresponding bromide using the method of Marir, and Sawaya (Synthesis, 1987, 479) and displacea with lithiophcsphinate according to the method of Corey anrd wiatkowski Am Chem. Soc., 1966, 88, 5654) Deprctecticn of the amine protecting group would be followed by phosphoramide formation according to the rethod described by Patel et il., (Tet Lett, 1990, 31, 5591). Alkylation with strong base would lead to the compounds where W is -C(R 2 5
(R
2 6
(R
2 4 a)N(R 2 3 Similarly, diazotization and nucleophilic displacement with hydroxide would lead to the compounds where W is
-C(R
2 5
(R
2 6 (R24a)- after cyclization.
-155- Compounds wherein W is
-C(R
25
(R
26
(R
2 4 a)C(R27) (R28)- or (R 2 4 and n is 1, could be prepared as shown in Scheme 16.
Secondary diol (VII) could be brominated by the method of Morin and Sawaya to give (XXXVIa), which could be elaborated to (XXXVIIIa) via earlier described (XXXVIIa). Grignard coupling with methyl dichlorophosphate using the method of Polniaszek and Foster Org Chem., 1991, 56, 3137) would lead to a cyclic phosphinate. Alkylation with strong base based on methods described in the literature see Polniaszek above) would provide the desired products.
Compounds of formula wherein W is 15 -(R 22
)N+=C(R
3 6
)N(R
23 and -N=C(R 3 6
)N(R
23 and n=l can be prepared according to Scheme 17. Intermediate (XXXIXa) can be cyclized under standard amidine reaction conditions, based on method known in the art.
Quaternary salt formation with alkyl halide leads to 20 compounds of the formula (XXXIXd) and (XXXIXe), which can be acid-deprozected according to method described herein..
Synthesis of intermediate (XLa) is described in Scheme 18a, and use thereafter is described in Schemes S. 18b-18c. N-Cbz-Phenylalaninal (XLb') is prepared from optically-active phenylalanine (XLa') by the route previously described. Compound (XLc') can be prepared by the reaction of (XLb') with an appropriate acetic acid anion equivalent such as a Reformatsky reagent derived from ethyl bromoacetate (prepared from bromoethyl acetate and zinc metal). Other acetic acid anion equivalents are contemplated and are recognized by those possessing skill in the art, Compound (XLd') can be prepared by reacting (XLc') with an acyl anion equivalent such as a dithiane anion (such as that -156derived from 1,3-dithiane upon reaction with butyllithium). Other acyl anion equivalents are contemplated and are recognized by those possessing skill in the art. The conversion of (XLc') to (XLd') can also incorporate the use of either or both oxygenprotecting groups and nitrogen-protecting groups. A suitable oxygen-protecting group is the SEM (trimethylsilylethyloxymethyl) ether and a suitable nitrogen-protecting group is the Cbz (carbobenzyloxy) carbamate. Other protecting groups are contemplated including those described in Protecting Groups in Organic Synthesis, Second Edition by T. W. Greene and P.
G. M. Wuts, John Wiley Sons Inc., 1991. Compound (XLa) can be obtained by the hydrolysis of (XLd') with 15 acid or base.
Alternatively, (XLa) can be obtained as follows: (XLe') can be prepared by reaction of (XLb') with a pyruvic acid anion equivalent such as a Reformatsky reagen:. Other pyruvic acid anion equivalents are 2 ccntemplated and are recognized by those possessing skill irn the art. (XLf') is prepared by the reaction of (XLe') with ar alkyl or aryl derived nucleophile such as a Grcrnard reagent or an organolithium reagent (such as benzvlr-anesium bromide or phenyllithium). Other Scrgancme:allic species are contemplated and are recognized by those possessing skill in the art.
Intermediate (XLa) can be obtained by reaction of (XLf') under hydrolytic conditions needed to induce ester cleavage and/or conditi ns necessary to remove any or all protecting groups.
Intermediates (XLa)-(XLk) can be derived from phenylalanine, for example, although all other naturally-occurring and other unnatural amino acids are also con-temlated.
Intermediate (XLb) can be prepared by the reaction of a methylene chloride solution of compound (XLa' wit Y- _1 L1-~b-C4-P- -157- SEM-Cl (trimethylsilylethyloxymethyl chloride) in the presence of an amine base (such as diisopropylethylamine). Intermediate (XLc) can be obtained by the reaction of (XLb) with a carboxylic acid activating reagent such as dicyclohexylcarbodiimide (DCC). Other peptide-forming conditions and reagents are contemplated and are recognized by those possessing skill in the art. Intermediate (XLd) can be obtained by the reaction of (XLc) with an appropriately protected (if needed) hydroxymethylbenzyl halide followed by the removal of the SEM protecting groups via reaction with fluoride ion (tetrabutylammonium fluoride) in a suitable solvent (tetrahydrofuran) Intermediate (XLe) is obtained by the reaction of 15 (XLa) with SEM-Cl under conditions to avoid/suppress bis-alkylation such as limiting molar equivalents of SEM-Cl and/or using lower reaction temperatures.
Intermediate (XLf) can be obtained reaction of (XLe) with phosgene in the presence of a suitable base.
20 Phosgene equivalents and various amine bases are also contemplated and are recognized by those possessing skill in the art. Compounds of the formula (XLg) can be S"obtaine- by the same methodology described above for the preparaL-on of (XLd) from compound (XLc) Compounds (XLh) can be obtained by reacting (XLb) with Cbz-Cl (carbobenzyloxy chloride) in the presence of a base. Intermediate (:XLi) can be obtained by reacting (XLh) with a carboxylic acid activating reagent in the presence of an amine such as ammonia. Other methods are contemplated and are recognized by those possessing skill in the art. Compound (XLj) is obtained by the reaction of (XLi) with a carbon monoxide equivalent such as phosgene in the presence of an amine base as previously described for the conversion of (XLe) to (XLf). Compounds of the formula (XLk) can obtained by -Y g Is~111 -158- N-alkylation and removal of protecting group(s) as described for the conversion of (XLc) to (XLd).
A more detailed description of the general formulas is provided in Scheme 18c.
Compounds such as lactam (XLIm) with an alkoxy substituent could be synthesized as shown in Scheme 19.
The alcohol (XLIh) obtained using the procedure of S.
Thaisrivongs, et al Med. Chem. 1991, 34, 2344-2356) can be alkylated with benzyl bromide using standard procedures to give (XLIi) Treatment with catalytic ptoluene-sulfonic acid in methanol cleaves the oxazolidine to give the free alcohol (XLIj) which can be then converted to the acid (XLIk) using the procedure 15 described by S. Tha.srivongs, et al Med. Chem. 1991, 34, 2344-2356). Protection of the alcohol as the tbuzzldimethylsily ether and cyclization to the lactam is analoagous to that described in Scheme 23.
20z Comnponds such as the cyclohexane fused 7-membered rir araF (XLIIh. could be synthesized as outlined in Scheme 20. The acid (XLIIa) is obtained following the proced-re cf J.A. Martin and G.J. Thomas (EP 0 512 .343 This can be treated witn methanzc and catalytic p- 2 o tluenesulfonic acid to give the free alcohol which can be protected as the t-butyldimethylsilyl ether to give the acid (XL:Ic). The cyclization to the fused lactam (XLIf) followed by an alkylation deprotection sequence car. lead to (XLIIh) Cooournds of formula (XLIII) can be converted to a variety of cyclic structures and the general outline of useful routes is detailed in Schemes 21, 21a and 21b.
Advanced intermediates (XLIIIh) and (XLIIIn) are known and details of their preparation are described in V9301166-A (ulished 21 Jaiiuary 1992), herein ~s -d -159incorporated by reference. The conversion of (XLIIIa) via known methodology and that described herein, to a 6memebered cyclic structure (XLIIIg), wherein P denotes a suitable hydroxyl protecting group (for example 2- (trimethylsilyl)ethoxymethyl (SEM), 2-methoxyethyl (MEM)) and X can be NH, O. R and R' are similar to R 4 and R 7 Further alkylation of the nitrogens can be performed. Conversion of (XLIIIh) to a 7-membered cyclic structure via known synthetic transformations is described, wherein P denotes a suitable protecting group (for example SEM, MEM) and R and R' are similar to R 4 and R 7 X and X' can be any nucleophile (nucleophilic carbon, nitrogen, oxygen, sulfur). Conversion of intermediate (XLII'n) to an 8-membered cyclic structure S 15 (XLIIIs) is described. P denotes an appropriate protecting group; R and R' are similar to R 4 and R 7 and X can be any nuclecphile; X' can be NH, O.
Compounds such as the benzo-fused 7-membered ring 20 lactam (XLIVh) can be synthesized as outlined in Scheme 22. The acid (XLIVa) is obtained following the procedure of M. Hammond and S.W. Kaldor (EP 0 526 009 A) The free alcohol can be protectec as the tbutyldime:hylsilyl ether to give the acid (XLIVc) The cyclization to the fused lactam (XLIVf) followed by an alkylation deprotection sequence can generate (XLIVh) by analogy to that described for Scheme 23.
Compounds of Formula wherein, W is
N(R
2 2
)C(=O)C(R
2 7
(R
2 8 n is 0 and R 7 is hydrogen, and
R
4 and R 27 are benzyl can be synthesized according to Scheme 23. Conversion of N-Boc-phenylalanine by an 8 step procedure can give intermediates of the formula (XLVa). Hydrolysis of the lactone, followed by activation of the acid functionality using methods known in peptide chemistry, followed by deprotection of the -160amine protecting group and intramolecular cyclization can give lactam (XLVe). Standard alkyation and alcohol liberation provide compounds of the formula stated above.
The preparation of compounds of the formula (XLVId) is shown in Scheme 24. The Wittig product from the first step is reduced to the allylic alcohol using DIBAL-H in methylene chloride at -78 0 C. This alcohol can be epoxidized using m-chloroperbenzoic acid or using Sharpless epoxidation methodology to give the epoxy alcohol (XLVIa). The epoxide can be opened selectively using TMS;:3 (Sharpless, K.B. J. Org. Chem (1988) 53 5185) to give the desired 1,2-diol. Exhaustive silylation followed by selective deprotection of the primary sily ether gives compound (XLVIb) Standard primary :csylate formation followed by displacement with sodium az-de car give the diazide (XLVIc). Reduction of the diazide using catalytic hydrogenation and cyclization using carbonyl diimidazole would give the 6membere c'yclic urea. Alkylation as described herein and deprctecticn would give the final product (XLVId).
The diazide (XLVIc) can be manipulated to give a variety cf cyclic structures as previously shown.
Com.ur.ds of the formula wherein W
-RNC~T(=)NR
2 3 n is 1, R 5 is OH or =0 and R 6
R
6 a is flucrine, can be synthesized as shown in Scheme Compound (:LVIIa) can be oxidized to the corresponding ketone by Jones oxidation (Org. Syn. Coll., Vol. V, 866) followed hy reaction of the carbonyl with a fluorinating agenr such as DAST. Deprotection, cyclization, alkylaticr. and removal of hydroxyl protecting groups (such as MEM) can give (XLVIIg), which can be further oxidized zc (XLVIIh) using the method of Gallina Giordan i~~1J. 8 1989, 466) -161- The preparation of compounds of the formula (XLVIIIc) is shown in Scheme 26. Starting from the known hydroxy ketone (XLVIIIa) (WO 92/00956, published January 23, 1992) the alcohol can be protected and the amine function deprotected to give diamine (XLVIIIb).
Cyclization and introduction of the R 2 2 and R 2 3 can be accomplished as described herein. Reduction of the ketone and deprotection can give the desired diol (XLVIIIc). Hydroxy ketone (XLVIIIa) can be converted to the triol (XLVIIIe). After alcohol protection, a second hydroxyl g-oup can be introduced a to the ketone using standard chemical procedures known to one skilled in the art. After protecting this hydoxyl, the amines can be 15 deprotected to give diamine (XLVIIId).
Using similar chemistry as discussed previously, the triol (XLVIIIe) ca:. be prepared as shown in Scheme 26a. The mono-cl (XLVIIIj) can be prepared starting 20 from the aldehyde (XLVIIIf) and an organometallic reagent (XLVIIIg). Both of these compounds can be prepared from amino acids using standard chemical :procedures known to one skilled in the art. The alcohol (XLVIIIh) can be protec:ed and manipulated as discussed previously to give the desired mono-ol (XLVIIIj) The cyclic carbonates of the formula (XLIXb) can be prepared, as shown on Scheme 27, starting from commercially available 3,4-O-Isopropylidene-D-mannitol.
Primary tosylate formation and base treatment can provide the diepoxide which can be opened with numerous nucleophiles to give compounds of the formula (XLIXa) Cyclization and deprotection would give the desired diol (XLIXb).
-162- Compounds wherein W is -N(R 22
(R
24 a)N(R 2 n=1 and R 2 4a is phenoxy or OH, can be synthesized as described earlier and as shown in Scheme 2B, Diarnine III could be cyclized with phenyldichlorophosphate using the method of Patois et al. (Heteroatom. Chem. 1990, 1, 369) to give the cyclic phosphoric amide. Alkylation with strong base and removal of the protecting groups using methods known to one skilled in the art would give the desired products.
Compounds of the formula wherein W is -j p22C(O)Np23-,and p 22 and R 23 are NH(R 22 a) and NH(RJa),respectively, can be prepared as shown in Scheme 29. intermediate (XXIc) can be treated with chloramine to yield dihydrazine (LIa) according to the met-hod S.R. Sandier and W. Karo (Organic Functional crcu.,: Preparat-iorns, Vol 1, Academic Press, 1983, p.45~ her in rcorporated by reference. Cyclization n g sgene ca-, give cyclic urea (LMb) Standard croceture fralkvlation and deprotection can provide La.:t-.7 d- t:Y razire (LIc) .Alternat:ively, (XXc) ca.o -reated with chloroamiriobenzene, according to the rrezhci of S.F. Sandler and W. Karo above, to yield ~*dihyarazLine (LId, Cyclization using phosgene, follow,!d iylto of the product as described previously, sr r~id.- corzmpczunds4 c1f the formula (LIe) Coinr.ounds of the formula wherein W is and n ~,car. be prepared as show,,n ir. Scheme 30. Intermediate (XXIc) can be treated with I, -bi-srnethylthio-2, 2'biscyanoethylene in acetonit-ri le, followed by the standard procedure of alkylat.io: and deprotection tc give compounds cf the Itorru2a (LIia).
_L I -163- Compounds of the formula wherein W is
-N(R
22
)C(=S)N(R
23
R
22 and R 23 are not hydrogen, and n can be prepared as shown in Scheme 31. Monoalkylated intermediate (XXVIIb) can be fur-'er reacted with a alkyl bromide under refluxing reaction cc,<c'itions (to facilitate the removal of byproduct methyl bromide) to give dialkylated thiocarbonyl compound (LIIIa), which can be acid-deprotected as described previously.
Compounds of the formula wherein W is
-N(R
22 )C(=0)C(R 27 n and R28 and R7a are taken to form a bond can be prepared as shown in Scheme 32. The aldehyaes required for coupling can be prepared by methods known to one of skill in the art. Acetylation 15 after coupling can provide dia-etate (LIVa). Amine protecting group modification can lead to (LIVb), afterwhich liberation of the carbonyl (LIVb) and Wittig olefination using stabilized Wittig can provide (LIVc), after separation of the geometric isomers. Liberation 20 of the amlne protecting group can provide (LIVd), which upon modificaticn of the es-er for standard amino-acid type coupling (via LIVe) can lead to compounds of formula (L:Vf)
C
r ~r o r r a *u S a a b s- P-P~RPI -164- The synthesis of compounds of the invention is described in further detail below.
Preparation of di-N-CBZ protected 1,4-diarnino-2,3dicls (XIX): ZN NZ Ph -0 1 HO 0OH (Xix) .4 4* 44 4 4 4 4 4..
4* 44 4* 4 *444 4* 4 4.
De':--led experimer,.aI procedures for the synthesis cf corzpound are described in copending commonly asslqnel paten-,: apciLication Jadhav et al. USSN 2. 07 714, 0 L, f i e d 5/321 91.
c o Frc-ected di-N-CBE 1,4-di~amino X- C. j
R
P =MOY, Y XX ~~etzo a~ 2-(~:hreth\'lsily- ethoxy methyl, -165- Compound (60 g, 105 mrnol) was dissolved in dry ME4 (600 mL) Diisopropylethylamine (75 mL, and SEMCl (b6.8 g, LlO0mxol) were added and the mixture stirred for 16 h at room temperature under N2. The solution was diluted with water and extracted with hexane (400mL) The organic layer was separated and washed with water (2xlO~mL) The aqueous layers were combined and extracted with hexa- k4.,300mL) The organic layers were combined, wab,.ed with watinr (2x-1.00m.) dried over MgSO4, filtered and evaporated. The residue was chroma-tographed on SiO2 and eluted with 3 Oe; ethyl acetate/hexane to afford a white solid (91c, 100k). NMP.CCDC1 3 57.0-7.4 Cm, 2flI, Ph) 5, 01 (br 15 s, 4H PhCH2CO)., 4,5-4,95 (in, 6H, NH, OCH 2 3.6-4.25 9' 4Hf, CH"H2, CHNH), 3.5 4H-, OCH 2
CH
2 2.76 (br d, PhCH 2 0.8B-1 .0 Cm, 4H, SiCH 2 MS: 846 (,M+NH 4 100), 695 (M-SE14, 2 20 B Protection as methoxytnethyl (MOM) ether (XXb) Compound CXIX) (.50 g, 0.88 mmrol) was dissolved in *4dry DMF (10mL') Dii-sopropylethylamine .46 m.L, 2 .64 r.mcoZ) and mnethoxymezhyl bromide (,165 mL, 2.02 intmol) 25 were added and the solution stirred at 40 OC under nitrogen for four h. TLC (50/30 ethyl acetate /methylene chloride) showed that the reaction was complete. The mixture was partitioned betweer. methylene chloride mL) and 5% HCl (30 rnL) The orcianic layer was separated, washed with water (5x20 mL), brine (20 mL), dried over MgS0 4 filtered and evaporated to a light yellow oil.
Chromatography on SiO 2 and elution with 1-20% ethyl acetate/methylene chloride afforded (XXb) as a clear oil (0.29 g, 53%).
NM. (CDCl 3 :86.95-7.42 (in, 20H, Ph), 5.1-3.8 Cm, complex) 3.,35 Cs, 6H-, OCR 3 2. 8-2 .95 Cm, 4H-, PhCH 2 -166- MIS: 657 (23, M-l) 674 (21, M+NH 4 5522 (84) 414 (100) 370 (34).
Deprotection of amnines (XXa) and (XXb) via hydrogenation to afford (XXIa) and (XXIb): 4'*O 4* S. S S S (XXIa) (XXIb) (XX I c)
R=SEM
R=MOM
R =ME M 5 A. Hydroqenaz ion off SE1, ether (XXa).
C::m-ourd (XXa) (90 g, 108.5 rnmol) was dissolved in abzz'i4-e etnanol L) 5% Pd/C (6,5 g) was added and the solution was stirred under hydrogen for 1.5 h until hydrogren uptake ceased. TLC (20/80 ethyl acetate/hexane) showed that the reaction was complete. The solution was z~:r~t*hroug*h, Cel ite and evapoorated at reduced pressure togive XXIa as a colorless gum (60 g, 99%).
NE. 5 7 1-7. 35 (in, I01OH, Ph) 4 .72 (br d, 4H, OCH2C)), (mn, 6H-, NH 2 CflOCH2), 3,15 (in, 2H, CEN19ij), 2.55-2. 95 (mn, 4H, PhCF1 2 0. 95 (in, 4H-, SiCH2) B. Hyidrorena-tion of MOM ether (XXb) Comnpournd (XXb) (0.29 g, 0.441 iniol) was dissolved ethyl2 acetate (6 mnl) and methanol (3 inL) 10% Pd/C wr)'.as added and the solution stirred under -167hydrogen until H2 uptake ceased. TLC (20/80 methanol/ethyl acetate) showed that the reaction was complete. The solution was filtered through Celite and evaporated at reduced pressure to afford XXIb as a clear oil (.132 g, 77.4%) NMR ((CDC1 3 ):87.l-7.35 m, Ph), 4.5C 4H, OCH 2 3.75 (br s, 2H, CH0CH2), 3.3- (in, 2H-, CHNH- 2 3.23 6H, OCH3), 2.85 (br d, 4H, Phd-i 2 MS: 389 100) 34 5 7) 280 (1 120 (6.1) Procedure 4 Formazion of cyclic ureas (XXII h) ,(XXIIb) and 00 ~*HN NH Ph n"-Ph OR 0,9 (XXIIa) R=SEM *(XXIIb) R=MOM 2 23 (XXIIc) R=lM A, Cyclization of SEM ether (XX.a) Compound (XXIa) (40 g, 71.3 mmcl) was dissolved in methylene chloride (200 mL) .Carbonyl diimidazole (13.87 g, 85.6 mnrol) was dissolved in methylene c'Y'oride (200 mL) in a separate flask. Each solution wa ien pumped into dry methylene chloride (6 L) at a rate of 90 inL/h.
The mixture was then stirred for 18h at room temperature under nitrogen. TLC (60/40 ethyl acetate/hexane) showed the reaction was complete. The solvent was removed at -168reduced pressure and residue chromatographed on SiO2 and eluted with 1-50% ethyl acetate/hexane to afford (XXTIa) as a white solid (38 .82g, 93%) inp: 75-76 0 C. NMR (CDC13): 57.05-7.4 (mn, 1011, Ph), 4.6-4.8 (dd, 4H, OCH2O), 4 .08 2H1, CHOCH 2 3.5-3.91 (mn, 8H1, NH-, CIINH, OCI 2
CH-
2 2.86, (br d, 4H, PhCH 2 0.8-0.95 (mn, SiCH2) MS: 587 100).
B. Cyclization of MOM ether (XXIb) Compound (XXIb) .53 9, 1.364 rnrol) was dissolved in dry methylene chloride (20 mL) In a separate flask, carbonyl diiinida zole 2 65 g, 1. 64 inmol) was dissolved in methylene chlori4de (20 mL) To a third flask 15 containinq pyridine .22 mL, 2 .73 nmol) in iethylene ~**chloride (100 mnL) room temperature under nitrogen were added the first two solutions via syringe pump at a :raze of 1.7 rw.L/h. The solution was stirred overnight at room~ temperature. TLC (50/50 ethyl acetate /methylene ch-ride) showed that the reaction was complete. The 'cnw=eF washed wih5 FIC1 (50 mL) NaHCO 3 (51C i.) cri.e dried over 1'IgSO4, filtered and evaporat-ed. The residue was chromatographed on SiO 2 and *e e'-:ed with 50-75% ethyl acetatey,ethylene chloride tc affcrd (XXI~t) as a colorless gum (198 mng, 35%) .NILR (=1 3 867.1-7,4 (mn, 10h1, Ph) 4.65 4H, OCH- 2 0) 4.13 2 H, NE-) 3. 89 2H1, CIINH) 3. 59 2H-, C11OCH 2 S 58 GH-, 0013) 2.87 (in, 4H1, PhCH 2 MS: 415 (M+l, 10;,102 (11) yn t he Si4S of Dimein DiZ Intermediate (XXc) DiZ Diol (XIX) 507g(0.89-nol) was stirred in 4L of dichloroinethane. To the slurry was added N,N- 3 S Diisopropylethylanine 780g(6.O0inol) in one portion at room temperature followed by the dropwise addition of 2- -169methoxyethoxymethyl choride 500g(4mol) (1 hour addition, exothermic). Heated the solution at reflux for 12 hours. TLC (10:1:10 EtOAc:EtOH:Hexanes, Rf=0.56) indicated a complete reaction. The solution was worked up by quenching with ice water(3L). Washed the dichloromethane extract with water(2x 2L) and dried over magnesium sulfate. The filtrate was taken to dryness.
The resultant semi-solid was dissolved in chlorobutane(lL). Passed the solution through a four inch pad of silica gel to remove most of the intense red color. To the chlorobutane extract was added hexane(2L) to precipitate the desired DiZ Dimem intermediate (XXc).
Washed the white solid with hexanes(3x 350ml). Dried at room temperature. Recovered the desired DiZ Dimem 15 intermediate as a white solid in a yield of 525g(79% yield). m.p. 52-54 C, 1H NMR(CDC13): 2.80(m, 4H)-CH2Ph, 3.38(s, 6H)-OCH3, 3.58(m, 8H)-OCH2CH20-, 3.80(m, 2H), 4.20 2H), 4.6-5.2 10H)NH, H2CC02, 7.25(m, 20H)C6H5 Synthesis of Cyclic Urea Intermediate (XXIIc) DiZ Dimem (XXc) 20g(26.8mmol) was dissolved in 200mi of tetrahvdrofuran. To the solution was added 2g of 10% Palladium on Carbon and the suspension stirred for 7 hours under hydrogen(l atm). TLC (10:1:10 EtOAc:EtOH:Hex, Rf=0.05) indicated a complete reaction.
The suspension was filtered through a bed of Celite to remove the catalyst. Washed the Celite bed with 150ml of tetrahydrofuran. Transferred the THF solution to a 500ml round bottom flask. To the THF solution was added 5.5g(33.3mmol) 1,1'-Carbonyldiimidazole in several portions as a solid. Stirred at room temperature for 12 hrs. TLC (10:1:10 EtOAc:EtOH:Hex, Rf=0.26) indicated a complete reaction. The mixture was worked up by quenching with ice-cold 0.5N HC1 (150ml) and extracting with diethyl ether (2x50ml). The organic extract was I- -170washed with water (2x100ml) and dried over magnesium sulfate. The filtrate was taken to dryness. The residue was purified on silica gel(200g; 1:1 EtOAc:Hex followed by 10:1:10 EtOAc:EtOH:Hex) to provide 10.2g (75.7% yield over two steps) of the desired cyclic urea intermediate (XXIIc) as a colorless oil. 1H NMR(CDC13): 2.90(m, 4H)-CH2Ph, 3.36(s, 6H)-OCH3, 3.40(m, 8H)- OCH2CH20-, 3.60(m, 2H), 3.90(t, 2H), 4.10(s, 2H)NH, 4.80(q, 4H)-OCH20-, 7.30(m, 10H)C6H5 Procedure General alkylation/hydrolysis procedure: 15 Compound (XXIIa) (1 mmol) in dry DMF (5 mL) was adoed to a flask containing sodium hydride (10 mmol, S"that had been washed with hexane, 3x20 mL) in DMF mL'. The solution was stirred at room temperature under nitrogen for 5 min. Evolution of hydrogen gas was 2C observed. The appropriate alkyl bromide (5 mmol) was *9 added ard the solution was stirred at room temperature under nitrogen for 1h. Hindered alkyl bromides required heating at 40-70 OC for up to 5 n. TLC (40/60 ethyl acetae/hexane) was used to ensure that no starting 25 material remained. The solution was quenched with methanol (1 mL), partitioned between ether (60 mL) and water (50 mL) and the organic layer was removed. The aqueous layer was washed with ether (50 mL), the organic layers combined and washed with water (4x30 mL), brine 3C (30 mL), dried over MgSO 4 filtered and evaporated. In cases where the alkyl bromide contained basic nitrogen, 1 N i.;OH was used in place of water.
The crude product was hydrolyzed directly in methanol (10 mL) and 4 N HCl/dioxane (5 mL) for up to 16 h at room temperature. The solution was evaporate, and chromatographed directly on Si02 to afford the bis- -171alkylated cyclic ureas. Where nitrogen was present, the solutions were first basified with 1 N NaOH and extracted with ethyl acetate, dried over MgSO 4 filtered, evaporated and chromatographed. Hydrolysis can also be carried out using saturated hydrogen chloride in methanol with shorter reaction times.
Hydrolysis of (XXIIb) under the same conditions gave 67% yield of the N,N-unsubstituted cyclic urea Example 1A, mp 170-174 OC.
f See -172- E~xample 1G N N P h H6 OH The experimental procedure is similar to the synthesis of Example 1E. The isomer, (2R,3R,4R,5R)-2,5diaminc-l, 6-diphenyl-3, .i-hexanediol, needed for the synthesis was isolated,- from the vanadium trichloride 1C coupling reaction, as described in copending commronly assigned- pater.: application Jadhav et al USSN 0-1,714, 042, filed 5/31/91 (see Procedure 1 above).
:Example 10: 13C NMR (CDC13) (75.48 M4Hz)~ 37,387, 5. 13E, 72 .779, 118,649, 126.540, 12' -29.714, 346,137,757, 162.705r.
cl Monoal %v Ulrea: Trne intermediate from previous step 2g(4mmo'L) was 2 C d-,Cssolveo in. 25mJ toluene and placed in a lO0ml round *bcztom flasck. To the solution was added 85-, KOH 8.2g 12r-r:I) and polyethylene glycol (M.W.=1000) W It,-h a Dean Stark trap in place the mixture was rze:f uxeJ for 4 hours until the theoretical amount of water (0 .20r-,1) was collected. Cooled to room temperature and added (bromomethyl)cyclopropane 1,78g(13.2mnol) Stirred at 75 C for 17 hours. TLC(l0:l:l0 EtOAc:EtOF:Hex.,, Rf=0.52) indicated that the reaction was complete. Worked up by quenching with aqueous ammonium chloride (50m!) and extractinc with ethyl acetatte -173- (2x35ml). Washed the organic layer with water(2x35ml) and dried over magnesium sulfate. The filtrate was taken to dryness. The residue was purified on silica gel(150g, 2:3 EtOAc:Hex) to provide 1.55g(70% yield) of the desired monoalkyl cyclic urea as a colorless oil.
C13 NMR(CDCl 3 3.331, 4.000, 10.619, 32.877, 34.159, 55.677, 58.294, 58.972, 64.085, 67.361, 67.437, 71.723, 71.753, 76.576, 78.023, 96.347, 96.519, 126.224, 126.316, 128.366, 128.563, 129.400, 129.447, 139.475, 139.555, 161.558. For reactive alkylating agents, e.g.
m-nitrobenzyl chloride, the reactions are carried out lower temperatures, such as room temperature.
An alternative procedure to make the monoalkylated cyclic urea involved using the procedure described 15 previously for formation of the dialkylated cyclic urea, however, varying the amount of sodium hydride to equivalents and alkylating agent to 1.0 equivalents.
Silica gel chromatography provided the desired product, as well as dialkylated cyclic urea and unreacted startin material.
Svnche is of Cyclic Guan-idines Cyclic guanidine compounds of the invention wherein 25 W NH(C=N-CN)NH, differ from the cyclic urea compounds of the invention wherein W NH(C=O)NH. Described below are representative methods for the preparation of cyclic quanidine compounds of the invention.
I- I- I -1 74- SYNTHESIS OF CYCLIC GUANIDINES
H
2 N NH 2 Ph SemO OeM
N'CN
MaS SWe SPh, Sem =CH 2 0CH 2
CH
2 Si(CH 3 3 4Mv HOI in Dioxane
S
S.
S.
OH
08239 S S S S. S r F *7 M= I 1 1 T C "Maj 4 a p XX T X'jL sci'l-4c'n of Example (150 Trg, 0.22 mmcl) in Dl-, wstreated with sodium. ioddde (160 mg, 1.2. mmol) and heated a: for 2 hrs. The mixture is cooled to room ternpera:ure, dciuT-ed with water and the precipitate is IC extracted int: CH 2 The extract 'is washed with water and dried over MgS0 4 and evaporated to give a yellow oil. This- is li ,LC chromatographed on silica gel EtOAc,"I-{ex:) tcive 50 mg of alkene intermediate (XXIX) as a whi te scnlid. Vf:: (C1,173) 589
_I~
-175- 0 N N
OH
Alkene intermediate (XXIX, A solution of alkene intermediate (XXIX) (40 mg, 0.07 mmol) in THF was treated with 20 mg of 10% Pd/C and hydrogenated in a Parr Hydrogenator at 50 psi overnight.
The catalyst was filtered off and the filtrate concentrated. The resulting residue was HPLC ;10 chromatographed on silica gel (7u% EtOAc/Hex) to give 1C of Example 8G as a white sol-d. MS: (CI,NH3) 591.5 6
S
Method 2 (As outlined in Scheme 15 A suspension cf Example 3U (20. g, 0.0033 mol) in
S.
ethylene chloride was treated at room temperature with a 2-acetcxyisobutryl bromide (2.09 g, 0.01 mol) and stirred for 1 hour until the solution became clear. The reaction was quenched with a solution of sat'd sodium S 2 cicarbonate and the organic layer was washed with water and brine. The solution was dried over magnesium sulfate, concentrated and chromatographed on silica gel EtOAc/Hexane elution) to give 1.3 g of the corresponding bromoacetate intermediate as a white solid. MS:(CI,NH3) 713.4 A solution of the bromo acetate i.termediate (0.45 g, 0.63 mmol) in acetic acid was treated with 1 g of zinc dust and stirred at room temperature until TLC analysis showed no starting material remained. The rixtured was diluted with ethyl acetate and filtered.
I- ar -176- The filtrate was concentrated and the resulting residue was dissolved in methanol and treated with lN aq. NaOH and stirred overnight. The solution was concentrated and the residue was3 dissolved in methylene chloride, washed with water and brine, dried over magnesium sulfate, and concentrated. The residue was chromatographed on silica gel (50% EtOAc/Hexane elution) to give 170 mg of Example 8G as a white solid. MS: (CI.NEH3) 591.5 aoe8 Method 1.
A. Svrthes -s of 6-membered ring cyclic urea (XXX) to H H N N* 0.
MEMO
(XXX)
Te v.:ie, of the six-mernbered cyclic Qrea (XXX) ctl~e~in Screre 8, A solution of N-Cbz-D- ~eni'anine C-dirt.ethylhyciro>:ylarnide (33.5 g 0.09S **F~l)in e--r.er was cooled to 0 0 C and treated with 300 r~L X, sz..u;tion- of vinyl magnesium bromide in THE'. The ~'~xurewas stirred for 30 mins and then poured into ar.
ice cclc sit o of 1 N H-Cl (500 rrL) The mixture was extracted a4,rIto ether and the extracts washed with water and brine. The organic layer was dried over M9SO 4 1 filtered and concentrated to give the desired vinyl ketone as a thick, light yellow resicue which was used w::hcc u~:erpurification. MIS: (CI,NH?) 310 -177- The crude ketone was dissolved in methanol (350 mL) and treated with cerium trichloride heptahydrate (37.2 g, 0.1 mol) and cooled in an ice bath. While stirring vigorously sodium borohydride (3.78 g 0.1 mol) was added slowly, a small portion at a time, over a period of min. After the addition was complete the mixture was al-owed to warm to room temperature and stirred for a:i additional 1 hr. The solvent was removed under vacuum on a rotorary evaporator and the residue was partitioned between 1 N HC1 and methylene chloride. The organic layer was washed with water, brine, and then dried over MgSO4, filtered and concentrated to give the desired allylic alcohol as an off-white s lid which was used without further purification.
15 A solution of the crude allylic alcohol and diisopropylethylamine (30 g, 0.23 mol) in methylene chloride was cooled in an ice bath and treated dropwise with methanesulfonyl chloride (28 g, 0.24 mol). The 6 solution was stirred for 30 mins, then washed sequentially with 1 N HCi, water, brine and dried over MgS$ 4 The solution was filtered and concentrated to Cgive the crude mesylate as a thick oil. To a flameddried flask was added copper cyanide (12 g, 0.144 mol) Sand 1 00 of TH. ne flask was cooled to -78 OC under nitrogen atmosphere. A solution of benzylmagnesium chloride (360 mL, 2M in THF, 0.72 mol) was added via *o syringe and the resulting thick solution was stirred at -60°C for 20 mins and at 0 OC for 30 mins. The solution was then cooled to 78°C and a solution of the mesylate in 130 mL of THF was added via syringe. The solution was stirred at 600C for 45 mins and then poured into a mixture of 1 N HCl/ice. This was extracted into ethyl acetate and the organic layer was washed sequentially with NH4C1 NH 4 OH, brine, dried over MgSG 4 filtered and concentrated. The resulting residue is chromatographed on silica gel (hexane, then -178- EtOAc/Hex) to give 11 .7 g of the cdesir. -kene as a white solid. MS: (CI,NH3) 386.3 403.2 A solution of the above alkene (11.0 g, 0.029 mol) in methylene chloride (75 mL) was cooled to 0 0 C in an ice bath and treated with 60% m-chloroperbenzoic acId (14 .0 g, 0.049 mol) The soluatior was stirred OOC fol. 7 hrs until TLC analysis showed no starting material remained, A precipitate formed during this time. The suspension was diluted wilh methylene chloride and washed sequentially with I N Na 2
S
2
O
3 I N sodium hydro~xide, water, brine, dried over MgS3 4 filtered and concent rated to give the epoxide as a thick oil which was used without further purification.
i5 To solution of crude epoxide in b0 mL of DUE' was :added sodi ur azide (20 g 0.3 mol), arm.cniurn chloride g .)7mcI_) and 2U mL of water. The mixture was heated at 9: 'C for 3 hrs and then stirred at rt cvernic~t, The solvent was removed under high vacuum on 2 a rotcrary evaporator and the residue was partitioned e'we~wa,_e- anci r'-hylenr- cnl-oride, the crgan-:z layer wa washed water and brine, dried over MgSO 4 fil.tered and concentrated to give a residue. This was the- cnromatographed on silica gel (20% EtOAc/H-ex) to iv ,4c fthe azide alcohol as a whit e solid, MS: (C*_i2 4"5. C (2 (M+H) 4 462.2 (1001, (M+NH 4 'A solut-or, cf the azide alcohol above g, 0.016 rtol1) in. metnylene chloride was: treated with 3 dii: cpropylethy'Iarine (4.2 g C.032 mol) and REM-21 g 0.032 mol) and heated to reflux overnight (18 hrs) The rixture was concentrated and the residue chromatographed on silica gel (20% ZtOAc/kHex EtO~/He> t~give 7.7 g of the MEM protected: azidco alcohol- ,clos oil. M_13: (CI,N1F3) 532_ To a solution of MEM protect azido alcohol (5.7 g 0.0107 mol) in ethyl acetate was added 2 mL of acetic acid and 1 g of Pearlman's catalyst (10 Pd(OH) 2 on Carbon) and the solution was hydrogenated at 55 psi for 22 hrs. The solution was filtered through Celite and the filtrate was extracted with 1 N HC1 (organic layer turn orange). The acidic aqueous extract was made basic with NaOH (while cooling in an ice bath) and the precipitate is extracted into ethyl acetate. The organic layer is washed with water, brine dried over MgSO 4 filtered and concentrated to g-ve 2,5 g of the MEM protected diamino alcohol as a colorless oil.
MS:(CI,NH3) 373.1 (100%, To a solution of the MEM protected diamino alcohol 15 (2,5 g 0,0067 mol) in THF was added 1,1carbonyldiimidazole (1,1 g, 0.0067 mol) and stirred over night at room temperature. The solution was concentrated and the residue partitioned retween 1 N HC1 and CH 2 ClI.
The organic layer is wa -ed with brine, dried over MgSO 4 filtered and concentrated. The residue is HPLC chromatographed ;n silica gel 5% MeOH/CHC13) to give 1,2 g of the MEM protected 6-membered ring cyclic urea (XXX) as a white solid, MS: (CI,NH3) 399.1 (100%, o* 25 B. The MEM protected 6-membered ring cyclic urea (XXX; (100 mg, 0,27 mmol) was alkylated with cyclopropylmethylbromide (250 mg 1.8 mmol) followed by removal of the MEM group, as described in general procedure 5, to give after chromatography on HPLC (silica gel, 10% MeOH/CHC1 3 20 mg of Example 8H as a clear, viscous residue. MS:(CI,NH3) 419.4 (100%, Method 2.
3,1 A solution of Example 8A (160 mg, 0,3 mmol) and thiocarbonyldiimidazole (55 mg, 0,3 mmol) in THF was -180heated to reflux for 4 hrs. The mixture was evaporated and the residue chromatographed on silica gel EtOAc/H-ex) to give 31 mg (0.055 mrnol) of the corresponding thiocarbamate. The thiocarbamate was dissolved in 2 mL of toluen~e and heated to reflux. To the refluxing solution was added t-Libutyltin hydride (32 mg, 0.1 mmol) and 2 mg of AIBN. The mixture was refluxed for 1 hour, concentrated, and the residue chromatography on HPLC (silica gel, 65% EtOAc/Hex) to give 20 mg of clear colorless oil, The oil was dissolved in MeOH, cooled in an ice oath and gaseous HCI was bubbled throuah the solution for 30 mins. The solution was then stirrec at room temperature overnight, concentrated and the residue chrcrnatography on HPLTC (silica gel, MOHC'0 3 to give 10 mg of Example 8H as a clear, M eD1 /CH 3 viscous rez:idue, XS: (CI,NV.3) 419.2 (100%, 2 0 ha a I aIP.
OHm 2?o,)n X~b 08g wshae ihmxueo *~t4 aC~ (95m.an ae 05 t8 Cfr4r Afe*x:ato -'hdch~rmtae olwdb washing~ Nh ra -etatwihstrtdsdu biabni adbie amxuewa rvdd hco seartinbycoun hrmtoxahy urisePhXIb :11 e'hy. actat/heaneP~f 0,4 0.4g)Phh ,achl- treit TC11 ty -181acetate/hexane Rf 0.1; 0.13g), and overhydrolysed diol (0.05g).
The above mono-alcohol intermediate 0.25g (0.466 mmol), triphenylphosphine 183mg (0.7 mmol), diethylazadicarboxyalte 0.11 mL (0.7 mmol), and chloroacetic acid 66mg (0.7 mmol) were stirred in 5 mL anhydrous tetrahydrofuran at 0 OC for 15 minutes and then at room temperature for 18 h The excess reagents were quenched with 0.5 mL methanol and the mixture allowed to stir for 20 minutes. The mixture was purified by silica gel column chromatography to provide the desired chloroacetate intermediate with inversion of configuration. 13C NMR (CDC13) (75.48 MHz) -1.373, 15 14.413, 14.487, 18.253, 25.591, 33.851, 35.741, 40.505, 48.824, 49.962, 57.507, 58.234, 66.589, 67.885,73.179, S*7* 77.423, 95.454, 117.296, 118.554, 126.588, 126.887, 128,518, 128.610, 129.117, 129.199, 129,479, 133.686, 134.:.68, 136.324, 138.285, 155.698, 166.323.
The above chloroacetate intermediate 73mg (0.12 mmol) ir. 2mL dry methanol was treated with 0.25 mL (0,5M) sodium methoxide and stirred for 30 minutes at room temperature. The contents were then treated with 0.3 mL HCi1 in methanol) and stirred for 4.5h at room temperature. The residue after removal of solvent was purified on silica gel column to provide Example 8AA.
13C NMR (CDC13) (75.48 MHz) 34.075, 37.672, 48.941, 48.985, 58.071, 60.640, 65.861, 73.212, 177.975, 118.669, 126.535, 126.858, 128.603, 128.815, 129.225, 133,605, 134.172, 137.637, 138.273, 155.497.
Example OR A solution of the bromoacetate irntermediate from Example 8G (0.10 g, 0.14 mmol) in methanol was treated -182dropwise with sodium hydroxide solution (IN, 1 mL) and s -rred at room temperature for 1 hour. The solution was diluted with water, acidified with IN HI-d(aq) and extra,-cted into methylene chloride. The extract was washed with water, brine and dried over magnesium sulf ate, The solution was filtered and concentrated to give 90 mg of Example 8R as white solid. MS: (CI, NH3) 6 71..2 (7 (M+RH) 6569 .2 (6 Table Id *0 *9 a *4bt a a 1" R23 st ereo YdU L9 0 h yt~rz: F.me thy I b eiz yl carbomethoxv R *=benzyi 7AN bernzyl
RSSR
SR
RSSR
benzyi, b e n~ Tah1'p le 0 -183- Ii. L 90 Mass Spec H OH 4+ 541.3 H OH 575.3 *t S V.
V.
B.
V V. 9 3-cyanobenzyl BP 0 8Q benzyl/H 8R 2-naphthylrnethyl 8S 3-hyclroxybenzyl/
H
ST N-methylamino benzyl BU 3-cvanobenzyl BV 3-hydroxyrnethyl benzyl D" N-methylamino benzy.
8X
CF
3
AN
BY 3-carbonethoxy benzyl 8Z 3-hydroxyrnethyl benzyl B AA allyl BAF 3-carbomethoxy benzyl 71C 4-hydcroxyrethyl berizyl BA benzvl 8AE 3-(H 2
NC(O))
benzvl BA- 3- (l-i 2 NC (=NOH) benz vl 8AG 3- (h 2 NC (=NOH)) benzvl BAH 3- (H 2 NC (0) benzyl 8AI 3 (H 2 1"C(0) fluorobenzyl 8AJ 3- (H 2 NC (=NOH) fluorobenzyl 8AK 3- (H 2 NC (0) benzyl 8AL 3- (H 2 NC (=NOH)) benzy.
8AY, 3- (3-pyrazolyl, benzyl BAN 3-cyanobenzyl 3- (H 2 NC (=NOH)l benz yl Br OH 629.2 H OH 44+ 577.2 Br CH 631 .2 H OH 4- 549.3 H OH 763. 4 H OH 607 .3 H OH 551 .4 417 .0 671 .2 417 .1 Not es 1 2 2 2, 3 2 2 2 2 4 OH OH H H 623.3 H H +4 535.2 H OH 491.2 H OH 577.2 H. OH 4+4 607.3 cEsiJ H OH 643.3
(ESI)
H OH 613.2 H OH 613.5 H OH 643.2
(ESI)
H OH 649.2 H OH H OH 623.3 541.2 +4 607.0 -184- 8 AP 3-(H 2 NC(O)) H O H 577. 3 6 benzyl 8 AQ 3-carbornethoxy H OH 60'7.,4 6 benzyl 8AR 3-hyciroxyrnethy.1 H OH 551. 4 6 benzyl Notes 1. As in Scheme 9: CF3COOH opening of aziricline followed by hydrolysis of the diester.
2. As in Scheme 3. The unsubstituted benzyls in the title structure are replaced with p-fluorobenzyls.
4. As in Scheme 9A: Hydrolysis of monoacetate followed by catalytic hydrocenolysis of aziridine ring.
5. The unsubst:ituted benzyls in the title structure are renlaced with 3,4-di4fluorobenzyls.
s. SS isomer F::r compounds of the presenz invention with re-duced OVt, suz y thas been found to be advantageous tc, crepare trodrugs to enhance the solubility and *bicavailabil1ity, of these compounds, The addition of a'-Ie roups byderivatization of free hyrx croulps cf compounds cf formula with bioreversible esters res-.lted in greatly improved water solubility.
Sclubility studies were performed by mixing an excess of s oliLd compoound in water or aqueous medium for at least 4 hours. Solublity was asessed either visually, if a weighez! amount clearly dissolved in a measured volume of solvent- (m-)ethod A) or by HPLO assay of filtiates of saturated solut:ions (method B) .Solubility results are summarized in Table A.
-185- Table A Ex. Solvent Method Solubility No. (mg/ml) water B 0.01 29A water B 2.25 29B water A >100 29C 0.1M citric acid A 29D water A >200 For these prodrugs to be useful therapeutic agents (assuming that the intact esters have relatively little inherent pharmacologic activity), the ester must be hydrolyzed after dosing to yield the parent hydroxy *4 compound. Compounds 29A-29E are hydrolyzed to parent compound 5U in biological fluids in vitro. This was 10 shown as follows. Plasma was collected from rats, dogs, or human volunteers, and was used within 24 hours.
Prodrug was added to plasma, which had been warmed to 37 at concentrations of 2-10 pg/ml. After various times of incubation at 37 OC, the hydrolysis reaction was quenched with the addition of an organic solvent.
The organic solvent was used for extraction of 5U, and concentrations of 5U in the plasma aliquots were determined using HPLC after extraction. Concentrations of 5U were thus measured vs. time of incubation of the 20 prodrug in plasma at 37 Similar studies were performed using a homogenate of rat intestinal tissue w/v) as the hydrolysis medium. Results for in vitro hydrolysis of prodrug 29B in dog plasma and rat intestinal homogenate (10% w/v) are given in Table B.
Results for in vitro hydrolysis of prodrug 29C in rat, dog and human plasma are given i;n Table C. Prodrugs 29B, 29C, and 29E were shown to readily convert to parent 5U when exposed to plasma or intestinal enzymes in vitro. These results indicate that these prodrugs -I Ir~~-p _C IIIII~- -186will convert to 5U in vivo. Other salt forms of these compounds, such as prodrugs 29A and 29D, will be similar to their free acid or free base forms.
Table B Time (min) 0 120 Converted to 5U (Dog plasma) 3.4 4.9 5.5 9.3 19.9 Converted to (Rat intestine homogenate) 16.0 16.6 22.7 46.0 47.1 TahIe C 9. 5
S
(min)
C
12 rt c*i c t Pd c 51.' (rat plasma) 29.4 69.0 74.6 77.6 61.6 90.
rru Sconverted to 5U (dog plasma) 1.8 3.1 3.3 6.7 10.1 15 31.0 converted to (human plasma) 6.7 12.9 12.9 14.5 31.3 45.6 73.4 74.9 2C 3C 12 24:.
36: Imprcven water solubility can result in increasing tl.e extent cf cral bioavailability. Oral czoavailability studies were performed in fasted beagle dog. Compounds were dosed orally using a solution vehicle or the solid drug powder filled into hard ge.atin capsules. Periodic blood samples were taken frc each dog and plasma was separated. Plasma drug concentrations were determined using extraction and HPLC analysis. Generally, after he administration of 5U or 2C its prodrugs 29A-E, the plasma concentrations of 5U were determined, rather than unchanged prodrug concentrations. Oral bioavailability was estimated by
IM
-187comparing the dose-normalized area under the plasma concentration vs. time curve (AUC) after oral dosing with the AUC after intravenous administration of Oral bioavailability is expressed as the percentage of the oral dose absorbed.
Compound 5U has reduced water soluble, and when administered as the solid powder gave reduced oral bioavailability. Therefore, in order to attain increased oral bioavailability, 5U was administered using a sc .tion with polyethylene glycol 400 or propyle- glycol as the vehicle. However, as the dose of 5U was increased, oral bioavailability was reduced, due to precipitation of 5U from the glycol vehicle upon mixing with the aqueous contents of the gastrcintestinal 15 tract. Improved oral bioavailability was attained when the water soluble prodrugs were administered in the o S. solid form, with no added excipients or solvents. One advantage of these water soluble prodrugs is that they can be formulated in conventional solid oral dosage 20 forms, whereas 5U gave reduced oral bioavailability when dosed in solid fcrm. The advantage of the water soluble prodrugs is especially clear at high doses. Both prodrugs 29B and 29D yielded good oral bioavailability at relatively high doses, whereas the administration of a similar dose of 5U in a non-aqueous vehicle resulted in reduced oral bioavailability.
Prodrug 29E resulted in lower bioavailability then prodrugs 29B-D, Additional assay of the plasma samples for intact ester (total of mono and bis ester) was performed by treating plasma with NaOH to hydrolyze any intact esters. Samples were then extracted again and assayed for 5U concentration. The AUC of intact esters was approximately 2 fold greater than that of 5U. Thus, plasma levels of both intact prodrug and hydrolysis product can be attained using these water soluble prodrugs. The results of the comparison of the oral -188bioavailability in doJgs of 5U and its water soluble prodrugs are shown in Table D.
Table D (Mean ±SE) glycol. 10-15 50±20 glycol 40 5±2 29B none 8 2 9±2 2'-none 27 2 7± 6 29C none 31 4 0±1 2 29E none 8 12±2 S* of zC hr~ I'T7 n c hs i nvent Ion poss es s ret rov ra I in partiular HIV nhiitc~' ff icacy, aS evidenced by their activity' In th-Ie assay:-, as describei below. The compounds of la -cssesE roteas,:s inhib itorv a-t ivI :y ar& *.:are thceref::re usef u. as ant Jvira. agents for the treatmnt H! in fe ct ion and associated diseases. The *coF0:uz~s:f orm,.:a possess HIV prozease .nhibitory a c y re effect-Ive as inhi1bitors of H:V crowth.
Tnc pL-ar-e in;- hitory activity of the compounds 27, c' tne pzesen:: :nvent.- I's demonstrated using standard 0assays ofprot:ease activity, for example, using the assay ciescrined below for aSsay. ng inhibitors of HIV Protease activity The ability of the compounds of Lt,_ present invention to inhibit viral growth or infectivity isdemonstrated in stnadasyo viral growth or infect>iv-, for exaMple, using the assays described below, TheI- ccmrpOunds of' the present invention inhibit hI_-iP..'-zro-ease activity in viLvo as demonstrated using the arnima, rmode-s for HIVI protease inhibiticr. described bel ow. The comprouro-S of the pi:,ento invention demonstrate 1r, vivo HIV inhibitor%, activity, as shown in the animal models described below. The HIV inhibitory activity in the animal models described below indicates that the presently claims compounds are useful for the treatment of HIV infection in humans.
As discussed above, the compounds provided by this invention are also useful as standards and reagents for use in tests or assays for determining the ability of a 1C potential pharmaceutical to inhibit HIV protease and/or h'.V growth, such as the assays described herein below.
Thus, the compounds of the present invention may be provod-ed r contmerc-a- kits or containers comprising a =czuno cf this invention, for use pharmaceutical E research.
Since the compounds of the present invention nhibit HIV growv.:r ano infectivity, they may be used as IF ::vatvrsfrteih tion ofC FI in a biological *san-o~e wno.con:aorns hV r is suspecoted to contain FIV oto be ex=osed-- tc A; set hereon "p'denotes r-'croaran, denotes ca grar-, "IL" denotes mncroliter, I"r L" dtenoteE rrllhilter, "!"denotes liter, "nM" denotes nanon-olar, "2"denotes roocron-olar, ar~ enotes 2 on-ooaar, denotes molar an-- "Inn" denotes nanoameter. "Sions"' stands for the Siqma-Aldrich Corp.
A compound is considered to be active if it has an
IC
50 or K 1 value of less than about 1 mV, for the inhibition of HIV protease or HiIV viral growth or infectivity.
HI!V Rrotease Inhilbition Assay- sL, ctroscopiac Method Mareria~s: -190- Prote ase: Incli)sion bodies of E. coli harboring plasmid containing H V protease under the control of an inducible T7 promoter were prepared according to Cheng et. al (1990) Gene 87: 243. Inclusion bodies were solubilized in 8 M urea, 50 mM tris pH 0.0. Protease activity was recovered by dilution 20-fold into buffer containing 50 ml- sodium acetate pH 5.5, 1 mM EDTA, glycerol and 5% ethylene glycol. Enzyme was used at a final concentration of 1.0-10 ug/ml.
Substrate: Peptide of sequence: Ala-Thr-His-Gln- Val-Tyr-Phe (N02) -Val-Arg-Lys-Ala, containing p-n'rophenylalanine (Phe(N02)), was prepared by solid pnase pezi-de synthesis as previously described by Cnen; et al. (19C.C Proc. Nal. Acad. Sci. USA 87: 9660.
S: 1 tc:: sl.:i cn.~ cf 1 mIX were prepared in DSC' ::nreC wcre dissslve ir. sufficient T L, stocK cl-tion E ll furthef .e
R
Va i u E cw Eli fcr inhit 2itor c aE5, pH 6.5, 1 M 1 m gycero. Reactions were i f epide substrate toa r 9Cu:,;ndasrbance at 30C nM: VaiUE. f i :cr tnhititor s n~-r 2 .Ecfor percer.: activity p:e resence~ Snd absence of known c~r~er rs c: l..Lltz Pno a value of 0.07 .nM f,- 2S. the K- of one~ su~:trat~ (Cheng et bl. (1990) Proc. NJat> cac. So:. U2A I'-l olr Feae inhibitry activity of Tfrlc=T, :'C1T.:icu,c C: trirz invent ion is nhu~.. r -191- Pr~'c- aF-- s a 14 Protease: Inclusion bodies of E. coi, harboring Splasmid containing plasmid T1.718R with a synthetic gene coding for a single-chain tethered dimer of HIUV protease were prepared as described in Cheng et al. (Proc. Natl.
Acad. Sci. USA, 87, 9660-9664, 2990). Acti;ve protease was prepared as described therein by extraction with 67% IC acetic acid, dilution 33-fold with water, dialysis acainst water and then against a "refolding buffer" conslstinaocf 2C ml.: IES, I nmJX dithiothreitol and cj'cerc, Prot-ease was stored as a stock preparation at uI M refoldina buffer, Suesrate Peptide of sequence: aminobenzoyl-Als r-s-Gin-Va 1- Tyr-Phe (N -Va 1 -Arg-Lys -Ala containing p-r.:trccnenylalanine, was prepared by solid phase s'nthes-s as crev;:ousl> deszribed Cheng et al, opcit.
Stor soutor~sof 2 mIn: substrate were prepared in DMSO, :n:-iboorxcompounas were dissolved in sufficient to mane 3 r2'' stock solutions. All further dilutions were preparet_ in "assav buffer": I M NaCi, 50 mN-1 KES, pV o 1in>ESA, lrn>, DT, 20 yl1ycerol.
Enzyme reaztior,: Ir. a 2 ml screw-cap centrifuge tube were adoed 50,.X. prctease (final concentration 0.25 n 11, and 0.1 rl, inhiDitory compound (final concentration 0.1-12,500). After 25 min preincubation at room temperature, the reaction was started with the addition of .05 ml substrate (final concentration 5 uM).
Incubation was carried out at 30 C. for 1 hr. The reaction was stopped with 1 ml 0.1 M ammnonium hydroxide.
HPLC measurement of product formation: The product (an-onobezoyl-Al-a-1rr-H-is-Gln-Val-Tlyr) was separated frc7 substrate on a P! .armacia Vlono-. an.~on excnange -l92cclum:'.. The injection volume was 0.2 ml The mobile ohases were: A (20 trisHCl, PH 9.3, 0.02% sod.-urr, Azide, 10 acetonitrile) B (20 rm trig HCl, PH 0.02% sodium azide, 0.5 M amnmonium formate, acetonitrile). The mobile phases were pumped at I ml/min, wit-h a gradient from 0 to 30% B in 5 min, ionl E for 4 min to wash the column, and a .e-equilibration for 4 min. The retention time of the product was 3.6 min.. Detection with a Shimadzu model RF535 fluorescence IC rr.itor was at 330 nm (excitation) and 430 (emission', The K-4 was calculated from the formula Ki ((mS where I inhibitory concentration, S ststa~econcentration., FA fractional activity =r peakwi~ innibi cr/rrpeak height without an- Xchaelis constant 20 uXM.
V 7 .7 r .,ibt ggadp Re.rovirusc 199 ,57ph :we~ r et HI prior tc the PR:z tra.:c:ripts using the Sy~h~:~ze R~ w~purified oy treatmer.t.
UceDlU;se (Promega), phenol-chlorofcorm Z 4.a~Jpreciri Jta*t c: INA transczir., sr~ v e -J .n water, and Fi: cred atL -70'C. The cf was detcexr~ined from the A260.- .y A :z -193termin -U end of the oligonucleotide, using the bic't-inphosphoramidite reagent of Cocuzza, Tet. Lett. 1989, 6287. The gag biotinylated capture probe CTASCTCCCTGCTTGCCCATACTA was complementary to nucleotides 889-912 of H-X132 and the poi biotinylated capture probe (5'-bio';in -CCCTATCATTTTTGGTTTCCAT 3' was complementary to nucleotides 2374-2395 of' HXB2.
Alkaline phosphatase conjugated oligonucleotides used as reporttr probes were prepared by Syngene (S~an Diego, CA.) T&he po1 reporter probe CTGTCTTACTTTGATAAAACCTC was compiementa.y to nucleotides 2403-2425 of HXB2. The gag reporter probe CCCAGTATTTGTCTACAGCCTTCT was complementary to nucleot! 's 950-9'73 offXB2. All nucleotide positions 5 are those of the GenBank Genetic Sequence Data B..nk as ac~essed through the Genetics Computer Group FeqL,=nce Analysis Software Package (Devereau Nucleic Acids Research 1984, 12, 387) The reporter probes were pr'epared as 0.5 A.1 oc-ks in 2 x SSC (0.3 M NaCl, 0.03 M C sociiurn citrate) 0,05 M Tris 9,~38, 1. mg/mL- BSA. The biotirnvlated capture probes were prepared as 100 g1M stocks it- water.
Nanc-im~munomodule micro'-iter plate strips were coated by addition of 200 4L of streptavidin (30 jlg/m.L, 'S Scripps, La Jolla, CA) in freshly preparcI 10 mM sodium carbonate (pH 9.6) Plates were incubated overnight at 4C, Streptavidin solution was aspirated from :he wells and a blocking buffer composed of phosphate buffered saline (PBS), 20 mg/mL bovine serum albumin (crystalline, nucleatce and protease free, Calbiochem) ana 100 mg/n.tL Zactose (Sigma) was added to the plates for 3 hrs at room temperature. Blocking buffer was removed3 from the wells. which were allowed to dry overnight at, roomr temperature and subsequently stored at -194- 4'C in zip lock bags with desiccant. For the majority of the compound evaluation experiments, streptavidin coat~zu. plates were obtaired from Du Pont Biotechnology Systems (Boston, VIA) MT-2, CEM, and H9 cells were maintained in RPMI 1640 supplemented with 5% fetal calf serum (FCS) 2 m.M L-glutamine and 50 gIg/ml, gentamycin, all from Gibco.
Laboratory strains of HIV-1 MN and IDI) were propagated in H9 cells in the same medium. Virus stocks were prepared apprcoximately 1 month after acute infection of F-9 cells by clarification of the tissue e c ;lture mediumr and storage of aliquots at :E rfzi~ titers of F-IV--l stocks were 1 3 PFV' a::e fc:rn ng units)/mZ~l as measured by plaque assay or.
cc-ls (see below) Eact. aliquot of virus stock *used_ for infection was thawed only once, In some cases, _rezted H-9 cells were shifted to Dulbecco's modified za reun days before collection of virus in cr~ier t: c-eraie vir-us stocks in, medium with low bi"oti.cz~e t :z .sclates of filV that had been sage-,cn~e :n M--2 cells were used to infect, fresh c s~rRZMm.iu Tnree days after infection, pe' resuspended and culture continued L cz 's mosdified Eagle's medium as above. Virus sto~.s:f linca isolates were prepared 10-15 days after infe:ction w,.hen cytopathic effects were apparent in F or e':aluation of antiviral efficacy, cells to be ~n~eterwere sutcultured one day prior to infection, 'n tn'e infection, cells were resuspended at 5 x 4n. ppt: 1640, 5% FCS for bulk infections or L either Dulbecco's modified Eaglec mc-cdiur,- minu. 1: iotir (Gibc-. custsn-: s for irnf-' ~Cr I- ct- !C -195plates. Virus was added and culture continued for 3 days at 37 0 C. In some experiments, virus was removed after an initial adsorption period.
Preparation of HTV-1. jifected cell lvsates: HIV-1 infected cells were pelleted by centrifugation. After removal of the supernatant the cells were resuspended at a concentration of 1 x 107 cells/mL in 5 M guanidinium isothiocyanate solution 1C (GED: 5 M guanidinium isothiocyanate (Sigma), 0.1 M EDTA, 10% dextran sulfate). Alternately, cells grown in biotin free tissue culture medium were mixed with 5 M GE: to a final concentration of 3 M guanidinium isothiocvanate, 0.06 M EDTA and 6% dextran sulfate.
e HFV RNA assay: Cell lysates or purified RNA in 3 M or 5 M GED were rxed with 5 M GED and capture probe to a final cqua.idiniumr isothiocyanate concentration of 3 M and a 2: fial biotir cligonucleotide concentration of 30 nM.
Hybridization was carried out in sealed microfuge tubes or in sealed U bottom 96 well tissue culture plates (Nunc cr Costar) for 16-20 hours at 37 0 C. RNA hycridization reactions were diluted three-fold with deionized water to a final guanidinium isothiocyanate concentration of 1 M and aliquots (150 were transferred to streptavidin coated microtiter plates wells. Binding of capture probe and capture probe-RNA hybrid to the immobilized streptavidin was allowed to proceed for 2 hours at room temperature, after which the plates were washed 6 times with DuPont ELISA plate wash buffer (phosphate buffered saline(PBS), 0.05% Tween A second hybridization of reporter probe to the imrmobilized complex of capture probe and hybridized target RNA was carried out in the washed streptavidin coated well by addition of 120 p of a hybridization -196cocktail containing 4 X SSC, 0.66% Triton X 100, 6.66% deionized formamide, 1 mg/mL BSA and 5 nMI reporter probe, After hybridization for one hour at 370C, the plate was again washed 6 times. Immobilized alkaline phosphatase activity was detected by addition of 100 4IL of 0.2 mM 4-methylumbelliferyl phosphate (MUBP, JBL Scientific) in buffer 6 (2.5 M diethanolamine pH 8.9 (JBL Scientific) 10 my, MgCl2, 5 m.M zinc acetate dihydrate and 5 m1,1 N-hydroxyethyl-ethylene-diamine-triacetic acid) The plates were incubated at 37'C. Fluorescence at 450 nM was measured using a microplate fluorometer (DynatLeck) ex.citing at 365 nM.
vicroKa-e corrr-ound evaluation in HTV-1 infected CoFzc~rcrtz re evaluated were dissolved in DNSO :ann; iuted in culture medium to twice the highest conzen~tration, to be tested and a maximum DMSO conzrentrat icr cf 2i. Further three-fold serial d: Iw.nr.Z c: cc .mound in culture medium were OV y in U bottom microtiter plates (Nunc).
A f::e r c_-.rz-,ur~d dilution, MT-2 cells (50 p1L) were added tc a final cocentration of 5 x 105 per mL (I x 0 wel C.s were incubated with compounds for rt:r~~esa: r. a 002 incubator. For evaluation of a- v ar.:ra. rc:encz,, an appropriate dilution of HIV-l (RF) v *vrus szotk (50 p1L) was added to culture wells contzai'ning cells and d3 lutions of the test compounds.
The final Nolume in each well was 200 gL. Eight wells De or Dlate were left uninfected with 50 p1L of medium adder- tn- p2-Ace of virus, while eight wells were infected in the e-nce cs' any antiviral compound. For evalua;.Lor. c-,).mound toxicity, parallel plates were uze~ w~hz.:virus infection.
Aft cz culture at 37'C in a humidified CIS, incubator, all bur 25 JIL, of -197medium/well was removed from the HIV infected plates.
Thirty seven PL of 5 M GED containing biotinylated capture probe was added to the settled cells and remaining medium in each well to a final concentration of 3 M GED and 30 nM capture probe. Hybridization of the capture probe to HIV RNA in the cell lysate was carried out in the same microplate well used for virus culture by sealing the plate with a plate sealer (Costar), and incubating for 16-20 hrs in a 37 0
C
incubator. Distilled water was then added to each well to dilute the hybridization reaction three-fold and 150 kL of this diluted mixture was transferred to a streptavidir. coated microtiter plate. HIV RNA was quantitated as described above. A standard curve, 12 prepared by adding known amourns of pDAB 72 in vitro RNA transcript to wells containing lysed uninfected cells, was run on each microtiter plate in order to determine the amount of viral RNA made during the infection.
In order to standardize the virus inoculum used in 2C the evaluation of compounds for antiviral activity, dilutions of virus were selected which resulted in an IC9C value (concentration of compound required to reduce the HIV RN;. level by 90%) for dideoxycytidine (ddC) of C.2 pg/.L. S values of other antiviral compounds, bct' r:zre an- less pctent than dd-, were reproducible using several stoc:s of HIV-1 (RF) when this procedure was followed. This concentration of virus corresponded to -3 x 105 PFU (measured by plaque assay on MT-2 cells) per assay well and typically produced approximately of the maximum viral RNA level achievable at any virus inoculum. For the HIV RNA assay, IC90 values were determined from the percent reduction of net signal (signal from infected cell samples minus signal from uninfected cell samples) in the RNA assay relative to the net signal from infected, untreated .ells on the same culture plate (average of eight wells). Valid -2.98performance of individual infection and RNA assay tests was judged according to three criteria. It was required that the virus infection should result in an RNA assay signal equal to or greater than the signal generated from 2 ng of pDAB 72 in vitro RNA transcript. The for ddC, determined in each assay run, should be between 0.1 and 0.3 g.g/mL. Finally, the plateau level of viral RNA produced by an effective protease inhibitor should be less than 10% of the level achieved in an uninhibited I1C infection.
For antiviral potency tests, all manipulations in M.cote plates, following the initial addition of 2X crn=entrated comzound solut.ion- to a single row of wells, were perforrned using a Perkin Elmer/Cetus ProPette.
ac~v-t ofrepresentative czru7tz f the -,:resen~t invention in the R14A assay oecieiaro*.e is snown in TLELE 3. The IC90 values in were determned using the assay conditions d eSzr~Dez- a'-ov.e unaer F.V% RNA Assa%,. The IC90 values u U uc/rV, Tn s used in th.E CasEs wne an. :C9; was deterrr.ined to be >50 ug/mL.
a hnumar 7-ceII- line, was culturec i mc~nsurple'-Iented with 51 heat :naota~zfet a: calf serum (FCS) L-glutamine and gent: irurunodeficiency virus strains, H-IV (B a-.c >a FF were propagated in H-9 cells in RPM.! wtE*-FCS.PoyLlsn (Sigma) cotdcell culture pIlatns were roae according to the method of Harada a KC& Scien e 2 2 S 56- -5 6 C INTT, 3- -199- Method: Test compounds were dissolved in dimethylsulfoxide to 5 mg/mL and serially diluted into RPIM: medium to ten times the desired final concentration. MT-2 cells (5 x 10 5 /mL) in 2.3 mL were mixed with 0.3 ml of the appropriate test compound solution and allowed to sit for 30 minutes at room temperature. HIV (3B) or HIV (RF) x 105 plaque forming units/mL) in 0.375 ml was added to the cell and compound mixtures and incubated for one hour at 36 0
C.
1C The mixtures were centrifuged at 1000 rpm for 10 minutes and the supernatants containing unattached virus were discarded. The cell pellets were suspended in fresh RPMI containing the appropriate concentrations of test compound and placed in a 36 0 C, 4% CO2 incubator. Virus 15 was allowed to replicate for 3 days. Cultures were centrifuqed for 1C minutes at 1000 rpm and the supernatan:s containing cell free progeny virus were removed for plaque assay.
The virus titers of the progeny virus produced in 2 the presence cr absence of test compounds were determined by plaque assay, Progeny virus suspensions were serially diluted in RPMI and 1.0 mL of each dilution was added to 9 ml of MT-2 cells in RPMI. Cells and virus were incubated for 3 hours at 36 0 C to allow 2: fcr efficient attachment of the virus to cells. Each "virus and cell mixture was a iquoted equally to two wells of a six well poly-L-lysine coated culture plate and incubated overnight at 36 0 C, 4% CO2. Liquid and unattached cells were removed prior to the addition of 1.5 mL of RPMI with 0.75% Seaplaque agarose (FMC Corp.) and 5% FCS. Plates were incubated for 3 days and a second RPMI/agarose overlay was added. After an additional 3 days at 36 0 C, 4% C02, a final overlay of phosphate-buffered saline with 0.75% Seaplaque agarose and 1 mg MIT/mL was added. The plates were incubated cverr.igh at 3E.C. Clear plaques on a purple background -200were counted and the number of plaque forming units of virus was calculated for each sample. The ar,tiviral activity of test compounds was determined by the percent reduction in the virus titer with respect to virus grown in the absence of any inhibitors.
HTV7 Tow Multiplicity Aissa\' M-at:erials: MT-2, a human T-cell line, was cultured ai-. PI medium supplemented with heat inactivated fetal calf serum (FCS) L-glut amine and 9en: a.,c (21300",) Human immunodeficiency virus s--r-mrns HIV andJ HIV (RE) were propagated in H-9 ce--n wt 5 FCS. XTT, benzene-sulIfonic acid, r~ocarbonyii-1,1 -teiirazolium)bis (I- V' -z s. drc u~iu sa was obtained from Starks E com~ooun,-: were dissolved in dimethyl s~.x zr i. Iaro zeri ally diiuted intco RPM: ,e ~r ed f:na concent rat ion 2I nL adovo to each wei-~ of a 99 1 r e dlae and 0.02 mrL of the appropriate t99 E n~ s: ,t on wa s added t o t he celIlIs s uch t hat e~~zn-~un~czncenizration was present in two wells, o rcou~oswere: allowed tc sit for 3C 5sinrCD7 t-emperature H V(3B) or H:V(RE) (-S :~rnnun nit s rLT) was diluteo in medium and to tell and compound mixtures to give a -'cf infection of 0.01 plaque forming *Th-e mnixtures were incubated for 7 days atl CCC d2~nowhic-h time the virus replicated and caused derrf u.-.oroec-ed cell-, The percentage of cells u::~czcifro-,virus induced c(ulLI death was determined t e c f i;e t ab zIi sm r uf th )e t e t r ao IIum d'.e >C "I O~zOt -201spectrophotometrically at 450 nr. The amount of colored f'.rmazan was proportional to the number of cells protected from virus by the test compound. The concentration of compound protecting either 50% (IC 50 or 90i (IC 90 with respect to an uninfected cell culture was determined.
The HIV inhibitory activity of representative compounds of the present invention in the whole cell C irfectivity assay described above is shown in Table E.
Svaues i TaL are indica.e as: ooer 1e• 1 Z .e *uc e I. the Tables herenr. the KIC values were determined *usri tne assay conditions described above uner HIV /In the Tables herein the values were determined using the assay conditions described above under I V RNA Assay. The IC 90 values are indicated as tne Tables here.r the I value wereunder HIV RN Assay. The IC30 values are indicated as follows: <IC pg/mL; 10 to 100 g/rL; 4 'Pa/aL. The is used in the cases where ar IC 90 was deIerm-nec hee t >50 pv.smL.
-202- V-2/CE Mos Xenotransplant Animal Model The HIV inhibitory activity of the presently claimed compounds in an animal was demonstrated in an animal model wherein HTV-l infected human CEM lymphcyte cells were xenotransplanted in nude mice and the growth of FIV in vivo in such xenotransplanted CEM cells was mcn'tored. The in vivo assay using this model conslsted cf :e::r-nc comrc-,nz ir. a prophylactic manner, wherehy' oe oa--x cose o: acef.: was ad-rI:::stered tc a group :f r: oy zroc: t challenge, The test and C I-.a &e :7 fc1lloWed Wh c rua fcr a oeri c czy or. e :mncternanation ard animl c0 'cser.. r:i ci e;n lve and relative pe-rc=-7.- re flu:rescercc assay (IF'A) Pc: oz7z ve ce J- w:ere oc-te 2 a:t exoer-menta- S -l r.
CCFK- r a we-- :r -If -o c ani EY peri.ssive cell lin~, i Culture CodlectoC:: I I a,,u mairnainrt e .PM ci e I5 c 15-L heat inact ivated fetal caU se:- [eto. ceoc.amc-i as aescribed by Weherall e 7 ari h-rzin!k, eds., Anima-l Models in AIL:, .os, c.stcroam, I c)99, pp 2 l-32) The cells we:r' r'C a humid 5. CC 2 atmosphere. Soo k c tr~ isolate kTLV-I1E were acquired from X ralI, Vanderbilt University, an- were f:ir c.tures of chronicafl y-infected CCP.7-CEMI rt: nc ro- ri yT the Ailro::i Cu I C .rrout irie propac-C;l rfieC ir -203cenzrifugation and passed through 0.45 [Lm filters.
Infectious virions were quantitated on MT-2 cells in ricroculture using cytopathic effect (CPE) as the end point for infection. (Scudiero et al., Cancer Res. 1988, -iS, 4827-4833) The 50% tissue culture infectious dose
(TIC:D
50 was calculated by the method of Reed and Muench (Amer J. Hygiene, 1938, 27, 493-497). CCRF'-CEM cells used for virus xenotransplantation were acutely infected with a stock dilution of HIV-1 at a MOI (input mulz~iplicity of infection) of 0,01 followed by adsorption for 1 h at 37 'C.
Sprague Dawley off 0 old female nude (nu/nu) mice were exposed to 452 Rad's of -arrad-,ation, Twenty-four hours later, 0*e the oruc dosina was started. C~m cell cultures, both F0I~;V infected or uninfected, were harvested and washed U U tnserum. free media and reharvested. Cells of a spe:-'f ied number were suspended ir C.2 ml media and *tr e7tec 2- ttre' (s .c into- t-he irntrascapular rez-:n cf th1e :711zel 24 in aft-er drug 6co.ing commnenced.
T.-e T,--ce were cbserved the following day and at least 000:'",ree times a week for the duration of the experiment.
each of tnese time points the anima.1 7roup weight is aezermineo, and the inoculation site is gently palpated a to aeter-mine the date of gross tumor onset At the ter,7inatlo. of ar, experiment, the animals were anesthesized and euthanized by exsanguination.
P24 En.-,1rre T runoassay The p24 enzyme immunoassay (EIA) used was the unmodified procedure commercially ava Ilable f rom Coulter Corporation (Hialeah, Fl) which uses a murine monoclonal antibody to the HIV core protein coated onto microwell stripi. The assay detects P;,4 ggaten n culture supernatants, plasma, and -204serum. Non-secific cross reactions with mouse serum are not seen with this assay.
Tnd rP Tmrno' nu'" Pnce Assan jli HIV-1 antigenexpressing cells are detected by IFA using the method described by Montefiori and Mitchell (Virology 2986, 155, 726-731). Slides were prepared by air drying and fix~ng in a 50:50 mixture of acetone/methanol for minutes, followed by adding a 1:200 dilutior in PBS-BSA (phosphate buffered saline containing 0.1% qlobin-free bovine serum albumin) of high-titer serum from pooled HIV-' zzsic:':' irsc viiuals (posiive by Weserr.
Sir.noc fo: ancacens) L? will bc aetecteJ us'na a c.l c f. 2or u t d, Iz fra::.cr; of go& cn ofho c q cha[;f spec(flc, Cappe.
a r. L CDunt Er anr.. f Iroes werr r:.nt~ez uriz c~'.zercI and cells exd.rineci for a K 7 2errs *00* r L a Co,-potundrw L.1 (wt/v met~r,;lcc::ulose solution, ari TOro.l One drop :f "weer, 8" s u spen s dro', n an: u ilio~:< c th stck susper::on 'cr-_r'f ulos,'Tween 8C, and stored at 4 C' cr. The suspenrio-nE were qen e x a r ii ow i. frrT t:.e refrlgerazc.
E ,I.ie o:icn to ensure proper suspension. Tht re admrnr.-.tered D! i.p. at doses of r r U, 20, cnd 600 rra.aki/)dav c- rv,a V2 P 2n Data in the p24 £11. and IPA is expressed as a percent of the control untreated levels.
Table FE fnDU1d Dosp n24_I IM Ex. 51 300, mg/kg bid 37.8 51.5 4p Ex. 51I 100 mg/kg bid 76.4 111.3 Ex 51 3C rni/k- bid 2 5 116.7 a. is ws.s e a e s n nt- c o-'c m o .d a transoer.i.C anrrma 1 mode-' s-ster, where:. the H-IV-1 protez-se proztein waE expcressed in th e mrouse lens using a OV. transoene wnere- t! e F-UV-' proteaL:- coding sequence was, Laceo ur~nrie timtrnsra tna contr. I of the mouse A-crysta-r: promrc:e. Suct. transoien-c animals wer-e flo-und tc disrlay a FIV' prctease-med.aatec cataract.
prienot ype. The Ii'protease inhibitory activity of the presently claimea compounds was measured in this animal system as a delay or prevention of the onset of cataract appearance in, the test animals.
EIA~in ons ti o The mammalian expression vector pMSG (Pharmacia) was modified by replacing the M1-1TV LTR promoter with the 412-bp Bgi II-BamH1 mouse alpha A-crystallin promoter fragment (Chepelinsky et al.
Proc. Natl. Acad. Sci. USA, 1985, 82, 2334-2338). The early splice and pnlyadenylation signals were retained and th.is plasmaid was renamred pO-SV 19. A singl.v Chain, tethered dimeric form of th, active HIV-l protease gene (BAA; Cheng et al., Proc. Natl. Acad. Sci.
USA, 1990, 67, 9660-9664 and Cheng et al., Gene, 1990, 67, 243-248) was modified for mammalian cell expression by replacing nucleotides 7 to 90 with CGTAATAGAAGGAGATATAACCATGGAG, The gene was cut with EcoRI ard Hind III and after blunt-end repair cloned into the Sra I site of the pCSV I" thus producing pCSV 19-kBA. The mutant form of tne construct (BA*A*) was proauced by site directed mutagenesis (GAT to GGT) resulting in the change of aspartic acid (25th residue) to clvcire in both monomers resulting in an inactive *frm of n~ rces T-r :r rf Trenaere,"'~ 3-2 2.c kt, I!' Z 19-bA ann p SS 19 -hA*A rtc we (rrodifecd from Sarrbrook at al L 2n J E d, 19 S; Cc-'d Sor--r1 Hartr Laboratory and used for the ccns: r. cf trar.soereic mnle using the pronuclei t:c (H-:non et a' M'rciuat no rhe M-: c orp'-',c1 Hart',r C a:z. o were screened for the IUV-1 protease n te Southern c icr Polymrerase Chain e DetL:x Mice of the FVuiB,'I strair.
P' c Na l Atad SA,99, cM*- w sec for the construct ion ard breedino: t rmr.:o mice, and were originally obtained f: Lr., har.ncr. (NIH) and bred in our facility.
t re m~oe were p ctzased fror Ctiarles Rive: M'rp Sout hern blot et. al. vide supra) was performed c our.fi' fI.( oal biopsies (Hogan et al vid tS~. 2.5 kb H'ind I11 fragment fror rC2W, labeleed) £TA for PCf waF i :cos iv e "O Ch: c, or' -207ma of Proteinase K (Boehringer-Manheim GmbH-) in 100 pil of water and 0.025% SDS. PCR primers specific for the mouse c-fos gene and and the transgene's segment were used as an intern-al control in some samples. Each PCR reaction contained 1-2 41l of tail digest, 60 4~g of each primer, 200 piN of Perkin Eimer Cetus d-ATP, dC1Pj dGTP,TTP (buffered at pH 8.8) and up to 5 units of Perkin Elmer Cetus Arnpli/Taq polymerase.
The reactions were run on a Perkin Elmer DNA Thermal 0 Cycler as fo2 lows: 1 min at 94 C, min at 67 C (2 sec extension/cycle) for 35 cycles. The PCR pro-ducts were analyzed by gel electrophoresis agarose,0.5 JIg/ml of e-hidium bromrid ,and tai-2 samples with a 625 PCR fragmen~t (SV40 specific) were considered positive for the transgene. Ni:~ce bearirz the active protease zransgene were als3 identified by their cataract pn enotype. Progeny of hom~zygouS parent were f% pzsitive for the transeiene and did not require Scutne.!PCR analysis :For n~ n~ F.pcd to be tested were ,n.lx'erized I'D% manu.=! c:indino with mortar and pestle.
;s prior to d~:sig cf mice, the compound was suspended in. C 25 rez,.y ce'!ulcs,/Tween 8C0 solution, homogenized in a manual Dou,^ce homroenizer and sonicated for 10 min asonicatJ 4~.a:er bath, The volume of suspension was adjusted sc- t~at the amount of compound required for dosing one mouse was 0,1-0.2 mL. In order to maintain the required~ mg/kg dose, an average mouse weight for each group was determined twice a week and the amount of ;0 compound ad-iustpd accordingly. Intraperitoneal (ip) and oral (po) dosing was performed using 25 G 5/8 in.
injection and 20 G 1-1/2 in. feedi,.g needles, respectively. The dosing was performed twice a day (bid) and the doses were administered 6-8 h apart. Eyes of control and dosed animals were examined daily by up to indit.,idua-s, and the day when cataracts became -208visible to the naked eye was recorded as the experimental end point (days after birth) Because cataracts do not always develop in both eyes of individual mice on the same day, each eye was scored as an independent observation, Results from individual eyes were used to calculate the average (mean) day of catarac- fLvelopment and its standard deviation for each group.
Ev~ ~ie~~ox~:Eyes were dissected from euthanized I r--ce and fixed with 105 neutral buffered formalin. Eye histology was performed at the Experimental Pathology Latzra--criesc (EPL), Inc., Sterling, VA.
Tnree lines of mice with the 1 prz,-ease gene were established. The eyes ~e t te :n-.ta-nz gene appear identical to those 7 v IA) ,bu blzatera cataract F r:~cL t r, a cZi v e q e r Tni. *z eEac y x'etecte.d even by an~ untrained ~zn ~nsie ofcataract eye I.s opaau t r IEH Cataracts appear ~ansen c lr,e, t *j 1 he time wher.
za ar a: t~e~r varies among the three transgenic theactive HIV-1 protease gene (BAA-, I.'2p ofr tte Tg 61 L~irie develop the L v: y;4: 1ren:-ta-l (day18 in uterci Mice of the r .tres ('Tg 602, and 72) develop the r E t lr a' y (at 24-30 Among the mice line, the timE dfference in cataract zr 'sIE than one: wee'-. N~one cf the m ~c 114U forr- of tt ae.- A* a.-Z Ea e or -209genetic evidence that cataracts develop only in transgenic mi~ce with the active but not inactive form of b'IV-l protease we conclude this phenotype is caused by the protease's enzymatic activity.
Mt A single homozygous male mouse CTg 72-11l0) was mated with three non-transgenic FVB/N females. From each litter, '4-5 mice were used as controls, were dosed with vehicle only (ip or po route) The remaining mice of each litter were dosed (ip or po) with test compound. When mice were 15 days old, dosing began in two groups of 5 mice each with ip, injections of 100 rng/kc,/'T: The comoound was administered ip to the mice in the fIrs: group until all had bilateral cat-aracts.
F- tre seccnd group, the compound was administered ip or 5 davs oivand fro.-. day 20 via the po route until cataracts azcpearted. A third grouc mice) was dosed i- startir:z on. cay IS but it 4CC. mg/kg/bid. Or, day 41, when nc catzaracts had vet developed in this .st cro-utr, three we--e removed fro-~ treatment, and the rerna- o r were doses uti da 52. mice were 0 OV.onservef-oa- fcr cataract forrmat.on.
Tne res-,; s :cr rerreser-tat Ive czrT-rounds cf the cresenr.::we nrr In.th above FHV- :transge, Ic mouse :model are sno r Ta -1e G below. The results show that the recresentative compounds of the present invention effective!%y inhibit HIVy protease activity in vivo.
Table G, DensiZny !2 r c.1c cort rol (relative tc control) I AQ 1 AnQ ix I x 60 mg/kg ip preg days 11-18 85 mg/kc ip preg days 11-18; 17 -18 15 mg/kg ip preg days 11-18 5 mg/kg ip prec days 2.1-18 mo/ko bid 4p days 15-19/ day: 2C0 ff 'kc bid :r ~v~15-20/ f ff -2 Tq 61 Tq 61 Tq 61 Tq 61 .16, 6 20. 6 28. 8 39. 8 Tq 72 6 days
C
C.
C
C. C
CC..
CC C
C
*CCC
CC
C C
'CCC
CC C
CC
To ",2 3.6 days 1, a a 211- Dosage and Formulation The antiviral compounds of this invention can be administered as treatment for retroviral infections by any means that produces contact of the active agent with the agent's site of action, the retroviral protease, in the body of a mammal. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents C1 or in a combination of therapeutic agents. They can be administered alone, but generally administered with a pharmaceutical carrier selected on the basis of the chose:. route of adminis:ration and standard S! c pharmaceu ica" practice.
1 Tne compouns of the present invention can be administered in oral dosage forms as tablets, capsules
S
(each of which includes sustained release or timed Srelease formula:ions), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.
2 T cc.mcuncs cf the present invention may also be S a .is:ered ir ir.t ra.'e-n us (bclus cr infusion), Si. :t raperior.ea su cut. aneous, or intramuscular form, al- using dosage forms well known to those of ordinary s til ir. the pharmace-utcal arts. An effective but t. norr.-tsxi: a-ou.nt of the compound desired can be employed fcr the ir.nb-t icr. of H-V and the treatment of HIV infectio..
The dosage administered will, of course, vary depending upcr. known factors, such as the pharmacodynarric characteristics of the particular agent and its mode and route of administration; the ago, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; and the effect desired.
pil 1 111 -212- BY way of general guidance, the daily oral dosage of each active ingredient, when 'w-ed for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, preferably between about 0.01 to 100 mg/kg of body weight per day, and most preferably between about 1.0 to 20 mg./kg/day. Intravenously, the most preferred doses may range from about I to about mg/kg/minute during a constant rate infusion.
Advantageously, compounds of the present invention may IC be adminis-tered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.
Te com-pound--s for the present invention may also be adzinIS:ered in. Iroranasaa forrr via topical use of s2~taze 22:anasal' veh icles, or via transdermal routes, s~z ~csefcrr- transder- L' skin patches wall know:.
~zs o cr~nr.skill in that art. Tc, be .stereo in the form of a trans-dermal delivery th dcseoe acanunis,:rat ion will, of course, be zrt~:rs~t~an~througho2: .V s. me-nn f. th resent inventior., the $goonz nereas. aescribed in detail can form the are z.pclyadministered an acirnaxtuzohsm~outic..ldiue-ts, excip~entr:, ~le::ve. yreferred to herein as carraic: aoy selected w.,'LL respect to the te.: -or of adim nistrat ion, thal is, oral tablets -uoc n ar.I te like, and r-onsiEtc.'1 vt:.:nv.n~ soalpharmaceutical practices.
araroane, cr oral administration in the forrm E. Ec, r ca ps ul1e, t he a ct .ve drug9 compone n 1 c an 17 zcrs~e: woha,, ora.l, non--toxjic, pharmaceutically nert carrier such as lact, -Zjrch,, me Ly 1c 0u fo~, rna gn2~a'scr ecasra-I n, mn -213and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage S forms include sodium oleate, sodium stearate, magnesium 9* stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without Slimitation, starch, methyl cellulose, agar, bentonite, S xanthan gum, and the like.
The compounds of the present invention can also be administered in the form of liposome delivery systems, S2 such as small unilamellar vesicles, large unilamallar vesicles, and multilamellar vesicles. Liposomes can be formed fro.- a variety of phospholipids, such as chiles:ercL, stearylamine, or phosphatidylcholines.
Compounds of tne present invention may also be 5 ccupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, pclyhydroxy butyric acid, polyorthoesters, -2 14 polyacetals, polyciihyciropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
Dosage forms (compositions suitable for administration contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amcunt of about 0.5-95% by weigh: based on the total weight of the composition.
-he active ingredient can be administered orally in soli-d dosage formrs, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, sy" S sus:pe'-Sor it can also be administered ar. i' s.teril- e liquid dosage forms.
I c±:sesmay conta~n the active ingredier.arz .er such. as lactcose, starcr.,,cel.lulcsc s:ear:e, Fstearic acid, and the :1Kar cue:Cal-. te used to make compressed t Bt _E~s arnc capsules can be manuf acturec' e r :duct: Z rov-i d e f or con t Ir2cz, car. te s_,oar cc:.azea or coated tc e& 5 taE te ano prc~te t the :.atl.et f rom.
L.c. or.:l or a atmin Ist'.ra* io Oncd flalvcr_,,ci t irncrease patient .a wtt, J~ sal..r., aqjecuc::rc Z*oo:e and relat-ed suzar solutions and s taE -_rcylene glclcr polyethy'1ene glycco>_ ca: r irs f or oarerntera' t ions.
oarr~tra admi crctic:. preferatLY a va:r scu salt of thle incredi-.
a 9t r_ s~n S, an: nie 1c sA:, vffe -215bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
Also used are citric acid and ils salts and sodium EDTA.
In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chiorobutanol.
Suitable pharmaceutical carriers are described in Pemiato~s~~.,~~'cca1Sciences, I-ack Publishing Company, a s-.cr~oard reference text in this field.
Useful pharmaceutical dosage-forms for admTinistration of the compounds of this invention can be Lllustrated as follows: larae number of uni:: capsules are prepared by f I s anda r t wo Fi e ce h a rd a e a In c aoDsuIe s, e a c 3~ jC i zr a m Scf p owie red ac,:ive inoredien:, 7* a r'jam s of lactose, 5C r'Illigrams of cellulose, and C -illcra7-.s maanes~uT- searate.
2' Amixture of active inaredient in a digest able O.
s as sc ybear- c 1, cotto:-,seed oi Ior oh ve o:l is p-repared anc n-ce by mreans of a positive 4. c~a cem.en p um itr gelatin to, form soft gelatin capsules cont-alr.ng 102 milligrams of the active :;ncreaient. Tne capsules are washed and dried.
A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 Milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium steara:ce, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose.
-216- Appropriate coatings may be applied to increase palatability or delay absorption.
1n ect able A parenteral composition suitable for administration by injection is prepared by stirring by weight of active ingredient in 10% by volume propylene glycol and water. The solution is made isot-onic with, sodium chloride a-;id sterilized.
Suspension: An aqueo-s suspension is prepared for oral ann:.:str:: r.s: thaz each, 5 r-L- cont~air 10C mg o-f :viced ve ingrede, s0 mo df soiur c~~se, 5 mu of: sodun benzoate, nd 0 TriLofvr:lr cnc~r z f fro :of the present t: L -e F-o. E :se rt combination with- a 7 &F:o nr~ .a a second HTV.
~~C:.r'ero oc anent, for or E of E>V associat:ed d:isease conditions. Th.
fc r7n...la and such'r second therapeut-ic erecseparately or at. a prnys -oal :ngc cosac, e unit, any ciosagFe for.c ~cj-f adr.ir,. st.ratiori, as descrioDed con.r~r of ormu'a may be formulat-ec tlh, second therapeutict agent in a single S, corL ineo together in one capsule-, qun~: .id etoL L When the compound of fz ia a) ar, th 'e second therapeuticz agent are not ~st-z cc in a single dosace unit, the c 2 :fcm and the secor.d therapeutic ager.- E. r c-ere essentia~y i: the saet.rec 2 thecompoun c or..- -217second agent. When not administered at tihe same time, preferably the administration of the compound of formula and the second therapeutic agent occurs less than about one hour apart, more preferably less thian about to 30 minutes apart, The present invention also includes pharmaceutical kits useful, ifrr example, for the treatment of HIV irnfection,, w* :h comprise one or more containers IC containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula :.Such kits may further include, if desired, one or more of various conventional pharmaceutical kit components, such, as, fcr example, containers with cone or mDre pharmaceutically acceptable carriers, additional c::ntainers, ecawIl be re:dil2y appa rent t c th- se a .*~lleinr tine art .Printed,- instructlions, either as 0 .rsert-s as labes', ndctngquantit the 00 comzzonentE t-o rcc admn.-,;stereo, guidelines for C.D7v -nce7t~. a' sz ce inclue rh k i 7nr tr.' present. c. .sclos-use it shl,;d bc, unders-tood n-r~ sru§e r mat--e r ia a 7: c on i icn s a r a pr:.~cthe inventi~on but that Unspeci: f iec: rr&ater ia-'s and ccn.t ions! arc not exc lude 2 slcona as tr. cy cc znz prevent the benefitE cof the invention fron ecr realized.
The Tables below provide representative compounds 1of formula of the present invention. Specifically incorporated herein by reference is the disclosure of POT International Application Publication Number WO 93/07128.
-218- The structures of the Examples below are shown in Table 2d through 2u and set forth representative compounds of the present invention.
Example 9R A solution of Example 90 (50 mg, 0.066 mnol) in methanol (2 ml) was treated with sodium borohydride mg, 0.66 mmol). After th, reactions was completed, the mixture was washed with hydrochlcric acid(2N), water and dried with magnesium sulfate. Concentration gave a residue w!.:ch was purified to give a good yield of the se. cEsire: croouc: MS 629.2015 for C31H38N20r; 1 H NM 4 2(031; 6.42-7.0 18H), 4.79-4.60 3H), 3.65- 4E. 0 E- 2 7 142.C0, 14.19, *E 7 3 1 4 2 13 .4c 131 61 C I C, C1 1CF- 7 i- .49 1-1 1 12 3, e acccrd.nq the general al y a i 5 ar F: J rres (see Procedure 61MS: %3.21 3 N, i Mass Spe: 603.21C fCI C 3 5 H37N 2C)3C: (2 6>3,-7.0 18H), 4.68 H 21;> 4 F5 4 4H 1. 3 65 3. 59 (rr, 4H) 3. C9 H2, 2H), 2.93-2.84 (in, 2h 2 cprr: 162.26, 139,74, 138.47, 138.16, 1: :28.82, 128.48, 1:b.09, 127.38, 125.97, C 4 1 5 45219. 3 22 -I -219- A solution of Example 9S (100 mg., 0.166 rmol) in tetrahydrofuran (1 ml) was treated with methyl amine in H20, 1 ml) and the resulting solution was stirred at roorr, temperature overnight. After the solution was concentrated on a rotary evaporator, the residue was obtained and was purified on Prep. T.L.C, to give a good yield of a neutral product which was acidified with 01 HCl in ether to give the desired product. NS: 593 100%); HPJS: 593.2483 for C-737H45N 4 03; 1 H NI-MP (CD30D) 8 7.38-7,07 18H), 1.69 J=14.3 Hz,2H), 3.93 4H), 3.66-3.64 4H), 3 02 4 i 6: 2F) 6pH); g, F3 14'E6.
7 5,c1.3C, 1C.r, 23.58 C, 12f- 2 7 129.1:1, 12 .3 !I 121.41, .91, E7. C, 1~ *1 X L a s per~c.S1ci Tf (24C FT', rrera. 0i, 7 nl n (4.L aieEi I<EM-r~teltz ExamFe 1IN G- 9. 98 ar.-l :-2t.1crcrEe:h 1 -','rsds (49' r-nic n I the resulting mixts' re was stirred at rcs7 terrerature overrioh After the reaclionr rixture was fslterez tBrz1s 8uchner funnel, the fltrate was treatea '71 roxare(25 frr 2r nours and ther. was ne:ra..zer with sat paHH=-, After aer.era. wcrk}up, thf res-Itir~a crucie was purified on plate using ethyl acetate to give the product in a good yield. 538 100 HRMS 538.2693 for C23H360413 130 NI'R (CD30D) ppm163.67, 151.07, 149,16, 141,11, 139.33, 135.91, 130,59, 130.51, 130.48, 129.62, 128,53, 138.24, 127.52, 127.47, 135.28, 71.96. 71.80, 68.68, 66.98, 64,81, 56,71, 55,10, 33.73, 33.66.
xarnple L I -220- To a solution of Example 9S (100 mg, 0.166 mmcl) in DKF (2 ml) was added K.2C3 (138 mg, 1.0 mmol) and diethylamine hydrochloride (80 mg, 1.0 inmol) and the resulting mixture was stirred for 24 hrs. T*,e mixture was diluted with EtOAc and washed with water. After the organic layer was dried over MgSO4, the solution was concentrated under vacuum to give 70 mg. of the product, LS: 677 100%); HRMS: 677.4444 for C43H57N403; 1
H
NMUO(-CDCZ): 6 7.26-6.96 18H)), 4.84 (d,J=14,3 Hz, IC 2H), 3 5.C-3.4 4H, 3.3" 4H), 2.97-2.78 6H), 2.23 J=E.9 hr., 9H), 09 J=6.9 HZ, 6H), 13C Nt.1p 3,a Cl .9 139 52, 138.52, 138.17, 129.99, 4 4 ;1 2, S, 1F! 84, :2 4 126.3C, 1.C, 4 C7 3 i- I I rn a t 7"CwSdows de *c a a *ve I 1 Czv (0D 32L pp'- 6t -r Ei'' CC) 6+r 7.U, t 2 >3-692 U.
r. I, i 4 CE at -78 0 C wx. dropwise addeci C" 41; 4.4 mmol), and the resultinq al-" to ari tc. rDOrr temrperature. Thie wl.: cmtc wrih ether ~ahed wth satuxated arc d~ied ever NOC2 Aft r czrnce:t rte -221gi.e a good yield of the product; MS: 675.5 100%); HRXS: 675.3805 for C43H51N205; 1H NMR (CDCl3): 7.56-7.54 Cm, 2H), 7.43 7.33-7.25 (s,1OH), 7.08- 7.06 4H), 4.88 (d,J=14.3 Hz, 2H, 3.64-3.5' (m,4H), 3.09-2.87 Cm, 6H), 1.29 18H); 13 C NMR CCDC13): 209.24, 161.87, 139.35, 139.05, 138.23, 131.66, 129.43, 128,70, 128,36, 126.96, 126.62, 71.58, 64.76, 55.80, 44.21, 32.89, 27.94.
Example Tc a solution of trifluoromethyl trimethylsilane (2 2n. 2 m-2z9, ir. THF (3 ml) in an ice-water batt wa. aaaec a sclu:orn of t4EM-protected Example 5V (400 r, 0.55 rrmc) ir Th. (2 mL); and then tc the resultina sol-,ution was adaei terabutylammniurr fluoride catalyst 3 ng, C.C rrmcl. After the reaction mixture was atrre- a f 0 4' rrr. the cooling bath was removed an.: %ne reaction Fixtre was trought tc roorr temperatur? 2: arnc was c: ntinuec for an add:: onal hour. The reactior.
:e was ter treated w th 4m HC ir. dioxane (5 mI.) General wor'-up and purification on TLC plaze 41- 2 ECA: c: C)-2CI2 to furnish a quantitative yield c f z, a. 7 e 7013 (M4-th, 10k) HRMS: 703.2 6 11 f or LZ C37i-i2N:$6" N (CD C'0013, ppm) 162.40, 139.70, :35.7E, 129.6., 129.18, 128.30, 128.14, 126.74, -2E.G3, 71.
3 9 J=32.4 Hz), 70.55, 65.88 (d, J=6.2 Hz), 55.66, 32.12; 19F NIR CCDC13. 79.72 Cq.J=6.C )CCfl- 67.83-7.04 CT, 18), 5.01-4.98 (rr,, 2H), 4,72 Cd,J=14.2 Hz, 2H), 3.67-3.58 Cm, 4H), 3.09- 2.92 Cm, 6H), Example To a solut.,on of N-SEX protected imidazole rr, 2 7 E ric TH: (10 ml I at -78cC was added n-Buli -222- (1.6M, 2.5 mL, 4 mmol) dropwise and the resulting solution was allowed to warm to -20 0 C over one hour.
After a solution of MEM-protected 5V(510 mg., 0.697 mmol) in THF (10 mL) was added, the reaction mixture was allowed to warm to room temperature and was stirred for an additional hour. Workup by general procedure and pzification on T.L.C. plate with 50% ether in CH2C12 gave an oily intermediate (160 mg., 21.3% of yield), which was deprotected with 4M HC1 in dioxane to give the product in good yield: MS: 695 100%); HRMS: 695.2977 for C 4 1 H39N605, 13 C NMR (CD30D, ppm): 183.16, 164.07, 146.2', 141.34, 139.59, 137.92, 135.08, 133.06, 132.70, 130.53, 120,74, 120.57, 127.45, 71.92, 66.93, 33.72; 1 H NI, (CD30D): 6 8.50 2F), 8.29-8.2' S61-7.2 18H), 4 94 J=14.3 Hz, 2 J. (Tc 09 6H).
E;a-.zie E F x: 15X-, in MeOH was acid.i- l .v t e product H NMI (E,3=11 z, 2H), 8.42 (dd,J, 1.1 Hz, J=34 7.7 (bs, 1 7.30-7.00 12H), 6.7 4.C1 (c,J=14,2 Hz, 1H), 4.32 (dd, 4. '=14.28, 2F), 4 02-3.9 1H), 3.71 3 6, .21 J=13.2 Hz, 11), 3.02-2.90 4H), 3 MI, 13 NMR (CD3CL, ppm) 163.80, 148.6(, 1 .22, 1413E 140.. 140.44, 137.59, 130. 4 S 4 1, 12.4 12.2 127.L6, 127.53, 71-54, E C1, 5, 64.67, 54.02, 34.36, 33.05.
6U~ N. -223- 18H), 4.82 (d,J=1.3 Hz, 2H), 4.65 (d,J=13.9 Hz, 2H), 4.37 2H), 3.31-3.30 4H); 3.08-3.04 2H), 3.98 (d,J=13.9 Hz, 2H), 2.89-2.84 2H) Example To a solution of MEM-protected-m-indobenzyl cyclic urea (980 mg., 1.07 mmol) in THF (10 ml) at -78 0 C was added t-BuLi (1.7M in hexane, 2.64 mL, 4.5 mmol) and the resulting solution was stirred for another 30 mins. The N,N-dimethyl trifluoroacetamide (560 mg., 4 mmol) was added and the mixture was stirred for 2.5 hours. The mixture was diluted with ether and acidified with 2N HCI tcc pH=i. The ether layer was neutralized and washed with water, brine, and dried over MgSO 4 The solution was concentrated to give a residue which was purified on silica gel column with gradient solvents (0-20% ethyl a-etate in CH2C2) tc give an oily intermediate (350 C The cil was dissCived in CH2C12 (5 ml) and was treatec with 4: HIC ir. dioxane overrniaht. General wzrkup and purification on Prep. T.L.C. plate with E:.OAC i. CH2C12 gave the the product (300 mg) in 40.2% yield. NS4: 699.4 1001); HR; MS: 699.228b for SC37H331:205F6; 1 NMF, (CD3COCD3): 6 7.97 (bs, 4H), 7.73- 7.59 4H), 7.14-6.96 10H), 4.75 (d,J=13.9 Hz, 2H), 3.72-3.63 4H), 3.32 (d,J=14.3 Hz, 2H), 3.18- 3.13 2H), 2.95-2.79 4H); 1 9 FNMR (CD3COCD3): 8 72.54; 1 3 C NtMR. (CD3COCD3) 180.83 (q,J=34.3 Hz), 162.39, 0 141.27, 141.06, 137.90, 131.60, 130,43, 130.35, 130.23, 129.73, 129.16, 127.05, 117.62 (q,J=291.4 Hz), 71.83, 67.40, 56.55, 33.59.
Example -224- To a solution of '-M-protected 4P (750 mg, 1.02 mmol) in T-F (20 mL) was added ethyl magnesium bromide (2M in Et20, 4 mL) and the resulting mixture was allowed to reflux for 2 hours, After removing all solvents on rotary evaporator, the resulting residue was dissolved in MeOH (15 mL) and was treated with 4M HCl in dioxane overnight. After general workup and purification on T.L.C. plate with 40% EtOAc in CH2Cl2. Example 15XN was obtained (600 mg) in 95.2% yield. MS: 636 (11+N H4, 1o200%; HR1MS: 619.3181 for C399H43N205; 1 H NI4 Clj) 6 7,77-7.71 (in, 4H), 7,39-7,22 10H), 7.06-7.03 im, 4H) 4.E2 (d,J=4.3 H2, 2F), 3.75 (bs,2H) 3.64-3.60 2H 2 3 .14 J=24.: P.z, 2.'i 3.10 J= EF:, 2 .9 2H 2,8? (q,87 Hz, I 1!L (C 2 1 3, p p 2 0 C *2 9 2 82. 7 4 60 4 C..,r V 00 Z.0 a e 5, Table 2- was 64 1001'); 1F, (CDCDC) 8 >62- 3. 6 4 E m d, .9 E, 2E) E,' iz 6, N;t:(f3CI, Fpr LK. .4 Al 13E.0C, 3 64 5, 129.31, 129.17,
.L
2 0 a E I o. i I. rote c r, :zcber2zv yz (IS t; C I -225- Sulfur dioxide gas was introduced into the basic solution at the same temperature for 15 mins. The mixture was allowed to warm to R.T. over 2 hours and then was cooled to -78 0 C again. Sulfuryl chloride (0,72g., 5.35 mmol) was added and the resulting mixture was allowed to warm to R.T. and stirred overnight.
After all volatile reagents and solvents were removed under vacuum, the residue was dissolved in THF (10 mL) at -60 0 C and was treated with excess ammonia gas for minutes. The final mixture was diluted with EtOAc and washed with water, brine and dried over anhydrous MgSO4 followed by filtration, The solvents were removed on a rotary evaporator and the residue was deprotected by general procedure. Finally, the crude was purified on 1 T.L.C plate and further purified on HPLC to give the desired product nr. moderated yield. MS: 682 (M+NH 4 10%i HR.MS: 665.21C3 for C33H37N407S2; 13C NMR (CD3CCD3, pp.r) 162.3 145,25, 141.16, 140.81, 133.59, 13C.38, a* "29.86, 129.21, 127 .7 1-6.95, 125.85, 71.87, 67.52, 2: 56.7 33.56; H NM?. (CD30D) 5 8,19-7.32 18H), 5.06 S, =14.3 2H) 4 .08- 95 4H), 3.49-3.16 6H) -,ar.r _e e* 5. T.e experimen'ta procedure in Note 5 of Table 2d wa fcllowe MS: 745 (M+18, 100%); HRMS: 729.2500 for C37H35N405N6; H N. (CD30D): 5 7.47-7.39 6H) 7.29- 7.24 8H), 7.06-7.03 4H), 4.71 (d,J=13.9 Hz, 2H), 3.66 2H), 3.62 (d,J=11.7 Hz, 2H), 3.08 (d,J=12.5 Hz, tC 2H), 2.98 (d,J=14.2 Hz, 2H), 2.95-2.89 2H), 1 3 C NMR ppm) 163.87, 141.26, 139.71, 132.08, 131.04, 130.64, 129.75, 129.56, 128.95, 128.92, 127.45, 122.57 (q,J=2 7 3,1 Hz), 72.02, 67.42, 57.02, 33.67; 1 9
F
N.R(CD
3 OD) 67.75, Examplie -226- The experimental procedure of Note 5, Table 2D was followed. The obtained product was further pur3.fied on chiral-HPLC to give the product: MS: 621 100%); I E- NMi. [CDC13+CD30D(1:1)) 57.26-6.76 18H), 4.4t (d,J=14.3 Hz, 2H), 3.24-3.03 4H), 2.76-2.56 6H, 1.86 6H); 13 C N-MI [CDCl3+CD30D(1:1), ppm) 163.28, 155.56, 240.48, 138.76, 138.18, 130.34, 130.09, 129.22, 129.12, 127.62, 127.04, 125.84, 71.45, 66.00, 56.42, IC) 331,5, 12.25; Example ISYG Tz a smrrea F.Y.;re of cyclic urea Example 5T (300mc, C- 58 rnr:> ar,: anhcrsus ceriu.- carbonate (9:2 mg, 2.8 :7,7L z rec base Cf N- (2-chioroeh:Iyl) r- r (c rC. mr wa E added (prepared by zioscl va; .Ir c: t'ne hydrochicrice ir. 5 mL of water a c f s ad NaHI.,, extra::rno with, IOC mL of 2 T r z ?OSC and~ concentratin) (Tnm.pScr; 9 C 9 an dJ hea ed ,c rraxturc wa: folterez, rinsed w-l -:ilica (e J cethanol r;ct wo prepo L; alkylating LZ a rrz;: e rmon oaI-vIated compoun d with m-cyanobenzy 1 iu7 aluminum hydride (158 rng, 4 ,8 m.mc2 a :c C 3 mg, 1.39 nimnc1) in ether at. OCc a rie&n4 up to RT and stirred for 15 rrir, l- i of- tL above in:nezntedia (S5 ardC-d crcpw n se Ur -227- NaOH and washed with H 2 0, sat'd NaCi and dried over MgSC- 4 Following the same hydrolysis procedure, the product was isolated (70 mg) in 10% yield, M. P. 132- 134C. M.S. 566 100%) Example To the mixture of I mL of DMF and 4 rnL CH 2
CI
2 oxalyl chloride (0.72 rnL, 2M4 in CH 2 C1 2 was added dropwise at -20 0 C under 2 After 20 mine, 500 mg (0.65 mmol) of bis(N-m-benzoic acid) cyclic urea Example 6A (Table 2c) and 0,14 rL. (2 rmrol) of N-me--hyl-morpholine were added.
Tr.E: mi'.>:ure was stirr-ed a: -2 0C for 20 min. Nme' hylhydroxylarrine hydrochi'Dride (2117 mg, 4 mmol) and -E ar. additional 0.56 mL (8 mnzK) of N-methyimorpholine were added. The reaction mi:xture was diluted with ethyl ace-:ate, shed wtr cocld5 HC, sa:' d Na1-",CC,, HK,) near.-ipr e- or a ae 1.10 95 M et ha nol ch' srcfcz= Fc0$n tre same -ydrolysis proced-ure, 1 :.~crczz, wu.sc-azez 2C yie. I. P Us :c an anloqcO25 procedure tc that reported by Paul Urnangst, elt (r J. Med. Chem-. 1992, 35, 3691-3698) the title compound can be prepared from the h ydroxyam'idine. To a stirred solution of hydroxyamidine 3 0 analog (150 mg, 0.19 mmol) containing triethylamine (0.13 mL., 0,95 mmol), ethyl chioroformate in 10 m.L chloroform was added dropwise at 0 0 C. The mixture was sti4rred at RT for 2h and washed with water, brine and uried over MgS04. The residue was purified on silica gel (2eth.K.- acetate: met~hylene chl'oride).* The product (:37 mc:, 7E'. yield) was isolated as ester intermediate.
-228- To the above ester intermediate, toluene was added and the solution was heated up to 1100C for 48h. The scivent was removed on rotary evaporator. Following the same hydrolysis procedure. The product(45 mg) was in 35% yield. H. P. 223-2240C (decomp.).
Example A sclutiori of blsN-m-benzaldehyde) cyclic urea Example (Tabie 2c) (120, mg, 0.21 mmol) containing small amount cf A rrl~l:sieves was treated with toluenesulfonylh-..'raz-oe cro-w: Se a:i COL under The mnxture was r :eoci a fo c :cve rr.1'.gr. The solvent waE removed or.
rc:ar: o: a:.no nri r. silica gel :4 ethylI a e a~ reh e Z o.c- ga1ve 92 ma (54*i pure r. .c r :::UrQ was s-.irred fo: v.'a twarr tco roorr .r~j C2.e2f L: T. ocrzv cy c ic ure, (4E, T (2ri) a~r (PE.
3 (77 mg, ).C a rrc wi e ur n I r o g n arnd resultant mixture wa 1o r fI x ove rn ight. work-up and 'I y oeerlproce'J::z-., followed b* :n pIaE-f wl Cft EtLoAc in CP.
2 Ci 2 gavea: s C -229- Hz, 2H), 3.18-3.03 4H), 2.96-2.88 2H), 0.90 (t, J 8.0 Hz, 2H), O 00 9H); 13C NMp (CD30D): ppm 164.91, 150.71, 143.28, 42.52, 142.43, 141.37, 141.11, 139.14, 135.08, 135.06, 134.43, 134.33, 133.13, 132.84, 132.72, 132.34, 131.96, 131.38, 131.35, 131.22, 131.03, 130.94, 130,91, 130,84, 129.79, 128.84, 128.80, 124.79, 96.36, 77.82, 73.27, 73,24, 69.49, 68.97, 68.84, 58.54, 58.32, 35.16, 34 .91, 19.94, 0.00.
Example To a s onr. cf N-SEM protected pyrazole (1.98 g., I mmclc in TH- (4 rr.L) at -78 0 C was added n-BuLi (1.6 X 7.5 12 mrrol) dropwise and the resulting solutior was stirred for ar. adaltional half hour, and then Sriisoprocvlbora-e (9.4 g, 5C mmcl) was added. After bein allowed to wrr- to roc.- temoerature over 2 hours, tne reazcor. m>ixre was acidified witr 2 N HC., S e:xt:racted with ete:ric, washed with water and brine, ana dcrzec over .:SL4. Filtration and concentration gave N- SER- 5-hxdr:r orc-ryrazcle (2.4 g, 100 as a solid.
1
H
rNM? (C>C 6 .5 1 6.8 Cs, 1H) 5.70 2H), 7 C .E Hz:, 21, C.E9 J 8.0 Hz, 2H., 0.0, r' '(DSCi pp.- 138.54, 1 5. E 5, 78.95.
(5.9E, -2.32.
To a soluticrn of m-iodobenzyl cyclic urea (932 mg, 1 mmol) in THE (5 mL) was added N-SEM-3-hydroxyboricpyrazole (968 ma, 4 mmol), Pd(FPh3) 4 (57.8 mg, 5 and Na 2
CO
3 (1.7 g in H 2 0 (4 mL) under nitrogen and the resultant mixture was allowed to reflux over 48 hours.
The organic layer was concentrated on rotary evaporatior to give a residue, which was deprotected by the general procedure, followed by purification on TLC plate with 203 EtOH ir. hexane to give Example 15YL (560 mg, 87.8%) as a solid. MS 639 100 HRMS calcd foi -230- C39H_19140O 3 639.3064, Found 639.3081; 1 14 NMR (CD30D) 6 7.76-7.69 Cm, 6H) 7,45-7.15 24H), 6.66 2H), 4 .87 12.3 .Hz, 2H1), 3.77 4H), 3.19-2.98 (m, 6H);1C 130 NM (CCD 3 0D) ppr-, 162.82, 140.19, 139.01, 129.67, 129.22, 128.96, 128.59, 127.06, 126.49, 125.03, 102.41, 71.02, 66.69, 56.37, 32.65.
Exam..e A soluzior. cf Example 15YL (200 mg) in methanol r.9 wactr: 1K cas fz seconds and the sVe.- wa< rermzvC z "ncer full vacuur tc Q:ve Exam..
l'Y a F! a so L 8,i 6 834-8.32 2Hi) 3 C 21), h5 E, 9,4', 3 Cc:, 13.9 1-i'4 J 4 1 3 9 7.N M, 4 1 7 .07, I37.
rr r_ ci'' :it yraZole zc &e 76 Sn-- TH7 (4i, e- -nK2 was added t-Bula (I1 a rc p;4 5 ar t h r e: L1 i no so c) ~K.t .r Lr.r au ticnal 30 minutes. The slulcri re tc another so,'ution of MEM-protected isurea (732 mI ol) in TH (10 mL) a The r':-_tr'ncj reaction mixtur: was allowec.
tr :r~c tr rso, etnor.'ature and was stirred overriqP.t.
tCt ronr.)Uu -231procedure and purification on reverse phase T.L.C. plate with 70% MeDH in H20 gave Example 15YN in good yield: MS: 605 100); HRMS cald for C4H39N 6 0 5 695.2983, Found 695.2967; 13r NMR (CD3OD): ppm 183.16, 164.07, 146.27, 141.34, 139.59, 137.92, 135.08, 133.06, 130.70, 130.53, 120.74, 120.57, 127.45, 71.92, 66.93, 56.72, 33.72; 1H Nl4FR (CD3OD) 68.50 8.29-8.27 Cm, 2H), 7, 61-7.21 18h), 4.94 J=14.3 Hz, 2H), 3.77-3.72 CM, 4H) 3.20-3,09 Cmr, 6H) Example 158: A sCZ-2:oo:, of ri:E-:--~ro~et co reunu *1S4 c', C0 mzml) was treater witT n-Bu at 6 for 20 rr-ri,,teE, followed by querching with N- .hzxy:)- me ylr berzylI ox ya c e t a mi de (1.35 g, 6 mmol) prepared by a reactic:, cf benzyloxyace-yl crIoride wit:.
metho:y--mer.;.a pyridire and CH2CII at rocr- ,e:eperaure. evaal cf M EV-groupz s genera.
i~f~ ~lc~ly.s r0:ed3~rE f ,,llwed by pu:rficatoon N', z r erarativ 7. rcrro ISE; 1 moivrtb~c y'IeC: NMT-:. (C0013) 6j 66 0,41Hr, 24WI 479 d, C 14, HzE i, 2Wi, 4.6 C, 2Wl, 4,57 Cd, 3 H 4 H 4 r, 14 ,HC C. E C 8 4 39 3 3 133E 9 6S8I 134 .40, 129,4, :29.4C, :28.9, 126.58, 128.4, 28.02, 127.9C, 6. -97, 126.54, 73,2E, 72.29, 71.12, 65.40, 55.82, 32.72; HPXIS: calcd. for C 5 1 Ht 1
N
2 0 7 83.3696; found 8'03.3693.
Example To a solution of SEll protected imidazole (2 g) in :7 (20 riZ) was added t-BuLi (2.7 V, 6.9 rrL) at -78 C 3I an d the mo,>xt.u-re was stirred for 20 minutes. After adzitiorn cf T"S2 (I.25 qK the resl1nc: roxture was -232allowed to warm to 0 C over 2 hours, and then cooled to agairn. The mixture was treated with t-BuLi (1.7 6.9 nL), stirred for 20 minutes, followed by addition of B(Oe)j (10.4 The reaction mixture was warmed to room temperature and stirred overnight.The reaction was poured into EtOAc/H20 and the organic layer was washed to PP 7, dried with NaSO4, and purified on column with MeOH to give pure N-SEII-5-borono-imidazole (2.3 g 95 as a solid. It' NtIt (CD30D) 87.63 J 0774 Hz, Il) 6.e7 d, J 1H), 5.47 2H), 3.55 3 4 Hz, 2H), 0,9 C 8.4 Hz, 2H), 0.00 9H); 13C 4' 5 4 7 8 6 C C, 2 0 9, C 0: Sf ,c l.m1'da-,c 1 pr epared a, ''Vf ec ted cpd X (C.9<7 q, f mrr a nd .a m.L deacsse and then w rr-' :-rEer:ture and partiti onetc~'H rHy': i layer wa!s dried over tt W if, E tr t C Ve 7, :i 2 20li ?.G-77 4. 5 i.i Ct. 07 V 7 S w tr'ateri w i{ in di3xane u Att-r the s:-2vent was removec Cor;ir f u tnee residue was purified on reverr c ~L~te, r: v t h ciesred c orr :r.i a!7 I 1 i -233- 7.10-7.08 6H) 4 .78 J 13.9 Hz, 2H), 3.71-3.65 4H) 3.32-3.00 4H), 2.96-2.87 2H); 13C NMR (CD 3 OD) 8163.80, 141.26, 139.94, 137.20, 134.78, 130.67, 130.11, 129.52, 128.88, 127.40, 127.08, 125.22, 72.00, 67.72, 57.38, 33.60; HRMS: calcd. for C3 9 H39N603: 639.3084; found 639.3089.
Example Compound 15BK in MeOH was treated with 4M HC1 in dioxane and the resulting solvents ware evaporated under full vacuum to aive the hydrochloride salt. 1H NMR (2C 30 D) 8 .C2 7 I,1 Hz, 2H), 7.87 J 1.1 Hz, 7,65-7'.3E8 m, 8H), 7,19-7.17 6f) 6.93-6.90 S 1 4H), 4.65 j 14.3 Hz, 2H), 3.78-3.72 4H), J 14.3, 2H), 3.06-3.02 2H), 2.81-2.7 (m, 2 NIM? (CD 3 0D)6 163.41, 141 11, 141.04, 135.91, 134 97, 131.95, 130.89, 130.51, 129,47, 128.16, 128.10, 743, 126.09, 116.38, 73180, 69,21, 57.87, 33.73.
Z a mQ I 159 7 2-r:ime hy l zin-N-dimethy s u l f amoy l -imidazole was 2 prepared in situ by lithiation of N-dimethylsulfamoylimidazole (1.75 g, 10 mmol) in THF (30 mL) at -78 0 C with n-BuLi (I,6M, 7.5 mL), followed by quenching with trimethyltin chloride (2,19 g, 11 mmol)), A coupling reaction of the tin reagent (1.2 g, crude) and MEMprotected compound 12J (0,8 g, 0.86 mmol) in the presence of Pd(Ph3P)4 (0.18 g, 0 16 rmol) was carried out under reflux overnight, After Lb'ing cooled to room temperature, the reaction mixture was poured into The organic layer was dried over MgSO4 and concentrated onr a rotary evaporator. The residue was dissolved in Me H, saturated with IHC (gas) at 0 C for -234minutes and then stirXted at that temperature for 1 hour.
The resulting mixture was worked up and purified on column with EtOAc to give compound 15BM as a solid(450 mg, 61 1 H N-M (CD3OD) 5 7.61-7.11. 22H), 4.86 (d, J 14.3 Hz, 2H), 3.61-3,59 4H), 3.10-2,92 6H), 2.54 6H); 1 3 C NjI4R (CD3OD) 8 163.98, 148.97, 141.21, 139.37, 132.57, 132.17, 131.55, 130.98, 130.69, 129.63, 129.50, 128.30, 127.53, 123.61, 71.92, 66.99, 56.66, 38.22, 33.74, HRIES: calcd. for C43H 49 NB07S2: 853.3166; found 852.3163.
Example 15 EI: A sclutzcr cf 4-iodopyrazole (1.54 9, 8 mnol) ir, (2C. Ws r reatei wi t h N a (4 .3 g, 10.6 mol) cuen:>.re wizh dimethylsulfainovl chloride c, t- form the N-protected pyrazole (4 .c.
s inzier. e" a 1 a, 5 mmol was reacted 12- (C,932/q, 1.0 mn.cDl) in the presence o- 2~~C ,016 iniol) uinde r re flux to f orm the r r:t7:r wh1ch was deprotecteo by general in.ymcc~ys- c-ed-re, followed by purification on ra';ese hase TLC plate with 85 NMeOH- in water to giive c~r2r~~ a solid, IJ4 NMR (CD 3 OLV) 6 7.77-Y7.'2 (mi, 4H, 1H ,mc 1 ,472 (ci, J =14,3 Hz, 2F), v, 2.02-2, 8 8 6 AC NIM4R (CD3OD) 6 3 S, 2 2 7 12, 125.47, 122.79, 71.64, 66.46, -235- MEM-protected mono-mr-bromobenzy. cyclic urea was made by general procedure for preparation of monoalkylated cyclic ureas. The monoalkyated.
intermediate (2.4 g, 3.56 rnrol) was dissolved in DMIF mL) and treated with NaH (0.43 g, 10.75 mmol), followed by addition of methyl mn-bromomnethylbenzoate (1.63 7.1 mmol) to give pure desired asyrrmetric cyclic urea (1.6 g, 55 This asymmetric urea (1.6 g, 2 mmol) was coupled with 5-borono-N-SEM-pyrazole (0.48 g, 2 mrnol) by the same procedure described for example 15BJ above to prov.-de pure coupled product, which was further decrotectei; bv general hydrolysis procedure to form *.corroound 153? c, 73.2 %for the two steps), N m, R (CD-3OD) 5 7.25-7.82 7 .66-7 .5 (in, 4H) 7.35-7.01 H) 6.56 E s 1F), 4 .7 6 S 14 .3 li z, 4 .6 9 JT 14.3 Hz, 3.77 3H), 3.72-3,58 (mn, 4H), 02- .2 2. 9 4- 2. 84 (mr, 2 H) 13 I NM- (CD 3 2. 166,79, 162.24, 139.62s. 139.59, 138.56, 132.50, 1.33.63, 13~C9,129.16, 128.78, -28.61, 184, 2,2,128.16, .0:26,59, 12 08, 124. 6V, 102,.00, 70, 50, 66. 36, 66,31, 5:95.2 32, 32 223, 3 2,125; LRNS: 632 .4 (11-1, 100 C) HRN-F; caicz-, for C38H3 9 N405: 631.2920; found ?5 621.2 916, Example To a solution o-f compound 153? (63 mg, 0.1 minol) in THE (I mL) was added LiBH4 (2H in THF, 0.3 mL) and MeOH (57.6 mg, 1.8 rnrol) and the resulting mixture was stirred at room temperature overnight. The mixture was acidified to pH 1 with 2N HC1 and extracted with EtOAc.
The organic layer was washed with H20, brine, dried over 4 and concentrated, The residue was purified on TLC plate wit-h EtO7,.t to give the desired compound (46 mg, -236- 76.3 )0 NMiR (CD30D) 5 7.78-7.60 Cm, 4 7.50-7.07 15H), 6.68 Cd, 3 2.2 Hz, 1H), 4 .90-4.81 2H), 4.66 Cbs, 2H), 3.79-3.63 4H), 3.18-3.00 Cm, 6H)); 13C NMR (CD3OD) 6163.92, 143.24, 141.32, 141.23, 139.41, 130.67, 130.17, 129.93, 129.69, 129.57, 129.53, 129.30, 129.04, 128.04, 127.45, 127.41, 127.25, 126.01, 103.33, 72.02, 71.96, 67.04, 64.97, 57.30, 57.07, 33.63, 33.57; LRtS: 603.2 CM+1, 100 RIMS: calcd. for C37H39N404: 603.291; found 603.2968.
Ic Example V\'-c2'1 erny lsuif'arnoyl-imida l zinc chloride was creparet 4n sizu ty lithiation of N-- .44 E 1 fda (zI .7 c E mmo in TH.- C 6.7 rL,, fc1-owed by quenching r.1~ raZztr: cf th zinc reagent (crude) and cod 12J (0.932 9, 1.3 mio) in the 'd P:-S CY,12 c, 2 .1 mrnrc; was carrie- cur A' zt cr.oli n: c room e r ature, ne rea:trion r:ixcure was poured into crgar. ic laver was dried over ?.gSZ ana z e. a r-iary evaczatcor. The residue was ad trEa.euj wit 4;Y HCI in dioxane 2" Ther resulrinc mixure was i:e~ I; ac pLr7.*f"Cd or, a reverse phase TLC plate witr.
7 I E it; war f zto give comtpound I5 8R as a solid. 1 S2- 0 Cm, 4 7.42-7.33 2Fi), 1214) ,00-6.94 m, 4.73 Cd, 3 14,3 S1 (bs, 4H), 3.14 Cd, J 12.9 Hz, 2H), 3,04- Z. 2.85-2.77 Cm, I WMMF (CD30D) a 2, 7, 139.5 I38, 129 3 120.1, 126.20, 125.8t, i24.3E 122.64, 70,2.
,22; HRXZ: cail.. r (2r C-o 9N E 19 -237- Ex:ample Compound 15BR was dissolved in MeOH, and treated with 4M HCI in dioxane at r.t. for I minute. The resulting mixture was concentrated in vacuo to give the solid dihydrochloride sal~t. 1 H NM?. CCD3OD) 5 7.81-7.79 Cm, 2H) 7 .73 7 .65 Cs, 4H-) 7 .61-7. 57 (in, 4H) 7, 13-7. 11 (in, 6H) 6. 86-6. 84 (in, 4H) 4 .59 3 13.9 1 C Hz, 2H) 3. 84 Cs, 21-) 3. 76 3 11 .7 Hz, 2H), 3.4 3 14.,1 Hz, 2F) 3 .06 J 12 .2 Hz, 2H) 2 2.68 Cr., 2P) 1 3 C (CD3OD) 6 1 63. 39, 145. 94, 141 .63, 240.9'4, 134. 79, 131.2E, 130, 46, 129. 44, 129. 13, 12-7.38, 127,14, 124.31, 121 .37, 71.56, 69.54, 57.82, 33.84.
Ex,,ampe lS'ET ;To compounc Th5E? (C3 mc, 0.1. minol) was added 4-C(2amlnoe :hyl)inzrpholine C0.13 a, 1 mrnol) and the resulting Z F4ix-ture was st 1-red at 110 C overniah:. The mixtuire was evaoczrated in vacuc- tc remove the excess 4-C 2a7m: noet hyl )mcrpholi3ne, and the residue was purified on L ate v;ith*- 1' Me H in EtOAc to give pure product C, mS.4 K -HN? C 3 O)68.0e4 Cs, H) 7.73- ~.6.99 Cm-, 6,50, 3 2.2 Hz, 1H) 4 .72 Cd, J 14.4 H z, 2 H) .69- 3.64 Cm, 8 H) 3. 36 Ct, 3 6. 6 Hz2, 2P) 3. 14 (31 14.2 Hz, 2H) 3. 08-2. 85 Cm, 4H 2 .54 Ct, 3 6. 6 H z, 2-H) 2. 51- 2. 45 Cm, 41H) 1 3 C NKIR (CD3OD) 6 169.84, 163.68, 141.25, 141,12, 140.09, 136.07, 133.65, 130.63, 129.87, 129.56, 129.51, 128.02, 127.44, 103.31, 71.98, 71,91, 68.26, 67.75, 58.62, 53.31, 58.45, 54.68, 37,76, 35.76, 33.69, 33.62; HRMS: calcd. for C43H4914605: 729.3764; found 729.3753.
E :amnle -238- MEM-orotected mono-m-bromobenzvl cyclic urea was made by general procedure for preparation off monoalkylated cyclic ureas. The mono cyclic urea (2.4 g 3.56 mnmol) in DKF (15 mL) was coupled with SEM-pyrazole by the same procedure used to make compound to provide pure coupled product, tEM-protected mono m- (N-SE-pyraz-5-yl) benzyl cyclic urea.
This intermediate (0.2 g, 0.25 mmol) in DMF (5 mL) was treated with NaH- (0.04 g, 1,0 minol), followed by 2C quenching with m-picolyl chloride hydrochloride (0.123 g0.75 mmol) to give desired asymmet-ric cyclic urea, which was firrther deprotected by general hydrolysis procea.re or,: compound l5BU. IF NMR (CD3OD) 8 8.51- E .4 7,63-7.63 7.48-7.03 (Cm, 13H), 6.6? 4 14.3 Pz, 1H), 143 1 6 '9 1.2 0 H 2~ 3 6, 2 2 4 9. 22 150,1.-, 2.5 1203.35, 6. 0 2 4 t -benzv2 mg,, I rnm,, ciescribed in procedure of o~ do4s-,o.7Lved in D (8 and treated with c. 4 m.nzl, GO In m-inera I oil), f ollowed bv' C E W wt I Q- nzi-,m- tcCI'rn t--r Ie 3 92 g, 2 .0 nmol1 e z dv aZ ed ayn trc cyclic urea, which was f z -e.r c 'rct ected by general hydrolysis procedure to If C~n 35B' :7 :7F (C D 7.9 Q- 7. 07 (mn, 191H), 3 9 4 6- 4 -239- 129.82, 129.71, 128.16, 127.66, 119.67, 113.62, 103.40, 71.92, 71.87, 68.67, 57.14, 33.79, 33.62; HRMS: calcd.
for C37H36N50 3 598.2818; found 598.2813.
Example To a solution of compound 15BV (50 mg, 0.084 mrnmol) in pyridine (3 mL) was added hydroxylamine hydrochloride (36 nmg, 5.2 mmol) and the resulting mixture was refluxed 0 overniahz. After being cooled to room temperature, the uixture was evaporated in vacuo to remove pyridine. The resultina residue was worked up and purified on TLC plaze with EtOAr to give pure amidoxime (32 mg, 60.6 1 NVR (CD3D) 6 7.96-7.05 19H), 6.59 J 2.2 Hz, -i 4.78 j 14.3 Hz, 1H) 4.75 J 14.3 Hz, 3.70-3.59 4H), 3.11-3.03 4H), 2.96-2.88 (m, U- 2M (c30Z)6 163.E2, 142.25, 241.14, 140.02, 134.52, 134.0:, 131.6, 130.62, 130.16, 129.93, 12. C, :29.5e, 129.54, 128,04, 127.44, 126,01, 103,32, 9 7, 6. ES, t 5E, 5 3.67, 33.56, a ono-mr- (-SE-p5yra-5-yl) -benzyl cyclic urea S pepared above in procdure of Example 15BU was l deprozected by general hyrdrolysis procedure to give compound XS618. 'H NMR (CD30D) 6 7.67-7.05 6.56 J 4.0 Hz, 1I), 4.80 J 14.7 Hz, 1H), 3.86-3.82 1H), 3.71-3.62 (mn, 21H), 3.51-3.48 1H), 0 3.18-2.99 4H), 2.80-2.72 1H); 13 C NMR (CD30D) 6 163.90, 141.47, 140.89, 130.63, 130.49, 130.09, 130.01, 129.64, 129.49, 129.27, 127.52, 127.25, 125,85, 103.33, 72.99, 72.55, 66.50, 66.47, 55.27, 35.13, 34.32; HP.MS: calcd. for C2 9 H31N403: 483.200; found 483.2401.
7xT.Lne MEMI-protected mono m- (-SEM-pyraz-5-Yl) benzyl cyclic urea described above (220 mg, 0.28 mmol) was dissolved in (3 mL) and treated with NaH (0.045 g, 1.12 mmol, 60% in mineral oil), followed by quenching with p-benzyloxybenzyl chloride (0.13 g, 0.56 mmol) to give the desired asymmetric cyclic urea, which was deprotected by general hydrolysis procedure to give compound 15BY. 1 H NK4R (CD3QD) 87.68-6,91 24H), 6.58 j 2.2 Hz, IH), 5.02 2 4.78 Cd, J 13.9 Hz, 1H), 4.66 Cd, J 13.9 Hz, lH), 3.67-3.54 (in, 411), 3.08- 2.8E (rn, 6C-) ;NIMI (CD30D) 6 163.88, 159.84, 141.29, 6, 31.23,~ 58, 130.69, 130.64, 130.15, 129.56, 2210.4--, 129.46, -2E.82, 128,50, 128.02, 127.46, 127.37, .32, 72.06, 72.02, 66.8:, 56.45, S33,8% 236; .U'P Calcd, fcr C43H421.Z410: 6779.3284; :284 as added 3- (aT.lra~r~-t.x)p' ((.077 0.71 mmol) and the rs r t overnioht The r r w, eva-z!rrazed in vacuo to remove the excess 3d ne The residue was purified on T-" e.r. wz:. 15i4eH in EtOAc to cive pure product (37 73 E (CD-3OD) 57.e0-6,95 23 6.59 J C 1 4 4.77-4. 72 (rr lH), 4.68 3 1,31.z, 1K 4 ,g 3 2.2 Hz, 214), 3.66-3.64 Cm, 4E 3 1 3 24.3 Hz, 1H) 3.06-2.82 (in, 5H); 130 WG: C5033 170.09, 163.83, 152.96, 149.63, 141.32, 23 12 3Z), :37 .40, 136.94, 135. 8, 134.0 4, 130.71, 129,75, 129,66, 128.:2, 227,67, 127.54, 2" 1 9 C F -241- Example Hydrogenation of compound 15BY in MeOH in the presence of catalytic amount of 10% Pd/C produced the hydroxymethyl compound in good yield. 1 H NMPR (CD30D) 6 7.68-7.58 3H), 7.39-7.05 12H), 6.98 J 8.4 Hz, 2H), 6.73 J 8.4 Hz, 2H), 6.58 J 2.2 Hz, IH), 4.78 J 14.3 Hz, 1H), 4.66 J 13.9 Hz, 1H) 3.68-3.50 4H), 3.08-2.83 6H) 1 3C NMR (CD30D)6 163.94,, 8.15, 141.31, 140.11, 131.73, 130.69, 130.65, 130.16, 129.96, 129.56, 129.48, 128.04, 127.46, 127.25, 125.98, 116.39, 103.32, 72.10, 72.02, 66.42, 57.22, 56.37, 33.56; HRM:S: calcd. for C36H 3 714 4 5E9.2815; found 589.2811.
en.0 Example Ic comrcound (44 mg, 0.07 rrjmi) was added 2- (a 1;r: id ne (C 077 C.7 m-,ol) and the 2 2 res lir mixture wa-- s:irred a110 C overniqht, The mi:ure was evaoorated ir vacuo to remove the excess 2- (a.inomethyl)pyridine. The residue was purified on a TLC lare wth 2C% MeOH in EtOAc to give pure product mig 71 H NMR (C 3 0D) 6 8,45 J 4.8 Hz, 1H), 7.80-6.98 (rr, 22H), 6.58 J 1.5 Hz, 1H), 4.77 J 14.3 Hz, 1H), 4.71 J 14.3 Hz, 1H), 4.66 J 4.8 Hz, 2H), 3.68-3.65 4H), 3.17-2.82 6H); 13
C
NER (CD3OD) 5 169.99, 163.i71, 159.28, 149.75, 141.25, 141.14, 140.17, 139.98, 138.80, 135.79, 133.94, 130,63, 130.18, 129.96, 129.92, 129.57, 128.03, 127.64, 127.45, 126,03, 123.72, 122.76, 103.32, 71.99, 71.92, 68.32, 67.72, 57.50, 57.30, 45.92, 33.69, 33.65; HRMS: calcd.
for C43H43N604: 707.3346, found 707.3344.
Examole -242lHI-protected mono i- (N-SEM-pyraz--5-yl) benzycvclic urea (200 mg, 0.254 miol) was dissolved in DI-T mL) and treated with NaH (0.041 g, 1.02 mnol, 60% in mineral oil), followed by quenchi.-g with m,pdibenzyloxybenzyl chloride (0.172 g, 0.51 mmol) to give the desired asymmetric cyclic urea. After deprotection by general hydrolysis procedure, the urea was hydrogenated to give the dihydroxy compound. 1 H Nt4R (CD3OD) a 7.83-7.07 15H), 6.81-6.71 3H), 6.53 iC 1H), 4.86 J 13.9 Hz, 1H), 4.72 3 13.6 Hz, 1H), 3,80-3.66 (in, 4H), 3.19-2.82 6H) 13 C Nl4R (C E4.2rC, 1, 9.97, 146.56, 146,12, 142.43, 133.55, 13C.82, 130.71, 130.67, 33.2 3.64, 29.53, 126.23, 127.51, 127.42, 126.14, If LI-44, 1:635,?C35~, 72,23, '72.01, 67 77, 3>4S; H7.MS: calcd. for o 5" 2 51E~ 5 s 1E. .7 e I E z r E(56" ma., ,71 was dissolved in DIMF (C r. r e a z e d w t:h Na HL (0 .114 cl, 2, 8 4 mino 6 0 1 r ,E fslloed by quenching of m-nitrobenzy: -:IG c, e~3mmal to give desired asymmnetric deprotection byl general de-KE1,1 r o C d ureai~r~~e7t was puified on TLC plate with EtOAc ,o ryt~i 17 r c. z u ct 8GS3OD .11-8,06 (m, (r,13H) 7.06-6.95 4H), 6,59 J (dj J 13. 9 HzZ 1H) 4 .61 J3 ,cZ 3.78-3.56 4H), 3.15-2.79 6H); 13C 1 63 7 1 49, 67, 16 5 1 1 12 14 0. 97 13'-.72, 230.53, 130.2.1, 129.93, 129.73, 129.57, 12-* .4 126.07, '125. 1, 123. !03.-3 ml, 07 )HR1w: d ialcd r-.fter u n ry, e-4E -243- Example Hydrogenation of compound 15CD (210 mg, o.34 mmol) in MeOP (5 mL) and IN HCl (1 mL) in the presence of Pd/C was carried out at roor. temperature overnight. The catalyst was removed by filtration, and the filtrate was concentrated. The residue was purified on TLC plate with EtOAc to aive the amino compound (140 mg, 61 1H NMR Ic (CD3OD) 568,31 IH) 7.81-6.88 (in, 19H), 4.60 J 13. 6 Hz, 2H), 3l. 80-3 .57 4H-) 3.16-2 .68 (in, 6H) 13
C
lsKlR- (C-D-,OD)6 163.99, 249.C9, 141.328, 141.23, 140.01, 13.-73, 2370-.65, 13C.35, 13t-.15, 129. 93, 129.55, 129.46, 12E.04, -27.42, 1*27.35, 22-S.97, 120.06, 117.33, 115.81, 03.,32, 7 2. 11, 1. 9 9, 6 6. 39, 57, 28, 5 6. 97, 33. 66, 33. 53; HPd.:S ca lcd., f Or C3 6H3 81,C 588. 297 5; f ound 5 82.2 983.
E xample ISOT 2 124!-prot.ected mcnc rrn- f1N-SEX.-pyra z- S-y) -benzyl cxzcurez: (240 mc, 0.3( mnol) was d--sso~ved in DK7 (f: and treated w-:Y.Na- (C.049 9, 2 .2 60 in mlnera.' ol), fc-'lowed by addition of rn-cyano-p- 4'uorobe~z%-l broide (0.32 g, C,6 inmol) to give desired asymmetric cyclic urea. After deprotection by general hydrolysis procedure, the urea was purified on TLC plate wit-h EtOAc to give pure compound 15CF (72 mg, F1 1111R (CD3OD) 567. 66- 6, 86 (in, 18H) 6.,57 J 0. 07 Hz, 1h) 4 .7 2 j 14.1I H z, I H 4 .3"6 3 13,.8 H z, 1 H) 3. 82 -3 55 (in, 4 H) 3,.16 2,6 9 6H) HRNIS: calcd.
for C37H3 5 14503F: 616.2713; found 616.2710, Example A solution of compound 15BX in MeOH was treated with 4X 1HICl In dic-xane, and the resulting solution was -244evaporated to dryness in vacuo to give the hydrochloride salt. IF NIKM (CD30D) 58.31 J 2.6 Hz, 1H), 7.72- 7.06 (rr, 15H), 4.68 J 15 Hz, 1H), 3.83-3.;5 (m, 3H), 3.73-3.60 1H), 3.59-3.41 1H), 3.23-3.03 (m, 3H), 2.69-2.65 13C NM-R (CD30D) 6263.52, 148.75, 141.25, 140.30, 136.47. 132.50, 130.88, 130.49, 130.35, 129.62, 129.46, 128.,32, 127.53, 127.35, 127.04, 106.27, 73.14, 72.49, 67.06,7'58 97, 55.16, 35,61, 34.93.
Example A sol-:ion cf the compound of Example 9P (0.11 g, C..2 mmn.c' a: d hv-,o>:ylamie hydrochloride (C.014 ma, 0.2 (2rr L) was refluxed overricjtL., Workup .H .iCr. uslnc }PLC wi-~ a solvent gradient froh a 7.e to l00 of EtO Fprovide' compound (C3E; 6.E-7,86 C, iN6)( 7.82 'Fj 7 4 0 5z, 4 7. 1 5H) 4 z, 7, (C J 14 2 Pz, I H) 4 3 4 J ~2 liz, I 3 0 b 9 r l2 (CD3DZ)) 200.03, 14 19,, 14 1 4. 1111G, 7.40C, 139.0, r 2 =13-U. G2, 130,59, 13,.48, 130.07, 5 1.2E 73 28.11, 127.5-, 126. C E, 67.24, 575, 57.09, 33.C5, 26.72, A. fo 37H4(J~5i 606,2966; found L x a:7 :5C3 t-r c. s~c-~-lurobtiylcyclic urea was prep red L z: cr. e I lkv.aticn and cerotection procedures.
4 C, nnz'l 7rt 9Xi:: r. L) wa s tretE -3 m 5nun undj: re flu>; for 3 .Ltl:, pl~leitt~liL P 1 a t e w:
-I
-245- EtOAc in CH2C12, followed by further purification on HPLC with 85% hexane in EtOH gave compound 15CI (40 ma) and compound 15CJ (80 mg).
Example 15CI: 1 H N14R (CDC13) 67.64 (dd, S Hz, J 2.2 Hz, 2H), 7.40-7.00 14H), 4.72 (dd, 14.6 Hz, 2H), 3.75 2W), 3.55 J 11.4 Hz, 2H), 3.22 J 14.6 Hz, 2H), 3.08 (dd, J 13.6 Hz, J 2.6 Hz, 2H), 2.83 (dd, J 13.2 Hz, J 11.0 Hz, 2H), 2.59 J 4.8 Hz, 6H), 2.51 2H); 1 3 C NtIR (CDC13) 6196.31 3 3.1 Hz), 161.71, 161.46 J 255.6 Hz), 139.39, 135,78 3 9.2 Hz), 134,74, 130.82 (d, 3 2.3 Hz), 129.31, 128.60, 126,48, 125.38 J 13,0 Hzt, 116.97 J 14.4 Hz), 70.89, 65.58, 55.08, S 32.78, 31.26 J 7.6 Hz); HRM4S: calcd, for S C ?H37N20572: 627.2671; found 62.2670.
Example 15Cj: tH NMR (CDC13) 7.74 (dd, 3 Hz, J 2.2 Hz, 2H), 7.57-7.CO 14H), 4.80 J t Hz, 4.62 14,3 Hz, 1H), 3.90 (bs, 2H), 3.71-3,61 2H), 3.53 3 14,6 Hz, 1H), 3.29 J 4. HZ, 1H) 3,25-3.17 im, 4F), 2.93-2.82 2H), 2.68 3E), 2.66 3H)W 13C NMtl (CDC'3) 6196.48 (d, 2.3 162.37 Cd, 259.4 Hz), 161,75, 161>58 to C, 2 2-55.6 Hz), 13., 391 1, 236.02 Cd, T 8,4 H 135.85 d, 8.4 Hz), 135.34 3 3.8 Hz), :34.62 J 3,0 Hz), 134,31, 130.76, 129,24, 128.68, 12.62, 126.63, 126.59, 125.42 J 13.0 Hz), 117.03 J 14.4 Hz), 116,41 3 19.9 Hz), 113,67, 101 2F J 15.3 Hz), 70.85, 65.96, 65.75, 55.09, 54.95, 32.96, 32,79, 31,25 J =6.9 Hz); HRP2S: calcd, for C 3 6
H
3 4N304F2; 610.2517; found 610.2534.
Example 1SCK In the synthesis of compound 9Q, compound 15CK was a minor stereoisomer and was isolated on HPLC with hexane in EtoH, 1 NM. (CD30JD) 5 7.55-7.53 2H), 7.48 11331 1 -246- Cs, 2H), 7.33-7.24 Cm, IOH), 7.10-7.07 4.75 (d, 3 14.6 Hz, 21), 3.61-3.58 4H), 3.08-3.04 211), 2.99 Cd, J =14. 3 Hz, 2H), 2.96-2.90 Cm, 2H), 2.17 (s, 6H) )3C NMIR (CD3OD) 5 163.94, 155.44, 141.22, 139.43, 138. 96, 130.76, 130. 63, 129 68, 129.56, 128.09, 127.46, 126.30, 72.00, 67.09, 57.03, 33.59, 11.97; ERMS: calcd.
for C37H44O05: 623.3077. found 620.3091.
Example By the same procedure used to make Example 9Q cori; d 15-L was obtained from compound 15CI in good D 0- 'C73 .31-7.02 Crr, 161-i), 4.63 3 1 32-3.66 Cm, 45), 3.09-2.99 4H), 2 3 2 hz, 6H); 1 3 C N t-I i- 2 Cd, j i 46.? Hz), 1S3.70, 4 38 Hz), 132.67? 3 8,4 Hz), ,136 6, 129. 9, 127,49, 1-7.13 Hz), 7 3 2.9 Hz), 71.90, 67,41, ?.46 C(t, 4 4.6 Hz'; HRX: calcd, f:: se e 2 1 .6 H 6 C 4 H H a 9 0 .6 Cr, 1W, .66 Cd, 3 14.2 Hz, 64 R 2 14.1 Hz, 21-2 3.64-3. 14 Cm, 4 3.09-2.83 JC,. 'C N (Cc30:) c 3r :J j 248, Fiz), 16.08 J 250.3 I "C1.6,26:.f, 14: .22, 14116, 13c,44, 133.40 (d, 1 3 132. C 8 .4 3, 32. ,231,98 (d, V 13.Cl 29. 63, 12".19 ~2?14 Cd, -12 :12.77 r J- 3.77 lz), 17.43 (Cd, 3 22,9 Hz), 2 ,ii.84Z, p7,4~ -247- 56. 98, 33 74, 33. 1411.78 J 5.,3 Hz); HRES: calcd. fOr C36H38N505F2: 658,2841; found 658.283r,.
Example To a stirred solution of 3.66 g(10 mmol) of compound XXVII~f in 15 mL of DtMT and 7 mL of THF, cooled to 0O-C, was added 1.2 g(40 mrnol) oi- n dispersion of sodium hydride in mineral oil. The ixture was stirred 5 min., and .66 g(40 mrnol) of 3-furylmethylchloride was added, The mixture was war-med to ambient temperature over 3.0 m. and then. recooled to 000. The reaction was ouenched by the addition of 0.4 N HCl, and the resulting n.i::ure was extracted with Et 2 C, The organic extract D was washed with sa:'d aq. NaHC10 3 then brine, dried (aS0 4 and concentrated under reduced pressure to ffcrd 4 .02 o of a lk-ylated intermediat-e. 1 H N t4F, C13) 7. 7,i- 7. 42 7 V) 6. 32 1H) 4.72 Ili) To 0.20 9(0,3E mw2r, of acetonide protected bis(N- L;rylmethyl cyclic urea above was added 8 mL of MeOH 2 of con-c. aq. HC: The solton was stirred I h aar-t--ent temperatzure a.nd poured into water. The white cc! cooidal sispension was extracted with I :1 Et 2 O-EtOAc, an-- the organic ext:"rac-t was washed with sat'd aq.
Nax-2O3, brine, dried (MqSQ 4 and concentrated under reduced pressure to afford an off-white solid, This material was dissolved in 7 raL of EtOAc and warmed to 0 boiling. Hexane, 20 ji.L, was introduced, and the sojution was concentrated to -6 ML. The product was triturated with 3 mL of hexanes ard allowed to cool, Solvent was removed by, pipette, and the white cryStalline solid was washed with 9:1l hexanes-EtOAc.
The diol l5FN, following, removal of residual solvent at -24 6vacuum pump pressure, weighed 111mg (60% of zheoretical) Example 15F'0 To 0.22 rnh (2.3 rnrol) of stirred, cooled POC13 was dded 0.20 mb 25 ml of DtM'. The solution was stirred 5 min., and a solution of 530 mg (1.0 mmol) of acetonide protected bi's(tN-3-furylmethyl)cyclic urea, described in example 15FN above, in 0. 3 rnLL of THF and C .5 rnL of D14F was introduced. The solution was warmed 0 armbient temperature with stirring over 25 min., w'nereupon an additional 0.10 mL of POC1 3 was introduced.
reation was heat~ed to ref~lux for 30 min. cooled, 0a.- a: e r The resulting colloidal solid S~ cz i Et 2 3-Et Okc, an d t he. or ga n ic 00r: a sat' q aC 3 water, then, ~zne. c (:XzS-ct) ,and concent ration under reduced ~suz a::-zred a hrown o)l, Ch1romatography on silica 7 7 -c 3 2 hexanes-ELOAc' a: :te r cf rr,onoidehvo%,e intermediate as ar, ~9,41 l1H, CH0) 7.52 11i, 7 7~'4 T,'-T3S, 12 11, a ryl) 6. 59 (s I1H, f u ryl1 z, tryU;~.8Od, E, J 14,6 Hz, one of Cil:2 2 2 .68-302 (mn, 5E, one 2~,4x.RH 3F, C;R 3 42 31i, CH3) a E rred sol."ion of4 100 mg 18 mrnol) of t he d *nyr Ar.:ermediate in 10 mL of MeOH and 1 ml, of 2 wat e r w.tr adu itd 0,5 mL of conc. aq, HC1, The solution waa t~red cr 1Inh at ambient terperature, poured into n~ trat~dwith 1:1 EZ 2 O-EtOAc, The organic tx-:ract was w.-shed witlh brine, dried (MgSOj), and tra'~. ':n'~zred2.,cd pressurve i-o afforo dic" an CC~~ 5 9.43(:t, 114i); 1P.); -249- J 2.5 Hz) 4 .64 1H, J 15 Hz) 3 .55-3,78 2. 62-3. 14 8H) Example To a stirred solution of 530 mg (1.00 mmol) of acetonide protected bis(N-3-furylmethyl cyclic urea, described in example 15FN above, in 8 ml, of Ti-F, coolec-.
to -78 0 C, was added 1 .6 mL (2 .5 mmol) of a 1. 6 M D solution of n-BuLi in THE. The solution was stirred min. at- -78 CC, and DI4F was added. The reaction was stirred Ih -78 0 C, whereupon it was cuenched with 1N HiC I, The mxrewas extracted with Et 2 0, and the or-can~c ex:tract was washed with brine, dried Ut-I9SO4) and concentrated under reduced pressure. Chromatography on 'Iica gel (elut.ion with 1:1 Et-OAc-hexanes) afforded, :after reimoval o-f solver.:, 310 mc of dialdehyde n-ermrecfa,:e as an ol. H NEMR (CDCl 3 5 9. 42 PH); .52 J 2 Hz:Y; 7. 2G-7. 36 5H) 6,.58(d, lIH, J 2H) 4 4.1 E (A:3 2F, 13 Hz-, 6v =330 Hz) 4 .00(br.
sP; J I Hz); 2,84(ABx, 2H, JA_ 3.
z, jl> Hz, JB>: 3 Hz, 6v 7 8 H 1.45(s, **Tc a s:-irrec, cooled (-78 0 C) solution of 120 mg (0,,21 mmcl:) of the di4aldehyde intermediate in 4 .71 of :9Et 2 C was added 2 (2 mmol) of I M diisobutylaluminum hydride in CN 2 Cl 2 The solution was stirred 15 mmn at -78 C, the dry ice bath was removed, and the reaction was quenched with saturated aqueous sodium potassium tartrate. The mixtur-e was diluted with Et; ind the two phases were stirred together for 30 mmn. fhe phases were separated, and the organic phase was dried (MgSO 4 concentrated, and chromatographed on silica gel. The product was eluted with EtOAc, concentrated, and redissolved in 8 rnL of MeOH. This solution was treated wih0,4 r.mL of: con. aq. HCl, stirred lh, and poured into -2 water. The colloidal suspension was extracted with EtOAc, and the organic extract was washed with brine, dried (MgSO 4 and concentrated under reduced pressure.
Chromatography on- silica gel (elution W4 th EtOAc) afforded a glass which was lyophilized from benzeneacetonitrile to give 62 mng of tetraol 15F'P as a powder. 1 H NI4R (CD 3 OD) 8 7.43 1H, J 2 Hz) 7 7.37(m, 3H); 7.11 (dd, 2H, J3 8.1, 1.1 Hz); 6.37(d, lH, J= 2 4 .2 2(ABq, 2 H, Jp 13 .3 Hz2, 6V= 3 3 H z) 3. 76 (Aq, 2H, 3 14 .6 H z, Av' 1 60 H z) 3. 65 (br. s, 1H); 3 .56 (br, d, 1H, 3 11 Hz) 2. 98 (ABx., 2H, Jt_ 13.3 Hz-, JAX 1. HzP, 3p' 12 .1 Hz, Av 54 Hz). Mass Oqr,(H 3 -Cl 'DDI) 52091(Ij+H-H 2 0) 4 100%).
of EEmam lo ir e j ineme-C-. rpa!- I an; c' a ddd3 m 05 uo *h *6ut o, a i~ernc~.t pl' repre 3n examplr xe 15FQ ins a ae was acoe rs mg MasSu.-(!H-I/) 7* C. a 1 7, ernr3H)6.47r, poured 6 int wat, Ea:e w3r 5rre 5-ie 3, SO 1 H ,a2n2d cocnrtd, under rs:,Iuces r z ford 33 5 mg of orneI :t fas Epc 0H-I~1P) add *C an -251rewarmed to ambient temperature with stirring over 6h.
The reaction was quenched with 10% aq. HOAc, stirred for min., and extracted with EtOAc. The organic extract was washed with brine, dried (MgS04), and concentrated under reduced pressure. Chromatography on silica gel (elution with EtOAc) followed by lyophilization afforded mg of triol 15FR as a white powder. 1 H NMR (CDC13) 6 7.05-7.38(m, 11H); 6.85(s, 1H); 6.82(s, 1H); 6.30(s, 2H); 4.51-4.61(m, 2H); 4.31(d, 1H, J 13 Hz); 0 3.93(dd, J 14, 5 Hz); 3.65-3.77(m, 2H) 3.51-3.60(m, 1H); 2.74-3.12(m, 6H). Mass Spec (NH 3
-CI/DDIP)
517 NH 4 -H20; 499( (M+H-H 2 0) 100%).
Examle 15FS and A flask was charged with lithium chloride (1.02 g, 24.0 nmD.-l, 1.2 eauiv.) and flame dried in vacuo. A S nitroaer. atmosphere was introduced and dry dimethyforma=ide (12,0 nm) was added. The flask was c cooled tc 0 C and the starting alcohol, 2-furylmethano'.
.7 r i, 20.C mrmol) was added via syringe. The reagents, 2, 6-lutidne (3.5 ml, 30 0 mmol, 1.5 equiv., distilled from. calcum. hydride) and methanesulfonyl chloride (1.7 Sr.- 22 L:,i 1.1 equiv.), were added and stirring continued for one hour. The reaction was poured onto ice and extracted with ether, The ethereal layer was washed with a saturated aqueous solution of sodium carbonate, whereupon a precipitate formed. The precipitate was removed by filtration and the layers separated. The organic layer was dried with anhydrous sodium carbonate, The product was isolated by filtration and removal of solvent on an ice cooled rotary evaporator. When the volume neared 20 ml, the flask was removed from the rotary evaporator, flushed with nitrogen and diluted with dry dimethylformamide (20.0 ml). This solution 1' -252containing 2-chloromethylfuran was used without characterization in the next reaction.
The cyclic urea acetonide XXVIIIf (1.02 g. 2.79 rmol) was added to the solution of 2-chioromethylfuran.
Sodium hydride (490 mg, 16.3 minol, 5.9 equiv., 80% oil dispersion) was added and stirring continued for one hour. The reaction was then quenched by the addition of water and extracted with ethyl acetate-hexanes (1 :1) The organic phase was washed twice with water, once with brine, and dried over anhydrous magnesium sulfate.
Filtration and evaporation gave the crude product which was o',-r-fied bv flash- column chromatography ethyl aceza:e-7G4 hexanes) The ccXum.'- provided two ma jor raz.crs:a non-pciar fraction containing the Can".: I czF,-am-.nazed product and a **tar rac:_.o. ccn-.a in r acequate 1 pure mono- a lkylat ed c ure& Intermediate 3 4 3 m r aH-NIR (300 1Hz, 4i .8 3(21-: 4.22 dd) 3 .88 (2P, in), 2 .7 I t 8 4 Caruaze -rcr C 27
H
31 N2C 4 264, ohserved 447.2277. The nonpolar fr~rt?.was, "furthe.r purified by -!lash column ~rar:; (15 ezhyl acetate 851. hexanes) to give bs-a...2.aedintermediate mc, IH 1 *7 .iz C.2' C" 0(IIB 62 7 (2H, dd), E(2, ,4 .94 2 d) 90 (2 E, s) 3 .8 2 (2H, b), F 6. e, i 5l.93, 142. 9, 138 86, 12 9.4 1 2I,2,_.46 110. 21, 108. 71, 75. 26, 62 .4 9, 48 32 E7 m,7. (14(H CI) m/e 527 (M+fi) -,n)akylated cyclic urea acetonide above (33.
.C7 rrzt1i was dissolved in rn'ethano-. (3,0 ml) :r:ca :oI monohydrate f2.9 inc 1 was adde an'4 tiued for four icur. Tt reactvor -253carbonate. The solvent was removed on a rotary evaporator and the residue appl~ied to a flash silica gel column. The column was Auted with initially 50% ethyl hexanes and finally 100% ethyl acetate. This provided 15FS (27.8 mg, 91%) in, excellent yield. IH-NMR (300 M4Hz, CD 3 OD) 6 7.43(1K, 7.34-7.12(10H, in), 6.31(1K, mn), 6.10(1K, 4.75(1H, 3.86(1K 1 dd), 3.65 (2 H, mn), 3. 3 9 in), 3. 11(2KH, in), 3. 0 1 di) 2.88(1H, 2,77(1K, dd) 13 C NI4R (75.4 MJ-z, CD3OD) 162.17, 151.45, 142.30, 139.79, 139.74, 129.10, 129.06, 128.08, 127.91, 125.96, 125.64, 109.80, 108.15, 70,90, 70.53, 65.28, 58,73, 32.70, 31.94. HRMS(NH3 CI) Calculated for C20K27N204 407,1971; Observed 4G7.161.
The bisalkylated acetonide was deprotected usi.ng the same procedure, Flash silica gel chromatography using 50%i ethyl acetate-505,% hexarnes gave 15FT in 83% yield. lli-NMIR (400 IiCD30D) 8 7 .44 (2H, dd) 7232- 7 7,13 (1I0K mt, 6. 33(2, cid), 6,15 (2KH, di), 4.75(2 H, d), 3,6(K d,36(K s) 3. 05-2. 8 9(6H, m)6 60(21C NIIR (CV',6MC CD3OD) 6 1163.11, 153.01, 143.93, 130.63, 129.47, -127 E, 111.316, 110,01, 71.75, 67.24, 48.88, -22.99. XR!d'S(N.H3 CI) Calculated for C29K3lN2OS (M+H) 4P-7-2233; Observed: 4B7.2226.
Examj-.e The starting 3-carbomethoxy-2, was prepared f rom 1,f 4 -dithiane-2, trimethylphosphonoac-rylate and triethylamine as described in the literature Org. Chem. 43 (23) 4431 (1978)). The resulting ester (1.03 g, 7,15 mrnol) was dissolved in dry methylene chloride (16.0 mrl) and cooled to 7 8 0 C under a nitrogen atmosphere. A solution of dukisobutzylaluminum hydride (11,9 ml, 17.88 mxnol, equiv., 2.5 M in toluene) was added and stirring -254continued for two hours. The reaction was then briefly warmed to room temperature then recooled to -78 C.
Ex:cess reagent was then quenched with methanol (5.0 nil) and the reaction was allowed to warm to room temperature. The reaction was diluted with ether and treated with a saturated solution of sodium potassium tartrate. The clarified aqueous phase was extracted with two additional portions of ether. The combined organic layers were dried with magnesium sulfate, filtered and evaporated. Purification was accomplished by flash silica gel chromatography methanol 95% methylene chlor-ide),. The resulting 3-hydroxymethyl-2,5c- nycrot-hiophe:,e was isol.ated in 91% yield (753.7 mg) (00Y-i~ CC~3 S5.77(114, bs), 4,22(2H, d), N H R. 7 0NM 754 M}.Hz CDCI3) 2~ E 38.4$ 38. Z. MS(CH 4 CI) m/e 117 a7h acchol (663. C g, 5. 72 mmzci) was diF>> 9d in u~:'.K~.ecrhoridF. (20 ml) under a nitrog ~;zcnr~.r;:r!Cetrxlam'ine m, 8,.57 n ci: c .oled to G. C.
Vde (1 .2 g, C. 8 mmcl, 1.2 equ.4v.) a:.was reacti:on continued for 0.5 hours. The r~ o~tezw~nmethylene chloride and washed -c '.~.r-hori-c acid and brine. Drying over eee f i-ratio and evapcration gave the cr. ne s' wasz used without purification.
L-rcs-u waa dissolved in dry dimethylformamide ne ci clic urea acetonide XXVIIIf (524.5 r, was added. Sodium hydride (172 mg, 5.72 rr: 4 e civ. 80% oil dispersion) was added and zt:2~7;cz:-_'ued overnight. The reaction was quenched tecaref~. adedition of water and extracted with hex~arne The organi-c phase was washeo- ,onrewithbir,-, and dried over I on a r rt ao oa." C L") -255crude product which was purified by flash silica gel chromatography (15% ethyl acetate-85% hexanes) The desired bisalkylated product was obtained in excellent yield (720.1 mg, 90%) 1 H-NMR (300Mliz, CDCl 3 7.29(6H, mn) 7.14 (4H, 5.40(211, s) 4.32(2H, d), 4.06(2H, 3.83(2H, d) 3.78-3.49(8H, in), 3.06(2H, dd) 2.87 (2H, d) 2 .83 (2H, dd) 1. 31 (6H, s) HRMS(NH-3 CI) Calculated for C32H-39N20 3
S
2 563.2402; Observed: 563.2394, 0 Removal of the acetonide protecting group using the hydrolysis procedure described in the procedure of exampr,-le 15FS gave compound 15FU. (34.1 mg, 1 H-NI4R (UMIU, CEC3) 6 7,36-7.11(10H-, m) 5.45(2H, bs), 4 .2 (2h, d) 3 ,93 (214., bs) 3. 82-3. 49 (10H, mn), 3. 16(2H, dd/ 2.,87 dd) 2. 64 a) 2. 62 (2h, bs) 13
C-NMP.
(7 E 43 KH~q., CDC! 3) 5 162,14, 139. 66, 1391,10, 129. 36, 12E,66, 126.5:, 126.70, 71.61, 631.01, 50.907, 390.70, 32,9, 1-iR.:S( Calculatedi for C29IH3 5 N203S2 152--,2069; Oserved: 523.201.
Compound 15.7U, protected as the acetonide, (53.2 mg, 0.09071ml was dissolved in dry methylene chloride ri-) under- a nirgnatmosphere The reaction was coded to 0c C and solid m-chloroperoxybenzoic acid (82.-7 mg, 0,388 mrol, 4.1 equiv. circa 80% active) was added and stirring continued for three hours with gradual warming to room temperature The reaction was then. diluted with methylene chloride and washed successively with saturated 5odium bisulfite, saturated sodium carbonate, and brine, The organic phase was dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash silica gel chr-omatoarap*hy ethyl acetate-50% hexanes) to give the bis-sulfone aceton'ide (61.5 mg,. slightly more t tan thecretical). T*hiS- material was of sufficient purity for -256the subseauent transformations. 1 N-NMR (300 14Hz, CDC13) 57.39-6.95(10H, i) 5.60(2H, bs), 4.22(2H, 4.06(2H, 3.83-3,47(10Y, m) 3.13(2H, 2.99(2H, d), 2.73(2H, dd) 1.31(6H, MS(NH3 CI) m/e 563(M+H-S02), 4 99 -2S 02) Removal of the acetonide protecting group using the hydrolysis procedure described in the procedure of example 15FS gave compound 15FV (17.4 mg, 1
H-NMR
MHz, CDCl 3 5 7.28(6H, 7.11(4H, 5.57(2H, bs), 4.16(2H, 3.92(2H, 3.83-3.45(10H-, i), 3.23(2M, 2.92(2F, 2.74(2H, 13 C-N1MR (100.6 M-z, CDC3) 5 161.99, 139.00, 135.52, 129.32, 128.84, -27,34, -23.2E, 71.-04, 63.84, 56.53, 53.07, 33.14.
E(cler- )Calculazed for C 2 9 H35N207S2 OtS=_ ve: 51,7.1829, ow'i 25TUC, 5 :o ected as the ;Ptnide, (46.6 .27 w s 1 ve d- Cry dr dI c-dic lor oeth Pn e _2 33 -rL CL (n.e 4 rng, .182 2.2 equiv.) res:ec ar, i-.saraneous conversion to product. The a:7- r. w~ ap pied to a f lash silica gel column and w mersz inetnylene chloride then 5' methanolie- c'l' r dV. The desired b s-thiophene .:rez isolated in 92% yield (42.4 mg).
.f t (I C D:-L CI3) 6 7.37-7.20 (8H, m, 7.10 (4H, d) 9.9- 4,88(2i, 3. 3(2H, bs), L3.16(2H, 2.92 (2H, dd), :.37 s) 1 3C-Nt.R (75.4 MHz, CDCI3) 6 1 32, :3604, 129.4-, 120.73, 127.74, 126.53, 75,59, 60.89, 51 ,00, 33.56, -2 57- After deprotection of the acetonide as descirbed for example 15FS, the result..rg residue was applied to a preparative silica gel plate (0.25 mm) and e.luted with ethyl acetate-50% hexanes. Isolation of the appropriate fractions gave compound 15FW (12.9 mg, 61%).
NMR (300 MHz, CDCl3) 8 7 .38 (8H, in), '7.12 (4H, di) 7.06 (2H, dd), 6,.97(2H, bd) 4.82 (2H, d) 3. 64 (2H, s) 3,58 (2H, bc, 1 3.16 (2H, di), 3,04 (2H, di) 2 89 cid), 2.34 bs) 1 3 C-Nj4R (75 .4 MHz, CDCl 3 8 161. 69, 139.4, ~2 138. 92, 129,46, 128.68, 127.98, 126.58, 126.43, 124 .07, 71.77, 64.04, 50.20, 32.81. MS (NH3 CI) m/e 519 (M+H- Compound 2I5FVX, prozected as the acet-on-lae, (15,5 mc, 0.024 mmoli was dissolved in dry toluene 0 ml) under nitrogen. The reaction. was heated at reflux for seven~ hours the.- allow, to cozl overnight ,The solvent was removed under reduce-_ pressure and the residue .appoliedi to a preparative silica gel plate (0.25 mm) and eluted witt 25,, ethyl acetate-75% hexanes The bis-diene _4ntermeciate was isolated in. 61% yield 5 mg) 2 H11P 30 C C'i_ C 8 1 7 1 H, im) 6 31 (2H, cd) c 35 1 5 2 4.8 2 d 4 .7C (2K, d. 3. 88(21Hi, 3,85(2H in), 2,89(411, in), 2.641(2h1, 1,44 (6H, sy 13C-NmR (100. 6 I.MHz, CDCl3) 161. 68, 142. 93, 139,49, 136.85, 129,39, 128, 64, 126.49, 120 .23, 115.4 6, 110. 22, 75 .76, 59 .19, 52 .81, 33. 26. 90. MS(NH3 CI) True 4 99 After deprotection of the acetonide as described for example 1SFS, the resulting residue was appl ied to a preparative silica gel plate (0.25 mm) and elutedi with ethyl acetate-505, hexanes. Isolation of the appropriate fractions gave compound 1SFX (2.9 mg, 42%).
IH-NMRi (400 M~z, CDC13) 8 7.37-7.16(011, in), 6.31(2H1, cid), 5,34(2H, di), 5.12(2H, di), 4.79(2H1, s),
I
-258- 4 .74 (2P, 3. 76(2H, 3 .64 (2H, d) 3 .06-2 .88 (4H, n), 2 .67 (2F, 2 .28 (2h, s) 1 3 C-NlPa (100. 6 mHz, CDCl3) 6 162.02, 143.05, 139.93, 136.88, 129.48, 128.68, 126.47, 120.08, 115.61, 71.89, 63.06, 52.42, 32.68. HRMS(NH3 CI): Calculated fOr C29H35N203 459.2648; Observed: 459.2653, LZ ELE9 17801 Lz 9E -6L9 9 ,K!6 i+ t cviyyH9-d IDHDHfD U 13H ZW 31 OfHN (0)1D (HO)-d T3H -'H3'H 9 0
-D~(HN
1 0 )0 -(HN(0)3 -CO 13WH ZHO'H93 (CHOHN) CS T L E'LOL S :-6 9 E'99S 9-101l f,.r *i+ f f t F Trnw HiW 1
,UN
S
*5
S..
(69 t A q low! A xoqOja'jr'j -4xOLI low tp_ 'i, I i f t f L z -I c 9 0 1 L 9 E 6L 9 E "II f L. O '6O0t 6 L tE L E L 6 9 u 0 L ZI q9 L Ci L Z 9 t; I
Z)
Ia.
-a H VAS I (Ha (0)3 Z) -uI iii Ji 0 u 1 j)a.
S S S S -S S C a S a S *S fl C S C C S S S 5 9 0 S* SC MS CCC
'R
4e- taxim(e) cryn-ch )li y int I Iy v 451 (M +i- OCH 3) 581 (598) CHINHC (CH2) 5 I SVE HoiCH216 1tO (CH2-)s
H
I~V HOfCH 2 5 l5V1 HO(CH 2 5 flo{Cl[) RO(CH;)5 cli 1 NfiC (0 Hio (GBi 2 b-Naphthyl-CH2 4 +4 +-4 4 +4+ 62C (637) SA -6 5571 Cf,li' 1 Cfi; CIIIS (CU;2) p- (IIOC112)r4H 4 CH2 f-4 if i t 19S 619 t 9S itt (:Ili) OScil 14 4 1 WJ~HtOH-t]I (41t~3)-01 (NO)1~ ODH i tZ 4t r rC X 3*11, HZ) SAS I )IAS t GA,_ I d-si OAl9T
HZ)
T L t Z Ybf i-/i I Olu 2I p3 l: IA
C
4 S a.
4' a a a *8 a *a.
a a a a a.
a a a. a *44 HO (CH 2 5
CIH
5 CfH?
CH
3
O(CH
2 5 HO (C- 2 5 HO (CH 2 5 110(CH 2 5
CH
3 CH (OH) (CH2) 4
CH
3 CH(OH) 1 C14 3 C (C14 2 4 I 5WC CH 3
C(-NOH)-
(CH2) 4 C113O(Cil;),.
CH
3 O(C'W)s m-CN-Cf01 4 CH; m- (C 2 H",OC 0)- Cf,1{ 4 C11 2
CH
3 CH (OH) (CH 2 4 b-Na phr hy I.-Cli, C113C 4
CH
3 C (-NOH)
(CH
2 )4 4-4+ 44- 1 -1if+ +4- 5 27 (544) 528 (545) 5-75 (592) 527 (544) 4- 4+4 144 80<7 567 36 (584) 44 44 4-4-4- 'r'L11. 0: i 1WG M-tHeOZ'C) C j;d I 4 C f i- M-P OC7 l.wJ r-(HCHm-(HOCH2-)- CG~i 4 CH2m irN p- (IIOCP m- UIJLdH +4 1 4 1 533 (550) Mn- (FNz I) m- 1 HC11; n-t (RNCb I (nEtNC
C
6
H
4 CI!, in- (EtNH, C 10) CfH 4 Cli, 2 f~ I f f I R9- 91 (722) (G81) (653) 447 I; 176- 177 ~i 4 +4 88.9- 636 90.0 +1 44 1 1 67 y a a 000 P a a a. a a 0e a. as a.
a a a..
C a .0 a. a a a. a a. a.
1Table (cont>) m-(PrNHC(Ol- C6H 4
CH
2 in-
(HO
2 C) C6H 4
C:H?-
in-
(HO
2 C) C 6 I Cli2m-
(HO
2 C) C6HlCil 2 in-
(HQ
2 C) C 6H 4
CH?-
p-(HOCH 2
C
6
H
4
CH
2 in-(HOCH 2 C0i4 CH 2 p- (HQCH 2
C
6
H
4
CH
2 in- (H 2 N) C611 4 Cfi2in- (P rNBC in- (i P rNHc in- (P r JC +4 4 4 i 44 f I1 16~4- 1-+1 f 44- 122- 124 135- 137 EBenzyl 636 636 (32%) (568) (532) (598) Cyclopropy 1in- 3-picolinyl m- OHft~c C6H 4
CH
2 nph th y liethy 130- 132 4-4-4- 4-44 123- 124 580 572 +9 9-114 0 I (r-nrit 1 1:wv Cv,_ I p I.opy! in, i i 16K in- (IOCP) C w M- 1,.CH1 2 in- I 5XA p P- (fie Q))
C
6
H
4
CH
2 n- (MeNHCH?) Cr,Hlii 1(7 in- tCli 3 CEICl) Cf 11 4 CI1 2 in- (f1 ltF{ in- 2- IlphthV3 n' it III1- 1 4 4 128- ]in~ i4 1 4' 188 I-8 9 580 4 111- 1 13 100 P-0po11l I 1 4 4 (598) p- (110011
C
6
H
4 C11)in- (melitCi 2 M -l II1C,),
C
1 ,Iil 1 Cl 2 i 4 44 4+ i If 593.3483 595.3177 (612)
S
la1bil(, d (conl.-) 3-picolinyl in- (Et7,NCl1 2
C
6
H
4
CH?-
in-(N-iinidazolinethy.) C 6
R
4
CH
2
C
6
H
4
CH
2 n- (CF 3 CIi)
CGHCH
2 rn-12irnidazolyl- C 1]C 6 H4Ctl 2 3-picoilinyl- HC 1 in- (HOC11 2 CC) C6H 4
CH
2 lSXM m-(CF 3 C
C
6
H
4
CH
2 i-(EXt 2
NCI'
2 n- (N-iinidazolmethyl) C(,H4CH 2 in- (tRuC mn- (CF IflH011) C611,4CH 2 I 12irnida 70 1y I C 1 C 6N C 11.1 ID- (HOCH2)
C(;H
4 CI1 2 in- (lioiI 2 cc)
C
6
!HCH-
in- (CF)-C Cj~fieClH 2 +-i ~i i 4 4 f I f 4 t4 4 4 +4 538.2693 6-7-7.4444 667.3394 675-3805 703.2611 695 -2 977 1 4 4 4+-44 1 4 1 1 (538) 615 .2853 (632) 699.2286 0
C
I a 1- 1 1 r r) r) I C'fV, 4 fb in-n C0~ 4 CH 1SxR m- (CE 1 -Cf'i OH) C M- f e- OH) I C 6 r 2 mn- N m(2- (4morpholinn) ethy IN"C '-li 4 CHi 639.3181 (A 36) 639.3100 65 6) I I I 649) 4 f4 665.2103 6 s2) '729. 2S00 ('74 6) 621 .3070 I 5XT I f; 4 6 45.2?0 (14 2
NCH
2 C NH)
-C
6 H 4
CH
2 t'C' I 5X"J m- (4morpholino) ethy 1INHC C 61ICII 4 1f 4 102-105 81Q.4435 TabLe2d (c on t m- Ndimethylamino) ethyINHC C 04 CH 2 lsxw dixnethylamino) ethylNHC C 6
H
4 CH2 CI{3 CR3 1SXZ CH3 cyclopropylmreth yl cyclopropylmeth yl cyclopropylmeth yl m- Ndimethylamino) ethyIN11C C 6 1 4 C f' mn- Ndimethylamino) e thy I NHC C0 6 4 CI1 2 m- Ndimethylamino) ethy1NHC m- (2 U4,N dimethylaminn) Ot hIy NIIC benzyl (3- (py rroIid; no ethyl) benzamido methyl m- Ndimethylamnino) ethyNH-C
C
6
H
4
CH
2 m- (4morpholino) ethy 114HC C6H 4 Cfi benzyl (3- (pyrrolidino ethyl) henzamido methyl f+ 735-4226 +4*f 100-101 7 35.42267 6 4 01-103 I 4/ 4 1 18-120 587.323422 f+ 134-136 571.327642 4+ 41+ 4 9-7-99 585.343057 4 103-105 627.354642 ++i4 +4 110-112 611.359872 Tab1!>.2 (cant rn(p-to luy 1 s i fonlylhvrram-(N-rnorpholinef h.oxy) C,I,CtI p-.4 CF2C0 4
CII-
_-(CM
3
NEOC=O)
zol idinon-3m-(2iniidazole) C6Ri 4
CK
2 (3 -oyr ;,Iy 1) Muet "Iy-i N[C I Of) mn-( -pyr i!y I 2,ulfonylprIr- 7 0 fI l) C. mn- RN-m( I A x i -w ethoxyl 1 ",I p-i- NCi-- H in- (Cli~HC1)- C,H 1 C11', n- 2, 4-oxad iz zolidin-n-3y 1 C 'I.CH2 imicipob*;
C
6
H
4
CII
.4 11' -117 05.311364 i 69-171 110-112 765 4 132-134 566 223-224 i 2102 (dec) i 4 4 TabI~~~ro (nt m-(3-pyrazole)-
C
6
H
4
CR
2 (3-py ra zale)
C
6 iH 4 C14 2 8CI n- (3-pyrazole- CO) -C 6 H4CI1 2 in- (CICH 2 C N C N4I) -Cf, clim-H 2 NC6H 4
CH
2
-HCI
in- (3-pyra.olp) f,"4lChi mn- (3-pyra1zole)
C
4 Hi-CH 2 -HC I mn- (3-pyrazo le- CO) -CfH 4
CI-)-
in- (C1CH 2 C INH f NH) -C~jjH 1 14 41 208-210 639.4 4+44 44 t 195-197 4414- 4 41 +4 1 44 1 in-i~nC'ntjnanilo-4 4+ Cr11l 4cl, -Ec I mn-isonicot inranirnin-ison icat i riido- I
C
6
H
4
CH
2 -HCI CjH'CH"-f1C1
(CH
3 2
NCH
2
CH
2 in-CH3C C 6
H
4
CH
2 +4 C )-C6H 4 Ci 2 208 (dec) 642 20 5 (d r-c) 147 44 1-70 (dec) 64 6 164 (dec) -701 183-186 529 n- ((CH 3 2
NCH
2
CH
2 C -Cf;HICllinn- (Cli 3) 2 1C CI 4 C -C,1 4
CH?
Mn- H 2 NC cyclopropylinethy1 tf4
C
6
,H
4 C-1 2 S S S** *S S S *C 'r q J 3, 4-xd.- AL ~f (CM 1 H CC :0 S Al i C 2
H
5 OC C,I1CH 2 ra- (H2NC r,11WCF1 x 1 I~t v I V 4 1li 4 4 4 jqrj-jqq in- 5-a-u4 2-yl) r yc 1, y, me, I v I 2 08-209 690 4 221-228 808 ni t (C H) .0C~ I 3, 4-c YaiA'f7l- 2-naphthN-linethyl 44" i +4 91-193 615
S
Ta L- -d (cont 15A0 3 (5 (CH 3 2 t4CRl2 4-oxadiazo1l yl) -C 6
H
4 Cib Hl1 r-(N-rethyl-N'piperazinyl) propyl iCL n-cyanoC 6
H
4
CH
2 in-cyanoCfd1 4
CHR
2 rn-(N-Iethy1-N'piperazinyl) propyl-HCI i- (H 2 NC (=140H))
C,
6
R
4
CR
2 Mn- fH 2 NC (=NOR) Cr1 4 ,C1 2 mn- (IHNC f=NOH)
C
6
H
4
CH
2 3-c( (GUI 2
N~,
tic 1 i 4 44 :i 65 (dec) 1 '17-14 'V 167 p-hydrm.:y(> 1,CH m-3-pyr iry Imm hy I I4 Il I i 4- f 44 4 172-179 47 p-hydtxyr-, F1 4 ('11 p-benzylc'xy- C04'CR.- 180-182, 671 a e S
S
Tui~- (con I AX r-7 rn- (2- Ibenlz iinid oyI- CF w..ci! 1-7P- 192 5G6 mn- (2- 217-219 -739 I 5AZ Wn- C.flNHC l) 11 {N H1
CC
4 jJWnfI: CHJcI;:- TM- IC 3 I{-!71!C (-N.lIi) -in- tC-,1-dJIC C N011l i i I- lq:'(dec) 651 II 1 7 7 1 513S ini- (2-ani nopyriidin4-v m- (2-ami no.pyrimidi n -4-yl) 226-22 7 693 i 55C cyclcpropybo,?rhyi thienyl) -C41H 4 CH,1 thieny! C1i- IRE m-lpay~n~ty rn(2-aimino4 4I; 4 1A-160 703 4 4 i i 444- 1--I 118-127 569 a. C a C C C C C *C
C
latl e ,Zd (rcnnt 155F m- (2-chloromet-hyl -2-propenyll)
C
6 H 4
CH?-
155C m (2-hydrox'ymnehy1 -2-propen y1- I5,8H cyclopropylrnethyl mn-(benzvloxy ffethylca-.rbon, 1~
C
6 1 4 C1{ 2 m-(1-SEM-Simidazoy1l
C
6
H
4 CI1 2 xn-(5imnidazoyl)
C
6 1- 4 Cl-- 15.1L M-{5imidazoyl) C6sl 4 Cli 2 4HCI dimE thyl 3ulfamuoyl) -2imidazoyl)
C
6 Fi 4 C1I 2 in-(2-chloromethylH 2-propeny I) (2 -h y 1c x, ymet h y -P cP;-nyU met hyl ca rhnnyl I C~,f1 4
CJ{
2 178-181 503 I-Po 467 41 4+ f 155-164 643 4 4 f+ 803.5 imidazoyfllin- ~idazoy1} C01 4 CH-- i2 in- flclitethyl sulfamoyl! -2 iridazoyl CGH4C H 2 -f 1 4 899.5 H- 4- 171-175 639 4; c~g1 r li in- (4-pyrart..} 1$E~ rn(2- C611S C1-2- C6114CI2-yl 11 m- 2 -rorpito I io et hylI) am i n o carbonyl) -J 4
H
L~CH
I f i rn- f a-p'" I 4 P ~4'1I I Ii Ij 12'1-130 631.4 in-(3-p.
(7~1I-~ 603.2 i- (2 iMiCIA7-y Cf 14ci- (2incia-. I~ +4 I 17 8-18 0 639.
i. x 44 191-194 3-pyridinylmfothyl 1'iBV rn-cyano-CfH 4 CH, 1SF3W mn- (H2NC (-Nf7H) mn- (3-pvt I 24 n- (3-pyr,,:o'ie) ff.H 4 C!1?in- (3-py ia.zo Ic) vn- (3-py'7d1- CI.1 4 i~7i7 4~1* -729.-5 I i 4 i 133-136 574.2 598.2 i 4 1 C Ta b (co n t. m- (3-pyrazole) 4 4 F H Cl
H
p- (benzyloxy) C~f1 4
CH
2 m- ((3-pyridinyl methyl) amino carbonyl) -C(;H 4 CH2 in- (3-pyra'zo>r) C0H 4 CH12- Tn- (3-pyrazole) C ,H 4 0i1- 14 1 f 4 4 83 .2 679.3 707.5 p-hydroxy-C 6
H
4
CH
2 m- (3-pyrazole) cf 6 HCl,-- 41-4- 4 f 15 0-15 3 5 89. 3 in- ((2-pyridinyl methyl) amino carbonyl) -C 6 114CH? m, p-dihydroxy-
C
6
H
4
CH-
2 m-nitro-Cf1 C11-.m-ainnO-C 6 11IC1 2 m- (3-pyrazol,) n- (3-pyra7.olc) C6H~Cfl 2 in- (,3-pyra 7o Le) m- C3-pyra7ol.)
C
6 H4Cf1-- +41 f 4 f il I I ff 177-180 622 (635) +i f f 1 136-138 605 +4-4 4 +4 118-120 616 m-cyano-p-fluoro- m- (3-pyrazole)
C
6
H
4 CH7- C6,f1 4
CH
2 3 inl 152-154 c.r.
I 9iC I r--icet y fI lin F o -a'tv 1 f tr~ o f HII t. C (,it J I. n-(cy.3r.0-p-! 11ioro- V!-a -PrftI- u Fl 1 40 1 C1 2 C0,' qci, 18,6-188 60O6 -4 20 3- 20 4 649.3 (M4 Na) I C2-193 632.3 (M iNa) (CH 3 C NO")- Cr-l11 4 Cf'2 rn- (CH IC t4C') 1) 1- ISCI, m- (CHIC (=N0H) M- ('Ill (-Mlll) P- f luoro-CU! 4 C8"- P-F f 15C1Mm- (H 2 1C in- (11 ('-NofH) p-f luorO--C 6 '1 4
CH
2 P-f lUor"'C6I 4
C'-
621-4 6 537.3 658 .4 2-naphthylrnethyl Isco 2-naphthylricthyl 5-methyl-5ca rbornpr h,)-y hoxv I.
5-mnethyl ca tbox,;lxyl ii; i-jI Thh1~_2c (or it 5,5-dimethyl-6hydroxyhe~yl p-aminobenzyl 5-benzimidazo1 yl methyl 5-benzotriazolyl methyl 3-hydroxy-5benzotriazolyl methyl 5, 5-dimethyl-6hydrc4yh-xyl F-aminobenzyl 5-1)enz imida zolyl methyl 5-berizotriazolyl methyl 3 -hydiroxy -5benzot rii lylI m'M by 4 f f+ 44 f 1 14 -116 +1 4-4 209-212 444-+ >31 0 185-192 2-oxo-Sbenzimidazolylmethyl 5- (2,2-dioxobenz-2, 1,3thiadiazolyl) methyl 5-indazolylmethyl 2-oxo- 5benzimiolyl methyl 5- 2-dioxobenz-2, 1,3thiadiazolyl) methyl 5-indazolylmethyl f+ 240-245 444 144f 165-170 *9 0 0 0* 0*
S
S.
S
0 5* *o S
S..
cn)f, I 1 ZJ ivni~i' ri-t h n y I ,i--oxo- I ''l'U~1y -mr'thI 170-175 192-200 I q6200 2-12-24l5 I 5DTI 3-hydroyvi- i 3-hyrir-- i mi nohyl oxindo! Ilyl 4 t (2-oxo--5-ben7 oxazolin- mthF~ y] (2oxoi- -yher mthyl 4 1 181-385 5-n.-c4-ndolvlm-t.tiyl A f 4- 170-175 I. Pr 5.-indulylmethyi (3-amino-5indazolyl)inethyl (3-ami-no-5benziiomazolyl) methyl 5-z;ndr.- ly! PnfLhVl 3-amino- 5ncla'ol, 1 I met hyl methbyl I 17 0(dec) 110-184 41 I +1 1'93-158 Ta L( (cont.
150H (3-methylamino-5- (3-methylaimino-5- -fi4indazolylimethyl indazolylimethyl (3-chloro-5indazolyl) methyl (3-ethylamino-5indazolyl.) methyl (3-methylamino-5benzisoxazolyl) methyl (3-chloro-5- 4ff indazolIylI) methyl (3-ethylamino-5- 1+4indazolIylI) m-thy I 44+1 1741-177 4-f 4 2 q 0(dec) +4 158-162 (3-methylamino-5- benziaoxazolyl) methyl ISDL (3-l,.opropylamiflo-(3-i3opropylamino- fif methyl methyl 1 50-153 1-11-152 188-190 Hi 5-benzot r azol yl methyl 5-benzot ri azoly 1 mnethyJ f- I benzyl 1500 2-naphthylmethyl 5-benzotriazolvl methyl cyclopropylmethyl 5-benzotria7olyl j44 methyl 4 268-270 +44+ 155-159 ff1 146-150 0 7 f yTItl: m-(3-pyrat~nlvl) ISDT m- doCO rlU iL Th-ou in-.yanomet hyl j 5D!- in-(B Nc CW')- I SOW in- (carbomet~hoxy methyl) GC0 4 C11 2 i f 1',1-153 t. 7 7. 0 t hy I ItIt t I.
296-298 ii 193-156 M-cyalfr.l h y C-611, 1 cli.in- (ca rbcinet hoxy methyl)-
IM-
(2-hydi.'---vothyl) C61'4CH" +4- 585.2 621 .4 651.4 595.4 539-3 I 5DX in- 12-hydroxy t-yl)
C
6 fl 4 C'12i iIt 44o-hydroxy 44o-yr-.
o'hydi nxv 4- 1 i I mn- (minethy lain ino) t-i++ H 500.2 o-hyciroxy- Cr,"A.Cl12o-hycdroxy-
C
6
H
4
CH
2 p- hyd r o:.ym t hy 1 m-hydroxymetLhy 1 4 +4+ 1 4 1 i-cyano-p-fluoro- i-cyanio-p-fluoro-
C
6
H
4
CH
2 Cr.H 4 CIi.~- 553.3 553.3 (61i0.2) (646.4) (6-76. 3) mn-(H 2 NC f uo ro-C 6
H
4 C~i2in- (I Nc -pf I uo r O-~ 1
,II
1 CIt 4t f If r-carboinethoxy-p- in-carbornothoxy-pf luoro-CH 4
CH
2 f 1uoro-Cti.C~H,- Mn- (H 2 NC N0R) p-f luo roCEH 4
CH?-
in- (Y"INC (vtrloff) p-f fuor',C,,H 4 659.1 603. 3 m-(hydroxyrnethyl) r-(hydroxymethyl) 4+4 P-flUOrO-C 6 iI 4 C7H,' p-f Iuoro-C 1 I1 4 Cfi
M-(H
2 4C P-f luorOC6H4CH2- [Th (H 2 NC (=NOM) 44p-f 1uorocrHqC11 2 4-+4+ 644 .0 a S S S a Jab!': 2J (CorO 'I 5- (met hylarzi I ca~ rbony Ioxy) T-r. ,t ylI met hyl 1, 2, 3, 4 t etrahvdro napit hy I) neth".y I p-hyrid h y I r-(motj I imi.
cIrhonv I* 7- 11, 1,4, 4- tnt r- .met hy I- I 4r-et ra hy,! 1-1,75 551 4 If i i i 5EN 5- (met hy I u If-t 1 (mr r h I f Iv i SEO 5- (p-xethylphenvi 5- (p-methylphenyl nulfony1)peFnty1 sulfonylr-rntyl 4 j I, 4 (566) (670) (822) -4 4/ arioti 5-aminopentyl 9 5-aminoperityl 497
S.
S S S S a a S. *S labi& (rC) niL-2 15E0 5-metYhoxycarbonyl 5-methoxycarbonyl aminopentyl aminopenLyl +4/4 (630) 5- (phenylamino carbonylamino) pen tyl 5-(methylamino ca rbonyiamino) pentyl ISET 5- (acetylainino) penty.
ISEU 5-((3-pyridinyl methoxy) carboiny amino) pentyi -HC 5-C (methylamino thioca rbonyl amino) -pentyl 5- ((phenyiam: thiocarbonyl amino) -pentyl 5- (phenylamino carbonylamino) pentyl 5- (methylamino ca rbony lami no) pentyl 5- (acetyiami no,, pentyl 5-C (3-pyridinyl 1 m;t hoxy)ra rbnv I Iamino) pent yI-flC I 5-C(methylamino) thiocarbonyl amino) -pentyl 5- ((phenylamino) thiocarbony L amrino) f 4 4 4 f/I 611 (628) (598) 4+ 4 4+ f- 4/4 4+ +/4 +4+/4 4 4 4 5-(benzoylamino) 5-(benzoylamino) pentyl penty] (722) 5-((3-fluoro benzoyl) amino) pentyl 5-C (3-fL'uoro benzoyl) amino) pentyl 1 It i y r- 01-fn( -r 1 A,31 y, I L j pn ll I y I I ami Iw) I !t I 4 4- I f 1zu z bo'nzov I am; io) 5-U(4-fJuorrt beflzoy 1)am i 0I) pent Y 1 5FE) A -yanrokbuty I mrethylca rbonyl ami~no) -pentyl -HCI 5-(2-pyrazinyl carbonylamino) pentyl SFG N3, 5-di f uorn benzoyl) amnr) pentyl 14-1-YE fly I y chc'Zyl. I-enzoyl i pentyl (4 t ~plh0I i nv~ rnethy I ca rbony 1 anzino) -p-ntylIW' 5- (2-py raz iny L carbonylamino) henzoyl)irnirin] pentyl 741 (758) 741 (758) 489 (506) 4 1 1 4 (726) (7Q4) 4- (dirneth-v].amino) 4-( 4 .inwethylamtnn ii k~r1HC1butyl-HCI
V.
T-ahb- t- (Cot 4-aminobuty' HCI 4-aminobutyl-fiCl 1- 4 4/ i 5-((3-trifluora mtethylbenzoyl) amino) pen tylI 4-(1-irnidazolyl).pentylaHCI ISFL 5-(l-pyrazolyll) pentyl 5- C 3-trif Itoro f methylbenzoyl) amino)pen tyl '-(1-imida)zclyl)pentyl -HC pent y I 5-t4-morpholinyl) 5-(4--morpholinyl) peatyl -HC I pentyl-fHCI lSFN 3-furylmethyl 3-furylmethyl 3ifry1ety (S-carbonyl-3furyl) -methyl 4 i 4+ 352.5- 153 oilI (5-hydroxymethyl- (5-hyciroxyinethyl- f4A 3-furyl)-methyl 3-furyl)-methyl metthyl- i!P 1 'Fr 'lrV fl' NY- I 5FS 5-dihy~lro) -3trenvin-, dihydro--3- 1 5FV 2 [I ry lmn-'zhyt 1 3FW 2 f iry Imet rv, 1 2-metbylene-3buteny 1 5-hydroxymethyl- 2- furyllmethyl T~lnw- t hIy (7 *l n.~1r -3 's ih ri Y 1,1 thiew-ji -thyl 14f j4 4 2-furylmt'rhvl 2-rethylene- 1but enyl 5-h--iroxymrt hyl 2-furylmi(- hyl -289- Notes (for Table 2d): Monoalkylated compounds were prepared by following the procedure 5 under the title of synthesis of ronoalkyl cyclic urea. Further functional group eJaboration is similar to the corresponding dialkylated cyclic ureas described L rein.
Isolated as the side product due to incomplete reaction.
(17) Prepared from Example 15J using the conditions described fco, Example 6ZI in Table 'C.
(28) Prepared from the compound of Tabi> 2C, Ex:ample 6Z1 tusing mez an~es-Kfon'c an~hydride, 2: (19) Prepared from Example 6ZI using isocyanic acid.
A solution (6Qmi zf borane in tetrahydrofucao 2Xk) was added drcpwise into a cooled solution (0)of bi;s-formnda QZM 25.5 mmoles) 1-n 1" 20 ahydrou T (0l) h mxtuie was stirred for 26 ours rocx- temperature 1 "ollowed by dropwise addition of mez"hanc'! (Scimij hen the effervescence had susde, rc--lor c acid, (conc. 35m1) was added.
resi'due: waS s:irred for 30 minutes, evaporated to 2. d:7yness, and porctitio'ed between ethyl acetate and o c! _4u m h y -Jon i d e (I 1) The organic layer was washed wit)- brine, dried over, magnesium sulfate, filtered and evaporated to give 8.65g of the product.
(221) Prepared from Example 6ZI using benzyl chloroformate, (22) Prepared from Example 150 using the conditions described of 6Z.
-290- (23) Prepared from Example 15E using the conditions described for Example GZI.
(24) Prepared from Example 15F using the procedure described for Example PrL- red form Example GZI using methyl isocyanate.
(26) The formamide of Example 15A was prepared by the IC procedure Example followed by reduction described for Example (>The a.oe bond is for-med between an amiric acid and *'.a~noenv.cyclic urea using dicyclohe :yl'carbodtlimi-de' d- m a. de~~ m r. the proper proportions. When the *.:ceL tret prodirt iz to be a primary or secondary amine, '-zermi.nus cf tce aminco acid was first suitably prr: Zt, W-ed on the compatability with lazer 'C se. Guen arid W'jts, "tr -otect'nc rn>e r re m ov ed, ~0 Cvz~c urea XX:c was alkylated with sdu yrd ~ez~v~and TF;l2'QCC-,) 5 Br (prepared in 2 steps fro, 4 eqL:Iv, in DMIF to give the monoalkylated tro~. neze upon, further treatment with sodium .r'o E7:r a second 17romo-alkylating agent provided an wr~n was deprot-ecced using met-hanol2ic H 'provide the product 1 ~rar~:by acdcdeproteccion of the monoalkyatei -291- Prepared from intermediate (XXII) by treatment with phenyllithium, boron trifluoride and 1,2-epoxybutane, followed by acidic deprotection.
(31) Prepared fromn intermediate (XXII) by treatment with ohenyllithium, boron trifluoride and 1,2-epoxyhexane, followed by acidic deprotection.
(32) Prepared by pyridinium chlorochromate oxidation of I C the corresponding alcohol.
(33) Preroared from Example 15%'Q using hydroxylamine -d ~r o- cr i de.
2 Sepera.of a Example l5'VW usina excess reagerts.
(25) Prepared by selec-tive monoalkvlazion of he d~a'kylated diol usinrc sociiur, hydride/ methyl iodide, (3E) Prepared by substizuz ino CH3CF(OTHP) (CH2)4Br in the =rocedure described -for ExamzIe l5VE, Bromide is prepared from CHiCH (OH) (CH2) 4 0H by the following seciuence: AC 2 T*-7 NaOHi, CBr 4 (37) Prepared by subst ituting Ph2C=N (CH2) 2Br in the procedure described for Example 15VE, Bromide is prepared from H 2 N (CH2) 20H by the following sequence: (1) Ph 2 CO: CBr 4 Ph 3 P (38) See note 7, Tabl1e 2d.
(29) See note 3, Table 2d.
See note 2, Table 2d.
-292- (42) The intermediate was prepared by following Procedure 5 under the title of synthesis of monoalkyl cyclic urea. This was followed by alkylation with Bromo-m-tcolunitrile. This intermediate (670 mg, 0.82 mmol) was treated with potassium hydroxide (0.4g, 7.13 mmol) in ethylene glycol at 140 0 C overnight. The solution was acidified with pre-cooled hydrochloric acid (11q) and extracted with ethyl acetate. The organic phase was ;concentrated to give 415 mg of MEM-orotected diol. Procedure for hydrolysis of this product is covered under procedure L4(4; he lrjermediatie was orepareo by following ?rc::ed,,_re 5 ,:nder the title of synthesis of monoalkyl 'vlchue. f>I,,z alk-ation, with Br-omo-m- F hi ermediater (210 mg, 0.26 ramol) was zreat e- witr. EAL-1H. (0.19 mL, 1.5M4 ir. toluene, 0.286 -7E>'C un;der nitroge n, stirred at -78 0 C for 1 f: The reaction was quenched with anci worked u r h sa mg of th ME!'-protected r -ivr .sc fthis product is covered under cia.m..~y -c ta 5.t9 nmcl)wat aciJed to a solution of Ketone 9P (940 mg, 1.59 rnm) e:.az>The mixture was heated at reflux cyrrr.cY.anir, th-e solvent was rerno ed on a rotary ea:trza residue was purified on silica gel re rarc' lco.rc form)0 to provide the iproduct 94 0 mg, r, i. r-rze-iate was prepared by following u:ncec:, the zitle of- eynthe .is of i mo 1oa yl nre morca_ viat ion produc.:. was~ further alkylated with bromo-m-tolunitrile. This intermediate (185mg, 0.24 mmol) was treated with hydroxylamine-Hll mg, 0.37 rmol), and triethylamine (0.05 ml, 0.37 rmm!n) in refluxing ethanol for 16 h. The resulting solution was partitioned between ethyl acetate/water.
The organic layer was washed twice with water and concentrated to give MEM-pretected product which can be further hydrolyzed as described above to yield 90 mg product 9C, Guanidine carbonate (7,29, 40,23 mmol) was added to 15AE in :.vlene. The mixture was heated at 130 0 until nstartina material was lestz, The solution was oar.ta:oned bet-weer. ethyl acetate/water and the organic layer washec war water twice. The organic residue was fied orn cslic=a e1' (10k methanol! ethyl acetate) to ~r ov~dethe:z-e prod,,;t (347 mQ, 37%i (ATo a so.2tazon of ME-protected formaldoxime .5 Sg, C, 65 mcIl) in was added 1/3 of 14ccrosuccinimiae (173 mg;, 1.3 mmol) ,The mixture was zs:*arred for rrnin followed by 2 man of heating at C Z. After s--rr .1c anotner 10 min, the rest of NCS w~acoec -nerr2e was s-':rred at: roorr temperature -rovernio t. The solution was then partitioned between etnx-.-- acetate /water, Tne organic layer was washed with water and dried over 1'1SO 4 Treatment of the hydroximoyl chloride with 3) eouivalents of o-phenylenediamine in ethanol gave a single product which can be further C) hydrolyzed to the product (126 mg, 43%) (47) To a solution of aniline 3K (146 mg, 0.27 mmol) in methylene chloride, was added isonicotinoyl chloride hydrochloride (110 mg, 0.59 minol) followed by potassium 0vi carbonate !E7 mg, 1.35 mmol) at 0C. The mixturewa stirred for 2 h, an-- then slowly warmed up to room 294temperature overflight. The mixture was partitioned between ethyl acetate/water. The ory~anic layer was washed twice with water and dried over MgSO 4 The residue was purified on silica gel methanol/ethyl acetate) to gave the product (52 mg, 26%).
(48) The benzoyl chloride intermediate (0.51g, 0.72 mmol) was prepared by following procedure (41) (7) without removing KEN-protecting group. To the residue, 20 ml met-hylene chloride was added, followed by pyridine (0.11 1.44 mrnol) and tert-butyl carbazate (190 mg, 1.44 mmol) The mixture was stirred at room temperature over~c~ n T he mixture was washed with water dried cver The residue was purified on silica gel azetaate/metn.vlene chloride) Follow ,ing the S zroce d~ de x cribe d abovE., the p rodu c (16 2 ~:-rztete~hycrazide 10N, e,50 mg, 0.72 a~ aded mmoi)ofCt ad d e:.r d~ K:r m o SCUL~ r~azzLt ,r wa ter TY. resu It, ng mixture was n at rccm., temoerature The solution was c~re:; vc-lume invco The mixture was cf water arid the resulting solid ~and p .>rified on s>Li11ca gel (151, r~~)to prov'de (38,4 mg, (I caL~aate(264 ir j, 2 mrino!2) was added to 3' nc ~V45C mr.8ml)in ethanol. The mixture at r-jor* temperature for 2 h and heated at ver~igt. he residue was purified on silica gel ':Aacezate/methylene chlcride) to provide the 6g 26% -295- (51) To a solution of aniline 3K(160 mg, 0.3 mmol) in 0 THF, chioroacetyl isocyanate was added dropwise at 0 C.
The mixture was stirred for 0.5 h and then slowly warmed up to room temperature overnight, The solution was partitioned between ethyl acetate/water. The organic phase was washed with water and dried over MgSO 4 The residue was purified on silica gel methanol/chloroform) to gave 217 mg in 93% yield.
(53) To a solution of 333 mg 6.16 mmol) of anhydrous NaOCH3 in 20 ml of anhydrous methanol at 0°C was added 855 ma (6.16 mmol) of aminoguanidine carbonate followed 2 ml methanol. The resulting mixture was treated droowise with 500 mg (0.77 mmol) of ethyl ester 11F 1:5 which was made by following procedure (10) in 5 ml of methanc. The mixture was heated at reflux overnight, then poured into ice water, brought to PH 7 with
S
aauecus HC1, filtered, and purified on silica gel methanol chloroform to give 20 mg product.
(54) A solution of MEM-protected cyclic urea wherein
R
22 and R 23 are (-H2C (=NOH))benzyl (210 mg, 0.26 mmol) and Et-: (0.18 1.3 mmol) was treated dropwise with a soluton. of chloroacetyl chloride 0.046 ml, 0.57 mmol) 2E in CHC1S3 The mixture was stirred at room temperature for 2 days and then evaporated, and the residue was redissolved in ethyl acetate. The solution was washed with water, brine,dried over Na2SO4. The residue was purified on silica gel (10% ethyl acetate/methylene chloride) to provide 140 mg intermediate. The intermediate was dissolved in DMF and treated with excess dimethylamine gas. The mixture was stirred overnight, then poured into ice water, and extracted with ethyl acetate. The extracts were washed with water, dried over MaSO4 Following the usual hydrolysis -296procedure, the product (15.6 mci was isolated. in yield.
Listed below are a representative list of data for compounds listed in Table 2d: Example 15VA: NVUR (CDCl 3 6 7.19-7.40 10F) 4.66 1K) 3.99-4 .12 2H) 3.59-3.69 2H) 3.37-3.49 2H) 3.10-3.21 Cm, 2H) 2.25-2.38 3H) 1.90-2.00 2P) 0,85-0,92 8H), Example 15VE: I1*M (CD3OD): 87.50-7,70 1H) 7.10-7.35 M,9) 3.95 Ci., 2:i) 3.53-3.7C 2H) 3.40-3.50 2H) 3.C-3.2O Cr., 2.75 1r) 2.30 m, 1H) 1.60-2,10 Wr, 71-i) 1.2E C, 2H) C,81-1.I1 2H) cs:6~~ ;5VC: !5 3 0 0 .7 2 3. S( 3 CC 3K- 3.57 1 5(d 3.07 s, E 2, 9s 2.75 1) 2.59 xaF I E I N~ (CaC3) 6 .34-(m30 (In, Czzs, 2. 3.93 Cs, 43C- 3.C Cr, 41), 3.53 d, 2Y 2% 2KI) 2.8-2.2 2,81 6K).
.5V h (C23 173 m, 10), 3.99 3 2.9-.00 21), 2,3 (1,r d, 2K), 2.15- 2.2E C: 1 12-1. BC (br m, 171).
13): 8 OH) 4.5 2H), 3.99 C, 2.60-3.72 (in, i 59 2.X 4, 6 21 I~- -297- 2.89-3.00 2H), 2.78 3H), 2.70 (br s, 2H), 2.14- 2.24 2H), 1,12-1.80 (br m, 17H).
Example 15VG: N1T (CDC13): 6 7.10-7.37 10H), 4.80 1H), 3.92 2H), 3.20-3.70 Cbr m, 6H), 3.00-3.19 Cm, 4H), 3.61-3.77 11), 2.21 (br s, 1H), 1.10-1.50 (br m, 7H) Example 15VH: N41-4P (CDC13) 5 7.64-7.84 3H), 7.05- 7.57 14H), 4.96 1H), 3.92 1H), 3.38-3.80 (m, 6H) 3.21 iN), 2.99-3.18 Cm, 3H), 2.75-2.98 21), 2.43 Cbr s, 2.20-2.35 1H), 1.10-1.88 Cbr m, 7H) Z xam Ie 15V:: N 2 (C 3) 7.04-7.40 15N), 4.80 1Hi, 3.94 C, 3.42-3.80 (rr, 7H), 2,83-3.17 (m, 6F), 2. 4 Cbr s, IN), 2,19-2.31 Cm, 1H), 1.16-2.50 (br S2 Exm 1V (72Ci: 6 71-7,35 1iN), 3.99 s, 3,43-3.69 6H), 3.10 21-H), 2.95 3H), 2 .C 8H) 2.36 2H), 2.2 0 2H), 2.02 Cs, 3:) E 118-1 5 6 Cbr in, 13-)11 Examne 5V a: mMKc IeC 5 7.05-7.4', 44HC 479 C, 1, F ,.5-45 7 2H), 1.50 i 3.29 Cm, lii), 4 30-3 ,75 C, 61-H), 2 98-3.14 4-H) 2.81-2.95 Cm, 2H) 2.72 2.25 1H), 2,07 Cbr s, 1H), 1.16-1.50 (br m, 6H).
Example 15VL: NKLR CCDC13) 6 7.18-7.36 (10H, m) 4.53 C11,s) 3.95 (2H,s) 3.79 C11,m) 3.51 (1Nin) 3.33 C2H,m) 3.13 (6H,m) 2.72 C11,t) 2.60 1.33 (2H,m) 0.84 I :i -296- Example 15V'-: NVIPR (CDC 3) 6 7.20-7.34 (J.0H,m) 4.57 (1 Fs) 3.94 (2H,s) 3.79 (1H,m) 3.52 (1H,m) 3.38 (1H,m) 3.33 t IIi,d) 3.13 (5H,m) 2.94 (2H,.bs) 2.72 (1 H, t) 1.26 (6P,m) 0.86 (3H,t)
S
Example 15VQ: NMIR (CDC1 3 6 7.14-7.35 (10H, m) 4.63 (2H,cd) 4.41 (2H,s) 3.49 (2H,d) 34 (2H,m) 3.14 (2H,m) 2.85 (2 11,d) 2.45 (2H,s) 2.10-2.32 (4H,m) 0.99 (6H,t).
Example 15VF: NIKPICDC13) :6 8.21 7.23 (10H, m) 4.80 (2H,d) 4.14 (4H, m) 3.68 m) 3,14 (2H, m) 2,60 (2h.d) 2.44 (2H,m) 2.03 (2H,rr) 0.98 t H,t).
E: Eam p e 15V:: (CDC-3) 7.64-7 2 3) 7.C7- 9 1 3. 1, 6 11, 4 4 E 0- j) C 1H) 2 84-2.9;- IH C, 2. 1- C, 2- 2 1 08-1 .56 (br :rn, 21q) 6- S2 H 4.73 02- (E 3.4-3.96 38 38-3,76 (brim 7H, 2 E 2 C 19S I H I 1 6 1 5 (br tCCC3)7 1 13.? (rn, 1014, .O S 4 3 "i3.E 5H)) 3 10 cd, 2fl), 2 88-2 9)8 2 G 2 7 C, (ri, 2 2.I- -2 c r, (CDC13) 3 6 I QH) 4 46 9 2 79, 7 7 H)i) 2 7 6- 3. 22 (b r m, 6 H), .2 J 15-1*52*br EN V 1 I -299- Example 1SV\': NMR (CDC1 3 a 7.15-7.33 10H), 3.99 2H), 3.65 2H) 3.49 3.25 6H), 3.21- 3.33 Cm, 4H), 3.04-3.14 2H), 2.89-3.00 Cm, 2H), 2.63 21), 2.18 21), 1.72 (br s, 2H), 1.15-1,52 (br m, IOH) Example 15VW: NMM (CDC13) 5 7.13-7.33 10H), 3.99 2H), 3,45-3.71 (br m, 6H), 3.24 Cs, 3H), 3.20-3.33 1c 31), 3.10 3H), 2.89-3.00 2H), 2.10-2.28 (i, 2H), 1.85 (br d, 21), 1.15-1.53 (br m, 11H) E>:am~e Nl (CDC13): 8 7,13-7.57 Cbr m, 11H), ,9F 4.6- (Cd, 1H), 3.98 3.74-3.83 Cm, 2: 46-3 .69 3.22 Cd, iF), 3.01-3,18C, 2.81-2.93 Cr, 3P) 2.66 Cbr i, 2H), 2.23 1H), 1.18- C ,'H *I -e 15 V'1, N! (CDC13) 7.91 Cr, Ii), 7,83 Cs, 2 2CX T.09 Cd, 4.84 IH), 43: 2 H 3.9 1 3,62-3.72 Cmr, 2F), 3.48- 4H) 286,EE-3 26 (br m, 5H), 2,57 Cbr s, 11), 2.39 Cbr s, 2,29 Cm, Ii), 1. 05-1.52 Cbr m, 2E Ex al i5V: (CDC13) a 7,17-7.32 (10H 3. 99 s) 3. 6 (4FHr,) 3.50 (2Fd) 3.09 (2H,dd) 2. 94 (2Ht) 2.E2 2.23 C21i,) 1,233 (14H,m) 1.12 (6Hd), Example 15WB: NMA (CDC13): 8 7,13-7.33 Cm, 1O), 4.02 2H), 3.61 Cm, 2H), 3,50 3.10 (dc, 2H), 2.85-2.97 2H) 2 .82 2H), 2.33 t, 4H), 2.18 (m, 2.06 61), 1.18-1,50 Cbr m, 8H).
Example 15WC: NMR (DMSOd6) 5 10.17, 10.09 (2 singlezs, 21- 3:1 mixture of isomers), 7,08-7.32 Cm, 14) 5.21 2F), 3.70 Cs, 2H), 3,48 Cm, 2H), 3.38 Cd,
I
-300- 2H), 3.03 2H), 2.81 Cm, 2H), 1.91-2.19 (br m, 611), 1.61-1.71 61i), 1.15-1.39 8H) Example 15WD: NIMR CDMSO-d6) a 6.91-7.40 (br m, 14W), 5.01-5.22 1H), 4.61 1H), 4.42-4.50 3.66 1H), 3.12-3,54 (br m, 7W), 3.06 1H), 2.75-2.99 4H), 2.32-2.57 Cm, 4H), 1.94-2.07 1H), 1.05-1.38 (br m, 8H), Example I5W: N MR (CDC13 5 7.18-7.38 Cm, 10H), 7.33 Cs, 1H), 7.06 (rr, 311), 4 .80 Cd, 1H) 4.60 Cd, 2H), 3.94 3.46-3.75 7H), 2.80-3.15 Cm, 7H), 2.23-2.42 rm 2H) E 5 D (br 6H) :E 15E; (ID CW 1 100%) 1 NiR CCD 3
OD,
z 2, 4C 2h, 0.8 Cm, 1W), 1.9 CrT., t. 4, 1E), 2.4 Urm, 2H), 3.6 114 7 rh: C r, 4.4 I) 6.8-7. 4 rn,13H) C 3 OCt, 6H), 3.6 C. C!i, 0 i K NNi (CD3OC 300MHz ,C.C E 4 2H), 4.8 S.4 C, 1 E, >8-P.0 C rr. 3H).
KNP'i (CD30D, 300miJ.z: 3, 6 (r 4 F 6 Ot8 2 -7 ,8 7- :5 :1S 533 10> .ii N11,5 (CD30D, 300Mz) S 2.0 Cr, 3,C (n 4H), 4.7 (al, 2H), 6,8-7d, Ili, Z -0 Cm, 4W), X4, d, 1W), 2. C 2. Cs 4W, 'V8t Li -1W, c~- 7 -301- The structures of the Examples below are shown in Table 2e, Ketal formation: Preparation of Triacetonide (XXVIa): Lithium borohydride (1 .2 gr, 5 6. 2 mmol) was added in four portions to a suspension of L-mannonic--g--lactone gr, 28. 1 ramol) in methanol (250 mL) at 0 0 C over min. Ice bath was removed and reaction stirred at room temperature for 30 min, Reaction was quenched at 0 'C with 2N HC1. Solvent was evaporated and residue taken up in. aceton~e (725 to which 2,2-dimethoxypropaie (20 mL, '6E.6 rnnrz-' and camphorsu~phonic acid (20 cjr, 84,3 rmol were added in fo*u.r portions. Reaction becomes cleier for a few,, minutes arjd then a precipitate forms Reaction stirred roomp temperature for 14 Solvent volume then red-,ced by, 2/3 at reauced pressure and then poured into EtOA:z, washed with saturated NaHC0j,, dried (MgSO 4 C and concentrated., So' -d residue taken up in hexane and f~lvered a pad of si~ca gel. Filtrate concentrated t give tr~acetornide (X'XV-a) as a yeliowi sh solid (7.,1 w< '2-74 1,1S: 303 (M+H,l100%); N MF a. 3 ~m 4 .25 21-H) 15 '21) H W.5 r, 4 V, 1 .5 ts 6H), 1.4 5 6H), 2.4 6H-) *a,0 Selective Acetonide Deprotlection: Preparati.on of Tetraol (XXVIb) Compound (XXVIa) (14 gr) in 70% AcOH (200 mL) was stirred at 45 'C for 2 h, Solvent removed at reduced pressure with a bath temperature of 45 0 C. Residue recrystalized from ether. Mother liquors concentrated and chromatographed (silica, 10% methanol in methylene chlor-ide) to give the desired product as a white solid (6.2 grr, 80%) rr..p. 91-93 0 C; ta)D =-26.40 H120); -302- MS: 240 (M+IIH,- 4 100t); NM (CDC3,300H) 63.95 611) 3.75 4H), 2.5 Cbs, 2H), 1.4 6H) Epoxide Formation: Preparation of Diepoxid?- (XXVIc) A solution of Compound (XXVIb) (1 g, 4.5 mmol) in pYridine (5 mL) was cooled to -20 OC and treated with ptoluenesulfonyl chloride (1.89 g, 10 mmol) Stirring continued at -20 OC for 20 min, 0 OC for 20 min, and 23 OC for 20 min The -eact on was then diluted with methylene chloride and washed with 2N HCl and NaHCO 3 The organic extract was dried over MgSO 4 and co,-centrate; The crude p~oduct was then taken up in megns (4 rr.( and cooled to 0 OC, Next, K 2
CO
3 (3.11 g, 22 mntmc- was added and the reaction stirred at room Tne methanol was then stripped off rcz svaporalte to dryness, epoxide is volatile) r *a thc crde was washed witlh water, extracted with
S
et-heZ, over filtred, and concentrate'.. The wt a p if2.e on Si 0: and elued with 30- 60 0 a 3 300M 63 .8 m 211) 3, 120, Z 2.F Ct, 4 .6F 2H), 1.40 6H, 0H3).
f EpoxiOe: epepartion of Diol (XXVId) *to onzfr. of crrus brcmide--dimethbylJ sulflde ot.. c, E.7 m c in anhydrous TFIF (S mL) at -23 rr- Er 1 rr.1 benzylmagnesium chloride (2t' in THF, "7L3:I, stirr-ed at -20 %I for 30 m..n and at C Vext, Compound (XXVIc) (0,54 g, 3 mmol) it, j: wa *ded, and the reaction stirred at 0 0O sxcess reagent wa- quenched with saturat,,I i ilh-. &and allowed to warm to roes temperature.
Sw~r'. then washed with wateLt and brine e~lh: r ethr:r, dried oler 140504, fte tcid, an 1~ KltWii t, V:ar -303chiomat-ography (30-60% ether/petroleum ether) to yield C.84 g o f an oil, MS 371 (M+H,6 6 NMR
(CDCI
3 300MHz) 7 6 .2-7 .4 10H) 4 65 2H) 3 8 4 H) 2 3. 0 Cm, 4 H) 1.8-2.2 (in, 4H), 1.4 6H-) Hydroxyl Displacement: Preparation of Diazide (XXVIe) To a solution of Compound CXXVId) (0.48 g, 1.3 inmol) and triphenyl phosphine 9, 3.9 mrnol) in THF (5 mL) at 0 00 was added dieth, lazodicarboxylate 61, mL, 3. 9 mmol) and dipheylphosphorylazide (0,84 mL,, 3.9 minol) Contents 1C were allowed to warm to room temperature in the ice bath f or 1 h. The excess, reagents were quenched by the add..tior Of -tethano- (0 .2 mL, 5 mmol) at 0 OC. The rr-i>:ure was then stirred at room temperature for 30 min and then concenzrazed, to a small1 volume. Crude was then p, tu-ified On Si0 2 using 1:4C ethyl acetate/hexane giving C0.245 g of anr c I I. MS: 438 1'H 4
NMR
C.i,300u'zj :u72-7 .4 (mn, IlOH'), 4.18 2.7-3,0 X, 61 2.-0 2 4H) 1.-5 8 6H-), 1ed-zciucn qf Gl.azide XXV Ie I Tc Com;;ound (>XXV e) (0,245 g, 0.58 mmol) in ethanol (6 g)under N 2 was added 10% Pd'C (73 ,5 mng, 30% /weight) Reac-tion st~rred under F.2~ atmosphere at roomr temperature overnite Crude was then f iltered through celite and concentrated. 0,21 g of the diamine was collected as an oil and taken onto next step without further *purification. IS: 369 (M+11l,100%) 141R (CDCl 3 300MHz) 6 7, 05-7,3 1011), 3. 9 Cbs, 211) 3. 05 Cbs., 4H-) 2. 8 Cm, 2 2. 6 Cm, 4 H) 1 ,7 Cbs, 4 H) 1. 35 Cs, 6H).
Cyci~ization of the Diamine: Formation of Cyclic Urea '0 CXXVIf): The diamine (0.21 9, 0,.57 minol) was dissolved in methylene, chloride (SC 5 0tr) and carbonyldiimidazole i:I -304- (0,102 g, J.63 mmol) was added and the reaction stirred at 23 0 C overnite. The solution was then concentrated and purified on SiO 2 using 75% ethyl acetate/hexane as elutenx. which gave 85mg of (XXVIf) as a foam. MS: 395 NMR. (CDC1 3 3001H z) 7.0-7.2 3.6-4.0 4H), 3,6-2.7 4H), 1.8-1.9 4H), 1.3 s, 6H) Mlkylation of the Cyclic Urea (XXVIf): To Compound (XXVIf) (85mg, 0.22 inmol) in dry DMF (3 mL) was added 60% NaH (0.07 g, 1.7 mmol) The solution was stirred for 5 min at room temperature. Next, benzyl brcride (0.1 Tr.L, 0,86 mmo2' was added and the reaction st rred at 23 OC overnite Reaction was then quenched Wi. rc:h anc. (several drops), washed with e: :traCez with ether, dried (MgSO), and concentrated.
u-e wss then purified on silica ge using I:2 Shexanre.'ethyI- acetat- zffording 0.03 g of the bisa a eia t u rea as foa"' M: 575 (M H 1. 00 NNRTI 6 C, 21, 2 2H, 2. C (m, M 1.25 f Cr, .ZS 1 c. :7 -z F.cotnrlide: Pr-epiation of E: epaz-~d bis-alkylated c ,c!c urea (0.03 g, C. in THF (2 mL) at room temperature was added c7:.s cf concentrated I-CI. Reaction stirred at rc :r',r-orature for 2 h. Reaction was then washed with ex.racted with ethyl acetate, dried (MgSO4), r cc ent~rat ed. Chromatography (silica, methanol echl~r gave 0,024 g of example 16A at ScMS. S'3; £35 (MH, 100%); NWI, (CDC13, 300MF.z) 67 1d 2.P Cc, 2W, 2.5 2(21, -305- 3.3-3.4 2H), 2.7-2.8 2H), 2. 5-2.6 2H) 2.1 6H) Alternate Route to XXVIf: Ester Hydrolysis: Synthesis of diacid LIVa To a solution of 100.7 g (458.0 mmol) of (-)-dimethyl- 2 ,3-O-isopropylidine-L-tartrate in 450 mL of ethanol was added 450 ml of 15% sodium hydroxide in water. After stirring 5h the solvent was partially removed under reduced pressure and the residue was diluted with water and extracted with EtOAc. The aqueous layer was then acidified with conc. HC1, 1 saturated with NaC1, and extracted with EtOAc. The ccmbined organic layers were washed with brine and dried over MgSO4. The solvent was removed under reduced 6* I pressure and the solid residue was triturated with
CH
2 C1 2 and hexanas to give 72.2 g of the diacid S as a white solid, .mp 98-100 0 C, H NMR (300 MHz, C C 6 4.83 2H, CH), 1.54 6H, CH 3 Preparation cf Weinreh Amide: Synthesis of LIVb E[ Tc a solution of 30 g (157.8 mmol) of LIVa in 1L of me:hylene chloride was added 60 g (370.0 mmol) of 1,1'carbonyldiimidazole, After stirring 6h, 34.0 g (350 mmcl) of N,Q-dimethylhydroxylamine hydrochloride was added and the resulting solution was stirred overnight.
0 The solvent was partially removed under reduced pressure and the residue was diluted with ethyl acetate, The solution was then acidified with 4N HC1, saturated with NaC1, and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and the residue was triturated with ethyl acetate and hexanes to -306give 35 .6 (g of the bis-Weinreb amide LTVb as a tan solid., 78-80 0 C, 1H NIR (300 ODC1 3 5 5 .16 (s, 2H-, Cl-) 3 .70 6H, OCH 3 3 .22 6H-, CH3) 1 .52 (s, 6H, CH 3 IS (CI ,NH 3 m/e 277 (M+l) Addition of Grignard Reagent Synthesis of diketone LIVc To a solution of 4 .0 g (14.5 rnrol) of the LIVb in 100 mL cf THE was added 20 mL (40 mmol) of 2M octYlmagnesium bromide in THE dropwise. After stirring the solution was quenched with saturated NH 4 C1, acidified with 1N HC11, and was extracted with EtOAc. The comb 'ined_ organic layers were washed with brine and dried over McSO4. The solvezt was removed under reduced 2: pressure an-, tne residuje was chrornatographed on silica ~t~or. wit 7 ethyl acetate i n hexane s gave &C a of b- is-oczyl ket-one L7Vc as an; oil 1
F
CE2I 6 ~5 5 CH-) 2.6e, (dt, 4H-, 1 2~ 4.1H%, C1 2 1 1. 42 61-I, CHj), 1.27 (broad ,2C, 1iC 3 S(IR)m/e 387, 7 Z on. S'ntesi~c of LIVd a z 2:z. C C' 4 .C g (12 .2 mmol) o f L IVc in rt 1, ar.35 rr I of water was added 2.22 g (32.21 o hydroxylamire hydrochloride. After stirrinc cvrr~a~xtthe solvent was partially removed under red'ce~crcssure and the residue was diluted with watei 22 and c- ,:zracz .th EtOAc The combined organic layers were wasnej with brine and dried over NgSO4. The scdlvc- war. removed under reduced pressure and the ~es ws chroma!:ographed on silica gel. Elution with et',K a:etate in hexanes gave 3.76 a of the cxt.mi LIVd as a mix of isomers. tS(i Hj -307- Reduction of Oxime: Synthesis of diamine LIVe To a solution of 3.68 g (8.9 mmol) of LIVd in 70 mL of toluene at 0°C was added 53 mL (80 mmol) of diisobutylaluminum hydride in toluene over 15 min. and the solution was allowed to warm to room temperature.
After stirring overnight the solution was quenched with saturated Rochelle's salt and gently stirred at room temperature. After stirring overnight the solution was extracted with EtOAc and dried over MgSO4. The solvent was removed under reduced pressure and the residue was chroma=ographed on silica gel. Elution with methanol in methylene chloride gave 2.33 g of the 1 diamine LIVe as an oil. 1H NMR (300 M,4z, CDCl 3 6 3.80 2H, CH), 2.68 2H, CH), 1.43 4H, CH 2 1.41 6 .27 (broad s, 24H, CH 2 0.88 6H, 2C Cy'clatior. cf the Diamine: Formation of Cyclic Urea (XXVI f) Tc a solution of 1.35 a (3.5 mmol) of LIVe in 50 mL of 1,2,2-tetrachloroethane was added 620 mg (3.8 25 mmcl) of 1,1'-carbonyldiimidazole. After stirring min the solution was added dropwise over 30 min to 150 mL of refluxing 1,1,2,2-tetrachloroethane. The solution was cooled and was washed with dilute HC1, water, brine, and was dried over MgSO4 The solvent was removed under reduced pressure and the residue was chromatographed on silica gel. Elution with 33% ethyl acetate in hexanes increasing to 50% ethyl acetate in hexanes gave 379 mg (27k) cf the cyclic urea XXVIf. 1H NMR (300 MHz, CDC1 3 6 5.24 2H, NH), 4.07 2H, CH), 3.33 2H, CH), -308- 1.60 4H, CH 2 1.43 6H, C- 3 1.26 (broad s, 24i, CE 2 0.88 61-, CH3); MS CCINH 3 m/e 411 (M+1) ExP.me 15A3 Alkylation of the cyclic urea XXVIf and removal of the acetonide protecting group was carried Out using the procedures described above to give compound 15AJ in a 68% yield. mp. 66-70 0 C. 1 H NMI. (300 MHz, CDCl 3 5 7.32 .0 10,R, aromatic),5.15 2H, CHI2), 3.87 Cd, 2H, CR2), 3.46 2H, CH), 3.26 (br d, 2H, CE), 1.96 2H, OH), 1.60 4H, CE 2 1.26 Cm, 24H, CH 2 0,89 6H-, CE 3 XS M: 3 55- (M-rI p.7 :H H HOc OH
S
0 2n phhy- 7 2 ez -naphhyl nieW rmethyl 3-cyanobenzyl 3--cyenobonzyl 2-naphthy3.
methyl 2 1 3,4-dlhydro;y 3, 4-6hhydrc:y 2-naph;thy, erzyl bery;: methyi* 2E. c yc 1o~p r c 'orrc-.q"w. 2-thier'\ Me Z Yirie 1. hy, meth,' 1 6F 1 6Q a16R a16S I 6T 1 6U 2 EX
EL
S. a6Az- 1 6/ I 6AkE I 6AEF RS SR
RSSR
RSSR
RSSR
RSSR
RSSR
RE -cF RE SRm RE SK.
RE SF, R S -5 F R sS R R z R S S r.
RS SR
RSSR
RSSR
3- VqC (=NOH) benzy.
benzy.
3methoxybenzyl c ycla pr opy a me thyla benz yl benzy a oen zy! Se r. zyI' he xy ben z y be.- zy: ycyloropy: methyl benzyben zy a n-buty! 4hydroxyrnethyl benzy I -309- 3-
(H
2 NC benz yl benzyl 3methoxybenzyl cyclopropyl met hyla benzyl benzyl benzyl benzyl n -hex yll benzy! benzyl' benzyl cyclopropy.
met hyl benzyl benzyl n-butyl 4rydroxymethyl b en zyl 2-thienyl methyl 4..
methylthio ben zy a 2-met ho xy benz yl2 2-met ho xy benzyl 2-met hoxy benz yl 4methylsulfo nylben zyl 3aminoben zyl 4..
ami~nobe n zya irsopropyl 3indc; ylme t I sobut y 2mnethyl thio e t hy 2methyithio ethyl 1-be-nzyl-3in dol1yl2 isobutyl i3 obu tyl 2methylthio ethyl 2 a a 2 2 2 2 2 -310- 16 A' RSSR benzyl ben n-butyl 3 16A~k RSSP. benzy. benzyl n-pentyl +4f 3 16 7% RSSR benzy. benzyl n-hexyl +4 3 1 6Aj RSSR benzyl benzyl n-octyl 3 1 6AY RSSR. benzyl benzyl 3-butenyl 3 1 6AL RS S benzyl benzy 1 4-pentenyl 3 16A.M b~e n z y-'en 2- 3 ethyl bu ty a C RES- ~z yI ez y I 5-hydroxy 4 *pe nr- y 4* **LACb~rtvi4-hydroxy .*but yl L al n-octyl -4-penteny-I 4 :.~3-buteny: 5.3 4- n-buty. 4,4 y o x ra- h yl1 h y d r o Yyt. n y e n Z I~f2. Nriz.~~: rearej as in Scherm- 4.
N c c: ?epa re.-I as cornpovnL, ir, Tarz~e !A.
e repared as in Scheme 28, 2. e pa ?ret ar Iliby 'ydroborat jor c'f the corresponding Sbe~o &re przysical ciaza for retrresenta,:iv,- -312- Example 16AG: mp 109-114C MS m/e 439 (M+H) Example Example Example Example Example Example Example Example Example Example E:x: a mpl e E xa mz le Ex.am= I 1 6AH: 16AI 2 GAJ: 16AK: 16AL: 167VI: 16AO: 16AP: 1 6AQ: 16AR: 16 AS mp mp mp mp
MS
mp mp
S
mp mp mp rrP rrp 94-97 00C MS m/e 457 (M+H) 7 9 L12 MS m/e 495 (M+H) 66-70'C. MS m/e 551 (M+H) 123-12 6 0 C. MS m/e 435 (M+H) m/e 453 91-94 0 C. MS m/e 495 (M+H) 111-11G6 0 C. IMS m/e 4991 (M+H) m/e 483 (M+H) 73-74 0 C. 1MS m/e 451 (M+H) 73-75'C. MS m/e 395 (M-I-H) 1o-111 0 C, MS m/e 353 (M+H) 11Q-1140C. MS m/e 335 114-116 0 C. 1%S m/e 499 (M+H) r
I
1 i r
P,~
.r r Sx' es 5 of 0 uiorea (XXVITa) iar -,loirr. Ccs.z:ouno (XXIc, (22.459, 4>1 mmol) d Csc>; r 2*0 rL of tetranydrofurar ancr-; tc thi 23~ (5.5 rwn.;ol of thiocarbcnr," Afe stirrng the mixture for 18 hours at: roc:7 zemperaure "7L (10.1:10 ethyl acetate: ethanol: irz-cat ez cc-.lete a r Ion. The reartion r r; re wi= taker: tc dryresE and the solid residue :f..rt:e~f r f&sz :hc~r~ireogrl-p (silica gel, 250q, 1:1 e r.er:ar: to prcvioe solid which tr;t rate; wizh I-exane to provide 17.8g (73% yield) of S''thei~s of Compound (XXVIIb) m: (XXV-a) (3,1084, Grnmol) was dissolved in an:- to this solution was added methy' 4m.24mx v-'a ,ri~loe anv. zirred at roo- ?ii;LiW C' T h e t a K~i~~ -311- Example 16Q: mp 214 0
C
Example 16R: mp 192-193 0
C
Example 16S: mp 155-1560C Example 16T: mp 194-1950C Example 16U: mp 244 0
C
Example 16X: mp 112-113 0 C. MS 427 (100, K 1) Example 16Y: MIS: 585.2 (100, NMR(CDC1 3 88.02 (s, 2H), 7.55 2H), 7.4 2H), 7.01 4H), 6.79 (s, 2H), 4.84 2H), 3.78 4H), 3.2 6H) Example 162: MS: 475,2 (100, NMR(CDCl 3 6 7.48- 7.22 10H), 4.76-4.4 (dd, 41), 3.8 2H), 3.62 (m, 2H), 2.23 2H), 1.73 2H), 1.59 4H), 1.36 (m, 4H), 0,76 6H), 0.61 6H) 1 xiample 16A.: S: 475.0 (100, M+H) NMR(CDCl 3 .41-7.18 10 5.01 2H), 4.01 2H), 3.65- 3..41 5H), 3.C01 (di, 2.6-2,3 2.0 (m, 1,25 2H) :ample 16AE: MS: 403.2 (100, NMR(CDCl 3 8 3,97 2C 28), 3.8-3.6 41, 2.8-2.4 8H), 2.24 2H), C62 2,03 28), 0,52 41H), 0.32-0.14 (m, 4H) I *xamiple 16AI: MS: 765.5 (59, M+H) 382.1 (100), 274 (97).
NMR(CDC1 3 6 7.53 21i;, .35-7.0 268), 6.63 (s, 2 2H), 5,24 2 l, 5.23 (Cs, 21), 4.82 2H), 3.8 (s, 41), 3.-3.08 GM), 2.37 2H) :ample XS: 439. 2 NMIR (CDC1) 6 7, 39-7 28 5.29 4H: 3.85 4H), 3.50 28), 3.38 2H), 1,95 2H), 1,75 4H), 1.38 2H), 0.92 2: 0.85 6H) Example 16A-: KS: 4 9.2 NMR (CDC1 3 7.39-7.28 5,19 48), 3,85 4H), 3.50 2H), 3,38 2H), 1,95 2H), 1.75 Cm, 41H), 1,38 2H), 0.92 61), 0,85 6H) 35 MS: 439 .2 *Example 16KE: MS: 371 NKR (CDC13) 6 4.0 28) 3,85 28), 3,35 2,65 2H), 2.35 2H1), 1.82 Cm, 2H), 1,75-1.24 128), 0.91 18H) Example 16AF: MS: 552 (100, M+N1 4 535 (61, MfH)), 516 NKR(CDC1 3 6 7.38 8H), 5.05 2H), 4,68 3.98 2H), 3.65 2H), 3.52 28), 3,43 2H, 2.57 2H), 2.42 2H)I, 2.03 61H), 1.97 4R), 0.84 4H) -313to dryness. The residue was dissolved in 3Oml dimethylformamide and to this solution, cooled in a O 0
C
ice bath, was added NaH (60% in oil) 720mg (18mmoI) slowly (EVOLUTION!i), The contents were stirred at room temperature for 30 minutes, The mixture was cooled in a 000 ice bath and benzyl bromide (2 .052g, 12mmol) was added via syringe and stirred at room temperature for 18 hours, TLC (2:3 EtOAc:Hexane Rf=0,25) indicated a complete reaction, The reaction was worked up by diluting with water (300m1) and extracting with iiethyl ether (3x50m1), The organic layer was dried over magnesium sulfar.e and the filtrate taken to dryness.
The residue was purified on SiO 2 gel (200g; 2:3 EtQAc:Hexane) tc prcvide 2.923g (78,21,, yield) of XXVIIb :~as a cclorless oill 4 Snhes 2O rc (XXV\'c)o (XXVTd) Comopoun" (2 930a, 4, G5mmrno> was di-'ssolved in 2: 25m! pyd-'ne andz tz tnis solution was added 7 42mg (4 ~5z) ben-zyhydroxylam~ne hydrochloride. The corten~s were refluxed in a 125*0 oil bath for 18 hours, (0-auzion: merhyl mercaptan is a by-product and the reaz rn snould be ven"-ed to a Clorox scrubber) .TLC 'nidnca:ed a complete reaction. The reaction was diluted wi:h dic".1-ororrethane. The organiLc layer was wased wth l H1 (2x300m1) followed by sat, sodium bcarbonate solution (100m1). It was separated and dried over magnesium sulfate and the filtrate taken to 3C dryness, The residue was purified on SiO 2 gel (130g,, using 1:3 EtOAc:Rexane) to provide 584mrg (18.0% yield) of Compound (XXVI1c) as a colorless oil. 1:2 EtOAc:Hex:ane was used to provide 2,113g of a side product thiourea CXXVIld).
S,.*-,zhesis of Oxime (XXVIe) Compound (XXVI1c) (584mg, 0.8lmmnol) was dissolved in 5ml dimethylformamide and to -this solution, cooled in a O'C ice bath, was added NaH( 60% in oil) 80mg (2mmol) slowly (EVOLUTION!) The contents were stirred at room temperature for 30 minutes. The mi:~ture was cooled in a O'C ice bath and benzyl bromide (0.24ml, 2mmol) was added via syringe and stirred at room temperature for 18 hours TLC (1 :3 EtQAc :Hexane Rf=O. 26) indicated a complete reaction, The reaction was worked uip by diluting with water (50m1) and extracting with diethyl ether (2x25m1) The organic layer was dried over mragrlesium sulfate and the filtrate taken to dryness.
The resid*K;e was puri fied On Si0 2 gel (33g; 1:3 E tC:h;:r- tc przvz,_de 491,- (74,24 yield) of a cf trE, ,e below are shown in X >$7g,7,58mrnol) was dissolved in 7. t Cr to solutaor., cooled in a C 0 C ice batr, 'to z ~hl~rnprdn and 16r.ml rrhcidk Tie contents were s*tlrrezi4 L. rn:: ts :n-e r a -ir e ffcr 18 h ou rs. TLC (1:43 EtQAc:Rexane tateo a complete reaction. The reaction was *~wi:.2E50i. oichloromethane. The organic layer wasw~sed ithIN HCI (2x300m1) followed by sat, sodiur zazatesolution (lO0ml) It was separated and r~r~ an, siut% sulfate and the filtrate taken to reridue wa ai dOn SiO Qel 201 .roPV~2,. of XV -315- Nitration of Benzyl Group: Compound (XXVIIIb) and (XXVIIIc).
Compound (XXVII~a) (518mg, lmrnol) was dissolved in 41ml acetonitrile and to this solution, cooled in a dry ice-acetone bath, was added 4,Aml (2.2mmo.) 0.511 Ni4tronium tetrafluoroborate in sulfolane. The contents were stored in a -40'C freezer for 18 hours. TLC irndicated a complete reaction. The reaction was diluted I C w .h lO0mi ether and washed with water (2Y50mL) The organic layer was dried over magnesium sulfate and the filtrate ta~zen to dryness. The residue was purified o:, S ge (7 5g; 3 E' -AC: Hex'ane f or XXVI b, I2:2 E:-z:.Hexan e f cr XXVI 11c) t c provide 10 6r, (1'7.4 1 y, e -0 I. cf XXVII li a. a wh:.te sol id and 1 59m t2 6.2 yield) of as a w~ieso, d.
A. ynthesciz of 4-Fl-utrobenzx'l Cyclit Urea (XXXI) F* 0 N0 N F.
M00 E i bMEM (XXX1) The synthesis of 4-fluorobenzyl cyclic urea is oi;tlined in Scheme 7. N-acetyl-D-4-fluorophenylalanine methyl ester (23.9 g, 0.1 mol), obtained using the procedure of MJ. 4,urk Am. Chern. Soc, 1991, 113, 8518), was dissolved in 40 mL of acetic acia and treated with 100 mL of concentrated HCl, 40 mL, of water and heated to reflux for 5 hrs. The solution was cooled to room temperature anid then made basic (pH -10) with NaOS4 while cooling in an ice bath, Benzyi' chlorofor-mate -316m-1, 29 g, r,.17 and NaOF, are added in four portions and the solution is maintained alkaline by the addition of NaO-L The mixture is then stirred at rt for min. The alkaline solution is extracted wit-4 ether (2 X 500 mL) and the solution acidified with conc HCI to pH 1. The precipitate is extracted into methylene chloride and dried over tMgSO 4 The solution is filtered and concentrated to give 20 g of the N-Cbz-D-4fluorophenylalanine as a white solid that is used without -further purification.
A solution of N,O-dimethylhydroxylamine hydrochloride (8.0 g, 0.082 mol) in DIM is prepared by ae7ntle wiurninc The solution is allowed to cool slightly ant_ treatec it N-me:hylrnorphoiine (8.2 g, 0.082 mol) 2 a: :e with~r -iF to facilitate t.ransfering of the t..C 4 f uc o h n l .Ln n (2 9 rr-z is :reared ith- N-methylmorpholzine Cc ma'ti a ,d4 codedr~ to 000 in an ice bath To, cc* 1n n is! ad-ied isobutylI f I Tnie r. the solution of N,C0c>:~amr~ein EDtF prepared above is added and e- r eZ i:t n m x ir c is Stie -or 20 mins. M~ost of th r vcz'z or. a rotorary evap~orator and the -nedbete,.i water and methylenec- ci or-nic layer is washed successively wt i~ 2 2 Na4~,wat*el,, brine and then dried over then filtered and concentratea a -t !,et rtciue chroratographed on silica gel (50-1.
togivc 16 g of the amnide.
o2~c the p~rocedure Of LY J-A. F~hrentz and B.
Z~ tr (Zyrzh;ess, 1983, 676) Eil g (0.03) mol) of N-Cbz- L"-.-~2:r~tren~lalanne ,0-dimethylhydroxylamide wa.6 zu- 9.C of N-',Cbz-D--fluorophenyl%,alan' nal -317obtained as a thick oil that was used without further purification.
N-Cbz-D-4-fluorophenylalaninal (9.0 g 0.031 mol) was converted, using procedure 1, to (2R,3S,4S,5R)-2.5bis (N-Cbz-arnino) 4-dihydroxy-1, 6-di (4fluorophenyl)hexane (4 g) obtained as a white solid.
MS:' (CI, NqH 3 605, The (2R, 3S, 4S, 5R) 5-bis (N-Cbz-arnino) 4dihyd~roxy-1, 6-di (4-fluorophenyl) hexane (4 .0 g, 0. 0066 mol) was converted, as described in procedure 4, to 1.3 g of the 4-fluorobenzyl cycli~c urea (XXXI) obtained as a white solid. MS: (CI, NH 3 539.3 E. The- 4--'luorobenzyl cyclic urea (XXXI) (270 mg, C .5mm: was alk\'iated with 3-benzoxybenzyl chloride mc, 12.5 mmcl) according to general procedure 5. The resul;t ing inzermediate was dissolved in THE' and rhydrogenated for 12 hours (200 mrg 10% Pd/C, 55 psi4) to remove the benzyl protecting groups. The MEM group was 23 then removed, acco-rding to general procedure 5, to give, after chromatoar ap-,;y on HRLC (silica gel, Me-OH/CXCl 3 143 mc: of Exampl~e 20G as a white foam. MS: (M1- 575.2 (100%) F:,amle Evariaio othabv-described methods, the title compound was prepared. NM4R (C~DC 3 67.12-7.32 (n 12H-) 6,61-6.83 (mn, 6H) 4.91 2H) 3.80 6H) 3.64 (m,2H) 3,55 2H) 3,10 2H1) 3.00 (in, 4H) 2.11 (s, 2H), 0 R. 22 N ,R 23
'OH
Lx, No.
E
22 a 23
HPLC
0r Spef (6 6, 4.
S 4.
4*4 4 4* 4. 4 6. *4 .4 S 4* 4.
*4 44 4 94 4.
S
*54* 4, *4 4 3- (Ii 2 ?C 1 benzyl 2 C, (C ben:y r. ;yz ny 2CC 0 Z en: 4-f iuoro ben zyl benz yl 4-f luoro bernzyl ben y 4 1u orc, ber, be nz 1 be r. Z'; 4-fluoro benz yl benzyl, 4-fluorc benzyl 4 -f luor-o benzy2.
4-fJluoro ben zyl benzyl (64 4., be r, I 77755 .4 9* 4. 0 Sn.
44 4 4 4.
W been", V C benz.v- Zv oa riz,,, d 7 Z X %Ie22W4 2, 4- 4-f 1u~rc benz yl 4-f I uoro be nzv 4 U1 0 r 0 be n 1; b 1,z' 3rhe 1hc>:ybe n zvI 4 -fluoro ben 2,v 2 3, 4d~ fluoro b er.z v 4d _4f 1u otc ben z y 1 3, 4di fIuo..' I, .z z.
v +1 +i 4 4 (7:2.
+1 4-hydroxylnethyl 3,4'benzyl difluoro benz y! 3-(X 2 3,4benzy! difluorr, benzy-I 3-(H2NC-(=NOH))- 3,4benzyl difluoro ben zy I 2 OA.E R 22 4-fluoro cyclopropyl benzyl me thy a,3_ 3- (3-pyrazolyl benzy- -319- 3, 4dif luoro benz yl 3, '4difluoro benzyl 3, 4difluoro benzyl 4-fluoro benz yl 639. 4 665.2 695.
573.2 495 567 123- 126 145- 147 2 0AF c' 2 OM-* 2 4 c 2 0 72 4-h_ 20 OAY .9 en.
96 00 0 0@ 6 0 00 S 0@ 0@ 00 SO 0 0 0* 0 0 0 00 50 0 6060 00 0 00* o 0600 *0 6 0 0060 60 0 00
S@
2OAL 2 0 Al: 2 cA 2 GL.
yclopropyl 4-methcxy methyl benzyl1 benzyl 4-methoxy benzyL' -naph~hvl 4-methoxy me Z. h bernzyv arbomethoxy 4-me-h zy benzy! benzy\K ciroxyme hy 14 -me zhc.:y benzy. benzyl benzy" 4-hydcirxy benz y alyI- 4-ezhz, benzvl'4e thoxy, benzv- benzy morphol tr, y 1e th ox v) bennz' p 3-mezhcxv be nz y n-zuth 3-ydr:cx y ben zvl* h y-4r oxy 3 -h ydr ox y benzyl benzy.2 n-butyl 3- (P 2 NC (0)
CH
2 0) benz yl 'clopropyl 3-methoxy methyl benzyl droxy 3-metlhoxy ylbenzyl benzyl methoxy 3-methoxy benzyl benzyl 'clopropyl 3methyl (Etoc (0) b en z yl 4 methoxy benzyl 4 -methoxy benzy-' 4 -met ho.x.y benzy-* 4 -metho'.y benzy.' 4 -methoxy benz yl 4 -hydroxy benz y 4-me thoxv be nz yl 4- (2hyd rox y e tho xy) benz y 4- (2hy\dc ox y e th ox y) benzyl 3-me thoxy benz yl 3 -hyd rox y benzyl 3-hydra xy benzy, 3-.
(11 2 NC (0) benzyl 3-me thoxy benzyl 3-imethoxy ben zy 1 3-methoxy benzyl 3- (Etoc (0) benz 1
K
179- 180 +44 4 -t 129- 627 13~ 1 6 44) 101- 103 205.,4 3 E7- 182. 1 54 1 181,2 5r7 1 201-.- 2 O;AR cy 4-hy meth 3cy 4+4 101.3 581 -320- Tal 2- 0 R 2 2 4N
AN
IL
9 0 +41+
MS
(MNHI)
505 .2 424 2 bezz 2y i (414) cf Mc Examples Mo are Fnj rai.% Athe Cy.clic Urea (xD:1:ia, 0 HN H ;Ai 1 cn r-Amino-- xyca rbony lamino) -j ptnw-?- (-ezhox:yethoxyraethyl) pentane, -321- A mixture of 595 mg (12.50 rnmole) of 4-azido-2- (tbutoxycarbonylamino-1, 5-diphenyl-3-hydroxypentane (EP 0 402 646 Al) 10 ml of dioxane, 0.2 ml (1.75 mynole) of IEX chloride, and 0.32 ml (1.83 mmole) of diisopropylethylamine was heated at 80'C for 16 hrs.
Evaporated the solvent and purified the residue by flash chromatography on silica gel with 85:15 hexane-ethyl.
acetate to give 0.64 g of an oil. Mass spec 485.2. This was reduced to the title compound IC with hydrogen using 100 mg of 10 Pd on carbon in ml of ethyl acetate and 0.6 ml of acetic acid in 49% yield.
E. Fre-,arat icn 3- 2, 4-d iamino- I5-dpnenyl -3hvr o.:v'oe:-,an e The produczt fromr Part ;A (218 mg) was dissolved in 2 rr-I of ice cold trif'luoroacet ic acid d-ic hl1o r hian e After 1 hr the solution was poured n~c a rrixzure ofso~~ bicarbonate solution and ethyl acetat-e. The acetate extract yielded 163 mg o'f tndesiret c-a7.-nc =ccocund.
U. C.ztc. of the Diamine The pr-odJr* -from Part B (146 mg) 1 ,75 mg of carbonyl d.l.uridazole, and 0. 15 r-.1 of diisopropylethylamine were dissolved in 2.5 ml of anydrous THF and stirred at room temperature for 16 hrs. The solvent was evaporated, The residue was purified by preparative TLC on silica gel with 90:10 dichioromethane methanol to give 108 mg (69 of the cyclic urea. Mass spec 385 V1 N-Alkylation of the Cyclic Urea (XXXIIIa): -32 2- D. The product from Part C (93 mg) was dissolved in ml of anhydrous DICE, and 100 mg of 60% NaH in mineral oil was added. The mixture was stirred for one hr, m-Benzyi.oxbenzyl chloride (350 mg) was added, and the mixture was stirred for 16 hrs at room temperature.
Water and ethyl ace':ate were added. The ethyl acetate extract was washed with water, dried and evaporated.
The residue was purified by prep TLC on silica gel with 60:40 hexane ethyl acetate to give 105 mg of the desired bis-alkylated product. Mass spec (M-fH) 777.,5 Depr~eztor- o- Prczeczirnc Groups (Examplp 22A): RTh~e prcauc'_ from part 0 (103 mg) was dissolved in 41.
I~ d HC f Cr I C rrS. The soluzion was evaporated anc' pur' e z prez T-C~ on. silica gel- with 60:40 hexane eu..acetaze. Mass spec =689 The purified rster,:l ws ',ydrogenate6 for 16 hrs in the presence of e~ar~. .0.2 ml of acetic acid, and 35 mg of 1C 110 ~a~nle227 Ms soec Mh sr";c:urcEs cf the E>:am:.'les below are snow,- ir es; nt e raidia te (XXXT Compound XXIc E 4 S-5mincl) was dissolved in pyridine (37.5mL' z: th-s solution was added sulfamide (572mg, iz.. r"r~ e contents were refluxed in a 125'C oil h fr I hours. (Caution: Ammonia is a by-prodiuct an. tJ~ reacz'.:cn should be we>. vented). TLC(121 x ie Rf 2) indicated a complet e react-o i ws 'Ilut-ediwt 200rt,.' ''1ehr n. h.
w.wasr-d wi'th f~tr30~ ~z~c'w t.% -323- 1iN HCL(2x100ml) and sat. sodium bicarbonate solution The organic- layer was dried over magnesium sulfate and the filtrate taken to dryness. The residue was purified on Silica gel (130g; using 1:1 EtOAc:Hexane followed by 20:1:20 EtOAc:EtOH:Hexane) to provide 2.412g (75.3% yield) of the desired intermediate (XXIVa) as a white solid.
Intermediate (XXXIVa) (269mg, 0.Smmol) was dissolved in dimethylformamide (3mL) and to this solution, cooled in a 0°C ice bath, was slowly added sodium hydride (60% in oil, 80mg, 2mmol) (EVOLUTION!).
The contents were stirred at room temperature for minutes. The mixture was cooled in a 0°C ice bath and (bromomethyl)cyclopropane (C.19.r.L, 2mmol) was added via svringe and stirred at room temperature for 18 hours.
TLC(2 :2 EtOAc:Hexane Rf=0.3) indicated a complete reaction. The reaction was worked up by diluting with water (50r.L) and extracting with diethyl ether (2x25mL) 2 The orcanic layer was dried over magnesium sulfate and t*ce filtrate taken to dryness. The residue was placed a 50mI- R.B. flask and dissolved in methanol (3mL) and tc the flask was added 4M Hi1 in dioxane (3mL, 12mmol) an. the mixt:ure stirred at room temperature for 18 2E hours. TLC (2:3 EtOAc:Hexane Rf=0.3) indicated a coplete reaction. The mixture was worked up by quenching in sat. sodium bicarbonate (25ml) and extracting with dichloromethane (2x25mL) The organic extracts were dried over magnesium sulfate and the filtrate taken to dryness. The residue was purified on silica gel (55g; 1:2 EtOAc:Hexane followed by 1:1) to provide 129mg (54 8% yield) of the title compound as a white solid. m.p,71-72°C Example 23r Intermediate (XXXIVa) from Example 23F (538mg, 2.Ommol) was dissolved in N,N-dimethylformamide and to thi3 solution, cooled in a 0 0 C ice bath, was slowly added sodium hydride (60% in oil, 160mg, 4mrnol) (EVOLUTION!). The contents were stirred at room temperature for 30 minutes. The mixture was cooled in a 0 0 C ice bath and m-benzylox:ybenzyl chloride (931mg, 4rnmol) was added as a solid and thc- mixture stirred at room Lemperatuzz- for 18 hours. TLC (1:2 EtOAc:iiexane Rf=0.25) indicated a complete reaction. The reaction w-=z worked u lv diluting with water(1O0mL) and ciethyl ether (2x5OML) The organic 1 lave-- was reD ver magnesium sulfate and the filtrat-e Sc cryne s. The residue was purified on silica 7E:- 2 cwed EtOAc:1-Hexane) to provide.
yieldi othintermediate (XXXI%,bh) (where **m-benzylo :\benzyl) aE a colorless foam.
VO~m, 75nunol, a :r ocoano:(3,5rl) and to this solution z:e 'n a bath, was added 4M HCl ir dioxane (2 1r:L ff.zc": ar.- the mixture stirred at room z c o~ 1 1,ou r s. TLCr- (1:2 EtOAc:H-exane r:;7 eJ a ccmpI .e te reac t ion The mi: ture wat cV zjecc"nng in satsodiur. bicarbonate Sm anne:.nr~zrro wth dichioromethane (2x50mL), The oror.~ exr~.n~w-2re dried over magnesium 3ulfate ann the Cnira-nc tak-en to dryness. The residue was purifiedon s.ncegti(75--; 1:2 followed by 2:3 EtOAc:Hexane) to crc~ 37no(EC2J,-5 yiEld) of th, title compound as a -32 Example 23C (257mg, 0.34mmol) was dissolved in a mixture of ethanol (5mL) and dioxa,,e (5KW) .To the mixture was added palladium hydroxide on Carbon 100mg) and the suspension stirred for 18 hours under hydrogen (I atm) TLC(10:l:l0 EtOAc:EtO-i:H-exane Rf=0.3) indicated a complete reaction, The suspension was filtered through a celite pad and the filtrate taken to dryness, The residue was purified on silica gel (33g; 1:1 EtOAc:Hexan, followed by 20:1:20 EtOAc:EtOR:Hexane) to provide 162mg (82.9%1 yield) of the desired compound as a white scl rr.p. 123-124 0
C.
0 0 R 22 N N N 23 Ph Ph HC OH 237, 235 2 3C 23-- 23E 23F 2 3G 23 H 231 233 23K 23L 2 31- 2 3N 2 3,Q
H
p- (HOCH 2 -C6X 4
CH
2 r (CEh5Ck O) -CEH 4 chZm- (HO) -C6H 4 CH2allyl c yelop ropy lineth y1 n-butyl 2-naphthylmethyl benzyl p- (CGH 5
CH
2 0) C 6 4
CH:--
P- (HO) -C 6
H
4
CH
2 m-nitrobenzyl m-aminobenzyl m- (HOCH 2
-C
6 H4CH 2
M((CH
3 2
NCH
2 CZO)
C
6 H4CH7m- (CH 3 0CHZ) -C 6
H
4
CH
2 M- (CH0) C6H 4
CH
2 cH 2 -tet rahydrofuran-3-yl' +4 4+ 4+4 ++4 Ma ssSpec M H 1C 9 C M;2 0
C
+4 +4+t ++4 ++4 +4+ 253-255 363.1387 189-190 603,2528 194-195 755.3155 123-124 575.2216 212-113 443.2005 71-72 471.2318 oil 475.2631 211-212 643.2631 159-161 543.2306 755.3147 223-225 (592.2486) 196-198 633.2014 212-214 573.2535 603.2540 137-139 743.3596 152-154 +4-4 +4+4 91-93 +4 97-99 631 .2832 599.2211 531 .2533 23S mn-(HON=CH) -C6H- 4 CH2- 2 37 m- (CH-,CO) -C 6
H
4 CH2- 23U m- (HON=C (Ch, 3
-C
6
HCH
2 23V
CH
3 23W CH 2
CH
3 23X
CH
2
CH
2 CH3 23Y m- (CN) -C 6
H
4
CH
2 23Z m-(2-(4-morpholino)ethlllNHC
C
6
H
4
CH
2 23AA m- N-dimethylamino) -ethyNHC
C
6
H
4
CH
2 23AB m- (2-amidno-4-thienyl)
C
6 H4CH2,- 23AC 5-hyciroxypentyl 23AkD 6-hvdroxypentyl 2 3A- p' 2 2 5-hydroxypentyl R, H 2 3A7 p2 2 yd z-OxyPe n-V 1 n a h I.r me hyl h' n'0dxyoe r.zy1 -3256- +44 105-107 96-99 110-113 2 00-203 182-185 145-248 146-149 119-122 (646.2708) 627.2523 657.2739 391 .1696 419.2007 447 .2316 593.2227 855. 4111 127-130 771.3903 4+4 285-190 4+i +4 +4 1 4/.
(552) (580) (466) (606) (586) (586) +4, -e a- e s> n. C. n eo.aeSl z a scluzior, of diamine XX I c C0 rz C2 m r7.) :r ethamz2c (3 mwas added moobyd ra ze, (2 9 mg, 0 .2 2 rmcl) A~ s:.:ic :Cn-.ir dims- hyla ce amide dime thyrr2 C.2 mmc.) waE added. The reaction w a t n )m Ueinperature for 25 min, and f :f'x ed fc2 Af ter cool ng to room o ~t ra t~ethe rea±ction was evaporated in vacuo arnd r~aror-.ceb berwN.een 5 NaOH and CH2C!2. The organic V- -r."en washE- with sutiuirated NaCl, dried C. a.:eva-. rrated leav. 100 m~of Intermedia-te C- .cSo.'C' 9 -32 7- E:amoles 21E anid 21C To a suspension of 605c NaH' (160 mg, 4 .0 rnol; washed twice with hexane) in DMF (3mL) was added a solution of Intermediate (XXXIVb) (100 mg, 0.20 mmol.) in DI4F (7 mL) After stirring for 35 min. a solution of 4-tetrahydro-pyiranyloxymethylbenzyI chloride (XXXIVc) (0.53g, 2.20 mmol.) in D1,1F (2 mL) was added followed by addition of potassium iodide (0.33 g, 2.0 mmol.) After stirring overnight, additional chloride (XXXIVc) (0.53 g, 2.20 mnrol,) was added arid the reaction was heated to an 'trred overnight. The reaction was quenched by *ad- t ion of acet ic acid (1 mL) in E:2C (100 mL) After 7C -~bsficaticn% with NaOHI, the organic phase was washed wi'th water briLne (2X) dried (Na2SOO) and e evap tr a dI e a v_4nc 2. a o f a v.e 11ow o Th is ma ter ia I WazS zt.en uc in, met.na-c-, (10 rmL-) and 41r HCl in dioxane (5 was added. After str~aoverrnight, the reaction .:2C w=as evaporated in vacua a nd partitioned between 5% NaOH arnc CH22, T".z organ~ic phase was dried and evaporated ieavlr. i 1 a of an orange ol. Colurm chromatography (lsh* sIlica gel; 5% MeOH/ CF2012 and NH4Ol-i) gave I 2rrr: cf' Ex:a-m-'E 24 E and 300V of ExampI e 2 40-, bot h a s wie s:i.
E 7' L ~4T Mass spec. 1 2 j=445.2; nip 105-1100C (PC! salt) Examnle 240: mass spec. V1 4 565.5; mp 72-75 OC (Note: The mass spec is M 4 since this is already a charged species,) Ex:ample 24A -328- By an analogous process reported above, and instead using benzy! chloride, the desired product was obtained.
The acid deprotection step was not performed in this instance.
Exampnie 24A 1IH NKR (3001Mlz, CDC1 3 90-7. 35 (mn, 4 .0 9 4. 1 2 H) 3. 56 (dd, 2 H) 3 .13 (dd, 1 H), 2.50-2.95 (mn, 5 1.97 3 Mass spec, H+- 415.1, inn 130-137 OC, Tahlp 2n 6 0 0** 0*
S
4 4 CH2 2 L 4 7 be zy ben z.y M S~ 0B~ 4 #0 6 6 6* re c :e L:~i~sbelow, ar Fnown
C..
r ~~cu~e(XLVa) (3S, 5R) -5-f (1 IR) -11-f[ (t Ewy vyc~bonl) inin~-2-phenethyll-3- 2tezz-.drofuran-2-ane, can be prepaced frc'- I 5:-rh .n an tre following the 8-step procedure of c zee, c< j Iocherrn, 1992, ji, 664E-E659.T i. 7d (XL1A'I usirc he c~ -329- B.E. Evans, ec al Org. Chem. 1985, 50, 4615-4625), wherein a solution of Butyloxycarbonyl) amino)-2'-phenethyl]-3phenylmethyltetrahydrofuran-2-one (XLVa) (11.0 g, mmol) in 15 mL of dioxane/7.5 mL of water was treated with 2.7 mL of 1 N NaOH dropwise. The mixture was stirred at room temperature for 30 min. and then concentrated at rt on a rotary evaporator. The residue was acidified with 10% citric acid and extracted into ether. The ether extract was washed with water, brine and dried over MgSO4. The solution was filtered and concentrated to give the hydroxy acid as white solid.
The hydroxy acid was immediately dissolved in dry D:-F and treated wiTh t-butyldimechylsilyl chloride 15 (2.6g, 17.5 mmul) and imidazole The mixture was stirred overnight at room temperature. Analysis by TLC (50:50 EtOAc/Hex) showed no starting material remained,
C
a= which time the solution was concenti. ted in vacuo and the residue acidified tc pH 4 with 10% citric acid and C extracted into ether. The ether extract was washed with *1 water, brine ar;. dried over MgSO 4 The solution was filtered and concentrated to give 1,7 g of the silyl ether-silyl ester as a colorless syrup.
A solution of the silyl ether-silyl ester in 5 tetrahydrofurar, (THF, 10 mL) was treated with 10 mL of glacial acid and water (3 mL) The solution was stirred at roor temperature for 2.5 hrs until analysis by TLC showed complete conversion to silyl ether- acid (XLVb).
The solution was concentrated in vacuo and the resulting residue diluted with water and extracted into ether.
The ether extract was washed with water, brine and dried over MgSO4. The solution was filtered and concentrated to give the acid (XLVb) as a solid.
A solution of the acid (XLVb) in dioxane was Streated with N-hydroxy succinimide (290mg, 2.5 mmol) and 1,3-dicyclohexylcarbodiimide (DCC, 500rmg, 2.5 mmnol) and -330stirred overiiight., The solution was cooled in an ice bath and the solids were filtered off. The filtrate was concentrated to give the activated ester (XLVc) as a sticky foam. MS =625,5 (M±H-BOC)+= 525.4 (100%), The above activated ester (XLVc) was dissolved in ether, cooled in an ice bath and treated with }iCl(g) for minutes and stirred at 0 0 C for a- additional hour.
The solution was con--entrated i. 'acuo at RT to give a white foam, This was dissolved in THF (100 mL) and made basic with tr4,ethyamine (3 rnL) The resulting suspension was stirred at roomr temperature overnight. The soluition was concen rated and the residue was chromatographed on gel (mediurr. pressure LC, ethyl acetate) This :E furzher pu,.rified by HPLC chromnatography on silica gel 5':5 £tAc/}iex)tcgive 170 mg (17% overall yield.' C *s -er-z cf' the laco:a7 (XLV.) a s a colorless il. XIS =410.2 (100%) I, s:2utJ'on of (XLVd) (170 mg, 0,42 mmoi.) in DI 2treated witt. G NaHl in oil ~re n~ d 5 tl 1- re d eat 0C. ft. r 30 minute-ss.
n Zao (205 mrg, 0,44 rrn,l) was added and sti~rred f-1hoz' r an~d the reaction was allowed to warm to rooTc Th mi~urewas cooled to C"C a, d quenched~ w" dluted wi th wapter, The suspension wa e :ate i~tzeth1-yl acetate, washed with water, brin~e, ~rie ov: MS'4anc concentrated, The residtue was Ht ,C cnra:~rathe r n sillica. gol (.20t~ EtOAc/Hex) toqiv (Zhas a Cc -oIec s, fIM. MS 0 SOC s:ilsvl ether-lactan (XLVfl (130 Mgt 0,2Smol) was Cs2:11ved in- tetrabutylamnonivnt fluoride (TEAF, 1 M sc.1Qtior, and stirzed at room temperature .<ute. The solution was diluted with water ~t yl cette ThO ex*tracts werse WaSheG- ~dr-ied over Mrj,;C51h1 n. roc,-tratv2 -33>- The residue was H?LT chromatographed or s~ilica gel EuOAc/Hex) to give 79mg of Example 25A (XLVg) as a white foari. I-S (+-h=386.2 (100%) -332"- Taabi 2o 0
R
22 R2
'IN
R
4
OH
M S Fz~ B22 a 2 3 B4h mH+ b.zy.rZ1 benz y I +382 D e, 38 ~r.z'uescf the E'a'i below are shoQ- ir.
*7 b r -id and a c, e S-h laeaeTn rai ay.
wa brnoidvSr ansu cocnrt- nvcs h ocnrt wit a miiu amuto mtil SOSa.If SW a d d e y p i h war0 '-lec t ieopqefn (4 r.4 60. ml, IO" S 107.9 M S. S 12 333- 5.03; Found: C, 714.70; E, 5.01. IH- NMR (CDCl 3 7 ,8 5( mn), 7.6 7(2 in), 757(2H, 7. 4 4(2 H, in) 02 (2H, mn), 3.03 (2Fi, nm).
HO0 OH
IIS
~C 2. sefuse 107,5- 241, a roa 'Z a r oiat 108 .1 he trz:~esc: e Ex-arples below are shown in I 2 c ur d .5b30 4, ml a dsovdi rl.4 r nd t h s s l t o reovedund reduce (3.0ure The crud inmnol) was dsovdi chroathvdrosapeon ilrica (40el nd etoy thissotioxne *11a the eodue 2$ The onjent fereahtedn cnane r 2,5u g (76% yield) of Intermediate (LIIla) as a white solid.
MS, 699.4, 1 H N HR (C~DC 3 25 (in, 12 6 .99 (i,3H) 4 .95 1H), 4. 82 1H), 4.65 (d, IH) 4. 50 1H-) 41. 15 (m,l1H), 3. 85 (mn, 1f), 3.,62 (mn, 3. 60 r,1H-) 2 35 6 (rn, lH) 3, 4 311), 3. 39 (in, -334- 1, 3.35 3F), 3.12 (m,1lH), 2.92 1H), 2.10 (s, 3H) Intermediate (LIIIa) (300 mg, 0.48 mmol) was dissolved in methanol (5 ml) and a solution of hydrochloric acid in dioxane (4M, 5 ml) was added. This mixture was stirred at room temperature for 4 h and then the solvent was removed under reduced pressure (the excess HCl can be removed by extensive washing with methanol followed by evaporation). The crude residue was chromatographed on silica gel using a 10% ethyl acetate in methylene chloride as the eluent. The major product contained 175 mg of Example 27A. mp: 91- 93C MS: (M+Hi' 523.2, IR (KBr, cm-1) 3416, 3 0E, 15E4 and 1282. 11-1 NM?. (CDC1 3 ):67.25 (rm, 10 H), I E5 3.80 (rr, 1H), 3.65 1H), 3.38 1h, C. 2,2.21 H) 3 C NMR (CDC13, ppmT) :aboe reac:or, (removal of the MEX Drotecting S2 t -I bui dcyne b, dlseolvir.g the star-ino -;c2 lowed '1:v bubbling HC, c.: SI 5 :n at -iCc and then stirring at zermera-ure fcr 20 min. Sim-lar work up of the rroLerur leazis -c the cc -red Example 27A, F x a rrr222 sx-rr zju Jrr cycJop -ro-pylmethyl bromide into ::er cf Example 27A and using the appropriate monca'k l :tez cyclic thiourea, Example 27B was prepared in coi i mv: 84-860C; MS: 451.1; 1 H NMR .c2 -7.26 SH), 5.'1 1 4.85 1H), .11 2.95 1H), 3.75 1) 3,45 2F! .2 C1 2 2 U 1 i c. W -335- Using an analogous procedure to that described for Example 27B, Example 27C was prepared in good yield.
mp: 257-259 OC; MS: (M+H) 4 583.2; 1.H NMR (CDC1 3 7.25- 7.15 9H), 5.80 2H), 4.75 Cs, 2H), 3.82 1H) 3.42 Cm, 1H), 3,35 Cm, 2H) 2.95 (m,21)f EL: ample 27D Using an analogous procedure to that described for Example 277, Example 27D was prepared in good yield Cm- 1. 2 C05CH23r was the alkylating agent) mp: 253- 255C; MS m/e 583.3 (1001, M+H) 1H NNMF, (CD 3 0D, 300 MI''z) 62,95 2Efl, 3.2C IB), 3.4 0 Cm, 1H), 3.78 Cm.
62 (rr, 1H) and 7.15-7.30 9HI) 2C 27 usi1,z the aorooriate alkylating agent (mcya nobenzylbromide), Example 27E was prepared in an a-og,slo2 s procedure to Example 27A; mp: 154-1551C; 5 m.s (cDi) m/ e 54E,2 (100, 1 H NMR (CD3OD, 300 MHz) 2.95 (mr, 2H), 3.20 11H), 3.25 Cm, 2 H), 3.85(, 3. 9C C(m, I 5.25 1H) 5.80 1H), 7, C0(m, 5F), 7.15 lO) and 7.25 Cm, 4H) 0 Exa)InQi2.7F Exarj,,iLe 27F wa': made by using p-t4EMOC6H5CB2Br as the alkylating agent, in the procedure of Example 27A.
mp- 162'C; t.1S(CDI): m/e 555.2 (100%, M+BH); 1 H NMR (CD~rD) 3 6 2.85 Cm,, 2F) 3.:2 Cm, 21i), 3.8 Cm, 1H), 5.80 Cm, 6.75 Cm, 2F), 6.95 2H) and 7,15 (mn, -336- Ex:ample 27G Example 27G was prepared according to the procedurdescribed for Example 27A, using m-MEMOC 6
H
5
CH
2 Br as the alkylating agent. mp: 82 0 C; MS(CDI): m/e 583.2 (100%, M+H) 1H NMR (CDjOD, 300 M4Hz) 62.85 2H) 3.25 2H), 3.62 3H), 3.90 1H), 5.80 1H), 6.80 3H) and 7.10-7.20 6H) Examoe 27l Exam'p ie 27P. was prepared using an analogous crocedure to that described for Example 27A by employing Ic -cc 6 Br as tne alYlating agent. mp: 110C; to r- e 57 2 (M "5 me 57>i 1H NNFR (CD30D, 300 14Hz) 62.8 2. 2. E 3. 45 (rn,2HH 3.65 11H, 3.70 I H, 3 Hi 4..5 (mn, I 5.28 (mn, IH 5,82 Eamf: -e 27K was prepared by treating Example 27H wi:: .vrcXx'Vtfe. HCl, u sing an ana logou s procecu re toc .:too cde z- I'b e E r E:am z,1e 2 7N. rrt 130-13201C; MS (CDI' 1 1F (CD-X, 300 M4Hz) 62.81 21E), 21 3, 6 (rr, 2 H)n 4 7 2 (m andc 7 .25 I~ Ea-, tr 27'- was synthesized in a similar fashion to C' -Z ribed lo: Example 27F by using in-11OC 6
H
5
CH
2 Br e a~kv'7at-n: aae rap: 125 (CDT): e M C555.3 K0 3< (c2 3 e, 2 0 2 X -337- 3.41-3.60 2H), 3.95 1H), 5.82 1H), 6.80 (m, 3H) and 7.20 -7.45 6H) Examope 27K Example 27M was prepared using an analogous procedure to that described for Example 27A by using m-
NCC
6
H
5
CH
2 Br as the alkylatlng agent. mp: 1020C; MS(CDI) m/e 573.3 (100%, M+H) 1H NMR (CD 3 0D, 300 MHz) 62.80 (m, 1H), 3,05 1H), 3.20 1H), 3.42 1H), 3.78 (m, 1H), 5,15 1H), 7.15 2H), 7.25 3H), 7.45 (m, 1H) and 7.60 3H).
Examc3e 27L "2 :5 To a solution containing 200 mg (0.34 mmol) of Example 27M in 10 mL of anhydrous ethanol was added mn, (0.87 mmol) of hydroxylamine.HCl and 87 mg mrnmol) of :riethylam.ine The reaction mixture L :i.2ted a: reflux unt the starting material could not L., detecte b" TLC2, and then the solvent was removed under reduced pressure. The residue was chromatographed on a S Ci silica columrn using a 20% solution of water in methanol as the eluent. The major fraction isolated conrained 97 mg 45% yield) of thiourea, Example 27N.
mr: 150 C; MS (DCI) m/e 639.2 (100%, M-H) 1H NMR (CD 3 0, 300 M z) 2. 85 2H), 3.15 1H), 3.25 1H), 3.80 IH), 5.82 7.15 5H) and 7.45 4H) Examnle 27M To a solution of containing 5.0 g 10.5 mmol) of Di-amine-Di-MEM compound III in 75 ml of THF was added 2.20 g (22.0 mmol) of K2CO3 and 4,48 g (23.0 mmol) of 4fluoro-3-cyanobenzyl bromide. The reaction mixture was stirred at room temperature for 18 h and then 100 mL of -338water was added. The mixture was extracted with CH2Cl 2 and the organic layer was dried over MgSO 4 and filtered.
The filtrate was treated with 1.73 g (15.0 mmol) of thiophosgene and 2.0 g (20.0 mmol) of triethylamine.
The reaction was stirred at room temperature overnight and then washed with 100 mL of 10% citric acid. The organic layer was washed with brine, dried over 14gS04 and filtered. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel using a 50% solution of ethyl acetate in hexane as the eluent to give 2.45 g (30% yield of the alkylated intermedicate, Removal of the the MEM orouos was done Lv uscl ana-ocus procedure to that described for -r.erine"a-e LT7a The thiourea compound obtained frort th;e p::'io'2s Sste w.6s converted to examrle 27P b,, arctin: the same porcedure described for Example 27N.
2; m/e 675.2 (IML 1 H N14R (CD 3 O0, 2> 2.5c 3.35 1H) 3.52 1H), 3.75 F)i, SG1 IHi, 7,10 (mn, 1H) and 7.25 (rr, 8P) R R23 4V-- R 7~L a HO OH !e e HPt P 4 E_ J_: kL _~1L jjlEI 1l rn:d m, £I 2 7A F.S F CCH 5
CH
2 C0H5C12- ++1t 92-94 523.1 27B R~r (C 3 H )CH 2 -2 C 6
H
5
CH
2 84-86 451.
27 SSF p-HO& 4 CH 2 CGH.CH12-' 257-258 583.: m-HOOH?1 in-HOCH,. 253-355 583,2
C
6 H4CH2- C01 4 C1 2 in-cyaino- C 6 HCH2-- 4-55 4.
CEH 4 cH;p-HO I.
C C 27G RSSR r-CH3O- C6H 4
CH
2 27H RSSR m-cyano- C6H 4
CH
2 272 RSSR m-HNN-2-
C
6
H
4 CH2- 273 RSSR m-HO-
CGH
4
CH
2 27K RSSR m-cyano-
C
6
H
4
CH
2 27L RSSR i- (HpNC (-NOH)
C
6
H
4 CH2- 2 7 RSSR M-
(H
2 NCU NOH) -p-fluoro-
C
6 H4CH 2 -339m-CH 30- C6H 4 CH2? p-HOCH 2
C
6 H4CH 2 p-HOCH2.
C
6
H
4
CH
2 r-HO-
C
6 H4CH 2 r-cyano- C6H 4
CH
2 i-
(H
2 NC (-NOH)
C
6
H
4
CH
2 i-
(H
2 NC (-NOH) -p-fluoro- C6H 4
CH
2 82 583.2 .10 577.2 130-132 611.2 125 555.3 102 573.3 150 639.2 152-153 675.2
S
CA A me structures o- the Examples belcw are shown in Table 2r. Compounds in Table .r were prepared as shown 4- Scheme 28.
E a'1 2P r Preparation of D2, amine (La) iC To a. suspension of 10 g of 3$,4S,5R)-2, (U -Cbz-amino)-3,4-(dihydcrox:y)-1,6-diphenyihexane in 200 0: methylene chloride was added 10,8 mL of 2,2d-methoxypropane and C.41 g of camphorsulfonic acid.
The mixture was stirred at room temperature for 48 hr, then washed successively with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, The organic phase was dried over anhydrous magnesium sulfate and concentrated on a rotary evaporator. The residue was crystallized from ether/hexane (1/10 v/v) to give 6.6 g (60% yield) acetonide as white needles, mp 76-77'C.
To a solution of 6,6 g of this acetonide in 100 mL of tetrahydrofuran/ethanol (1/1 v/v) was added 0,7 g of 0 Pd/C. The mixture was stirred vigorously under 1 atmosphere of hydrogen gas for 18 hr. The catalyst was -340isolated by filtration and washed with tetrahydrofuran.
The combined filtrate &ad washings were concentrated on a rotary evaporator. The residue cor-sisted of 3.6g (100% yield) of diamine, La, which was used without further purification.
To a solution of 2 g of compound La in 15 mL of anhydrous tetrahydrofuran, maintained at 0-10'C under a nitroomn atmosphere with efficient stirring, was added 1.8 mL (2.2 eq) of triethylamine followed by dropwise addition of a solution of 0.9 mL (1 eq) of phenyldichlorophosphate in 4I mL of tetrahydrofuran, The xure was stirred for 16 hr at room temperature. The resul:in z ri ethylamine hydrochloride was isolated by f ilzraicr, and washed with tetrahydrofuraa. The .cz,7:tned filt:-ate and washinas were concentrated on a evI/=or a:ar, taken in methylene chloride/ethyl' e~n: v/v and washed successively with water (2:,and- Ea,:urat-ed sodium chlor-ide solut ion crx'Er, over anhydrous magnesium sulfate, the :rc: w- concentrated or a rotary evaporatcr c: z- z e sid ue b y colIu r.n ch ro m at"Iocr-a ph y u~r~ra shcrt pad of siica gel eluting with e/ehxlacetate (1/1 v/v) cave 1.8 g(645% yield, cf cy' phc>sphoramide, Lb, as a sticky white foam.
o!,,tion of v. 1 g of compound Lb, in 3 mL of an.v::.s N-imetylfrmamdemaintained under a nrzzgen azm, sphere at room temperature, was added 35 mg c f 6' i 14a- (ty weight, dispersed in oil) .The mixture ~~edfct 10-15 min followed by addition of 0.16 m. zomm~yl cy clopropa n e The mixt'ire was s-tirred for 8. roor. temperature, then cruencned by water a~z..Tne product was extracted with ethyl acetate (3:.Tne comtbined extracts were washed successively wazez (2X) and saturatc-ed sodiurr chloride solut -or.
~'n''ezanhydrous mnagnes ium sulfatc-, an..
c~.arotary% eva'",Or"vr T~ e a -341purified using rotary preparative tic eluting with hexane/ethyl acet'ate 14/1 v/v) to give 97 mg (79% yield) of the bisalkylated product as an amber oil.
To a solution of 97 mg of this bisalkylated product in 2 mL of anhydrous methylene chloride, maintained under an argon atmosphere at -78'C, was added 0.5 m.L of a 2.0 Msolution of dimethylboron bromide in methylene chloride by dropwise addition, The addition was completed in min, and the mixture was thereafter stirred for 1 hr at -76'C. The mixture was then transferred via syringe to a rapidly stirring mixture of 1 mL tetrahydrofuran and 0.5 mL aqueous saturated sodium hydrogen carbonate Lution, After sta x:rinq for 5 min, the mixture was *extracted with ethyl acetate (3X) The combined extracts were washed successively with 10% aqueous potassium hydrogen sulfate solution and saturated sodiur' *chloride solution. After drying over anhydrous magnesium sulfate, the organic layer was concentrated by rotary evaporation, The residue was purified by rotary 20 preparative tic eluti"ng wiLth hexane/ethyl acetate (4/1 to give 7C rnc- yield) of compound 2P 1 0 as an amctrphous wiesolid, MS 5'17 453 (100%, M+IH- 4 4:0N (C D C 160,24 (4H,m) 0.44 (MIim 0.95 (2X,rrfl 2,22 2.52 (lH,umI 3.18 (4H,m) 3.38 (2H',m) .62 3l-im 3. 90 4.03 (2H,m) 7 .00 (1H,m) *(2wh,t) 7.24 2 CH' H 7.50 (2H,m) Exar1 XB Compound of example 28M was prepared from compound Lb using the alkylation procedure described for example 28D by replacing the bromomethylcyclopropane with 3-(Nmethyl-N--trifluoroacetamido)benzyl bromide. A solution of 0,27 g of the bisalkylation product, thus prepared, in. 7 mL of methanol was treated with 4 eq of solid potassiumr carbon8-te. The mix:ture was stirred for 48 hr -342a: room, temperature, diluted with water, and extracted with methylene chloride, 'The extract was washed successively with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, then dried over anhydrous magnesium sulfate. Concentration by rotary evaporation and purification of the residue by column chromatography using silica gel eluting with hexane/ethyl acetate (1/1 v/v) gave the free amino compound in 57% yield.
To a solution of this diamine in 3 mL of methanol was added 0,01 g p-toluenesulfonic acid monohydrate. The solution was stirred for I1 hr at room temperature, then concentrated byrotary, evaporatcir, The residue was taken up in ethyl acetate, washed with saturated sodium hviroaer. carbonate solution, and dr~ied over anhydrous :7 a e s U fa Concentration rotary evaporatic:.
J ~i:.cat~rby column crnrorsatography on silica aeusc.c rr'C ln chloride/ethyl acetate/ethanol (2/2/C.$voliume rattos) gave a 19 yield of comnpound 2 2i*: 2 <-CH5.HH 3 tCZ,3 (6 2 C,2h; 42 (d cf d, 21-H); 3. 5 0-3. 73 2 H) 3 Bi Cs X2, 4.23- 4.59 G, 4 2- 6. S2 (in, 4 H) ;6.55- E r 95 3o 21i;?C- 7 Cm, IC Q F; 7.52z 0 R n' .4A R Ey'' p,2 23 28S 2-naphthyl methyl 28C cyclopropy methyl 28D n-butyl 28E 4-(HOCH 2 benzyl 28F H 28G cyclopropyl methyl 28X 4-(HOCH2)benzyl 2 4-(HOCH; benz yl 26; 3-(HOCH'benz yl 28Y benzy: 2E-: 3-(CHiNH)benzyl R4 R7 R24 benzyl phenyloxy benzyl phenyloxy benzyl phenyloxy benzyl phenyloxy benzyl phenyloxy
HLC
++4 +4 +4+ +4+t Spec
(M+H)
456 (M4NH4) 547 551 K, IC. mp, 0 C Mass benzyl benzyl benzv ethoxy cimethyl amino methoxy 245-246 408 391 +4 498 -1-4 +4t 9.9 .4 .9 9 .9 9 9* Oerzy dimethy! arr.ino benzy2 pheiioxy +4 159-160 63Z +4 4+ 109-110 benzvl benzyl methyl phenox y *r 9 *9 *9 S 9 *4 9.
The Examnles below are representative procedures fz: zhe prepara:icr. cf the compounds shown in Table 2s below I-'"Rzsr! 29J Compound Qff exampi'? 5V (1,340g, 'Ommcl) was dis solved in 60-: tetrahydrofuran. and cooled to DOC, di-t-but -yl- N, ,N-diethy lphosphorami dite 13. 000g (52mmol) in 40 ml tetrahvdr--furan was added followed by additon of 7,28o(104mmol) of tetrazole. The contents were stirred for 5 minutes in tre DOC ice bath and then for minutes in a water bath at approximately 23'C. The contents were cooled in a -40 0 C bath and 21.Sg(62.4=nol) of 50% m-chloroperoxybenloic acid in 100ml dichloromethane added over a 10 minute period and stirred for 5 minutes in the same bath and then minutes in a water bath at approximately 230C. The reaction was quenched wirh 250ml of 10% aqueous sodium
WEEMM
bisulfite at O'C, The aqueous layer was extracted with ether (lO0mi) The organic extracts were combined and washed with sat, sodium bicarbonate (1O0mi), 20% aqueous sodium bisulfite (250m1) and then sat. sodium bicarbonate (lO0ml) The organic layer was separated and dried over magnesium sulfate and the filtrate taken to dryness. The residue was purified on SiO 2 gel [750g; using chloroform (500mi) followed by 1% Methanol:Chloroform (4 liters) followed hy 1.5% (4 liters)) to provide 14.410Q (75.8% yield) of the bisphosphate ester as a white solid, Caution! The "flash chromatography" column should be done as fast as possible to avoid any decomposition on the column 3 0upo: OX N (3Gz) (CDC1 3 5 1 .4 4 Q6 H, dJ 4 H z) 4 9 7 S 2 .4 9 4. m)14z Er 1.9 01 r J= 3 ~flP IM 224z C~ S ~cn wa, acide. C ex a, Z2/ rz e:ca e rs The contents were a hurs The mixture was filtere 3 e2ie pai dn concen!trated to afford 27o 5 .0 s a wh- te solid, IH NK? (DIS- 2 1. 9 5 32,~ 3 3G( 2Hs; 12F 46f,2 (2iKd, 04.2Pz) E, 27Z2 (4H E, =r 9z) 7, 0 4 F4, di, 0-6 .9H z) 1,7, rC H, ;31p Nt.Ig (DI4SQ:-d61 Czu~~A (2,1760, mo.j- wp, treat kll wit -345was filtered through a sintered glass filter funnel and lyophilized to afford 2.433g (92.3% yield) of desired tetrapotassiun salt as a white solid.
ZLml 9 Compound 5U (8.2 g, 14.4 mmol) was dissolved in methylene chloride (170 ml) under a nitrogen atmosphere.
N, N-Dimeth~lglycine (1.78 g, 17.3 mmol, 1,2 equiv.) was added followed by the reagents, 1-(3dimethylaminoproTylj-3-ethylcarbodiimide hydrochloride (3,32 g, 27.3 mrnol, 1.2 equiv.) and 4- _J imehylainopyridine 11 g, 17, 3 mrnol, J, .2 equiv.) After stirr 4 .nq overnight, silica gel (40 g, 230-400 z mesh) was added and the solvrent removed on a rotary evaporator, The residu was applied to the top of flash silica gel colum and eluted with 20% methanol-80% ether to give partially purified Further chrotiatography using 1551 isopropanol-25% methylene chloride gave the desired monoeszer (2.54 9, IF14 (300 14Hz, C Z'3) 3 ,5-7 C2 .06(2H, s) 4.85 (1IH, d), 4 60(1H, 4.50 (2H, 3.4 6(6H, in), 3.07 (2H, s) 2,6(7 H, in), 2. 22 (61H NMR (75.4 MHz, CDCl3)6 170. 2, 162.21, 140 139. 6, 138,4, 137.3, 134 129. :29.4,128,9, 128.5, 126,5, 128.1, 127.1, 126.4, 71,1, I.C, 66.0, 643, 63.8, 60.1, 55.3, 55.1, 45.1, 32.6, This mono-ester (2 .39 g, 2,14 mniol) was dissolved in a mnixed solvent system (88 ml, 9% isopropanol-91% ether) 7- solution off hydrochloric acid 59 ml, 2. Cmrnol, 1,1 equiv. 4 .0 M4 in dioxane) was added dropwise.
After stirring for 1_,5 hours, the reaction was filtered under nitrogen. The filtrate was rinsed into a. flask with water and frozen, The frozen solution v~as lyophilized ri give 29D as its mono- hydroch.1or ideinnohydrate (1.39 o, 92% for the monohydrate) IR NMR (300 W4Hz, Ct0-On) 6 7.38-7.01 (18H, in) 5,26(2-, s) -346- 4.82(1H, 4 .7 (l1H, 4.56(2F., 4.12(2.H, dd), 3.58(4F, 3.09-2.78(6H, 2.91(6-H, s) 1 3 C NMR (100.6 14Hz, CD30D) 6 166.89, 163.83, 142.37, 141.30, 141.24, 140.17, 138.14, 135.64, 130.86, 130.65, 130.48, 129.93, 129.67, 129.57, 128.24, 127.48, 72.05, 71.90, 68.81, 67.81, 66.93, 64.79, 57.99, 57.07, 56.72, 44.49, 33.64, 33.58. MS (N-3 CI) m/e 652 (M+H-HC1) Compound 5U (5.0 g, 8.82 ranol) was dissolved in methylene chloride (50 ml) under a nitrogen atmosphere.
Ar, excess of 2, 2-dime thoxypropane (10 ml) and a cat:alyzic amount of p-toluenesulfonic acid monohydrate Ii (230, rrgi were then added. After stirring for one hour, waze (25 rI) was added and stirring continued for ten ees. reacticr was then transferred to a separatory funnel where the layers were separated. The crgA:.L: phase was was successively with a saturated 2 ce ss ti of sodum bicarhonate and brine. After LV~r 8 rrBCnec~IuI~. L'lfate, the crucc.
Sc~rz~c',: w-s isc2&ted by filtration and evaporation.
*FL Prificazicr. was accomplished by flash silica gel columr..
c-,ronmatzrapr.y (51. me thanol-95% methylene chloride) Tb: 2' ac,:cn. was cbt-.-ned in 90% yield (4 .75g) H NbT 5, 7.37-7,23 (101, 7.09(8H, d;, 4 d, 4,CE5 (4H, d) 3,82(2H, s) 3.76(2H, b), 0 4'Lli c 2 9 2 (419, if.) 1 9 (211 t) 1 .34 (6H, S) 13Cj z, ?C -13, C )83) 6 161.7, 1402, 138.8, 137.6, 712 223, a 12a,2, 128,7, 127.2, 126.6, 110.2, 75.5, CC E, 56,0, 33.5, 26,7.
is ia:etoznide (999 mg, 1,67 imol) was diss.lved in rn~t. hylen ch loride (10,0 ml) under a nitrogen a'ztnsS-, e. l; ,1-Diiniethylglycine (431 mg, 4.18 rnsl, 2.
qi a teR r enag nt 1- (3 diimet n y larr.inopropyl) 7 rn Ir~d hyddroch lo-rl e t, 8 C, -347equiv.) and 4-dimethylaminopyridine (511 mg, 4.18 mxnol, equiv.) were added and stirring continued overnight.
The reaction was applied directly to a flash silica gel column and eluted with 10% methanol-90% ether. The desired bis-ester was obtained in 73% yield (0.95 g).
1NMR (300 MI-z, CDCl3) 8 7.36-7.04 (18H, in), 5.14 (4H-, 4.92(2H, 3.86(2H, 3.77(2Hi, 3.18(4Hb s), 3.08(2H, 2.92(4H, in), 2.33(12H, 1.37(6H, s) MS (NH-3 CI) m/e 777 (M4H).
This bis-ester (402 mg, 0.518 mrnol) was dissolved in methanol (5.0 ml) and hydrochloric acid (1.0 ml, N solution) was added, After stirring for 0.5 hour the scIvent wa=s removed by rotary evaporation and the residue azeotropically dried with toluene, Further I i ryinc in, vacuo gave 29E (383 mgj) **ah 2 s 0 N0 N OR' 2* 1 HO OH Exs E R4: I iC 9 Mp/ 0 C Mass (HPLC) Spec
(H+H)
29A 0H 2983 P03 29C Me 2
NCH
2 C(0) 29D p2-H, R 2 3 652 Me 2
NCH
2
'HC)
29E M.eNCH 2 C *HCI 737 29F (5-pyridinylH' 0 CH2C 29G (4-pyridinyl)- -7
CH
2 C(0) 29P- (I-morpholinyl)- 821
CF
2 C(0) -348- 291 293 29K 29L 2 9M, 2 9 N 290 29P 9* I* S S. S *4 0* 4 *5 (3-pyridinyl) CH=CHC (1-morpholinyl)
(CH
2 (4-met hyl-2piperazinyl) (H2) 3 C (1-pipericlinyl)
(OH
2 )30(0) (4-methyl-lpiperazinyl)
CH
2 C (1-pipericiinyl)
CH
2 C(0) (4-phenyl-1piperazinyl)
CH
2 C (1-morphol.inyl) (OH?3) 2C(,)C
(H
3 )C oz(N o 0C mre hvy: K~C C 2) n 1 me h C, 4C 829 877 903 837 847 817 971 849 16 7 -1C 165-167 S S S 5 9* 5
S.
*S
S
*.SS
12 4-12 6 +4 169-170 22 4- 22 195-196 ~:~n~:shwnin '1TI oIe 2 t werro. prep are3 Table 2t 18 23 X Y Ex Nc. W
C=O
C=C
C=C
C=C
S02
R
2 2
=R
2 3 benzyl 1- (HOCH 2 -benzyl 3-cyanobenzyl 4-hydroxybenzyl cyclopropyl methyl 2-n aph thylmeth y 1 6-hydroxyhexyl benzyl 2-na phthylmethyl n X, Y I H, OH I H, OH I H, OH I H, OH mp, 0
C
52-56 7 0- 7 6 56-65 78-85 59-66 9* S 6*O 0 fr 0~ S. 6 S6 6 *0 S S .5 95 S 6
S.
S
9.
9O 6* 6* S
S
*50* @6 6 9 65@S *5 S 9* *0 H, OH H, OH H, OH H, OH.
12 3-12 188. 190 SQ0 cyclopropyl methyl SQi 4 -hydrox yrethy! C='C berizyl C=C 2-naphth ylrnethy2 C=Z 4-(hD0CH;) -benzvL C=C cyclopropyl methyl 3-cyanobenzyl SO-, benzyl C= 3- (H 2 0C (=INOh)) benzyl, C=O benzyl, C=O benzyl C=C benzyl I H, OH H, OHi H, OH H, Oh H, Oh H, OH.
134-136 179-181 72-7 2 H, OH 142. 14 4 118.120 H, OH, H, OH.
2 2 =NOH I ft,OH
(R)
I H, OH
(S)
C=O benz yl The Ex:amples in Table 2u were prepared using the procedures outl~ined in Example 23f above, Compounds where R 4 R7 4-fluorobenzyl were prepared from (2R, 2S, 4 S, 4 R) 5-bis (N-Cbzamino) -3,4 dimec ho>yethoxymethoxy-1, 6-c- (4-ffluorophenyl) hex:ane.
-350- Further manipulations to X and Y were carried out using methods well known to one of ordinary skill in organic chemistry.
R
22 N~ NR 23 x 0O *0 0 000
OSS@
0O *0 0 3* 0 0 0* S. S S S 0O 0@ OS 5 0
S
S S S
S
0@55 0* *S S S S 0e S @055
S
0@ 0 4 5S S 0@
*S
Ex.
N--
3 1A st erec 2 "4,
RSSR
R'S S R S i p, 2 2 R 2 3 3-carbometnoy: benzyl 4-ca rbornethoy, ben z y I hydroxvmethy ben zv I 4 -hydroxvrtelhy berizybe Table 2u R' 4-f=ur'7 benzyl V 4-f luoro benz yl 4-fluoro benzyl 4-fluoro ben z yl 4 f luoro benzylI ht-,r' 7"
(H
OH, O H OH, OH OH, OH'.
OH, OHF OH, H e pox~y Ki IC90 Mas P LC I Spe 712.
44- 695 f 639 656.
527.
a..
0* a a a. S. SCHEME 1 Ph
H
2
OH
TBDMSCI/
Et 3 NI CH 2 C 1 2 Ph
-J
7HN NH OTBDMS CARBONYL Phw DIIMIDAZOLE *,,Ph TBDMSO OTBOMS 0 N N Ph,, 00 SWERN P N N
TA
Ph HO OH 0 N N Ph,"P TBDMSO OTBDMS 0 HN RNH tV Cl 3 Zn-Cu 0 VN NH SWERN [01 Ph VC1 3 I Zn-Cu HO OH Scheme 2 1) n-ihili 2) /xN Km S S 3) n-BuLi 41, 1) N;nN3, Ph3P 2) SIICHCl-S1-1 or Ph3lP/H20( 3) Carbonyl Diirniidazole NuI Ar' 4) I-igO/Ilg(OAc)2 NaI3H 4 a Scheme 3
MEMCA
(W~r) 2 NEt PcG ,-ph NaOAc 0 R22
R
23 N N Ph- Ph MEM 0 Example 1 X (XXVa) 110A
HONH
2 1-401 0 Ph HO 0 "-Ph (XXVb) 0 R2 R23 Ph-e 0 R22)tR23 Ph-P
X
NaH, RX Example I X -3r4 Scheme 4
OH
HO, 0 o L-mannonlc- r-Iactone 1.LIBH Me OH 2. 2,2-dlmethoxypro pane,
CSA
xx Via AcOH 0 OH
OH
HO">
HO
1. TsCI, pyr.
2. K 2 C0 3 MeOH S. S XXVIb RLI, CuBr-r'e 2
S
XXVId xxvkC (PhO) 2 P(O)fl DEAD, Ph3P 1, H 2' 10% Pd/C 2, CDI, CH 2
C'
2 XX VO 'N H XI) 1"R 1. NaHi, 11 1 X, DMF 2, conc. HCI, THP 0 HO OH 1 22 213 R R =fR R2 4 RR t:Rt Xxvif -355- Scheme
H
2 N NH 2 %h .,,Ph MEMO MEM
S
H N' NH P Ph -:Ph MEM~O 4ME M 'S*CH3 N NH Ph Ph MEMO MEM XXVIlt 4*44 4. Ph N HN N Ph Ph MEMO OMEMA XXV lic Ph N N Ph-* Ph MEM 4MEM xxZvtlL
S
HN
OM EM XXVIld XXVIlb -356- Scheme 6 7 4 0 Hlo OH Example 1X N
N,)
Ph Ph CH,-loC0 OCOCH 3 XX Villa 4 4* 4 *4 4 4 4*4 4.
4. 4 0444 4 4 4*44 4.
4 4 .4.4 44 4 4* 4.
xxviii; X X Y/ Ii;1 b 357- Scheme 7
F/
H 0
F
10 Cz ,H 0H
F
Cbz H C
F,/
.9 -OMEM
H
Cbz., N "b
F
0 F H N H MEMO O0MEM,
(XXXI)
-OH
H
Cbz N N.Cbz
F
-358- Sch em e 8 Ph ,Ph z N ",OH Z N N \Me Ph F' 7 7NP I, omK Ph z NN ,Ph Z N
H
OH
S S 0*S*
S
S I *1 S. S S S
SO
S.
S S
S
*5 S. S
C.
z Pr,
S.
S S IS S S S
IS
~Ph
N
3 SN' P h H OH 0
N
3
N,
Ph 6MEM
(XXX)
3S9 Scheme 9 0
H,
DAST
CH
2 ci 2 0
C
(XXXIla) 1. NaFID~vfF 2. R.X a a a.
a.
S S a a a S4 a S a
S.
pNV 2C~
$CF
3 crxl Zn ((lus)IA cO H R 22 NaOHIM ,cONf -360- Schemne 0 0 -iJ.Br AcO
C*
C C
C
C. C
CC
*4 SC C
C
CC
C C
C
CC
C 6 B r Z n(d Us t)A c 0 H Na 0 H/MceQH CC 0
*GCC
CCC.
C CC 6
CCC.
-l Scheme 11 Ph
OMEM
HNNH
2 Ph, OMEM Ph
(XXIC)
Ph MEMO OMEM (XX XIVa) Ph N, Ph MEMO OMEM (XXXIVb)
'A
HO OH .e Scheme 12 00
ASYMMETRIC
DIHYDROXYLATION
0 OH
O
OH 0 1. 4 LDA 2 2. Benzyl bromide 1. MEM chloride/ dilsopropyiamine 2. LAH (-XXVile) 1. OHS 02011 pyrldlne 2. Na 2 s 3 1 EtOH/ 8 0' 0C Oxone 4 Ph MEMO OMEM MEMO OMEM -63 Scheme 13 Br r, Ph BuLl hOR 6 Ph 0 h R Ph R6 0 R 2 1 P h R 5 R P h R6 Z 8 27 Ph R 5 R? P h
C
C
Scheme 14
R?
5 BrS
S
Ph P h BuLl *where R R 7 CH2Ph 0 FR7 R 4A6
.R'
z
R
7 R 4A Scheme
.NH
2 'Ph 0 li L ICH 2 -P(OC U-r') 2 ZHI4 0)(OCH 3 2 6. 1 (XXX VB) 0 OCH,
R
2 where R 4=R 7=CH2Ph y~P(XOCH3) whore R= R =CH2F h -365- Scheme 16
NH
2 ph
R
B r B r Ph (XXXV18) S
S.
S S (XXXVIla) (X XX VIla)
R
4 R 7 (XXXVla) wAhere R 4 =R 7
=CH
2 Ph whore R 4 R 7
CH
2 Ph -366- Schome 17
NH
2
NH
2 Ph/ MEMO Ph
OMEM
MO OH 3 TsOH
H
3 0 x
CH
EtOH-
CO
OH
3
NJH
MEMO Ph
OMEM
XXXIXb
XNXIXR
THPO
I CI NaH DM F XXXIXc Ki 6G t *o St S S S. S
OH
3 Ph- M EM OMEMPh
OH
XX X IN d
THPO
1M E M Hp XXXIXe Hcl NI C(H diouln,- S.
OH,
HOP Ph \.OH
OH
X' CH- -36/-
H-
2 N OOOH Schcrne 18ai General Scheme for prcparaiion of comnpounds of (Xaa) P 0 (XLb') M
R
0 MX
R
4 Ht j
R
7 P HO 0 R 4 HN'Z BJ P HO o 0*
(XW)C
0 P HO OH
R
7
.MX
R
4 HN. R P HO OH- (XLc) (XLF) R4 B 7
H
2 N I- COOH OH OH Ma~) P suitable protecting group j Uo Scheme 18b
H
2 tqN-y COGH H 2 N COOH OH OH 0 0 1 1 P P (XLa)
H
2 21
COOH
O OH
P
(XLe0 (XLb) W COOH P 0 0 1 1 P P (XLh) I0 O C 0 NH 2 R4T C
R
P P (XLc)
H^
2 R 4
C
HO
a 9* 4 4*
CXL:'
C-
I,,2 1 t, -OH
H,
0I o R*n22N 0)
R
4
QOH
OH
(1-I M.Ji (L~zP suitable protecting group 369- Scheme 18b (continued)
NH
2 0 N OH HC Ku"c) OH OH
S
(X2,Lg")
(XLK-)
-37 (J Scheme l8c (detailed)
H
2 N' COOH
I
0 0 SEM SEM (XLc) Lb) *E4*
S
*9 0 ~9 99 9 9 4 .4 a 9. 4 9 9*59 9 9 9 4 0*
H
2 t4 COOH~ 0 OH
SEW
H, 1 ,N
R
CC)OIV
HNt' COOH CBzO 0 SEM SEM
(XU-
'XLd) CBZ 0 0 NH1 2 $E41 SEM
(XI
0
SEM
SF MX~ (Ho (X4v)
(XU)
Schemie 19 -71 Nali Bn-Br
BOO-N
(XLli)
MXLIN
S.
S.
S S S
S
S. TsOFH Ni cOli
HO
BOC-N
.OH LIOH, H1202 (N 'Li k 55 S S *5 S S 55 I .TBDNDMS-Cl/ON4F/Im ITH F/AcOHIH 2
O
as in O H Scheme 23 (XL Ii)
TBDMSO
BOO-N.
(XLlm) (XLI I) Scheme coo (XLIla) TsOH TBDMS.CI Me~l-f DNIF/lr 0
COOTBDMS
H
TB DMS 0 (XLI Ib) THF/AcOH/H 2 0 0 O.N9 00 0 0 0 090* 4 0* 9 00 0 0 00 00 0 4 00 00 00 40 04 S 0 4 #9 0 0 000 0 50* 0 I 00 0 0000 04 00 4 4009 0 0000 *0 0 0 0000 0
DCC
(XLIld,,
HC
T BS D t: (XLI IE
COOK
BOC.N Y TB DMS0 (XXLlc) 0
H,
N
OTBDMS
(X~L I) EbN 11 H~ NaH/t\F Bn~r 0 (XLIlhj ThlArFTIF (XLIlg) 373 Scheme 21
CHO
Z(H)N
Wle~ OH OH-R' Z(H)N R
A
),H
Z(H)N A XLIIlb XLJIlc 3 3 3 HO X
HO-C-A'
H
Z(H)N R XL[IId PO X I I
HC-C-R
1"H
H
2 (4 A
XLIIII
C
RU, N 1 x R YR
OP
PO X
HOC-C-BR
H
Z(H)N R XLIIle 0 H N A O P XLlIlg R R'A R' R'A x C. rIH1 P suitable hydroxyl protecting group Z 0CH 2
C
6
H
-374- Scheme 21a
R
H h Z N C--OE 0 XLIJlh PO X HC-C-COOEt
,H
Z N R HO X I I
H
Z(H)N R WllI PO X I I
HC-C-CHO
H-
Z(H)N R 00 4* 0 0
XLIIIJ
PO X HO- -CH O H R
),H
Z H) k R XLI'fl P~O X H H I I I I H O H X XLIIln WLilk P0 X Hi H
HC-O--C,-CR
Z(H)V R XLIIlm P0 X H H I I I I H C-C-C -C-R' H O H
H
2 N R XLIIlo H 0 XR 2 2 -N R
R
OP X
OP
XIIlip R R P =hydroxyl protecting group X and X can be independently Fil NHR, CR 3
OR
0(H) B -375- Scheme 21b P0 X H H I _I I I HC-~ H O H Z(H)N
R
XLIIln Po X H H I I I I HC-C-C-CCRm I I I H OP X
H
2 N' R XLIIlr R 22 0 RI..N
N-
x
OP
P0 X H H I I I I
HC--T-YR'
O P X Z(H)N
R
XLIIlq 9* 0 0 0* *0 0 0 0000 0* 0 00 6 0 0 0* HP0 X
OP
XL Ills R =R4 P hydroxyl protecting group X and X, can be independetly S(R)n, N(R1n, C(R)n- 375- Scheme 22
CO
2
H
BOO- N N H O
TBDMS
TB DM S C DN{fF/Irn
BOC*
OTBOMs (,XL[V b) ()LIYaI) T1-UYACOH/H 2
O
'N
0 C0 a a.
OTBDI-S
G"QUVd)
HO-ND
0
DCC
TH); /T{ BOG- N
H
C0 2 1-.
OMBMS
(XLGI \c) 0
OTBDMS
CY \VC SNaH/DMF Bn Br U0
OH
TBAF/THF
(XLI Vg) 3 Scheme 23 BO
N
H
8 steps Uitezatumr Reference BOC, N 0 H O H (Xt.Va) 3steps Literature
OH
H
OTBOMS
(XLVb) a a H ON 0
DCC
NI-
BOC...N 00
H
OTBDMS
(XLVc) Ether 0
O-N
0 0 Et 3 NI[hF
KCI-HN
(XLVe)
OTBDIAS
jNaH/MF BnBr 0 TBD0MS (XLVd) TB AFflF
OTBOMS
(XLVf) (L~f)(XLVg) -378- Sqcheme 24 1) Ph 3
P=CHCO
2 Me 2) DIBAL-H 3) MCPBA or Sharp less
R
4
CHO
R
4 N<h OH 0 XL V a 1) TMSN 3 2) 2 eq. TBDMSCI 3) CSA, MeCH
OTBODMS
R 4y l----OH
N
3 XLVIb 1) Reduction 2) Cycllzation 3) Aikylatlon 4) Deprotect 1) TsCI 2) NaN 3 0 TB DNMS R
N
0
R
2 2 R2
R
4 0OH XL VId X L V.~ TEDDtlS- t- Ltyldirnethyislllyi -379- Scheme OH osoiao0 ZHNNHZ Nsxki~ H NZ MEMO
ZHMEMO
XLVIta XLVIlb
DAST
S
S S S. S F FH
ZHN
MEMO XLVflc Pd(Q H) 2 cyck~iexene EtGH
FF
NH
2
MEMO-
XLVIlcI
NE
323/ NaH RBr XL VIle
XLVIII
S
HOL
Na 2 Cr 2
O)
7 HOAdCH 2
SO
4 HO F XLVIlg XL Viii Scheme 26 PHN '-)NHP O H
XLVIU
1) Protection 2) Deprotactlon
R
4
R
7
H
2 N INH 2 OP 0 XLVIlb 1) Cycllze 2) Alkylate urea 3) Reduce ketone 4) Deprolect alcohol R2 N~ R 23 XLVIIc 1 Protect alcohol 2) Hydroxylatlon 3) Protect alcohol 4) Deprotect amino 0 N 0 R 4 00 R 7
H
2 N l- H OP 0 XLVIIld XLVIIh? 4 4* 1) Cycllze 2) Alkylate Urea 3) Reduce ketone 4) Deprotect alcohol 0 1- j
N
O H XLYVIle P suitable proterhng grouip for either amine or hydroxyl Scheme 26a XL VIIIg
R
4
CHO
XLVI It P HN1 NH P R 4 O H R 7 XLVIIIh
S
S. S S S 1) Protect alcohol 2) Deprotect amine 3) Cycllze 4) Alkylate urea Deprotect XL-VII Ij is an organometallic such as Li, MgX or variant therot compatable witni the functionality present P suitable protecting group 3b? Scheme 27 1) TsCI 2) K 2 C0 3 p O H
R
3) epoxide opening
R
HO
HO0 XLIXa 1) Cycllze 2) Deprotect 0 HO?
OH
XLIXb -363- Scheme 28
NH
2 "A2 TEArTHF c0 DR 24 HN P, NH a a. a NaHiDMF RBt TsOH-H 2
Q
a. a a. a HO OHF Scheme 29 H2N N H 2 RlMEMO
OMEM
Ri
H
2 NHN NINHi 2
NH
2 Oi RMEMO OMEM COC1 2 PhN HO!
S
S
S
F
S S S St. S S S S. S .5 .9 .5.5 lryNi M1 NHNHEtM.
0 H 2 N' NH2 PMEMO OMEM 1, NaH, BnC 2)HOC1,tv Me0-H C
H
NW~
P
H H C Brin t Nn H 0 0 H -385- Scheme
H
2 N NH 2 Ph Ph MEMO
OMEM
NC SMe 2) NaH, BnCl 3) HCI, MeOH Ph XX Ic Scheme 31 0O S S S.S S
'SQ.
SC
US S S S
S.
S. C a
S.
5S S S
S*
S C
S..
5,55 S S I. U 55..
S C 5* 5* 55
S
5*SS 5* S S 5.
SMe Rl P MEMO OMEM me7 N I- N MJM OMiEM~ reflu,,1
BU
4 Nl re nlu x, 18 11
BU
4 N1 then FICI
S
RlN N ~R M E MO OMEM Lln
FIC!
HO OH
NANY
HO OH LMli -386- Scheme 32 H OH H 0 N YH
~~H
R
4
R
0 O XH 0 1) Ccoup~ng Z' N'H 1l
R
4
P
7
W
AcO OAc L IVa 1) Pdc. H, 2) H30- 3) TEA, TrCI R 4
RP
7 AcO OAc LIVb 9 9* 1) OH R,27 2) MIi Tr,~ N~ H EtO 2
C.
0
,C
3) Pn~(2)o~
RPR
4 M EMOi OM'D/M I Eq TSQH H 2 0) LI Vc MEMO 0 NIE M 21 ;wll n'd 11 H H H0 2 0.C1 MEMO OMEN' LIV .1 LIVe 4* 1) DGC HOBT 2) Base, R41X 3) H301 0 HO OH -337- Scheme 34-a
CHO
1, PtV jP.CHC0 2 Me 2, DIBAL, CH 2 C1 2
,OH
MCPB A
OH
0 1. TMSNj, FiPO) 4 2 T&CI, pyricno 3, NaN 3
DMF
S S I SEM-CI. TEA 2 iAtH EtjO OS EM I COI, C-tOAc 2 NaH, RDr 3 HC! 2 NiH, RE~r 3 HCI 0 0 R23N NR2 -388- SCHEME 34b Ri Ph CbzNH CHO Fi Cb2NH 0 ITBDIMS3'i 2 YJALH, ~PdIO HH 3 P =0H 2 CbzNH, Et 2
AICN
MC PEA C bzN H 9 0* 0* 0 0.0.
0* 0**0 0* Ph NH )X N' NH, 0 TEDMS 2. NaH, R8!r 3 HCI 0 Rj 22 N NR" 2 no I. H 2 NS0 2
NH
2 pyridine 2. NaH, R~r 3.HCI 0 0
R
2 2 N' NR 23 no 389 Table A 0 0
R
2 2 -1 1 R 23 HO OH EX. Table/Ex R 7R2=R3K~M Al.. A2 2m/23B H A3 2m1230 0 4--b A4 2m/23E
OH+
2mI23E 0 A7 2ml/23G
-CH
2
CH
2
CH
2 CH3 A9 2m/23i 0C
C
CCC. C C C C
CCCCCC
C
390 Table A continued A23 2mf23 .7111!-R= Ki 0 0 H gm/23K All1 A12 A13 Al14 Al S 2m/23L 2ml23M 2m/23N NO2+
SNHE
SOH
0
H
N
0
H
Al 9 2m/230 2M/l23P 2m/230 2rTV23R .5 S S S *5 2mI23S I
S
550555 0
*.SSS.
S
391 E. Table/Ex A-21- 2m/23T Table A continged R4 R7
RH
22 =R2 0 Ki(nM) A22 A23 A24 A26 2m/23U 2m/23V 2m/23W 2m/23X 2mf23Y 2rnI23Z
N-OH
-CH3
*CH
2
CH
3
-CH
2
CH
2
CH
3
C--N
A27 A2..
A31 2m/23AA 0
N
H
NH
2 j~ S OMe 0 2U/31 B
F
a a 392 A32 Table/Ex.
2u/31 A Table A continued R4 R7 R 22 23 N 0
F
Ki(nM) A33 A34 A36 A37 *.A38 A$g 550 0. a so A42 0 0 A43 0. 0.
0 2U/31 D 2U/31 0 2MI23AC 2m/23AD NO2H(H) -CH2CH(CHS) 2 0 OH N OH
-CH
2
CH
2
CH
2
CH
2
CH
2 0H -CH2CH 2
CH
2
CH
2
CH
2
CH
2 0H
N
NN
H
H
NH
2
NN
N-OH
44+ 393 Table A continUed Ex.
A44 A46 A47 Table/Ex.
KI(nM)
-CH
2 0H(C-H3)p -rH 2 CH(CH3)2 C-
H
N-OH
H
N,
NH
*9
Q
S S S9 S. S S S
S.
S S 99 0 S. OS 0* 9* *9 0 S S
S.
OSSO 9*
S
394 Table B Nz B2 B3
K-
B4 -CH 2 CH(CH3)2 0 S 0 00 S 5S S 5* ~5 *CH 2 CH(CHS)2 S. S S 5
S.
55 S S 9 5 0 OH
RC
2
C
2 CHC2HO
-CH
2
GH
2
CH
2
CH
2
CH
2
OH
-CH
2
CH
2
CH
2
CH
2
CH
2
OH
H
K+1*M B6 B7 K-
N
N
5.
S
S
.550 S S
S
395 Table C Ex Table/Ex, R2 4 a 2 2 Ki(nM) cl 2r/28K C2 2r/28E C$ 2r/28L C4 2r/2815 C5 2r/28C 06 2r/28D 07 2r/28J 9 S 9 9 .5 5 5* S 9 .5 4 0e 4* 95 9 9. 0 S* *9 0* *5
ZOO
OH
-CH
2 CHpCH 2
-CH
3
OH
OH
08 2r/28G 09 2r/28H
-OCH.
3 0055 010 2r/281 -N (CH 3 2 x
L
F
396 Where the terms "comprise", "comprises", "comprised" or "comprising" are used in this specification, they are to be interpreted as specifying the presence of the stated features, integers, steps or components referred to, but not to preclude the presence or addition of one or more other feature, integer, step, component or group thereof.
S S* Se 0 4 a a o 'o 1 Y r h l

Claims (6)

1. A compound of the formula or a pharmaceutically acceptable salt form thereof wherein: 1 1 49 0 S S. .r R 4 and R 7 are independently selected from the following groups: hydrogen; C,-CB alkyl substituted with 0-3 R"; C2-C, alkenyl substituted with 0-3 R"; C2-C 8 alkynyl substituted with 0-3 R"; a C 3 -C 14 carbocyclic ring system substituted with 0-3 R" or 0-3 R 1 2 a heterocyclic ring system selected independently from indolyl, furanyl, pyridyl, thienyl, pyrrolyl, benzo thienyl, pyrazolyl, thiazolyl, benzofuranyl, tetrahydroisoquinolinyl, benzotriazolyl, benzimidazolyl, or imidazolyl, said heterocyclic ring system being substituted with 0-2 R1 2 C0 2 R 1 3 R 4 A and R 7 A are independently selected from the following groups: 0 0004 4 r 398 hydrogen; Cl-C 4 alkyl substituted with 0-6 halogen or 0-3 cl-c? alkoxy; benzyl substituted with 0-6 haiogen or 0-3 Cl-0 2 alkoxy; CO 2 R 13; R 4 and R 4 A can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R1 2 R 7 and R IA can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R 12 nr is 1; R 5 is selected from H; halogen; Cl-c6 alkyl substituted with 0-3 -N(R 20 2 SR 20 -OR 2 0 or is independently selected from: hydrogen, halogen, Cl-C, alkyl substituted :with 0-3 R 1 1 -N.(R 20 2 SR2w, -0192 1 or -N 3 R6 and R'3 can alternatively join to form an epoxide or aziridine ring; 1 -OCH 2 SCH 2 OC( OCH 2 -OC( -0OC(= 0)0-; -OC(CH 3 2 -OC((CH 2 3 NH 2 (OH 3 OC(OCH 3 )(CH 2 CH1 2 CH 3 -OS( 0-; -OCOHO)NH-;- -NHCH 2 OOH 2 NH-' 0066 S-NHOC(=S)0-; -NHc( -NHC(CH 3 2 -OC(CH 3 ),zNH-; R~ is selected from hydrogen, halogen, CI-C. alkyl, -N(R 2 0 2 SR 20 or 0 0M9DMTN. 9 R~a. is selected from: hydrogen, halogen, Cl-C6 a2lkyl, -N(R 20 -SR 20 or -OR 2 1 R 5 and R~a can alternatively join to form or a ketal ring; R 6 and R 6 a can alternatively join to form or a ketal ring; R 20 and R 21 are independently selected from: hydrogen; C1-CG alkyl. substituted with 0-3 Rll; C 3 -C6 aJJkoxyalkyl substituted with 0-3 Rilly CI-C6 alkylcarbonyl substituted with 0-~3 Rll 1 Cl.-C6 alkoxycarbonyl substituted with 0-3 Rll; Cl-C6 alkylaininocarbonyl substituted with 0-3 Rll; henzoyl substituted with 0-3 R 12 pherioxycarbonyl substituted with 0-3 R1L2; phenylaminocarbonyl substituted with 0-3 R 12 or .phosphate ester; 25 R1i eetdfo n rmr ftefloig H, keo aoecyn,-HN.R1,-R33 4C2R13 -I(OR3 O1,-()R3 -NC*-HNR3 -C=HNR1,-.O)R3]4 -N1C=*R3 =Np4 -N1C=4CR as H, ketoRhalogen,1cyl4, -14NR1 3 R, p14-R~, -C02 1 3 C(~OR' 3 S02 3 -SO2R 3 -N1(OC (ORWU)2t, C--C C-C4 (=0)yl NR 13 R 1 (=O)R 1 3 h, benR' 4 -NR 1 4 C yl (=0)0R 1 4 benzyloxy, nitro, C7-CIO arylalkyl, hydzoxaxnic acid, hydrazide, boronic acid, sulfonamide, -399.- formyl, C 3 -C6 cycloalkoxy, CI-C 4 alkyl substituted with -NR 13 pl 4 C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, Cl-C4 haloaltkyl, Ci-C4 haloalkoxy, Cl-C4 alkoxycarbonyl, pyridylcarbonyloxy, Cl-C4 alk.ylcarbonyl, C 1 -C4 alkylcarbonylanino, -OCH2CO211,
2-(l-miorpholino)ethoxy, azido, or 1-3 amino acids linked together via amnide bonds, said amiu.no acid being linked via the amine or carboxylate terminus; C3-CIO cycloalkyl substituted with 0-2 R 1 2 Cl-C4 alkyl substitued with 0-2 R 12 axyl(CI-C3 alkyl) substituted with 0-2 p12; C2-CG alkoxyalkyl, sulbstituted with 0-2 R1- 2 C1-C4 alky:[carbonyloxy substituted with 0-2 R1 2 C6-CjO arylcarbonyloxy substituted with 0-2 R 12 a C5-C14 carbocyclic residue substituted with 0-3 p1j2; a 5- to 10-rnezbered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring systemn being substituted with *0-3 R 1 2 R11A is gelected from one or more of the following: 5 H, keto, halogen, cyano, -CH 2 N(Rl 3 B) (R14B), -N(Rl 3 B) (R14B), -CO2H, -OC(r=O) (Cl-C 3 alkyl), -OH, C2-C6 alkoxyalkyl, -C (=O)NH2, -Oc (=O)NH 2 0 -H(ON2 -SO2NH 2 Cj-C4 alkyl, C2-C4 alkenyl, C3-ClO cycloalkyl, C3-C6 cycloalkylmethyl, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C7-ClO arylalkyl, hydroxamic acid, hydrazide, boronic acid, C 3 -C6 cycloalkoxy, CI~-C 4 alkyl substituted with -NII2, Cl-Cd hydroxyalkyl, &os 35 methylenedioxy, ethylenedioxy, Cl-C4 haloalkyl, 400 0. 20 0000 0 9 00 0 *0 0 0 00 0 0 0 *0 00 00 0 0 25 0000 0 0 0000 00 00 0 Cl-C4 haloalkoxy, CI-C4 alkoxycarbonyl, C1-C4 alkylcarbonYloxy, Cl-C4 alkylcarbonyl, Cl-C4 alkylcarbonylanino, -OCH2CO2H, 2-(l-morpholino)ethoxy, azido, aryl(C 1 -C 3 alkyl), a CS-C14 carbocyclic residue; a 5- to 10-rnembered heterocyclic ring system containing 1 to 4 heteroatoms, independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system substituted with 0-3 R1 2 when a substituient on carbon, is selected from one or more of the following; phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, Cl-C 4 alkyl, C3- C6 cycloalkyl, C3-CG cycloalkylmethyl, C7-CIO arylalkyl, C1-C4 alkoxy, -CO2H, hydroxamic acid, hyarazide, boronic acid, sulfonamiide, formyl, C 3 CG cyc:loalkoxy, -OR, 1 3 C 1 -C 4 alkyl substituted with -NR 13 Rl 4 -NR1 3 R 1 4 C-C6 alkoxyalkyl optionally substituted with -Si(CH3) 3 Cl-C 4 hydroxyalkyl, methylenedioxy, ethylenedioxy, Ci- C4 haloalkyl, C1-C4 haloalkoxy, Cl-C4 alkoxycarbonyl, CI-C4 alkyl-carbonyloxy, C 1 -C4 alkylcarbonyl, Cl-C4 alkylcarbonylanino, -S(O)MR 13 -S02NR 1 3 RI 4 -N1SQ2R 1 4 -OCH2CO2R' 2-(l-morpholino)ethoxy, -C(R1 4 or a 5- or 6-menibered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur; or R 12 may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused or 6-inembered ring, said 5- or 6- mnembered ring being optionally substituted oni the aliphatic 0 000000 0 000000 0 0 401 carbons with halogen, Cl-C4 alkyl, Cl-C4 alkoxy, hydroxy, -NR1 3 R 14 or, when R 1 2 is attached to a saturated carbon atom, it may be =0 or or when R 12 is attached to sulfur it may be =0; R1 2 when a substituent on nitrogen, is selected from one or more of the following! phenyl, benzyl, pheneth,_!, hydroxy, Cl-C4 hydroxyalkyl, Cl-C4 alkoxy, Cl-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR 1 3 Rl 4 -NR 1 3 p 14 C-CG alkoxyalkyl, Cl-C4 haloalkyl, C1-C4 alkoxycarbonyl, -C02H, &jl-C4 alkylcarbonyloxy, Cj-C4 alkylcarbonyl, -C (R1 4 (ORI 4 Rl2A, when a substituent on carbon, is selected from one or more of the following: phenyl, benzyl,, phenethyl, pherioxy, benzyloxy, halogen, hydroxy, nitro, cYano, Cl-C 4 alkyl, C3~- CG cycloalkyl, C3-C6 cycloalkylmethyl, *~*arylalkyl, Cl-C4 alkoxy, -CO2H, hydroxamic acid, C. C hydrazide, boronic acid, sulfonamide, formyl, C 3 C 6 cycloalkoxy, -OR, 13 C 1 -C 4 alkyl substituted 2S with -NH 2 -NH 2 -NHMe, C2-C6 alkoxyalkyl optionally substituted with -Si(CH 3 3 Cl-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, Cap" C4 haloalkyl, C1-C4 haloalkoxy, Cl-C4 alkoxycarbonyl, Cl-C4 alkylcarbonyloxy, Cl-C4 alkylcarbonyl, cl-C!4 alkylcarbonylirmino, -S(OmMe, -S02NH2, -NHSQ2MC, -OCH2CO2R' 3 2- (1-inorpholino) ethoxy, -C (=NOH)NH2; Or a 5- or 6-men'~bered heterocyclic ring containing from I to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur; -402 or R1 2 A may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused or 6-merbered ring, said 5- or 6- membered ring being optionally substituted on the aliphatic carbons with halogen, C 1 -C4 alkyl, Cl-C4 alkoxy, hydroxy, -NH 2 or, when R1 2 A is attached to a saturated carbon atom, it may be =0 or or when R 12 is attached to sulfur it may be =0; R1 2 A, when a substituent on nitrogen, is selected from one or more of the following: phenyl, benzyl, phenethyl, bydroxy, Cl-C4 hydroxyalkyl, Cl-C4 alkoxy, C1-C4 alkyl, C3-CG cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NH 2 -NH 2 C 2 -C6 alkoxyalkyl, C 1 -C4 haloalkyl, Cl-C 4 alkoxycarbonyl, -C02H, Cl-C4 alkylcarbonyloxy, Ci-C4 alkylcarbonyl, -C(=NOH) NH 2 R 13 is selected from- H; phenyl substituted with 0-3 RIIA; benzyl substituted with 0-3 R1lAI Cl-C6 alkyl substituted with 0-3 R11A; C 2 -C 4 alkenyl substituted with 0-3 Rl1A; CJ-C6 aiky]carbotyl substituted with 0-3 RIlA; Cl-'C6 alkoxycarbonyl substituted with 0-3 R11A; Cl-C6 alkyl.aminocarbony1 substituted with 0-3 RI1A; C3-C6 alkoxyalkyl substituted with 0-3 RiA; R1 4 is hydrogen, hydroxy, CF 3 C 1 -C 6 alkyl. substituted with ii 0-3 groups selected from OH, C 1 -C 4 alkoxy, halogen, 6:000: 35 NH2, -NH(CI-C4 alkyl), C 1 -C6 alkoxy, C 2 -CG alkenyl, -403- 404 phenyl, benzyl, R' 3 and R" 4 can alternatively join to form (OH 2 4 -(OH 2 5 -0H 2 0HN(R 15 )0CH 2 0H 2 or -0H 2 0H 2 0-H 2 CH 2 R"' 8 and R"' 8 are independently selected from H or 01-06 alkyl, or R 13 B and R 14 B can alternatively join to form -(OH 2 4 -(OH 2 5 -CH 2 CH 2 N(R 1 5 )CH 2 0H 2 or -OH' 2 CH 2 00H 2 OH 2-; R 1 5 is H or CH 3 m is 0, 1 or 2; W is selected from: 1 ID.~ -N(R 2 1)S( 2 N (R 23 *-N(R 22 (R 24 a) N(R 23 *wherein: is 0or NR 24 R 22 and R 23 are independently selected from the following: iS....hydrogen; 01-08 alkyl substituted with 0-3 R" 1 02-08 alkenyl substituted with 0-3 R 31 -31 0C2-08 alkynyl substituted with 0-3 Ri a 03-014 carbocyclic ring system substituted with 0-5 R 31 ar 0-5 R 32 *a heterocyclic ring system selected independently from pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, tetrazoyl, triazinyl, pyrazinyl, pyridazinyl, oxazolidinyl, and thiazolyl said heterocyclic ring system being substituted with 0-2 R 3 1; 10/2/99DIJPONT.SP3,- 401 -405 -OR 2 2 a; -N(R 22 a) (R 2 2 b); R 2 2 and R 2 2 b are independently selected from the following: hydrogen; alkyl substituted with 0-3 R 31 C2-8 aikenyl substituted with 0-3 R 31 C2-C8 alkynyl substituted with 0-3 R 31 a C3-C14 carbocyclic ring system substituted with 0-5 R 31 or 0-5 R 32 a heterocyclic ring system selected independently from pyridinyl, furanyl, thienyl, pyrrolyl, thiazo!yl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl, 1 H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl said heterocyclic ring system being substituted with 0-2 R 3 2 R is selected from: hydrogen; hydroxy; amino; C,-C4 alkyl; C1-C4 alkoxy; mono- or di-(C 1 -C alkyl) amino; cyano; nitro; benzyloxy; -NHSO 2 aryl, aryl being optionally substituted with alkyl; H* R 2 4 a is selected from: hydroxy; amino; C, 1 -C 4 alkyl; C,-C4 alkoxy; mono- or d C. alkyl) amino; cyano; nitro; benzyloxy; or phenoxy; IP 0,. alternatively, R 2 2 R25, Or R26, independently, can join with R 4 or R 4 A to form a 2 or 6-membered fused heterocyclic ring selected from pyrrolidine, morpholine, thiomorpholine, piperidine, or piperazine or alternatively, R 23 can join with R 7 or R 7 A to form a 5- or 6-membered fused heterocyclic ring or carbocyclic ring substituted with 0-2 R 1 2 said heterocyclic ring selected from pyrroidine, morpholine, thiomorpholine, piperidine, or piperazine or S10/2/990UP0NTSI',i 405 406 alternatively, R 22 or R 2 3 can join with R 5 or R 6 to form a 0- to 7- membered bridge to form a carbocyclic or heterocyclic ring, said bridge being subsituted with 0-2 R 12 and heterocyclic ring being selected from pyrrolidine, morpholine, thiomorpholine, peperidine, or peperazine; alternatively R 23 can join with R 7 A to form a direct bond; alternatively R 22 can join with R 4 A to form a direct bond; R 31 is selected from one or more of the following: keto, lialogen, cyarlo, -CH 2 NR 1 3 R1 4 -NR 1 3 R1 4 -CO20' 3 3 -OR 1 3 C2-C6 alkoxyalkyl, -S(0),mR 1 3 -NHC(=4E)NHR 13 -C(=NH)NHiR 13 -C(=Q)NR 13 RI 4 -NR1 4 C(=C))R 13 =N0R 14 -NR 14 C OR 14 -0C (=0)N1R 13 Rl 4 *-NR 13 NR 13 R 14 -NR 13 C(=S)NR 13 Rl 4 -NR 14 S02NR 13 R 14 -NR1 4 S02R 13 -SO2NR 13 'Rl 4 Cl-C 4 alkyl, C2-C 4 alkenlyl, C3-Clo cycloalkyl, C3-CG cycloalkyrnethyl, benzy'., phenethyl, pbenioxy, benzyloxy, nitro, C7-C1O arylalkyl, hydroxanic acid, hydrazide, oxime, boronic acid, sulfonam~ide, forinY1, C 3 -C6 cycloalkoxy,, C 1 -C 4 101299)UPONTSr13,- 406 alkyl substituted with -NR13RI- 4 Cj-C4 hydroxyalkyl, methylenedioxy. ethylenedioxy, C 1 C4 baloalkyl, Cl-C4 haloalkoxy, C1-C4 alkoxycarbonyl, Cl-C 4 aJlkylcarbonyloxy, Cl-C 4 alkylcarbonyl, Cl-C4 alkylcarbonylamino, -OCH2CO2R' 3 2- (1-morpholino) ethoxy, azido, -C (R 1 4 (0R 1 4 or 1-3 amino acids, linked together via arnide bonds, said amino acid being linked via the amine or carboxylate terminusi A CS-C14 ca-_ocyclic residue substituted with 0-5 R 32 a 5- to 1O-meinbered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrog n or sulfur, said heteroc~yclic ring system being substituted with 0-2 R 32 R 32 when a substituent on carbon, is selected from one or more of the following: *:phenethyl, phenoxy, C3-C 1 0 cycloalkyl, C3-C6 ***cycloalkylmethyl, C7-Clo arylalkyl, hydrazide, oxime, boronic acid, C2-C6 alkoxyalkyl, methylenedioxy, ethylenedioxy, Cl-C4 alkylcarbonyloxy, -NHS02R 14 benzyloxy, halogen, 2- (l-rorpholino) ethoxy, -C02R3- 3 bydroxamic acid, -C0NgR 1 3 NR 1 3 R 1 4 cyano1, sulfonamide, -CHO, C 3 -C 6 cycloalkoxy, -NR 1 3 RI 4 -C(R 1 4 1 4 -N02, -OR 1 3 _NR 4 0 R 4 1 _SOmp 1 3, -SOMNR 1 3 RI 4 -C(=O)NkO- 3 RI 4 -OC(=O)NR 13 Rl 4 1 ~_OC(=O)R1ti> -'OCO2RI 3 phen~yl, -C(z=O)NR 3 4 alkyl) -NR 1 3 R 1 4 -C(=O)NR 40 R 4 1 Cl-C 4 haloalkyl, *sets:C 1 -C 4 haloalkoxy, C 2 -C 4 haloalkenyl, CI-C 4 0 haloalkynyl, 35 -C NR1 3 C (R11) 2 NR 13 Rl 4 -407 -C NR 1 3 C (R 11 2 NR 13 C0 2 R 1 3 C(=)NR 3 -(Cl-C 4 alkyl) -N 13 CO 2 RI- 3 3 alkyl)-R 1 1 -C C (R 1 1 2 NR R, -C (R 1 1 2 NR' 3 C0 2 R 1 3 -C 4 alkyl)-NR 1 3 R 1 4 -C -(Cl-C 4 alkyl) -NR 13 C0 2 R 13 or C1-C4 aikoxy substituted with 0-4 groups selected from: R 11 C 3 -C 6 cycloalkyl, -C0 2 R 1 3 -C(0O)NR 13 Rl 4 -NR1 3 RI 4 or OH, CI-C 4 alkyl. substituted with 0-4 groups selected from: R11, =NR14, =NNR 1 3 C(=O)NR 13 R1 4 =NNR 1 3 C(=C)0R 1 3 or -NR 1 3 R 1 4 C 2 C 4 alkenyl substituted with 0-4-11; C2-C 4 alkynyl. substituted with 0-4 a or 6-rnembered heterocyclic ring containing from 1 to A heteroatoms independenitly selected from oxcygen, nitrogen or sulfur, substituted with 0-2 v12. 9* or R 3 2 m~ay be a 3- or 4- carbon chain attached to
4.adjacent carbons on the ring to form a fused 44 or 6-rmembered. ring, said 5- or 6- membered ring :being optioially substituted on the aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydlroxy, -NR1 3 R1 4 or, when R 32 is attached to a saturated carbon it may be =NQE; or when R 32 attached to sulfur it may be =O R 32 when a substituent. on nitrogen, is selected from one or more of the following: phenyl, benzyl, phenethyl, hydroxy, Cl-C4 &fee*:hydroxyalkyl, C1-C4 alkoxy, CI-C4 alkyl, C3-C6 cycloalkyl, C 3 -C6 cycloallcylmethyl, -CH2NR 13 R- 4 *3S -NR 13 R 1 4 C2-C6 alkoxyalkyl, C1-C4 haloalkyl, -408- 409 Cl-C4 alkoxycarbonyl, -CO 2 H, Cl-C4 alkylcarbonyloxy, 01-04 alkylcarbonyl, -0(R 14 =N(R1) R 40 is selected from: H, Cl-C3 alkyl; R 4 1 is selected from: =0)NR1 3 R 1 4 =0)NR1 3 NR 1 3RR1 4 =0)C(R 1 2 NR 13 R 14 =O)C(R 11 2 NR1 3 NR1 3 R 14 1 2 NR 13 0C0 2 R 13 we. =O)-(Cl-04 alkyl)-NR 13 R 1 4 0)-(Cl-C,4 alkyl)-NR 13 C0 2 R 1 3 1-3 amino acids linked together via amide bonds, and linked to the N atom via the carboxylate terminus; wherein said aryl group is phenyl or naphthyl; provided that: R R 4 R 4 A R7 and R 7 A are not all hydrogen; when W- and RA are hydrogen, R 2 is not hydrogen, *ese tOtVl9qDUMr'oN'..s-, -410- A compound of Claim 1, of formula (11): RS R 6 (IT) or a pharmaceutically acceptable salt form thereof wherein: a ,J 9 *4 9 S. S
9. *5 Oh a 0 R 4 and R 7 are independently selected from the following groups: hydrogen; 01-04 alkyl substituted with 0-3 Ri 1 C 3 -C 4 alkenyl substituted with 0-3 R"; R 5 is -OR 20 R 6 is hydrogen or -OR 21 R 20 and R 2 1 a re H; R" is selected from one or more of the following: H, keto, halogen, -CH 2 NR1 3 R 1 4 -NR1 3 R 14 -OR'1 3 02-04 alkoxyalkyl, 02- 04 alkenyl,; C3Cl cycloalkyl substituted with 0-2 Ri1 2 10tV99)DUPONT5P3,- 410 f C 1 -C4 alkyl substituted with 0-2 R 1 2; aryl(Cl-C3 alkyl) substituted with 0-2 R121 aryl substituted with 0-3 R1 2 or a 5- to L-membeered heterocyclic ring -ystem containing 1 to 4 heteroatoms indepenc>'x.tly selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R1 2 p12, when a substituent on carbon, is selected. from one or more of the following: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, Ci-C4 alky], C7-ClO arylalkyl, C1-C4 alkoxy, 2-(l-morpholino)ethoxy, -CO2H, hydroxamic acid, hydrazide, -C(R 1 4 )N(0 1 4 cyano, boronic acid, sulfonamide, forxnyl, C 3 -C 6 cycloalkoxy, -OR 1 3 C 1 -C 4 alkyl substituted with -NR13R 1 4 -NR1 3 R 1 4 methylenedioxy, Cl-C4 haloalkyl, CI-C4 alkylcarbonyl, C1-C4 alkylcarbonylanino, hydroxy, hydroxyrnethyl; or a 5- or z-membered 1heterocyclic ring containing from 1 to 4 heteroatons independently selected from oxygen, nitrogen or sulfur; R 12 when a substituent on nitrogen, is selected from benzyl or methyl; 36 R 1 3 is 1J, C 1 -C 4 aikyl, C3-C6 alkoxyalkyl, C 2 -C 4 alkenyl, or benzyl; R 1 4 is OH, H, CF 3 C 1 -C 4 alkyl, CI-C 4 alkoxy, NH 2 C 2 -C 4 alkenyl, or benzyl; o13 and R 14 can alternatively join to form 6 35 -(CH2)5-0 -CH2CH 2 N(Rl 5 )CH2CH2-, or -CH2CH2OCH12CH2-; -411 412 is H or CH.; W is selected fromn: -N(R 22 (R 24 a N(R 23 wherein: Z' i S 0; 1 S S 0 S. 0* S S *5 S S S. SS*S* S S R 22 and R 23 are independently selected from the following: hydrogen; 0 1 alkyl substituted with 0-2 R'I 1 C2_C, alkenyl substituted with 0-1 R 3 1; C2_C4 alkynyl substituted with 0-1 R 31 R 24 is selected from -OH, C 1 -C 4 alkoxy, mono- or di-(Cl-C 6 alkyl) amino; R 3 1 is selected from one or more of the following: keto, halogen, -CH 2 NR' 3 R' 4 -NR1 3 R 14 -OR 13 C2_C4 alkoxyalkyl, 01--4 alkyl, C2-04 alkenyl, 03-C1, cycloalkyl, -0(R 14 (R1) -CO 2 R' 3 -S(O)mR 13 aryl substituted with 0-5 R 3 1; or a 5- to lO-membered heterocyclic ring system cooitaining 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0- 2 R 3 2 R 3 ,when a substitL ?nt on carbon, is selected from one or more of the following: phenethyl, phenoxy, 03-06 cycloalkyl, 03-0 cycloalkylmethyl, tont199[)u"'Nr'r r- 412 -413- arylalkyl, hydrazide, oxime, boronic acid, 02-06 alkoxyalkyl, methylenedioxy, ethylenedioxy, 01-04 alkylcarbonyloxy, -NHSO) 2 R 14 Benzyloxy, halogen, 2-(l1-morpholino)ethoxy, -C0 2 R 13 hydroxamic acid, -CONR 3 NR 3 R 1 cyano, boronic acid, sulfonamide, -CHO, C 3 -0 6 cycloalkoxy, -N l 13 R 1 4 -C(R 1 4 =N(OR 4 NO 2 -OR1 3 -NR 4 (R 4 1 SOR 3 _Sr, C( O)NR 13 R 1 -OC(=O)NR 13 R 1 4 =O)R' 1 -O0( -000 2 R 13 phenyl, =O)NR 1 3 -(0 1 -C 4 alkyl)-NR 13 R 14 =O)NR 40 R 41 01-04 haloalkyl, 01-04 haloalkoxy, 02-04 haloalkenyl, 02-04 haloalkynyl, or O)C(R 11 2 NR 13 R 1 4 O)C(R' 1 2 NR1 3 C00 13 O)-(Cl-04 alkyl)-NR 13 C0 2 R1 3 1 or 01-04 alkoxy substituted with 0-3 groups selected from: R 11 03-Co ~~cycloalkyl, -00 2 R' 3 -C(=O)NR 13 FiR N 1 R 4 o H Cl-C4 alkyl substituted with 0-3 groups selected from: 1 1 =NNR'1 3 0( -O)NR 3 R 14 or -NR 13 R 14 02-04 alkenyl substituted with 0-3 Ri 1 02-04 alkynyl substituted with 0-3 Fe"1; a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently ,selected from oxygen, nitrogen or S sulfur, substituted with 0-3 R1 2 R" 2 when a substituent on n~rogen, is selected from benzyl or methyl; m is 0,1, or2; R 4 1 IS selected from: H, CI-C, alkyl;, I IMMUMMUM-113 414 R" 1 is selected from: =O)NR 13 R 14 =O)NRdNR 1 4 O)C(R") 2 NR 13 R 14 O)C(R 11 2 NR1 3 NR 1 4 O)C(R 11 2 NR 13 C00 2 R 13 1 -C 4 alkyl)-NR1 3 R 14 )-(CTC4 alkyl)-NR 1 3 C0 2 R 13 1-3 amino acids linked together via amide bonds, and linked to the N atom via the carboxylate terminus; *.provided that: R R 4 and R 7 are not both hydrogen; 1 5 when R 4 is hydrogen, R 22 is not hydrogen. 9W4 06 to 0 3. A compound of Claim 2, or a pharmaceutically acceptable salt form thereof, wherein:, R 4 and R 7 are selected from benzyl, fluorobenzyl, pyrrolylmethyl, methoxybenzyl, isobutyl, nitrobenzyl or aminobenzyl, 26 thienylmethyl, hydroxybenzyl, pyridylmethyl, na phthylm ethyl; R 5 is -OH; R' is hydrogen or -OH; R 1 3 is H, C 1 ,-C 4 alkyl, C 2 -C 4 alkenyl, or benzyl; 10/2/99DLJPONT.H.,- 414 415 R'1 4 is OH, H, OF 3 O1-O4 alkyl, Ol-O4 alkoxy, N2' 02-04 alkenyl, or benzyl; R'1 3 and R 14 can alternatively join to form -(OH 2 4 -(OH 2 6 -CH 2 OH 2 N(R 1 5) 0H 2 0H 2 or -0H 2 0H 2 00H 2 0H 2 W is selected from: -NR 0 N( 3 R 22 and R 23 are independently selected from the following: .00 000 9 *g 0 9 S, go* 41 S too a: 0 7 L) tOn/V)I)U POW,$ Pll,- 415 hydrogen; Cl-CS alkyl mibstituted with 0-2 R 3 1 C2-CG alkenyl substituted with 0-2 R 3 1 C 2 -C4 alkynyl substited with 0-2 R 31 R 3 1 is selected from one or more of the following: halogen, -OR' 3 C-C4 alkyl, C-l ylakl -C(RI 4 )=N(0R 1 4 C0 2 RI 3 -S(Q)mRl 3 aryl. substituted with 0-5 R 32 or a heterocyclic ring system chosen from pyriciyl, pyrimidinyl, triazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, indolyl, quinol-i-nyl, isoquinolinyl, oxazolidinyl, benzirnidazolyl, 15benzotriazolyl, indazolyl, benzoxazolinyl, benzoxazolyi., said heterocycl~ic ring being .9*substituted with 0-2 R 32 R 32 when a substituent on carbon, is selected from one or 20 more of the following: -CONH 2 -C0 2 H, -CHO,, -CH 2 NHOH, -CH 2 NR 13 Rl 4 -NR1 3 R 14 hydroxy, hydzoxyniethyl, -C (R 1 4 =N (QR 14 halogen, methoxy, methyl, nitro, cyano, allyloxy, 9 -CO2CH3, -NHCHO, -NHCOCH3, -OCO 2 C i3, .:25 -CH=NCH2CH2OH, -OCONHCHi2C6H5, -OCONHCH3, 00 oxazolidiniyl, -C=C-CH2OH, -COCH3, hycdroxyethyl, CI-C 3 alkyl (said a1kyl substituted with 0-4 *fee*:halogen, or OH), tetrazolyl, -OCH2CONH2, -CONHNH2, -CH=NNHCONH2, -CQN-IIQCH3, -CH2CH(OH)CH2OH, adarnantarnido, hydroxyethoxy, dihydroxyethyl, -C(N2H2)=NH, -CONIHCH3, -B(OHi)2, benzyldxy, -CONHCH2CH3, -CON (CR2CR3) 2, methylthio, -SO2CH3, -NHCONH2, -NHCONHCH3, -NTICOCH2N (CH3 2 -NHCOCH2NHCH3, -NIICOCH2NHiCO2CJ4206H5, -NHCOCH2NH2, -416- -NHCOCH (CH3 NICO 2 CH2C6H5, -M{COCE (CH2C6H5 )NHCO2CH2C6Ii5, -N1iCOCH (CH NH2, -NHCOCHi(CE2C6HS )NH2, -CO2CH2CH3, -CONIHACH2CH2CH3, -CONHiCH(CH3) 2, -CH2-imidazole, -COC (CH3) 3, -CH(OH1)CF3, -CO-imidazole, -CO-pyrazolyl, oxadiazolidinoayl, -COCF3, -COCH2CI4l3, -COCH2CH2CH3, pyrazolyl, -SO2NH2, -C(C2CH-3)=N(OHi) or phenyl, acetoxy, hycdroxyamiio, -N(CH 3 (CHO), cyclopropylme thoxy, -CONR 1 3 R 14 -CONIIOH, (die thylaminoethyl) amiriocarbonyl, (IN-ethyl, N -methyl.amino ethyl) amiriocarbonyl, (4-mreiylpiperazinylethyl) aminocar'bonyl, (pyrrolidcinylethyl) arinocarbonyl, (piperidinylethyl) aminocarbonyl, -NHCOCH 2 NHiCH3, N- (4-rorpholino) ethyl) arninocarbonyl, or N- (2- N-dinethylafiflo) ethyl) arninocarbonyl; *R 32 when a svbsti.tuent on nitrogen, is methyl. A compound of claim 1 of formula (lid) 0 0* R22N~ NR23 R 4 R HO O (lid) or a pharmaceutically acceptable salt form thereof, where in-, -417- R 4 and R 7 are independently select ed from:u benzyl, fluorobenzyl, pyrrolyirnethyl, inethoxybenzyl, isobutyl, nitrobenzy. or aminobenzyl, thienylmethyl, hydroxybenzyl, pyridylmethyl, naphthylnethyl; R 2 2 and R 2 3 are independently selected from the group consisting of! hydrogen, allyl, methyl, ethyl, propyl, cyclopropylmethyl, n-butyl, i-butyl, CH2CH=C(CH3) 2 pyridinylnethy., rnethallyl, n- pentyl, i-pentyl, hexcyl, benzyl, isoprenyl, propargyl, picolinyl, inethoxyethyl, cyclohexylmethyl, dimethyl-butyl, ethoxyethyl, mnethyl-oxazolinyJlnethyl, naphthyJ.methyl, is* methyloxazoinylmethyl, vnlxehl pentafluorobenzyl, guinolinylmethyl, carboxybenzyl, chioro-thienyl, benzyloxybenzyl, :pheny),benzyl, adaaantylethyl, inethylbenzyl, ethoxybenzyl, hydroxybenzyl, hydroxymethyibenzyl, aminobenzyl, formylbenzyl, cyanobenzyl, ciru-amyl, allyloxybenzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl, chloromethylbenzyl, fluoromethylbenzyl, .:25 iodobenzyl, bromobenzyl, cyclobutylznethyl, forialdoximebenzyl, cyclopentylmethyl, nitrobenzyl, (H2NC -benzyl, carbometboxybenzyl, carboethoxybenzyl, tetrazolylbenzyl, and dimethylallyl, 3C arninorethylbenzyl, (O-benzyl- forxnaldoxime) benzyl, (0-niethyl fornaldoxime)benzyl, (CH3O2CO) -benzyl, (HOCH2CH2N=CH) -bonzyl, N-benzylaminocarbonylbenzyl, N- methylaminobenzyl, N-ethylaminobenzyl,
418- N-ethylaninonwethylbenzyl, acetylbenzyl, acetoxcybenzyl, N-hydroxylaninobenzyl, phenylniethyl-boronic acid, N- hydroxylaminone thylbenzyl, (hydxroxy~,) ethylbenzyl, (CI43C (=NOH) )-benzyl, (H2NNHC(=O) )-benzyl, (H2NC(=O)NHN=CH) -benzyl, (CH3ONHC(=O) )-benzyl, (1{ONHC(=O) )-benzyl, (CH3NHC(=O) )-benzyl, NN-dirnethylarinocarbonyvlbenzyl, (HOCH2CH (OH) CH2O) -benzyl, hydro>Wetho,-.ybenzyl (oxazolidinyl) -benzyl, (hydroxyl)hexyl, hexenyl, (hyciroxy) octyl, (hydroxyl) pentyl, (carboxy) pentyl, (carbomethoxy) pentyl, (methylthio)benzyl, (methylsulfonyl) berizyl, N, N-dime Lhylaminome thylbenzyl, N-rnethylarninomethylberizyl, glycylarninobenzyl, N, N-dirnethylq1lcylariobenzyl, alanylaininobenzyl, (N- phenylmethoxycarbonyl) alanylaninobenzyl, phenylalanylamrinobenzyl, (N- phenylinethoxycarbonyl) pheaylalanylaxninobenizyl (CH3CH2NHiC(:;O) )-benzyl, N,N- die thylaxnirocarbonylbonzyl, N-ethylaninoca-banylbenzy., N-'propylaminocarbonxylbenzyl, N, N-diisopropylanlinocarbonylbenzyi, N, N-di-n- propylarninocarbonylbenzyl, (hydroxypropynyl) benzyl, (imidazolyl-C benzyl, (pyrazoly1-C(=O) )-benzyl, (pyridytxnethylaininocarbonyl) benzyl, (oxadiazolidinonyl) benzyl, trifluoroacetylbenzyl, (pyrazolyl) benzyl, (Ii2NSO2) -benzyl, dihyclroxyethylbenzyl, (MeHNC(=O)NH)-benzyl, (H2NC(=O)NH)-benzyl, (HC -benzyl, rethanesulfonylpentyl, V 4SVO@* V V OV VVV e V
419- methoxypentyl, N.-formyl-N-methylanobenl), acetylaniinobenzyl, propionylbenzy-, butyrylbenzyl, (CH3CH2C(=NOH) )-benzyl, (trifluorohydrox<yethyl) benzyl, (CF3C benzyl, (N-me thyiglycyl) arinobenzyl, ((4-norpholino) ethy1)aminocarbonylbenzY1, N-dimethylaminoethyl) aminocarbanylbenzy-. N-diethylaminethyl) arinocarbonylbenzyl, (4 -iethylpiperaz in-i1- ylethyl) aiinocarboniylbeizyl, (benzyl- NHC benzyl, (CH 3 NWC(=O))benzyl, (NH 2 C(=O)CH 2 O)benzyl, (NH 2 C(=NH) )benzyl, ((N-phenylmethoxycarboonyl) glyc-ylanino) benzyl, (imidazolylrnethyl)benzyl, ((CH3) 3 C-C (=:O))ben7,yl, is ;1 (N-methyl-NT-etylaminoethyl) amninocarbonylbenzyl, (pyrrolidinylethyl) aminocarbonylbenzyl, (pipcaridinylethyl) aminocarbonylbenzyl, (H2NC(=NOH))benzyl, (2NC(NOH))fluorobenzy1, bezmdaoymehl *.ztiz~~r-ei.I indazolylrnethyl, benzoxazolinylmeth24I, benzisoxazolylmethyi, thienylrnethyl, furylmethyf, (aminoindazoly!)methyl, (methylaminoindazolyl)methyl, (ethylaminoindazolyl)methyl, ~(isopro pylam ino in dazo lyl) methyl, (chloroindazolyl)methyl. A compound of Claim 1 of formula (11d); 00 0 HO OH -420- (I'd) or a pharmaceutically acceptable salt form thereof, selected from the group consisting of: the compound of formula (I-rd) wherein R 2 2 is 4- hydroxymethylbenzyl and R 23 is 4- hydroxyrnethyl-benzyl; the compound of formula (lid) wherein R 2 is 3- hydzcoxybenzyl and R 23 is 3--hydroxybenzyl; the compound of formula (lid) wherein R 22 is cyclopropylmethyl and R 2 3 is cyclopropylmethyl; the compound of formula (Tid) wherein R 22 is 2- naphthylmethyl and R 2 3 is 2-naphthylmethyl; the compound of formula (Ild) wherein R 22 is 4- hydroxybenzyl and R 2 3 is 4-hydroxybenzyli the compound of formula (lid) wherein R 22 is 3- 20 theaminobenzyl and R 23 is 3-aminobenyl; th compound of formula (lid) wherein R 22 is 3-- hydroxymethylbenzyl anid R23 is 3- ~hydroxyxnethylbibnzyl; :o the compound of formula (Id) wherein R 22 is S 3-(Me2NCH2C(=O)NH)-benzyl and R. 23 is 3- (Me2NCH2C(=Q)NH)-benzy1; the compound of form~ula (ld) wherein R 22 is 3-'forxadoximebenzyl and R 23 is 3- formaldoximebeny.; the compound of formula (lid) wherein R. 22 is 3- (CHi3C(=N-OH))-benzyl and R 23 is 3-(CH3C(=N- OH) )-benzyJ.; the compound of formula (116d) wherein P. 22 is 3-(2- amino- 4-thienyl) benzyl and R 23 is 3-(2-anino-4- thienyl) oenzyl; 421 the compound of formula (TId) hydroxypentyl and R 2 3 is the compound of formula (Ild) hydroxypentyl and R 23 is the compound of formula (Id) hydroxypentyl and R 23 %is the compound of formula (Id) hydroxypentyl and p 23 is the compound of formula (Ild) hydroxypentyl and R 23 is wherein R 22 is wherein R 22 is 6- G -hydroxypen tyl; Wherein R 22 is 2 -naphthylrnethyl; wherein R 22 is 4 -hydroxymethylbenzyl; wherein R 22 is 3 -hydroxymethylbenzyl. 99 9 9 9 9* 9 4.. 99 9. 9 @9 9* *9 9 9 9 9 9 @9.9 90 .9 9 @99999 9 9 422 6. A compounv of Claim 1 of formula (IId) R22N NR 23 (Ild) or a pharmaceutically acceptable salt form thereof, wherein: R 1 3 is H, CI-C 4 alkyl, C3-CG alkTxyalkyl, C 2 -C 4 alkenyl, or benzyl; R 1 4 is OH, H, CF 3 C1-C 4 alkyl, C 1 -C 4 alkoxy, N- 2 C 2 -C 4 15 alkenyl, or benzyl; R1 3 and R 1 4 can alternatively join to form -(CH2)4-, (CH2)5-, -CH2CH2N(R 1 5 )CH2CH2-, or -CH2CH20CI2CH2-; R 2 2 is selected from the following: C1CB alkyl substituted with 0-2 R 31 C2-C6 alkenyl substituted with 0-2 R 31 C2-C4 alkyneyl substituted with 0-2 Ri- 25 R 23 is indazolylmethyl optionally substituted with halogen or -NR 13 P) 4 R 3 1 is selected from one or more of the following: halogen, -OR1 3 Cl-C4 alkyl, C3-ClO cycloalkyl, -C(R 1 d)=N(0R 1 4 -C02R13, -S(O)mR 1 3 -423 7 aryl substituted with 0-5 R 3 2 or a heterocyclic ring systemr chosen fromt pyridyl, pyrinidiny., triazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, indolyl, cppinolinyl, isoguinolinyl, oxazolidainyl, benzimidazolyl, benzotriazoly., indazolyl, berizoxazolinyl, benzoxazolyl, said heterocyclic ring being substituted with 0-2 R3 2 R 3 2 when a substituent on carbon, is selected from one or more of the following; -CONH2, -CO 2 H, -CHO, -CH 2 NHOH, -CH2NR 1 3 P)- 4 -PqR 1 3 R' 4 hydiroxy, hydroxymethyl, -C (R 1 4 =NtOR' 4 halogen, niethoxy, methyl, nitro, cyato, allyloxy, -CO2CH3, -NHCHO, -NHCOCH3, -OCO2CH3, -CH=NCH2CH-2 OH, 0CONHCH2CGH5, -OCO1NHCH3, oxazolidinyl, -C=C-CH{2OH, -COCH3, hydroxyethyl, Cj,-C 3 alkyl (said alkyl substituted with 0-4 halogen, or OR), tetrazolyl, -OCHi2CONH2, :-CONHiNH2, -CH=NNRCONH2, -CONHOCH3, -CH2CH (QH) CH2OH, adarnantamido, hydroxyethoxy, dihydroxyethyl, -C (NHi2) =NH, -CON1ICH3, -B (Oi) 2, benzyloxy, -CONHC9-2CH3, -COD (CH2CH3) 2' inethylthio, -SO2CHi3, -NHCONH2, -NIICONHCH3, -NHCOCH2N (CH13) 2, -NHCOCH2NHCH3, -NHCOCH2NHCX)2 CH-2C 6H, -NHCOCH2NH2, -NHCOCH (CH3 NHiCO2CH2C6H5, -NHCOC~i (CH2C6H5)NHCO2CH2C6,HS, -NHCOCH(CH3 )NH-2, -NMHCOCH(CH2C6H5)NH2, -CO2CH2CH3, -CONHCH2CH2CH3, -CONHCH(CH3) 2, -CH2-iraidazole, -COC(CH3) 3. -CHi(OH) CF3, -Co-imidazole, -CQ-pyrazolyl, *fees:oxacliazolidinonyl, -CQCF3, -CQC'H2CIH3, COCFL2Cf{2CH3, pyrazolyl, ,q02NH2,, 35 -C(CH2CH3)=N(OH) or -C(CF3)=N(OH), phenyl., 424 -425- acetoxy, hydroxyamino, -N(CH 3 (CHO), cyclopropylmethoxy, -CONR1 3 R 1 4 -CONHOH, (diethylaminoethyl)aminocarbonyl, (N-ethyl,N-methylaminoethyl) aminocarbonyl., (4-methylpiperazinylethy1) amninocarbonyl, (pyrrolidinylethyl) aminocarbonyl, (piperidinylethyl) aminocarbonyl, -NHCOCH2NHCH3, 4 -morpholino) ethyl) ariinocarbonyl, or W-(2- N-dimethylamino) ethyl) aminocarbonyl; R 32 when a substituent on nitrogen, is methyl. 8* 7. A compound of the formula (I1) as defined in claim 1, substantially as herein described with reference to any one of the Examples. S8. A pharmaceutically composition comprising a compound of any one of claims 1 to 7 together with a pharmaceutically acceptable carrier, adjuvant, excipient and/or diluent. 9. A pharmaceutical composition of claim 8, substantially as herein described with reference to any one of the Examples. A method for the treatment or prophylaxis of HIV infection in a patient which method comprises administering to said patient Un effective 8 amount of at least one compound according to any on" of claims 1 to 7 or a composition according to claim 8 or 9, 0IQ2/9)CXt,3SI 42 i 426 11. Use of a compound of any one of claims 1 in the preparation of a medicament for the treatment of HIV infection. DATED this 10Oth day of February, 1999. THE DU PONT MERCK PHARMACEUTICAL COMPANY their Patent Attorneys: CALLINAN LAWRIE see.V *6- S es :00690 0 a. *Sso's 0 N j0/V99Cj19353,S 426
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Publication number Priority date Publication date Assignee Title
EP1311515A2 (en) * 2000-08-15 2003-05-21 The University Of Kansas Amino acid-derived cyclic phosphonamides and methods of synthesizing the same

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2871592A (en) * 1991-10-11 1993-05-03 Du Pont Merck Pharmaceutical Company, The Cyclic ureas and analogues useful as retroviral protease inhibitiors

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2871592A (en) * 1991-10-11 1993-05-03 Du Pont Merck Pharmaceutical Company, The Cyclic ureas and analogues useful as retroviral protease inhibitiors

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1311515A2 (en) * 2000-08-15 2003-05-21 The University Of Kansas Amino acid-derived cyclic phosphonamides and methods of synthesizing the same
EP1311515A4 (en) * 2000-08-15 2003-12-03 Univ Kansas Amino acid-derived cyclic phosphonamides and methods of synthesizing the same
EP1806351A2 (en) 2000-08-15 2007-07-11 The University Of Kansas Amino acid-derived cyclic phosphonamides and methods of synthesizing the same
EP1806351A3 (en) * 2000-08-15 2007-09-26 The University Of Kansas Amino acid-derived cyclic phosphonamides and methods of synthesizing the same

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