WO1994008977A1

WO1994008977A1 - Substituted caprolactams and derivatives thereof useful for treatment of aids

Info

Publication number: WO1994008977A1
Application number: PCT/US1993/009807
Authority: WO
Inventors: Carl Nicholas Hodge; Christina Howard Fernandez
Original assignee: DuPont Merck Pharmaceutical Co
Current assignee: Bristol Myers Squibb Pharma Co
Priority date: 1992-10-22
Filing date: 1993-10-20
Publication date: 1994-04-28
Anticipated expiration: 1995-04-22
Also published as: AU5359594A

Abstract

This invention relates to novel substituted caprolactams of formula (I), including 4-azacaprolactams, and derivatives thereof which inhibit HIV protease and are useful for treatment of HIV disease. Also included in this invention are pharmaceutical compositions containing such substituted caprolactams and to methods of using such caprolactams for the treatment of HIV disease.

Description

SUBSTITUTED CAPROLACTAMS AND DERIVATIVES THEREOF USEFUL FOR
TREATMENT OF AIDS
FIELD OF THE INVENTION
This invention relates to novel substituted caprolactams, including 4-azacaprolactams, and derivatives thereof which inhibit HIV protease and are useful for treatment of HIV disease. Also included in this invention are pharmaceutical compositions containing such caprolactams, and to methods of using such caprolactams for the treatment of HIV disease.

BACKGROUND OF THE INVENTION
Current treatments for viral diseases usually involve administration of compounds that inhibit viral
DNA synthesis. Current treatments for AIDS (Dagani,
Chem. Eng. News, November 23, 1987 pp. 41-49) involve administration of agents such as 2',3'-dideoxycytidine, trisodium phosphonoformate, ammonium 21-tungsto-9antimoniate, l-b-D-ribofuranoxyl-1,2,4-triazole-3carboxamide, 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 immunosupression 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 bone marrow cytopenia.

Proteases are enzymes which cleave proteins at specific peptide bonds. Many biological functions are controlled or mediated by proteases and their complementary protease inhibitors. For example, the protease renin cleaves the peptide angiotensinogen to produce the peptide angiotensin I. Angiotensin I is further cleaved by the protease angiotensin converting enzyme (ACE) to form the hypotensive peptide angiotensin
II. Inhibitors of renin and ACE are known to reduce high blood pressure in vivo. However, no therapeutically useful renin protease inhibitors have been developed, due to problems of oral availability and in vivo stability.

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. 98 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 virions. It has been shown that in vitro mutagenesis that produces proteasedefective virus leads to the production of immature core forms which lack infectivity. See Crawford, J. Virol.

53 899 (1985); Katoh et al., Virology 145 280 (1985).

Therefore, retroviral protease inhibition provides an attractive target for antiviral therapy. See Mitsuya,
Nature 325 775 (1987).

Moore, Biochem. Biophys. Res. Commun., 159 420 (1989) discloses peptidyl inhibitors of HIV protease.

Erickson, European Patent Application No. WO 89/10752 discloses derivatives of peptides which are inhibitors of HIV protease.

U.S. Patent No. 4,652,552 discloses methyl ketone derivatives of tetrapeptides as inhibitors of viral proteases. U.S. Patent No. 4,644,055 discloses halomethyl derivatives of peptides as inhibitors of viral proteases. European Patent Application No.

WO 87/07836 discloses L-glutamic acid gammamonohydroxamate as an antiviral agent.

Japanese Patent Number 02306992 and Kimura, Agric.

Biol. Chem., 53, 1811 (1989) describe compounds of the formula:
EMI3.1
wherein R is a fatty acid. These compounds were isolated from streptomyces and shown to be useful as peptidoglycan inhibitors.

French Patent Number 2396002 describes quaternary amines, of the formula shown below, which are useful as vasodilators:
EMI3.2
wherein R1 is hydrogen or ester and R2 is C1-C2 alkyl.

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 less prone to drug resistance when compared to current treatments.

The topic of the present invention is substituted caprolactams and derivatives thereof, which compounds are capable of inhibiting HIV protease and are, therefore, useful for combating HIV diseases, such as
AIDS. The caprolactams and derivatives thereof of this invention provide significant improvements over protease inhibitors that are known in the art. A large number of compounds have been reported to be inhibitors of proteases, such as renin, but these have suffered from lack of adequate bioavailability and are thus not useful as therapeutic agents, particularly if oral administration is desired.

This poor activity has been ascribed to the relatively high molecular weight of most protease inhibitors, to inadequate solubility properties, and to the presence of a number of peptide bonds, which are vulnerable to cleavage by mammalian proteases in vivo and which generally cause the molecules to be extensively bound in human serum. The substituted caprolactams and derivatives thereof of the present invention and described herein have a distinct advantage in this regard, in that they do not contain peptide bonds, are of low molecular weight, and can be hydrophilic yet still inhibit the viral protease enzyme.

The structures disclosed also have a particular advantage in the presence of a basic amine in the ring; which provides good in vitro potency and aids in formulation, in vivo absorption and CNS penetration of the compound.

The substituted caprolactams of the present invention are particularly useful as inhibitors of HIV protease and similar retroviral proteases.

Other HIV protease inhibitors have been reported, but to date none have been shown to be clinically effective. This lack of utility is due in part to the factors discussed above for renin inhibitors, particularly low bioavailability. The compounds of the invention offer a valuable solution to this problem in that they are of low molecular weight and thereby may provide good oral absorption properties in mammals, ranging from 1-100% absolute oral availability.

DETAILED DESCRIPTION OF THE INVENTION
There is provided by this invention a compound of the formula (I):
EMI5.1
or a pharmaceutically acceptable salt or prodrug form thereof wherein:
X is S, O or N-R7;
R4 and R7 are independently selected from the following groups:
hydrogen;
C1-Cg alkyl substituted with 0-3 R1l;
C2-Cg alkenyl substituted with 0-3 RÚÚ;
C2-Cg alkynyl substituted with 0-3 RÚÚ;
C3-Cg cycloalkyl substituted with 0-3 RÚÚ;
C6-C10 bicycloalkyl substituted with 0-3 Roll;
aryl substituted with 0-3 R12;
a C6-C14 carbocyclic residue substituted with 0-3
R12;
a heterocyclic ring system substituted with 0-2
R12, composed of 5 to 10 atoms including at least
one, preferably 1-4, nitrogen, oxygen or sulfur
atom;

;
R4A is selected from the following groups:
hydrogen;
C1-C4 alkyl substituted with halogen or C1-C2
alkoxy;
benzyl substituted with halogen or C1-C2 alkoxy;
R4 and R4A can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R12;
R5 is selected from =0, or -OR20;
R20 is independently selected from:
hydrogen;
C1-C6 alkyl substituted with 0-3 RÚÚ;
C3-C6 alkoxyalkyl substituted with 0-3 RÚÚ;
C1-C6 alkylcarbonyl substituted with 0-3 RÚÚ;
C1-C6 alkoxycarbonyl substituted with 0-3 RÚÚ;
benzoyl substituted with 0-3 R12;
phenoxycarbonyl substituted with 0-3 RÚê;
phenylaminocarbonyl substituted with 0-3 R12;
C1-C6 alkylsulfenyl substituted with 0-3 R1l;
C1-C6 alkylsulfonyl substituted with 0-3 R1l;

or
any group that, when administered to a mammalian
subject, cleaves to form a free hydroxyl; R11 is selected from one or more of the following:
keto, halogen, cyano, -CH2NR13R14, -NR13R14,
-C02R13, -OC(=O)R13, -OR13, C2-C6 alkoxyalkyl,
-S(O)mRÚ , -NHC(=NH)NHRÚ , -C(=NH)NHRÚ , -C (=0) NR13R14, -NR14C(=O)R13, =NoR14,
-NR14C(=O)0R14, -OC(=O)NR13R14, -NR13C(=O)NR13R14,
-NR14SO2NR14, -NR14SO2RÚ , -SO2NRÚ R14, C1-C4
alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C3-C6
cycloalkylmethyl;
1-3 amino acids, linked together via amide bonds
and linked to R4 or R7 via the amine or carboxylate
terminus;
a C5-C14 carbocyclic residue substituted with 0-3
R12;
aryl substituted with 0-3 R12;

or
a heterocyclic ring system substituted with 0-2
R12, composed of 5 to 10 atoms including at least
one, preferably 1-4, nitrogen, oxygen or sulfur
atom; R12, when a substituent on carbon, is selected from one or more of the following:
phenyl, benzyl, phenethyl, phenoxy, benzyloxy,
halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C3-C6
cycloalkyl, C3-C6 cycloalkylmethyl, C7-C10 arylalkyl,
C1-C4 alkoxy, -CO2H, hydroxamic acid, hydrazide,
oxime, boronic acid, sulfonamide, formyl, C3-C6
cycloalkoxy, -OR13, C1-C4 alkyl substituted with
-NR13R14, -NR13R14, C2-C6 alkoxyalkyl, C1-C4
hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4
haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl,
C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl,

C1-C4
alkylcarbonylamino, -S(O)mR13 -502NR13R14,
-NHS02R14 -OCH2CO2H, 2- (1-morpholino) ethoxy; or
a 5- or 6-membered heterocyclic ring containing from
1 to 4 heteroatoms selected from oxygen, nitrogen or
sulfur;
or R12 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 the aliphatic carbons with
halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or
-NR13R14;

or, when R12 is attached to a saturated
carbon atom, it may be carbonyl or thiocarbonyl; R12, when a substituent on nitrogen, is selected from one or more of the following:
phenyl, benzyl, phenethyl, hydroxy, C1-C4
hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6
cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR13R14,
-NR13R14, C2-C6 alkoxyalkyl, C1-C4 haloalkyl, C1-C4
alkoxycarbonyl, -CO2H, C1-C4 alkylcarbonyloxy,
C1-C4 alkylcarbonyl;
R13 is H, phenyl, benzyl, C1-C6 alkyl, or C3-C6 alkoxyalkyl;
R14 is OH, H, C1-C4 alkyl, or benzyl;
R13 and R14 can alternatively join to form -(CH2)4-, -(CH2)5-, -CH2CH2N(R15)CH2CH2-, or -CH2CH2OCH2CH2-;
R15 is H or CH3;

m is 0, 1 or 2;
Z is O, S, or NR24;
R22 is independently selected from the following:
hydrogen;
C1-Cg alkyl substituted with 0-3 R31;
C2-Cg alkenyl substituted with 0-3 R31;
C2-Cg alkynyl substituted with 0-3 R31;
C3-Cg cycloalkyl substituted with 0-3 R31;
C6-C10 bicycloalkyl substituted with 0-3 R31;
aryl substituted with 0-3 R32;
a C6-C14 carbocyclic residue substituted with 0-3
R32;
a heterocyclic ring system substituted with 0-2
R32, composed of 5 to 10 atoms including at least
one, preferably 1-4, nitrogen, oxygen or sulfur
atom;
R24 is selected from: hydroxy; amino; C1-C4 alkyl; C1-C4 alkoxy;

C1-C4 aminoalkyl; cyano; nitro;
R27 is selected from the following:
hydrogen;
C1-Cg alkyl substituted with 0-3 R31;
C2-Cg alkenyl substituted with 0-3 R31;
C2-C8 alkynyl substituted with 0-3 R31;
C3-Cg cycloalkyl substituted with 0-3 R31;
C6-C10 bicycloalkyl substituted with 0-3 R31;
aryl substituted with 0-3 R32;
a C6-C14 carbocyclic residue substituted with 0-3
R32;
a heterocyclic ring system substituted with 0-2
R32, composed of 5 to 10 atoms including at least
one, preferably 1-4, nitrogen, oxygen or sulfur
atom;
R28 is independently selected from:
hydrogen;
C1-C4 alkyl substituted with halogen or C1-C2
alkoxy;
benzyl substituted with halogen or C1-C2 alkoxy;

alternatively, R22 can join with R4 or R4A to form a five- or six-membered fused heterocyclic or carbocyclic ring substituted with 0-2 R12; and alternatively, R27 can join with R7 to form a five- or six-membered fused heterocyclic or carbocyclic ring substituted with 0-2 R12;
R31 is selected from one or more of the following:

:
keto, halogen, cyano, -CH2NR13R14, -NR13R14,
-CO2RÚ , -OC(=O)R13, -OR13, C2-C6 alkoxyalkyl,
-S(O)mR13, -NHC(=NH)NHR13, -C(=NH)NHR13,
-C(=O)NR13R14, -NR14C(=O)R13, =NOR14,
-NR14C(=O)OR14,-OC(=O)NRÚ R14, -NRÚ C(=O)NR13R14,
-NR14SO2NRÚ R14, -NR14SO2RÚ , -SO2NRÚ R14, C1-C4
alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C3-C6
cycloalkylmethyl;
1-3 amino acids, linked together via amide bonds
and linked to R4 or R7 via the amine or carboxylate
terminus;
a C5-C14 carbocyclic residue substituted with 0-3
R32;
aryl substituted with 0-3 R32;

or
a heterocyclic ring system substituted with 0-2
R32, composed of 5 to 10 atoms including at least
one, preferably 1-4, nitrogen, oxygen or sulfur
atom;
R32, when a substituent on carbon, is selected from one or more of the following:
phenyl, benzyl, phenethyl, phenoxy, benzyloxy,
halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C3-C6
cycloalkyl, C3-C6 cycloalkylmethyl, C7-C10 arylalkyl,
C1-C4 alkoxy, -CO2H, hydroxamic acid, hydrazide,
oxime, boronic acid, sulfonamide, formyl, C3-C6
cycloalkoxy, -OR13, C1-C4 alkyl substituted with
-NR13R14, -NR13R14, C2-C6 alkoxyalkyl, C1-C4
hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4
haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl,
C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl,

C1-C4
alkylcarbonylamino, -S (O)mR13, -502NR13R14,
-NHSO2R14, -OCH2CO2H, 2-(1-morpholino) ethoxy,
-C (R14)=N (OR14); or
a 5- or 6-membered heterocyclic ring containing from
1 to 4 heteroatoms selected from oxygen, nitrogen or
sulfur;
or R32 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 the aliphatic carbons with
halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or
-NR13R14;

or, when R32 is attached to a saturated
carbon atom, it may be carbonyl or thiocarbonyl;
R32, when a substituent on nitrogen, is selected from one or more of the following:
phenyl, benzyl, phenethyl, hydroxy, C1-C4
hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6
cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR13R14,
-NR13R14, C2-C6 alkoxyalkyl, C1-C4 haloalkyl, C1-C4
alkoxycarbonyl, -CO2H, C1-C4 alkylcarbonyloxy,
C1-C4 alkylcarbonyl, -C (R14)=N (OR14);
R33 is C1-C3 alkyl substituted at the C2 or C3 carbon with C1-C2 alkoxy, halogen, or hydroxy; alternatively, R33 can join with R7 to form a fused 5- or 6- membered carbocyclic ring;

provided that:
when R4 and R4A are hydrogen and X is N-R7, at
least one of the following is not hydrogen: R7,
R22, R27 or R28;
when R4 and R4A are hydrogen and X is S or O, at
least two of the following are not hydrogen: R22,
R27 or R28.

This invention includes compounds of formula I described above wherein:
X is S, O or
R4 and R7 are independently selected from the following groups:
hydrogen;
C1-C4 alkyl substituted with 0-3 RÚÚ;
C3-C4 alkenyl substituted with 0-3 RÚÚ;
C3-C4 alkynyl substituted with 0-3 RÚÚ;
R4A is hydrogen;
R5 is selected from =0 or -OR20;
R20 is independently selected from:
hydrogen;
C1-C6 alkylcarbonyl;
C1-C6 alkoxycarbonyl;
benzoyl;

or
any group that, when administered to a mammalian
subject, cleaves to form a free hydroxyl; Rll is selected from one or more of the following:
keto, halogen, cyano, -CH2NR13R14, -NR13R14,
-C02R13, -OC(=O)R13, -OR13, C2-C6 alkoxyalkyl,
-S(O)mR13, C1-C4 alkyl, C2-C4 alkenyl, C3-C6
cycloalkyl;
a C5-C14 carbocyclic residue substituted with 0-3
R12;
aryl substituted with 0-3 R12;

or
a heterocyclic ring system substituted with 0-2
R12, composed of 5 to 10 atoms including 1-4
nitrogen, oxygen or sulfur atom;
R12, 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, C7-C10 arylalkyl,
C1-C4 alkoxy, -CO2H, hydroxamic acid, hydrazide,
oxime, boronic acid, sulfonamide, formyl, C3-C6
cycloalkoxy, -OR13, C1-C4 alkyl substituted with
-NR13R14, -NR13R14, C2-C6 alkoxyalkyl, C1-C4
hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4
haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl,
C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl,

C1-C4
alkylcarbonylamino, -S(O)mR13 -502NR13R14,
-NHS02R14 -OCH2CO2H, 2- (1-morpholino)ethoxy; or
a 5- or 6-membered heterocyclic ring containing from
1 to 4 heteroatoms selected from oxygen, nitrogen or
sulfur;
or R12 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 the aliphatic carbons with
halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or
-NR13R14;

or, when R12 is attached to a saturated
carbon atom, it may be carbonyl or thiocarbonyl;
R12 when a substituent on nitrogen, is selected from one or more of the following:
phenyl, benzyl, phenethyl, hydroxy, C1-C4
hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6
cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR13R14,
-NR13R14, C2-C6 alkoxyalkyl, C1-C4 haloalkyl, Cl-C4
alkoxycarbonyl, -CO2H, C1-C4 alkylcarbonyloxy,
C1-C4 alkylcarbonyl;
R13 is H, C1-C6 alkyl, or C3-C6 alkoxyalkyl;
R14 is OH, H, C1-C4 alkyl, or benzyl;
R13 and R14 can alternatively join to form -(CH2)4-, -(CH2)s-, -CH2CH2N(R15)CH2CH2-, or -CH2CH2OCH2CH2-;
R15 is H or CH3;

m is 0, 1 or 2;
Z is O, S, N-CN, N-OH, N-OCH3;
R22 is independently selected from the following:
hydrogen;
C1-Cg alkyl substituted with 0-3 R31;
C3-Cg alkenyl substituted with 0-3 R31;
C3-Cg alkynyl substituted with 0-3 R31;
C3-C6 cycloalkyl substituted with 0-3 R31;
R27 is selected from the following:
hydrogen;
C1-Cg alkyl substituted with 0-3 R31;
C2-Cg alkenyl substituted with 0-3 R31;
C3-Cg alkynyl substituted with 0-3 R31;
R28 is hydrogen;
R31 is selected from one or more of the following:

:
keto, halogen, cyano, -CH2NR13R14, -NR13R14,
-C02R13 -OC(=O)R13, -OR13, C2-C6 alkoxyalkyl,
¯S(o)mRl3 C1-C4 alkyl, C2-C4 alkenyl, C3-C6
cycloalkyl, C3-C 6 cycloalkylmethyl;
a C5-C14 carbocyclic residue substituted with 0-3
R32;
aryl substituted with 0-3 R32;

or
a heterocyclic ring system substituted with 0-2
R32, composed of 5 to 10 atoms including 1-4,
nitrogen, oxygen or sulfur atom;
R32, when a substituent on carbon, is selected from one or more of the following:
phenyl, benzyl, phenethyl, phenoxy, benzyloxy,
halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C3-C6
cycloalkyl, C3-C6 cycloalkylmethyl, C7-C10 arylalkyl,
C1-C4 alkoxy, -CO2H, hydroxamic acid, hydrazide,
oxime, boronic acid, sulfonamide, formyl, C3-C6
cycloalkoxy, -OR13, C1-C4 alkyl substituted with
-NR13R14, -NR13R14, C2-C6 alkoxyalkyl, C1-C4
hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4
haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl,
C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4
alkylcarbonylamino, -S(O)mR13, - SO2NR13R14,
-NHS02R14,

-OCH2CO2H, 2- (1-morpholino) ethoxy,
-C(R14)=N(oRl4); or
a 5- or 6-membered heterocyclic ring containing 1 to
4 heteroatoms selected from oxygen, nitrogen or
sulfur;
or R32 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 the aliphatic carbons with
halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or
-NR13R14;

or, when R32 is attached to a saturated
carbon atom, it may be carbonyl or thiocarbonyl;
R32, when a substituent on nitrogen, is selected from one or more of the following:
phenyl, benzyl, phenethyl, hydroxy, C1-C4
hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6
cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR13R14,
-NR13R14, C2-C6 alkoxyalkyl, Cl-C4 haloalkyl, C1-C4
alkoxycarbonyl, -CO2H, C1-C4 alkylcarbonyloxy,
C1-C4 alkylcarbonyl, -C (R14)=N (OR14); provided that:
when R4 and R4A are hydrogen and X is N-R7, at
least one of the following is not hydrogen: R7,
R22, R27 or R28;
when R4 and R4A are hydrogen and X is S or O, at
least two of the following are not hydrogen:

R22,
R27 or R28
This invention includes compounds of formula I described above, wherein:
X is S, O or
R4 and R7 are independently selected from the following groups:
hydrogen;
C1-C4 alkyl substituted with 0-3 RÚÚ;
C3-C4 alkenyl substituted with 0-3 RÚÚ;
R4A is hydrogen;
R5 is -OR20;
R20 is H or any group that, when administered to a
mammalian subject, cleaves to form a free hydroxyl; Rll is selected from one or more of the following:
keto, halogen, -CH2NR13R14, -NR13R14, -OR13, C2-C4
alkoxyalkyl, C1-C4 alkyl, C2-C4 alkenyl, C3-C6
cycloalkyl;
aryl substituted with 0-3 R12;

or
a heterocyclic ring system substituted with 0-2
R12 composed of 5 to 10 atoms including 1-4
nitrogen, oxygen or sulfur atom;
R12, when a substituent on carbon, is selected from one or more of the following:
phenyl, benzyl, phenethyl, phenoxy, benzyloxy,
halogen, C1-C4 alkyl, C7-C10 arylalkyl, C1-C4 alkoxy,
-CO2H, hydroxamic acid, hydrazide, oxime, boronic
acid, sulfonamide, form, C3-C6 cycloalkoxy, -OR13,
C1-C4 alkyl substituted with -NR13R14, -NR13R14
methylenedioxy, C1-C4 haloalkyl, C1-C4 alkylcarbonyl,
C1-C4 alkylcarbonylamino, -OH, hydroxymethyl;

or
a 5- or 6-membered heterocyclic ring containing from
1 to 4 heteroatoms selected from oxygen, nitrogen or
sulfur;
R12, when a substituent on nitrogen, is benzyl or
methyl;
R13 is H, C1-C2 alkyl, or C3-C6 alkoxyalkyl;
R14 is OH, H, or C1-C2 alkyl;
R13 and R14 can alternatively join to form -(CH2)4-, -(CH2)5-, -CH2CH2N(R15)CH2CH2- or -CH2CH2OCH2CH2-;
R15 is H or CH3;
Z is O, S, or N-CN;
R22 is independently selected from the following:
hydrogen;
C1-C4 alkyl substituted with 0-3 R31;
C3-C4 alkenyl substituted with 0-3 R31;
R27 is selected from the following:
hydrogen;
C1-C4 alkyl substituted with 0-3 R31;
C2-C4 alkenyl substituted with 0-3 R31;
R28 is hydrogen;
R31 is selected from one or more of the following:

:
keto, halogen, -cH2NRl3Rl4 -NR13R14, -OR13, C2-C4
alkoxyalkyl, C1-C4 alkyl, C2-C4 alkenyl, C3-C6
cycloalkyl;
aryl substituted with 0-3 R32; or
a heterocyclic ring system substituted with 0-2
R32, composed of 5 to 10 atoms including 1-4,
nitrogen, oxygen or sulfur atom;
R32, when a substituent on carbon, is selected from one or more of the following:

:
phenyl, benzyl, phenethyl, phenoxy, benzyloxy,
halogen, C1-C4 alkyl, C7-C10 arylalkyl, C1-C4 alkoxy,
-CO2H, hydroxamic acid, hydrazide, oxime, boronic
acid, sulfonamide, formyl, C3-C6 cycloalkoxy, -OR13,
C1-C4 alkyl substituted with -NR13R14, -NR13R14
methylenedioxy, C1-C4 haloalkyl, C1-C4
alkoxycarbonyl, C1-C4 alkylcarbonyloxy, -OH,
hydroxymethyl, -C (R14)=N (OR14); or
a 5- or 6-membered heterocyclic ring containing from
1 to 4 heteroatoms selected from oxygen, nitrogen or
sulfur;
R32, when a substituent on nitrogen, is benzyl or
methyl; provided that:
when R4 is hydrogen and X is N-R7, at least one of
the following is not hydrogen: R7, R22, or R27;
when R4 is hydrogen and X is S or O, at least two
of the following are not hydrogen:

R22 or R2.

This invention includes compounds of formula I described above, wherein:
X is S, O or
R4 and R7 are independently selected from the following groups:
hydrogen;
C1-C3 alkyl substituted with 0-3 Roll;
R4A is hydrogen;
R5 is -OR20;
R20 is H or any group that, when administered to a
mammalian subject, cleaves to form a free hydroxyl; R11 is selected from one or more of the following:
halogen, -OR13, C1-C4 alkyl, C3-C6 cycloalkyl;
aryl substituted with 0-3 R12;

or
a heterocyclic ring system selected from pyridyl,
pyrimidinyl, triazinyl, furanyl, thienyl, pyrrolyl,
pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl,
indolyl, quinolinyl, isoquinolinyl;
R12, when a substituent on carbon, is selected from one or more of the following:
benzyloxy, halogen, methyl, C1-C4 alkoxy, CF3,
2- (1-morpolino) ethoxy, -CO2H, hydroxamic acid,
hydrazide, oxime, cyano, boronic acid, sulfonamide,
formyl, C3-C6 cycloalkoxy, C1-C4 alkyl substituted
with -NR13R14, -NR13R14, -OH, hydroxymethyl;

or
R12, when a substituent on nitrogen, is methyl;
R13 is H or methyl;
R14 is OH, H, or methyl;
R13 and R14 can alternatively join to form -(CH2)4-, -(CH2)5-, -CH2CH2N(R15)CH2CH2- or -CH2CH2OCH2CH2-;
R15 is H or CH3;
Z is O or N-CN;
R22 is independently selected from the following:
hydrogen;
C1-C4 alkyl substituted with 0-3 R31;
C3-C4 alkenyl substituted with 0-3 R31;
R27 is selected from the following:
hydrogen;
C1-C4 alkyl substituted with 0-3 R31;
C3-C4 alkenyl substituted with 0-3 R31;
R28 is hydrogen;
R31 is selected from one or more of the following:
halogen, -OR13, C1-C4 alkyl, C3-Cs cycloalkyl;
aryl substituted with 0-3 R32;

or
a heterocyclic ring system selected from pyridyl,
pyrimidinyl, triazinyl, furanyl, thienyl, pyrrolyl,
pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl,
indolyl, quinolinyl, isoquinolinyl;
R32, when a substituent on carbon, is selected from one or more of the following:
benzyloxy, halogen, methyl, C1-C4 alkoxy, CF3,
2-(1-morpolino)ethoxy, -CO2H, hydroxamic acid,
hydrazide, oxime, cyano, boronic acid, sulfonamide,
formyl, C3-C6 cycloalkoxy, C1-C4 alkyl substituted
with -NR13R14, -NR13R14, -OH, hydroxymethyl,
-C (R14)=N (OR14); or
R32, when a substituent on nitrogen, is methyl; provided that:
when R4 is hydrogen and X is N-R7, at least one of
the following is not hydrogen:

R7, R22, or R27;
when R4 is hydrogen and X is S or O, at least two
of the following are not hydrogen: R22 or R27.

This invention includes compounds of formula I described above, wherein:
X is S, O or
R4 and R7 are benzyl;
R4A is hydrogen;
R5 is -OH;
R13 is H or methyl;
R14 is H or methyl;
Z is O or N-CN;
R22 is independently selected from the following:
hydrogen;
C1-C4 alkyl substituted with 0-3 R31;
R27 is hydrogen or C1-C4 alkyl substituted with 0-3 R31;
R28 is hydrogen;
R31 is selected from one or more of the following:
C3-Cs cycloalkyl;
aryl substituted with 0-3 R32; or
a heterocyclic ring system selected from pyridyl,
thienyl, quinolinyl, isoquinolinyl;
R32, when a substituent on carbon, is selected from one or more of the following:
-CONH2, -CO2H, -CHO, -CH2NHOH, -NR13R14, -CH2NR13R14,
-OH, hydroxymethyl, -C (R14)=N (OR14); or
R32, when a substituent on nitrogen, is methyl.

This invention includes compounds of formula I described above, wherein:
X is N-R7;
R4 and R7 are benzyl;
R4A is hydrogen;
R5 is -OH;
Z is O or N-CN;
R28 is hydrogen;
Rêê and R27 are independently selected from the group consisting of:
hydrogen, allyl, propyl, cyclopropylmethyl,
n-butyl, i-butyl, CH2CH=CH(CH3)2, pyridylmethyl,
methallyl, n-pentyl, i-pentyl, hexyl, benzyl,
pyridylmethyl, isoprenyl, propargyl, picolinyl,
methoxyethyl, cyclohexylmethyl, dimethyl-butyl,
ethoxyethyl, methyl-oxazolinylmethyl,
naphthylmethyl, methyloxazolinylmethyl,
vinyloxyethyl, pentafluorobenzyl, quinolinylmethyl,
carboxybenzyl, chloro-thienyl, picolinyl,
benzyloxybenzyl, phenylbenzyl, adamantylethyl,
cyclopropylmethoxybenzyl, ethoxybenzyl,
hydroxybenzyl, hydroxymethylbenzyl, aminobenzyl,
formylbenzyl, cyanobenzyl, cinnamyl,
allyloxybenzyl, fluorobenzyl,

cyclobutylmethyl,
formaldoximebenzyl, cyclopentylmethyl, nitrobenzyl,
nitrilobenzyl, carboxamidobenzyl,
carbomethoxybenzyl, tetrazolylbenzyl, and
dimethylallyl.

Preferred compounds of the invention of formula I are compounds of formula II:
EMI26.1
or a pharmaceutically acceptable salt or prodrug form thereof wherein:
X is S, O or
R4 and R7 are independently selected from the following groups:
hydrogen;
C1-C4 alkyl substituted with 0-3 Roll;
C3-C4 alkenyl substituted with 0-3 RÚÚ;
C3-C4 alkynyl substituted with 0-3 R1l; R11 is selected from one or more of the following:
keto, halogen, cyano, -CH2NR13R14, -NR13R14,
-CO2RRÚ , -OC(=O)R13, -OR13, C2-C4 alkoxyalkyl,
-S(O)mR13, C1-C4 alkyl, C2-C4 alkenyl, C3-C6
cycloalkyl;
a C5-C14 carbocyclic residue substituted with 0-3
R12;
aryl substituted with 0-3 R12;

C1-C4
alkylcarbonylamino, -S(O)mR13
-502NR13R14, -NHS02R14; or
a 5- or 6-membered heterocyclic ring containing from
1 to 4 heteroatoms selected from oxygen, nitrogen or
sulfur;
or R12 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 the aliphatic carbons with
halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or
-NR13R14;

or, when R12 is attached to a saturated
carbon atom, it may be carbonyl or thiocarbonyl;
R12 when a substituent on nitrogen, is selected from one or more of the following:
phenyl, benzyl, phenethyl, hydroxy, C1-C4
hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6
cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR13R14,
-NR13R14, C2-C6 alkoxyalkyl, C1-C4 haloalkyl, C1-C4
alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4
alkylcarbonyl, -CO2H;
R13 is H, C1-C6 alkyl, or C3-C6 alkoxyalkyl;
R14 is OH, H, C1-C4 alkyl, or benzyl;
R13 and R14 can alternatively join to form -(CH2)4-, -(CH2)5-, -CH2CH2N(Rl5)CH2CH2- or -CH2CH2OCH2CH2-;
R15 is H or CH3;

m is 0, 1 or 2;
R22 is selected from the following:
hydrogen;
C1-Cg alkyl substituted with 0-3 R31;
C3-Cg alkenyl substituted with 0-3 R31;
C3-Cg alkynyl substituted with 0-3 R31;
C3-C6 cycloalkyl substituted with 0-3 R31;
R27 is selected from the following:
hydrogen;
C1-Cg alkyl substituted with 0-3 R31;
C2-Cg alkenyl substituted with 0-3 R31;
C3-Cg alkynyl substituted with 0-3 R31;
R31 is selected from one or more of the following:

:
keto, halogen, cyano, -CH2NR13R14, -NR13R14,
-C02R13, -OC(=O)R13, -OR13, C2-C4 alkoxyalkyl,
-S(O)mRÚ , C1-C4 alkyl, C2-C4 alkenyl, C3-C6
cycloalkyl;
a C5-C14 carbocyclic residue substituted with 0-3
R12;
aryl substituted with 0-3 R32;

C1-C4
alkylcarbonylamino, ¯S(o)mR13, -502NR13R14,
-NHS02R14, -C(R14)=N(0R14); or
a 5- or 6-membered heterocyclic ring containing from
1 to 4 heteroatoms selected from oxygen, nitrogen or
sulfur;
or R32 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 the aliphatic carbons with
halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or
-NR13R14;

or, when R32 is attached to a saturated
carbon atom, it may be carbonyl or thiocarbonyl;
R32, when a substituent on nitrogen, is selected from one or more of the following:
phenyl, benzyl, phenethyl, hydroxy, C1-C4
hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6
cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR13R14,
-NR13R14, C2-C6 alkoxyalkyl, C1-C4 haloalkyl, C1-C4
alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4
alkylcarbonyl, -CO2H, -C (R14)=N (OR14); provided that:
when R4 and R4A are hydrogen and X is N-R7, at
least one of the following is not hydrogen: R7,
R22, R27 or R28;
when R4 and R4A are hydrogen and X is S or O, at
least two of the following is not hydrogen:

R22,
R27 or R28
Further preferred compounds of the invention of formula I are compounds of formula IIa:
EMI31.1
wherein R4 and R7 are independently selected from the following groups:
hydrogen;
C1-C3 alkyl substituted with 0-1 R1l; R11 is selected from one or more of the following:
halogen, -OR13, C1-C4 alkyl, C3-Cs cycloalkyl;
aryl substituted with 0-2 R12; or
a heterocyclic ring system chosen from pyridyl,
thienyl, pyrrolyl, pyrazolyl, imidazolyl,
tetrazolyl, quinolinyl, isoquinolinyl;

said
heterocyclic ring system being substituted with 0-2 R32 ;
R12, when a substituent on carbon, is selected from one or more of the following:
benzyloxy, halogen, methyl, C1-C4 alkoxy, CF3,
2- (1-morpholino) ethoxy, -CO2H, hydroxamic acid,
hydrazide, oxime, cyano, boronic acid, sulfonamide,
formyl, C3-C6 cycloalkoxy, C1-C4 alkyl substituted
with -NR13R14, -NR13R14, hydroxy, hydroxymethyl;

or
R12, when a substituent on nitrogen, is methyl;
R13 is H or methyl;
R14 is OH, H or methyl;
R13 and R14 can alternatively join to form -(CH2)4-, -(CR2) 5-, -CH2CH2N(R15)CH2CH2-, or -CH2CH2OCH2CH2-;
R22 is selected from the following:
hydrogen;
C1-C4 alkyl substituted with 0-1 R31;
C3-C4 alkenyl substituted with 0-1 R31;
R31 is selected from one or more of the following:
halogen, -OR13, C1-C4 alkyl, C3-Cs cycloalkyl;
aryl substituted with 0-2 R32; or
a heterocyclic ring system chosen from pyridyl,
pyrimidinyl, triazinyl, furanyl, thienyl, pyrrolyl,
pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl,
indolyl, quinolinyl, isoquinolinyl;

said
heterocyclic ring system being substituted with 0-2
R32;
R32, when a substituent on carbon, is selected from one or more of the following:
benzyloxy, halogen, methyl, C1-C4 alkoxy, CF3,
2- (1-morpholino) ethoxy, -CO2H, hydroxamic acid,
hydrazide, oxime, cyano, boronic acid, sulfonamide,
formyl, C3-C6 cycloalkoxy, C1-C4 alkyl substituted
with -NR13R14, -NR13R14, hydroxy, hydroxymethyl,
-C (R14)=N (OR14); or
R32, when a substituent on nitrogen, is methyl; provided that:
when R4 is hydrogen, at least one of the following
is not hydrogen: R7, R22 and R23.

More preferred compounds of the invention of formula I are compounds of formula IIa wherein:
R4 and R27 are benzyl;
R13 is H or methyl;
R14 is H or methyl;
R22 is selected from the following:
hydrogen;
C1-C2 alkyl substituted with 0-1 R31;
R31 is selected from one or more of the following:
C3-Cs cycloalkyl substituted with 0-1 R32;
aryl substituted with 0-2 R32; or
a heterocyclic ring system chosen from pyridyl,
thienyl, quinolinyl, or isoquinolinyl; said
heterocyclic ring system being substituted with 0-2
R32;
R32, when a substituent on carbon, is selected from one or more of the following:
CONH2, CO2H, CHO, CH2NHOH,, -CH2NR13R14, -NR13R14
hydroxy, hydroxymethyl, -C (R14)=N (OR14); or
R32, when a substituent on nitrogen, is methyl.

Specifically preferred are compounds of the formula
IIb:
EMI35.1
selected from the group consisting of:
the compound of the formula IIb wherein R22 is hydrogen and R7 is hydrogen;
the compound of the formula IIb wherein R22 is hydrogen and R7 is benzyl;
the compound of the formula IIb wherein R22 is cyclopropylmethyl and R7 is hydrogen;
In the present invention it has been discovered that the compounds above are useful as inhibitors of HIV protease and similar retroviral proteases, and for the treatment of HIV infection and associated diseases, and similar retrovirus infections.

The present invention also provides methods for the treatment of HIV infection and associated diseases by administering to a host infected with HIV a therapeutically effective antiviral amount of a compound of formula (I) as described above.

Also provided by this invention are pharmaceutical compositions containing a pharmaceutically acceptable carrier and a therapeutically effective compound of formula (I) described above.

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.

When any variable (for example, R11, R12, R13 R14
R31, R32, and m) occurs more than one time in any constituent or in formula (I) or (II), or any other formula herein, its definition on each occurrence is independent of its definition at every other occurrence.

Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; "alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge; "cycloalkyl" is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl;

and "biycloalkyl" is intended to include saturated bicyclic ring groups such as [3.3.0]bicyclooctane, [4 .3.Oibicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]blcyclooctane, 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 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. "Halo" 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" is intended to mean phenyl or naphthyl; "carbocyclic" is intended to mean any stable 5- to 7- membered monocyclic or bicyclic or 7- to 14-membered bicyclic or tricyclic carbon ring, any of which may be saturated, partially unsaturated, or aromatic, for example, indanyl or tetrahydronaphthyl (tetralin)
As used herein, the term "heterocycle" is intended to mean a stable 5- to 7- membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is either saturated, partially saturated, or unsaturated, and which consists of carbon atoms and at least one, preferably 1-4, heteroatom selected from the group consisting of N, 0 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 abovedefined heterocyclic rings is fused to a benzene ring.

The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable 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, pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl or benzimidazolyl, piperidinyl, 4piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl or octahydroisoquinolinyl.

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.

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, "pharmaceutically acceptable salts and prodrugs" refer to derivatives of the disclosed compounds that are modified by making acid or base salts, or by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Examples 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 acids; acetate, formate and benzoate derivatives of alcohols and amines; and the like.

Pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in
Remington's Pharmaceutical Sciences, 17th ed., Mack
Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

Synthesis
Compounds of the invention can be prepared by methods described herein, or variations thereon as appreciated by those skilled in the art.

Any of the compounds can be derived from the joining of two amino acids derivatives, followed by elaboration of substituents as necessary. Natural amino acids are available in abundance, and a great array of unnatural amino acids have been prepared by techniques well known to those skilled in the art of organic synthesis. D.C. Roberts and F. Vellaccio provide a comprehensive listing of unnatural amino acids, and techniques for the synthesis of many variations thereof [The Peptides Vol. 5: Analysis. Synthesis. Biology,
Academic Press, NY, 1983]. A more recent description of additional routes to chirally pure unnatural amino acids is found in Cintas, P. Tetrahedron, 47(32), 6079-111, 1991.

Thus, one skilled in the art can synthesize the amino acid precursors used in the preparation of the compounds of the invention by a judicious selection of one or more of the methods outlined above. Each of the references cited herein are hereby incorporated by reference.

The substituent R4 is chosen first, and the corresponding amino acid III with the desired stereochemistry is synthesized or purchased as necessary:
EMI40.1
wherein R4 has the meaning designated above. If substituents on R4 are deemed to be sensitive to the reaction conditions employed in the following steps, then appropriate protecting groups are used, and the desired substituents are freed from protection at the end of the sequence. Extensive descriptions of the correct choice of protecting groups for various reaction conditions, and the correct method of removal, are described in T.W. Greene and P.G.M. Wuts, Protective
Groups in Organic Synthesis, 2nd Edition, Wiley, New
York, 1991.

A protecting group is also chosen for the amine terminal of amino acid III. For example, the above reference can be used to assist the choice of protecting group, or M. Bodanzky and A. Bodanzky in The Practice of
Peptide Synthesis. Springer-Verlag, Berlin, 1984 can be consulted. A preferred amine protecting group is the Ncarbobenzyloxy (CBZ) group. In the following structures, a protecting group is designated PG.
EMI40.2

The protected amino acid is then converted to the protected amino epoxide by known techniques, such as the
Wittig or Petersen olefination of a protected amino aldehyde followed by epoxidation of the olefin; or by addition of a methylene sulfur ylide to an amino aldehyde or by the following, preferred method: treatment of the protected amino acid with diazomethane to generate the diazoketone, followed by treatment with aqueous hydrochloric acid to generate the chloroketone, followed by reduction with a hydride reducing agent, preferably a metal borohydride to form the chloroalcohol. Stereochemistry of the hydroxyl group can be controlled by the choice of reducing agent; preferably a mixture can be obtained which can optionally be separated by chromatography and each diastereomer can be evaluated independently.

This step is followed by base-catalyzed elimination of hydrogen chloride in an aprotic solvent, preferably potassium tert-butoxide in tetrahydrofuran, to form the protected amino epoxide V.
EMI42.1

Next the desired R27 substituent is chosen, with the desired stereochemistry, and the appropriate acid is synthesized or purchased. Protecting groups are added as necessary to the functionality on R27. The acid terminus is protected, preferably with the t-butyl ester, to form compound VI:
EMI43.1

V and VI are coupled in the presence of a solvent, preferably methanol, at a temperature between 0 and 1000C, to form the amino alcohol VII:
EMI43.2

The hydroxyl group of VII is protected, preferably with a silyl protecting group such as t-butyldimethylsilyl (TBDMS) chloride. The selected protective group must withstand the conditions used to remove the nitrogen and carboxylate protecting groups.

The wide variety of protecting groups described in the references above make the selection of the proper combination of groups straightforward to one skilled in the art.

The amine and acid protecting groups are removed to form amino acid VIII:
EMI44.1
which depending on cleavage conditions used may be isolated as a salt of the amines. VIII is cyclized to the lactam IX: any number of standard conditions can be used to form lactams, although the preferred procedure involves activating the carboxylate with a group such as dicylohexylcarbodiimide under conditions dilute enough to favor intramolecular condensation.
EMI44.2

Intermediate IX can be deprotected to form hydroxy lactam X. In instances where the protecting group is
TBDMS, the preferred cleavage conditions are tetra-nbutylammonium fluoride in tetrahydrofuran.

When R4 and R27 are benzyl, X is Example 1. Other representative compounds of the invention are listed in
Table 1.
EMI45.1

Alternatively, IX can be further modified to add substituents R7 and R22. Beginning with the protected alcohol, using methods known to one skilled in the art one may alkylate either the amide nitrogen or the basic nitrogen with a group R22-LG or R7-LG, respectively, where LG is a leaving group. If alkylation of the basic nitrogen is desired while keeping the amide nitrogen unsubstituted, it is advantageous to protect the amide nitrogen using one of the many protective groups discussed in the above references. A preferred protecting group is benzyl, which can be selectively removed from the basic nitrogen by hydrogenolysis.

For obtaining compounds with R7 f hydrogen and R22 = hydrogen, the preferred method is to treat IX with a base, such as potassium carbonate, in a polar aprotic solvent, such as dimethylformamide, and add to the mixture between 0 and 1000C an alkylating agent R7-LG, preferably an alkyl chloride, bromide iodide, or tosylate. Preferred alkylating agents are substituted benzyl chlorides, substituted C1-C6 alkyl bromides, (heterocyclic)methyl chlorides and substituted (alicyclic)methyl bromides and tosylates.
EMI46.1

If compounds wherein R22 = R7 2 hydrogen are desired, the preferred method is that described in the preceding paragraph, but substituting a stronger base, preferably sodium hydride, for potassium carbonate and employing 2 equivalents alkylating agent. If R7 * R22, the product XI can be further alkylated in the same fashion to give XII, by substituting a stronger base, preferably sodium hydride, for potassium carbonate and employing 1 equivalent alkylating agent R22-LG.

Preferred alkylating agents are as described above.
EMI46.2

For the case in which R22 + H and R7 = H, as exemplified in XIII, a preferred method is one in which the above procedures are followed, such that IX is first alkylated with benzyl bromide in dimethylformamide (DMF) in the presence of postassium carbonate; the material is purified and subjected to R22-LG in the presence of sodium hydride in DMF to give XIIa; after which the Nbenzyl is removed by catalytic hydrogenation or preferably by transfer hydrogenation, e.g. formic acid and palladium on carbon in methanol.
EMI47.1

(R7 = CH2Ph)
The protecting group on XI-XIII is removed to give removed structure XIV, where Z = O as described above.

The representative compounds of the invention listed in
Table 1 can be prepared by these methods.
EMI47.2

By the proper manipulation and choice of protecting groups by one skilled in the art, compounds of the formula II, wherein X is S or 0, can be obtained by substitution of a suitably protected form of acid VIa in the above described sequences. Further modification of these compounds are detailed above.
EMI48.1

The preferred compounds are those in which Z = 0; however, standard techniques can be employed to convert the carbonyl oxygen to sulfur or an amidine or substituted amidine. These techniques are described in detail in copending application U.S. Patent Application 07/883,944, filed May 15, 1992, which is incorporated by reference.

The preferred compounds are those in which R4A and
R28 are hydrogen. However, compounds in which R4A and
R28 are substituted benzyl or substituted lower alkyl can be prepared by choosing alpha, alpha'-substituted amino acids as starting materials. For example, if, in structure III, the alpha hydrogen is replaced by substituted benzyl or substituted lower alkyl, then the product derived from the synthesis described herein is
XV:
EMI49.1
and if in structure VI the alpha hydrogen is replaced by substituted benzyl or substituted lower alkyl then the product of the above-described sequence is XVI. These alpha, alpha' substituted amino acids can be prepared by the means described in the references above, and by other means well known to skilled in the art of organic synthesis.
EMI49.2

Compounds in which the side chains on the same side of the seven-membered ring are joined to form a fused ring are contemplated as part of this invention.

Specifically, compound XVII can be formed by choosing amino acid VI such that R27 is protected 4-hydroxybutyl (n=2) or protected 3-hydroxypropyl. Release of the hydroxy group, conversion to the tosylate or mesylate in dilute solution in a polar aprotic solvent at 0-1000C in the presence of a weak base will result in the fused ring system.
EMI50.1

If a similar procedure is employed with R4, and the resulting tosylate or mesylate is heated in dilute solution with a stronger base such as sodium hydride in a polar aprotic solvent, the fused ring system XVIII can be obtained.
EMI50.2

The absolute and relative stereochemistry of the ring substituents are important for the degree of binding of these compounds to the HIV protease active site. Although a preferred diastereomer is shown in structure XIX, other diastereomers are also active and are contemplated as part of this invention. Control over stereochemistry is obtained by choice of starting materials III and VI, and by choice of reducing agent to form chloroalcohol as described above.
EMI51.1

The synthesis of representative compounds of the present invention is described in further detail below.

1. Preparation of N-Carbobenzyloxy-D
Phenylalanine chioromethylketone
EMI51.2

One equivalent [EQ] (15g)of CBZ-D-phenylalanine was dissolved in tetrahydrofuran [THF, 33mL] (1.5M) The solution was cooled to -200C (internal) using a dry ice/CCl4 bath and 4-methylmorpholine (5.5mL, 1 EQ) was added dropwise, maintaining a temperature below -150C, followed by isobutylchloroformate (6.5mL, 1 EQ) maintaining a temperature below -150C. After stirring for 15 min at -150C the precipitate was filtered and washed with 50mL cold THF. The combined THF solution was contained in a 1L Erlenmeyer cooled in an ice bath and added to this an excess of diazomethane in ether (see prep below).

After stirring for 25min, the bath was removed and stirred until reaction temperature reached -180C. The reaction was recooled in ice bath and 40mL 4M HCl in dioxane was added, until bubbling ceased and solution became nearly colorless. The pH was checked to confirm acidity and concentrated invacuo. Further evaporation was carried out in high vacuum overnight to afford 18.65g of the desired product, M.P. 880C. NMR (CDC13) : consistent with assigned structure.

2. Preparation of Diazomethane
A commercially available diazomethane distillation kit was charged with 2-(2-ethoxyethoxy)ethanol (84mL), anhydrous ether (84mL) and a solution of potassium hydroxide (15g) in distilled water (24mL). Upon heating to 600C, a solution of N-methyl-N-nitroso-ptoluenesulfonamide (30g, Diazald) in anhydrous ether (270mL) was added at the rate of product distillation.

Once the 270mL of expected diazomethane in ether was recovered, an additional amount of ether (100mL) was added to the reaction vessel and 50mL of distillate was collected. The diazomethane in ether was stored cold until ready for use.

3. CBZ-D-Phenyalanine Chioromethyl Alcohol
EMI52.1

Zinc chloride in ether (1.0M, 136mL) was added dropwise to a mechanically stirred flask containing a solution of sodium borohydride (10.30g, 1.25 EQ) in ether (552mL). A solution of Z-D-phenylalanine chloroketone (36g) (from step 1 above) in tetrahydrofuran (0.27M) was added dropwise and allowed.

to stir at room temperature overnight. The reaction was quenched by dropwise addition of water (400mL), followed by hydrochloric acid (1N, 200mL) and ethyl acetate (250mL). Upon separation of the layers, the organic layer was washed with water, saturated sodium bicarbonate and brine. Following drying over magnesium sulfate, the volatiles were removed in vacuo to recover 30.42g of crude product. Recrystallization using ethyl acetate (100mL) afforded 9.73g of two isomers. These were carried through as a mixture. NMR (CDC13): consistent with assigned structure. Mass Spec. 334.21 (M+H).

4. CBZ-D-Phenylalanine Epoxide
EMI53.1

CBZ-D-phenylalanine chloroalcohol (9.73g) from step 3 was dissolved in tetrahydrofuran (0.16M) and cooled in an ice bath. Potassium tert-butoxide (1.OM in THF, 32mL, 1.1 EQ) was added dropwise with stirring under nitrogen.

Thin Layer Chromatography (Tlc) after 30 min in 6:2:2 toluene: ethyl acetate: hexanes indicated reaction is complete. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over sodium sulfate. Filtration and concentration in vacuo afforded 7.98g of the desired product. NMR (CDCl3): consistent with assigned structure. Mass Spec. 298 (M+H); 315.17 (M+NH4).

5. Epoxide Condensation with L-phenylalanine
tert-Butylester
Referring to step 14, which describes the separation of the two chloromethyl alcohol isomers and subsequent epoxidation of these isomerically pure products, in step 15, the L-phenylalanine tert-butyl ester was reacted with each of these CBZ-D-phenylalanine epoxides in an individual series as follows:
EMI54.1

The commercially available amine (as the HCl salt) was converted to the free base by dissolution in saturated sodium bicarbonate and extraction with ethyl acetate. After drying and removal of the volatiles, free amine (2.11g, 1 EQ) was added to a solution of above described epoxide (from step 4) (2.84g) in methanol (0.2M) and heated until judged complete. Concentration in vacuo gave 4.95g of the desired product. NMR (CDC13): consistent with assigned structure.

Mass Spec. 519.29 (M+H).

6. tert-Butyldimethylsilyl Protection on
Hydroxyl Group
EMI55.1

The previously described product (4.95g) (from step 5) dissolved in anhydrous dimethylformamide (1.2M), was reacted with t-butyldimethylsilyl chloride (2.83g, 2.2
EQ) and imidazole (1.75g, 3 EQ) at room temperature overnight. Tlc (2% methanol in chloroform) indicated reaction was complete. The reaction was worked up by adding saturated sodium bicarbonate (100mL) and stirring for 10 minutes. Methylene chloride was added, the organic layer was separated, washed with brine and dried over sodium sulfate. Concentration in vacuo and purification on silica gel using 6:1:3 toluene: ethyl acetate: hexanes afforded 3.24g of the product. NMR (CDC13): consistent with assigned structure. Mass Spec 633.37 (M+H).

7. Removal of the CBZ Protecting Group
EMI55.2

The CBZ-protected amino acid (from step 6)(3.24g) was dissolved in tetrahydrofuran (66mL) and glacial acetic acid (6mL). Following a evacuation and purge sequence with nitrogen, palladium on carbon (10%, 200mg) we added. After an evacuation and purge sequence using hydrogen, the reaction was allowed to stir until judged complete by Tlc. The catalyst was filtered off and washed with THF/HOAc.Upon concentration in vacuo and further drying on high vacuum, the recovered acetate salt was used directly in the next step. NMR (CDC13): consistent with assigned structure. Mass Spec 499.34 (M+H).

8. Acid Catalyzed Hydrolysis of the t-Butyl
Ester
EMI56.1

The t-butyl ester (from step 7) (100mg) was dissolved in methylene chloride (8mL) and trifluoroacetic acid (2.6mL) at a concentration of 0.02M. Upon stirring under nitrogen, the reaction was judged complete by Tlc. Concentrated in vacuo while keeping cold, followed by further drying on high vacuum overnight afforded a product which was used directly in the next reaction. NMR (CDC13): consistent with assigned structure. Mass Spec. 443.27 (M+H).

9. General Procedure for Cyclization (Lactam
Formation)
EMI57.1

To a solution of the previously described product (from step 8) (3.08g) in tetrahydrofuran (140mL, 0.05M) was added 4-methylmorpholine (2.68 mL, 3.5 EQ),1hydroxybenzotriazole hydrate (0.942g, 1 EQ) and 1,3dicyclohexylcarbodiimide (1.45g, 1 EQ). After stirring at room temperature under nitrogen for 3 days, the precipitated dicyclohexylurea was filtered away and the filtrate was partitioned between methylene chloride and water. The organics were washed with saturated sodium bicarbonate and brine, dried over sodium sulfate and concentrated in vacuo. The crude material was purified by preparative thin layer chromatography (2mm thickness silica gel plate) using toluene: ethyl acetate: methanol.

NMR (CDC13): consistent with assigned structure. Mass Spec. 425.26 (M+H).

Example 1 10. Fluoride-induced Deprotection of the
t-Butyldimethylsilyl Ether
EMI57.2

A solution of silyl ether (from step 9 above)(38mg) dissolved in tetrabutylammonium fluoride (1M solution in tetrahydrofuran, 1.5mL) was allowed to stir under nitrogen until judged complete by Tlc. The reaction was quenched by addition of saturated sodium bicarbonate and stirred for 10 minutes. After diluting with methylene chloride, the layers were separated and the organics were dried over sodium sulfate. Following concentration in vacuo and purification by preparative Tlc using
Toluene: Ethyl Acetate: Methanol, 18mg of the desired product was isolated. NMR (CDCl3) : consistent with assigned structure. Mass Spec. 311.18 (M+H).

11. Benzylation of Basic Amine
EMI58.1

A solution of the starting lactam (from step 9) (62.5 mg) was dissolved in anhydrous N,Ndimethylformamide (0.15mL, 1M) and allowed to stir with potassium carbonate (30.5mg, 1.5 EQ) at room temperature under nitrogen for 10 minutes. Benzyl bromide (0.026mL, 1.5 EQ) was added and the reaction was stirred until judged complete by Tlc. After partitioning between methylene chloride and water, the organic phase was washed with saturated sodium bicarbonate, brine and dried over sodium sulfate. Concentration in vacuo affored 50mg of the desired product. NMR (CDC13): consistent with assigned structure. Mass Spec. M+H 515.31
Example 2 12. Deprotection of Benzylated Compound
EMI59.1

Material from step 11 (above) was treated as described above for step 10.

NMR (CDCl3) : consistent with assigned structure. Mass Spec. 401 (M+H).

13. Selective Debenzylation of Cyclized
N-benzylamine (Formic Acid Procedure)
EMI59.2

A general procedure based on that described in J.

Org. Chem, 1979, 44, 3442 was used. The starting
N-benzyl amine (from step 11) (30mg) was dissolved in
MeOH (0.02M) with formic acid (¯5%, 3mL). Following the addition of palladium on Carbon (10%, 30mg), the reaction was stirred under nitrogen until judged complete by Tlc. The catalyst was removed and the filtrate was concentrated in vacuo before the silyl ether cleavage. NMR (CDCl3) : consistent with assigned structure. Mass Spec. 425.26 (M+H).

14. Benzylation of Lactam Amine
EMI60.1

To a solution of the starting N-benzyl lactam (step 21) (0.300g, 1EQ) in anhydrous N,N-dimethylformamide (llmL, 0.05M) was added sodium hydride, 60% in mineral oil(0.047g, 2 EQ) and stirred under nitrogen for 5 minutes. 3 EQ (0.21mL) of benzyl bromide was added and the reaction stirred until judged complete by Tlc.

After partitioning between methylene chloride and water, the organic phase was washed with saturated sodium bicarbonate, brine and dried over magnesium sulfate.

Concentration in vacuo afforded 0.360g. Purification on silica gel and elution in 6:0.5:3.5 toluene:ehtyl acetate:hexanes afforded 0.250g of compound. Mass Spec.

605.36 (M+H).

15. Deprotection of Di-benzylated Compound
The products of step 14 are deprotected to yield the following compounds.
EMI61.1

16. CBZ-D-Phenylalanine Chloromethyl Alcohol (Modification of Step 3):
Zinc chloride in ether (1.OM, 136mL) was added dropwise to a mechanically stirred flask containing a solution of sodium borohydride (10.30g, 1.25 EQ) in ether (552mL). A solution of Z-D-phenylalanine chloroketone (36g) (from step 1 above) in tetrahydrofuran (0.27M) was added dropwise and allowed to stir at room temperature overnight. The reaction was quenched by dropwise addition of water (400mL), followed by hydrochloric acid (1N, 200mL) and ethyl acetate (250mL). Upon separation of the layers, the organic layer was washed with water, saturated sodium bicarbonate and brine.

Following drying over magnesium sulfate, the volatiles were removed in vacuo to recover 30.42g of crude product. (Recrystallization using ethyl acetate (l00mL) and hexanes (to turbidity) afforded 9.73g of a single isomer, whose x-ray crystal structure was consistent with the CIS configuration realtive to the D-phenylalanine. This product was designated Z-D
Phenylalanine Hydroxyl Isomer &num;1. The mother liquor was concentrated. 17g was purified by column chromatography on silica gel and eluted in 6:2:2 Toluene:Ethyl Acetate:
Hexanes to recover 4.32g of the second isomer component.

This product was designated Z-D-Phenylalanine Hydroxyl
Isomer &num;2. Mass Spec. 334.21 (M+H) for each isomerically pure product.
EMI62.1

CBZ-D-Phenylalanine CBZ-D-Phenylalanine
Hydroxyl Isomer &num;1 Hydroxyl Isomer &num;2
The indicated procedures below were carried out on each of the two hydroxyl isomer products indicated.

17. CBZ-D-Phenylalanine Epoxide
The CBZ-D-phenylalanine CBZ-D-phenylalanine epoxide isomers shown below were prepared from the material of step 16 using the procedure described in step 4.
EMI62.2

CBZ-D-Phenylalanine CBZ-D-Phenylalanine
Epoxide Isomer &num;1 Epoxide Isomer &num;2 18. Epoxide Condensation with D-phenylalanine tert-Butyl ester
The compounds below were prepared using the material of step 17 and the procedure described in step 5.
EMI63.1

CBZ-D-Phenylalanine-D-Phe-OtBu CBZ-D-Phenylalanine
D-Phe-OtBu
Hydroxyl Isomer &num;1 Hydroxyl Isomer &num;2 19. tert-Butyldimethylsilyl Protection on Hydroxyl
Group
The compounds below were prepared from the material of step 18 and using the procedure described in step 6.
EMI63.2

Z-D-Phe-D-Phe-OtBu Z-D-Phe-D-Phe-OtBu
Hydroxyl &num;1 TBDMS Hydroxyl &num;2 TBDMS 20. Removal of the CBZ Protecting Group
The compounds below were prepared from the material of step 19 and using the procedure described in step 7.

Mass Spec. 499.34 (M+H).
EMI64.1

isomer 1 isomer 2 21. Acid Catalyzed Hydrolysis of the t-Butyl Ester
The compounds below were prepared from the material of step 20 and using the procedure described in step 8 above.
EMI64.2

isomer 1 isomer 2 22. General Procedure for Cyclization (Lactam
Formation)
The compounds below were prepared using the material from step 21 and the procedure described in step 9. Mass Spec. 425.26 (M+H).
EMI64.3

D-phe-D-phe-azalactam D-phe-D-phe-azalactam hydroxyl isomer 1 TBDMS hydroxyl isomer 2 TBDMS
Example la and 1b 23. Fluoride-induced Deprotection of the t-Butyldimethylsilyl Ether
The compounds below were prepared from the material of step 22 and using the procedure described in step 10.
EMI65.1

24. Benzylation of Basic Amine
The compounds below were prepared from the material of step 23 and using the procedure described in step 11.
EMI65.2

Examples 2a and 2b 25. Deprotection of Benzylated Compound
Material from step 24 (above) was treated as described above for step 10. Mass Spec. 401 (M+H).
EMI66.1

26. Benzylation of Lactam Amine
To a solution of the starting N-benzyl lactam (step 24) (0.300g, 1EQ) in anhydrous N,N-dimethylformamide (l1mL, 0.05M) was added sodium hydride, 60% in mineral oil(0.047g, 2 EQ) and stirred under nitrogen for 5 minutes. 3 EQ (0.21mL) of benzyl bromide was added and the reaction stirred until judged complete by Tlc.

605.36 (M+H).
EMI66.2

Example 38 a & b 27. Deprotection of Di-Benzylated Compound
Material from step 26 was treated as in step 10 above. Mass Spec. 491.27 (M+H).
EMI67.1

Using the above-described techniques or variations thereof appreciated by those of skill in the art of chemical synthesis, the compounds of Table 1 (shown below) can also be prepared.

Table 1
EMI68.1

Example B4 B7 B22 B27 z 1 benzyl H H benzyl 0 2 benzyl H H benzyl S 3 benzyl H H benzyl N-CN 4 benzyl H H benzyl N-OCH3 5 benzyl H H (p-HO- O C6H4) CH2 6 benzyl H H (m-HO- O
C6H4)CH2 7 benzyl H H n-propyl 0 8 benzyl H H isobutyl 0 9 benzyl H H (m-CH3NH- O
C6H4)CH2 10 benzyl H H (m-CH302C- O
C6H4)CH2 11 benzyl H H cyclopropyl 0
methy 12 benzyl H H (m-F- O
C6H4)CH2 13 benzyl H H 2-naphthyl 0
Example R4 7 R22 R27 Z 14 benzyl H H 4-hydroxy- 0
n-butyl 15 benzyl H H 3-pyridyl 0 16 n-propyl H H benzyl 0 17 (p-F- H H benzyl 0 C6H4) CH2 18 n-butyl H H benzyl 0 19 (m-HO- H H benzyl 0
C6H4)CH2 20 (p-H2NCO- H H

benzyl 0
C6H4)CH2 21 (m-CH3C02- H H benzyl 0
C6H4)CH2 22 cyclopropyl H H benzyl 0
methyl 23 n-propyl H H cyclopropyl 0
methyl 24 benzyl benzyl H benzyl 0 25 benzyl benzyl cyclopropyl benzyl 0
methyl 26 benzyl H benzyl isobutyl 0 27 H benzyl (m-HO- ethyl 0 C6H4) CH2 28 benzyl benzyl (m-HOCH2- (m-HOCH2- o
C6H4)CH2 C6H4)CH2 29 benzyl benzyl naphthyl naphthyl 0 30 benzyl benzyl cyclopropyl methyl 0
methyl 31 benzyl benzyl benzyl methyl 0 32 benzyl H benzyl CH2-CONH2 O 33 benzyl benzyl cyclopropyl cyclopropyl 0
methyl methyl
Example R4 R7 R22 R27 Z 34 benzyl H benzyl (3,4-di-F- 0 C6H4) CH2 35 benzyl H benzyl cyclopropyl 0
methyl 36 benzyl H (m-HO- cyclopropyl 0
C6H4)CH2 methyl 37 benzyl H (m-HOCH2- (m-HOCH2- 0
C6H4)CH2 C6H4)CH2 38 benzyl benzyl

benzyl benzyl 0
Utility
The compounds of formula (I) possess retroviral protease inhibitory activity and are therefore useful as antiviral agents for the treatment of viral diseases.

More particularly, the compounds of formula (I) possess
HIV protease inhibitory activity and are effective as inhibitors of HIV growth. The protease inhibitory activity of the compounds of the present invention is demonstrated using standard assays of protease activity, for example, using the assay described below for assaying inhibitors of HIV protease activity. The ability of the compounds of the present invention to inhibit viral growth or infectivity is demonstrated in standard assay of viral growth or infectivity, for example, using the assays described below.

A compound is considered to be active if it has an IC50 or Ki value of less than about 1 mM for the inhibition of HIV protease or HIV viral growth or infectivity.

HIV Protease Inhibition Assay- Spectroscopic Method
Materials:
Protease: Inclusion bodies of E. coli harboring plasmid containing HIV 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 8.0. Protease activity was recovered by dilution 20-fold into buffer containing 50 mM sodium acetate pH 5.5, 1 mM EDTA, 10% glycerol and 5% ethylene glycol. Enzyme was used at a final concentration of 1.0-10 ug/mL (ug = microgram).

Substrate: Peptide of sequence: Ala-Thr-His-Gln
Val-Tyr-Phe(N02)-Val-Arg-Lys-Ala, containing para-nitrophenylalanine (Phe(N02)), was prepared by solid phase peptide synthesis as previously described by
Cheng et al. (1990) Proc. Natl. Acad. Sci. USA 87: 9660.

Stock solutions of 10 mM were prepared in DMSO.

Inhibitory compounds were dissolved in sufficient
DMSO to make 2.5 or 25 mM stock solutions. All further dilutions were done in DMSO.

Reactions:
Compound (1-5 uL) (uL or ul = microliter) and HIV protease were mixed in buffer containing 50 mM MES, pH 6.5, 1 M NaCl, 1 mM EDTA, 1 mM dithiothreitol, 10% glycerol. Reactions were initiated by the addition of peptide substrate to a final concentration of 240 uM (uM = micromolar), and absorbance at 300 nM monitored for 10 min. Values of Ki for inhibitor binding were determined from percent activity measurements in the presence and absence of known concentration of inhibitor, using a value of 0.07 mM for the Km of the substrate (Cheng et al. (1990) Proc. Natl. Acad. Sci.

USA 87: 9660).

The HIV-1 protease inhibitory activity of representative compounds of the invention is shown in
Table 2 (below).

HIV Protease Inhibition Assay- HPLC Method
Materials:
Protease: Inclusion bodies of E. coli harboring plasmid containing plasmid T1718R with a synthetic gene coding for a single-chain tethered dimer of HIV protease were prepared as described in Cheng et al. (Proc. Natl.

Acad. Sci. USA, 87, 9660-9664, 1990). Active protease was prepared as described therein by extraction with 67% acetic acid, dilution 33-fold with water, dialysis against water and then against a "refolding buffer" consisting of 20 mM MES, 1 mM dithiothreitol and 10% glycerol. Protease was stored as a stock preparation at 10 uM in refolding buffer.

Substrate: Peptide of sequence: aminobenzoyl-Ala Thr-His-Gln-Val-Tyr-Phe (NO2) -Val-Arg-Lys-Ala containing p-nitrophenylalanine, was prepared by solid phase synthesis as previously described Cheng et al., op.cit.

Stock solutions of 2 mM substrate were prepared in DMSO.

Inhibitory compounds were dissolved in sufficient
DMSO to make 3 mM stock solutions. All further dilutions were prepared in "assay buffer": 1 M Nail, 50 mM MES, pH 5.5, 1 mM EDTA, lmM DTT, 20% glycerol.

Reactions:
Enzyme reaction: In a 2 mL screw-cap centrifuge tube were added 50 ul protease (final concentration 0.25 nM) and 100 ul inhibitory compound (final concentration 0.1-12,500). After 15 min preincubation at room temperature, the reaction was started with the addition of 50 ul 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 ammonium hydroxide.

HPLC measurement of product formation: The product (aminobenzoyl-Ala-Thr-His-Gln-Val-Tyr) was separated from substrate on a Pharmacia MonoQ anion exchange column. The injection volume was 200 ul. The mobile phases were: A (20 mM trisHCl, pH 9.0, 0.02% sodium azide, 10% acetonitrile), B (20 mM tris HCl, pH 9.0, 0.02% sodium azide, 0.5 M ammonium formate, 10% acetonitrile) . The mobile phases were pumped at 1 mL/min, with a gradient from 0 to 30% B in 5 min, 100 %
B for 4 min to wash the column, and a re-equilibration for 4 min. The retention time of the product was 3.6 min. Detection with a Shimadzu model RF535 fluorescence monitor was at 330 nm (excitation) and 430 (emission).

The Ki was calculated from the formula Ki = I/(((Km+S
FA*S)/(FA*Km))-1) where I = inhibitory concentration, S = substrate concentration, FA = fractional activity = cm peak height with inhibitor/cm peak height without inhibitor, and Km = Michaelis constant = 20 uM.

HIV Yield Reduction Cell Assav
Materials: MT-2, a human T-cell line, was cultured in RPMI medium supplemented with 5% (v/v) heat inactivated fetal calf serum (FCS), L-glutamine and gentamycin. Human immunodeficiency virus strains, HIV (3B) and HIV(RF) were propagated in H-9 cells in RPMI with 5% FCS. Poly-L-lysine (Sigma) coated cell culture plates were prepared according to the method of Harada et al. (1985) Science 229: 563-566. MTT, 3-(4,5 dimethyl-thiazol-2yl) -2, 5-diphenyltetrazolium bromide, was obtained from Sigma.

Method: Test compounds were dissolved in dimethylsulfoxide to 5 mg/mL and serially diluted into
RPMI medium to ten times the desired final concentration. MT-2 cells (5 x 105/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) (-5 x 105 plaque forming units/mL) in 0.375 mL was added to the cell and compound mixtures and incubated for one hour at 360C.

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 360C, 4% C02 incubator. Virus was allowed to replicate for 3 days. Cultures were centrifuged for 10 minutes at 1000 rpm and the supernatants containing cell free progeny virus were removed for plaque assay.

The virus titers of the progeny virus produced in the presence or 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 360C to allow for efficient attachment of the virus to cells.

Aliquots of each virus and cell mixture were added equally to two wells of a six well poly-L-lysine coated culture plate and incubated overnight at 360C, 4% C02.

Liquid and unattached cells were removed prior to the addition of 1.5 mL of RPMI with 0.75% (w/v) 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 360C, 4% C02, a final overlay of phosphate-buffered saline with 0.75%
Seaplaque agarose and 1 mg MTT/mL was added. The plates were incubated overnight at 360C. Clear plaques on a purple background were counted and the number of plaque forming units of virus was calculated for each sample.

The antiviral 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.

HIV Low Multiplicity Assav
Materials: MT-2, a human T-cell line, was cultured in RPMI medium supplemented with 5% (v/v) heat inactivated fetal calf serum (FCS), L-glutamine and gentamycin (GIBCO). Human immunodeficiency virus strains HIV (3B) and HIV (RF) were propagated in H-9 cells in RPMI with 5% FCS. XTT, benzene-sulfonic acid, 3,3'-[1-[ (phenyl-amino)carbonyl]-3,4-tetrazolium]bis(4- methoxy-6-nitro)-, sodium salt, was obtained from Starks
Associates, Inc.

Method: Test compounds were dissolved in dimethylsulfoxide to 5 mg/mL and serially diluted into RPMI medium to ten times the desired final concentration.

MT-2 cells (5 x 104/0.1 mL) were added to each well of a 96 well culture plate and 0.02 mL of the appropriate test compound solution was added to the cells such that each compound concentration was present in two wells.

The cells and compounds were allowed to sit for 30 minutes at room temperature. HIV(3B) or HIV(RF) (-5 x 105 plaque forming units/mL) was diluted in medium and added to the cell and compound mixtures to give a multiplicity of infection of 0.01 plaque forming unit/cell. The mixtures were incubated for 7 days at 360C, during which time the virus replicated and caused the death of unprotected cells. The percentage of cells protected from virus induced cell death was determined by the degree of metabolism of the tetrazolium dye, XTT.

In living cells, XTT was metabolized to a colored formazan product which was quantitated spectrophotometrically at 450 nm. The amount of colored formazan was proportional to the number of cells protected from virus by the test compound. The concentration of compound protecting either 50% (IC50) or 90% (ICg0) with respect to an uninfected cell culture was determined.

The HIV inhibitory activity of representative compounds of the present invention in the whole cell infectivity assay described above is shown in Table 2.

Table 2
Example Number Ki IC90
1 +++ +++
24 ++ +++
The ICg0 values in Table 2 are indicated as: +++ = < 10 ug/mL.

In the Tables herein the Ki values were determined using the assay conditions described above under HIV
Protease Inhibition Assay-HPLC Method. The Ki values are indicated as follows: +++ = < 10 nM; ++ = 10 nM to 1 uM; + = > 1 uM.

In the Tables herein the ICg0 values were determined using the assay conditions described above under HIV Low Multiplicity Assay. The ICg0 values are indicated as follows: +++ = < 10 ug/mL; ++ = 10 to 100 ug/mL; + = > 100 ug/mL.

Dosage and Formulation
The antiviral compounds of this invention can be administered as treatment for viral infections by any means that produces contact of the active agent with the agent's site of action, the viral 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 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 chosen route of administration and standard pharmaceutical practice.

The dosage administered will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, 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. A daily dosage of active ingredient can be expected to be about 0.001 to 1000 milligrams per kilogram of body weight, with the preferred dose being 0.1 to about 30 mg/kg.

Dosage forms (compositions suitable for administration contain from about 1 milligram to about 100 milligrams of active ingredient per unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.

The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. It can also be administered parenterally, in sterile liquid dosage forms.

Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours.

Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.

Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.

Also used are citric acid and its salts and sodium EDTA.

In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing
Company, a standard reference text in this field.

Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:
Capsules
A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules
A mixture of active ingredient in a digestable oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules are washed and dried.

Tablets
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 stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose.

Appropriate coatings may be applied to increase palatability or delay absorption.

Claims

WHAT IS CLAIMED IS: 1. A compound of the formula (I): EMI80.1 or a pharmaceutically acceptable salt or prodrug form thereof, wherein: X is S, O or N-R7; R4 and R7 are independently selected from the following groups: hydrogen; C1-Cg alkyl substituted with 0-3 R1l; C2-Cg alkenyl substituted with 0-3 R1l; C2-Cg alkynyl substituted with 0-3 R1l; C3-Cg cycloalkyl substituted with 0-3 R1l; C6-C10 bicycloalkyl substituted with 0-3 R1l; aryl substituted with 0-3 R12; a C6-C14 carbocyclic residue substituted with 0-3 R12; a heterocyclic ring system substituted with 0-2 R12 composed of 5 to 10 atoms including at least one, preferably 1-4, nitrogen, oxygen or sulfur atom; R4A is selected from the following groups:

: hydrogen; C1-C4 alkyl substituted with halogen or C1-C2 alkoxy; benzyl substituted with halogen or C1-C2 alkoxy; R4 and R4A can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R12; R5 is selected from =0, or -OR20; R20 is independently selected from: hydrogen; C1-C6 alkyl substituted with 0-3 RÚÚ; C3-C6 alkoxyalkyl substituted with 0-3 RÚÚ; C1-C6 alkylcarbonyl substituted with 0-3 RÚÚ; C1-C6 alkoxycarbonyl substituted with 0-3 RÚÚ; benzoyl substituted with 0-3 R12; phenoxycarbonyl substituted with 0-3 R12; phenylaminocarbonyl substituted with 0-3 R12; C1-C6 alkylsulfenyl substituted with 0-3 R1l; C1-C6 alkylsulfonyl substituted with 0-3 R1l;

or any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl; R11 is selected from one or more of the following: keto, halogen, cyano, -CH2NR13R14, -NR13R14, -C02R13, -OC(=O)R13, -OR13, C2-C6 alkoxyalkyl, -S(O)mRÚ , -NHC(=NH)NHR13, -C(=NH)NHRÚ , -C(=O)NR13R14, -NR14C(=O)R13, =NOR14, -NR14C(=O)OR14, -OC(=O)NRÚ R14, -NRÚ C(-O)NRÚ R14, -NR14S02NR13R14 -NR14SO2RÚ , -502NR13R14, Cl-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl; 1-3 amino acids, linked together via amide bonds and linked to R4 or R7 via the amine or carboxylate terminus;

; a Cg-C14 carbocyclic residue substituted with 0-3 R12; aryl substituted with 0-3 R12; or a heterocyclic ring system substituted with 0-2 RÚê, composed of 5 to 10 atoms including at least one, preferably 1-4, nitrogen, oxygen or sulfur atom; R12, when a substituent on carbon, is selected from one or more of the following:

: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, C7-C10 arylalkyl, C1-C4 alkoxy, -C02H, hydroxamic acid, hydrazide, oxime, boronic acid, sulfonamide, formyl, C3-C6 cycloalkoxy, -OR13, C1-C4 alkyl substituted with -NR13R14, -NR13R14, C2-C6 alkoxyalkyl, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(O)mRÚ , -SO2NRÚ R14, -NHS02R14, -OCH2C02H, 2- (1-morpholino) ethoxy; or a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur;

; or R12 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 the aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or -NR13R14; or, when R12 is attached to a saturated carbon atom, it may be carbonyl or thiocarbonyl; R12 when a substituent on nitrogen, is selected from one or more of the following:

: phenyl, benzyl, phenethyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR13R14, -NR13R14, C2-C6 alkoxyalkyl, C1-C4 haloalkyl, Cl-C4 alkoxycarbonyl, -C02H, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl; R13 is H, phenyl, benzyl, C1-C6 alkyl, or C3-C6 alkoxyalkyl; R14 is OH, H, C1-C4 alkyl, or benzyl; R13 and R14 can alternatively join to form -(CH2)4-, -(CH2)s-, -CH2CH2N(R15)CH2CH2-, or -CH2CH20CH2CH2-; R15 is H or CH3; m is 0, 1 or 2; Z is 0, S, or NR24; R22 is independently selected from the following:

: hydrogen; C1-Cg alkyl substituted with 0-3 R31; C2-Cg alkenyl substituted with 0-3 R31; C2-Cg alkynyl substituted with 0-3 R31; C3-Cg cycloalkyl substituted with 0-3 R31; C6-C10 bicycloalkyl substituted with 0-3 R31; aryl substituted with 0-3 R32; a C6-C14 carbocyclic residue substituted with 0-3 R32; a heterocyclic ring system substituted with 0-2 R32, composed of 5 to 10 atoms including at least one, preferably 1-4, nitrogen, oxygen or sulfur atom; R24 is selected from: hydroxy; amino; C1-C4 alkyl; C1-C4 alkoxy;

C1-C4 aminoalkyl; cyano; nitro; R27 is selected from the following: hydrogen; C1-Cg alkyl substituted with 0-3 R31; C2-Cg alkenyl substituted with 0-3 R31; C2-Cg alkynyl substituted with 0-3 R31; C3-Cg cycloalkyl substituted with 0-3 R31; C6-C10 bicycloalkyl substituted with 0-3 R31; aryl substituted with 0-3 R32; a C6-C14 carbocyclic residue substituted with 0-3 R32; a heterocyclic ring system substituted with 0-2 R32, composed of 5 to 10 atoms including at least one, preferably 1-4, nitrogen, oxygen or sulfur atom; R28 is independently selected from: hydrogen; C1-C4 alkyl substituted with halogen or C1-C2 alkoxy; benzyl substituted with halogen or C1-C2 alkoxy;

: keto, halogen, cyano, -CH2NR13R14, -NR13R14, -C02R13, -OC(=O)R13, -OR13, C2-C6 alkoxyalkyl, -S(O)mRÚ , -NHC(=NH)NHRÚ , -C(=NH)NHRÚ , -C(=O)NRÚ R14, -NR14C(O)RÚ , =NOR14, -NR14C(=O)OR14, -OC(=O)NRÚ R14, -NRÚ C(=O)NRÚ R14, -NR14SO2NRÚ R14, -NR14SO2RÚ , -SO2NRÚ R14, C1-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl; 1-3 amino acids, linked together via amide bonds and linked to R4 or R7 via the amine or carboxylate terminus; a C5-C14 carbocyclic residue substituted with 0-3 R32; aryl substituted with 0-3 R32;

or

a heterocyclic ring system substituted with 0-2 R32, composed of 5 to 10 atoms including at least one, preferably 1-4, nitrogen, oxygen or sulfur atom; R32, when a substituent on carbon, is selected from one or more of the following: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, C7-C10 arylalkyl, C1-C4 alkoxy, -C02H, hydroxamic acid, hydrazide, oxime, boronic acid, sulfonamide, formyl, C3-C6 cycloalkoxy, -OR13, C1-C4 alkyl substituted with -NR13R14, -NR13R14, C2-C6 alkoxyalkyl, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl,

C1-C4 alkylcarbonylamino, -S(O)mR13 -502NR13R14, -NHS02R14, -OCH2C02H, 2- (1-morpholino) ethoxy, -C (R14)=N (OR14); or a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur; or R32 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 the aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or -NR13R14;

or, when R32 is attached to a saturated carbon atom, it may be carbonyl or thiocarbonyl; R32, when a substituent on nitrogen, is selected from one or more of the following: phenyl, benzyl, phenethyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR13R14, -NR13R14, C2-C6 alkoxyalkyl, C1-C4 haloalkyl, C1-C4 alkoxycarbonyl, -C02H, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, -C (R14)=N (OR14); R33 is C1-C3 alkyl substituted at the C2 or C3 carbon with C1-C2 alkoxy, halogen, or hydroxy; alternatively, R33 can join with R7 to form a fused 5- or 6- membered carbocyclic ring; provided that: when R4 and R4A are hydrogen and X is N-R7, at least one of the following is not hydrogen:

R7, R22, R27 or R28; when R4 and R4A are hydrogen and X is S or 0, at least two of the following are not hydrogen: R22, R27 or R28 2. A compound of Claim 1 of formula (I), or a pharmaceutically acceptable salt or prodrug form thereof, wherein: X is S, O or R4 and R7 are independently selected from the following groups: hydrogen; C1-C4 alkyl substituted with 0-3 R1l; C3-C4 alkenyl substituted with 0-3 Roll; C3-C4 alkynyl substituted with 0-3 R1l; R4A is hydrogen; R5 is selected from =0 or -OR20; R20 is independently selected from: hydrogen; C1-C6 alkylcarbonyl; C1-C6 alkoxycarbonyl; benzoyl;

or any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl; R11 is selected from one or more of the following: keto, halogen, cyano, -CH2NR13R14, -NR13R14, -C02R13, -OC(=O)R13, -OR13, C2-C6 alkoxyalkyl, -S(O)mRÚ , C1-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl; a C5-C14 carbocyclic residue substituted with 0-3 R12; aryl substituted with 0-3 R12;

or a heterocyclic ring system substituted with 0-2 R12 composed of 5 to 10 atoms including 1-4 nitrogen, oxygen or sulfur atom; RÚê, when a substituent on carbon, is selected from one or more of the following: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, C7-C10 arylalkyl, C1-C4 alkoxy, -C02H, hydroxamic acid, hydrazide, oxime, boronic acid, sulfonamide, formyl, C3-C6 cycloalkoxy, -OR13, C1-C4 alkyl substituted with -NR13R14, -NR13R14, C2-C6 alkoxyalkyl, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl,

C1-C4 alkylcarbonylamino, -S(O)mR13 -502NR13R14, -NHSo2R14, -OCH2C02H, 2- (1-morpholino) ethoxy; or a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur; or R12 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 the aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or -NR13R14;

or, when R12 is attached to a saturated carbon atom, it may be carbonyl or thiocarbonyl; R12, when a substituent on nitrogen, is selected from one or more of the following: phenyl, benzyl, phenethyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR13R14, -NR13R14, C2-C6 alkoxyalkyl, C1-C4 haloalkyl, C1-C4 alkoxycarbonyl, -C02H, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl; R13 is H, C1-C6 alkyl, or C3-C6 alkoxyalkyl; R14 is OH, H, C1-C4 alkyl, or benzyl; R13 and R14 can alternatively join to form -(CH2)4-, -(CH2)5-, -CH2CH2N(R15)CH2CH2- or -CH2CH20CH2CH2-; R15 is H or CH3;

m is 0, 1 or 2; Z is 0, S, N-CN, N-OH, N-OCH3; R22 is independently selected from the following: hydrogen; C1-C8 alkyl substituted with 0-3 R31; C3-Cg alkenyl substituted with 0-3 R31; C3-Cg alkynyl substituted with 0-3 R31; C3-C6 cycloalkyl substituted with 0-3 R31; R27 is selected from the following: hydrogen; C1-C8 alkyl substituted with 0-3 R31; C2-Cg alkenyl substituted with 0-3 R31; C3-Cg alkynyl substituted with 0-3 R31; R28 is hydrogen; R31 is selected from one or more of the following:

: keto, halogen, cyano, -CH2NR13R14, -NRÚ R14, -C02R13, -oC(=o)R13, -OR13, C2-C6 alkoxyalkyl, -S(O)mRÚ , C1-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl; a Cg-C14 carbocyclic residue substituted with 0-3 R32; aryl substituted with 0-3 R32;

or a heterocyclic ring system substituted with 0-2 R32, composed of 5 to 10 atoms including 1-4, nitrogen, oxygen or sulfur atom; R32, when a substituent on carbon, is selected from one or more of the following: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, C7-C10 arylalkyl, C1-C4 alkoxy, -C02H, hydroxamic acid, hydrazide, oxime, boronic acid, sulfonamide, formyl, C3-C6 cycloalkoxy, -OR13, C1-C4 alkyl substituted with -NR13R14, -NR13R14, C2-C6 alkoxyalkyl, Cl-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl,

C1-C4 alkylcarbonylamino, -S(O)mR13, -S02NR13R14, -NHSo2R14, -OCH2C02H, 2- (1-morpholino) ethoxy, -C (R14)=N (OR14); or a 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur; or R32 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 the aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or

-NR13R14;

or, when R32 is attached to a saturated carbon atom, it may be carbonyl or thiocarbonyl; R32, when a substituent on nitrogen, is selected from one or more of the following: phenyl, benzyl, phenethyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR13R14, -NR13R14, C2-C6 alkoxyalkyl, C1-C4 haloalkyl, C1-C4 alkoxycarbonyl, -C02H, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, -C (R14)=N (OR14); provided that: when R4 and R4A are hydrogen and X is N-R7, at least one of the following is not hydrogen: R7, R22, R27 or R28; when R4 and R4A are hydrogen and X is S or 0, at least two of the following are not hydrogen: R22, R27 or R28.

3. A compound of Claim 1 of formula (I), or a pharmaceutically acceptable salt or prodrug form thereof, wherein: X is S, O or N-R7; R4 and R7 are independently selected from the following groups: hydrogen; C1-C4 alkyl substituted with 0-3 Roll; C3-C4 alkenyl substituted with 0-3 R1l; R4A is hydrogen; R5 is -OR20; R20 is H or any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl; R11 is selected from one or more of the following: keto, halogen, -CH2NR13R14, -NR13R14, -OR13 C2-C4 alkoxyalkyl, C1-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl; aryl substituted with 0-3 R12;

or a heterocyclic ring system substituted with 0-2 R12 composed of 5 to 10 atoms including 1-4 nitrogen, oxygen or sulfur atom; R12 when a substituent on carbon, is selected from one or more of the following: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, C1-C4 alkyl, C7-C10 arylalkyl, C1-C4 alkoxy, -C02H, hydroxamic acid, hydrazide, oxime, boronic acid, sulfonamide, formyl, C3-C6 cycloalkoxy, -OR13, C1-C4 alkyl substituted with -NR13R14, -NR13R14, methylenedioxy, C1-C4 haloalkyl, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -OH, hydroxymethyl;

or a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur; R12, when a substituent on nitrogen, is benzyl or methyl; R13 is H, C1-C2 alkyl, or C3-C6 alkoxyalkyl; R14 is OH, H, or C1-C2 alkyl; R13 and R14 can alternatively join to form -(CH2)4-, -(CH2)s-, -CH2CH2N(R15)CH2CH2- or -CH2CH20CH2CH2-; R15 is H or CH3; Z is 0, S, or N-CN; R22 is independently selected from the following: hydrogen; C1-C4 alkyl substituted with 0-3 R31; C3-C4 alkenyl substituted with 0-3 R31; R27 is selected from the following: hydrogen; C1-C4 alkyl substituted with 0-3 R31; C2-C4 alkenyl substituted with 0-3 R31; R28 is hydrogen; R31 is selected from one or more of the following:

: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, C1-C4 alkyl, C7-C10 arylalkyl, C1-C4 alkoxy, -C02H, hydroxamic acid, hydrazide, oxime, boronic acid, sulfonamide, formyl, C3-C6 cycloalkoxy, -OR13, C1-C4 alkyl substituted with -NR13R14, -NR13R14 methylenedioxy, C1-C4 haloalkyl, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, -OH, hydroxymethyl, -C (R14)=N (OR14); or a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur; R32, when a substituent on nitrogen, is benzyl or methyl; provided that: when R4 is hydrogen and X is N-R7, at least one of the following is not hydrogen:

R7, R22, or R27; when R4 is hydrogen and X is S or 0, at least two of the following are not hydrogen: R22 or R27.

4. A compound of Claim 1 of formula (I), or a pharmaceutically acceptable salt or prodrug form thereof, wherein:: X is S, O or R4 and R7 are independently selected from the following groups: hydrogen; C1-C3 alkyl substituted with 0-3 R1l; R4A is hydrogen; R5 is -OR20; R20 is H or any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl; R11 is selected from one or more of the following: halogen, -OR13, C1-C4 alkyl, C3-C6 cycloalkyl; aryl substituted with 0-3 R12;

or a heterocyclic ring system selected from pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl; R12, when a substituent on carbon, is selected from one or more of the following: benzyloxy, halogen, methyl, C1-C4 alkoxy, CF3, 2-(l-morpolino)ethoxy, -C02H, hydroxamic acid, hydrazide, oxime, cyano, boronic acid, sulfonamide, formyl, C3-C6 cycloalkoxy, C1-C4 alkyl substituted with -NR13R14, -NR13R14, -OH, hydroxymethyl;

or R12, when a substituent on nitrogen, is methyl; R13 is H or methyl; R14 is OH, H, or methyl; R13 and R14 can alternatively join to form -(CH2)4-, -(CH2)5-, -CH2CH2N(R15)CH2CH2-, or -CH2CH2oCH2CH2-; R15 is H or CH3; Z is O or N-CN; R22 is independently selected from the following: hydrogen; C1-C4 alkyl substituted with 0-3 R31; C3-C4 alkenyl substituted with 0-3 R31; R27 is selected from the following: hydrogen; C1-C4 alkyl substituted with 0-3 R31; C3-C4 alkenyl substituted with 0-3 R31; R28 is hydrogen; R31 is selected from one or more of the following: halogen, -OR13, C1-C4 alkyl, C3-Cs cycloalkyl; aryl substituted with 0-3 R32;

or a heterocyclic ring system selected from pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl; R32, when a substituent on carbon, is selected from one or more of the following: benzyloxy, halogen, methyl, C1-C4 alkoxy, CF3, 2-(1-morpolino)ethoxy, -C02H, hydroxamic acid, hydrazide, oxime, cyano, boronic acid, sulfonamide, formyl, C3-C6 cycloalkoxy, C1-C4 alkyl substituted with -NR13R14, -NR13R14, -OH, hydroxymethyl, -C (R14)=N (OR14); or R32, when a substituent on nitrogen, is methyl; provided that: when R4 is hydrogen and X is N-R7, at least one of the following is not hydrogen:

5. A compound of Claim 1 of formula (I), or a pharmaceutically acceptable salt or prodrug form thereof, wherein: X is S, O or N-R7; R4 and R7 are benzyl; R4A is hydrogen; R5 is -OH;

R13 is H or methyl; R14 is H or methyl; Z is O or N-CN; R22 is independently selected from the following: hydrogen; C1-C4 alkyl substituted with 0-3 R31; R27 is hydrogen or C1-C4 alkyl substituted with 0-3 R31; R28 is hydrogen; R31 is selected from one or more of the following: C3-Cs cycloalkyl; aryl substituted with 0-3 R32;

or a heterocyclic ring system selected from pyridyl, thienyl, quinolinyl, isoquinolinyl; R32, when a substituent on carbon, is selected from one or more of the following: -CONH2, -C02H, -CHO, -CH2NHOH, -NR13R14, -CH2NR13R14, -OH, hydroxymethyl, -C (R14)=N (OR14); or R32, when a substituent on nitrogen, is methyl.

6. A compound of Claim 1 of formula (I), or a pharmaceutically acceptable salt or prodrug form thereof, wherein: X is N-R7; R4 and R7 are benzyl; R4A is hydrogen; R5 is -OH; Z is O or N-CN; R28 is hydrogen; R22 and R27 are independently selected from the group consisting of: hydrogen, allyl, propyl, cyclopropylmethyl, n-butyl, i-butyl, CH2CH=CH(CH3)2, pyridylmethyl, methallyl, n-pentyl, i-pentyl, hexyl, benzyl, pyridylmethyl, isoprenyl, propargyl, picolinyl, methoxyethyl, cyclohexylmethyl, dimethyl-butyl, ethoxyethyl, methyl-oxazolinylmethyl, naphthylmethyl, methyloxazolinylmethyl, vinyloxyethyl, pentafluorobenzyl, quinolinylmethyl, carboxybenzyl, chloro-thienyl, picolinyl, benzyloxybenzyl, phenylbenzyl, adamantylethyl, cyclopropylmethoxybenzyl, ethoxybenzyl, hydroxybenzyl, hydroxymethylbenzyl, aminobenzyl, formylbenzyl, cyanobenzyl,

cinnamyl, allyloxybenzyl, fluorobenzyl, cyclobutylmethyl, formaldoximebenzyl, cyclopentylmethyl, nitrobenzyl, nitrilobenzyl, carboxamidobenzyl, carbomethoxybenzyl, tetrazolylbenzyl and dimethylallyl.

7. A compound of Claim 1 of formula (II): EMI101.1 or a pharmaceutically acceptable salt or prodrug form thereof, wherein: X is S,O or N-R7; R4 and R7 are independently selected from the following groups: hydrogen; C1-C4 alkyl substituted with 0-3 R1l; C3-C4 alkenyl substituted with 0-3 R1l; C3-C4 alkynyl substituted with 0-3 R1l; R11 is selected from one or more of the following: keto, halogen, cyano, -CH2NR13R14, -NR13R14, -C02R13, -OC(=O)R13, -OR13, C2-C4 alkoxyalkyl, -S(O)mR13 C1-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl; a Cg-C14 carbocyclic residue substituted with 0-3 R12; aryl substituted with 0-3 R12;

or a heterocyclic ring system substituted with 0-2 R12 composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom; R12, when a substituent on carbon, is selected from one or more of the following: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, C7-C10 arylalkyl, C1-C4 alkoxy, -C02H, hydroxamic acid, hydrazide, oxime, boronic acid, sulfonamide, formyl, C3-C6 cycloalkoxy, -OR13, C1-C4 alkyl substituted with -NR13R14, -NR13R14, C2-C6 alkoxyalkyl, Cl-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, Cl-C4 alkylcarbonyl,

C1-C4 alkylcarbonylamino, -S(O)mR13 -502NR13R14, -NHSo2R14; or a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur; or R12 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 the aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or -NR13R14;

or, when R12 is attached to a saturated carbon atom, it may be carbonyl or thiocarbonyl; R12, when a substituent on nitrogen, is selected from one or more of the following: phenyl, benzyl, phenethyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR13R14, -NR13R14, C2-C6 alkoxyalkyl, C1-C4 haloalkyl, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, -C02H; R13 is H, C1-C6 alkyl, or C3-C6 alkoxyalkyl; R14 is OH, H, C1-C4 alkyl, or benzyl; R13 and R14 can alternatively join to form -(CH2)4-, - (CH2) 5-, -CH2CH2N(R15)CH2CH2- or -CH2CH20CH2CH2-; R15 is H or CH3;

m is 0, 1 or 2; R22 is selected from the following: hydrogen; C1-C8 alkyl substituted with 0-3 R31; C3-Cg alkenyl substituted with 0-3 R31; C3-Cg alkynyl substituted with 0-3 R31; C3-C6 cycloalkyl substituted with 0-3 R31; R27 is selected from the following: hydrogen; C1-Cg alkyl substituted with 0-3 R31; C2-Cg alkenyl substituted with 0-3 R31; C3-Cg alkynyl substituted with 0-3 R31; R31 is selected from one or more of the following:

or a heterocyclic ring system substituted with 0-2 R32, composed of 5 to 10 atoms including 1-4 nitrogen, oxygen or sulfur atom; R32, when a substituent on carbon, is selected from one or more of the following: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, C7-C10 arylalkyl, C1-C4 alkoxy, -C02H, hydroxamic acid, hydrazide, oxime, boronic acid, sulfonamide, formyl, C3-C6 cycloalkoxy, -OR13, C1-C4 alkyl substituted with -NR13R14, -NR13R14, C2-C6 alkoxyalkyl, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino,

-S(O)mRÚ , -S02NR13R14, -NHSO2R14, -C (R14).=N (OR14); or a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur; or R32 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 the aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or -NR13R14;

or, when R32 is attached to a saturated carbon atom, it may be carbonyl or thiocarbonyl; R32, when a substituent on nitrogen, is selected from one or more of the following: phenyl, benzyl, phenethyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR13R14, -NR13R14, C2-C6 alkoxyalkyl, C1-C4 haloalkyl, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, -C02H, -C (R14)=N (OR14); provided that: when R4 and R4A are hydrogen and X is N-R7, at least one of the following is not hydrogen: R7, R22, R27 or R28; when R4 and R4A are hydrogen and X is S or 0, at least two of the following is not hydrogen: R22, R27 or R28 8.

A compound of Claim 1 of formula (II):

EMI106.1 or a pharmaceutically acceptable salt or prodrug form thereof: wherein R4 and R7 are independently selected from the following groups: hydrogen; C1-C3 alkyl substituted with 0-1 R1l; R11 is selected from one or more of the following: halogen, -OR13, C1-C4 alkyl, C3-Cs cycloalkyl; aryl substituted with 0-2 R12; or a heterocyclic ring system chosen from pyridyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, quinolinyl, isoquinolinyl;

said heterocyclic ring system being substituted with 0-2 R32; R12 when a substituent on carbon, is selected from one or more of the following: benzyloxy, halogen, methyl, C1-C4 alkoxy, CF3, 2- (1-morpholino) ethoxy, -C02H, hydroxamic acid, hydrazide, oxime, cyano, boronic acid, sulfonamide, formyl, C3-C6 cycloalkoxy, C1-C4 alkyl substituted with -NR13R14, -NR13R14, hydroxy, hydroxymethyl;

or R12, when a substituent on nitrogen, is methyl; R13 is H or methyl; R14 is OH, H or methyl; R13 and R14 can alternatively join to form -(CH2)4-, -(CH2)5-, -CH2CH2N(Rl5)CH2CH2- or -CH2CH2oCH2CH2-; R22 is selected from the following: hydrogen; C1-C4 alkyl substituted with 0-1 R31; C3-C4 alkenyl substituted with 0-1 R31; R31 is selected from one or more of the following: halogen, -OR13, C1-C4 alkyl, C3-Cs cycloalkyl; aryl substituted with 0-2 R32; or a heterocyclic ring system chosen from pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl;

said heterocyclic ring system being substituted with 0-2 R32; R32, when a substituent on carbon, is selected from one or more of the following: benzyloxy, halogen, methyl, C1-C4 alkoxy, CF3, 2- (1-morpholino) ethoxy, -C02H, hydroxamic acid, hydrazide, oxime, cyano, boronic acid, sulfonamide, formyl, C3-C6 cycloalkoxy, C1-C4 alkyl substituted with -NR13R14, -NR13R14, hydroxy, hydroxymethyl, -C (R14)=N (OR14); or R32, when a substituent on nitrogen, is methyl; provided that: when R4 and R4A is hydrogen, at least one of the following is not hydrogen: R7, R22 and R23.

9. A compound of Claim 1 of formula (IIa), or a pharmaceutically acceptable salt or prodrug form thereof, wherein:: R4 and R27 are benzyl; R13 is H or methyl; R14 is H or methyl; R22 is selected from the following: hydrogen; C1-C2 alkyl substituted with 0-1 R31; R31 is selected from one or more of the following: C3-Cs cycloalkyl substituted with 0-1 R32; aryl substituted with 0-2 R32; or a heterocyclic ring system chosen from pyridyl, thienyl, quinolinyl, or isoquinolinyl;

said heterocyclic ring system being substituted with 0-2 R'32; R32, when a substituent on carbon, is selected from one or more of the following: CONH2, CO2H, CHO, CH2NHOH,, -CH2NR13R14, -NR13R14 hydroxy, hydroxymethyl, -C (R14)=N (OR14); or R32, when a substituent on nitrogen, is methyl.

10. A compound of Claim 1 of formula (IIa): EMI109.1 or a pharmaceutically acceptable salt or prodrug form thereof, which is selected from the group consisting of: the compound of the formula (IIa) wherein R22 is hydrogen and R7 is hydrogen; the compound of the formula (IIa) wherein R22 is hydrogen and R7 is benzyl; the compound of the formula (IIa) wherein R22 is cyclopropylmethyl and R7 is hydrogen.

11. A method for the treatment of viral infections which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of Claim 1.

12. A method for the treatment of viral infections which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of Claim 2.

13. A method for the treatment of viral infections which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of Claim 3.

14. A method for the treatment of viral infections which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of Claim 4.

15. A method for the treatment of viral infections which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of Claim 5.

16. A method for the treatment of viral infections which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of Claim 6.

17. A method for the treatment of viral infections which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of Claim 7.

18. A method for the treatment of viral infections which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of Claim 8.

19. A method for the treatment of viral infections which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of Claim 9.

21. A method for the treatment of viral infections which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of Claim 10.

22. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Claim 1.

23. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Claim 2.

24. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Claim 3.

25. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Claim 4.

26. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Claim 5.

27. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Claim 6.

28. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Claim 7.

29. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Claim 8.

30. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Claim 9.

31. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Claim 10.