PEPTIDE ISOTERS CONTAINING A HETEROCYCLE AS H.I.V. Inhibitors

FIELD OF THE INVENTION

This invention relates to inhibitors of proteases encoded in retroviruses, in particular, to inhibitors of the virally encoded protease of the Human Immunodeficiency Virus.

BACKGROUND

Retroviruses, that is, viruses within the family of Retroviridae, are a class of viruses which transport their genetic material as ribonucleic acid rather than deoxyribonucleic acid. Also known as RNA-tumor viruses, their presence has been associated with a wide range of diseases in humans and animals. They are believed to be the causative agents in pathological states associated with infection by Rous sarcoma virus (RSV) , murine leukemia virus ( LV) , mouse mammary tumor virus (MMTV) , feline leukemia virus (FeLV) , bovine leukemia virus (BLV) , Mason-Pfizer monkey virus (MPMV) , simian sarcoma virus (SSV) , simian acquired immunodeficiency syndrome (SAIDS) , human T-

lymphotropic virus (HTLV-I, -II) and human immunodeficiency virus (HIV-1, HIV-2) , which is the etiologic agent of AIDS (acquired immunodeficiency syndrome) and AIDS related complexes, and many others. Although the pathogens have, in many of these cases, been isolated, no effective method for treating this type of infection has been developed.

Current treatments for viral diseases generally involve administration of compounds which inhibit reverse transcriptase, such as 3'-azido-3'-deoxythymidine and 2',3'- dideoxycytidine. These treatments have not proven effective to arrest or reverse the disease, they may have adverse side effects _r and they may lose their efficacy over time. Accordingly, new treatments for viral disease are needed. Virally-encoded proteases function in many of these viruses to hydrolyze viral polyprotein precursors and to yield functional viral proteins. The proteolytic activity provided by the virally-encoded protease in processing the polyproteins cannot be provided by the host and is essential to the life cycle of the retrovirus. It has" been demonstrated that retroviruses which lack a protease or contain a mutated form of it, lack infectivity. See Katoh et al . , Virology, 145, 280-92(1985), Crawford et al., J. Virol . , 53, 899-907(1985) and Debouck et al . , Proc. Natl . Acad. Sci . USA, 84, 8903-6(1987). Inhibiton of retroviral protease, therefore, presents a method of therapy for retroviral disease.

Methods to express retroviral proteases in E. coli have been disclosed by Debouck et al . , Proc. Natl . Acad. Sci . USA, 8903-06(1987) and Graves et al. , Proc. Natl. Acad. Sci. USA, 85, 2449-53(1988) for the HIV-1 virus. The crystal structure of an HIV-1 protease has been disclosed by Miller et al . , Science, 246, 1149 (1989) .

The method of 'dipeptide' isosteric replacement has been disclosed as a strategy for the development of protease inhibitors for HIV-1. Published European Patent applications EP-A 337 714, EP-A 352 000 and EP-A 357 332, EP-A 346 847, EP-A 342 541 and EP-A 393 445 are representative. DeSolms et al., J. Med. Chem. , 34, 2852 (1991) disclose compounds which

employ such isosteres. Similar strategies have also been reported for inhibition of renin in U.S. Patents 4,713,445 and 4,§61,473. Other inhibitors of the HIV protease, which contain a symmetrical isostere are reported in EP-A 402 646. There remains a need for protease-inhibiting compounds which have a favorable balance of potency and pharmacokinetic properties.

SΠMMΆ Y OF THE INVENTION

This invention comprises compounds, hereinafter, of the formula (I) , which inhibit the retroviral protease of HIV-1, and are useful for treating infection by the human immunodeficiency virus and Acquired Immunodeficiency Syndrome (AIDS) .

This invention is also a pharmaceutical composition, which comprises a compound of formula (I) and a pharmaceutically acceptable carrier.

This invention further constitutes a method for treating retroviral disease, which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) .

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention are given by formula (I) :

(I) wherein

R ¹ is A-(B) _t ;

A is R ⁶ , R ⁶ C(=E), R ⁶ OC(=E), R ⁶ NR'C(=E), R ⁶ SC(=E), R ¹⁷ NR'C(=NR ^I ) , R ⁶ OCH(R )CO, R ⁶ NHCH (R ⁷ ) CO, R ⁶ SCH(R ⁷ )CO, R ⁶ S0 ₂ , or R ⁶ SO;

B is an amino acid, SCH(R ⁷ )CO or OCH(R ⁷ )CO;

E is 0 or S ;

R ² and R ³ are independently H, Ci-βalkyl, C ₂ - ₆ alkenyl, C ₃ - ₇ cycloalkyl, Ar, Het, T-Ci-εalkyl, T-C ₂ - ₆ alkenyl or T-C ₂ - ₆ alkynyl, optionally substituted by R ¹⁰ ; T is Ar, Het or C ₃ _7cycloalkyl;

R ⁵ , R ⁶ and R ⁷ are independently H, Ci-βalkyl, C3-iicycloalkyl, Ar, Het, T-Cι_ ₆ alkyl, T-(CH ₂ ) _n CH(T) (CH ₂ ) _n . optionally substituted by one or two halogen, SR ¹ , OR ¹ , NR' ₂ , C(=NR*)NR ^, R ¹⁷ , NR'C(=NR ^, )NR ^, R ¹⁷ ,or Cι_ ₄ alkyl; Q is OH or NH ₂ ; ϋ ^« and ϋ" are H or OH;

V is N or C-Y'; is NR ¹¹ or S;

Y and Y ¹ are H, halogen, CF ₃ , Ar, NO ₂ , Cι_ ₆ alkyl, CO-Z or (CR ⁸ R ⁹ ) _n -R', or together Y and Y' form a five or six-membered alkyl, aryl or heterocyclic ring substituted at any stable position by R ⁸ or R ⁹ ;

Z is H _r Ci-ςalkyl, OH, NR'R ⁵ , OR ⁵ or an amino acid with a blocked or unblocked carboxy terminus; R ⁸ is independently H, OH, NR'R ¹⁷ , NR'C(=NR')NR'R ¹⁷ ,

NR'-NR ^r ₂ , Cι_ ₄ alkyl, (CH ₂ ) _p Ar or (CH ₂ ) _q Het;

R ⁹ is independently H, Cι-4alkyl, C2-6alkenyl, CO-Z,

(CH2) pAr or (CH2) qHet, or, taken together, R ⁸ and R ⁹ are =0,

=N-0R ' or =N-NR' 2; R' is H, Cι-4alkyl, Ar-Cι_ ₄ alkyl;

_R ¹ 0 _is -χ' - (CH ₂ ) _q NR ¹² R ¹³ , X" [ ( (CH ₂ ) _r O) _s ] R ¹⁴ _A

CH ₂ X"[ ((CH ₂ ) _r O) _s ]R ¹⁴ r or benzofuryl, indolyl, azacycloalkyl, azabicycloC ₇ _ncycloalkyl or benzopiperidinyl, optionally substituted with Cι- ₄ alkyl; R ¹¹ is H, Cχ_ ₄ alkyl, Ar-Cι- ₄ alkyl, or together with Y forms a five or six-membered cycloalkyl, aryl or heterocyclic ring substituted at any stable position by R ⁸ or R ⁹ ;

R ¹² and R ¹³ are i) Ci-εalkyl, optionally substituted by

OH, Cι_ ₃ alkoxy, or N(R') ₂ , ii) the same or different and joined together to form a 5-7 member heterocycle containing up to two additional heteroatoms selected from NR", 0, S, SO,

SO ₂ , said heterocycle optionally substituted with Cι_ ₄ alkyl,

iii) aromatic heterocycle, optionally substituted with Cι_ ₄ alkyl or N(R")2;

R" is H or Cι_ ₄ alkyl;

R ¹⁴ is H, Cι- ₄ alkyl, C(=0)R ¹⁵ , C(=0)U'"[ (CH ₂ ) _m O]nR' , P (=0) (0M) ₂ , CO2R ¹⁵ , C(=0)NR ¹⁵ R ¹⁶ , where M is a mono or divalent metal ion, and U'" is NR' or O;

R ¹⁵ is Ci-galkyl or Ar, optionally substituted with one or more hydroxy, carboxy, halo, Cι_3alkoxy, CONR'2, NR'2. CO2R', Sθ2NR' ₂ , CH2NR2, NR'COR', NR'S02R', X" [ (CH2) _r O] _S R' or

R ¹⁶ is H, Ci-βalkyl or together with. R ¹⁵ forms a 5-7 membered heterocycle or a 6 membered heterocycle containing a heteroatom selected from N, 0 and S;

R ¹⁷ is R ⁶ , R ⁶ C0 or R ⁶ S0 ₂ ; X' is CH ₂ , 0, S or NH;

X" is CH2, NR', 0, S, SO or SO2; m is 2-5; n is 1 to 6; p and q are 0 to 2; s is 1-6 and r is 1-3 within each repeating unit s; and t is 0 or 1; or a pharmaceutically acceptable salts thereof.

Suitably is S. Preferably W is N and V is C-Y.

Suitably R ¹ is R ⁶ CO, R ⁶ OCO or R ⁶ Sθ2, or Ala, Val or Thr substituted on the amino group by R ⁶ CO, R ⁶ OCO or R ⁶ Sθ ₂ .

Suitably Y is H, Cι_6alkyl, CO- (CHR ⁸ ) (n-i)-R' _. CO-Z, (CHR ⁹ ) _n -OH, C(=N0H) -Cι_ ₆ alkyl or CHOH(CHR ⁸ ) (n- _l )-R' •

Preferably A is butyloxycarbonyl, carbobenzyloxy, pyridinylmethyloxycarbonyl. Suitably R ² is CH ₂ -T.

Suitably R ³ is Cι_ ₄ alkyl or CH2-T.

Suitably Z is H, NH2 or Ph.

Suitably R ⁹ is H, Cι- ₄ alkyl or Ph.

Preferably R ² and R ³ are benzyl. Preferably U and U' are H and Q is OH.

Representative compounds of this invention are:

2- [ (IR,3S, 4S)-l-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5-butyl-thiazole;

2-[(3S,4S)-l-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-thiazole;

2-[(3S,4S)-l-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]—5-ethyl-thiazole; 2-[(3S,4S)-l-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5-propyl-thiazole;

2-[(3S, S)-l-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-1,3,5-triazole;

2-[(IR,3S,4S)-l-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy ~5- phenylpenty1]-4(5)-acetylimidazole;

2-[(IR,3S,4S)-l-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy -5- phenylpentyl]-4(5)-(1-hydroxyethyl)-imidazole;

2-[(IR,3S,4S)-l-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy -5- phenylpentyl]- (5)-formylimidazole; 2-[(IR,3S,4S)-l-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-4(5)-propionylimidazole;

2-[(IR,3S,4S)-l-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy -5- phenylpentyl]—4(5)-(2-methylpropionyl)-imidazole; 2-[(IR,3S,4S)-l-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phen lpentyl]-4(5)-(l-hydroxy-2-methylpropyl)imidazole;

2-[(1R,3S,4S)-l-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy -5- phenylpentyl]-4(5)-(1-oxobutyl)imidazole;

2-[(1R,3S,4S)-l-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy -5- phenylpentyl]-4(5)-(2-methyl-l-oxobutyl) imidazole; 2-[(IR,3S,4S)-l-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phen lpentyl]-4(5)-carbomethoxyimidazole;

2-[(IR,3S,4S)-l-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy -5- phen lpentyl]-4(5)-(N-methylaminocarbonyl)-imidazole; 2-[(IR,3S,4S)-l-benzyl-4-[N-(benzyloxycarbonyl)-L- valyl]amino-3-hydroxy-5-phen lpentyl]—4(5)-(2- methylpropionyl)imidazole;

2-{ (IR,3S,4S)-l-benzyl-3-hydroxy-4-[N-( '- isopropoxycarbonyl)-L-valyl]amino-5-phenylpentyl}- (5)-(2- methylpropionyl)imidazole; 2-{(IR,3S,4S)-l-benzyl-3-hydroxy-4-[N-(N'-(l-oxo-3- phenylpropyl))-L-valyl]amino-5-phenylpentyl}-4(5)-(2- methylpropionyl)imidazole;

2- { (IR, 3S, 4S) -l-benzyl-3-hydroxy-4- [N- (3-methyl-l- oxobutyl) ]amino-5-phenylpentyl}-4 (5)- (2-methyl- propionyl) imidazole;

2-{ (lR,3S,4S)-l-benzyl-3-hydroxy-4-[N-(N'-acetyl)-L- valyl]amino-5-phenylpentyl}-4 (5)- (2-methyl- propionyl) imidazole;

2-{ (IR,3S, 4S)-l-benzyl-3-hydroxy-4- [N- (N'-acetyl)-D- valyl]amino-5-phenylpentyl}-4 (5)- (2- methylpropionyl) imidazole; 2-{ (IR,3S, 4S)-l-benzyl-3-hydroxy-4- [N- ( '-benzyloxycarbonyl)-

L-threonyl]amino-5-phenylpentyl}-4 (5)- (2- methylpropionyl) imidazole;

2-{ (lR,3S,3'S,4S)-l-benzyl-3-hydroxy-4-{l'-[5'-hydroxy-3'-(l- methylethyl)-2'-oxo-l'pyrrolidinyl] }-5-phenylpentyl}-4 (5)- (2- methylpropionyl) imidazole;

2-{ (lR,3S,3'R,4S)-l-benzyl-3-hydroxy-4-{l'-[5'-hydroxy-3'-(l- methylethyl) -2' -oxo-l'pyrrolidinyl] }-5-phenylpentyl }-4 (5) - (2- methylpropionyl) imidazole;

2- [ (IR, 3S, 4S) -l-benzyl-4-benzenesulf onylamino-3-hydroxy-5- phen lpentyl] -4 (5 ) - (2-methylpropionyl) imidazole;

2- { (lR, 3S, 4S) -l-benzyl-3-hydroxy-4- [N- (N ' -methanesulfonyl) -L- valyl]amino-5-phenylpentyl}-4 (5)- (2- ethylpropionyl) imidazole;

2-{ (lR,3S,4S)-l-benzyl-4-[N-(N'-tert-butoxycarbonyl)-L- valyl]amino-3-hydroxy-5-phenylpentyl}-4 (5)-(2- methylpropionyl) imidazole;

2-[ (IR,3S, 4S)-l-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-4 (5)- (2,2-dimethyl-3-butenoyl) imidazole;

2- [ (IR,3S,4S)-l-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-4 (5)- (2,2-dimethylbutanoyl)-imidazole;

3- [ (IR,3S, S)-l-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-6, 6-dimethyl-5-hydroxy-pyrrolo- [1,2-c]- imidazol-7-one;

2-[ (IR,3S,4S)-l-benzyl-4-tert-butoxycarbonyl-amino-3-hydroxy- 5-phenylpent l]- (5)- (cyclopentylcarbony1)-imidazole;

2-[ (IR,3S, S)-l-benzyl-4-tert-butoxycarbonyl-amino-3-hydroxy-

5-phenylpentyl]-4 (5)-benzoylimidazole;

2-[(IR,3S,4S)-l-benzyl-4-tert-butoxycarbonyl-amino-3-hydroxy - 5-phenylpentyl]-4(5)-(2-ethylbutanoyl)-imidazole; 2-[(IR,3S,4S)-l-benzyl-4-tert-butoxycarbonyl-amino-3-hydroxy - 5-phenylpentyl]-4(5)-(E)-1-(hydroxyimino)-2- ethylpropyl)]imidazole;

2-[(3S,4S)-l-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5-benzoyl-thiazole;

2-[(3S,4S)-l-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5-(α-hydroxybenzyl)-thiazole; 2-[(3S,4S)-l-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5-aminocarbonyl-thiazole;

2-[(3S,4S)-l-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5-hydroxymethyl-thiazole;

2-[(3S,4S)-l-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phen lpentyl]-5-formyl-thiazole;

2-[(3S,4S)-l-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5-(1-hydroxypropyl)-thiazole;

2-[(3S,4S)-l-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5-propyl-thiazole; 2-[(3S,4S)-l-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyll-5-(3-hydroxypropyl)-thiazole;

2-[(3S, S)-l-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phen lpentyl]-5-(1,2-dihydrox ethyl)-thiazole;

2-[(3S,4S)-l-benzyl-4-(benzyloxycarbonyl-alanyl)amino-3- hydroxy-5-phenylpentyl]-5-propyl-thiazole;

2-[(3S,4S)-l-benzyl-4-(benzyloxycarbonyl-valyl)amino-3- hydroxy-5-phenylpentyl]-5-propyl-thiazole;

2-[(3S,4S)-l-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5-propionyl-thiazole; 2-[(3S,4S)-l-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phen lpentyl]-5-carboxy-thiazole;

2-[(3S, S)-l-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phen lpentyl]-5-(2-methyl-l-hydroxy-propyl)-thiazole;

2-[(3S,4S)-l-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5-(N ¹ -benzyloxycarbonyl-guanidino)carbonyl- thiazole;

2-[(3S,4S)-l-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phen lpentyl]-5-(1-methox carbonyl)propyl-thiazole;

2- [ (3S, 4S)-l-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5- (1-methoxy)propyl-thiazole; and

2- [ (3S,4S)-l-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5- (1-aminocarbonyl)propyl-thiazole. Preferred compounds are:

2- [ (3S, 4S)-l-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5-propyl-thiazole;

2-[ (IR,3S,4S)-l-benzyl-4-tert-butoxycarbonyl-amino-3-hydroxy-

5-phenylpentyl]- (5)- (cyclopentylcarbonyl)-imidazole; 2- [ (1R,3S, 4S)-l-benzyl-4-tert-butoxycarbonyl-amino-3-hydroxy-

5-phenylpentyl]-4 (5)- (E)-l- (hydroxyimino).-2- methylpropyl) ]imidazole;

2- [ (1R,3S, 4S)-l-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]- (5)- (2,2-dimethylbutanoyl)-imidazole; 2- [ (IR,3S,4S)-l-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-4 (5)-(2,2-dimethyl-3-butenoyl) imidazole;

2-{ (IR,3S,4S)-l-benzyl-3-hydroxy-4- [N-( '-acetyl)-D- valyl]amino-5-phenylpentyl}-4 (5)- (2-methylpropionyl)- imidazole; 2-{ (lR,3S,4S)-l-benzyl-3-hydroxy-4-[N-(3-methyl-l- oxobutyl) ]amino-5-phenylpentyl}-4 (5)- (2-methyl- propionyl) imidazole;

2-[ (IR,3S, 4S)-l-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-4(5)- (2-methylpropionyl)-imidazole; 2- [ (IR,3S, 4S)-l-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-4 (5)-(1-oxobutyl) imidazole;

2- [ (IR,3S,4S)-l-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpenty1]-4(5)-propionylimidazole;

2- [ (IR,3S, 4S)-l-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-4 (5)-acetylimidazole; and

2- [ (3S, 4S)-l-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5-propyl-thiazole.

More preferred compounds are:

2- [ (3S,4S)-l-benzyl-4- (benzyloxycarbonyl-valyl)amino-3- hydroxy-5-phenylpentyl]-5-propyl-thiazole;

2-{ (IR,3S, 4S)-l-benzyl-3-hydroxy-4-[N- (N'-methanesulfonyl)-L- valyl]amino-5-phenylpentyl}-4 (5)- (2-methylpropionyl)- imidazole;

2-[ (IR,3S,4S)-l-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-4(5)-(2-ethylbutanoyl)-imidazole; and 2-[ (1R,3S, S)-l-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-4(5)-(2-methyl-l-oxobutyl) imidazole. The most preferred compounds are:

2-[ (1R,3S,4S)-l-benzyl-4-[N-(benzyloxycarbonyl)-L- valyl]amino-3-hydroxy-5-phenylpentyl]-4(5)-(2- methylpropionyl)imidazole;

2-{ (1R,3S,4S)-l-benzyl-3-hydroxy-4-[N- (N'- isopropoxycarbonyl)-L-valyl]amino-5-phenylpentyl}-4 (5)-(2- methylpropionyl) imidazole;

2-{ (1R,3S,4S)-l-benzyl-3-hydroxy-4-[N-(N ¹ -(l-oxo-3- phenylpropyl) )-L-valyl]amino-5-phenylpentyl}-4 (5)-(2- methylpropionyl) imidazole; 2-{ (1R,3S,4S)-l-benzyl-3-hydroxy-4-[N- (N'-acetyl)-L- valyl]amino—5-phenylpentyl}-4(5)-(2-methyl- propionyl) imidazole; and

2-{ (IR,3S,4S)-l-benzyl-3-hydroxy-4-[N-( '-benzyloxycarbonyl)- L-threonyl]amino-5-phenylpentyl}-4(5)-(2- methylpropionyl)imidazole.

According to this invention, it has been found that a substituted imidazole, 1,3,5-triazole and 1,3-thiazole constitute suitable moieties for replacement of the amide moiety for the amino acid in the PI' position in a non- hydrolyzable mimetic of a peptide substrate for the HIV-1 ' protease enzyme. The compounds of this invention have favorable pharmacokinetic properties, and are useful, in particular, for the treatment of infections by the human immunode iciency virus. Also included in this invention are pharmaceutically acceptable addition salts, complexes or prodrugs of the compounds of this invention. Prodrugs are considered to be any covalently bonded carriers which release the active parent drug according to formula (I) in vivo . The definition of any substituent moiety which may occur more than once in formula (I) is independent of any other occurrence. Formula (I) is intended to encompass all unique

nonracemic stereoisomers which may occur due to the presence of asymmetric carbon atoms in the molecule.

Cι- ₄ alkyl as applied herein is meant to include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl. Cχ-6alkyl additionally includes pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof. C2-6 alkenyl as applied herein means an alkyl group of 2 to 6 carbons wherein a carbon-carbon single bond is replaced by a carbon-carbon double bond. C ₂ -6^1kenyl includes ethylene, 1-propene, 2-propene, 1-butene, 2-butene, isobutene and the several isomeric pentenes and hexenes. Both cis and trans isomers are included.

C2-6 alkynyl means an alkyl group of 2 to 6 carbons wherein one carbon-carbon single bond is replaced by a carbon-carbon triple bond. C ₂ -6 alkynyl includes acetylene, 1-propyne, 2-propyne, 1-butyne, 2-butyne, 3-butyne and the simple isomers of pentyne and hexyne.

A substituent on a Cι-6alkyl, C ₂ -6alkenyl orC2-6 alkynyl, such as R ⁸ , R ⁹ or R ¹⁰ , may be on any carbon atom which results in a stable structure, and is available by conventional synthetic techniques.

Halogen indicates a fluorine, chlorine, bromine and iodine atom.

M indicates a mono- or divalent alkaline or earth metal ion, such as potassium, sodium, lithium, calcium or magnesium.

T-Cχ-6 alkyl refers to a Cι_6 alkyl group wherein in any position a carbon-hydrogen bond is replaced by a carbon-T bond. T-C2-6 alkenyl and T-C2-6alkynyl have a similar meaning with respect to C2-6alkenyl and C2-6 ^a l ^k y ⁿ yl« ^c 3-7cycloalkyl refers to an optionally substituted carbocyclic system of three to seven carbon atoms, which may contain up to two unsaturated carbon-carbon bonds. Typical of C3- ₇ cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl and cycloheptyl. Any combination of up to three substituents on the cycloalkyl ring that is available by conventional chemical synthesis and is stable, is within the scope of this invention.

C ₃ -ncycloalkyl indicates a stable mono- or bi-cyclic ring of 3 to 11 carbon atoms, which may be saturated or unsaturated, and may be substituted with one to three Cι- ₄ alkyl, Cι- ₄ alkoxy, Cι_ ₄ alkthio, trifluoroalkyl, guanidino, amidino, OH, NR' ₂ , Cl, Br or I groups. C ₃ _ncycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, cyclooctyl, tetralinyl, indanyl, phenyl and naphthyl. Azacycloalkyl indicates a C ₃ - ₇ cycloalkyl group wherein a carbon atom is replaced by a nitrogen atom, such as aziridine, azetidine, pyrrolidine, piperidine or tetrahydroazepine. Azabicyclo-C ₇ _ncycloalkyl indicates a C ₇ -ncycloalkyl group wherein one of the carbon atoms is replaced by a nitrogen atom.

Ar, or aryl, as applied herein, means phenyl or naphthyl, or phenyl or naphthyl substituted by one to three Cι_ ₄ alkyl, Cι- ₄ alkoxy, Cι- ₄ alkthio, trifluoroalkyl, guanidino, amidino, HetCι- ₄ alkoxy, HetCι- ₄ alkyl, OH, Cl, Br or I.

Het, or heteroaryl, indicates a five or six membered aromatic ring, or a nine or ten- embered aromatic ring, containing one to three heteroatoms chosen from the group of nitrogen, oxygen and sulfur, which are stable and available by conventional chemical synthesis. Illustrative heterocycles are morpholine, tetrazole, imidazole, benzimidazole, pyrrole, pyrazinyl, pyrazolyl, pyrazolidinyl,pyrazolinyl, indole, pyridine, pyrimidine, pyrimidone, quinoline, benzofuran, furan, benzothiophene or thiophene. The Het ring may optionally be substituted on the carbon or heteroatom by one to three Cι- ₄ alkyl, Cι- ₄ alkenyl, hydroxyCι- ₄ alkyl group, carboxyl, aminocarbonyl, alkoxycarbonyl, carboxyCχ- ₆ alkyl, aminocarbonylCi-βalkyl, alkoxycarbonylCi-galkyl, or a phenylCi-βalkyl group substituted by one to three Cι_ ₄ alkyl, Cι_ ₄ alkoxy, Cι- ₄ alkthio, trifluoroalkyl, OH, Cl, Br or I groups.

Any accessible combination of up to three substituents on the phenyl, naphthyl or Het ring which is available by chemical synthesis and is stable is within the scope of this invention. Ar-Cι_galkyl and Ar-C2-6alkenyl mean Cχ_galkyl or C2-galkenyl wherein a carbon-hydrogen bond is replaced by a

carbon-Ar bond. Het-Cι_galkyl and Het-C2-6 ^a lkenyl mean Ci-galkyl or C2-galkenyl wherein a carbon-hydrogen bond is replaced by a carbon-Het bond.

Boc refers to the t-butyloxycarbonyl radical, Cbz refers to the benzyloxycarbonyl radical, Bzl refers to the benzyl radical, Ac refers to acetyl, Ph refers to phenyl, tbs refers to t-butyldimethylsilyl, EDTA is ethylenediamine tetraacetic acid, BOP refers to benzotriazol-1-yloxy- tris(dimethylamino)phosphonium hexafluorophosphate, DIEA is diisopropyl ethylamine, DBU is 1,8 diazobicyclo[5.4.Ojundec- 7-ene, DMSO is dimethylsulfoxide, DMF is -dimethyl formamide, MeOH is methanol, pyr is pyridine, DMAP is 4-dimethylamino pyridine, Lawesson's reagent is 2,4-bis (4-methoxyphenyl)-1,3- dithia-2,4-diphosphetane-2,4-disulfide and THF is tetrahydrofuran.

Amino acid means the D- or L- isomer of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, gluta ic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine or valine. Typically, lipophilic amino acids are preferred. In general, the amino acid abbreviations follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature as described in Eur. J. Biochem., 158, 9 (1984) . When Y or R ⁹ are CO-Z and Z is an amino acid, the amino acid is joined by an amide bond via its amino terminus to the carbonyl group, and the carboxy terminus of the amino acid is blocked or unblocked. An unblocked carboxy terminus is a free carboxyl group. Typical blocking groups are esters and amides, such as NR'R ⁵ or OR ⁵ , wherein R ⁵ is as defined in formula (I) .

When t is 1 and B is an amino acid, the amino acid is joined via its carboxy terminus to the amino group of the isostere, and the amino terminus is substituted by A. When R ⁸ is NR'R ¹⁸ and R ¹⁸ is an amino acid, the amino acid is joined to the nitrogen atom via its carbonyl group, and the amino terminus of the amino acid may be blocked or unblocked. Valine, threonine and alanine are useful amino acids. Cbz-

Val, and 2-quinolinylcarbonyl-Val are illustrative blocked amino acids . An unblocked amino terminus is an unsubstituted amino group. Typical blocking groups for the amino terminus are R ⁶ , R ⁶ C0, R ⁶ 0C0, R ⁶ OCH(R ⁷ )CO, R ⁶ NHCH(R ⁷ )CO, R ⁶ SCH(R ⁷ )CO, R ⁶ Sθ2 or R ⁶ SO, wherein R ⁶ and R ⁷ are as defined in formula (I) . Acetyl, Boc, Cbz, pyridinylmethyloxycarbonyl and 3- quinolinyl ethyloxycarbonyl are illustrative of the A substituent and blocking groups for the amino terminus- The compounds of this invention are prepared by conventional methods of organic chemistry.

The compounds of this invention of the formula (I) :

(I) wherein R ¹ , R ² , R ³ , R ¹¹ , R', Q, ϋ', U", V, W and Y are as defined for formula (I) , may be prepared by deprotecting a compound of the formula:

(III) wherein Q* is a protected amino or hydroxyl group, and U* are independently H or a protected hydroxyl group. Suitable protecting groups for the amino and hydroxyl group, and reagents for deprotecting these functional groups are disclosed in Greene et al . , PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, Second Edition, John Wiley and Sons, New York, 1991. Deprotection indicates the removal of the protecting group and replacement with an hydrogen atom. In particular, suitably substituted acetyl and silyl groups are useful for protecting the hydroxyl group. The acetyl group is commonly removed by reacting the compound with a base, such as an alkali metal hydroxide, in a mixture of an alcohol and water. The silyl group, such as trimethyl silyl, dimethyl-t-butyl silyl, and t-butyl-diphenyl silyl may be removed by a

fluoride reagent, such as a tetra-alkyl ammonium fluoride, or by acid hydrolyis .

Compounds of formula (III) , wherein W is S and V is CH are thiazoles and may be prepared according to Scheme 1 by reacting a thioamide of the formula (IV) , wherein

Scheme 1

(IV) (III)

R ¹ is an amino-protecting group or R ¹ , with a compound of the formula R-CH(X)-CH0, wherein X is a suitable displaceable group and R is Y or a group which may be converted by common synthetic methods into Y. Suitable displaceable groups are those which are displaced by a sulfur nucleophile, such as chloride, bromide, iodide, mesylate, p-tolunesufonate, and the like. Introduction of substituents at the 4 position of the thiazole may be accomplished by conducting the reaction with a ketone of the formula X-CH ₂ ~C(0)R. Oxazoles, wherein W is 0 and V is CY', are prepared in an analogous manner, by reacting the corresponding carboxamide (eg., (VII)) with an a-halo ketone or aldehyde.

Suitable protecting groups for the amino group are those disclosed by Greene et al . , as indicated previously. The benzyloxycarbonyl and t-butoxycarbonyl groups are especially useful amino protecting groups. If the protecting group is not the desired group R ¹ , the protecting group may be removed, and the amino group may be alkylated or acylated to append the desired group as described hereinafter. In a typical reaction, thioamide (IV) is dissolved in chloroform, or another suitable halocarbon or hydrocarbon solvent, and refluxed with five to ten equivalents of a suitably substituted α-halo-aldehyde for from 12 to 24 hours.

The product is generally purified by chromatography. An alternate method for preparing compounds of formula (III), wherein W is S and Y is CO-Z, CO- (CR ⁸ R ⁹ ) (n-i)-R' _.

(CHR ⁹ ) ( _n _i)CR ⁹ R'-OH' or CHOH-(CR ⁸ R ⁹ ) (n- _l )-R' is given by Scheme 2. Accordingly, the thioamide (IV) is reacted with

Scheme 2

(IV) (V)

N,N-dimethylformamide dimethyl acetal to yield the thioamidino intermediate (V) . This intermediate is subsequently reacted with a suitably substitued halomethyl carbonyl reagent of the formula, R"CO-CH2-X, to yield the corresponding 5-acyl thiazole. If R ¹ is a protecting group (eg. , Boc, Cbz, Ac), but is not the desired substituent R ¹ , the protecting group may be removed and the desired substituent R ¹ may be appended by common methods of acylation, sulfonylation or alkylation as described hereinafter.

Typical halomethyl carbonyl reagents are 2-bromo- acetophenone, chloroacetaldehyde, iodoacetamide, 2-oxo-l- bromo-butane, methyl 3-bromopyruvate and the like. The CO-R" substituent of the thiazole may be converted by common methods of chemistry to the group CO-Z or CO-(CR ⁸ R ⁹ ) (n- _l )-R' • The R"CO substituent may be converted to the corresponding 5-(substituted)hydroxymethyl-thiazole, wherein Y is CHOH-(CR ⁸ R ⁹ ) (n_i)-R', by reduction.

The α-halo aldehydes, R-CH(X)-CHO, and the halomethyl carbonyl compounds, R"CO-CH2-X, of this invention are commercially available or available by common synthetic methods . For instance the α-halo aldehydes may be prepared by reduction of the corresponding α-halo ester, for example, with diisobutyllithiumaluminum hydride.

The intermediate thioamide of formula (IV) is prepared according to Scheme 3 from a 5-amino-4-hydroxy-2, 5- disubstituted-pentanoate ester, acid or corresponding γ- lactone.

Scheme 3

(VIII) Q'=OAC (IV)

A compound of formula (III) wherein W is NH and V is N is a triazole and is prepared according to Scheme 4. Carboximide (VIII), prepared as described in Scheme 3, is treated with dimethylformamide dimethyl acetal to yield the carboximidate (XIV) . The carboximidate (XIV) is subsequently treated with hydrazine which, in the presence of an acid, cyclizes to yield the triazine ring. Deprotection of the hydroxyl group yields the final triazine product.

(III)

(XVI)

Compounds of formula (III), wherein W is 0 and V is N are 1,3,4 oxadiazoles, and may be prepared by reacting the lactone of formula (VI) with hydrazine, acylating the resulting hydrazide with a compound (RC0) ₂ to form a diacyl hydrazide, which is then cyclized via acid catalysis. If necessary, the group R is then converted to the desired substituent Y by conventional techniques.

Compounds of formula (III) , wherein W is N-R' and V is CH are imidazoles and are prepared according to Scheme 5. Preparation of the substituted thioamide (XI) proceeds in a fashion analogous to thioamide (IV) of Scheme 3, where R ¹¹ is a protecting group or an incipient imidazole substituent.

The thioamide (XI) is treated with an alkylating agent, such as methyl iodide, to yield a thioimide (XII) , 'which is further reacted with ammonium acetate to yield the substituted amidine (XIII) . Reaction of the amidine with a compound of the formula R-CH(X)-CH0, wherein X is a suitable displaceable group and R is Y or a group which may be converted by common synthetic methods into Y, causes cyclization to yield the imidazole ring. Chloroacetaldehyde is a suitable reagent for producing the imidazole wherein Y is H. Deprotection of the hydroxyl group with mild base, and

optionally deprotecting the imidazole yields a compound of this invention .

Scheme 5

(X) (XI )

(XIII) (III)

An alternate method for preparing an imidazole is given by Scheme 6. Scheme 6

(III )

The acyl product of this method is amendable to modification by routine chemical techniques, such as oxidation, reduction, nucleophilic addition, such as by a Grignard or other organometallic reagent, alkylation, acylation and sulfonylation. Generally, the substituent Y may be modified by methods common in the art. For instance, alcohols may be prepared by reduction of a carbonyl group, such as by reduction of an aldehyde or ketone with sodium borohydride. Alternately, an alcohol may be prepared by reduction of an ester, such as with LiAlH4, or reduction of an acid, such as with diborane. A diol may be prepared by oxidation of a double bond in an alkylene substituent with osmium tetroxide.

A carbonyl group may be prepared from an alcohol by oxidation with manganese oxide, or by the Swern method (DMSO, TFAA and triethylamine) . Alternatively, an aldehyde or ketone may be prepared by oxidation of the double bond in an alkylene group, for instance with osmium tetroxide and sodium periodate in an ether-water solution (the Lemieux-Johnson procedure) .

A bromo or chloro group may be prepared from an alcohol by reaction with thionyl chloride or bromide.

An alkyl or alkylene group or a substituted alkyl or alkylene group, wherein any reactive functional groups are protected, may be prepared by a nucleophilic addition reaction, such as by addition of a Grignard reagent (or other suitable organometallic reagent) to a carbonyl compound. This also constitutes a method for preparing an alcohol.

An ester may be prepared from an aldehyde by treatment with an alkali metal cyanide, followed by oxidation, for instance with manganese dioxide, in the presence of an alcohol, such as methanol.

• A carboxamide may be prepared from an ester by treatment with ammonia or an organic amine. A carboxylic acid may be prepared by hydrolysis of an ester by acid or base, such as either HCl or sodium hydroxide in methanol, or by oxidation of an aldehyde by permanganate or dichromate.

- 21

An oxime may be prepared from an aldehyde or ketone by treatment with hydroxylamine and a base, such as sodium carbonate, in an alcoholic solvent.

Amines may be prepared from a carbonyl compound by reductive amination with ammonium chloride or bromide and sodium cyanoborohydride . Alternatively, an amine may be prepared by reduction of an oxime, either catalytically or with LiAlH4.

Combinations and variations of these methods and other conventional reactions will be apparent to one routinely skilled in the art. Scheme 7 is exemplary of such techniques.

Scheme 7

[/.e.,R=CH(CH ₃ )2]

If a group other than the protecting group is desired for the substituent R ¹ , then the protecting group is removed and the amino group is reacted with an appropriate alkylating or acylating reagent. Alkyl halides, acyl halide, sulfonyl halides, anhydrides, activated esters, and the like, of the appropriate group R ¹ are useful for this purpose.

For instance, carbamates may be prepared by reaction of the amino group with an appropriate chloro- or bromo-formate, such as R ⁶ OCO-Cl, or an activated carbonate. Haloformates may be prepared by reacting the appropriate alcohol with phosgene or carbonyldibromide. Activated carbonates may be prepared by reacting the appropriate alcohol with a suitable carbonate such as bis(4-nitrophenyl)carbonate. Sulfonamides may be prepared by reaction of the amino group with a sulfonyl halide, such as R ^& S0 ₂ ~C1 which may be prepared from the corresponding sulfonic acid.

Ureas may be prepared by reaction of the amino group with an isocyanate, such as R%CO. The isocyanate may be prepared from reaction of the corresponding amine, R H ₂ , with phosgene.

A thiourea may be prepared by reaction of the amino group with a thiocyanate, such as R CS. The isothiocyanate may be prepared by reaction of the corresponding amine, R%H ₂ , with thiophosgene.

Thiocarbamates may be prepared by reaction of the amino group with phosgene followed by a thiol, such as R ⁶ -SH.

Guanidines may be prepared by reaction of the amino group with O-methylisourea hydrogen sulfate, or S-methyl- pseudothiourea hydrogen sulfate, in the presence of a base, which may optionally be subsequently alkylated or acylated. Alternately, the amino group may be reacted with a cyanamide reagent, such as R%CN, which may in turn be prepared from the corresponding amine, R H ₂ , and cyanogen bromide. Acyl groups may be added by reaction of the amino group with an acyl halide, such as R ⁶ C0-C1, or an activated anhydride, or with the corresponding acid in the presence of a coupling agent.

Scheme 8 is exemplary of such techniques .

Scheme 8

Methods for preparing protected 5-amino-4-hydroxy-2,5- disubstituted-pentanoate esters and acids, and the corresponding γ-lactones and amides (VI) , (VII) and (VIII) , are well known and are disclosed, for instance, in Szelke et al., U.S. Patent 4,713,455, Boger et al., U.S. Patent 4,661,473, EP-A 0 352 000, Evans et al., J. Org. Chem., 50, 4615 (1985), Kempf, J. Org. Chem., 51, 3921 (1986), Fray et al., J. Org. Chem., 51, 4828 (1986), Halladay et al., Tett. Lett., 24, 4401 (1983), Wuts et al., J. Org. Chem., 53, 4503

(1988) and Szelke et al . , WO 84/03044, all of which are incorporated herein by reference.

Compounds wherein Q is amino are prepared from the corresponding 4-hydroxy intermediate by methods common in the art for converting a hydroxyl group into an amino group, such as by oxidation of the hydroxyl and subsequent reductive animation. For example, the alcohol may be oxidized via the Swern method, with DMSO, trifluoroacetic anhydride and triethylamine in methylene chloride solution, and the corresponding ketone reduced with sodium cyanoborohydride and ammonium bromide in an alcohol/water solution.

The compounds of formula (I) , wherein ϋ' or U" are OH, are also prepared by methods common in the art, such as those disclosed in U.S. Patent 4,864,017, Thaisrivongs et al . , J. Med. Chem. , 30, 976 (1987), Dellaria et al . , WO 87/04349, and Dellaria et. al . , J. Med. Chem. , 30, 1978, (1987).

As is clear from the foregoing description, intermediate compounds of the formula (XVII) and (XVIII) :

(XVII) (XVIII) wherein

R ¹ , R ² , R ³ and R ¹¹ are as defined for formula (I) ; R ²⁰ is H or Ci-βalkyl; Q* is a protected amino group or a protected hydroxyl group; are useful in the preparation of the protease- inhibiting compounds of this invention.

Suitably R ² and R ³ are benzyl or Ci-galkyl. Suitably R ¹ is R'O(CO) or R'CO. Preferably R ¹ is t-butyloxy, benzyloxycarbonyl or acetyl. Suitably R ¹¹ is H. Suitably Q' is R'CO-NH, R'CO-0 or (R') ₃ Si-0. Preferably Q' is acetyl. If a final compound (I) of this invention contains a basic group, an acid addition salt may be prepared. Acid addition salts of the compounds are prepared in a standard manner in a suitable solvent from the parent compound and an

excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, maleic, succinic or methanesulfonic. The acetate salt form is especially useful. If the final compound contains an acidic group, cationic salts may be prepared. Typically the parent compound is treated with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation. Cations such as Na ⁺ , K ⁺ , Ca ⁺⁺ and NH ⁺ are examples of cations present in pharmaceutically acceptable salts . Certain of the compounds form inner salts or zwitterions which may also be acceptable.

When compounds of formula (I) are administered to an animal infected or potentially infected with a virus, which is dependent upon a virally encoded protease for processing of viral polyproteins, viral replication is inhibited, hence, disease progression is retarded. Accordingly, the compounds of formula (I) are used to induce anti-viral activity in patients which are infected with susceptible viruses and require such treatment. The method of treatment comprises the administration orally, parenterally, buccally, trans- dermally, intra-vaginally, rectally or by insufflation, of an effective quantity of the chosen compound, preferably dispersed in a pharmaceutical carrier. Dosage units of the active ingredient are generally selected from the range of 0.1 to 25 mg/kg, but will be readily determined by one skilled in the art depending upon the route of administration, age and condition of the patient. These dosage units may be administered one to ten times daily for acute or chronic infection. The compounds of this invention are particularly useful for the treatment of HIV-1. No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention.

Pharmaceutical compositions of the compounds of this invention, or derivatives thereof, may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable

carrier prior to use. The liquid formulation is generally a buffered, isotonic, aqueous solution. Examples of suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution. Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.

Alternately, these compounds may be encapsulated, tableted or prepared in an emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition. Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline, alcohols and water. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. The carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit. The pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.

For intra-vaginal or rectal administration, a pulverized powder of the compounds of this invention may be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository. The pulverized powders may also be compounded with an oily

preparation, gel, cream or emulsion, buffered or unbuffered, and administered through a transdermal patch. These and other pharmaceutically acceptable formulations are found in REMINGTON'S PHARMACEUTICAL SCIENCES, 18th Edition, Alfonso R. Gennaro (ed.), Mack Publishing Company, Easton, Pennsylvania (1990) .

Beneficial effects may be realized by co-administering, individually or in combination, other anti-viral agents with the protease inhibiting compounds of this invention. Examples of anti-viral agents include nucleoside analogues, phosphonoformate, rifabutin, ribaviran, phosphonothioate oligodeoxynucleotides, castanospermine, dextran sulfate, alpha interferon and ampligen. Nucleoside analogues, which include 2',3'-dideoxycytidine(ddC) , 2',3'-dideoxyadenine(ddA) and 3'-azido-2',3'-dideoxythymide(AZT) , are especially useful. AZT is one preferred agent. Suitably pharmaceutical compositions comprise an anti-viral agent, a protease inhibiting compound of this invention and a pharmaceutically acceptable carrier. The Examples which follow serve to illustrate this invention. The Examples are intended to in no way limit the scope of this invention, but are provided to show how to make and use the compounds of this invention.

ENZYME ACTIVITY

The ability of the compounds of this invention to inhibit the HIV-1 protease enzyme may be demonstrated by using the assay disclosed by Dreyer et al . , Proc. Natl . Acad. Sci . , U. S.A . , 86, 9752 (1989), Grant et al . , Biochemistry, 30 8441 (1992), and EP-A 352 000. The Ki for the compounds of this invention are in the range of about 0.001 }1M to about 50 μM. Preferred compounds have Ki of less than 0.5 |1M. More preferred compounds have Ki of less than 0.0b μM. The most preferred compounds have Ki of less than 0.01 μM.

INFECTIVITY

The ability of the compounds of this invention to gain entry to cells infected with the human immunodeficiency

virus, and to inhibit viral replication in vitro may be demonstrated using the assay described by Meek et al . . Nature, 343, 90 (1990), and Petteway et al . . Trends Pharmacol . Sci, 12, 28 (1991) .

The Examples which follow serve to further illustrate this invention. The Examples are intended to in no way limit the scope of this invention, but are provided to show how to make and use the compounds of this invention. In the Examples, all temperatures are in degrees Centigrade. Microsorb® Siθ ₂ refers to a. silica gel chromatographic support manufactured by Rainin Instruments Co., Woburn, Mass. FAB indicates fast atom bombardment mass spectrometry. FAB mass spectra were performed upon a VG Zab mass spectrometer using fast atom bombardment. ESMS indicates electrospray ionization mass spectrometry. NMR • were recorded at 250 MHz using a Bruker AM 250 spectrometer. Multiplicities for NMR spectra are indicated as: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, dd=doublet of doublets, dt=doublet of triplets etc. and br indicates a broad signal.

Preparation of α-halo-aldehvdes.

The α-halo-aldehydes used were generally prepared via reduction of the commercially available corresponding esters with one equivalent of diisobutyl aluminum hydride in tetrahydrofuran solution at -78°C. Choloracetaldehyde was obtained commercially and purified by distillation.

Example 1

Preparation of 2- r (IR. 3S . 4S ) -l-ben yl -4- - butpχycarbQnyIaminQ-3-hydrQxy-5-phenylpentyl 1 -5-b._ tr.yl- thiaτ:ole

a) (5S,4S,2R) 6-phenyl-5-t-butoxycarbonylamino-4-hydroxy-2- phenylmethyl- (1-oxo)hexyl-amide

5-[1-(t-Boc-amino)-2-phenylethyl]-3- (phenylmethyl)- dihydrofuran-2 (3H)-one, JL, was prepared according to the method disclosed by Evans, et al . , J. Org. Chem., ϋH, 4615 (1985) .

A solution of benzyl lactone 1 (0.26 g, 0.67 mmol) in o methanol (4 mL) was cooled to 0 C. A steady stream of ammonia was bubbled directly into the solution until saturation was reached. The reaction flask was sealed with a rubber septum and allowed to warm to room temperature overnight. The flask was vented with a syringe needle and concentrated in vacuo to give the title compound as a white solid (0.27 g, 99%) . ¹ H NMR(CDCl3) δl.35 (s, 9H) , 1.75 (m,IH), 2.6-3.3 (m, 6H) , 3.55-3.8 (m,3H) , 4.75-4.85 (d, IH) , 5.2-5.4 (br s, IH) , 5.6-5.75 (br s, IH) , 7.05-7.35 (m, 10H) ; IR (film) : 3400 (br) , 2900-3080, 1650 (s), 1525 (m) , 1170 (m) cm- ¹ ; MS m/e 413 [M+H] ⁺ ; TLC: R _f 0.56 (100% EtOAc) ; ¹³ C NMR(CDCl3) δ28.3, 37.4, 38.8, 40.2, 46.2, 57.7, 70.8, 80.0, 127.1, 127.2, 129.3-130.4, 140.3, 140.9, 158.2, 180.5.

b) (5S,4S,2R) 6-phenyl-5-t-butoxycarbonylamino-4-acetoxy-2- phenylmethyl- (1-oxo)hexyl-amide

To a solution of the compound of Example 1(a) (0.27 g, 0.66 mmol) in methylene chloride (10 mL) was added acetic anhydride (0.136 g, 1.33 mmol), triethylamine (0.135 g, 1.33 mmol), and 4-dimethylaminopyridine (0.008 g, 0.066 mmol) . The mixture was stirred overnight at room temperature. The solution was quenched with methanol (2.0 mL) and stirred for 20 min. The reaction mixture was washed with 1.0 N HCl, water, dried over MgS0 , filtered and concentrated in vacuo to yield, as a white sticky solid, the title compound (0.26g, 86%) . ^λ ϋ NMR(CDCl3) δl.35 (s, 9H) , 1.7-1.85 (m, IH) , 1.85-

2.05 (m, IH), 2.1 (s, 3H) , 2.4-2.55 (br m, IH) , 2.57-2.75 (m, 3H), 2.95-3.1 (m, 2H) , 4.05-4.2 ( , IH) , 4.6-4.75 (d, IH) ,

4.85-4.95 (br m, IH) , 5.05-5.15 (br, IH) , 7.05-7.35 (m, 10H) ; IR (film, cm- ¹ ): 3310 (br) , 2910-3030, 1685 (s) , 1500 (m) , 1365 (m) , 1235 (m) , 1165 (m) ; MS m/e 477 [M+Na]+; TLC R _f 0.6

(2:1 EtOAcihexane) ; ¹³ C NMR(CDC13) δ21.0, 28.3, 3.50, 38.0, 39.0, 44.5, 53.5, 73.5, 80.0, 127.0, 127.5, 128.4-129.1, 138.0, 140.0, 156.0, 171.0, 177.0.

c) (5S,4S,2R) 6-phenyl-5-t-butoxycarbonylamino-4-acetoxy-2- phenylmethyl-(1-thiono)hexyl-amide

To a solution of the compound of Example 1(b) (0.25 g, 0.56 mmol) in benzene (10 mL) was added Lawesson's Reagent (0.113 g, 0.28 mmol) . Warmed at 80° ^c for 1.0 h. Diluted with ether, washed with 5% NaHC03, H2O, and saturated brine, dried over MgS04, filtered and concentrated to a crude white solid. This material was chromatographed (silica gel, 40% EtOAc:hexane) to yield the title compound as a sticky white solid (0.142 g, 54%) . ^H NMR(CDCl3) δl.35 (s, 9H) , 1.8-2.05 (m, 2H), 2.1 (s, 3H) , 2.65-2.95 (m, 4H) , 3.15-3.3 (m, IH) , 4.05-4.20 (br m, IH) , 4.65 (d, IH) , 4.8-4.95 (m, IH) , 7.1- 7.35 (m, 10H) ; IR (film) 3300 (br) , 2910-3010, 1700 (s) , 1260, 1130 cm- ¹ ; MS m/e 471 [M+H] ⁺ ; TLC R _f 0.42 (1:1 hexane:EtOAc) , single component; ¹³ C NMR(CDCl3) δ22.5, 28.3, 37.0, 38.0, 42.0, 53.0, 57.5, 61.0, 127.0-129.0, 138.0, 167.0

d) 2-[ (3S,4S)-l-benzyl-4-t-butoxycarbonylamino-3-acetoxy-5- phen lpentyl]-5-butyl-thiazole

The compound of Example 1(c) (60.5 mg, 0.13 mmol) was dissolved in CHCI3 (10 ml) and to this was added freshly prepared 2-bromohexanal (115.0 mg, 0.65 mmol, 5.0eq.) . The mixture was refluxed with stirring under Ar for 22.0 h. TLC (silica gel, 1:1 hexane:EtOAc) indicated no remaining thioamide. The reaction was concentrated in vacuo and the brown oily reside was chromatographed (silica gel, 60% hexane:EtOAc) . The 5-butyl-thiazole acetate diastereomers were isolated as a yellow oil (28.6 mg, 40%) . ¹ H NMR(CDCl3) indicated two absorptions for Boc (δl.35 and 1.40) and for OAc (δ2.0 and 2.05) and a peak at δ7.0 corresponding to the 4-H thiazole; TLC R _f 0.6 (silica gel, 1:1 hexane:EtOAc) .

e) 2- [ (3S, 4S)-l-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5-butyl-thiazole

The diasteromers of Example 1(d) (28.6 mg, 0.052 mmol) were dissolved in methanol (3.0 ml) and 3 drops of 2.5 N NaOH were added. The mixture was stirred for 2.0 h at room temperature. The reaction was concentrated in vacuo and the residue was chromatographed (silica gel, 2:1 hexane:EtOAc) . The title isomeric alcohols were isolated as a white solid (18.0 mg, 68%) . ^H NMR(CDCl3) δO.9-1.0 (t, 3H) , 1.35 + 1.4 (2s, 9H), 1.55-1.75 (m, 4H) , 1.8-2.15 (m, 2H) , 2.7-3.2 (m,

6H) , 3.35-3.8 (m, 3H) , 4.25 (br s, IH) , 4.95 (br m, IH) , 6.9 + 7,05 (2m, IH), 7.1-7.4 (m, 10H) ; TLC R _f 0.56, 0.51 (1:1 hexane:ethyl acetate); MS m/e 509 [M+H] ⁺ ; HPLC RT 4.24 min (46%), 5.95 min (54%) (Microsorb® Siθ2, 4.6 x 250 mm column, 50:48:2 CH2CI2:hexane:isopropanol, 2.0 ml/min) .

Example 2

Preparation of 2- r (3S.4 )-_.-benzy].-4-t-butoxycarbonylamino-3- hγdroxγ-5-phenγlpentyll-thiazole

Using the procedure of Example 1, except substituting chloroacetaldehyde for 2-bromohexanal in Example 1(d), the title compound was prepared. ¹ H NMR(CDCl3) δl.35 + 1.4 (2s,

9H), 1.55-1.7 (m, IH) , 1.8-1.95 (m, IH) , 1.95-2.2, (m, IH) , 2.7-2.9 (m, 2H) , 2.92-3.15 (m, 2H) , 3.45-3.65 (m, 2H) , 3.7- 3.85 (m, IH), 4.85-4.95 (d, IH) , 6.95 + 7.05 (2m, IH) , 7.1- 7.35 (m, 10H), 7.65(d, IH) ; TLC R _f 0.42, 0.36 (1:1 hexane:ethyl acetate); MS m/e 453 [M+H]+; HPLC RT. 6.52 min (44%), (10.5 min, 56%) (Microsorb® Siθ ₂ , 4.6 x 250 mm column, 50:48:2 CH2CI2:hexane:isopropanol, 2.0 ml/min) .

Example 3

Preparati on of ?.- T (3S . 4R _ -1 -benzyl -4-t-bπtoxycarbonγ_ amino- - hydroxy-5-phenylpentyn -5-et.hyl-thJ a7.o1 e

Using the procedure of Example 1, except substituting 2-bromobutanal for 2-bromohexanal in Example 1 (d) , the title compound was prepared . ¹ H NMR (CDCl3) δ l .25 (t, 3H) , 1 .35

+1.4 (2s, 9H) , 1.75-1.95 (m, 2H) , 1.95-2.15 (m, IH) , 2.6-3.2 (m, 6H), 3.55-3.85 (m, 3H) , 4.8-5.0 (br s, IH) , 6.95 + 7.05 (2m, IH), 7.1-7.4 (m, 10H) ; TLC R _f 0.58, 0.53 (1:1 hexane:ethyl acetate); MS m/e 481 [M+H] ⁺ ; HPLC RT. 4.8 min (46%), 7.0 min (54%) (Microsorb® Siθ ₂ , ^.6 x 250 mm column,

50:48:2 CH2CI2:hexane:isopropanol, 2.0 ml/min).

Example 4

Preparation of 2- r .3S.4S) -1 -benzyl -4-t-bπtoxyπarbonylamino-3- hydrgχy-5-phenylpentyl1-5-propyl-thiazole

Using the procedure of Example 1, except substituting 2-bromopentanal for 2-bromobutanal in Example 1(d) , the title compound was prepared. ^-H NMR(CDCl3) δθ.95 (2t, 3H) , 1.4 + 1.45 (2s, 9H), 1.55-1.75 (m, 4H) , 1.8-1.95 (m, IH) , 1.95-2.15 ( , IH), 2.65-3.25 (m, 6H) , 3.35-3.8(m, 2H) , 4.85-5.0 (br m, IH) , 6.95 + 7.05 (2m, IH) , 7.1-7.4 (m, 10H) ; TLC R _f 0.55, 0.50 (1:1 hexane:EtOAc) ; MS m/e 495 [M+H] ⁺ ; HPLC RT 3.9 min (46%), 5.6 min (54%) (Microsorb® Siθ ₂ , 4.6 x 250 mm column, 50.48.2 CH ₂ CI ₂ :hexane:isopropanol, 2.0 ml/min).

Example 5

Preparat on of 2- f .3S_ 4S_ -l-henzyl-4-t-hu o_cyrarhonylaιnino-3- hγdroxγ-5-phenylpentyl1-1.3. -t ia7.01e

a) N-2-[(5S,4S,2R)-6-phenyl-5-t-butoxycarbonylamino-4- acetoxy-2-phenylmethyl-(1-oxo)hexy1]-(N', '-dimethyl)- formamidine A solution of the compound of Example 1(b) (50 mg, 0.11 mmol) in dimethyl formamide dimethyl acetal (2 mL) was allowed to stir at 25°C for 2 h. The volatiles were removed in vacuo to leave a slightly yellow oil. The crude material was used without further purification.

b) 2-[ (IR,3S,4S)-l-benzyl-4-t-butoxycarbonylamino-3-acetoxy- 5-phenylpentyl]-l,3,5-triazole

The compound of Example 5(a)was dissolved in glacial acetic acid (0.5 mL) and hydrazine monohydrate (6.1 mg, 0.12 mmol, 5.9 μL) was added. The mixture was heated at 90°C for 1.5 h. The slightly pink solution was cooled, diluted with ethyl acetate, and 15% aqueous sodium hydroxide was added until the aqueous layer reached pH 11. The organic layer was dried (magnesium sulfate) , filtered, and concentrated to afford a slightly yellow oil. The crude material was purified by choromatography (silica gel, .2:1 ethyl acetate) to provide the title compound as a colorless oil (38.2 mg, 73%) .

c) 2-[ (1R,3S,4S)-l-benzyl-4-t-butoxycarbonylamino-3-hydroxy- 5-phenylpentyl]-l,3,5-triazole

To a stirred solution of the compound of Example 5(b) (28.9 mg, 60 μmol) in methanol (400 μL) , 3N aqueous potassium hydroxide (400 μL) was added. After stirring 1 h, the solution was diluted with water (2 mL) , saturated with solid sodium chloride and extracted with ethyl acetate (10 mL) . The extract was dried (magnesium sulfate) , filtered, and the volatiles were removed in vacuo to yield the title compound as a white solid (23.6 mg, 90%). mp 187-188.5°C; ^λ R NMR(CDC1 ₃ , 250 MHz) δ 1.36 (s, 9 H) , 1.84-2.05 (m, 2 H) , 2.82 (d, 2 H,

J=7.5 Hz), 2.95 (dd, 1 H, J=6.8, 13.5 Hz), 3.09 (dd, 1 H, J-8.6, 13.5 Hz), 3.48 (m, 3H) , 4.88 (d, 1 H, J=9.7 Hz), 6.97 (d, 2 H, J=7.5 Hz), 7.12-7.24 (m, 8 H) , 7.91 (s, 1 H) .

Example 6

Preparation of 2-T (IR.3S.4S)-l-benzyl-4-t-frutQxycarbonyl- amino-3-hγdroxv-5-ph nγ]pentv11-4 ( )-aπ tylimi azol e

a) (2R,4S,5S)-2-benzyl-5-t-butoxycarbonylamino-4-t- butyldimethylsiloxy-N-(5-methylisoxazol-4-yl)-6- phenylhexanamide

To a mixture containing (2R,4S,5S)-2-benzyl-5-t- butoxycarbonylamino-4-t-butyldimethylsiloxy-6-phenylhexanoic acid (270 mg, 0.51 mmol), 1-hydroxybenzotriazole hydrate (13.8 mg, 0.10 mmol) and 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (107.9 mg, 0.56 mmol) in DMF was added 4-amino-5-methylisoxazole (55 mg, 0.56 mmol). The resulting yellow solution was allowed to stir at room temperature for 24 h, then was poured into H ₂ O (25 mL) and extracted with EtOAc (25 mL) . The organic extract was washed successively with 0.1 N HCl, saturated aqueous NaHC0 ₃ and saturated aqueous NaCl and dried over MgS0 ₄ . The solvent was removed in vacuo, and the residue was purified by flash chromatography (silica gel, 1:4 EtOAc:hexanes) to afford the title compound (185.8 mg, 60%) as a white solid, m.p. 58- 60°C; NMR(CDC1 ₃ ) δ 8.37 (s, IH) , 7.60 (s, IH) , 7.38-7.19 (m,

8H), 4.75 (d, IH) , 4.12-4.03 (m, IH) , 3.68 (dd, IH) , 3.08 (dd, IH), 2.82-2.50 (m, 4H), 2.23 (s, 3H) ,. 1.87-1.69 ( , 2H) , 1.25 (s, 9H), 0.95 (s, 9H) , 0.12 (s, 3H) , 0.10 (s, IH) .

b) 2-[(IR,3S,4S)-l-benzyl-4-t-butoxycarbonylamino-3-t- butyldimethylsiloxy-5-phenylpentyl]-4(5)-acetylimidazole A mixture containing the compound of Example 6(a) (185.8 mg, 0.31 mmol) and 10% palladium on activated carbon (93 mg) in EtOH (3 mL) was stirred under a hydrogen atmosphere for 5 h. The mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. To the residue in EtOH (2.7 mL) was added 1 M NaOH (0.4 mL in EtOH, 0.4 mmol) . The resulting mixture was heated at reflux overnight, then was partitioned between EtOAc and aqueous NH ₄ CI. The organic extract was washed with saturated aqueous NaCl and dried over MgSθ . The solvent was removed under reduced pressure, and the oily residue was purified by flash chromatography (silica gel, 1:2 EtOAc:hexanes) to afford the title compound (136.8 mg, 76%) as a yellow solid, m.p. 74- 76°C; NMR(CDC1 ₃ ) δ (tautomers) 7.58 (s, IH) , 7.47 (d, IH) ,

7.34-7.07 (m, 18H) , 7.00 (d, 2H) , 4.78 (d, IH) , 4.67 (d, IH) , 4.08 (m, 2H) , 3.65-3.59 (m, IH) , 3.49-3.40 (m, 2H) , 3.30-3.22 (m, 2H) , 3.06 (m, IH) , 2.86-2.78 (m, 2H) , 2.71-2.64 (m, 4H) , 2.53 (s, 3H) , 2.36 (s, 3H) , 1.84-1.61 (m, 4H) , 1.36 (s, 9H) , 1.35 (s, 9H) , 0.91 (s, 9H) , 0.89 (s, 9H) , 0.05 (s, 6H) , 0.00 (s, 6H) .

c) 2- [ (IR,3S,4S) -l-benzyl-4-t-butoxycarbonylamino-3-hydroxy- 5-phenylpentyl]-4 (5)-acetylimidazole A solution containing the compound of Example 6(b) (61.6 mg, 0.10 mmol) in 1 M tetra-n-butylammonium fluoride (1.25 mL in THF, 1.25 mmol) was heated at 50°C for 5 h. The solution was then poured into EtOAc, washed successively with H ₂ O (2x) and saturated aqueous NaCl and dried over MgSθ ₄ . The solvent was removed under reduced pressure, and the residue was purified by flash chromatography (silica gel, 2:1 EtOAc:hexanes) to afford the title compound (41.7 mg, 84%) as a white solid. NMR(CDC1 ₃ ) δ 7.60 (br s, IH) , 7.24-7.13 ( ,

8H), 6.92 (m, 2H) , 4.92 (m, IH) , 3.61 (d, 2H) , 3.37 (m, IH) , 3.10-3.02 (m, IH) , 2.91-2.84 (m, 3H) , 2.42 (s, 3H) , 1.98-1.81 (m, 2H) , 1.36 (s, 9H) ; MS(ES) m/e 478.2 [M+H] ⁺ ; IR(CHC1 ₃ ) 3430, 3220, 3000-2860, 1700, 1660, 1500 cm" ¹ .

Example 7

Preparation of 2- r (IR. S.4S. -l-benzvl-4-t-butoxycarbonγl- amino-3-hydroxy-5-phenγlpentγll- .5 ) - .1-hydroxγethγl ) - imidazole

To a solution of 2- [ (1R,3S, 4S)-l-benzyl-4-t- butoxycarbonylamino-3-hydroxy-5-phenylpentyl]-4 (5)- acetylimidazole (20.8 mg, 0.044 mmol) in EtOH (0.5 mL) was added excess aBH . After stirring for 15 min, the reaction was quenched by the addition of aqueous NH ₄ CI, and the mixture was extracted with EtOAc. The organic extract was washed with saturated aqueous NaCl and dried over gSθ . The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with EtOAc to afford the title

compound (16.3 mg, 78%) as a white solid, m.p. 85-87°C; NMR(CDC1 ₃ ) δ (diastereomers) 7.31-7.17 (m, 16H) , 6.90-6.88 (m,

4H) , 6.66 (s, 2H) , 5.01 (d, 2H) , 4.84 (m, 2H) , 3.62 (m, 4H) , 3.24 (m, 2H), 3.01-2.86 (m, 8H) , 1.97 (m, 2H) , 1.75 ( , 2H) , 1.51 (d, 3H), 1.48 (d, 3H) , 1.36 (s, 18H) ; MS (ES) m/e 480.4 [M+H] ⁺ ; Anal. Calcd for C28H37 3θ4*l/2 H2O: C, 66.83; H, 7.84; N, 8.60. Found: C, 68.89; H, 7.61; N, 8.46.

Example 8

Preparation of 2-f (IR.3S.4S^-l-henzγl-4- -bntoxycarbonyl- 3mino-3-hyriroxy-5-phenylpentyll- (5)-formyl imidazole

a) (2R,4S,5S)-2-benzyl-5-t-butoxycarbonylamino-4-t- bu yldimethylsiloxy-N-(isoxazol-4-yl)-6-phenylhexanamide The title compound was prepared according to the procedure in Example 6, step (a) , except using 4- aminoisoxazole. m.p. 59-61°C; NMR(CDC1 ₃ ) δ 8.91 (s, IH) , 8.34

(br s, IH), 8.24 (s, IH) , 7.37-7.18 (m, 8H) , 7.02 (d, 2H) , 4.75 (d, IH), 4.11-4.01 (m, IH) , 3.64 (dd, IH) , 3.16 (dd,

IH), 2.81-2.50 ( , 4H) , 1.85-1.65 (m, 4H) , 1.32 (s, 9H) , 0.93 (s, 9H) , 0.10 (s, 3H) , 0.09 (s, 3H) .

b) 2-[ (IR,3S,4S)-l-benzyl-4-t-butoxycarbonylamino-3-t- butyldimethylsiloxy-5-phenylpentyl]-4 (5)-formylimidazole

The title compound was prepared according to the procedure in Example 6, step (b) , except using the compound of Example 8(a) . m.p. 70-72°C; NMR(CDC1 ₃ ) δ (tautomers) 10.71

(br s, IH), 10.47 (br s, IH) , 9.86 (s, IH) , 9.56 (s, IH) , 7.66 (s, IH), 7.51 (d, IH) , 7.36-6.99 (m, 20H) , 4.77 (d, IH) , 4.70 (d, IH), 4.14-4.04 (m, 2H) , 3.60 (t, IH) , 3.49-3.41 ( , IH) , 3.35-3.08 (m, 2H) , 2.90-2.62 ( , 6H) , 1.83-1.75 (m, 4H) , 1.36 (s, 9H), 1.35 (s, 9H) , 0.91 (s, 9H) , 0.89 (s, 9H) , 0.05- 0.02 (m, 12H) .

c) 2-[ (IR,3S,4S)-l-benzyl-4-t-butoxycarbonylamino-3-hydroxy- 5-phenylpentyl]-4 (5)-formylimidazole

The title compound was prepared according to the procedure in Example 6, step (c) , except using the compound of Example 8(b) . m.p. 90-92°C; NMR(CDC1 ₃ ) δ (tautomers) 9.85

(s, IH), 9.54 (s, IH), 7.68 (s, IH) , 7.47 (s, IH) , 7.35-7.16 (m, 16H), 6.99-6.91 (m, 4H) , 4.86-4.82 (m, 2H) , 4.47 (m, IH) , 4.02 (m, IH), 3.61 (m, 4H) , 3.36 (m, 2H) , 3.08 (dd, 2H) , 2.92-2.83 (m, 4H) , 1.89-1.81 (m, 4H) , 1.37 (m, 18H) ; MS(ES) m/e 464.2 [M+H] ⁺ ; Anal. Calcd for C27H33N3O -1/2 H2O: C,

68.62; H, 7.25; N, 8.89. Found: C, 68.63; H, 7.15; N, 8.76.

Example 9

Preparation of 2- \ (1R _r 3S. S )-1-ben yl-4- -bntoxvcarbonyl- amino-3-hydroxy-5-pheny1 entyl!-4.5 ) - (2-methγlpropionγl ) - imida ole

a) 2-[ (IR,3S,4S)-l-benzyl-4-t-butoxycarbonylamino-3-t- butyldimethylsiloxy-5-phenylpentyl]-4 (5)- (l-hydroxy-2- methylpropyl) imidazole

To a solution of 2-[ (1R,3S, 4S)-l-benzyl-4-t- butoxycarbonylamino-3-t-butyldimethylsiloxy-5-phenylpentyl]- 4 (5)-formylimidazole (138.4 mg, 0.24 mmol) in 1:1 Et2θ:THF (0.5 mL) was added 3 N isopropylmagnesium bromide (0.48 mL in THF, 1.44 mmol) . After stirring for 15 min, the reaction was quenched by the addition of aqueous NH ₄ CI, and the mixture was extracted with EtOAc. The organic extract was washed with saturated aqueous NaCl and dried over MgSθ4. The solvent was removed in vacuo, and the residue was purified by flash chromatography (silica gel, 1:1 EtOAc:hexanes) to afford the title compound as a white solid. NMR(CDC1 ₃ ) δ

(diastereomers) 7.28-6.58 (m, 11H) , 4.80-4.54 (m, IH) , 4.29 (m, IH) , 4.02 (m, IH) , 3.64-3.55 (m, 2H) , 3.25 (m, IH) , 3.02 (m, IH) , 2.72-2.54 (m, 3H) , 1.77 (m, 2H) , 1.35-1.23 (m, 9H) , 1.00-0.81 (m, 15H), 0.10-0.00 (m, 6H) .

b) 2-[ (IR,3S,4S)-l-benzyl-4-t-butoxycarbonylamino-3-t- butyldimethylsiloxy-5-phenylpentyl]-4 (5)-(2- ethylpropionyl) imidazole

To a solution of the compound of Example 10(a) (77.6 mg, 0.12 mmol) in CH ₂ CI ₂ (1 mL) was added Mnθ ₂ (775 mg) , and the resulting suspension was allowed to stir at room temperature for 5 h. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography, (silica gel, 1:2 EtOAc:hexanes) to afford the title compound (70 mg, 90%) as a white foam. NMR(CDC1 ₃ ). δ (tautomers) 7.60

(s, IH), 7.48 (d, IH) , 7.34-6.98 (m, 20H) , 4.77-4.66 (m, 2H) , 4.10-4.03 ( , 2H) , 3.64-3.59 (m, 3H) , 3.23-3.04 (m, 5H) , 2.87-2.60 (m, 6H) , 1.84-1.75 (m, 4H) , 1.36 (s, 9H) , 1.33 (s, 9H), 1.24-1.14 (m, 12H) , 0.91 (s, 18H) , 0.05-0.00 (m, 12H) .

c) 2-[ (IR,3S,4S) -l-benzyl-4-t-butoxycarbonylamino-3-hydroxy- 5-phenylpentyl]-4 (5)-(2-methylpropionyl) imidazole

The title compound was prepared according to the procedure in Example 6, step (c) , except using the compound of Example 10(b) . m.p. 76-78°C; NMR(CDC1 ₃ ) δ 7.62 (s, IH) ,

7.34-7.04 (m, 8H) , 6.91-6.88 (m, 2H) , 5.11-4.91 (m, 2H) , 3.61-3.52 (m, 2H) , 3.43-3.40 (m, IH) , 3.19 (septet, IH) , 3.10-3.02 (m, IH) , 3.07-2.83 (m, 3H) , 1.98-1.94 (m, IH) , 1.81-1.75 (m, IH) , 1.35 (s, 9H) , 1.21 (d, 3H) , 1.19 (d, 3H) ; MS(ES) m/e 506.2 [M+H]+; Anal. Calcd for C30H39^04-1/2 H ₂ 0: C, 70.01; H, 7.83; N, 8.16. Found: C, 69.64; H, 7.77; N, 7.78.

Example 10

Preparation of 2- ϊ (IR.3S. S. - -benzyl-4-fr-bπtoxycarbonγl- aτπ-inn-3-hydroxγ-5-phβnylpentγ11-4(5. -propionvlimidazole

The title compound was prepared according to the procedure in Example 9, steps (a-c) , except using 2- [ (1R,3S,4S)-l-benzyl-4-t-butoxycarbonylamino-3-t- butyldimethylsiloxy-5-phenylpentyl]-4 (5)-formylimidazole and

ethylmagnesium bromide in step (a) . m.p. 80-82°C; NMR(CDC1 ₃ ) δ 7.60 (s, IH) , 7.21-6.90 (m, 10H) , 5.07-4.87 (m, 2H) , 3.60-

3.40 (m, 3H), 2.83-2.76 (m, 5H) , 1.97-1.75 (m, 2H) , 1.35-1.19 (m, 12H) ; MS(ES) m/e 492.2 [M+H] ⁺ .

Example 11

Preparation of 2- r (IR. S.4fi. -l-benzyl-4- -butoxycarbonyl- amino-3-hydroxy-5-phenylpentyl1-4(5)- (2-methylpropiony1 ) - imidazole _r hydror.hloride salt

To a solution of 2- [ (IR,3S,4S)-l-benzyl-4-t- butoxycarbonylamino-3-hydroxy-5-phenylpentyl]-4 (5)- (2- ethylpropionyl) imidazole (36.9 mg, 73 μmol) in Et2θ (2.5 mL) was added 1 M HCl (80 μL in Et2θ, 80 μmol) . The mixture was concentrated under reduced pressure to afford the title ^• compound (39.6 mg, 100%) as a white solid, m.p. 122-124°C; NMR(MeOH-d ₄ ) δ 8.20 (s, IH) , 7.14-7.09 (m, 8H) , 6.95 (d, 2H) ,

3.62-3.49 (m, 2H) , 3.20-3.11 (m, 2H) , 3.03 (dd, IH) , 2.91 (dd, IH) , 2.69 (dd, IH) , 2.57 (dd, IH) , 1.97-1.82 (m, 2H) ,

1.23 (s, 9H) , 1.09 (d, 6H) ; Anal. Calcd for C30H40CIN3O -1/2 H2O: C, 65.38; H, 7.50; N, 7.62. Found: C, 65.43; H, 7.34; N, 7.75.

Example 12

Preparation of 2- ϊ (1R _r S.4S_ -l-benzyl-4- -butoxycarbonyl- amino-3-hydroxy-5-phenylpen yl1-4 (5 )- (l-hydroxy-2- methylpropyl ) imidazole

The title compound was prepared according to the procedure in Example 6, step (c) , except using 2- [ (IR,3S, 4S)- l-benzyl-4-t-butoxycarbonylamino-3-t-butyldimethylsiloxy-5- phenylpentyl]-4 (5)- (l-hydroxy-2-methylpropyl) imidazole. m.p. 82-84°C; NMR(CDC1 ₃ ) δ 7.26-7.15 ( , 8H) , 6.90 (m, 2H) , 6.63

(m, IH) , 5.04 (m, IH) , 4.34 (m, IH) , 3.61 (m, 2H) , 3.27 (m, IH) , 2.85 (m, 4H) , 1.96 (m, 2H) , 1.75 (m, 2H) , 1.35 (s, 9H) , 0.99-0.80 (m, 6H) ; MS(ES) m/e 508.2 [M+H] ⁺ ; Anal. Calcd for

C30H 1N3O4-H ₂ O: C, 68.54; H, 8.24; N, 7.99. Found: C, 68.50; H, 7.90; N, 7.55.

Example 13

Preparation of ?-. (IR.3S.4S. -1-benzyl-4- -bι_toxycarbonyl- amino-3-hydroxy-5-phenylpentyl1-4 ( . -(1-oxobutyl. imidazole

The title compound was prepared according to the procedure in Example 9, steps (a-c) , except using 2- [(IR,3S, S)-l-benzyl-4-t-butoxycarbonylaraino-3-t- butyldimethylsiloxy-5-phenylpentyl]-4 (5)-formylimidazole and 1-propylmagnesium bromide in step (a) . m.p. 70-72°C; NMR(CDC1 ₃ ) δ 7.60 (s, IH) , 7.20-7.12 (m, 8H) , 6.90 (s, 2H) , 4.96 (m, 2H) , 3.59-3.41 (m, 3H) , 3.05-2.70 (m, 5H) , 1.96-1.74 (m, 4H), 1.35 (s, 9H) , 0.98 (m, 3H) ; MS(ES) m/e 506.2 [M+H] ⁺ ; Anal. Calcd for C30H39N3O4-1/2.H ₂ O: C, 70.01; H, 7.83; N, 8.16. Found: C, 69.68; H, 7.65; N, 8.05.

Example 14

Preparation of 2- f (IR.3S.4S.-l-benz.y1 -4- -bι_toxycarbonyl- amino-3- ydroxy-5-phenylpentγll -4 ( . - (2-mβ hγl-l- oxobiityl ) midazol e

The title compound was prepared according to the procedure in Example 9, steps (a-c) , except using 2- [(1R,3S,4S)-l-benzyl-4-t-butoxycarbonylamino-3-t- butyldimethylsiloxy-5-phenylpentyl]-4 (5)-formylimidazole and 2-butylmagnesium bromide in step (a) . m.p. 79-84°C;

NMR(CDC1 ₃ ) δ 7.61 (s, IH) , 7.26-7.12 (m, 8H) , 6.89 (m, 2H) ,

4.96 ( , IH), 3.62-3.42 (m, 3H) , 3.06-2.84 (m, 4H) , 1.98-1.71 (m, 3H), 1.52-1.15 (m, 14H) , 0.90 (t, 3H) ; MS(ES) m/e 520.2 [M+H] ⁺ ; Anal. Calcd for C3iH4iN3θ -3/4 H2O: C, 69.83; H, 8.03; N, 7.88. Found: C, 70.02; H, 7.67; N, 7.97.

Example 15

Preparation of 2- , (IR.3S.4S) -1-benzγl-4-t-bntoxyπarbonvl- amino-3-hydroxy-5-phenylpentyll-4(5) -πarbomethoxyimidazole

a) 2- [ (IR, 3S, 4S) -l-benzyl-4-t-butoxycarbonylamino-3-t- butyldimethylsiloxy-5-phenylpentyl]-4 (5) - carbomethoxyimidazole

To a solution of 2-[ (IR,3S, 4S)-l-benzyl-4-t- butoxycarbonylamino-3-t-butyldimethylsiloxy-5-phenylpentyl]- 4 (5)-formylimidazole (10 mg, 17 μmol) in MeOH (0.3 L) was added potassium cyanide (5.6 mmol, 87 μmol) and nθ2 (30.1 mg, 0.35 mmol) . The resulting mixture was allowed to stir at room temperature for 2 h, at which time additional Mnθ ₂ (70 mg, 0.80 mmol) and potassium cyanide (13 mg, 0.20 mmol) were added. After stirring at room temperature for 20 h, the mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure. The colorless oily residue was chromatographed (silica gel, 1:2 EtOAc:hexanes) to afford the title compound (10.1 mg, 96%) as a colorless oil. NMR(CDC1 ₃ ) δ 7.55 (s, IH) , 7.34-7.04 (s, 10H) , 4.73 (d,

IH), 4.05-3.98 (m, IH) , 3.86 (s, 3H) , 3.41 (m, 2H) , 3.16 (m, IH) , 2.86 (dd, IH) , 2.67-2.64 (m, 2H) , 1.80 (m, 2H) , 1.34 (s, 9H) , 0.88 (s, 9H) , 0.00 (s, 6H) .

b) 2- [ (IR,3S,4S) -l-benzyl-4-t-butoxycarbonylamino-3-hydroxy- 5-phenylpentyl]-4 (5)-carbomethoxyimidazole

The title compound was prepared according to the procedure in Example 6, step (c) , except using the compound of Example 15(a) . m.p. 91-93°C; NMR(CDC1 ₃ ) δ 7.52 (s, IH) ,

7.26-7.16 (m, 8H) , 6.96-6.93 (m, 2H) , 4.89 (d, IH) , 3.85 (s, 3H), 3.56 (m, 2H) , 3.35 (m, IH) , 3.15-3.06 (m, IH) , 2.92-2.83 (m, 3H) , 1.85 (m, 2H) , 1.36 (s, 9H) ; MS(ES) m/e 494.2 [M+H]+.

F.xamplβ 1 6

Preparation of 2- [ (lR _r 3S.4S) -l-benzyl-4-t-hι_toxycarbonyl- amino-3-hydrnxy-5-phenylpen yl 1-4(5)- (N-me hylaminocarbonyl)- imidazole

a) 2-[(IR,3S,4S)-l-benzyl-4-t-butoxycarbonylamino-3-t- butyldimethylsiloxy-5-phenylpentyl]-4(5)-(N- methylaminocarbonyl)imidazole Into a solution of 2-[(lR,3S,4S)-l-benzyl-4-t- butoxycarbonylamino-3-t-butyldimethylsiloxy-5-phenylpentyl]- 4(5)-carbomethoxyimidazole (10.2 mg, 17 μmol) in MeOH (1 mL) at 0°C was bubbled methylamine. After 15 min, the reaction mixture was allowed to warm to room temperature and stirred for 6 d. The mixture was then concentrated under reduced pressure and used without further purification. NMR(CDC1 ₃ ) δ

7.40 (s, IH), 7.33-7.14 (m, 8H) , 7.01 (d, 2H) , 4.78 (d, IH) ,

4.11-4.07 (m, IH) , 3.49-3.47 (m, IH) , 3.30 (dd, IH) , 3.03 ( ,

IH), 2.97 (d, 3H), 2.88-2.50 (m, 3H) , 2.20-1.97 (m, IH) , 1.86-1.70 ( , 2H) , 1.35 (s, 9H), 0.90 (s, 9H) , 0.00 (s,.6H).

b) 2-[ (IR,3S,4S)-l-benzyl-4-t-butoxycarbonylamino-3-hydroxy- 5-phenylpentyl]—4(5)—(N—methylaminocarbonyl)imidazole The title compound was prepared according to the procedure in Example 6, step (c), except using the compound of Example 16(a). m.p. 101-103°C; NMR(CDC1 ₃ ) δ 7.26-6.93 (m,

11H), 4.90 (d, IH), 3.65 (m, IH) , 3.52 ( , IH) , 3.29 (m, IH) , 3.15-3.06 (m, IH) , 2.99 (d, 3H) , 2.89-2.81 (m, 3H) , 1.80 (m, 2H), 1.36 (s, 9H) ; MS(ES) m/e 493.2 [M+H] ⁺ .

Example 17

Prepa rat i on of 2- . ( 1 R _r S . 4S) -1 -ben zyl-4- . N- (benzyloxycarbonyl ) -I,-valy1 1 ami no-3-hvdroxγ-5-pheny l pentyl 1 - 4 (5) - f2-met_ ylpropior.yl) imidazole

a) 2- [ (IR, 3S, 4S)-4-amino-l-benzyl-3-hydroxy-5-phenylpentyl]- 4(5)- (2-methylpropionyl) imidazole

A solution containing 2-[ (IR,3S, 4S)-l-benzyl-4-t- butoxycarbonylamino-3-hydroxy-5-phenylpentyl]-4 (5)- (2- methylpropionyl) imidazole (200.4 mg, 0.40 mmol) in TFA (1 mL) was stirred at room temperature for 5 min, then was concentrated under reduced pressure. The residue was partitioned between EtOAc and 10% aqueous NaOH, and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried over MgS04 and concentrated in vacuo to afford the title compound (160.5 mg, 100%) as a white solid, m.p. 80-82°C; NMR(CDC1 ₃ ) δ 7.61 (s, IH) , 7.26-7.05 (m, 10H) ,

3.45 (m, IH) , 3.18 (m, 3H) , 2.89-2.82 (m, 3H) , 2.44 (m, IH) , 2.06 (m, IH) , 1.83 (m, IH) , 1.16 (d, 6H) .

b) 2- [ (IR, 3S,4S)-l-benzyl-4-[N- (benzyloxycarbonyl)-L- valyl]amino-3-hydroxy-5-phenylpentyl]-4 (5)- (2- methylpropionyl) imidazole

A mixture containing 2- [ (IR,3S,4S) -4-amino-l-benzyl-3- hydroxy-5-phenylpentyl]-4(5)- (2-methylpropionyl) imidazole (3.7 mg, 9 μmol), carbobenzyloxy-L-valine (2.3 mg, 9 μmol), 1-hydroxybenzotriazole hydrate (0.2 mg, 2 μmol) and l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.9 mg, 10 μmol) in DMF (0.2 mL) was allowed to stir at room temperature overnight. The reaction mixture was poured into EtOAc and washed successively with H2O, 0.1 N HCl, saturated aqueous NaHC0 ₃ and saturated aqueous NaCl and dried over MgSθ ₄ . The solvent was removed in vacuo, and the residue was purified by flash chromatography (silica gel, 4% eOH/CH2Cl2) to afford the title compound (5.5 mg, 94%) as a white solid, m.p. 89-91°C; NMR(CDC1 ₃ ) δ 7.55 (s, IH) , 7.31-6.68 (m, 16H) ,

5.44 (d, IH) , 5.18-5.04 (m, 2H) , 4.01-3.92 (m, 2H) , 3.60 (d, IH), 3.42 (m, IH) , 3.18-3.02 (m, 2H) , 2.85 (m, 3H) , 2.03-1.74 (m, 3H) , 1.18 (d, 6H) , 0.81 (d, 3H) , 0.74 (d, 3H) ; MS(ES) m/e 639.4 [M+H] ⁺ ; Anal. Calcd for C38H46N405-1/4 H ₂ 0: C, 70.95; H, 7.29; N, 8.71. Found: C, 70.93; H, 7.15; N, 8.63.

Example 18

Preparation of 2-f (IR.3S.4S)-1-bRn yl-3-hγdro*y-4-TN-fN'- isopropoxycarbonyl)-L-valyllamino-5-phenylpentyl>-4 (5)-(2- methylpropionyl)imidazole

a) (S)-N-(isopropoxycarbonyl)valine

To a solution of (+)-valine (1.76 g, 2.02 mmol) in 2 N NaOH (15.75 mL, 31.5 mmol) at 10°C was added isopropyl chloroformate (16.5 mL of 1 M solution in toluene, 16.5 mmol) . After stirring for 30 min, the pH was adjusted to pH 10, and the phases were separated. The aqueous phase was washed with Et2θ. The pH was then adjusted to pH 2 by the addition of 3 N HCl, and the aqueous phase was extracted with Et2θ (3x) . The combined organic extracts were dried over

MgSθ ₄ , and the solvent was removed in vacuo . The title compound was obtained (2.73 g, 89%) and used without further purification. NMR(CDC1 ₃ ) δ 5.13 (d, IH) , 4.94-4.89 (m, IH) ,

4.32 (dd, IH), 2.23 ( , IH) , 1.24 (d, 6H) , 1.01 (d, 3H) , 0.94 (d, 3H) .

b) 2-{ (lR,3S,4S)-l-benzyl-3-hydroxy-4-[N-(N'- isopropoxycarbonyl)-L-valyl]amino-5-phenylpentyl}-4 (5)-(2- methylpropionyl)imidazole The title compound was prepared according to the procedure in Example 17, step (b) , except using 2-

[ (IR,3S,4S)-4-amino-l-benzyl-3-hydroxy-5-phenylpentyl]-4(5)-

(2 -methylpropionyl) imidazole, 1-hydroxybenzotriazole hydrate,

1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and (S) -N- (isopropoxycarbonyl) valine . m.p . 90-92°C;

NMR(CDC1 ₃ ) δ 7 .57 (s, IH) , 7 .18-6. 91 (m, 10H) , 5 .23 (m, IH) ,

4.85 (m, IH), 4.02-3.90 (m, 2H) , 3.58 (d, IH) , 3.44 (m, IH) , 3.20 (m, IH), 3.12-3.03 (m, IH) , 2.86 (m, 3H) , 1.99-1.74 (m, 3H), 1.21 (d, 12H), 0.81 (d, 3H) , 0.75 (d, 3H) ; MS (CI/NH ₃ ) m/e 591.5 [M+H] ⁺ ; Anal. Calcd for C34H46N405-1/2 H2O: C,

68.09; H, 7.90; N, 9.34. Found: C, 68.25; H, 7.84; N, 9.18.

Example 19

Preparation of 2-f (IR.3S.4S)-l-benzyl-3-hydroxy-4-fN- (N ^» - (1- oxo-3-phenylpropyl) )-L-valyl1amino-5-phenylpentyl1-4 (5) -(2- methylpropionyl) imidazole

a) (S)-N-phenylethylcarbonylvaline

To a solution of (S)-valine (1.76 g, 15 mmol) in 1:1 Et2θ:2N NaOH (31.5 mL) was added dropwise over 5 min phenylpropanoyl chloride (2.45 mL, 16.5 mmol) . The temperature was maintained at 10°C during the addition, then was allowed to warm to room temperature and stirred for 30 min. The aqueous phase was adjusted to pH 10 and then extracted with Et2θ (4x8 mL) . The aqueous layer was adjusted to pH 2 by the addition of 3 N HCl, and the solid which formed was collected by filtration and dried in vacuo to afford the title compound as a white solid (3.66 g, 98%) . NMR(CDC1 ₃ ) δ 7.16 (m, 5H) , 4.29 (d, IH) , 2.92 (apparent t,

2H), 2.58 (apparent dt, 2H) , 2.09 (m, IH) , 0.88 (d, 6H) .

b) 2-{ (IR,3S,4S)-l-benzyl-3-hydroxy-4- [N- (N'- (l-oxo-3- phenylpropyl) )-L-valyl]amino-5-phenylpentyl}-4 (5)-(2- methylpropionyl) imidazole

The title compound was prepared according to the procedure in Example 17, step (b) , except using 2-

[ (lR,3S,4S)-4-amino-l-benzyl-3-hydroxy-5-phenylpentyl]-4 (5)-

(2-methylpropionyl) imidazole, 1-hydroxybenzotriazole hydrate,

1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and (S)-N-phenylethylcarbonylvaline. m.p. 99-101°C; NMR(CDC1 ₃ ) δ (diastereomers) 7.64 (s, IH) , 7.59 (s, IH) , 7.18-

6.96 (m, 15H), 4.58-4.06 (m, 2H) , 3.44-2.44 (m, 11H) , 1.82 (m, 3H), 1.23-1.10 (m, 6H) , 0.72-0.59 (m, 6H) ; MS(ES) m/e 637.2 [M+H] ⁺ ; Anal. Calcd for C39H 8 40 -1/2 H2O: C, 72.53; H, 7.65; N, 8.68. Found: C, 72.20; H, 7'.34; N, 8.56.

Ex m l e 20

Preparation of 2- (TR.3S.4S)-l-benzvl-3-hydroxy-4-TN-(3- methyl-1-oxobutyl) lamino-5-phenylpentyl -4 (5)- (2-methyl- propionyl) i idazole

The title compound was prepared according to the procedure in Example 17, step (b) , except using 2- [(IR,3S,4S)-4-amino-l-benzyl-3-hydroxy-5-phenylpentyl]-4(5)- (2-methylpropionyl)imidazole, 1-hydroxybenzotriazole hydrate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 3-methylbutanoic acid. m.p. 74-76°C; NMR(CDC1 ₃ ) δ 7.57

(s, IH), 7.20-6.93 (m, 10H) , 4.08-4.05 (m, IH) , 3.52 (m, 2H) , 3.18-3.09 (m, 2H) , 2.88 (m, 3H) , 1.97 (m, 5H) , 1.23 (d, 3H) , 1.21 (d, 3H) , 0.75 (m, 6H) ; MS(ES) m/e 490.2 [M+H] ⁺ ; Anal. Calcd for C30H39N3O3-1/2 H ₂ O: C, 72.26; H, 8.08; N, 8.43. • Found: C, 71.88; H, 7.87; N, 8.28.

Example 21

Preparation of 2-f (IR.3S . S) -l-benzyl-3-hydroxy-4- TN- (N' - acetyl) -L-valyll amino-5-phenylpentyl 1-4 (5) - (2-τnethyl - propionyl)imidazole

To a solution containing 2-[ (lR,3S,4S)-4-amino-l-benzyl- 3-hydroxy-5-ρhenylpentyl]-4 (5)-(2-methylpropionyl)imidazole (30.0 mg, 74 μmol), (S)-N-acetylvaline (13.0 mg, 81 μmol) and BOP reagent (36.0 mg, 81 μmol) in CH ₂ CI ₂ (37 μL) was added Et ₃ N (11.3 μL, 81 μmol) . The resulting solution was allowed to stir at room temperature for 24 h, then was diluted with EtOAc and washed successively with H ₂ O and 0.1 N HCl. The acidic wash was made basic by the addition of saturated aqueous NaHC0 ₃ and extracted with EtOAc. The combined organic extracts were washed successively with saturated aqueous NaHC0 ₃ and saturated aqueous NaCl and dried over

MgSθ . The solvent was removed in vacuo, and the residue was purified by flash chromatography (silica gel, 6% MeOH/CH ₂ Cl ₂ ) to afford a white solid (30.8 mg, 76%) . This material was

further purified by preparative HPLC (R.P., 70:30 MeOH:H2θ) to afford the title compound (15.6 mg, 39%) . m.p. 122-24°C; NMR(CDC1 ₃ ) δ 7.68 (s, IH) , 7.14-6.89 (m, 10H) , 4.11-4.02 (m,

2H) , 3.44 (d, 2H) , 3.22-3.17 (m, 2H) , 2.96-2.82 (m, 3H) , 2.12 (s, 3H), 1.90-1.82 (m, 3H) , 1.23 (d, 3H) , 1.22 (d, 3H) , 0.87 (d, 3H) , 0.75 (d, 3H) ; MS(ES) m/e 547.2 [M+H]+; Anal. Calcd for C32H 2N404-3/4 H2O: C, 68.61; H, 7.83; N, 10.00. Found: C, 68.66; H, 7.59; N, 9.87.

Example 22

Preparation of 2-f (lR _r fi.4S)-1-benzγl-3-hydroxy-4- TN- (N'~ aπetyl)-D-va3yllamino-5-phenylpenty11- (5)-(2- methylpropionyl) imidazole

The title compound was obtained from the preparative HPLC separation in Example 21 (4.8 mg, 12%) . m.p. 123-25°C; NMR(CDC1 ₃ ) δ 7.62 (s, IH) , 7.20-6.97 (m, 10H) , 4.25 (m, 2H) ,

3.46 (m, 2H), 3.19 (m, 2H) , 2.82 (m, 3H) , 1.82 (m, 6H) , 1.19 (m, 6H) , 0.77 (d, 3H) , 0.62 (d, 3H) ; MS(ES) m/e 547.2 [M+H]+.

Example 23

Preparation of 2- . (IR.3S. S) -l-benzvl-3-hγdroxγ-4- TN- ( '- benzyloxycarbonyl) -L-threonyll amino-5-phenylpentyl 1-4 (5) - (2- methylpropionyl) imidazole

The title compound was prepared according to the procedure in Example 17, step (b) , except using 2- [ (1R,3S, 4S)-4-amino-l-benzyl-3-hydroxy-5-pheny lpentyl] - (5)- (2-methylpropionyl) imidazole, 1-hydroxybenzotriazole hydrate, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-benzyloxycarbonyl-L-threonine . m.p. 89-91°C; NMR(CDC1 ₃ ) δ 7.56 (s, IH) , 7.31-7.13 (m, 12H) , 6.93 (m, 3H) , 5.81 (d, IH) , 5.06 (d, IH) , 5.04 (d, IH) , 4.14-4.04 (m, 3H) , 3.60 (m, IH) , 3.43 (m, IH) , 3.15-3.07 (m, 2H) , 2.88-2.79 (m, 3H), 1.84 (m, 2H) , 1.16 (d, 3H) , 1.15 (d, 3H) , 1.07 (d, 3H) ;

MS(ES) m/e 641.4 [M+H] ⁺ ; Anal. Calcd for C ₃ 7H ₄ N4θ6 ^# H2θ : C, 67.46; H, 7.04; N, 8.50. Found: C, 67.53; H, 6.98; N, 8.31.

Example 24

Preparation of 2-1 ( R.2S.3 S, S)-l-benzyl-3-hydroxy-4-f 1'- r5 -hydroxy-3 -(1-methylethyl)-2 -oxo-l'pγrrolidinvl11-5- phenylpentyl>-4 (5)-f2-methylpropionyl)imidazole

The title compound was prepared according to the procedure in Example 21, except using 2-f(IR,3S,4S)-4-amino- l-benzyl-3-hydroxy-5-phen lpentyl]-4(5)-(2- methylpropionyl)imidazole, BOP reagent, triethylamine and (2S)-2-(l-methylethyl)-4-oxobutanoic acid. The residue was purified by flash chromatography (silica gel, 1:1 ethyl acetate: exanes) , then with (2:1 ethyl acetate:hexanes) to afford the title compound. NMR(CDC1 ₃ ) δ 7.60 (s, IH) , 7.26-

7.16 (m, 6H), 7.05 (d, 2H) , 6.97 (d, 2H) , 5.14 (t, IH), 4.05 (dd, IH), 3.80 (m, IH) , 3.44 ( , IH) , 3.23 (m, 2H) , 2.99 (m, IH), 2.80 (dd, IH), 2.68 (m, IH) , 2.42 (dd, IH) , 2.27-2.23

(m, 2H) , 1.84-1.81 ( , IH) , 1.68 (m, 2H) , 1.43 (m, IH) , 1.24 (d, 3H), 1.22 (d, 3H), 0.96 (d, 3H) , 0.86 (d, 3H) ; MS(ES) m/e 514.2 (M-H ₂ θ+H) ⁺ .

Example 25

Preparation of ?.-■. (IR.3S_3'R.4S)-1-benzγl-3-hydroxγ-4-π - .5 ^r -hydroxy-3 -n-methylethyl)-2'-oxo-1 pyrrolidinyll V-5- phenylpentyl1-4 (5)-f2-methylpropionyl) imidazole

The title compound was obtained from the chromatographic separation in Example 24. NMR(CDC1 ₃ ) δ 7.69 (s, IH) , 7.23-

7.19 (m, 7H), 7.02 (m, 3H) , 4.76 ( , IH) , 3.82 (q, IH), 3.64

(m, IH) , 3.29 (m, IH) , 3.20 (m, IH) , 3.07 (m, IH) , 2.89-2.75 (m, 3H) , 2.52 (m, IH), 2.05-2.00 (m, 4H) , 1.72 (m 2H) , 1.23

(d, 3H) , 1.22 (d, 3H), 0.94 (d, 3H) , 0.87 (d, 3H) ; MS(ES) m/e 514.2 (M-H ₂ θ+H) ⁺ .

Example 26

Preparation of 2- . (IR.3S _r 4S)-l-benzyl-4-benzenesnlfonylami.no- 3-hydroxy-5-phenγlpentyl1-4 (5)- (2-methylpropionvl) imidazole

To a stirring solution of 2-[ (IR,3S,4S)-4-amino-l- benzyl-3-hydroxy-5-phenylpentyl]-4 (5)-(2- methylpropionyl)imidazole (10.0 mg, 0.025 mmol) and triethylamine (3.0 mg, 0.03 mmol, 4.2 μL) in CH ₂ CI ₂ (0.125 mL) was added benzenesulfonyl chloride (4.8 mg, 0.027 mmol, 3.5 μL) . After stirring at room temperature -for lh, the solution was diluted with CH ₂ CI ₂ , washed with saturated aqueous NaHC0 ₃ , dried (MgSθ ₄ ) , filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 1:1 ethyl acetate:hexanes) to provide the title compound (4.7 mg,

25%). m.p. 108-110°C; NMR(CDC1 ₃ ) δ 7.74 (d, 2H) , 7.56 (s,

IH), 7.50 (t, IH) , 7.41 (t, 2H) , 7.15 (m, 6H) , 7.01 (d, 2H) ,

6.83 (m, 2H), 5.35 (d, IH) , 3.68 (d, IH) , 3.30 (m, 2H) , 3.21

(m, IH), 2.95 (dd, IH) , 2.81 (m, 2H) , 2.55 (dd, IH) , 1.95 (m, IH), 1.67 (m, IH) , 1.22 (d, 3H) , 1.20 (d, 3H) ; MS(ES) 546.0 [M+H] ⁺ .

Example 27

Preparation of 2-U1R.3S.4S)-l-benzyl-3-hydroxy-4-TN-(N'~ ethanesnlfonyl)-L-valyl 1aτnino-5-phenylpentyl1-4 (5)-(2- methylpropionγl)imidazole

The title compound was prepared according to the procedure in Example 26, except using 2-[ (IR,3S,4S)-4-amino- l-benzyl-3-hydroxy-5-phenylpentyl]-4 (5)-(2- methylpropionyl) imidazole, (2S)-2-methanesulfonylamino-3- methylbutanoyl chloride, and triethylamine for 22h. m.p. 248-250°C; NMR(CDC1 ₃ /CD ₃ 0D) δ 7.60 (m, 2H) , 7.22-7.15 (m, 8H) , 7.03 (d, 2H) , 4.08 (m, IH) , 3.55 (d, IH) , 3.35-3.30 (m, 4H) ,

3.06 (dd, IH), 2.90-2.87 (m, 2H) , 2.72 (dd, IH) , 2.34 (s,

3H), 1.82 (m, 3H) , 1.20 (d, 3H) , 1.18 (d, 3H) , 0.88 (d, 3H) ,

0.73 (d, 3H) ; MS(ES) 583.2 [M+H]+.

Example 28

Preparation of 2- flR.3S_ 4S) -l-benzyl-4- TN- (N'-tert- butoxycarbonyl)-L-valyl1amino-3-hydroxy-5-phenylpentyl>-4 (5)- (2-methylpropionyl) midazole

The title compound was prepared according to the procedure in Example 17, step (b) , except using 2— [(IR,3S,4S)-4-amino-l-benzyl-3-hydroxy-5-phenylpentyl]-4(5)- (2-m thylpropionyl)imidazole, 1-hydroxybenzotriazole hydrate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-tert-butoxycarbonyl-L-valine. m.p. 101.5-104.5°C; NMR(CDC1 ₃ ) δ 7.57 (s, IH) , 7.23-7.12 (m, 8H) , 6.90 (d, 2H) , 6.63 (bs, IH), 5.06 (s, IH) , 3.99 (q, IH) , 3.85 (dd, IH), 3.62 (d, IH) , 3.44 (m, IH) , 3.22 (m, IH) , 3.06 (dd, IH) , 2.89-2.84 (m, 3H) , 2.03 (m, IH) , 1.93 (m, IH) , 1.75 (m, IH) , 1.38 (s, 9H), 1.21 (d, 3H), 1.19 (d, 3H) , 0.82 (d, 3H) , 0.74 (d, 3H) ; Anal. Calcd for C ₃₅ H ₈ N ₄ θ ₅ »3/4 H ₂ O: C, 67.99; H, 8.07; N, 9.06. Found: C, 67.73; H, 7.92; N, 9.39.

Example 29

Preparation of 2-T (IR. S.4S)-l-benzyl-4- -butoxycarbonyl- amino-3-hydroxy-5-phenylpentyl1-4 (5)- (2.2-dimethyl-3-

The title compound was prepared according to the procedure in Example 9, steps (a-c), except using 2- [(1R,3S,4S)-l-benzyl-4-t-butoxycarbonylamino-3-t- butyldimethylsiloxy-5-phenylpentyl]-4(5)-formylimidazole and 3-methyl-2-butenylmagnesium bromide in step (a) . m.p. 73- 75°C. NMR(CDC1 ₃ ) δ 7.65 (s, IH) , 7.25-7.14 (m, 8H) , 6.89 (bs,

2H), 6.12 (m, IH), 5.26 (d, IH) , 5.21 (d, IH), 4.95 (d, IH) , 3.63 ( , 2H) , 3.38 (m, IH) , 3.00 (m, IH) , 2.85 (m, 3H) , 2.05 (m, IH), 1.78 (m, IH) , 1.35 (s, 6H) ; MS(ES) 532.4 [M+H]+; Anal. Calcd for C ₃₂ H ₄ ιN ₃ θ ^« l/2 H ₂ O: C, 71.08; H, 7.83; N, 7.77. Found: C, 71.30; H, 7.75; N, 7.74.

Example 3Q

Preparation of 2- . (1R _r 3S.4S)-1-benzyl-4- -bntoxycarbonv1- amino-3-hydroxy-R-phenylpentyl!-4 (5)- (2.2-dimethylbutanoyl)- imidazole

a) 2- [ (IR,3S,4S) -l-benzyl-4-t-butoxycarbonylamino-3-t- butyldimethylsiloxy-5-phenylpentyl]-4 (5) - (2,2-dimethyl-3- butanoyl) imidazole.

To a solution of 2- [ (1R,3S, 4S)-l-beιjzyl-4-t- butoxycarbonylamino-3-t-butyldimethylsiloxy-5-phenylpentyl]- 4 (5)- (2,2-dimethyl-3-butenoyl) imidazole (26 mg, 0.04 mmol) in ethanol (0.4 mL) was added 5% palladium on carbon (6.5 mg) . The suspension was stirred vigorously under a balloon of hydrogen for 16h. The suspension was filtered through a bed of celite and the filtrate was concentrated. The residue was purified by flash chromatography (silica gel, 1:4 ethyl acetate:hexanes) to provide the title compound (13.8 mg, 53%) . NMR(CDC1 ₃ ) δ 7.60 (s, IH) , 7.31-7.15 (m, 8H) , 6.97 (d,

2H), 4.69 (d, IH) , 4.01 (m, IH) , 3.61 (m, IH) , 3.17 (m, IH) , 2.81 (m, IH) , 2.69 (m, IH) , 1.85 (m, 2H) , 1.74 (q, 2H) , 1.32 (m, 9H) , 1.26 (s, 3H) , 1.24 (s. 3H) , 0.91 (s, 9H) , 0.75 (t, 3H), 0.05 (s, 6H) .

b) 2-[ (lR,3S,4S)-l-benzyl-4-t-butoxycarbonyl-amino-3- hydroxy-5-phenylpentyl]-4 (5) - (2,2-dimethylbutanoyl) -imidazole

The title compound was prepared according to the procedure in Example 6, step (c) , except using 2- [ (IR,3S, 4S)- l-benzyl-4-t-butoxycarbonylamino-3-t-butyldimethylsiloxy-5- phenylpentyl]-4 (5)- (2,2-dimethyl-3-butanoyl) imidazole. m.p. 78-80°C; NMR(CDC1 ₃ ) δ 7.59 (s, IH) , 7.26-7.15 (m, 8H) , 6.89

(bs, 2H) , 4.94 (d, IH) , 3.67 (m, IH) , 3.60 (m, IH) , 3.38 (m,

IH), 3.01 (m, IH) , 2.87 (m, 3H) , 1.99 ( , IH) , 1.79 (m, 3H) , 1.35 (s, 9H), 1.27 (s, 3H) , 1.26 (s, 3H) , 0.77 (t, 3H) ; MS(ES) 534.4 [M+H] ⁺ .

Example 31

Preparation of 3- ϊ (1R.3S.4S) -1-benzyl-4-r-bι_toxγcarbonγl- a ino-3-hydroxy-5-phenylpentγl1-β.6-dimethvl-5-hvdroxv- pyrrolo-ri.2-πl-imidazol-7-one

A solution of 2-[(lR,3S,4S)-l-benzyl-4-t- butoxycarbonylamino-3-hydroxy-5-phenylpentyl]-4(5)-(2,2- dimethyl-3-butenoyl)imidazole (5.0 mg, 9.4 μmol) and sodium periodate (4.4 mg, 0.02 mmol) in 1:1 dioxane:H2θ (0.34 mL) , containing 7.9 μL of a 1% aqueous solution of osmium tetroxide, was allowed to stir at room temperature for 6h. The mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, dried (MgSθ ₄ ) , filtered and concentrated. The residue was purified by preparative TLC, developed with 2:1 ethyl acetate:hexanes, to provide the title compound (3.4 mg, 68%). m.p. 88-90°C; NMR(CDC1 ₃ ) δ 7.52 (s, IH) , 7.26-7.13 (m, 8H) , 6.96 (d, 2H) ,

6.31 (bs, IH), 4.90 (bs, IH) , 4.79 (d, IH) , 3.51 (m, IH) , 3.40 (m, IH), 3.31 (m, IH) , 3.14 (m, IH) , 2.99 (m, 2H), 2.83 (dd, IH), 2.14 (m, 2H) , 1.39 (s, 9H) , 1.17 (s, 3H) , 0.70 (s, 3H) ; MS(ES) 534.2 [M+H] ⁺ .

Example 32

Preparation of 2-. (IR.3S.4S) -l-benzyl-4-tert-butoxycarbonyl- amino-3-hydroxγ-5-phenylpentyl 1-4 ( ) - (cyclopentylearbonyl)- imidazole

The title compound was prepared according to the procedure in Example 9, steps (a-c) , except using 2- [(IR,3S,4S)-l-benzyl-4-t-butoxycarbonylamino-3-tert- butyldimethylsiloxy-5-phenylpentyl]-4 (5)-formylimidazole and cyclopentylmagnesium bromide in step (a). NMR(CDC1 ₃ ) δ 7.58 (s, IH), 7.20 ( , 9H) , 6.91 (m, 2H) , 4.97 (d, IH) , 3.61 (m, 2H) , 3.41 (m, 2H) , 3.06 (m, IH) , 2.89 (m, IH) , 2.86 (d, 2H) , 1.80 (m, 11H), 1.37 (s, 9H) ; MS(ES) 532.4 [M+H] ⁺ .

Example 33

Preparation of 2- . f1R _Γ 3S.4S) -1-benzy]-4-tert-butoxvcarbonvl- amino-3-hydroxy-5-phenylpentyl!-4 (5)-benzovlimidazole

The title compound was prepared according to the procedure in Example 9, steps (a-c) , except using 2- [ (IR,3S, 4S)-l-benzyl-4-t-butoxycarbonylamino-3-t- butyldimethylsiloxy-5-phenylpentyl]-4 (5) -formylimidazole and phenylmagnesium chloride in step (a) . NMR(CDC1 ₃ ) δ 7.89 (d,

2H) , 7.62 (t, IH) , 7.58 (s, IH) , 7.52 (t _r 2H) , 7.20 (m, 8H) ,

6.93 (d, 2H), 4.97 (d, IH) , 3.64 (m, 2H) , 3.53 (m, IH) , 3.12

(m, IH) , 2.93 (m, IH) , 2.86 (d, 2H) , 2.02 (d, IH) , 1.87 (d, IH) , 1.40 (s, 9H) ; MS (ES) 540.2 [M+H]+.

Example 34

Preparation of 2- . (IR.3S.4fi)-1-benzyl-4-t.ert.-bι_toxyca bonyl- amino-3-hydroxy- -phenylpenty11-4(5)- ( -ethylbutanoy1)- imidazole

The title compound was prepared according to the procedure in Example 9, steps (a-c) , except using 2-

[ (IR,3S,4S)-l-benzyl-4-t-butoxycarbonylamino-3-t- butyldimethylsiloxy-5-phenylpentyl]-4 (5) -formylimidazole and 3-pentylmagnesium bromide in step (a) . NMR(CDC1 ₃ ) δ 7.60 (s,

IH), 7.22 (m, 9H) , 6.90 (d, 2H) , 4.94 (d, IH) , 3.67 (d, IH) , 3.62 (m, IH) , 3.42 (m, IH) , 3.07 (m, IH) , 2.90 (m, IH) , 2.88 (d, 2H) , 2.00 (m, IH) , 1.83 (m, IH) , 1.72 (m, 2H) , 1.57 (m, 2H) , 1.36 (s, 9H) , 0.83 (t, 6H) ; MS(ES) 534.2 [M+H] ⁺ .

Example 35

Preparation of 2- . (IR. 3S . 4S) -l-henzyl -4-t.ert -butoxycarbonyl - amino-3-hydroxy-5-phenylpentyl l -4 ( 5) - (E) -l- (hydroxyimino) -2- methylpropyl) 1 imidazole

To a stirring solution of hydroxylamine hydrochloride (25 mg, 0.36 mmol) in ethanol (0.5 mL) at 0°C was added potassium carbonate (25 mg, 0.18 mmol) in water (0.5 mL) . The solution was stirred for 10 minutes and added to a solution of 2-[ (lR,3S,4S)-l-benzyl-4-tert- butoxycarbonylamino-3-hydroxy-5-phenylpentyl]-4(5)-(2- methylpropionyl) imidazole in ethanol (1 mL) at 55-60°C. After stirring for 24 hours the reaction mixture was diluted with water and ethyl acetate, extracted with ethyl acetate (2X) . The combined extracts were washed with saturated brine, dried (MgSθ4) , filtered and concentrated. The crude product was purified by flash chromatography on 230-400 mesh (silica gel, 3:2 ethyl acetate:hexanes) to provide the title compound. NMR(CDC1 ₃ ) δ 7.23 ( , 10H) , 6.96 (d, 2H) , 5.01 (d, IH) , 3.63 ( , 2H) , 3.42 (m, IH) , 3.00 (m, 2H) , 2.90 (m, IH) , 2.87 (d, 2H), 2.00 (m, IH) , 1.80 (m, IH) , 1.38 (s, 9H) , 1.27 (m, 6H) ; MS (ES) 521.2 [M+H] ⁺ .

Example 36

Preparation of (1R. S.4S)-2 '-(l-phenylmethyl-3-hydroxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'-benzoyl-thiazole

a) N-dimethylaminomethylidene-(2R,4S,5S)-2-phenylmethyl-4- acetoxy-5-t-butoxycarbonylamino-6-phenylhexanethioamide.

A solution of the compound of Example 1(c) (134 mg, 0.29 mmol) in CHC1 ₃ (1 mL) was treated with dimethylformamide dimethylacetal (1.2 equiv) and activated 4A molecular sieves, and stirred for 30 min. The reaction was filtered, the solvent thoroughly evaporated, and the residue chromatographed (silica gel, 75% EtOAc/hexane) , to yield the title compound (133 mg, 89%) . NMR(CDCl3) δ 8.32 (IH, s) ,

7.06-7.32 (10H, m) , 5.00 (IH, m) , 4.58 (IH, d) , 3.92 (IH, m) , 3.12 (3H, s), 2.96 (3H, s) , 2.50-3.34 (4H, ) , 2.02 (3H, s) , 1.76-2.32 (3H, m) , 1.35 (9H, s) .

b) (IR,3S,4S)-2'-(l-phenylmethyl-3-acetoxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'-benzoylthiazole

A mixture of the compound of Example 36(a) (111 mg, 0.21 mmol), phenacyl bromide (65 mg, 0.33 mmol), and Et3 (45 mg, 0.45 mmol) in MeCN (3 mL) was heated to 90°C for 30 min. The solvent was evaporated, and the residue taken up in EtOAc. The extracts were washed with 0.05N HCl, and water, dried, and the solvent removed. The residue was chromatographed (silica gel, EtOAc/hexane/CH2Cl2) to yield the title compound. NMR(CDCl3) δ 8.10 (IH, s) , 7.82 (2H, d) , 7.48-7.66

(3H, ), 7.00-7.30 (10H, ) , 4.92 (IH, m)., 4.65 (IH, d) , 3.98 (IH, m) , 3.48 (IH, m) , 2.40-3.12 (2H, m) , 2.56-2.75 (2H, m) , 1.94-2.34 (2H, m) , 2.08 (3H, s) , 1.38 (9H, s) .

c) (IR,3S,4S)-2'-(l-phenylmethyl-3-hydroxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'-benzoyl-thiazole

A solution of the compound of Example 36(b) (25 mg) in MeOH (3 mL) was treated with aqueous K2CO3 at ambient temperature for 4 h. The solution was diluted with H2O, and filtered. The filtrate was acidified and-extracted with Et2θ. The extracts were washed with H2O, dried, and the solvent removed to yield the title compound (13.2 mg, 59%) . NMR(CDCl3) δ 8.06 (IH, s) , 7.80 (2H, dd) , 7.62 (IH, m) , 7.52

(2H, m) , 7.00-7.26 (10H, m) , 4.80 (IH, d) , 3.76 (IH, m) , 3.60 (IH, m) , 3.52 (IH, m) , 3.05 (2H, m) , 2.82 (2H, m) , 2.06 (IH, m) , 1.82 (IH, ) , 1.70 (IH, broad s) , 1.40 (9H, s) .

Example 37

Preparation of (IR.3S. S)-2'-(1-phenylmethyl-3-hydroxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'-benzoylthiazole

A solution of the compound of Example 3D (86 mg, 0.14 mmol) in a mixture of THF (8 L) and Et2θ (8 mL) was cooled to 0°C and treated with a solution of LiAlH4 (1 mmol) in THF (1 mL) . The reaction was stirred at 0°C for 30 min, and ambient temperature for 40 min, then quenched with cold, dilute HCl. The mixture was extracted with Et2θ, the

extracts washed with water, dried, and the solvent removed. The residue was chromatographed (Florisil, EtOAc/hexane/MeOH) to yield the title compound. NMR(CDCl3/CD3θD) δ 6.92-7.42

(16H, m), 6.00 (IH, s) , 4.90 (IH, d) , 3.50-3.70 (2H, m) , 3.20-3.30 (IH, m) , 2.74-3.08 (4H, ) , 2.00 (IH, m) , 1.68 (IH, m) , 1.40 (9H, s) .

Example 38

Preparation of (1R.3S.4S)-2 '-(l-phenylmethyl-3-hydroxy-4-t- butoxyr.arbonylam no-5-phenylpentyl)-5'-aminocarbonylthiazole

A solution of the compound of Example 39(a) (20 mg) in MeOH (4 mL) was cooled to 0°C and saturated with NH3. The reaction was closed with a vented cap, allowed to come to ambient temperature and stirred overnight. The solvent was evaporated, the residue taken up in EtOAc, washed with water, dried, and the solvent evaporated. The residue was crystallized from a mixture of acetone and hexane to yield the title compound (9.3 mg, 46%) . NMR(CDCl3/Me2CO-D6/CD3θD) δ 8.12 (IH, s), 7.02-7.28 (10H, m) , 5.35 (IH, d) , 3.30-3.73

(3H, m), 3.06 (2H, m) , 2.78 (2H, m) , 1.80-2.10 (2H, m) , 1.38 (9H, s) .

Example 39

Preparation of (IR.3S.4S)-2'- (1-p nγlmethγl-3-hydroxy-4-t- butoxycarbonylamino-5-phenylpentγl)-5'-hydroxvmethylthiazol e

a) (IR,3S,4S)-2'-(l-phenylmethyl-3-acetoxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'-carbomethoxythiazole

Using the procedure of Example 36(b), except substituting methyl bromoacetate for phenacyl bromide, the title compound was prepared. NMR(CDCl3) δ 8.28 (IH, s) ,

6.95-7.30 (10H, m) , 4.88 (IH, m) , 4.60 (IH, d) , 3.96 (IH, m) , 3.86 (IH, m), 3.40 (IH, m) , 2.88-3.08 (2H, m) , 2.55-2.74 (2H, ), 2.08-2.30 (2H, m) , 2.06 (3H, s), 1.40 (9H, s) .

(b) (lR,3S,4S)-2'-(l-phenylmethyl-3-hydroxy-4-t- butoxycarbonylamino-5-phenylpentyl) -5 '-hydroxymethylthiazole Using the procedure of Example 37, except substituting the compound of Example 39(a), the title compound was prepared. NMR(CDCI3/CD3OD) δ 7.42 (IH, s) , 7.00-7.28 (10H, m), 5.30 (IH, d), 4.70 (2H, s) , 3.50-3.68 (2H, m) , 3.41 (IH, d), 2.90-3.08 (2H, m) , 2.38 (2H, d) , 1.98 (IH, m) , 1.86 (IH, m) , 1.34 (9H, s) .

Example 40

Preparation of (1R.3S,45)-2'-(l-pI.enylmethyl-3-hydroxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'-formylthiazole

A solution of the compound of Example 39(b) (65 mg, 0.125 mmol) in CH2CI2 (3 mL) and CH ₃ CN (3 mL) was treated with excess Mnθ2 and stirred at ambient temperature for 22 h.

The reaction was filtered, and the solvent evaporated to yield the title compound (59 mg, 91%) . NMR(CDCl3) δ 9.92

(IH, s), 8.26 (IH, s), 7.00-7.28 (10H, ) , 4.80 (IH, d) , 3.76

(IH, m) , 3.58 (IH, m) , 3.48 (IH, m) , 3.02 (2H, m) , 2, 80 (2H, m) , 2.06 (IH, m) , 1.88 (IH, m) , 1.79 (IH, s, broad), 1.40 (9H, s) .

Example 41

Preparation of (IR.3S.4S)-2 '- (1-phenylmethyl-3-hγdroxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'- (1-hydroxypropy1)- thiazole

A suspension of ethylmagnesium bromide (2 mmol) in Et2θ (5 mL) at 23°C was treated with a solution of the compound of Example 40 (50 mg, 0.1 mmol) in Et2θ (5 mL) and THF (0.5 mL) . A dense precipatate formed, and after 5 min the reaction was quenched by the addition of aq NH4CI. The layers were separated, and the organic layer was dried and the solvent evaporated. The residue was chromatographed (Florisil, 49%

EtOAc/49% hexane/2% MeOH) to yield the title compound (41 mg, 77%). NMR(CDCl3) δ 6.92-7.38 (11H, m) , 4.92 (IH, d) , 4.76

(2H, m), 3.48-3.68 (3H, m) , 2.88-3.08 (2H, m) , 2.82 (2H, d) , 2.02 (IH, m), 1.62-1.92 (4H, m) , 1.38 (9H, s) , 0.92 (3H, q) .

Example 42

Preparation of 2- r (IS.3S.4S)-l-benzyl-4-t- butoxycarbonylamino-3-hydroxy-5-phenγlpentγl1-5-propvl- thiazole; and

2-r C1R.3S _Γ 4S)-l-benzyl-4-t-b._toxycarbonylamino-3-hγdroxv-5- phenylpentyl 1-5-propyl-thiazole

The diastereomeric thiazoles of Example 4 were separated by chromatography (Microsorb® Siθ2, 10 x 250 mm column, 5 mL/min) to yield the following pure enantiomers: 2-[(lR or lS,3S,4S)-l-benzyl-4-t-butoxycarbonylamino-3- hydroxy—5-phenylpentyl]-5-propyl-thiazole (isomer A) . 3-H NMR(CDCl3) δ 0.95 (t, 3H) , 1.27 (m, 2H) , 1.35 (s, 9H) , 1.58-1.7 (m, 2H) , 2.02 (t, IH) , 2.7 (t, 2H) , 2.85-3.08 ( , 4H), 3.58 (m, 3H) , 4.92 (d, IH) , 6.95 (m, IH) , 7.1-7.3 (m, 10H) ; TLC R _f 0.55 (1:1 hexane:EtOAc) ; HPLC RT 3.9 min (Microsorb® Siθ ₂ , 4.6 x 250 mm column, 50:48:2 CH2CI2 hexane:isopropanol, 2.0 mL/min) . 2-[(lR or lS,3S,4S)-l-benzyl-4-t-butoxycarbonylamino-3- hydroxy-5-phenylpentyl]-5-propyl-thiazole (isomer B) !R NMR(CDCl3) δ 0.95 (t, 3H) , 1.28 (m, 2H) , 1.36 (s, 9H) ,

1.62 ( , 2H), 1.75-2.15 (2m, IH) , 2.7 (t, 2H) , 2.75-3.15 (m, 4H), 3.4 (br m, IH) , 3.55 (br m, IH) , 3.75 (br m, IH) , 4.9 (d, IH), 7.05 (d, IH), 7.1-7.3 (m, 10H) ; TLC R _f 0.50 (1:1 hexane:EtOAc) ; HPLC RT 5.6 min (Microsorb® Siθ2, 4.6 x 250 mm column, 50:48:2 CH2CI2 hexane:isopropanol, 2.0 mL/min) .

Example 43

Preparation of (IR.3S.4S)-2 '-(l-phenylmethyl-3-hydroxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'- (3-hydroxypropyl)- thiazole

a) (IR,3S, 4S)-2 '- (l-phenylmethyl-3-hydroxy-4-t-butoxy- carbonylamino-5-phenylpentyl)-5 '- (2-carboethoxyethenyl) - thiazole A solution of triethylphosphonoacetate (224 mg, 1 mmol) in dimethoxyethane (10 mL) was treated with NaH (40mg of a 60% dispersion) at 0°C. 1.7 mL of this solution (.17 mmol) was added at 0°C to a solution of (1R,3S,4S)-2 '- (1- phenylmethyl-3-hydroxy-4-t-butoxycarbonylamino-5- phenylpentyl)-5'-formylthiazole (29 mg, 0.056 mmol) in dimethoxyethane (2 mL) . After 1 h, a mixture of water and dilute HCl was added, and the mixture was extracted with Et2θ. The extracts were washed with water, dried, and the solvent removed. The residue was chromatographed (silica gel, 25% EtOAc/CH2Cl2) , to yield the title compound (35 mg, 53%) . NMR(CDCl3) δ 7.70 (IH, d) , 7.68 (IH, s) , 7.10-7.28

(8H, m) , 7.00 (2H, m) , 6.06 (IH, d) , 4.88 (IH, d) , 4.26 (2H, q) , 4.06 (IH, m), 3.46-3.75 (3H, m) , 3.00 (2H, m) , 2.82 (2H, m) , 2.04 (IH, ) , 1.80 (IH, m) , 1.40 (9H, s) , 1.32 (3H, t) .

b) (IR,3S,4S)-2'- (l-phenylmethyl-3-hydroxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'- (3-hydroxypropyl)- thiazole.

A solution of LiAlH4 (0.6 mmol) in THF (2.5 mL) at 0°C was treated with a solution of (IR,3S, 4S)-2 *- (1-phenylmethyl- 3-hydroxy-4-t-butoxycarbonylamino-5-phenylpentyl)-5 '-(2- carboethoxyethenyl)-thiazole (35 mg, 0.06 mmol) in THF (2.5 mL) . After 1 h at 0°C an additional LiAlH4 (0.6 mmol) was added, and stirring continued for 20 min at ambient temperature. Water was added, and enough HCl to dissolve all the solids. The mixture was extracted with Et ₂ θ, washed with H2O, dried, and the solvent removed. The resultant yellow solid was triturated with Et2θ to yield the title compound (10.5 mg, 32%) . NMR(CDCl3/CD3θD) δ 7.10-7.28 (9H, m) , 7.00 (2H, m), 5.10 (IH, d) , 3.60 (4H, m) , 3.42 (IH, m) , 3.00 (2H, ) , 2.90 (4H, m) , 2.00 (IH, m) , 1.82 (2H, quintet), 1.68 (IH, m) , 1.36 (9H, s) .

Preparation of flR,3S.4S)-2 '- (l-phenγlmethγl-3-hγdroxv-4-t- butoxycarbonylamino-5-phenylpenty1)-5'-(1 _r 2-dihydroxyethyl)- thiazole

a) (IR,3S,4S)-2 ^r -(l-phenylmethyl-3-acetoxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'-ketocarboethoxy- thiazole. A mixture of the compound of Example 36(b) (111 mg, 0.21 mmol), ethyl bromopyruvate (64 mg, 0.33 mmol), and Et3N (45 mg, 0.45 mmol) in CH ₃ CN (3 mL) was heated to 90°C for 30 min. The solvent was evaporated, and the residue taken up in EtOAc. The extracts were washed with 0.05N HCl, and water, dried, and the solvent removed. The residue was chromatographed (silica gel, 30% EtOAc/68% hexane/2% CH2CI2) , to yield the title compound (86 mg, 68%) . NMR(CDCl3) δ 8.65

(IH, s), 6.96-7.28 (10H, m) , 4.88 (IH, m) , 4.60 (IH, d) , 4.42 (2H, q), 3.98 (IH, m) , 3.40 (IH, m) , 3.02 (2H, m) , 2.65 (2H, ), 2.10-2.30 (2H, m) , 2.05 (3H, s) , 1.45 (3H, t) , 1.38 (9H, s) .

b) (IR,3S,4S)-2'-(l-phenylmethyl-3-hydroxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'-( 1, 2-dihydroxyethyl)- thiazole

A solution of the compound of Example 44(a) (86 mg, 0.14 mmol) in a mixture of THF (8 L) and Et2θ (8 mL) was cooled to 0°C and treated with a solution of LiAlH4 (1 mmol) in 1 mL of THF. The reaction was stirred at 0°C for 30 min, and ambient temperature for 40 min, then quenched with cold, dilute HCl. The mixture was extracted with Et2θ, the extracts washed with water, dried, and the solvent removed. The residue was chromatographed (Florisil, 40% EtOAc/58% hexane/2% MeOH) to yield the title compound (22 mg, 31%) . NMR(CDCl3/CD30D) δ 7.40 (IH, d) , 6.96-7.28 (10H, m) , 4.98

(IH, m), 3.46-3.82 (5H, m) , 2.88-3.08 (2H, m) , 2.80 (2H, d) , 2.00 (IH, m), 1.75 (IH, m) , 1.40 (9H, s) .

Example 45

Preparation of (3S, 4S) -2 '- (l-phenylmethyl-3-hydroxy-4- (benzyloxyπarbonyl-L-alanyl)amino-5-phenylpentyl)-5 '-propyl- thiazole

A solution of the compound of Example 4 (171 mg, 0.34 mmol) in 50% trifluoroacetic acid/methylene chloride (10 mL) was stirred at room temperature under argon for 3.5 h and then concentrated under reduced pressure to give the TFA salt of (3S,4S)-2 '- (l-phenylmethyl-3-hydroxy-4-amino-5- phenylpentyl)-5'-propyl-thiazole as a white solid (176 mg, 100%) .

The TFA salt (90.4 mg, 0.178 mmol) was diluted with DMF (10 mL) , cooled to 0°C, and diisopropylamine (23 mg, 0.178 mmol) , 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (37.6 mg, 0.196 mmol), 1-hydroxybenzotriazole (28.9 mg, 0.214 mmol), and carbobenzyloxy-L-alanine (43.8 mg, 0.196 mmol) were added. The reaction mixture was allowed to stir and warm to room temperature overnight. The DMF was evaporated and the resulting oil was diluted with EtOAc, washed successively with l.ON HCl, H2O, 5% NaHC0 ₃ , brine, and dried (MgSθ ₄ ) . Filtration, evaporation of the solvent and flash chromatography (silica gel, 33% hexane/ethyl acetate) yielded the title compound as a white solid (27 mg, 25%) . The diastereomeric mixture was separated by chromatography (Microsorb® Si02, 50:48:2 CH2CI2:hexane:isopropanol) to yield the pure enantiomers . (IR or lS,3S,4S)-2'-(l-phenylmethyl-3-hydroxy-4- (benzyloxycarbonyl-L-alanyl) amino-5-phenylpentyl)-5 '-propyl- thiazole (isomer 1) . NMR(CDC1 ₃ ), (250 MHz) δ 7.4-7.1 (m,

15H), 6.95 (d, IH), 6.3 (d, IH) , 5.25 (d, IH) , 5.05 (s, 2H) , 4.1 ( , 2H) , 3.9 (m, IH) , 3.65 (m, 2H) , 3.0 (m, IH) , 2.85 (m, 2H) , 2.7 (m, 2H) , 1.9-1.6 (m, 5H) , 1.35 (m, IH) , 1.2 (d, 3H) , 0.9 (t, 3H) , 0.75 (d, 3H) ; TLC Rf 0.35 (2:1 EtOAc:hexane) ; HPLC RT 10.2 min (Microsorb® Siθ2, 50:48:2 CH2CI2:hexane:isopropanol, 2.0 mL/min); MS m/e 600 [M+H] ⁺ .

(IR or lS, 3S, 4S) -2 '- (l-phenylmethyl-3-hydroxy-4-

(benzyloxycarbonyl-L-alanyl)amino-5-phenylpentyl)-5 '-propyl- thiazole (isomer 2) . NMR(CDC1 ₃ , 250 MHz) δ 7.4-7.1 (m, 15H) ,

7.05 (d, IH), 6.3 (d, IH) , 5.25 (d, IH) , 5.05 (s, 2H) , 4.15 (m, IH) , 4.05 (m, IH) , 3.6 (m, IH) , 3.45 (m, IH) , 3.0 (m,

IH) , 2 .8 (m, 2H) , 2. 7 (m, 2H) , 2.0 (m, 2H) , 1 . 8 (m, IH) , 1.55 (m, 2H) , 1. 25 (m, 4H) , 0 . 9 (t, 3H) ; TLC Rf 0 .32 (2 : 1 EtOAc : hexane) ; HPLC RT 15 . 7 min (Microsorb® Siθ2, 50 : 48 : 2 CH ₂ CI ₂ : hexane -. isopropanol, 2 .0 mL/min) ; MS m/e 600 [M+H] ⁺ .

Example 46

Preparation of (3S.4S)-2'-(l-phenylmet.hyl-3-hydroxv-4- (benzyloxyπarbonyl-T.-valinyl) amino-5-phenylpentγl)-5 '-propyl- thiazole

Following the procedure of Example 45, except substituting the benzyloxycarbonyl-L-valine for benzyloxycarbonyl-L-alanine, the title compounds are prepared.

The diastereomeric thiazoles were separated by chromatography (Zorbax® Siθ2) to yield the pure enantiomers: (IR or IS,3S,4S)-2'-(l-phenylmethyl-3-hydroxy-4-

(benzyloxycarbonyl-L-valinyl)amino-5-phenylpentyl)-5'-pro pyl- thiazole (isomer 1). NMR(CDC1 ₃ , 250 MHz) δ 7.4-7.1 (m, 15H) ,

6.95 (d, IH), 6.25 (d, IH) , 5.25 (d, IH) , 5.05 (s, 2H) , 3.9 ( , 2H), 3.65 (m, IH) , 3.6 (m, IH) , 3.0 (m, IH) , 2.8 (m, 2H) , 2.7 (m, 2H) , 2.05-1.75 (m, 3H) , 1.7-1.45 (m, 4H) , 0.95 (t, 3H), 0.85 (d, 3H) , 0.75 (d, 3H) ; TLC Rf 0.55 (2:1 EtOAc:hexane) ; MS m/e 628 [M+H] ⁺ .

(IR or lS,3S,4S)-2'-(l-phenylmethyl-3-hydroxy-4- (benzyloxycarbonyl-L-valinyl)amino-5-phenylpentyl)-5'-propyl - thiazole (isomer 2) . NMR(CDC1 ₃ , 250 MHz) δ 7.4-7.1 (m, 15H) ,

7.05 (d, IH), 6.25 (d, IH) , 5.25 (d, lH) , 5.1 (s, 2H) , 4.05 (m, IH) , 3.95 (m, 2H) , 3.6 (m, IH) , 3.4 (m, IH) , 3.05 (m,

IH) , 2.8 (m, 2H), 2.7 (m, 2H) , 2.1-1.9 (m, 3H) , 1.8-1.5 (m, 4H), 1.0-0.85 (dt, 3H), 0.7 (d, 3H) ; TLC Rf 0.50 (2:1 EtOAc:hexane) ; MS m/e 628 [M+H] ⁺ .

Example 47

Preparation of (IR.3S.4S)-2 '- (l-phenylmethyl-3-hγdroxγ-4-t- butoxycarbonylamino-5-phenylpenty1)-5'-(1-oxo-propy1)- thiazole

Using the procedure of Example 40, except substituting the compound of Example 41, the title compoound was prepared. NMR(CDCl3) δ 8.14 (IH, s) , 7.00-7.30 (10H, m) , 4.82 (IH, d) ,

3.46-3.82 (3H, m) , 2.98-3.10 (2H, m) , 2.76-2.92 (4H, m) , 2.06 (IH, ), 1.80 (IH, m), 1.38 (9H, s) , 1.22 (3H, t) .

Example 48

Preparation of (1R.3S.4S)-2'-(l-phenylmethyl-3-hydroxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'-carboxythiazole

A solution of the compound of Example 39(a) (25 mg, 0.045 mmol) in MeOH (3 mL) was treated with aqueous K2CO3 at ambient temperature for 4 h. The solution was diluted with H2O, and filtered. The filtrate was acidified and extracted with Et2θ. The extracts were washed with H2O, dried, and the solvent removed to yield the title compound (13.2 mg, 59%) . NMR(CDCl3) δ 8.22 (IH, s) , 6.88-7.30 (10H, m) , 4.85 (IH, d) ,

3.72 (IH, m) , 3.42-3.65 (3H, m) , 3.02 (2H, m) , 2.80 (2H, m) , 2.02 (IH, m) , 1.85 (IH, m) , 1.30 (9H, s) .

Example 49

Preparation of (IR.3S, 4S)-2 '- (l-phenγlmethγl-3-hvdroxy-4-t- butoxycarbonylamino-5-phenγlpentyl)-5 '- (l-hydroxy-2- methylpropyl)-thiazol

Using the procedure of Example 41, except substituting the isoproyl magnesium bromide for ethyl magnesium bromide, the title compound was prepared. NMR(CD3θD) δ 7.32 (IH, d) ,

6.90-7.15 (10H, m) , 6.10 (IH, d) , 4.42 (IH, dd) , 3.52 (2H,

m) , 3 .32 (IH, m) , 2. 88 (2H, m) , 2 . 70 (IH, dd) , 2 .55 (IH, dd) , 1. 62-1. 90 (3H, m) , 1 .25 (9H, s) , 0 . 86 (3H, d) , 0 . 68 (3H, dd) .

Example 50

Preparation of (IR. 3S , 4S ) -2 ' - ( 1 -phenvlmethvl-3-hγdroxv-4-t- frutoxycarbonylamino-S-phenylpentyl ) -5 ' - (N ' - benzyloxycarbonyl guanidino) carbonylthiazole

A solution of the compound of Example 48 (70 mg, 0.13 mmol) in CH2CI2 (4 mL) was treated with N- hydroxybenzotriazole (18 mg, 0.13 mmol), J.-(3— dimethylaminopropyl)-3-ethylcarbodiimide methiodide (39 mg, 0.13 mmol), and carbobenzyloxyguanidine (25 mg, 0.13 mmol). After 2 h at ambient temperature, the solvent was evaporated, and the residue taken up in Et2θ. The extracts were washed with 0.05N HCl, aq. NaHC03, and aq. NaHS03. The extracts were dried, and the solvent evaporated, and the residue chromatographed (silica gel, 74% EtOAc/25% hexane/1% MeOH) to yield the title compound (58 mg) . NMR(CDCl3) δ 8.88 (IH, broad s) , 8.42 (IH, broad s) , 8.16 (IH, s) , 7.35 (5H, s) ,

7.10-7.30 (8H, m) , 6.96 (2H, dd) , 5.20 (2H, s) , 4.84 (IH, d) , 4.26 (IH, broad s), 3.63 (2H, m), 3.52 (IH, d) , 3.06 (IH, dd), 2.92 (IH, dd) , 2.80 (2H, d) , 2.02 (IH, m) , 1.72 (IH, m) , 1.62 (IH, broad s) , 1.38 (9H, s) .

Example 51

Preparat on of (1 .3S.4S)-2 '-(1-phenYl thYl^-hYdroxy^-t- hn yo bonyl m no-5-phenylpentyl)-5'-(1- aminoπarbonylpropyl )-thia o1

a) (lR,3S,4S)-2'-(l-phenylmethyl-3-acetoxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'-(1-chloropropyl)- thiazole A solution of (IR,3S,4S)-2'-(l-phenylmethyl-3-acetoxy-4- t-butoxycarbonylamino-5-phenylpentyl)-5*-(1-hydroxypropyl)- thiazole (49 mg, 0.089 mmol) in CH2CI2 (5 mL) at 0°C was treated with Et3 (9 mg, 0.089 mmol), and thionyl chloride

(11 mg, 0.089 mmol) . After 30 min at 0°C, water was added, and the layers were seperated. The organic layer was washed with cold, dilute HCl, and water, and the extracts were dried and the solvent removed. The residue was chromatographed (silica gel, 5% EtOAc/CH2Cl2) to yield the title compound (20 mg, 41%) . NMR(CDCl3) δ 7.52 (IH, d) , 7.08-7.30 (8H, m) , 6.98

(2H, m), 5.00 (IH, t) , 4.90 (IH, m) , 4.58 (IH, dd) , 3.98 (IH, m), 3.34 (IH, m), 3.04 (IH, dd) , 2.90 (IH, dd) , 2.62 (2H, t) , 2.10 (4H, m), 2.00 (3H, s) , 1.38 (9H, s) , 1.00 (3H, q) .

b) (lR,3S,4S)-2'-(l-phenylmethyl-3-acetoxy-4-t-butoxy- carbonylamino-5-phenylpentyl)-5 '- (1-carbomethoxy-propyl)- thiazole

A solution of the compound of Example 51(a) (135 mg, 0.24 mmol) in DMF (3 mL) and MeOH (2 mL) was treated with Pd (OAc) 2 (14 mg, 0.0625 mmol), PI13P (33 mg, 0.125 mmol), and Et3N (48 mg, 0.48 mmol) . Carbon monoxide was bubbled through the reaction for 30 min, the vessel was sealed, and heated overnight at 45°C. The mixture was cooled, diluted with water, acidified with dilute HCl, and extracted with Et2θ. The extracts were washed with water, dried, and the solvent removed. The residue was chromatographed (silica gel 10% EtOAc/CHCl3) to yield the title compound (45 mg, 32%) . NMR(CDCl3) δ 7.75 (IH, m) , 7.45 (IH, d) , 7.04-7.40 (7H, m) , 6.96 (2H, m) , 4.90 (IH, m) , 4.56 (IH, d) , 3.96 (IH, m) , 3.69 (3H, s), 3.32 (IH, m), 3.02 (IH, dd) , 2.90 (IH, dd) , 2.62 (2H, m) , 2.00 (3H, s) , 1.68-2.10 (4H, m) , 1.32 (9H, s) , 0.88 (3H, m) .

Also isolated from this reaction and chromatography was (IR,3S,4S)-2 '-(l-phenylmethyl-3-acetoxy-4-t-butoxycarbonyl- amino-5-phenylpentyl)-5 '- (1- methoxypropyl)-thiazole. NMR(CDCl3) δ 7.50 (IH, s) , 7.08-7.30 (8H, m) , 6.94 (2H, d) ,

4.90 (IH, ), 4.58 (IH, d) , 4.20 (IH, t) , 3.96 (IH, m) , 3.35 (IH, m), 3.18 (1.5H, s) , 3.12 (1.5H, s) , 3.00 (IH, dd) , 2.90 (IH, dd) , 2.69 (IH, dd) , 2.58 (IH, dd) , 2.18 (IH, m) , 2.10 (IH, m), 2.02 (3H, s) , 1.85 (IH, m) , 1.60 (IH, ) , 1.32 (9H, s), 0.84 (3H, q) .

c) (1R,3S,4S)-2'-(l-phenylmethyl-3-hydroxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'-(1-carboxypropyl)- thiazole

Following the procedure of Example 48, the compound of Example 51(b) was hydrolyzed to yield the title compound.

d) (IR,3S,4S)-2'-(l-phenylmethyl-3-hydroxy-4-t- butoxycarbonylamino-5-ρhenylpentyl)-5'-(1- carbomethoxypropyl)-thiazole A solution of (IR,3S,4S)-2'-(l-phenylmethyl-3-hydroxy-4- t-butoxycarbonylamino-5-phenylpentyl)-5'-(1-carboxypropyl)- thiazole in Et2θ was treated with an excess of an ethereal solution of CH2N2. The solvent was evaporated to yield the title compound. NMRCCDCI3) δ 7.42 (IH, s), 7.12-7.28 (8H, m), 6.90 (2H _r d), 4.90 (IH, d), 3.72 (3H, s), 3.58 (4H, m) , 3.02 (IH, dd), 2.90 (IH, dd) , 2.85 (2H, m) , 2.00 (2H, m) , 1.62-1.80 (2H, ) , 1.32 (9H, s) , 0.88 (3H, ) .

Example 52

Preparation of (IR. S.4S)-2'- (l-phenylmethyl-3-hvdroxv-4-t- butoxycarbonylamino-5-phenylpentyl)- '-(1-methoxypropyl ) - thiazole

(IR,3S, S)-2'-(l-phenylmethyl-3-acetoxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'-(1-methoxypropyl)- thiazole, isolated from the reaction of Example 51(b), was hydrolyzed according to the procedure of Example 48 to yield the title compound. NMR(CDCl3) 7.42 (IH, s) , 7.10-7.28 (8H, m) , 6.92 (2H, d) , 4.90 (IH, d) , 4.20 (IH, t) , 3.58 (3H, m), 3.20 (1.5H, s), 3.14 (1.5H, s) , 3.02 (IH, dd), 2.90 (IH, dd) _Λ 2.85 (2H, m) , 2.04 (IH, m) , 1.86 (IH, m) , 1.68 (IH, dd) , 1.60 (IH, dd), 1.35 (9H, s), 0.86 (1.5H, t), 0.82 (1.5H, t) .

Example 53

Preparation of IR.3S.4S)- '-(1-phenylmethyl-3-hvdroxv-4-t- butoxγcarbonylamino-5-phenylpentyl)-5'-(l-aττιinocarbonv l- propyl)-thiazole

A solution of the compound of Example 51(b) (30 mg, 0.05 mmol) in MeOH (5 mL) was cooled in an ice bath, and saturated with NH3 gas. The reaction vessel was sealed with a vented cap, allowed to come to ambient temperature, and stirred 16 h. The solvents were evaporated, and the residue taken up in EtOAc. The extract was washed with water and dilute HCl, dried, and the solvents evaporated. Trituration of the residue with Et2θ gave the title compound (7.2 mg, 27%) . NMR(CDCl3) δ 7.42 (IH, s) , 7.10-7.30 (8H, m) , 6.92 (2H, m) ,

5.60 (IH, br s), 5.50 (IH, br s) , 5.42 (IH, broad s) , 4.92 ^• (IH, d), 3.68 (IH, m), 3.42-3.60 (3H, m) , 3.00 (IH, dd) , 2.90 (IH, dd), 2.80 (2H, d) , 1.92-2.14 (2H, m) , 1.58-1.80 (2H, m) , 1.32 (9H, s), 0.90 (3H, m) .

Example 54

Parenteral Dosage Unit Composition

A suitable dosage form for intravenous administration is prepared by dissolving the compound of Example 1 (25 mg) in dimethyl sulfoxide or formamide (1 mL) , diluting to 20 mL with a 70% propylene glycol/30% ethanol solution, and filtering the resultant solution under sterile conditions. This solution is also suitable for use in other methods of administration, such as addition to a bottle or bag for IV drip infusion.

Example 55

Oral Dosage Unit Composition

A capsule for oral administration is prepared by mixing and milling 200 mg of the compound with 450 mg of lactose and

30 mg of magnesium stearate. The resulting powder is screened and filled into a hard gelatin capsule.

The above description fully discloses how to make and use this invention. This invention, however, is not limited to the precise embodiments described herein, but encompasses all modifications within the scope of the claims which follow.