TITLE

CYCLIC UREAS AND ANALOGUES USEFUL AS RETROv RAL PROTEASE INED IT KS

rmss-rf-ffirsnr.P tτ> Ra rl i r Fi l eri Appl ^* i πaf. i nn

This application is a continuation-in-part of U . S . Patent Application Serial Number 07/883 , 944 , filed May 15, 1992, which is a continuation-in-part of U . S . Patent Application Serial Number 07/776, 491 , filed October 11, 1991 .

FIELD OF THE INVENTION

This invention relates to substituted cyclic carbonyls and derivatives thereof useful as retroviral protease inhibitors, to pharmaceutical compositions comprising such compounds, and to methods of using these compounds for treating viral infection.

BACKGROUND OF THE INVENTION

Current treatments for viral diseases usually involve administration of compounds that inhibit viral DNA synthesis. Current treatments for AIDS (Dagani, Chem . Eng. News, November 23, 1987 pp. 41-49) involve administration of compounds such as 2 ',3'- dideoxycytidine, trisodium phosphonoformate, ammonium 21-tungsto-9-antimoniate, l-b-D-ribofuranoxyl-1,2, 4- triazole-3-carboxamide, 3 '-azido-3 '-deoxythymidine (AZT) , and adriamycin that inhibit viral DNA synthesis; compounds such as AL-721 and polymannoacetate which may prevent HIV from penetrating the host cell; and compounds which treat the opportunistic infections caused by the immunosupression resulting from HIV

infection. None of the current AIDS treatments have proven to be totally effective in treating and/or reversing the disease. In addition, many of the compounds currently used to treat AIDS cause adverse side effects including low platelet count, renal toxicity, and bone marrow cytopenia.

Proteases are enzymes which cleave proteins at specific peptide bonds. Many biological functions are controlled or mediated by proteases and their complementary protease inhibitors. For example, the protease renin cleaves the peptide angiotensinogen to produce the peptide angiotensin I. Angiotensin I is further cleaved by the protease angiotensin converting enzyme (ACE) to form the hypotensive peptide angiotensin II. Inhibitors of renin and ACE are known to reduce high blood pressure in vivo. However, no therapeutically useful renin protease inhibitors have been developed, due to problems of oral availability and in vivo stability. The genomes of retroviruses encode a protease that is responsible for the proteolytic processing of one or more polyprotein precursors such as the pol and gag gene products. See ellink, Arch. Virol . __ ^' l (1988). Retroviral proteases most commonly process the sa≤[ precursor into the core proteins, and also process the pol precursor into reverse transcriptase and retroviral protease.

The correct processing of the precursor polyproteins by the retroviral protease is necessary for the assembly of the infectious virions. It has been shown that in vitro mutagenesis that produces protease- defective virus leads to the production of immature core forms which lack infectivity. See Crawford, J. Virol . 53 899 (1985); Katoh et al., Viroloσγ 145 280 (1985). Therefore, retroviral protease inhibition provides an

attractive target for antiviral therapy. See Mitsuya, Nature _2_ 775 (1987) .

Moore, Biochem. Biophys . Res . Commun . , 159 420 (1989) discloses peptidyl inhibitors of HIV protease. Erickson, European Patent Application No. WO 89/10752 discloses derivatives of peptides which are inhibitors of HIV protease.

U.S. Patent No. 4,652,552 discloses methyl ketone derivatives of tetrapeptides as inhibitors of viral proteases. U.S. Patent No. 4,644,055 discloses halomethyl derivatives of peptides as inhibitors of viral proteases. European Patent Application No. WO 87/07836 discloses L-glutamic acid gamma- monohydroxamate as an antiviral agent. The ability to inhibit a viral protease provides a method for blocking viral replication and therefore a treatment for viral diseases, such as AIDS, that may have fewer side effects, be more efficacious, and be less prone to drug resistance when compared to current treatments.

The topic of the present invention is substituted cyclic carbonyls and derivatives thereof, which compounds are capable of inhibiting viral protease and which compounds are believed to serve as a means of combating viral diseases, such as AIDS. The substituted cyclic carbonyls and derivatives thereof of this invention provide significant improvements over protease inhibitors that are known in the art. A large number of compounds have been reported to be inhibitors of proteases, such as renin, but these have suffered from lack of adequate bioavailability and are thus not useful as therapeutic agents, particularly if oral administration is desired. This poor activity has been ascribed to the relatively high molecular weight of most protease inhibitors, to inadequate solubility properties, and to the presence of a number of peptide

bonds, which are vulnerable to cleavage by mammalian proteases in vivo and which generally cause the molecules to be extensively bound in human serum. The substituted cyclic carbonyls and derivatives described herein have a distinct advantage in this regard, in that they do not contain peptide bonds, are of low molecular weight, and can be hydrophilic yet still inhibit the viral protease enzyme.

Additionally, known inhibitors of other non-HIV proteases do not inhibit HIV protease. The structure- activity requirements of such inhibitors differ from those of HIV protease inhibitors. The substituted cyclic carbonyls and derivatives of the invention are particularly useful as inhibitors of HIV protease and similar retroviral proteases.

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

DETAILED DESCRIPTION OF THE INVENTION

There is provided by this invention a compound of the formula (I) :

(I)

or a pharmaceutically acceptable salt or prodrug form thereof wherein:

R ⁴ and R ⁷ are independently selected from the following groups:

hydrogen;

C1-C8 alkyl substituted with 0-3 R ¹¹ ;

C2 ^-c 8 alkenyl substituted with 0-3 R ¹¹ ; ^c 2~ ^c 8 alkynyl substituted with 0-3 R ¹¹ ;

C3-C8 cycloalkyl substituted with 0-3 R ¹¹ ; 6-C10 bicycloalkyl substituted with 0-3 R ¹¹ ; aryl substituted with 0-3 Rl2; a C6-C1 carbocyclic residue substituted with 0-3

Rl2; a heterocyclic ring system substituted with 0-2 R-^-2, composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom;

R^ ^A and R^ ^A are independently selected from the following groups:

hydrogen;

C1-C4 alkyl substituted with halogen or Cχ-C2 alkoxy; benzyl substituted with halogen or C1.-C2 alkoxy;

R ⁴ and R ^4A can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R ² ;

R ⁷ and R ^7A can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R ¹² ;

n is 0, 1, or 2;

R5 is selected from fluoro, difluoro, =0, C1-C3 alkyl or -OR ²⁰ ;

R6, when n is 1, is selected from: hydrogen, =0, fluoro, difluoro, C1-C3 alkyl or -OR ²¹ ;

R6, when n is 2, is independently selected from: hydrogen, =0, fluoro, difluoro, C1-C3 alkyl or -OR ²¹ ;

R5 and R^ can alternatively join to form an epoxide ring; -OCH ₂ SCH ₂ O-; -OS(=0)0-; -0C(=0)0-; -OCH ₂ O-; -0C(=S)0-; -0C(=0)C(=0)0-; -0C(CR_) ₂ 0-;

-0C(0C_ ₃ ) (CH ₂ CH ₂ CH ₃ )0-; or any group that, when administered to a mammalian subject, cleaves to form a free dihydroxyl;

R ²⁰ and R ²¹ are independently selected from:

hydrogen;

Cl-Ce alkyl substituted with 0-3 R ¹¹ ; C3-C6 alkoxyalkyl substituted with 0-3 R ¹¹ ; C1-C6 alkylcarbonyl substituted with 0-3 R ¹¹ ; C1-C6 alkoxycarbonyl substituted with 0-3 R ¹ ; benzoyl substituted with 0-3 R ¹² ; phenoxycarbonyl substituted with 0-3 R ¹² ; phenylaminocarbonyl substituted with 0-3 R ¹ ;or

any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl;

R ¹¹ is selected from one or more of the following:

keto, halogen, cyano, -CH2NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -C02R ¹³ , -0C(=0)R ¹³ , -OR ¹³ , C2-C6 alkoxyalkyl, -S(0) _m R ¹³ , -NHC(=NH)NHR ¹³ , -C (=NH)NHR ¹³ , -C(-=0)NR ¹³ R ¹⁴ , -NR ¹⁴ C(-=0)R ¹³ , =N0R ¹⁴ , -NR ¹⁴ C(=0)0R ¹⁴ , -OC(=0)NR ¹³ R ¹⁴ , -NR ¹³ C (=0)NR ¹³ R ¹⁴ , -NR ¹ S02NR ¹³ R ¹⁴ , -NR ¹ S02R ¹³ , -Sθ2NR ¹³ R ¹⁴ , C1-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl;

1-3 amino acids, linked together via amide bonds and linked to R ⁴ or R ⁷ via the amine or carboxylate terminus;

a C5-C14 carbocyclic residue substituted with 0-3 R ¹² ;

aryl substituted with 0-3 R ¹² ; or

a heterocyclic ring system substituted with 0-2 R ¹ ^, composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom;

R ¹² , when a substituent on carbon, is selected from one or more of the following:

phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, C7-C10 arylalkyl, C1-C4 alkoxy, -CO2H, hydroxamic acid, hydrazide, oxime, boronic acid, sulfonamide, formyl, C3-C6

cycloalkoxy, -OR ¹³ , C ₁ -C ₄ alkyl substituted with -NR ¹³ R ¹⁴ , -NR ^1S R ¹⁴ , C2-C6 alkoxyalkyl, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(0) _m R ¹³ , -Sθ2NR ¹³ R ¹⁴ , -NHSO2R ¹⁴ , -OCH2CO2H, 2-(l-morpholino)ethoxy; or

a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur;

or R ¹² may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6- membered ring, said 5- or 6- membered ring being optionally substituted on the aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or -NR ¹ R ¹⁴ ; or, when R ¹² is attached to a saturated carbon atom, it may be carbonyl or thiocarbonyl;

R ² , when a substituent on nitrogen, is selected from one or more of the following:

phenyl, benzyl, phenethyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , C2-C6 alkoxyalkyl, C1-C4 haloalkyl, C1-C4 alkoxycarbonyl, -CO2H, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl;

R ¹³ is H, phenyl, benzyl, C1-C6 alkyl, or C3-C6 alkoxyalkyl;

R ¹⁴ is OH, H, C1-C4 alkyl, or benzyl;

R ¹³ and R ¹⁴ can alternatively join to form -(CH2)4~,

(CH2)5~, -CH2CH2N(R ¹ 5)CH2CH2-, or -CH2CH2OCH2CH2-

R ¹⁵ is H or CH3;

m is 0, 1 or 2;

W is selected from:

Z is 0, S, or NR ²⁴ ;

R ²² and R ²³ are independently selected from the following:

hydrogen;

C1-C8 alkyl substituted with 0-3 R ³¹ ; C2-C8 alkenyl substituted with 0-3 R ³¹ ; C2-C8 alkynyl substituted with 0-3 R ³¹ ; C3-C8 cycloalkyl substituted with 0-3 R ³¹ ; C6-C10 bicycloalkyl substituted with 0-3 R ³¹ ; aryl substituted with 0-3 R ³² ;

a C -C14 carbocyclic residue substituted with 0-3 _R 32. a heterocyclic ring system substituted with 0-2 R ³² , composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom;

R ²⁴ is selected from: hydroxy; amino; C1-C4 alkyl; C1-C4 alkoxy; C1-C4 aminoalkyl; cyano; nitro; benzyloxy;

R ²⁵ and R ²⁷ are independently selected from the following:

hydrogen;

C1-C8 alkyl substituted with 0-3 R ³¹ ; C2-C8 alkenyl substituted with 0-3 R ³¹ ;

C2-C8 alkynyl substituted with 0-3 R ³¹ ;

C3-C8 cycloalkyl substituted with 0-3 R ³¹ ;

C6-C10 bicycloalkyl substituted with 0-3 R ³¹ ; aryl substituted with 0-3 R ³² ; a C6-C14 carbocyclic residue substituted with 0-3

R32; a heterocyclic ring system substituted with 0-2

R ³² , composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom;

R ^ and R ²⁸ are independently selected from:

hydrogen;

C1-C4 alkyl substituted with halogen or C1-C2 alkoxy; benzyl substituted with halogen or Cχ-C2 alkoxy;

R ² -* ¹ is selected from:

hydrogen;

C1-C4 alkyl substituted with halogen or C1-C2 alkoxy; benzyl substituted with halogen or C1-C2 alkoxy;

alternatively, R ²² , R ² -*-, or R ² ^, independently, can join with R ⁴ or R ^4A to form a five- or six-membered fused heterocyclic, aromatic, or alicyclic ring substituted with 0-2 R ¹² ; and

alternatively, R ²³ , R ²⁷ , or R ²⁸ , independently, can join with R ⁷ or R ^7A to form a five- or six-membered fused heterocyclic, aromatic, or alicyclic ring substituted with 0-2 R ¹² ; and

alternatively, W can join with R^ or R^ to form a three- to seven-membered fused heterocyclic or carbocyclic ring substituted with 0-2 R ¹² ;

R ³¹ is selected from one or more of the following:

keto, halogen, cyano, -CH ₂ NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ ,

-C02R ¹³ ,

-0C(=0)R ¹³ , -OR ¹³ , C2-C6 alkoxyalkyl, -S(0) _m R ¹³ , -NHC(=NH)NHR ¹³ , -C(=NH)NHR ¹³ , -C(=0)NR ¹³ R ¹⁴ , -NR ¹ C(=0)R ¹³ , =NOR ¹⁴ , -NR ¹⁴ C(=0)OR ¹⁴ , -OC(=0)NR ¹³ R ¹⁴ , -NR ¹³ C(=0)NR ¹³ R ¹⁴ , -NR ¹⁴ S02NR ¹³ R ¹ , -NR ¹ S02R ¹³ , -S02NR ¹³ R ¹⁴ , C1-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl;

1-3 amino acids, linked together via amide bonds and linked to R ⁴ or R ⁷ via the amine or carboxylate terminus;

a C5-C14 carbocyclic residue substituted with 0-3 R ³² ;

aryl substituted with 0-3 R ³² ; or

a heterocyclic ring system substituted with 0-2 R ³² , composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom;

R ³² , when a substituent on carbon, is selected from one or more of the following:

phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, C7-C10 arylalkyl, C1-C4 alkoxy, -CO2H, hydroxamic acid, hydrazide, oxime, boronic acid, sulfonamide, formyl, C3-C6 cycloalkoxy, -OR ¹³ , C ₁ -C4 alkyl substituted with -NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , C2-C6 alkoxyalkyl, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(O)-χ-R ¹³ r -S02NR ¹³ R ¹⁴ , -NHSO2R ¹⁴ , -OCH2CO2H, 2-(l-morpholino)ethoxy, -C(R ¹⁴ )=N(OR ¹⁴ ) ; or

a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur;

or R ³² may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6- membered ring, said 5- or 6- membered ring being optionally substituted on the aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or -NR ¹ R ¹⁴ ; or, when R ³² is attached to a saturated carbon atom, it may be carbonyl or thiocarbonyl;

R ³² , when a substituent on nitrogen, is selected from one or more of the following:

phenyl, benzyl, phenethyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , C2-C6 alkoxyalkyl, C1-C4 haloalkyl, C1-C4 alkoxycarbonyl, -CO2H, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, -C(R ¹⁴ )=N(OR ¹⁴ ) ;

provided that:

R ⁴ , R ^4A , R ⁷ and R ^A are not all hydrogen;

when W is -OC(=Z)0-, R ⁴ and R ⁷ are not hydrogen;

when R ⁴ , R ^4A are hydrogen, at least one of the following is not hydrogen: R ²² , R ²³ , R ² 5, R ² 6, R ²⁷ and R ²⁸ .

Preferred compounds of this invention are compounds of the formula (I) :

(I)

or a pharmaceutically acceptable salt or prodrug form thereof wherein:

R ⁴ and R ⁷ are independently selected from the following groups :

hydrogen; C ₁ -C ₄ alkyl substituted with 0-3 R ¹¹ ;

C ₃ -C ₄ alkenyl substituted with 0-3 R ¹¹ ; C3-C ₄ alkynyl substituted with 0-3 R ¹¹ ;

R4 _ _n _ R A _{are h} y _d rogen;

n is 0 or 1;

R5 is selected from fluoro, difluoro, =0, or -OR ²⁰ ;

R is selected from: hydrogen, =0, fluoro, difluoro, or -OR ²¹

R5 and R^ can alternatively join to form an epoxide ring; -OCH ₂ SCH ₂ O-; -OS(=0)0-; -0C(=0)0-; -0CH ₂ 0-; -0C(=S)0-; -0C(=0)C(=0)0-; -0C(CH ₃ ) ₂ 0-;

-0C(0CH ₃ ) (CH ₂ CH ₂ CH ₃ )0-; or any group that, when administered to a mammalian subject, cleaves to form a free dihydroxyl;

R ²⁰ and R ² are independently selected from:

hydrogen;

C1-C6 alkylcarbonyl; C1-C6 alkoxycarbonyl; benzoyl; or any group that, when administered to a mammalian subject, cleaves to form a free hydrox 1;

R ¹¹ is selected from one or more of the following:

keto, halogen, cyano, -CH ₂ NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -C02R ¹³ ,

-0C(=0)R ¹³ , -OR ¹³ , C2-C4 alkoxyalkyl, -S(0) _m R ¹³ , C1-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl;

a C5-C14 carbocyclic residue substituted with 0-3 R ¹² ;

aryl substituted with 0-3 R ¹² ; or

a heterocyclic ring system substituted with 0-2 R ¹² , composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom;

R ¹² , when a substituent on carbon, is selected from one or more of the following:

phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, C7-C10 arylalkyl, C1-C4 alkoxy, -CO2H, hydroxamic acid, hydrazide, oxime, boronic acid, sulfonamide, formyl, C3-C6 cycloalkoxy, -OR ¹³ , C ₁ -C ₄ alkyl substituted with -NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , C2-C6 alkoxyalkyl, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(0) R ¹³ , -S02NR ¹³ R ¹⁴ , -NHS02R ¹⁴ ; or

a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur;

or R ¹² may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6- membered ring, said 5- or 6- membered ring being optionally substituted on the aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or

-NR ¹³ R ¹⁴ ; or, when R ¹² is attached to a saturated carbon atom, it may be carbonyl or thiocarbonyl;

R ¹² , when a substituent on nitrogen, is selected from one or more of the following:

phenyl, benzyl, phenethyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , C2-C6 alkoxyalkyl, C1-C4 haloalkyl, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, -CO2H;

R ¹³ is H, C1-C6 alkyl, or C3-C6 alkoxyalkyl;

R ¹⁴ is OH, H, C1-C4 alkyl, or benzyl;

R ¹³ and R ⁴ can alternatively join to form -(CH2)4~, -(CH2)5~r -CH2CH2N(R ¹ )CH2CH2-, or -CH2CH2OCH2CH2-;

R ¹⁵ is H or CH3;

m is 0, 1 or 2;

W is selected from:

-N(R ²² )C(=Z)N(R ²³ )-; -N(R ²² )C(=Z)0-;

-C(R ²⁵ ) (R ²⁶ )C(=Z)C(R ²⁷ ) (R ²⁸ )-; -N(R ²² )C(=Z)C(R ²⁷ ) (R ²⁸ )-;

-C(R ²⁵ ) (R ²⁶ )C(=Z)0-;

-N (R ²² ) C (=0) C (=0) (R ²³ ) -;

-C(R ²⁵ ) (R ²⁶ )C(F2)C(R ²⁷ ) (R ²⁸ )-;

wherein:

Z is 0, S, N-CN, N-OH, N-OCH3;

R ²² and R ²³ are independently selected from the following:

hydrogen;

C1-C8 alkyl substituted with 0-3 R ³¹ ; C3-C8 alkenyl substituted with 0-3 R ³¹ ; C3-C8 alkynyl substituted with 0-3 R ³¹ ;

C3-C6 cycloalkyl substituted with 0-3 R ³¹ ;

R ² 5 and R ²⁷ are independently selected from the following:

hydrogen;

C1-C8 alkyl substituted with 0-3 R ³¹ ; C2-C8 alkenyl substituted with 0-3 R ³¹ ; C3-C8 alkynyl substituted with 0-3 R ³¹ ;

R 6 and R ²⁸ are hydrogen;

R ³¹ is selected from one or more of the following:

keto, halogen, cyano, -CH2NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ ,

-C02R ¹³ , -0C(=0)R ¹³ , -OR ¹³ , C2-C4 alkoxyalkyl, -S(0) _m R ¹³ , C1-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl;

a C5-C ₁₄ carbocyclic residue substituted with 0-3 R ² ;

aryl substituted with 0-3 R ³² ; or

a heterocyclic ring system substituted with 0-2 R ³² , composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom;

R ³² , when a substituent on carbon, is selected from one or more of the following:

phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, C7-C10 arylalkyl, C ₃ .-C4 alkoxy, -CO2H, hydroxamic acid, hydrazide, oxi e, boronic acid, sulfonamide, formyl, C ₃ -C ₆ cycloalkoxy, -OR ¹³ , C ₁ -C ₄ alkyl substituted with -NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , C2-C6 alkoxyalkyl, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(0)m " ¹ " ³ / -S02NR ¹³ R ¹⁴ , -NHS02R ¹⁴ , -C(R ¹ )=N(0R ¹⁴ ) ; or

a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur;

or R ³² may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6- membered ring, said 5- or 6- membered ring being optionally substituted on the aliphatic carbons with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, or

-NR ¹³ R ¹⁴ ; or, when R ³² is attached to a saturated carbon atom, it may be carbonyl or thiocarbonyl;

R ³² , when a substituent on nitrogen, is selected from one or more of the following:

phenyl, benzyl, phenethyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, -CH2NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , C2-C6 alkoxyalkyl, C1-C4 haloalkyl, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, -CO2H, -C (R ¹⁴ )=N(OR ¹⁴ ) ;

provided that:

R ⁴ , R ^A , R ⁷ , and R ^7A are not all hydrogen;

when W is -OC(=Z)0-, R ⁴ and R ⁷ are not hydrogen;

when R ⁴ and R ^4A are hydrogen, at least one of the following is not hydrogen: R ²² , R ²³ , R ²⁵ , R ²⁶ , R ²⁷ and R ²⁸ .

Further preferred compounds of the invention of formula (I) are compounds of formula (II) :

(II)

R ⁴ and R ⁷ are independently selected from the following groups :

hydrogen;

C1-C4 alkyl substituted with 0-3 R ¹¹ ;

C3-C4 alkenyl substituted with 0-3 R ¹¹ ;

R ⁵ -is -OR ²⁰ ;

R ⁶ is hydrogen or -OR ²¹ ;

R ²⁰ and R ²¹ are independently hydrogen or any group that, when administered to a mammalian subject, cleaves to form a free hydroxy1;

R ¹¹ is selected from one or more of the following:

keto, halogen, -CH ₂ NR ¹³ R ¹⁴ , -NR ^l3 R ¹⁴ , -OR ¹³ , C2-C4 alkoxyalkyl, C1-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl;

aryl substituted with 0-3 R ¹² ; or

a heterocyclic ring system substituted with 0-2

R ¹² , composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom;

R ² , when a substituent on carbon, is selected from one or more of the following:

phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, C1-C4 alkyl, C7-C10 arylalkyl, C1-C4 alkoxy, -CO2H, hydroxamic acid, hydrazide, oxime, boronic acid, sulfonamide, formyl, C ₃ -C ₆ cycloalkoxy, -OR ¹³ ,

C ₁ -C ₄ alkyl substituted with -NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , methylenedioxy, C1-C4 haloalkyl, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, hydroxy, hydroxymethyl; or

a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur;

R ¹² , when a substituent on nitrogen, is selected from benzyl or methyl;

R ¹³ is H, C1-C2 alkyl, or C3-C6 alkoxyalkyl;

R ¹⁴ is OH, H or C1-C2 alkyl;

R ¹³ and R ¹⁴ can alternatively join to form -(CH2)4~, -(CH2)5-, -CH2CH2N(R ¹⁵ )CH2CH2-, or -CH2CH2OCH2CH2-;

W is selected from:

-N(R ²² )C(=Z)N(R ²³ )-; -C(R ²⁵ ) (R ²⁶ )C(=Z)C(R ²⁷ ) (R ²⁸ )-; -N(R ²² )C(=Z)C(R ²⁷ ) (R ²⁸ )-; -C(R ²⁵ ) (R ²⁶ )C(=Z)0-;

wherein:

Z is 0, S, or N-CN;

R ²² and R ²³ are independently selected from the following:

hydrogen;

C1-C4 alkyl substituted with 0-3 R ³¹ ; C3-C4 alkenyl substituted with 0-3 R ³¹ ;

R ² --* and R ²⁷ are independently selected from the following :

hydrogen ; C1-C4 alkyl substituted with 0-3 R ³¹ ;

C3-C4 alkenyl substituted with 0-3 R ³¹ ;

R ² -*- and R ²⁸ are hydrogen;

R ³¹ is selected from one or more of the following :

keto, halogen, -CH ₂ NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -OR ¹³ , C2-C4 alkoxyalkyl, C1-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl;

aryl substituted with 0-3 R ³² ; or

a heterocyclic ring system substituted with 0-2 R ³² , composed of 5 to 10 atoms including at least one nitrogen, oxygen or sulfur atom;

R ³² , when a substituent on carbon, is selected from one or more of the following:

phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, C1-C4 alkyl, C7-C10 arylalkyl, C1-C4 alkoxy, -CO2H, hydroxamic acid, hydrazide, oxime, boronic acid, sulfonamide, formyl, C ₃ -C ₆ cycloalkoxy, -OR ¹³ , C ₁ -C ₄ alkyl substituted with -NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , methylenedioxy, C1-C4 haloalkyl, C1-C4 alkylcarbonyl, C1-C4 alk lcarbonylamino, hydroxy, hydroxymethyl, -C(R ¹⁴ )=N(0R ¹⁴ ) ; or

a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur;

R ³² , when a substituent on nitrogen, is selected from benzyl or methyl;

provided that:

R ⁴ and R ⁷ are not both hydrogen;

when R ⁴ is hydrogen, at least one of the following is not hydrogen: R ²² , R ²³ , R ²⁵ , R ²⁶ , R ²⁷ and R ²⁸ .

More preferred compounds of the present invention are compounds of the further preferred scope above, wherein:

R ⁴ and R ⁷ are independently selected from the following groups:

hydrogen;

C1-C3 alkyl substituted with 0-1 R ¹¹ ;

R ⁵ is -OR ²⁰ ;

R6 is hydrogen or -OR ²¹ ;

R ²⁰ and R ² are independently hydrogen or any group that, when administered to a mammalian subject, cleaves to form a free hydroxy1;

R ¹ is selected from one or more of the following:

halogen, -OR ¹³ , C1-C4 alkyl, C3-C5 cycloalkyl;

aryl substituted with 0-2 R ¹² ; or a heterocyclic ring system chosen from pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl;

R ¹² , when a substituent on carbon, is selected from one or more of the following:

benzyloxy, halogen, methyl, C1-C4 alkoxy, CF3, 2-(l-morpholino)ethoxy, -CO2H, hydroxamic acid, hydrazide, oxime, cyano, boronic acid, sulfonamide, for yl, C3-C6 cycloalkoxy, C ₁ -C ₄ alkyl substituted with -NR ¹ R ¹⁴ , -NR ¹³ R ¹⁴ , hydroxy, hydroxymethyl; or

R ¹² , when a substituent on nitrogen, is methyl;

R ¹³ is H or methyl;

R ¹⁴ is OH, H or methyl;

R ¹³ and R ¹⁴ can alternatively join to form -(CH2)4~, -(CH2)5~, -CH2CH2N(R ¹⁵ )CH2CH2-, or -CH2CH2OCH2CH2-;

W is -N(R ²² )C(=0)N(R ²³ )- or -N(R ²² )C(=N-CN)N(R ²³ )-;

R ²² and R ²³ are independently selected from the following:

hydrogen;

C1-C4 alkyl substituted with 0-1 R ³¹ ; C3-C4 alkenyl substituted with 0-1 R ³¹ ;

R31 i _s selected from one or more of the following:

halogen, -OR ¹³ , C1-C4 alkyl, C3-C5 cycloalkyl;

aryl substituted with 0-2 R ³² ; or

a heterocyclic ring system chosen from pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl;

R ³² , when a substituent on carbon, is selected from one or more of the following:

benzyloxy, halogen, methyl, C1-C4 alkoxy, CF3, 2- (l-morpholino)ethoxy, -CO2H, hydroxamic acid, hydrazide, oxime, cyano, boronic acid, sulfonamide, formyl, C3-C6 cycloalkoxy, C ₁ -C ₄ alkyl substituted with -NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , hydroxy, hydroxymethyl, -C(R ¹⁴ )=N(OR ¹⁴ ) ; or

R ³² , when a substituent on nitrogen, is methyl;

provided that:

when R ⁴ is hydrogen, R ⁷ is not hydrogen;

when R ⁴ is hydrogen, at least one of the following is not hydrogen: R ²² and R ²³ .

Still more preferred compounds of the present invention are compounds of the further preferred scope above, wherein:

R ⁴ and R ⁷ are benzyl;

R ⁵ is -OH;

R> is hydrogen or -OH;

R ³ is H or methyl;

R ¹⁴ is H or methyl;

W is -N(R ²² )C(=0)N(R ²³ )- or -N(R ²² )C(=N-CN)N(R ²³ )-;

R ²² and R ²³ are independently selected from the following:

hydrogen;

C1-C4 alkyl substituted with 0-1 R ³¹ ;

R ³¹ is selected from one or more of the following:

C3-C5 cycloalkyl;

aryl substituted with 0-2 R ³² ; or

a heterocyclic ring system chosen from pyridyl, thienyl, quinolinyl, or isoquinolinyl;

R _r when a substituent on carbon, is selected from one or more of the following:

-CONH2, -CO2H, -CHO, -CH ₂ NH0H, -CH2NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , hydroxy, hydroxymethyl, -C(R ¹⁴ )=N(OR ¹⁴ ) ; or

R ³² , when a substituent on nitrogen, is methyl.

Also preferred are compounds of formula (Ila) :

(Ha)

wherein R ²² and R ²³ are independently selected from the group consisting of:

hydrogen, allyl, propyl, cyclopropylmethyl, n-butyl, i-butyl, CH2CH=CH(CH3) 2, pyridylmethyl, methallyl, n-pentyl, i-pentyl, hexyl, benzyl, pyridylmethyl, isoprenyl, propargyl, picolinyl, methoxyethyl, cyclohexylmethyl, dimethyl-butyl, ethoxyethyl, methyl-oxazolinylmethyl, naphthylmethyl, methyloxazolinylmethyl, vinyloxyethyl, pentafluorobenzyl, quinolinylmethyl, carboxybenzyl, chloro-thienyl, picolinyl, benzyloxybenzyl, phenylbenzyl, adamantylethyl, cyclopropylmethoxybenzyl, ethoxybenzyl, hydroxybenzyl, hydroxymethylbenzyl, aminobenzyl, formylbenzyl, cyanobenzyl, cinnamyl, allyloxybenzyl, fluorobenzyl, cyclobutylmethyl, formaldoximebenzyl, cyclopentylmethyl, nitrobenzyl, nitrilobenzyl, carboxamidobenzyl, carbomethoxybenzyl, tetrazolylbenzyl, and dimethylallyl.

Specifically preferred are compounds of formula

(Ha)

(Ila)

selected from the group consisting of:

the compound of formula (Ila) wherein R ²² is allyl and R ²³ is allyl;

the compound of formula (Ila) wherein R ²² is propyl and R ²³ is propyl;

the compound of formula (Ila) wherein R ²² is cyclopropylmethyl and R ²³ is cycloprop lmethyl;

the compound of formula (Ila) wherein R ²² is n-butyl and R ²³ is n-butyl;

the compound of formula (Ila) wherein R ²² is CH2CH=CH(CH3)2 and R ²³ is CH2CH=CH(CH3)2;

the compound of formula (Ila) wherein R ²² is i-pentyl and R ²³ is i-pentyl;

the compound of formula (Ila) wherein R ²² is 4-pyridylmethyl and R ²³ is 4-pyridylmethyl;

the compound of formula (Ila) wherein R ²² is 2-methallyl and R ²³ is 2-methallyl;

the compound of formula (Ila) wherein R ²² is n-pentyl and R ²³ is n-pentyl;

the compound of formula (Ila) wherein R ²² is i-butyl and R ²³ is i-butyl;

the compound of formula (Ila) wherein R ²² is benzyl and R ²³ is benzyl;

the compound of formula (Ila) wherein R ²² is 3-pyridylmethyl and R ²³ is 3-pyridylmethyl;

the compound of formula (Ila) wherein R ²² is allyl and R ²³ is isoprenyl;

the compound of formula (Ila) wherein R ²² is 3-propargyl and R ²³ is 3-propargyl;

the compound of formula (Ila) wherein R ²² is 2-picolinyl and R ²³ is 2-picolinyl;

the compound of formula (Ila) wherein R ²² is 2-methoxyethyl and R ²³ is 2-methoxyethyl;

the compound of formula (Ila) wherein R ² _ is cyclohexylmethyl and R ²³ is cyclohexylmethyl;

the compound of formula (Ila) wherein R ²² is 3,3-dimethyl-l-butyl and R ²³ is 3,3-dimethyl-l-butyl;

the compound of formula (Ila) wherein R ²² is 2-ethoxyethyl and R ²³ is 2-ethoxyethyl;

the compound of formula (Ila) wherein R ²² is 3-methyl-5-oxazolinylmethyl and R ²³ is hydrogen;

the compound of formula (Ila) wherein R ²² is 1-naphthylmethyl and R ²³ is 1-naphthylmethyl;

the compound of formula (Ila) wherein R ²² is 3-methyloxazolinylmethyl and R ²³ is 3-methyloxazolinylmethyl;

the compound of formula (Ila) wherein R ²² is 2-vinyloxyethyl and R ²³ is 2-vinyloxyethyl;

the compound of formula (Ila) wherein R ²² is 2,3,4,5,6-pentafluorobenzyl and R ²³ is 2,3,4,5,6-pentafluorobenzyl;

the compound of formula (Ila) wherein R ²² is benzyl and R ²³ is 2-quinolinylmethyl;

the compound of formula (Ila) wherein R ²² is 4-carboxybenzyl and R ²³ is 4-carboxybenzyl;

the compound of formula (Ila) wherein R ²² is 5-chloro-2-thienyl and R ²³ is 5-chloro-2-thienyl;

the compound of formula (Ila) wherein R ²² is 2-quinolinylmethyl and R ²³ is 2-quinolinylmethyl;

the compound of formula (Ila) wherein R ²² is 2-propyl and R ²³ is 2-picolinyl;

the compound of formula (Ila) wherein R ²² is 3-benzyloxybenzyl and R ²³ is 3-benzyloxybenzyl;

the compound of formula (Ila) wherein R ²² is 4-phenylbenzyl and R ²³ is phenylbenzyl;

the compound of formula (Ila) wherein R ²² is 2-adamantylethyl and R ²³ is 2-adamantylethyl;

the compound of formula (Ila) wherein R ²² is hydrogen and R ²³ is cyclopropylmethyl;

the compound of formula (Ila) wherein R ²² is 2-picolinyl and R ²³ is 2-naphthylmethyl;

the compound of formula (Ila) wherein R ²² is 3-allyl and R ²³ is hydrogen;

the compound of formula (Ila) wherein R ²² is 3-allyl and R ²³ is 2-picolinyl;

the compound of formula (Ila) wherein R ²² is 3-allyl and R ²³ is 4-picolinyl;

the compound of formula (Ila) wherein R ²² is 3-benzyloxybenzyl and R ²³ is 3-benzyloxybenzyl;

the compound of formula (Ila) wherein R ²² is 3-cyclopropylmethoxybenzyl and R ²³ is 3-cyclopropylmethoxybenzyl;

the compound of formula (Ila) wherein R ²² is 3-ethoxybenzyl and R ²³ is 3-ethoxybenzyl;

the compound of formula (Ila) wherein R ²² is 4-benzyloxybenzyl and R ²³ is 4-benzyloxybenzyl.

the compound of formula (Ila) wherein R ²² is 3-hydroxybenzyl and R ²³ is 3-hydroxybenzyl;

the compound of formula (Ila) wherein R ²² is 4-hydroxybenzyl and R ²³ is 4-hydroxybenzyl;

the compound of formula (Ila) wherein R ²² is 3-hydroxymethylbenzyl and R ²³ is 3-hydroxymethylbenzyl;

the compound of formula (Ila) wherein R ²² is 4-hydroxymethylbenzyl and R ²³ is 4-hydroxymethylbenzyl;

the compound of formula (Ila) wherein R ²² is 3-aminobenzyl and R ²³ is 3-aminobenzyl;

the compound of formula (Ila) wherein R ²² is 3-carboxylbenzyl and R ²³ is 3-carboxylbenzyl;

the compound of formula (Ila) wherein R ²² is 3-formylbenzyl and R ²³ is 3-formylbenzyl;

the compound of formula (Ila) wherein R ²² is 3-cyanobenzyl and R ²³ is 3-cyanobenzyl;

the compound of formula (Ila) wherein R ²² is 2-naphthylmethyl and R ²³ is 2-naphthylmethyl;

the compound of formula (Ila) wherein R ²² is n-butyl and R ²³ is benzyl;

the compound of formula (Ila) wherein R ²² is allyl and R ²³ is cyclopropylmethyl;

the compound of formula (Ila) wherein R ²² is n-butyl and R ²³ is eyelopropylmethyl

the compound of formula (Ila) wherein R ²² is 3-methallyl and R ²³ is benzyl;

the compound of formula (Ila) wherein R ²² is benzyl and R ²³ is ethyl;

the compound of formula (Ila) wherein R ²² is benzyl and R ²³ is 4-picolinyl;

the compound of formula (Ila) wherein R ²² is cyclopropylmethyl and R ²³ is 4-picolinyl;

the compound of formula (Ila) wherein R ²² is benzyl and R ²³ is cyclopentylmethyl;

the compound of formula (Ila) wherein R ²² is cyclopropylmethyl and R ²³ is cyclopentylmethyl;

the compound of formula (Ila) wherein R ²² is benzyl and R ²³ is n-propyl;

the compound of formula (Ila) wherein R ²² is cyclopropylmethyl and R ²³ is cinnamyl;

the compound of formula (Ila) wherein R ²² is cyclopropylmethyl and R ²³ is 2-naphthylmethyl;

the compound of formula (Ila) wherein R ²² is cyclopentylmethyl and R ²³ is 2-naphthylmethyl;

the compound of formula (Ila) wherein R ²² is benzyl and R ²³ is 2-naphthylmethyl;

the compound of formula (Ila) wherein R ²² is cyclopropylmethyl and R ²³ is 2-picolinyl;

the compound of formula (Ila) wherein R ²² is 3-cyanobenzyl and R ²³ is 3-cyanobenzyl;

the compound of formula (Ila) wherein R ²² is 3-allyl and R ²³ is 2-naphthylmethyl;

the compound of formula (Ila) wherein R ²² is n-propyl and R ²³ is 2-naphthylmethyl;

the compound of formula (Ila) wherein R ²² is n-butyl and R ²³ is 2-naphthylmethyl;

the compound of formula (Ila) wherein R ²² is H and R ²³ is 2-naphthylmethyl;

the compound of formula (Ila) wherein R ²² is 4-picolinyl and R ²³ is 2-naphthylmethyl;

the compound of formula (Ila) wherein R ²² is 3-allyl and R ²³ is cyclopentylmethyl;

the compound of formula (Ila) wherein R ²² is 3-allyl and R ²³ is 2-quinolinylmethyl;

the compound of formula (Ila) wherein R ²² is 3-picolinyl and R ²³ is cyclopropylmethyl;

the compound of formula (Ila) wherein R ²² is 3-picolinyl and R ²³ is 2-naphthylmethyl;

the compound of formula (Ila) wherein R ²² is 3-allyloxybenzyl and R ²³ is 3-allyloxybenzyl;

the compound of formula (Ila) wherein R ²² is 3-allyloxybenzyl and R ²³ is 3-hydroxybenzyl;

the compound of formula (Ila) wherein R ²² is 3-picolinyl and R ²³ is 3-picolinyl;

the compound of formula (Ila) wherein R ²² is 2-naphthylmethyl and R ²³ is 4-fluorobenzyl;

the compound of formula (Ila) wherein R ²² is 3-carbomethoxybenzyl and R ²³ is 3-carbomethyoxybenzyl;

the compound of formula (Ila) wherein R ²² is 4-formylbenzyl and R ²³ is 4-formylbenzyl;

the compound of formula (Ila) wherein R ²² is 4-cyanobenzyl and R ²³ is 4-cyanobenzyl;

the compound of formula (Ila) wherein R ²² is 4-hydroxybenzyl and R ²³ is n-propyl;

the compound of formula (Ila) wherein R ²² is 3-hydroxybenzyl and R ²³ is n-propyl;

the compound of formula (Ila) wherein R ²² is 3-carboxybenzyl and R ²³ is 3-carboxybenzyl;

the compound of formula (Ila) wherein R ²² is cyclobutylmethyl and R ²³ is cyclobutylmethyl;

the compound of formula (Ila) wherein R ²² is cyclopentylmethyl and R ²³ is cyclopentylmethyl;

the compound of formula (Ila) wherein R ²² is n-butyl and R ²³ is 3-methallyl;

the compound of formula (Ila) wherein R ²² is n-butyl and R ²³ is cyclopentylmethyl;

the compound of formula (Ila) wherein R ²² is 3-formaldoximebenzyl and R ²³ , is 3-formaldoximebenzyl;

the compound of formula (Ila) wherein R ²² is cyclopropylmethyl and R ²³ is 3-hydroxybenzyl;

the compound of formula (Ila) wherein R ²² is cyclopropylmethyl and R ²³ is 4-hydroxybenzyl;

the compound of formula (Ila) wherein R ²² is 3-(N-methylamino)benzyl and R ²³ is 3-(N-methylamino)benzyl;

the compound of formula (Ila) wherein R ²² is 3-acetylbenzyl and R ²³ is 3-acetylbenzyl;

the compound of formula (Ila) wherein R ²² is 3-hydroxylaminobenzyl and R ²³ is 3-hydroxylaminobenzy1;

the compound of formula (Ila) wherein R ²² is 2-naphthylmethyl and R ²³ is 3-hydroxybenzyl;

the compound of formula (Ila) wherein R ²² is 4-hydroxymethylbenzyl and R ²³ is 3-hydroxybenzyl;

the compound of formula (Ila) wherein R ²² is N- methyl-(3-amido)benzyl and R ²³ is N-methyl-(3- amido) enzyl;

the compound of formula (Ila) wherein R ²² is N- methyl-(3-amido)benzyl and R ²³ is 3-(amidino)benzyl;

the compound of formula (Ila) wherein R ²² is 3-(5-tetrazolyl)benzyl and R ²³ is cyclopropylmethyl;

the compound of formula (Ila) wherein R ²² is 3-(5-tetrazolyl)benzyl and R ²³ is 3-(5-tetrazolyl)benzyl;

the compound of formula (Ila) wherein R ²² is phenylmethyl-3-boronic acid and R ²³ is phenylmethyl-3- boronic acid.

More specifically preferred are the following compounds of formula (I), which have IC50 or Ki values of less than about 10 nM for inhibiting HIV protease:

the compound of formula (Ila) wherein R ²² is allyl and R ²³ is allyl;

the compound of formula (Ila) wherein R ²² is propyl and R ²³ is propyl;

the compound of formula (Ila) wherein R ²² is cyclopropylmethyl and R ²³ is cyclopropylmethyl;

the compound of formula (Ila) wherein R ²² is n-butyl and R ²³ is n-butyl;

the compound of formula (Ila) wherein R ²² is CH2CH=CH(CH3)2 and R ²³ is CH2CH=CH(CH3) 2;

the compound of formula (Ila) wherein R ²² is i-pentyl and R ²³ is i-pentyl;

the compound of formula (Ila) wherein R ²² is 2- methallyl and R ²³ is 2-methallyl;

the compound of formula (Ila) wherein R ²² is n- pentyl and R ²³ is n-pentyl;

the compound of formula (Ila) wherein R ²² is benzyl and R ²³ is benzyl;

the compound of formula (Ila) wherein R ²² is allyl and R ²³ is isoprenyl;

the compound of formula (Ila) wherein R ²² is 3-hydroxybenzyl and R ²³ is 3-hydroxybenzyl;

the compound of formula (Ila) wherein R ²² is 4-hydroxybenzyl and R ²³ is 4-hydroxybenzyl;

the compound of formula (Ila) wherein R ²² is 3-hydroxymethylbenzyl and R ²³ is 3-hydroxymethylbenzyl;

the compound of formula (Ila) wherein R ²² is 4-hydroxymethylbenzyl and R ²³ is 4-hydroxymethylbenzyl;

the compound of formula (Ila) wherein R ²² is 3-aminobenzyl and R ²³ is 3-aminobenzyl;

the compound of formula (Ila) wherein R ²² is 3-carboxylbenzyl and R ²³ is 3-carboxylbenzyl;

the compound of formula (Ila) wherein R ²² is 3-formylbenzyl and R ²³ is 3-formylbenzyl;

the compound of formula (Ila) wherein R ²² is 3-cyanobenzyl and R ²³ is 3-cyanobenzyl;

the compound of formula (Ila) wherein R ²² is -naρhthylmethyl and R ²³ is 2-naphthylmethyl;

the compound of formula (Ila) wherein R ²² is n-butyl and R ²³ is benzyl;

the compound of formula (Ila) wherein R ²² is allyl and R ²³ is cyclopropylmethyl;

the compound of formula (Ila) wherein R ²² is n-butyl and R ²³ is cyclopropylmethyl

the compound of formula (Ila) wherein R ²² is 3-methallyl and R ²³ is benzyl;

the compound of formula (Ila) wherein R ²² is benzyl and R ²³ is ethyl;

the compound of formula (Ila) wherein R ²² is benzyl and R ²³ is 4-picolinyl;

the compound of formula (Ila) wherein R ²² is cyclopropylmethyl and R ²³ is 4-picolinyl;

the compound of formula (Ila) wherein R ²² is benzyl and R ²³ is cyclopentylmethyl;

the compound of formula (Ila) wherein R ²² is cyclopropylmethyl and R ²³ is cyclopentylmethyl;

the compound of formula (Ila) wherein R ²² is benzyl and R ²³ is n-propyl;

the compound of formula (Ila) wherein R ²² is cyclopropylmethyl and R ²³ is cinnamyl;

the compound of formula (Ila) wherein R ²² is cyclopropylmethyl and R ²³ is 2-naphthylmethyl;

the compound of formula (Ila) wherein R ²² is cyclopentylmethyl and R ²³ is 2-naphthylmethyl;

the compound of formula (Ila) wherein R ²² is benzyl and R ²³ is 2-naphthylmethyl;

the compound of formula (Ila) wherein R ²² is cyclopropylmethyl and R ²³ is 2-picolinyl;

the compound of formula (Ila) wherein R ²² is 3-cyanobenzyl and R ²³ is 3-cyanobenzyl;

the compound of formula (Ila) wherein R ²² is 3-allyl and R ²³ is 2-naphthylmethyl;

the compound of formula (Ila) wherein R ²² is n-propyl and R ²³ is 2-naphthylmethyl;

the compound of formula (Ila) wherein R ²² is n-butyl and R ²³ is 2-naphthylmethyl;

the compound of formula (Ila) wherein R ²² is H and R ²³ is 2-naphthylmethyl;

the compound of formula (Ila) wherein R ²² is 4-picolinyl and R ²³ is 2-naphthylmethyl;

the compound of formula (Ila) wherein R ²² is 3-allyl and R ²³ is cyclopentylmethyl;

the compound of formula (Ila) wherein R ²² is 3-allyl and R ²³ is 2-quinolinylmethyl;

the compound of formula (Ila) wherein R ²² is 3-picolinyl and R ²³ is cyclopropylmethyl;

the compound of formula (Ila) wherein R ²² is 3-picolinyl and R ²³ is 2-naphthylmethyl;

the compound of formula (Ila) wherein R ²² is 3-allyloxybenzyl and R ²³ is 3-allyloxybenzyl;

the compound of formula (Ila) wherein R ²² is 3-allyloxybenzyl and R ²³ is 3-hydroxybenzyl;

the compound of formula (Ila) wherein R ²² is 3-picolinyl and R ²³ is 3-picolinyl;

the compound of formula (Ila) wherein R ²² is 2-naphthylmethyl and R ²³ is 4-fluorobenzyl;

the compound of formula (Ila) wherein R ²² is 3-carbomethoxybenzyl and R ²³ is 3-carbomethyoxybenzyl;

the compound of formula (Ila) wherein R ²² is 4-formylbenzyl and R ²³ is 4-formylbenzyl;

the compound of formula (Ila) wherein R ²² is 4-cyanobenzyl and R ²³ is 4-cyanobenzyl;

the compound of formula (Ila) wherein R ²² is 4-formylbenzyl and R ²³ is.4-formylbenzyl;

the compound of formula (Ila) wherein R ²² is 4-cyanobenzyl and R ²³ is 4-cyanobenzyl;

the compound of formula (Ila) wherein R ²² is 4-formylbenzyl and R ²³ is 4-formylbenzyl;

the compound of formula (Ila) wherein R ²² is 4-hydroxybenzyl and R ²³ is n-propyl;

the compound of formula (Ila) wherein R ²² is 3-hydroxybenzyl and R ²³ is n-propyl;

the- compound of formula (Ila) wherein R ²² is 3-carboxybenzyl and R ²³ is 3-carboxybenzyl;

the compound of formula (Ila) wherein R ²² is cyclobutylmethyl and R ²³ is cyclobutylmethyl;

the compound of formula (Ila) wherein R ²² is cyclopentylmethyl and R ²³ is cyclopentylmethyl;

the compound of formula (Ila) wherein R ²² is n-butyl and R ²³ is 3-methallyl;

the compound of formula (Ila) wherein R ²² is n-butyl and R ²³ is cyclopentylmethyl;

the compound of formula (Ila) wherein R ²² is 3-formaldoximebenzyl and R ²³ is 3-formaldoximebenzyl;

the compound of formula (Ila) wherein R ²² is cyclopropylmethyl and R ²³ is 3-hydroxybenzyl;

the compound of formula (Ila) wherein R ²² is cyclopropylmethyl and R ²³ is 4-hydroxybenzyl;

the compound of formula (Ila) wherein R ²² is 3-(N-methylamino)benzyl and R ²³ is 3-(N-methylamino)benzyl;

the compound of formula (Ila) wherein R ²² is 3-acetylbenzyl and R ²³ is 3-acetylbenzyl;

the compound of formula (Ila) wherein R ²² is 3-hydroxylaminobenzyl and R ²³ is 3-hydroxylaminobenzyl;

the compound of formula (Ila) wherein R ²² is 2-naphthylmethyl and R ²³ is 3-hydroxybenzyl;

the compound of formula (Ila) wherein. R ²² is 4-hydroxymethylbenzyl and R ²³ is 3-hydroxybenzyl;

the compound of formula (Ila) wherein R ²² is N- methyl-(3-amido)benzyl and R ²³ is N-methyl-(3- amido)benzyl;

the compound of formula (Ila) wherein R ²² is N- methyl-(3-amido)benzyl and R ²³ is 3- (amidino)benzyl;

the compound of formula (Ila) wherein R ²² is 3- (5-tetrazolyl)benzyl and R ²³ is cyclopropylmethyl;

the compound of formula (Ila) wherein R ²² is 3- (5-tetrazolyl)benzyl and R ²³ is 3-(5- tetrazolyl)benzyl;

the compound of formula (Ila) wherein R ²² is phenylmethyl-3-boronic acid and R ²³ is phenylmethyl- 3-boronic acid.

The following preferred compounds of formula (I) exhibit IC90 values of less than about 10 mg/mL for the inhibition of HIV growth:

the compound of formula (Ila) wherein R ²² is allyl and R ²³ is allyl;

the compound of formula (Ila) wherein R ²² is cyclopropylmethyl and R ²³ is cyclopropylmethyl;

the compound of formula (Ila) wherein R ²² is n-butyl and R ²³ is n-butyl;

the compound of formula (Ila) wherein R ²² is CH2CH=CH(CH3)2 and R ²³ is CH2CH=CH(CH3)2;

the compound of formula (Ila) wherein R ²² is propyl and R ²³ is propyl;

the compound of formula (Ila) wherein R ²² is i-pentyl and R ²³ is i-pentyl;

the compound of formula (Ila) wherein R ²² is benzyl and R ²³ is benzyl;

the compound of formula (Ila) wherein R ²² is 3-hydroxybenzyl and R ²³ is 3-hydroxybenzyl;

the compound of formula (Ila) wherein R ²² is 4-hydroxybenzyl and R ²³ is 4-hydroxybenzyl;

the compound of formula (Ila) wherein R ²² is 3-hydroxymethylbenzyl and R ²³ is 3-hydroxymethylbenzyl;

the compound of formula (Ila) wherein R ²² is 4-hydroxymethylbenzyl and R ²³ is 4-hydroxymethylbenzyl;

the compound of formula (Ila) wherein R ²² is 3-aminobenzyl and R ²³ is 3-aminobenzyl;

the compound of formula (Ila) wherein R ²² is -carboxylbenzyl and R ²³ is 3-carboxylbenzyl;

the compound of formula (Ila) wherein R ²² is 3-formylbenzyl and R ²³ is 3-formylbenzyl

the compound of formula (Ila) wherein R ²² is

3-formaldoximebenzyl and R ²³ is 3-formaldoximebenzyl;

the compound of formula (Ila) wherein R ²² is 3- (N- methylamino)benzyl and R ²³ is 3- (N-methylamino)benzyl;

the compound of formula (Ila) wherein R ²² is 3-acetylbenzyl and R ²³ is 3-acetylbenzyl;

the compound of formula (Ila) wherein R ²² is 3-hydroxylaminobenzyl and R ²³ is 3-hydroxylaminobenzyl;

the compound of formula (Ila) wherein R ²² is 2-naphthylmethyl and R ²³ is 3-hydroxybenzyl;

the compound of formula (Ila) wherein R ²² is 4-hydroxymethylbenzyl and R ²³ is 3-hydroxybenzyl;

the compound of formula (Ila) wherein R ²² is N- methyl-(3-amido)benzyl and R ²³ is N-methyl-(3- amido)benzyl;

the compound of formula (Ila) wherein R ²² is N- methyl-(3-amido)benzyl and R ²³ is 3- (amidino)benzyl;

the compound of formula (Ila) wherein R ²² is 3- (5-tetrazoyl)benzyl and R ²³ is cyclopropylmethyl;

the compound of formula (Ila) wherein R ²² is 3- (5- tetrazolyl)benzyl and R ²³ is -3- (5-tetrazolyl)benzyl;

the compound of formula (Ila) wherein R ²² is phenylmethyl-3-boronic acid and R ²³ is phenylmethyl-3- boronic acid.

Also preferred in the present invention are compounds of formula (lb) :

(lb)

or a pharmaceutically acceptable salt or prodrug form thereof wherein:

R ²² and R ²³ are independently selected from the group consisting of: hydrogen, cyclopropylmethyl, CH2(C6H4)-P-OCH2C6H5, CH2 (C6H4)-p-OH, cyclopentylmethyl, allyl, n-butyl, beta-napthylmethyl, benzyl, CH2 (C6H4)-m-OCH2C6H5, p-nitrobenzyl, -nitrobenzyl, CH2 (C6H4)-m-OH, p-aminobenzyl, m-aminobenzyl, p-nitrilobenzyl, m-nitrilobenzyl, dimethylallyl, cyclohexylmethyl, cyclobutylmethyl, propyl, 3-methyl-l-butyl, carboxamidobenzyl, and formaldoximebenzyl.

More specifically preferred are the following compounds of formula (I) , which have IC50 or Ki values of less than about 10 nM for inhibiting HIV protease:

the compound of formula (lb) wherein R ²² is 3-formaldoximebenzyl and R ²³ is 3-formaldoximebenzyl,

Also preferred in the present invention are compounds of the formula:

or a pharmaceutically acceptable salt or prodrug form thereof wherein:

R ³³ is OH, halogen, H, N3;

R ²² and R ²³ are independently selected from the group consisting of:

hydrogen, allyl, propyl, cyclopropylmethyl, n-butyl, i-butyl, CH2CH=CH(CH3) 2, pyridylmethyl, methallyl, n-pentyl, i-pentyl, hexyl, benzyl, pyridylmethyl, isoprenyl, propargyl, picolinyl, methoxyethyl, cyclohexylmethyl, dimethyl-butyl, ethoxyethyl, methyl-oxazolinylmethyl, naphthylmethyl, methyloxazolinylmethyl, vinyloxyethyl, pentafluorobenzyl, quinolinylmethyl, carboxybenzyl, chloro-thienyl, picolinyl, benzyloxybenzyl, phenylbenzyl, adamantylethyl, cyclopropylmethoxybenzyl, ethoxybenzyl, hydroxybenzyl, hydroxymethylbenzyl, aminobenzyl, formylbenzyl, cyanobenzyl, cinnamyl.

all loxybenzyl, fluorobenzyl, cyclobutylmethyl, formaldoximebenzyl, cyclopentylmethyl, nitrobenzyl, nitrilobenzyl, carboxamidobenzyl, carbomethoxybenzyl, and dimethylallyl.

In the present invention it has been discovered that the compounds above are useful as inhibitors of HIV protease and similar retroviral proteases, and for the treatment of HIV infection and similar retrovirus infections.

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

The compounds herein described may have asymmetric centers. All chiral, diastereomeric, and racemic forms are included in the present invention. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention.

When any variable (for example, R ¹ through R ²⁸ , R ^4A and R ^A > m, n, W, Z, etc.) occurs more than one time in any constituent or in formula (I) or (II) , or any other formula herein, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

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

ring groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; and "biycloalkyl" is intended to include saturated bicyclic ring groups such as [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4. O]bicyclodecane (decalin) , [2.2.2]bicyclooctane, and so forth. "Alkenyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like; and "alkynyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like. "Halo" as used herein refers to fluoro, chloro, bromo, and iodo; and "counterion" is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like. As used herein, "aryl" or "aromatic residue" is intended to mean phenyl or naphthyl; "carbocyclic" is intended to mean any stable 5- to 7- membered monocyclic or bicyclic or 7- to 14-membered bicyclic or tricyclic carbon ring, any of which may be saturated, partially unsaturated, or aromatic, for example, indanyl or tetrahydronaphthyl (tetralin) .

As used herein, the term "heterocycle" is intended to mean a stable 5- to 7- membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from 1 to 3 heteroatoms selected from the group consisting of N, 0 and S and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is

fused to a benzene ring. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. Examples of such heterocycles include, but are not limited to, pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl or benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2- pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl or octahydroisoquinolinyl. The term "substituted", as used herein, means that an one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. By "stable compound" or "stable structure" is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. As used herein, "pharmaceutically acceptable salts and prodrugs" refer to derivatives of the disclosed compounds that are modified by making acid or base salts, or by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Examples include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; acetate, formate and benzoate derivatives of alcohols and amines; and the like.

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

Synthesis

The compounds of the present invention may be synthesized using the general synthetic procedures described below. Each of the references cited below are hereby incorporated herein by reference.

Compounds of the invention wherein:

W is -N(R ²² )C(=Z)N(R ²³ )- or -N(R ²² )C(=0)C(=0)N(R ²³ )-;

R ⁵ is -OR ²⁰ or H;

R ⁶ is -OR ²¹ or H; and

n is 1; can be formed from diamines of formula (III) :

(III)

The diamines of formula (III) can be synthesized as described in copending commonly assigned patent application Jadhav et al. USSN 07/714,042, filed 5/31/91. Alternative methods which can be used to synthesize the compounds of structure (III) above are described in European Patent Application Publication Number 402646A1, U.S. Patent 4,837,204, and Canadian Patent Application 2,026,832 .

The compounds of formula (III) can be cyclized to form compounds of formula (IV) under conditions normally used to form cyclic ureas, as is known to one skilled in the art. Reagents J-(C=Z)-J', where J and J' are leaving groups, are employed, preferably under relatively dilute conditions (for example, less than about 0.1 M) , to effect ring closure to provide compounds of formula (I) . Many examples of J and J ¹ are known; preferred are carbonyl diimidazole, thiocarbonyldiimidazole, phosgene, thiophosgene, diphenyl carbonate, or diphenyl thiocarbonate. Additionally, for compounds wherein W is

-N(R ²² )C(=0)C(=0)N(R ²³ )-, compounds of formula (III) can be reacted with activated derivatives of oxalic acid, preferably oxalyl chloride, under the above conditions to form the diamide.

For compounds of the invention where R ²⁰ or R ²¹ is -OH, it is advantageous to protect the free hydroxyl before cyclization. Protecting groups used can include any of those listed in Greene, Protective Groups in Organic Synthesis. Chapter 2, Wiley, NY (1981) . The preferred protecting groups are trimethylsilylethoxymethyl (SEM) , methoxyethoxymethyl (MEM) , or methoxymethyl (MOM) .

Cyclization of compounds of formula (III) results in structure (IV) (i.e., structure (I) wherein W is -N(R ²² )C(=0)C(=0)N(R ²³ )- and n is 1) .

(IV)

Another, preferred method to form compounds of formula (IV), in cases wherein R ²² and R ²³ are linked to their respective nitrogens by a CH2 residue, is to cyclize a compound of structure (III) where R ²² and R ²³ are hydrogen, and to alkylate the nitrogens using a base, a phase transfer catalyst, and an alkylating agent, using methods well known in the art. The preferred base is sodium hydride, and the preferred alkylating agents are R ²² Y and R ²³ Y, wherein Y is a halogen, triflate, or mesylate, preferably a bromide or iodide. Preferred conditions are in polar aprotic solvents between 0 and 100 °C.

Cleavage of protecting groups, if employed, yields structures of formula (I) wherein R^ and R> are hydroxyl.

When R ⁵ and R ⁶ are other than OR ²⁰ and OR ²¹ , some chemical manipulation of functional groups may need to be performed in the preparation of the compounds of formula (III) or (IV) , as is appreciated by one of skill in the art of organic synthesis. Described below are examples of such procedures.

Methods for obtaining compounds wherein Bp is OH and R^ is OR ²¹ include protection of nitrogen, if necessary, followed by reaction of the diol with one equivalent of base and one equivalent of acyl halide, alkyl halide, alkoxyalkyl halide, alkoxycarbonyl halide, benzoyl halide, diphenyl carbonate or phenylisocyanate, and purification by column chromatography of the unwanted bis-alkylated and unreacted material.

Methods for obtaining compounds wherein R^ is OH and R*-* is H include protection of nitrogen, if necessary, and reduction of the diol to the monool using techniques known in the art (see, for example, Chem. Comm. 1971, 1097; J. Org. Chem. 1969, 3923) . The preferred method is formation of cyclic diol ester and reduction using hydride. Deprotection of nitrogen, if necessary, results in the desired compound.

Methods for obtaining compounds wherein R-** is OH and R> is F include protection of nitrogen, if necessary, followed by formation of mono-protected diol as described above. Reaction with a fluorinating agent, preferably

diethylaminosulfurtrifluoride (DAST) (Reagents for Organic Synthesis. Vol. 13, p. 110, Wiley Interscience, NY, 1988) , provides the alkyl fluoride. Deprotection of nitrogen, if necessary, and hydroxyl results in the desired compound.

Methods for obtaining compounds wherein R5 is OH and R^ is =0 include protection of nitrogen, if necessary, and standard conditions for oxidizing glycols to pinacols. The preferred oxidant is one equivalent of pyridinium dichromate in dichloromethane, or one equivalent of NaOCl in HOAc. Deprotection of nitrogen, if necessary, results in the desired compound. Alternatively, a monohydroxy compound described above can be oxidized to the ketone under standard conditions, preferably Swern oxidation using oxalyl chloride, DMSO and Et3N, followed by alpha-hydroxylation of the ketone (see Tet . Lett . 1981, 607; Tet . Lett . 1982, 2917) .

Methods for obtaining compounds wherein R5 is OH and R*> is difluoro include protection of nitrogen, if necessary, and hydroxyl of the above obtained pinacol, followed by reaction of the carbonyl with a fluorinating reagent, such as DAST. Deprotection of hydroxyl and nitrogen, if necessary, results in the desired compound.

Methods for obtaining compounds wherein R^ and R^ join to form an epoxide include protection of nitrogen, if necessary, followed by standard conditions for the formation of an epoxide from a glycol (see, for example, J. Org. Chem. 1981, 3361) . Preferred is the reaction of the glycol

with more than 2 equivalents of base and one equivalent of an activating group, such as methanesulfonyl chloride. Deprotection if necessary results in the desired compound.

Methods for obtaining compounds wherein R-*" is OH and R> is C1-C3 alkyl include protection of nitrogen, if necessary, and reaction of the epoxide prepared above with C1-C3 alkylmetal reagents. Preferred is the reaction of lithium dialkyl cuprates in aprotic solvents at low temperatures (- 78 to -40 °C) (see Carruthers, Some Modern Methods in Organic Synthesis, p. 64, Cambridge University Press, 1978) .

With a judicious selection of reagents, as is well appreciated to one skilled in the art, these manipulations can be performed in a straightforward manner to yield the claimed combinations of R-* ⁵ and R^.

Compounds of the invention wherein:

W is -N(R ²² )C(=Z)N(R ²³ )- or -N(R ²² )C(=0)C(=0)N(R ²³ )-, and n is 0;

can be synthesized from diamines of formula (V)

(V)

which can in turn be synthesized as described in European Patent Application Publication Number 402 646 Al.

Protection, if necessary, cyclization, and functional group manipulation if desired is performed as described above to obtain compounds of structure (VI) :

(VI)

Compounds of the invention wherein:

W is -OC(=0)0- and n is 1;

can be formed from diols of structure (VII)

(VII)

which can in turn be synthesized as described in copending, commonly assigned U.S. patent application Jadhav et al. USSN 07/714,042, filed 5/31/91.

Functional group manipulation, if desired, may be performed as described above, followed by cyclization to the carbonate using standard conditions, preferably phosgene or thiophosgene in the presence of 2 equivalents of a base such as potassium hydride, to obtain compounds of structure (I) .

Compounds of the invention wherein:

W is -N(R ²² )C(=Z)0- and n is 1;

can be formed from aminoalcohol of structure (VIII) :

(VIII)

which can in turn be synthesized as described in a copending, commonly assigned U.S. patent application Jadhav et al. USSN 07/714,042, filed 5/31/91, by employing a single equivalent of azide in the reaction of the diol of formula (VII) to obtain the azidoalcohol, followed by reduction as described in USSN 07/714,042, to form the aminoalcohol.

Protection, if necessary, and functional group manipulation, if desired, is performed as described above, followed by cyclization to the carbamate using

standard conditions, preferably phosgene or thiophosgene in the presence of 2 equivalents of a base, such as potassium hydride, to obtain compounds of structure (I) .

Compounds of the invention wherein:

W is -0C(=Z)0- and n is 0;

can be formed from the diol of structure (IX)

(IX)

which can in turn be synthesized by the reaction of R ⁴ CHO with the lithium anion of 1,3 dithiane, followed by the reaction of R ⁷ CHO with the anion of the product (see Carruthers, Some Modern Methods in Organic Synthesis _r p. 45, Cambridge University Press, 1978) . Cleavage of the dithiane with mercuric ion yields the acyclic alpha, alpha' dihydroxyketone.

Functional group manipulation, if desired, is performed as described above, followed by cyclization to the carbonate using standard conditions, preferably phosgene or thiophosgene, in the presence of 2 equivalents of a base such as potassium hydride, to obtain compounds of structure (I) .

Compounds of the invention wherein :

W is -N (R ²² ) C (=Z) 0- and n is 0;

can be formed from aminoalcohol of structure (X)

(X)

which can in turn be synthesized by the techniques described in European Patent Application Publication Number 402 646 Al for the synthesis of compounds of structure (V), above; however, in place of azide, in opening the oxirane (shown below) , an oxygen nucleophile, such as acetate or hydroxide ion, is reacted in the presence of a polar aprotic solvent, such as DMSO.

Alternatively, the oxirane is treated with a catalytic amount of a strong acid in water and a cosolvent, if necessary, which technique also removes the BOC protecting group.

Protection, if necessary, and functional group manipulation, if desired, is performed as described above, followed by cyclization to the carbamate using standard conditions, preferably phosgene or thiophosgene in the presence of 2 equivalents of a base such as potassium hydride, to obtain compounds of structure (I) .

Compounds of the present invention wherein:

W is -C(R ²⁵ ) (R ²⁶ )N(CH3) (O)C(R ²⁷ ) (R ²⁸ )-;

can be synthesized from amihoalcohols (VIII) and (X) by the following steps: protection of nitrogen, if necessary, preferably with a benzyloxycarbonyl group; activation of the alcohol to displacement, preferably with a sulfonate derivative, such as mesyl chloride; removal of the nitrogen protecting group, preferably with hydrogen in the presence of a catalyst, such as palladium on carbon; and heating under dilute conditions in the presence of a base such as triethylamine to effect cyclization.

The secondary cyclic amine is then methylated, preferably with formic acid/formaldehyde, and oxidized, preferably with a peracid, such as MCPBA, to form compounds of formula (I), wherein W is

-C(R ²⁵ ) (R ²⁶ )N(CH3) (O)C(R ²⁷ ) (R ²⁸ )-. The secondary cyclic amine can alternatively be directly oxidized to form structure (I), where W is

-C(R ²⁵ ) (R ²⁶ )N(OR ²⁹ )C(R ²⁷ ) (R ²⁸ )-.

Compounds wherein:

W is -C(R ²⁵ ) (R ²⁶ )C(=_)C(R ²⁷ ) (R ²⁸ )- and n is 0;

can be prepared by the alkylation of protected cyclohexanedione (XI) with the required R -LG and R ⁷ -LG, and optionally R ^4A -LG and R ^7A -LG groups, wherein LG represents a leaving group such as halogen or sulfonate ester.

(XI)

Reduction of the ketone to the alcohol, preferably with LiAlH4, or manipulation to other values of R-* ⁵ as described above, is followed by cleavage of the ketal (see Greene, Protective Groups in Organic Synthesis.

Chapter 2, Wiley, NY, 1981) . Protection of the alcohol or other reactive groups, followed by alkylation ketone and deprotection, provides compounds of structure (I) , wherein W is -C(R ²⁵ ) (R ²⁶ )C(=Z)C(R ²⁷ ) (R ²⁸ )- and n is 0.

Compounds wherein:

W is -C(R ²⁵ ) (R ²⁶ )C(=Z)C(R ²⁷ ) (R ²⁸ )- and n is 1;

can be prepared from the protected hydroxyketones described immediately above by ring expansion, for example via the Tiffeneau-Demyanov reaction (March, Advanced Organic. Chemistry, p. 965, Wiley, NY, 1985), or by treatment with dimethylsulfonium ylide to form the spiro-epoxide, followed by acid-catalyzed ring expansion to the cycloheptanone (ibid. _f pp. 871, 966).

The above routes have the advantage of producing a number of stereoiomers which, upon purification, can be evaluated for the best combination of potency, safety and in vivo availability.

Compounds wherein:

W is -C(R ²⁵ ) (R ²⁶ )C(F2)C(R ²⁷ ) (R ²⁸ )- and n is 0 or 1;

can be obtained from the above-described protected hydroxyketone by treatment with a fluorinating reagent, preferably DAST, as described above.

Compounds wherein:

W is -N(R ²² )C(=Z)C(R ²⁷ ) (R ²⁸ )- and n is 0;

can be obtained by cyclization of compound (XII) to the lactam using techniques known in the art (March,

Advanced Organic Chemistry, p. 371, Wiley, NY, 1985) .

(XII)

Compounds of structure (XII) can in turn be obtained as described in European Patent Application Publication Number 434 365 A2, European Patent Application Publication Number 386 611 A2, European Patent Application Publication Number 389 127 Al, and CA 2005337, each of which are hereby incorporated by reference. OP in structure (XII) designates protected oxygen. Hydroxyl can be protected by the use of any of a number of groups as described in Greene, Protective Groups in Organic Synthesis. Chapter 2, Wiley, NY (1981) .

If desired, the resulting lactam (XIII) :

(XIII)

can be further functionalized, for example by the following techniques: the lactam nitrogen can be alkylated with an R ²² -LG group, preferably employing sodium hydride in DMF; an R ^4A , R ⁷ or R ^7A group can be added by deprotection and oxidation of the alcohol, followed by alkylation of the enolate using R ^4A -LG, R ⁷ - LG or R ^7A -LG; and reduction of the ketone to hydroxyl or otherwise functionalizing to obtain the R^ group of choice as described above.

Compounds wherein:

W is -N(R ²² )C(=Z)C(R ²⁷ ) (R ²⁸ )- and n is 1;

can be obtained through techniques known in the art from ketones of structure (I) wherein W is

-C(R ²⁵ ) (R ²⁶ )C(=Z)C(R ²⁷ ) (R ²⁸ )- and n is 0, preferably via the Beckmann rearrangement (March, Advanced Organic Chemistry, p. 987, Wiley, NY, 1985) . Manipulation of the R5 group, if desired, as described above provides R ⁵ and R^-substituted examples of (I), wherein W =

-N(R ²² )C(=Z)C(R ²⁷ ) (R ²⁸ )- and n = 1.

Compounds wherein:

W is -C(R ²⁵ ) (R ²⁶ )C(=Z)0- and n is 0 or 1;

can be obtained from compounds of structure (I) , wherein W = -N(R ²² )C(=Z)C(R ²⁷ ) (R ²⁸ )-, n = 0 or 1, and R ²² = H, for example, by hydrolysis of the lactam, followed by displacement of the primary amine by hydroxyl, and closure to the lactone (March, Advanced Organic

Chemistry, p. 348, Wiley, NY, 1985).

Similarly, compounds wherein:

W is -C (R ²⁵ ) (R ²⁶ ) C (=Z) S- and n is 0 or 1 ;

can be obtained from compounds of structure (I), wherein W = -N(R ²² )C(=Z)C(R ²⁷ ) (R ²⁸ )-, n = 0 or 1, and R ²² = H, for example, by hydrolysis of the lactam, followed by conversion of the primary amine to the diazonium salt, displacement by NaSH, and closure to the thiolactone (March, Advanced Organic Chemistry, p. 601, Wiley, NY, 1985) .

Compounds of structure (I) described above wherein Z = O can be converted to the thio derivatives, Z = S, using standard conditions (March, Advanced Organic Chemistry, p. 792, Wiley, NY, 1985); preferred is the use of the disulfide described in Bull. Soc. Chim. _lgs_ 1978, 223.

Structures (I) described above wherein Z = 0 can be converted to the imino derivatives, Z = NR ²⁴ , using standard conditions. When R ²⁴ is OH or 0-alkyl, the oximes can be formed and alkylated if desired as described in March, Advanced Organic Chemistry, pp. 359,

805, Wiley, NY, 1985. The hydrazones and imines can be formed similarly (ibid,, pp. 533, 797) .

It is expected that the compounds of the invention can also be prepared as shown in Scheme 1 (shown below) . The intra-molecular coupling of the N-substituted or unsubstituted dialdehydes may be achieved by organometal reagents derived from vanadium, titanium, samarium etc. The dialdehyde precursors can be prepared from the commercially available materials by the methods known to those skilled in the art of organic synthesis, preferably by the techniques disclosed in copending

commmonly assigned U.S. Patent Application, Hodge, USSN 07/659,442, filed 2/21/91.

Compounds wherein W is -N(R ²² )C(=0)N(R ²³ ) - and n is 2 can be synthesized as shown in Scheme 2 (below) . The eight-membered cyclic urea in Scheme 2 can be protected, if necessary, and manipulated as described above to yield the desired compounds.

Compounds wherein W is -N(R ²² )C(=0)N(R ²³ ) - and n is 1 can likewise be synthesized as shown in Schemes 3, 4, 6, 7 (below) . If necessary, intermediates described herein can be manipulated by methods known to those skilled in the art of organic synthesis to provide compounds within the scope of the invention.

Compounds wherein W is -N(R ²² )C(=N-OR)N(R ²³ )- or -N(R ²² )C(=S)N(R ²³ )- and n is 1 can be synthesized as shown in Scheme 5 (below) . If necessary, intermediates described herein can be manipulated by methods known to those skilled in the art of organic synthesis to provide compounds within the scope of the invention.

Compounds wherein W is -N(R ²² )C(=0)N(R ²³ )- and n is 0 can likewise be synthesized as shown in Scheme 8

(below) . If necessary, intermediates described herein can be manipulated by methods known to those skilled in the art of organic synthesis to provide compounds within the scope of the invention.

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

Procedure 1

Preparation of di-N-CBZ protected 1,4-diamino-2,3- diols (XIX) :

(XIX)

Detailed experimental procedures for the synthesis of compound (XIX) are described in copending commonly assigned patent application Jadhav et al. USSN 07/714,042, filed 5/31/91.

Procedure 2

Preparation of di-0 protected di-N-CBZ 1,4-diamino diols (XXa) and (XXb) :

(XXa) R=SEM (XXb) R=M0M

A. Protection as 2-(trimethylsilyl) ethoxy methyl (SEM) ether (XXa) :

Compound (XIX) (60 g, 105 mmol) was dissolved in dry DMF (600 mL) . Diisopropylethylamine (75 mL) and SEMC1 (66.8 g, 400mmol) were added and the mixture stirred for 16 h at room temperature under N ₂ . The solution was diluted with water (IL) and extracted with

hexane (400mL) . The organic layer was separated and washed with water (2xl00mL) . The aqueous layers were combined and extracted with hexane (2x300mL) . The organic layers were combined, washed with water (2xl00mL) , dried over MgS0 ₄ , filtered and evaporated. The residue was chromatographed on Siθ2 and eluted with 10-

30% ethyl acetate/hexane to afford a white solid (91g, 100%) . NMR(CDC1 ₃ ) : δ 7.0-7.4 (m, 20H, Ph) , 5,01

(br s, 4H, PhCH ₂ CO) , 4.5-4.95 (m, 6H, NH, OCH ₂ 0) , 3.6- 4.25 (m, 4H, CfiOCH ₂ , CHNH) , 3.5 (s, 4H, OCH2CH2) , 2.76 (br d, 4H, PhCH2), 0.8-1.0 (m, 4H, SiCH2) . MS: 846 (M+NH ₄ , 100) , 695 (M-SEM, 40) .

B. Protection as methoxymethyl (MOM) ether (XXb)

Compound (XIX) (.50 g, 0.88 mmol) was dissolved in dry DMF (lOmL) . Diisopropylethylamine (.46 mL, 2.64 mmol) and methoxymethyl bromide (.165 mL, 2.02 mmol) were added and the solution stirred at 40 °C under nitrogen for four h. TLC (50/50 ethyl acetate /methylene chloride) showed that the reaction was complete. The mixture was partitioned between methylene chloride (50 mL) and 5% HCl (30 mL) . The organic layer was separated , washed with water (5x20 mL) , brine (20 mL) , dried over MgSθ ₄ , filtered and evaporated to a light yellow oil. Chromatography on Siθ2 and elution with 1-20% ethyl acetate/methylene chloride afforded (XXb) as a clear oil ( .29 g, 53%) . NMR (CDCI3) : δ 6.95-7.42 (m, 20H, Ph) , 5.1-3.8 (m, complex), 3.35 (s, 6H, OCH3) , 2.8-2.95 (m, 4H, PhCH ₂ ) .

MS: 657 (13, M+l), 674 (21, M+NH ₄ ) , 522 (84), 414 (100), 370 (34) .

Procedure 3

Deprotection of amines (XXa) and (XXb) via hydrogenation to afford (XXIa) and (XXIb) :

(XXIa) R=SEM (XXIb) R=MOM

A. Hydrogenation of SEM ether (XXa)

Compound (XXa) (90 g, 108.5 mmol) was dissolved in absolute ethanol (2.5 L) . 5% Pd/C (6.5 g) was added and the solution was stirred under hydrogen for 1.5 h until hydrogen uptake ceased. TLC (20/80 ethyl acetate/hexane) showed that the reaction was complete. The solution was filtered through Celite and evaporated at reduced pressure to a colorless gum (60 g, 99%) . NMR (CDCI ₃ ) : δ

7.1-7.35 (m, 10H, Ph) , 4.72 (br d, 4H, OCH ₂ 0) , 3.5-3.9 ( , 6H, NH ₂ , CaOCH ₂ ), 3.15 (m, 2H, CHNH ₂ ), 2.55-2.95 (m, 4H, PhCH ₂ ), 0.95 (m, 4H, SiCH ) .

B. Hydrogenation of MOM ether (XXb) .

Compound (XXb) (.29 g, .441 mmol) was dissolved in ethyl acetate (6 mL) and methanol (3 mL) . 10% Pd/C (70 mg) was added and the solution stirred under hydrogen until H ₂ uptake ceased. TLC (20/80 methanol/ethyl acetate) showed that the reaction was complete. The solution was filtered through Celite and evaporated at reduced pressure to afford 3b as a clear oil (.132 g, 77.4%). NMR (CDCI ₃ ) : δ 7.1-7.35 ( m, 10H, Ph) , 4.58 (s,

4H, OCH ₂ O) , 3.75 (br s, 2H, CH.OCH ₂ ) , 3.3-3.5 (m, 2H,

CHNH ₂ ), 3.23 (s, 6H, OCH3), 2.85 (br d, 4H, PhCEtø) . MS: 389 (M+l, 100), 345 (3.7), 280 (1.8), 120 (6.1) .

Procedure 4

Formation of cyclic ureas (XXIIa) and (XXIIb)

(XXIIa) R=SEM

(XXIIb) R=MOM

A. Cyclization of SEM ether (XXIa) .

Compound (XXIa) (40 g, 71.3 mmol) was dissolved in methylene chloride (200 mL) . Carbonyl diimidazole (13.87 g, 85.6 mmol) was dissolved in methylene chloride (200 ^• mL) in a separate flask. Each solution was then pumped into dry methylene chloride (6 L) at a rate of 90 mL/h. The mixture was then stirred for 18h at room temperature under nitrogen. TLC (60/40 ethyl acetate/hexane) showed the reaction was complete. The solvent was removed at reduced pressure and residue chromatographed on Siθ2 and eluted with 1-50% ethyl acetate/hexane to afford (XXIIa) as a white solid (38.82g, 93%) . mp: 75-76°C. NMR (CDCI3) : δ 7.05-7.4 (m, 10H, Ph) , 4.6-4.8 (dd, 4H, OCH2O , 4.08 (s, 2H, CH.OCH ₂ ), 3.5-3.91 (m, 8H,

NH, CfiNH, OCfl2CH ₂ ), 2.86, (br d, 4H, PhCH ₂ ) , 0.8-0.95 (m, 4H, SiCH2) . MS: 587 (M+l, 100) .

B. Cyclization of MOM ether (XXIb)

Compound (XXIb) (.53 g, 1.364 mmol) was dissolved in dry methylene chloride (20 mL) . In a separate flask, carbonyl diimidazole (.265 g, 1.64 mmol) was dissolved in methylene chloride (20 mL) . To a third flask containing pyridine (.22 mL, 2.73 mmol) in methylene chloride (100 mL) at room temperature under nitrogen were added the first two solutions via syringe pump at a rate of 1.7 mL/h. The solution was stirred overnight at room temperature. TLC (50/50 ethyl acetate/methylene chloride) showed that the reaction was complete. The solution was washed with 5% HCl (50 mL) , NaHC0 ₃ (50 mL) , brine (50 mL) , dried over MgS0 ₄ , filtered and evaporated. The residue was chromatographed on Siθ ₂ and eluted with 50-75% ethyl acetate/methylene chloride to afford (XXIIb) as a colorless gum (198 mg, 35%) . NMR (CDCI ₃ ) : δ 7.1-7.4 (m, 10H, Ph) , 4.65 (q, 4H, OCH2O) ,

4.13 (s, 2H, NH) , 3.89 (t, 2H, CflNH) , 3.59 (s, 2H, ^• CHOCH ₂ ), 3.18 (s, 6H, OCH ₃ ), 2.87 (m, 4H, PhCH ₂ ) . MS: 415 (M+l, 100) , 102 (11) .

Synthesis of Dimem DiZ Intermediate:

DiZ Diol 507g(0.89mol) was stirred in 4L of dichloromethane. To the slurry was added N,N-

Diiso rop lethylamine 780g(6.05mol) in one portion at room temperature followed by the dropwise addition of B- methoxyethoxy methylchoride 500g(4mol) (1 hour addition, exothermic) . Heated the solution at reflux for 12 hours. TLC (10:1:10 EtOAc:EtOH:Hexanes, Rf=0.56) indicated a complete reaction. The solution was worked up by quenching with ice water(3L) . Washed the dichloromethane extract with water(2x 2L) and dried over magnesium sulfate. The filtrate was taken to dryness. The resultant semi-solid was dissolved in chlorobutane(lL) . Passed the solution through a four

inch pad of silica gel to remove most of the intense red color. To the chlorobutane extract was added hexane (2L) to precipitate the desired DiZ Dimem intermediate. Washed the white solid with hexanes (3x 350ml) . Dried at room temperature. Recovered the desired DiZ Dimem intermediate as a white solid in a yield of 525g(79% yield) . m.p. 52-54 C, 1H NMR(CDCl3) : 2.80(m, 4H)-CH2Ph, 3.38 (s, 6H)-0CH3, 3.58 (m, 8H)-OCH2CH2O-, 3.80 (m, 2H) , 4.20 (m, 2H) , 4.6-5.2 (m, 10H)NH, H2CCO2, -OCH2O-, 7.25 (m, 20H)C6H5

Synthesis of Cyclic Urea Intermediate:

DiZ Dimem 20g(26.8mmol) was dissolved in 200ml of tetrahydrofuran. To the solution was added 2g of 10% Palladium on Carbon and the suspension stirred for 7 hours under hydrogen(1 atm) . TLC (10:1:10 EtOAc:EtOH:Hex, Rf=0.05) indicated a complete reaction. The suspension was filtered through a bed of Celite to remove the catalyst. Washed the Celite bed with 150ml of tetrahydrofuran. Transferred the THF solution to a

500ml round bottom flask. To the THF solution was added 5.5g(33.3mmol) 1, 1'-Carbonyldiimidazole in several portions as a solid. Stirred at room temperature for 12 hrs. TLC (10:1:10 EtOAc:EtOH:Hex, Rf=0.26) indicated a complete reaction. The mixture was worked up by quenching with ice-cold 0.5N HCl (150ml) and extracting with diethyl ether (2x50ml) . The organic extract was washed with water (2x100ml) and dried over magnesium sulfate. The filtrate was taken to dryness. The residue was purified on silica gel(200g; 1:1 EtOAc:Hex followed by 10:1:10 EtOAc:EtOH:Hex) to provide 10.2g (75.7% yield over two steps) of the desired cyclic urea intermediate as a colorless oil. 1H NMR(CDCl3) : 2.90 (m, 4H)-CH2Ph, 3.36 (s, 6H)-OCH3, 3.40 (m, 8H) -OCH2CH2O-, 3.60(m, 2H) , 3.90(t, 2H) , 4.10(s, 2H)NH, 4.80(q, 4H)- OCH20-, 7.30(m, 10H)C6H5

Procedure 5

General alk lation/hydrolysis procedure:

Compound (XXIIa) (1 mmol) in dry DMF (5 mL) was added to a flask containing sodium hydride (10 mmol, that had been washed with hexane, 3x20 mL) in DMF (5 mL) . The solution was stirred at room temperature under nitrogen for 5 min. Evolution of hydrogen gas was observed. The appropriate alkyl bromide (5 mmol) was added and the solution was stirred at room temperature under nitrogen for lh. Hindered alkyl bromides required heating at 40-70 °C for up to 5 h. TLC (40/60 ethyl acetate/hexane) was used to ensure that no starting material remained. The solution was quenched with methanol (1 mL) , partitioned between ether (60 mL) and water (50 mL) and the organic layer was removed. The aqueous layer was washed with ether (50 mL) , the organic layers combined and washed with water (4x30 L) , brine (30 mL) , dried over MgS0 ₄ , filtered and evaporated. In cases where the alkyl bromide contained nitrogen, 1 N NaOH was used in place of water. The crude product was hydrolyzed directly in methanol (10 mL) and 4 N HCl/dioxane (5 mL) for up to 16 h at room temperature. The solution was evaporated and chromatographed directly on Siθ ₂ to afford the bis- alkylated cyclic ureas. Where nitrogen was present, the solutions were first basified with 1 N NaOH and extracted with ethyl acetate, dried over MgSθ ₄ , filtered, evaporated and chromatographed.

Hydrolysis of (XXIIb) under the same conditions gave 67% yield of the N,N-unsubstituted cyclic urea Example 1A, mp 170-174 °C.

Example IG

The experimental procedure is similar to the synthesis of Example IE. The isomer, (2R, 3R, 4R, 5R) -2 , 5- diamino-1, 6-diphenyl-3, 4-hexanediol, needed for the synthesis was isolated from the vanadium trichloride coupling reaction, as described in copending commonly assigned patent application Jadhav et al. USSN 07/714,042, filed 5/31/91 (see Procedure 1 above) .

Example IG: ¹³ C NMR (CDC13) : (75.48 MHz) 37.387, 51.51, 65.136, 72.779, 118.649, 126.540, 128.409, 129.714, 134.618, 137.757, 162.705.

Example IF

Compound (XXIIb) (0.85g) was heated with mixture of acetic acid (9.5 mL) and water (0.5 mL) at 85 °C for 4h. After extraction with dichloromethane, followed by washing the organic extract with saturated sodiumbicarbonate and brine, a mixture was provided

which, on separation by column chromatography, furnished (XXIIb) (TLC 1:10 ethyl acetate/hexane Rf = 0.4; 0.54g), the desired mono-alcohol intermediate ( TLC 1:10 ethyl acetate/hexane Rf = 0.1; 0.13g), and overhydrolysed diol (0.05g) .

The above mono-alcohol intermediate 0.25g (0.466 mmol), triphenylphosphine 183mg (0.7 mmol), diethylazadicarboxyalte 0.11 mL (0.7 mmol), and chloroacetic acid 66mg (0.7 mmol) were stirred in 5 mL anhydrous tetrahydrofuran at 0 °C for 15 minutes and then at room temperature for 18 h. The excess reagents were quenched with 0.5 mL methanol and the mixture allowed to stir for 20 minutes. The mixture was purified by silica gel column chromatography to provide the desired chloroacetate intermediate with inversion of configuration. ¹³ C NMR (CDC13) : (75.48 MHz) -1.373, 14.413, 14.487, 18.253, 25.591, 33.851, 35.741, 40.505, 48.824, 49.962, 57.507, 58.234, 66.589, 67.885,73.179, 77.423, 95.454, 117.296, 118.554, 126.588, 126.887,

128.518, 128.610, 129.117, 129.199, 129.479, 133.686, 134.168, 136.324, 138.285, 155.698, 166.323.

The above chloroacetate intermediate 73mg (0.12 mmol) in 2mL dry methanol was treated with 0.25 mL

(0.5M) sodium methoxide and stirred for 30 minutes at room temperature. The contents were then treated with 0.3 mL (4% HCl in methanol) and stirred for 4.5h at room temperature. The residue after removal of solvent was purified on silica gel column to provide Example IF.

Example IF: ¹³ C NMR (CDC13) : (75.48 MHz) 34.075, 37.672, 48.941, 48.985, 58.071, 60.640, 65.861, 73.212, 177.975, 118.669, 126.535, 126.858, 128.603, 128.815, 129.225, 133.605, 134.172, 137.637, 138.273, 155.497.

Synthesis, of Monoalkyl Cyclic Urea:

The intermediate from previous step 2g(4mmol) was dissolved in 25ml toluene and placed in a 100ml round bottom flask. To the solution was added 85% KOH 0.82g(12mmol) and polyethylene glycol (M.W.=1000) 0.20g. With a Dean Stark trap in place the mixture was refluxed for 4 hours until the theoretical amount of water (0.20ml) was collected Cooled to room temperature and added (bromomethyl) cyclopropane 1.78g(13.2mmol) . Stirred at 75 C for 17 hours. TLC(10:1:10 EtOAc:EtOH:Hex, Rf=0.52) indicated that the reaction was complete. Worked up by quenching with aqueous ammonium chloride (50ml) and extracting with ethyl acetate (2x35ml) . Washed the organic layer with water(2x35ml) and dried over magnesium sulfate. The filtrate was taken to dryness . The residue was purified on silica gel(150g, 2:3 EtOAc:Hex) to provide 1.55g(70% yield) of the desired monoalkyl cyclic urea as a colorless oil. C13 NMR(CDCl3) : 3.331, 4.000, 10.619, 32.877, 34.159,

55.677, 58.294, 58.972, 64.085, 67.361, 67.437, 71.723, 71.753, 76.576, 78.023, 96.347, 96.519, 126.224,

126.316, 128.366, 128.563, 129.400, 129.447, 139.475, 139.555, 161.558.

Examples 1A-17.. 1AA-1AZ. and IBA-IBD

The compounds listed in Table la (Examples 1A-1Z, 1AA-1AZ, and 1BA-1BD) were synthesized using the above- described procedures.

Table la

Example Stereo- _ 22 _ 23 Ki

Number iso er

IBB 2-furylmethyl 2 - furylmet yl 1BC CH2CH2θCH ⁽ CH2 ⁾ 2 CH2CH2θCH ⁽ CH2 ⁾ 2 1BD isoprenyl methyl

The Ki values in Table 1 were determined using the assay conditions described below under HIV Protease Inhibtion Assay. The Ki values are indicated as follows: +++ = <10 nM; ++ = 10 nM to 1 μM; + = >1 μM.

Listed below are physical data for representative compounds of the invention.

Example IW: mp 170-174 °C (67% yield) . MS: 355 (M+l, 100). NMR (CDCl ₃ )δ 7.1-7.35(m, 10H, Ph) ,

4.03(s,2H,CflOH) , 3.5(d, 2H, NCH), 2.8-3.1(m, 6H, PhCH ₂ , OH) , 2.58(s, 6H, NH ₃ ) .

Example IAD: mp 214-215 °C. MS: 383(M+l, 100). NMR (CDCl ₃ )δ 7.1-7.35 (m, 10H, Ph) , 3.95 (s, 2H, CHOH), 3.5

(d, 2H, NCH), 2.8-3.1 ( , 4H, PhCH ₂ OH), 2.7 (br s, 2H, OH), 2.3 (m,2H, NCH), .95(t, 6H, CH ₃ ) .

Example 1AF: mp 180-182 °C. MS: 411 (M+l, 100) . NMR (CDCl3)δ 7.05-7.3 (m, 10H, Ph) , 4.0(s, 2H, CHOH),

3.68 (m,2H, NCH ₂ ), 3.52 (d, 2H, NCH), 3.05 (m, 4H, PI1CH2) , 2. l(m, 2H, NCH2), 1.6 (s, 2H, OH), 1.4 (m, 4H, MeCH ₂ ) , .79 (t, 6H, CH3) .

Example 1Z: HRMS: Calc. 439.2960. Found: 439.2959.

Example 1AK: mp 125-127 °C . MS : 467 (M+l, 100) .

NMR (CDCl3) δ 7 . 15-7 .35 (m, 10H, Ph) , 3 . 95 (s, 2H, CHOH) ,

3.68 (m, 2H, NCH2) ,3.55 (d, 2H, NCH), 2.9-3.15 (m, 4H, PhCH ), 2.75 (s, 2H, OH), 2.18 (m, 2H, NCH ₂ ) , >8-1.45(m, complex, pentyl) .

Example 1Y: mp 110-112 °C. MS: 495 (M+l, 100) . NMR(CDCl3)δ

7.1-7.35 (m, 10H, Ph) , 4.0 (s, 2H, CHOH), 3.65 (m, 2H, NCH- H) , 3.52 (d, 2H, NCH), 2.8-3.2 (m, 4H,PhCH2) , 2.15 (m,2H, OH), .9-1.45 (m, 11H, hexyl) .

Example 1AB: mp 100-101 °C. MS: 523 (M+l, 100) . NMR(CDCl3)δ 7.1-7.35 (m, 10H, Ph) , 3.95(s, 2H, CHOH), 3.65 (m, 2H, NCH-H) , 3.5 (d, 2H, NCH), 2.9-3.1 (m, 4H, PhCH2) , 2.6(s, 2H, OH), 2.15(m, 2H, NCH), .8-1.4 (m, complex, heptyl) .

Example II: MS: 507 (M+l, 100) . NMR(CDCl3)δ 7.05-7.4 (m, 20H, Ph) , 4.91(d, 4H, PhCH ₂ N) , 3.5-3.65 (m, 4H, NCH, CHOH), 3.05 (m, 4H, PhCH ₂ ) , 2.35 ( br s, 2H, OH) .

Example 5i (R ²² and R ²³ = allyl; R ²⁰ and R ²¹ = C(=0)CH3) : mp 164-166 °C. MS: 407 (M+l, 100) . NMR(CDCl3)δ

7.1-7.4 (m, 10H, Ph) , 5.65 (m, 2H-, CH2CH) 5.01 (m, 4H, CH2.CH) , 4.26(m, 4H, NCH ₂ ) , 3.91 (s, 2H, CHOH), 3.59 (d, 2H, CHN), 3.1 (m, 4H, PhCH2) , 2.7 (m, 2H, CHCU ₂ ) , 2.41(s, 2H, OH) .

Example 1AO: MS 439(M+l, 100) . NMR(CDCl3)δ 7.15-7.35(m, 10H, Ph), 4.05 (s, 2H, CHOH), 3.7(m,2H, NCH ₂ ) , 3.55 (d, 2H, NCH), 3.0-3.2 (m, 4H, PI1CH2) , 2.65(s, 2H, OH),

1.78 (m, 2H, NCH), 1.6(s, 2H, CH2C ) , .82(d, 12H, CHM& ₂ ) •

Example 1AH: mp 194-195 °C. MS: 467 (M+l, 100) . NMR(CDCl ₃ )δ

7.15-7.35 (m, 10H, Ph) , 3.95 (s, 2H, CHOH), 3.65 (m, 2H, NCH), 3.49 (d, 2H, NCH), 2.9-3.1 (m, 4H, PhCH ₂ ) , 2.61 (s,

2H, OH), 2.2(m, 2H, NCH), 1.1-1.5 (m, complex), .9 ( , 12H, CH___2) .

Example 1AM: mp 120-122 °C. MS: 495 (M+l, 100) . NMR(CDCl ₃ )δ 7.1-7.35(m, 10H, Ph) , 3.95(s, 2H, NCH), 3.45-3.7 (m, 4H, NCH ₂ , NCH), 2.9-3.2(m, 4H, PhCR_) , 2.1(m, 2H, NCH2) , .78-1.45(m, complex, hexyl) .

Example IAN: mp 105-107 °C. MS: 523 (M+l,100) . NMR(CDCl ₃ )δ 7.18-7.31(m, 10H, Ph) , 3.95 (s, 2H, CHOH), 3.7 (m, 2H,

NCH ₂ ), 3.56 (d, 2H, NCH), 2.9-3.15 (m, 4H, PhCH ₂ ) , 2.18 (m, 2H, NCH2) , .9-1.45 (m, complex, hexyl) .

Example lAL: mp 144-145 °C. MS: 551(M+l,100) . NMR(CDCl ₃ )δ 7.15-7.35(m,10H, Ph) , 3.95 (s, 2H, CHOH), 3.65 (m, 2H, NCH ₂ ) , 3.55 (d, 2H, NCH), 2.9-3.15(m, 6H, PhCH ₂ , OH), 2.15 (m, 2H, NCH2) , .9-1.5 (m, complex, heptyl) .

Example 1AC: mp 160-163 °C. MS: 463 (M+l, 100) . NMR(CDCl ₃ )δ 7.15-7.35(m, 10H, Ph) , 5.06(br t, 2H, NCH2CH.) , 4.1(dd,

2H, NCH2), 3.9(S, 2H, CHOH), 3.5(d, 2H, NCH), 2.8-3.1(m, 4H, PhCH _∑ ), 1.65(S, 6H, CHCH ) , 1.38(s, 6H, CHCH.3) .

Example 1AJ: mp 205-207 °C. MS: 435 (M+l, 100) . NMR(CDCl3)δ 7.1-7.35(m, 10H, Ph) , 4.85(s, 2H, C=CH) , 4.58 (s, 2H,

C=CH), 4.28 (d, 2H, NCH ₂ ) , 3.95 (s, 2H, CHOH), 3.7 (br d,

2H, CHOH), 2.9-3.2 ( , 4H, PhCH ) , 2.5 (d, 2H, NCH ₂ ) , 1.75 (s, 6H, CH3) .

Example 1AI: MS: 509 (M+l, 100) . NMR(CDCl3)δ 7.0-8.4(m,

18H, Ph, pyr.), 4.8-5.0 (m, 4H, NCH2) , 3.7 (s, 2H, CHOH), 3.5(d, 2H, NCH), 2.9-3.2(m, 8H, PhCH2, pyrCH ) .

Example 1AP: mp 198-200 °C. MS: 403 (M+1,100) . NMR(CDCl3)δ 7.2-7.35(m, 10H, Ph) , 4.5(s, 2H, CCH) , 4.42(s, 2H, NCH),

4.1 (s, 2H, CHOH), 3.8 (d, 2H, NCH), 2.9-3.2 (m, 4H, PΪ1CH2), 2.7-2.85 (m, 4H, NCH2) .

Example 10: mp 105-106 °C. MS: 531 (M+l, 100) . NMR(CDCl3)δ 7.1-7.35 (m, 10H, Ph) , 3.0-4.15 (m, complex), 2.25 (m, 2H, OH) .

Example IS: MS: 619(M+l, 100) . NMR(CDCl3)δ 7.18-7.3 (m, 10H, Ph) , 3.0-4.2 (m, complex), 2.25 (m,2H,OH) .

Example IP: mp 80-82 °C. MS: 607 (M+l, 100) , 257(9.6) . NMR(CDCl ₃ )δ 7.05-7.35(m, 10H, Ph) , 3.95(s, 2H, CHOH),

3.4-3.75 (m, 4H, NCH, NCH2) , 2.9-3.15 (m, 4H, PΪ1CH2) ,

2.1 (m,2H, OH), .85-1.6 (m, complex) .

Example 1AA: mp 70-75 °C. MS: 553 (M+l, 100) . NMR(CDCl ₃ )δ

7.05-7.4 (m, 10H, Ph) , 3. -4.25 (m, complex), 2.9-3.15 (m, 4H, PhCH2), 2.2-2.8(m, complex) .

Example IX: mp 210-212 °C. MS: 435 (M+l, 100) . NMR(CDCl3)δ 7.18-7.35 (m, 10H, Ph) , 4.06(s, 2H, CHOH), 3.68 (br d, 2H, NCH), 3.55 (q, 2H, NCHCH) , 3.1 (m, 4H, PhCH ₂ ) , 2.55 (s, 2H, OH), 2.05 (q, 2H, CHCH) , .9(m, 2H, NCH2CH) , .42(m, 4H, -CH2-) , .008(m, 4H, -CH2-) .

28

Example 1AR: mp 85-87 °C. Example 1C: mp 164-166 °C. Example 1A: mp 170-174 °C.

Using the above-described techniques or variations thereon appreciated by those of skill in the art of c _h emical synthesis, the compounds of Tables l ^b can be prepared.

Table lb

Example R22 R23 ZA B2 Number

1BE

1BF

1BG

1BH

1BI

1BJ

1BK

1BL

IBM

1BN

Synthesis of Cyclic Quanidines

Cyclic guanidine compounds of the invention wherein W = NH(C=N-CN)NH, differ from the cyclic urea compounds of the invention wherein W = NH(C=0)NH. Described below are representative methods for the preparation of cyclic quanidine compounds of the invention.

SYNTHESIS OF CYCLIC GUANIDINES

Sem = CH ₂ OCH ₂ C H ₂ Si(CH ₃ ) ₃

4M HCI in Dioxane

Q8239

The structures of the Examples below are shown in Table lc.

Example IBS (08239)

SYNTHESIS OF INTERMEDIATE _: Diamino Disem 561mg(lmmol) was dissolved in 2ml pyridine and to this solution was added 175mg(1.2mmol) Dimethyl

N-cyanodithioiminocarbonate. The contents were refluxed in a 125°C oil bath for 2 hours. (Caution: Methyl mercaptan is a by-product and the reaction should be vented to a Clorox scrubber). TLC(1:2 EtOAc:Hexane Rf=0.4) indicated a complete reaction. The reaction was

diluted with 100ml dichloromethane. The organic layer was washed with IN HCL(2x25ml) followed by sat. sodium bicarbonate solution(25ml) . It was separated and dried over magnesium sulfate and the filtrate taken to dryness. The residue was purified on Siθ ₂ gel(55g; using 1:3 followed by 1:2 EtOAc:Hexane) to provide 372mg(60.9% yield) of the desired intermediate A as a colorless oil.

SYNTHESIS OF INTERMEDIATE _: Intermediate _

305mg(0.5mmol) was dissolved in 2ml dimethylformamide and to this solution, cooled in a 0°C ice bath, was added NaH(60% in oil) 80mg(2mmol) slowly. The contents were stirred at room temperature for 30 minutes. The mixture was cooled in a 0°C ice bath and

(bromomethyl)cyclopropane 0.19ml(2mmol) was added via syringe and stirred at room temperature for 18 hours. TLC(1:4 EtOAc:Hexane Rf=0.31) indicated a complete reaction. The reaction was worked up by diluting with water(50ml) and extracting with diethylether (2x25ml) . The organic layer was dried over magnesium sulfate and the filtrate taken to dryness. The residue was purified on Siθ2 gel(33g; 1:5 followed by 1:4 EtOAc:Hexane) to provide 243mg(67.6% yield) of the desired intermediate _ as a colorless oil.

SYNTHESIS OF EXAMPLE IBS: Intermediate _ llOmg (0.153mmol) was placed in a 10ml R.B. Flask and cooled in a 0°C ice bath. To the flask was added 4M HCl in dioxane 1ml (4mmol) and the mixture stirred at room temperature for 15 minutes. TLC(1:1 EtOAc:Hexane Rf=0.15) indicated a complete reaction. The mixture was worked up by quenching in sat. sodium bicarbonate(25ml) and extracting with dichloromethane (2x25ml) . The organic extracts were dried over magnesium sulfate and the filtrated taken to dryness. The residue was

purified on Siθ ₂ gel(33g; 1:1 EtOAc:Hexane followed by 10:1:10 EtOAc:EtOH:Hexane) to provide 27mg(38.5% yield) of the desired Q8239 as a white solid. m.p.211.2°C

Example 1BT

SYNTHESIS OF INTERMEDIATE _: Intermediate _ 1.515g(2.48mmol) was dissolved in 7.5ml dimethylformamide and to this solution, cooled in a 0°C ice bath, was added NaH(60% in oil) 397mg(9.92mmol) slowly. The contents were stirred at room temperature for 30 minutes. The mixture was cooled in a 0°C ice bath and p-benzyloxybenzyl chloride 2.308g(9.92mmol) was added as a solid and the mixture stirred at room temperature for 18 hours. TLC(1:4 EtOAc:Hexane Rf=0.31) indicated a complete reaction. The reaction was worked up by diluting with water(100ml) and extracting with diethylether (2x50ml) . The organic layer was dried over magnesium sulfate and the filtrate taken to dryness. The residue was purified on Siθ ₂ gel(130g; 1:4 followed by 1:3 EtOAc:Hexane)to provide 2.068g(83.1% yield) of the desired intermediate _ as a colorless foam.

SYNTHESIS OF EXAMPLE 1BT: Intermediate _ 1.928g (1.92mmol) was placed in a 100ml R.B. flask and cooled in a 0°C ice bath. To the flask was added 4M HCl in dioxane 15ml (60mmol) and the mixture stirred at room temperature for 15 minutes. TLC(1:1 EtOAc:Hexane Rf=0.25) indicated a complete reaction. The mixture was worked up by quenching in 0.5N sodium hydroxide solution(100ml) and washing with sat.sodium bicarbonate(50ml) and extracting with dichloromethane (3x50ml) . The organic extracts were dried over magnesium sulfate and the filtrate taken to dryness. The residue was purified on Siθ ₂ gel(130g; 1:1

EtOAc:Hexane) to provide 1.284g(89.9% yield) of the desired Q8241 as a white solid. m.p.90.1°C

Example 1BU

SYNTHESIS OF EXAMPLE 1BU: Example Number 1BT 1.161g(1.56mmol) was dissolved in 15ml of ethanol. To the mixture was added l.lg of 5% Palladium on Carbon and the suspension stirred for 18 hours under hydrogen(1 atm) . TLC indicated an incomplete reaction. The mixture was treated with 1.Ig of 10% Palladium Hydroxide on Carbon and stirred for 2 hours under hydrogen(1 atm) . TLC(10:1:10 EtOAc:Hexane Rf=0.31) indicated a complete reaction. The suspension was filtered through a celite pad and the filtrate taken to dryness. The residue was purified on Siθ ₂ gel(130g; 10:1:10 followed by 10:2:10 EtOAc:EtOH:Hexane) to provide 458mg(52.2% yield) of the desired Q8242 as a white solid. m.p.l03.3°C

Table In

Example Ki IC90 M+H .p. (°C) Number (M+NH4)

IBS cyclopropylmethyl ++ +++ 459 211.2

1BT CH2(C6H4)-p-0CH2C6H5 ++ 743 90.1

1BU CH2(C6H4)-p-OH +++ +++ 563 103.3

1BV cyclopentylmethyl +++ +++ 515 99.7

1BW allyl ++ ++ 431 70.2

1BX n-butyl +++ +++ 463 58.3

1BY Beta-napthylmethyl ++ 631 111.1

1BZ benzyl ++ +++ 531 94.0

1CA CH2(C6H4)-m-OCH2C6H5 ++ 743 75.2

1CB p-nitrobenzyl ++ ++ 621 130.3

ICC m-nitrobenzyl 114

1CD CH2(C6H4)-m-OH +++ +++ 563 124

ICE p-aminobenzyl ++ +++ 561 226.3

1CF m-aminobenzyl +++ +++ 561 114.4

ICG p-nitrilobenzyl ++ +++ 581

1CH m-nitrilobenzyl ++ +++ (598) 108.5

1CI dimethylallyl +++ 487 72.9

1CJ cyclohexylmethyl +++ +++ 543 96.4

1CK cyclobutylmethyl +++ +++ 487 235.5

1CL propyl ++ +++ 435 216.6

1CM 3-methyl-l-butyl ++ +++ 491 76.1

1CN CH2(C6H4)-P-CH2OH ++ +++ 591 100.9

ICO CH2(CgH4)-m-CH20H +++ +++ 591 193.8

1CP CH2(C6H4)-m-CHO +++ +++ 587

ICQ CH2(C6H4)-m-CH=N-OH +++ +++ 617 121.2

The structures of the Examples below are shown in Tables Id and le.

Example 7F

A solution of Example IX (120 mg, 0.27 mmol) in methylene chloride (25 mL) was cooled in an ice bath at 0 °C and treated with triethylamine (110 mg, 1.1 mmol) .

Then a solution of thionyl chloride (150 mg, 1.3 mmol) in methylene chloride (10 mL) was added dropwise. The mixture was stirred for 10 minutes and then washed with sat'd NaHCθ3 (aq) , brine, and dried over MgSθ4. ^τhe solution is filtered and the solvent removed on a rotary evaporator and the resulting residue is HPLC chromatographed on silica gel (50% EtOAc/Hexanes) to give 100 mg of a white foam. HRMS calculated for ^C 27 ^H 32 ^N 2°4 ^S: 481.2161; found: 481.2152.

Example 7G

A solution of Example IX (120 mg, 0.27 mmol) in methylene chloride (25 mL) was cooled in an ice bath at 0 °C and treated with triethylamine (80 mg, 0.8 mmoi) . Then a solution of trichloromethyl chloroformate (DIPHOSGENE) (53 mg, 0.27 mmol) in methylene chloride (5 mL) was added dropwise. The mixture was stirred for 60 minutes and then washed with sat'd NaHCθ3 (aq) , brine, and dried over MgSθ4. The solution is filtered and the solvent removed on a rotary evaporator and the resulting residue is chromatographed on silica gel (50% EtOAc/Hexanes) to give 90 mg of a white foam. MS NH3

(M+H) ⁺ = 461.

Example 71

A solution of Ex. IX (500 mg, 1.15 mmol) in THF (25 mL) was treated with thiocarbonyldiimidazole (410 mg, 2.3 mmol) and heated to reflux for 1.5 hours. The solvent is removed on a rotary evaporator and the resulting residue is chromatographed on silica gel (50% EtOAc/Hexanes) to give 320 mg of a white solid. MS NH3 (M+H) ⁺ = 477.3

Example 7H and 7ϋ

A solution of Example 71 (220 mg, 0.46 mmol) in dry toluene (25 mL) was heated to reflux and treated with Bu3S H (0.4 mL, 1.5 mL) and 20 mg of AIBN. The mixture was heated at reflux for 2.5 hours. The solvent is removed on a rotary evaporator and the resulting residue is chromatographed on silica gel (20% EtOAc/Hexanes) to give 70 mg of 7H as a white solid. MS NH ₃ (M+H) ⁺ = 447.2. A later fraction gave 30 mg of Example 7U as a white solid. MS (M+H) ⁺ 419.2.

Example 7V

A solution of Ex. IX (112 mg, 0.26 mmol) in methylene chloride (5 mL) was cooled in an ice bath at 0 °C and treated with DAST (110 mg, 1.1 mmol) . The mixture was stirred for 10 minutes and then washed with sat'd NaHCθ3(aq) , brine, and dried over gSθ4. The solution is filtered and the solvent removed on a rotary evaporator and the resulting residue is HPLC chromatographed on silica gel (65% EtOAc/Hexanes) to give 40 mg of a colorless residue. HRMS calculated for C27H33N2O2F:

437.2604; found: 437.2593.

Example 7_

A solution of Ex. 3U (600 mg, 1.9 mmol) in pyridine (10 mL) is treated with methanesulfonyl chloride (170 mg, 1.5 mmol) and stirred at room temperature for 3 hours. The mixture is quenched with 5 L of methanol. The solution is concentrated on a rotary evaporator and the resulting residue is dissolved in ethyl acetate and then washed with dilute HCl(aq) , brine, and dried over MgSθ4. The solution is filtered and the solvent removed on a rotary evaporator and the resulting residue is

chromatographed on silica gel (40% EtOAc/Hexanes) to give Example 7o (420 mg ) as a white solid, ms (M+H) ⁺ = 685.

Example 7Y

A solution of Example 7o (100 mg, 0.15 mmol) in DMF (4 mL) was treated with aN3 (100 mg, 1.5 mmol) and heated at 80 °C for 2 hrs and then stirred overnight at 40 °C. The solution was diluted with water and the resulting white solid is extracted into ethyl acetate. The organic extract is washed with water, brine, and dried over MgS04. The solution is filtered and the solvent removed on a rotary evaporator and the resulting residue is HPLC chromatographed on silica gel (50%

EtOAc/Hexanes) to give Example 7Y (80 mg ) as a white solid. MS (M+H) ⁺ = 632. IR (CHCI3) 2214 cm ^-1 for N ₃ .

Example 7J and 7K

A solution of Ex. 3U (100 mg, 0.165 mmol) in pyridine (3 mL) is treated with acetic anhydride (84 mg, 0.824 mmol) and stirred at room temperature for 2 hours. The mixture is quenched with 5 mL of methanol. The solution is concentrated on a rotary evaporator and the resulting residue is dissolved in ethyl acetate and then washed with dilute HCl (aq) , brine, and dried over MgSθ4.

The solution is filtered and the solvent removed on a rotary evaporator and the resulting residue is HPLC chromatographed on silica gel (40% EtOAc/Hexanes) to give Example 7J (24 mg ) as a white solid. HRMS:(M+H) ⁺ calculated for C45H43N2O5: 691.317198; found:

691.316252.

Also gives as a later fraction Example 7K (27 mg) as a white solid. HRMS:(M+H) ⁺ calculated for 043^-^204:

649.306633; found: 649.304918.

Example 7R

A solution of Ex. 3U (100 mg, 0.165 mmol) in methylene chloride (5 mL) is treated with 2,2dimethoxy propane (174 mg, 1.65 mmol), p-toluenesulfonic acid (10 mg) and stirred at room temperature for overnight. The mixture is diluted with methylene chloride and washed with saturated NaHCC> ₃ , brine, and dried over MgSθ4. The solution is filtered and the solvent removed on a rotary evaporator and the resulting residue is HPLC chromatographed on silica gel (50% EtOAc/Hexanes) to give Example 7R (73 mg ) as a white solid. HRMS:(M+H) ⁺ calculated for C44H43N2O3: 647.327369; found: 647.327531

Example 7P

A solution of Ex. 3U (200 mg, 0.33mmol) in methylene chloride (5 mL) is treated with oxalyl chloride (249 mg, 2.0 mmol) and stirred at room temperature for overnight. The solvent removed on a rotary evaporator and the resulting residue is HPLC chromatographed on silica gel (50%.EtOAc/Hexanes) to give a tan solid. This was recrystallized from CH2Cl2/he ane to give Example 7P (80 mg ) as a white solid. MS:(M+H) ⁺ 661.4.

Exampl 7S

A solution of Ex. 3U (100 mg, 0.165 mmol) in methylene chloride (5 mL) is treated with trimethylorthobutyr te (244 mg, 1.65 mmol) p- toluenesulfonic acid (10 mg) and stirred at room temperature for 30 minutes. The mixture is diluted with methylene chloride and washed with saturated NaHCθ3, brine, and dried over MgSθ . The solution is filtered

and the solvent removed on a rotary evaporator and the resulting residue is HPLC chromatographed on silica gel (50% EtOAc/Hexanes) to give Ex. 7S. MS: (M+H) ⁺ 691.5

5 Example 7B

A solution of the Di-MEM protected Ex. 1C (550 mg, 0.94 mmol) in pyridine (11 mL) is treated with P ₂ S ₅ (420 mg, 0.94 mmol) and heated to reflux for 3 hrs . The 10 pyridine is evaporated off on a rotary evaporator and the residue is taken up in methylene chloride and washed with water, NaHC03, and brine. The solution is dried over MgS0 ₄ , filtered and the solvent removed on a rotary evaporator and the resulting residue is chromatographed 15 on silica gel (40% EtOAc/Hexanes) to give Example 7B (120 mg) as a clear oil. HRMS: (M+H) ⁺ calculated for C27H33N2O3S: 465.221190; found: 465.220899.

Example 7A

20

A solution of Example 1C (330 mg, 0.8 mmol) in pyridine .(5 mL) is treated with acetic anhydride (160 mg, 1.6 mmol) and stirred at room temperature for 4 hours . The mixture is quenched with 5 mL of methanol. 25 The solution is concentrated on a rotary evaporator and the resulting residue is dissolved in ethyl acetate and then washed with dilute HCl (aq) , brine, and dried over MgSθ4. The solution is filtered and the solvent removed on a rotary evaporator and the resulting residue is 30 chromatographed on silica gel (50% EtOAc/Hex) to give Example 7A (120 mg) as a white solid. MS: (Cl, NH3)

(M+H) ⁺ = 449.1.

_ Example 7W

35

A solution of example 1C (160 mg, 0.39 mmol) in methylene chloride (5 mL) was cooled in an ice bath at 0 °C and treated with DAST (63 mg, 0.4 mmol) . The mixture was stirred for 10 minutes and then washed with sat'd aHCθ3(aq) , brine, and dried over MgS04. The solution is filtered and the solvent removed on a rotary evaporator and the resulting residue is HPLC chromatographed on silica gel (50% EtOAc/Hex) to give 80 mg of a colorless residue. HRMS calculated for C25H30N2O2F: 409.2291; found: 409.2291.

Example 7X

A solution of example 3U (100 mg, 0.16 mmol) in methylene chloride (5 mL) was cooled in an ice bath at 0 °C and treated with DAST (26 mg, 0.16 mmol) . The mixture was stirred for 10 minutes and then washed with sat'd aHCθ3(aq) , brine, and dried over MgSθ4. The solution is filtered and the solvent removed on a rotary evaporator and the resulting residue is HPLC chromatographed on silica gel (50% EtOAc/Hex) to give 35 mg of a white foam. HRMS calculated for C ₄₁ H38N2θ2F: 609.2917; found:

609.2911.

Example 8ft

A solution of example IX (2.06 g, 4.74 mmol) in methylene chloride was treated with diisopropylethylamine (1.53 g, 11.8 mmol), MEM-C1 (0.71 g, 5.7 mmol) and heated to reflux for 5 hours and let stir overnight at rt. The solution is concentrated on a rotary evaporator the residue is HPLC chromatographed on silica gel (5 % MeOH/CHCl3) to give 1.3 g of the mono- MEM mono-ol intermediate. MS: (Cl, NH3) (M+H) ⁺ = 523.4. A solution of mono-MEM mono-ol intermediate from above (1.0 g, 1.9 mmol) in THF was treated with

triphenylphosphine (1.0 g, 3.8 mmol), diethylazadicarboxylate (DEAD) (0.7 g, 4.0 mmol), and chloroacetic acid (0.4 g, 4.2 mmol). The solution is stirred overnight at rt. The solvent is evaporated and the resulting residue is chromatographed on silica gel (50% EtOAc/Hex) to give 0.9 g of the chloroacetate intermediate. MS: (Cl, NH ₃ ) (M+H) ⁺ = 599.3 (100%); 600

(39%) .

The chloroacetate intermediate (0.9 g, 1.5 mmol) was dissolved in MeOH (15 ml) and treated with NaOH _(a q ₎

(4 ml, IN) and stirred at rt for 15 min. The solution was evaporated to dryness and the residue partitioned between water and ethyl acetate. The organic layer was washed with water and brine and then dried over MgSθ4. The solution is the filtered, concentrated and the residue is HPLC chromatographed on silica gel (85% EtOAc/Hex) to give 400 mg of example 8A. MS: (Cl, NH3)

(M+H) ⁺ = 523.4.

Example 17.

A solution of example 8A (100 mg, 0.2 mmol) in MeOH is cooled in an ice bath and treated with HCl ₍ g ₎ for 20 min and then stirred for an additional 40 min at 0°C. The solution is then evaporated to dryness at rt and the residue is HPLC chromatographed on silica gel (80% EtOAc/Hex) to give 48 mg of example 7Z as a white foam. MS: (Cl, NH ₃ ) (M+H) ⁺ = 435.2

Example 8C

A solution of example 8A (160 mg, 0.3 mmol) in methylene chloride (10 ml) is cooled to 0°C in an ice bath and treated with DAST (50 mg, 0.3 mmol) . The solution is stirred at rt for 15 min and then quenched with water. The organic layer is washed with water and

brine and dried over gSθ4. The solution is filtered, the solvent evaporated and the residue HPLC chromatographed on silica gel (50% EtOAc/Hex) to give 100 mg of example 8C. MS: (Cl, NH3) (M+H) ⁺ = 525.4

Example 8B

A solution of example 8C (70 mg, 0.13 mmol) in MeOH is cooled in an ice bath and treated with HCl ₍ g ₎ for 20 min and then stirred for an additional 40 min at 0°C.

The solution is then evaporated to dryness at rt and the residue is HPLC chromatographed on silica gel (80% EtOAc/Hex) to give 40 mg of example 8B as a white foam. MS: (Cl, NH3) (M+H) ⁺ = 437.3

Example 7ftft

To a stirred suspension of 750 mg (1.72 mmol) of the diol (IX) in 35 mL of methylene chloride was added 445 mg (3.45 mmol) of diisopropylethylamine and 322 mg (2.59 mmol) of MEM chloride. After stirring 5 days the resulting solution was washed with dilute HCl, brine and was dried with anhydrous MgS0 ₄ . The solvent was removed under reduced pressure and the residue was chromatographed on silica gel. Elution with 50% ethyl acetate in hexanes gave 430 mg (48%) of the mono protected ether (XXVa) . MS:523 (M+l,100); NMR (CDCI ₃ ) : δ

7.20 (m,10H), 4.96 (s,2H), 4.08 (m,1H) , 3.90 (m,2H) , 3.61 (m,7H), 3.42 (s,3H), 3.13 (m,4H) , 1.99 (m,2H) , 0.88 (m,2H), 0.40 (m,4H) , 0.06 (m,4H),

To a stirred solution of 78mg (0.15mmol) of Compound (XXVa) in 3 ml of methylene chloride was added 60 mg (0.74 mmol) of sodium acetate and 95 mg (0.44 mmol) of PCC. The resulting suspension was stirred 3 days and was diluted with ether and filtered through

florisil. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel. Elution with 2.5% methanol in methylene chloride gave 68 mg (885) of example 7AA. MS:521 (m+l, 100); NMR (CDCI3) : δ 7.21 (m, 10H) , 4.90 (d, 1H) , 4.70 (dd,2H),

4.10 (t,lH), 3.80-3.37 (m, 8H) , 3.36 (s,3H), 3.26-2.82 (m,4H), 2.22 (q,lH), 1.03 (m,2H), 0.51 (m, H) , 0.20 (m,4H),

Oxidation of monoprotected diol: Preparation of (XXVb) :

To a stirred solution of 51 mg (0.10 mmol) of example 7AA in 4 mL of methanol was added 1 mL of concentrated HCl. The resulting solution was stirred 5h and the product was precipitated by adding water. The suspension was extracted with methylene chloride and the combined organic layers were dried with anhydrous MgS0 . The solvent was removed under reduced pressure and the residue was chromatographed on silica gel. Elution with 33% ethyl acetate in hexanes gave 34 mg (80%) of the ketol (XXVb) . MS:433 (m+l, 100); NMR (CDCI3) : δ 7.21

(m,10H), 4.82 (m,1H) , 4.24 (t,lH), 3.85 (m,lH), 3.74

(d,lH), 3.44 (m,3H), 3.22-2.73 (m, 4H) , 2.27 (q, 1H) , 1.01

(m,2H), 0.51 (m,4H), 0.20 (m,4H),

Example 7AC

To a stirred solution of 37 mg (0.09 mmol) of the ketol (XXVb) in 4 mL of ethanol and 2 mL of water was added 40 mg (0.48 mmol) of methoxylamine hydrochloride. The resulting solution was stirred overnight and the product was precipitated by adding water. The suspension was extracted with methylene chloride and the combined organic layers were dried with anhydrous MgS0 ₄ . The solvent was removed under reduced pressure to give 40 mg (100%) of example 7AC. MS: 462 (m+l, 100); NMR

(CDCI3) δ 7.20 (m, 10H), 5.30 (m,2H), 4.80 (t,lH), 4.24 (t _r lH), 3.77 (m,4H), 3.40 (m,3H), 2.90 (m, 4H) , 2.25 (dd,lH), 1.03 (m,2H), 0.48 (m, 4H) , 0.23 (m, 2H) , 0.12 (m,2H) . •

Example 7ftg

By substituting hydroxylamine hydrochloride in the above procedure, the desired product can be obtained: MS: 448 (m+l, 100); NMR (CDCI3) : δ 8.13 (s,lH), 7.20

(m,10H), 5.42 (t,lH), 4.83 (t,lH), 3.75 (m,2H), 3.40 (m,3H), 2.94 (m, 4H) , 2.22 (dd,lH), 1.17 (m, 1H) , 0.90 (m,lH), 0.47 (m,4H), 0.23 (m,2H) , 0.11 (m,2H) .

Example 7AD

To a stirred solution of 98 mg (0.23 mmol) of ketol (XXVb) in 5 mL of butanol was added 57 mg (0.71 mmol) of formamidine hydrochloride and 40 mg (0.75 mmol) of sodium methoxide. The resulting suspension was stirred 30 min and was refluxed overnight. The butanol was removed under reduced pressure and water was added. The suspension was extracted with methylene chloride and the combined organic layers were dried with anhydrous MgS0 ₄ . The solvent was removed under reduced pressure and the residue was chromatographed on silica gel. Elution with 25% ethyl acetate in hexanes gave 28 mg (28%) of example 7AD. MS: 42 (m+l,100); NMR (CDCI3) : δ 7.58 (S,1H), 7.20

(m,10H) _r 4.55 (m,2H), 3.51 (m,2H), 3.24 (m,2H), 3.05 (m,2H), 2.53 (q, 1H) , 2.27 (q,lH), 0.91 (m,2H) , 0.45 (m,4H) , 0.11 (m,4H) .

Examples 7AE and 7AF

To a stirred solution of 65 mg (0.15 mmol) of the diol (IX) in lmL of DMF was added 5.5 mg (0.18mmol) of

80% sodium hydride. The resulting suspension was stirred 20 min. and 68 mg (0.48 mmol) of methyl iodide was added. After stirring overnight, the suspension was quenched with water, extracted with ethyl acetate, and the combined organic layers were dried with anhydrous MgSθ4. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel. Elution with 25% ethyl acetate in hexanes gave 19 mg (28%) of example 7AE along with 25 mg (37%) of Example 7AF.

Example 7AE: MS: 449 (m+l, 100); NMR (CDCI3) : δ 7.26 (m,10H), 4.05 (dd, 1H) , 3.84 (m, 1H) , 3.67 (m,2H), 3.60 (s,3H), 3.53 (m,2H), 3.13 (m,3H), 2.90 (m,2H) , 1.94 (dt,2H), 0.89 (m,2H), 0.41 (m,4H) , 0.04 (m,4H),

Example 7AF: MS: 463 (m+1,100); NMR (CDCI3) : δ 7.21

(m,10H), 3.67 (m, H) , 3.62 (s,6H), 3.58 (s,2H), 3.10

(m,4H), 1.92 (dd,2H), 0.83 (m,2H), 0.41 (m, 4H), 0.04 (m,4H) .

Examples 7AG and 7AH

By substituting benzyloxymethyl chloride in the above procedure, example 7AG and 7AH were obtained.

Example 7AG: MS: 615 (m+1,100); --H NMR (CDCI3) : δ 7.50- 7.06 (m,20H), 4.88 (ab,4H), 3.92 (s,2H), 3.56 (m,2H), 3.47 (dd,2H), 3.14 (m, H) , 1.88 (dd,2H), 0.62 (m,2H), 0.34 (m,4H), 0.05 (m, 4H) .

Example 7AH: MS: 525 (m+1,100); *-H NMR (CDCI3) : δ 7.45- 7.10 (m, 15H), 4.74 (ab,2H), 4.13 (dd, 1H) , 3.82-3.50 (m,5H), 3.09 (m, 4H) , 2.76 (s,lH), 1.95 (dt,2H), 0.92 (m,2H), 0.40 (m, 4H) , 0.03 (m,4H) .

Examples 7ΛI and 7ftJ

By substituting allyl bromide in the above procedure, example 7AI and 7AJ were obtained.

Example 7AI: ^•■ _ NMR (CDCI ₃ ) δ 7.26 (m,10H) , 6.05 (m,2H),

5.30 (dd,4H), 4.28 (m,2H) , 3.76 (s,2H), 3.60 (m,4H), 3.10 (m,4H), 1.93 (dd,2H) , 0.86 (m,2H) , 0.40 (m,4H), 0.01 (m,4H) .

Example 7AJ: MS: 475 (m+1,100); NMR (CDCI ₃ ) δ 7.27 (m,10H), 6.01 (m,1H), 5.32 (dd,2H), 4.34 (dd,1H) , 4.18 (dd.lH), 4.66 (m,5H), 3.10 ( ,4H) , 2.82 (s,lH), 1.95 (m,2H), 0.85 (m,2H) , 0.40 (m,4H) , 0.04 (m,4H) .

Example 8E

A solution of Example 5F (500 mg, 0.7 mmol) in methylene chloride (10 ml) is cooled to 0°C in an ice bath and treated with DAST (112 mg, 0.7 mmol) . The solution is stirred at 0°C for 15 min and then quenched with sat'd N HCθ ₃ . The organic layer is washed with water and brine and dried over MgSθ ₄ - The solution is filtered, the solvent evaporated and the residue HPLC chromatographed on silica gel (50% EtOAc/Hex) to give 250 mg of example 8E as a white foam. MS: (Cl, NH ₃ )

(M+H) ⁺ = 721

Example 8F

A solution of example 8E (200 mg, 0.28 mmol) in MeOH is cooled in an ice bath and treated with gaseous HCl for 20 min and then stirred for an additional 40 min at 0°C. The solution is then evaporated to dryness at rt and the residue is HPLC chromatographed on silica gel

(5% MeOH/CHCl3) to give 120 mg of example 8F as a white foam. MS: (Cl, NH ₃ ) (M+H)+ = 541

Example 8G (via Alkene Intermediate XXIX : -

A solution of Example 7_ (150 mg, 0.22 mmol) in DMF was treated with sodium iodide (160 mg, 1.1 mmol) and heated at 90°C for 2 hrs . The mixture is cooled to room temperature, diluted with water and the precipitate is extracted into CH2CI2. The extract is washed with water and brine, dried over MgSθ4 ^ar -d evaporated to give a yellow oil. This is HPLC chromatographed on silica gel (50% EtOAc/Hex) to give 50 mg of alkene intermediate (XXIX) as a white solid. MS: (Cl, NH ₃ ) (M+H) ⁺ = 589

Alkene intermediate (XXIX)

A solution of alkene intermediate (XXIX) (40 mg, 0.07 mmol) in THF was treated with 20 mg of 10% Pd/C and hydrogenated in a Parr Hydrogenator at 50 psi overnight. The catalyst was filtered off and the filtrate concentrated. The resulting residue was HPLC chromatographed on silica gel (70% EtOAc/Hex) to give 10 mg of Example 8G as a white solid. MS: (Cl, NH ₃ ) (M+H) ⁺ =

591.5

Example 8H

Method 1

A. Synthesis of 6-membered ring cyclic urea (XXX) :

(XXX)

The synthesis of the six-membered cyclic urea (XXX) is outlined in Scheme 8. A solution of N-Cbz-D- phenylalanine N,0-dimethylhydroxylamide (33.5 g , 0.098 mol) in ether was cooled to 0°C and treated with 300 mL of a 1 M solution of vinyl magnesium bromide in THF. The mixture was stirred for 30 mins and then poured into an ice cold solution of 1 N HCl (500 mL) . The mixture was extracted into ether and the extracts washed with water and brine. The organic layer was dried over MgS0 ₄ , filtered and concentrated to give the desired vinyl ketone as a thick, light yellow residue which was used without further purification. MS: (Cl, NH ₃ ) (M+H) ⁺ = 310 (77%); (M+NH ₄ )+ = 327.1 (100%).

The crude ketone was dissolved in methanol (350 mL) and treated with cerium trichloride heptahydrate (37.2 g, 0.1 mol) and cooled in an ice bath. While stirring vigorously sodium borohydride (3.78 g 0.1 mol) was added slowly, a small portion at a time, over a period of 30 min. After the addition was complete the mixture was allowed to warm to room temperature and stirred for an additional 1 hr. The solvent was removed under vacuum on a rotorary evaporator and the residue was partitioned between 1 N HCl and methylene chloride. The organic layer was washed with water, brine, and then dried over MgS0 ₄ , filtered and concentrated to give the desired

allylic alcohol as an off-white solid which was used without further purification.

A solution of the crude allylic alcohol and diisopropylethylamine (30 g, 0.23 mol) in methylene chloride was cooled in an ice bath and treated dropwise with methanesulfonyl chloride (28 g, 0.24 mol) . The solution was stirred for 30 mins, then washed sequentially with 1 N HCl, water, brine and dried over MgSθ ₄ . The solution was filtered and concentrated to give the crude mesylate as a thick oil. To a flamed- dried flask was added copper cyanide (12 g, 0.144 mol) and 100 mL of THF. The flask was cooled to -78 °C under nitrogen atmosphere. A solution of benzylmagnesium chloride (360 mL, 2M in THF, 0.72 mol) was added via syringe and the resulting thick solution was stirred at -60°C for 20 mins and at 0 °C for 30 mins. The solution was then cooled to - 78°C and a solution of the mesylate in 130 mL of THF was added via syringe. The solution was stirred at -60°C for 45 mins and then poured into a mixture of 1 N HCl/ice. This was extracted into ethyl acetate and the organic layer was washed sequentially with NH ₄ C1 (aq) , NH OH, brine, dried over

MgS0 ₄ , filtered and concentrated. The resulting residue is chromatographed on silica gel (hexane, then 10% EtOAc/Hex) to give 11.7 g of the desire alkene as a white solid. MS: (Cl, NH ₃ ) (M+H) ⁺ = 386.3 (98%); (M+NH ₄ ) ⁺

= 403.2 (100%) .

A solution of the above alkene (11.0 g, 0.029 mol) in methylene chloride (75 mL) was cooled to 0°C in an ice bath and treated with 60% m-chloroperbenzoic acid

(14.0 g, 0.049 mol) . The solution was stirred 0°C for 7 hrs until TLC analysis showed no starting material remained. A precipitate formed during this time. The suspension was diluted with methylene chloride and washed sequentially with 1 N Na ₂ S2θ3, 1 N sodium hydroxide, water, brine, dried over MgS0 ₄ , filtered and

concentrated to give the epoxide as a thick oil which was used without further purification.

To solution of crude epoxide in 80 mL of DMF was added sodium azide (20 g , 0.3 mol), ammonium chloride (2.5 g , 0.047 mol) and 20 mL of water. The mixture was heated at 90 °C for 3 hrs and then stirred at rt overnight. The solvent was removed under high vacuum on a rotorary evaporator and the residue was partitioned between water and methylene chloride, the organic layer was washed with water and brine, dried over MgS0 ₄ , filtered and concentrated to give a residue. This was then chromatographed on silica gel (20% EtOAc/Hex) to give 7.4 g of the azide alcohol as a white solid. MS: (Cl, NH ₃ ) (M+H) ⁺ = 445.0 (25%); (M+NH ₄ -BnOH) ⁺ = 462.2 (100%) .

A solution of the azide alcohol above (7.2 g, 0.016 mol) in methylene chloride was treated with diisoprop lethylamine (4.2 g , 0.032 mol) and MEM-C1 (4.0 g 0.032 mol) and heated to reflux overnight (18 hrs) . The mixture was concentrated and the residue chromatographed on silica gel (20% EtOAc/Hex - 35% EtOAc/Hex) to give 7.7 g of the MEM protected azido alcohol as a colorless oil. MS: (Cl, NH ₃ ) (M+H) ⁺ = 533.2

(100%) . To a solution of MEM protected azido alcohol (5.7 g 0.0107 mol) in ethyl acetate was added 2 mL of acetic acid and 1 g of Pearlman's catalyst (10 % Pd(OH) ₂ on Carbon) and the solution was hydrogenated at 55 psi for 22 hrs. The solution was filtered through Celite and the filtrate was extracted with 1 N HCl (organic layer turn orange) . The acidic aqueous extract was made basic with 50% NaOH (while cooling in an ice bath) and the precipitate is extracted into ethyl acetate. The organic layer is washed with water, brine, dried over MgS0 ₄ , filtered and concentrated to give 2.5 g of the MEM

protected diamino alcohol as a colorless oil. MS: (Cl, NH ₃ ) (M+H) ⁺ = 373.1 (100%) .

To a solution of the MEM protected diamino alcohol (2.5 g 0.0067 mol) in THF was added 1,1- carbonyldiimidazole (1.1 g, 0.0067 mol) and stirred over night at room temperature. The solution was concentrated and the residue partitioned between 1 N HCl and CH ₂ C1 ₂ .

The organic layer is washed with brine, dried over MgS0 ₄ , filtered and concentrated. The residue is HPLC ' chromatographed on silica gel ( 5% MeOH/CHCl ₃ ) to give

1.2 g of the MEM protected 6-membered ring cyclic urea (XXX) as a white solid. MS: (Cl, NH ₃ ) (M+H) ⁺ = 399.1

(100%) .

B. The MEM protected 6-membered ring cyclic urea (XXX) (100 mg, 0.27 mmol) was alkylated with cyclopropylmethylbromide (250 mg , 1.8 mmol) followed by removal of the MEM group, as described in general procedure 5, to give after chromatography on HPLC (silica gel, 10% MeOH/CHCl ₃ ) 20 mg of Example 8H as a clear, viscous residue. MS: (Cl, NH ₃ ) (M+H) ⁺ = 419.4 (100%)..

Method 2.

A solution of Example 8A (160 mg, 0.3 mmol) and thiocarbonyldiimidazole (55 mg, 0.3 mmol) in THF was heated to reflux for 4 hrs. The mixture was evaporated and the residue chromatographed on silica gel (50% EtOAc/Hex) to give 34 mg (0.055 mmol) of the corresponding thiocarbamate. The thiocarbamate was dissolved in 2 mL of toluene and heated to reflux. To the refluxing solution was added tributyltin hydride (32 mg, 0.1 mmol) and 2 mg of AIBN. The mixture was refluxed for 1 hour, concentrated, and the residue chromatography on HPLC (silica gel, 65% EtOAc/Hex) to give 20 mg of clear colorless oil. The oil was dissolved in MeOH, cooled in an ice bath and gaseous HCl was bubbled

through the solution for 30 mins. The solution was then stirred at room temperature overnight, concentrated and the residue chromatography on HPLC (silica gel, 10% MeOH/CHCl ₃ ) to give 10 mg of Example 8H as a clear, viscous residue. MS: (Cl, NH ₃ ) (M+H) ⁺ = 419.2 (100%).

7A r>~ OH OAc RSSR + +++ 449.1

^

.0

^7C jp-J ^ sS^ ^{RSSR +++ +++ 453} - ²

" IIII

O

7D Bu 0 \ / 0 RSSR +++ ++ 469.2

II

0

7F RSSR +++ +++ 481.2

7H J .S RSSR + ++ 447.2 CH ₂

-in-

^7J ([ JL J ^{0AC 0AC RSSR ++ + 691} - ³

^M (T ___»S __*r ^" s ^{RSSR +++ +++ 653,2}

IL o

Q Q f TT " ° , *° SSR ++ ++ 619 ^ CH ₂

^R (f ._Y£ .Y_> ^{^} CH ⁽ ₃ C°H ₃ ^{RSSR + + 647} - ³

Table Id (continued)

Ex. 22 £23 stereo ______ MS No. 2-3.4-S Ki (M+H)

7AA f MEM 0= RS-R + 521

7AB hydroxy H0-N= RS-R + 448

7AC _r- hydroxy MeO-N= RS-R ++ 462

7AD <r-Y oxazole oxazole R—R ++ 442

7AE methoxy hydroxy RSSR ++ 449

7AF „f■ methoxy methoxy RSSR + 463

7AG benzyloxy benzyloxy RSSR + 615

7AH benzyloxy hydroxy RSSR + 525

7AI allyloxy allyloxy RSSR

7AJ <_-f/ allyloxy hydroxy RSSR ++ 475

8

AK 2-naphthyl OCH ₂ OH H RR-R +++ 621 methyl

Table le

Ex. R _L IC90 MS (M+H)

__.

7V r OH ++ +++ 437.26

7W r ¹ OH ++ ++ 409.23

Using the above-described techniques or variations thereon appreciated by those of skill in the art of chemical synthesis, the compounds of Tables 3-13 (shown below) can also be prepared.

Utility

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

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

HIV Protease Inhibition Assay- Spectroscopic Method

Materials:

Protease: Inclusion bodies of E. coli harboring plasmid containing HIV protease under the control of an inducible T7 promoter were prepared according to Cheng et. al (1990) Gene 87: 243. Inclusion bodies were solubilized in 8 M urea, 50 mM tris pH 8.0. Protease activity was recovered by dilution 20-fold into buffer containing 50 mM sodium acetate pH 5.5, 1 mM EDTA, 10% glycerol and 5% ethylene glycol. Enzyme was used at a final concentration of 1.0-10 μg/ml.

Substrate: Peptide of sequence: Ala-Thr-His-Gln- Val-Tyr-Phe(Nθ2)-Val-Arg-Lys-Ala, containing p- nitrophenylalanine (Phe(Nθ2)), was prepared by solid phase peptide synthesis as previously described by Cheng et al. (1990) Proc. Natl. Acad. Sci. USA 87: 9660.

Stock solutions of 10 mM were prepared in DMSO.

Inhibitory compounds were dissolved in sufficient

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

Reactions:

Compound (1-5 μL) and HIV protease were mixed in buffer containing 50 mM MES, pH 6.5, 1 M NaCl, 1 mM EDTA, 1 mM dithiothreitol, 10% glycerol. Reactions were initiated by the addition of peptide substrate to a final concentration of 240 μM, and absorbance at 300 nM monitored for 10 min. Values of Ki for inhibitor binding were determined from percent activity measurements in the presence and absence of known concentration of inhibitor, using a value of 0.07 mM for the Km of the substrate (Cheng et al. (1990) Proc. Natl. Acad. Sci. USA 87: 9660).

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

HTV Protea se Inh ibit i on Assay- HPLC Method

Materials :

Protease: Inclusion bodies of E. coli harboring plasmid containing plasmid T1718R with a synthetic gene coding for a single-chain tethered dimer of HIV protease were prepared as described in Cheng et al. (Proc. Natl. Acad. Sci. USA, 87, 9660-9664, 1990) . Active protease was prepared as described therein by extraction with 67% acetic acid, dilution 33-fold with water, dialysis against water and then against a "refolding buffer" consisting of 20 mM MES, 1 mM dithiothreitol and 10% glycerol. Protease was stored as a stock preparation at 10 μM in refolding buffer.

Substrate: Peptide of sequence: aminobenzoyl-Ala- Thr-His-Gln-Val-T r-Phe(NO ₂ )-Val-Arg-Lys-Ala containing p-nitrophenylalanine, was prepared by solid phase synthesis as previously described Cheng et al., op.cit. Stock solutions of 2 mM substrate were prepared in DMSO.

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

Reactions:

Enzyme reaction: In a 2 ml screw-cap centrifuge tube were added 50ul protease (final concentration 0.25 nM) and 0.1 ml inhibitory compound (final concentration 0.1-12,500). After 15 min preincubation at room temperature, the reaction was started with the addition of .05 ml substrate (final concentration 5 μM) .

Incubation was carried out at 30 C. for 1 hr. The reaction was stopped with 1 ml 0.1 M ammonium hydroxide.

HPLC measurement of product formation: The product (aminobenzoyl-Ala-Thr-His-Gln-Val-Tyr) was separated from substrate on a Pharmacia MonoQ anion exchange column. The injection volume was 0.2 ml. The mobile phases were: A (20 mM trisHCl, pH 9.0, 0.02% sodium Azide, 10% acetonitrile), B (20 mM tris HCl, pH 9.0, 0.02% sodium azide, 0.5 M ammonium formate, 10% acetonitrile) . The mobile phases were pumped at 1 ml/min, with a gradient from 0 to 30% B in 5 min, 100 % B for 4 min to wash the column, and a re-equilibration for 4 min. The retention time of the product was 3.6 min. Detection with a Shimadzu model RF535 fluorescence monitor was at 330 nm (excitation) and 430 (emission) . The Ki was calculated from the formula Ki = 1/ ( ( (Km+S- FA*S) / (FA*Km) )-l) where I = inhibitory concentration, S = substrate concentration, FA = fractional activity = cm peak height with inhibitor/cm peak height without inhibitor, and Km = Michaelis constant = 20 μM.

HIV Yield Reduction Cell Assay

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

Method: Test compounds were dissolved in dimethylsulfoxide to 5 mg/mL and serially diluted into RPMI medium to ten times the desired final concentration. MT-2 cells (5, x 10-VmL) in 2.3 mL were mixed with 0.3 ml of the appropriate test compound

solution and allowed to sit for 30 minutes at room temperature. HIV (3B) or HIV (RF) (~5 x 10 ⁵ plaque forming units/mL) in 0.375 ml was added to the cell and compound mixtures and incubated for one hour at 36°-C. The mixtures were centrifuged at 1000 rpm for 10 minutes and the supernatants containing unattached virus were discarded. The cell pellets were suspended in fresh RPMI containing the appropriate concentrations of test compound and placed in a 36°C, 4% CC_ incubator. Virus was allowed to replicate for 3 days. Cultures were centrifuged for 10 minutes at 1000 rpm and the supernatants containing cell free progeny virus were removed for plaque assay.

The virus titers of the progeny virus produced in the presence or absence of test compounds were determined by plaque assay. Progeny virus suspensions were serially diluted in RPMI and 1.0 mL of each dilution was added to 9 ml of MT-2 cells in RPMI. Cells and virus were incubated for 3 hours at 36°C to allow for efficient attachment of the virus to cells. Each virus and cell mixture was aliquoted equally to two wells of a six well poly-L-lysine coated culture plate and incubated overnight at 36°C,- 4% C02-' Liquid and unattached cells were removed prior to the addition of 1.5 mL of RPMI with 0.75% (w/v) Seaplaque agarose (FMC

Corp.) and 5% FCS. Plates were incubated for 3 days and a second RPMI/agarose overlay was added. After an additional 3 days at 36°C, 4% C02, a final overlay of phosphate-buffered saline with 0.75% Seaplaque agarose and 1 mg MTT/mL was added. The plates were incubated overnight at 36°C. Clear plaques on a purple background were counted and the number of plaque forming units of virus was calculated for each sample. The antiviral activity of test compounds was determined by the percent reduction in the virus titer with respect to virus grown in the absence of any inhibitors.

HTV Low Multiplicity Assay

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

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

MT-2 cells (5 x 10 ⁴ /0.1 mL) were added to each well of a 96 well culture plate and 0.02 mL of the appropriate test compound solution was added to the cells such that each compound concentration was present in two wells . The cells and compounds were allowed to sit for 30 minutes at room temperature. HIV(3B) or HIV(RF) (~5 x lθ5 plaque forming units/mL) was diluted in medium and added to the cell and compound mixtures to give a multiplicity of infection of 0.01 plaque forming unit/cell. The mixtures were incubated for 7 days at 36°C, during which time the virus replicated and caused the death of unprotected cells. The percentage of cells protected from virus induced cell death was determined by the degree of metabolism of the tetrazolium dye, XTT. In living cells, XTT was metabolized to a colored formazan product which was quantitated spectrophotometrically at 450 nm. The amount of colored formazan was proportional to the number of cells protected from virus by the test compound. The concentration of compound protecting either 50% (IC ₅ g)

or 90% (IC ₉₀ ) with respect to an uninfected cell culture was determined.

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

The ICgo values in Table 2 are indicated as: +++ = <10 μg/mL.

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

In the Tables herein the IC ₉₀ values were determined using the assay conditions described above under HIV Low Multiplicity Assay. The IC ₉₀ values are indicated as follows: +++ = <10 μg/mL; ++ = 10 to 100 μg/mL; + = >100 μg/mL.

Dosage and Formulation

The antiviral compounds of this invention can be administered as treatment for viral infections by any

means that produces contact of the active agent with the agent's site of action, the viral protease, in the body of a mammal. They can be administered by any conventional means available for use in conjunction with 5 pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard 0 pharmaceutical practice.

The dosage administered will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, 5 health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; and the effect desired. A daily dosage of active ingredient can be expected to be about 0.001 to 1000 milligrams per 0 kilogram of body weight, with the preferred dose being 0.1 to about 30 mg/kg.

Dosage forms (compositions suitable for administration contain from about 1 milligram to about 100 milligrams of active ingredient per unit. In these 5 pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.

The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and 0 powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. It can also be administered parenterally, in sterile liquid dosage forms .

Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch,cellulose 5 derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed

tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.

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

In general, water, a suitable oil, saline, aqueous dextrose (glucose) , and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents .

Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences. Mack Publishing

Company, a standard reference text in this field.

Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150

milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.

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

Tablets

A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.

Tables 3-16 below set forth representative compounds of the present invention. In Tables 3-12, each of the Examples 1-5763 includes all stereoisomers of the indicated structure.

WO 93/07128

O 93/07128

Scheme 4

XXVIb

XXVIc XXVId

XXVIe

7128

Scheme 5

XXYIIa

XXVIIb

XXVIId xxvπc

XXVII?

Scheme 6

CH ₃ 0CO COCH ₃

/0712

Scheme 7

T

(XXXI)

Scheme 8

(XXX)

071

Scheme 9

XXXIIa

Table 2A

I

H

GO n

I

Table 2A (continued)

440 +++ +++ 76

^

CH2C6H4M-OCF3 675 ++ "TTT 128.3 CH2C6H3 -C 3p-F 679 ++ +++ 167.2 CH2C6H4POCF3 675 ++ +++ 136.8 CH2C6H3m-Fm-CF3 679 ++ 162.3

σ\ 1

Table 2B

r ¹

Table 2B (continued)

Table 2B (continued)

3K m-NH2-C6H4CH2 IT1-NH2-C6H4CH2 537 .28 +++ 3 , 4

NOTES :

1. Prepared according to the general alkylation procedure (Procedure 5) . Yields of monoalkyl compounds were favored by using one equivalent of alkylating agent.

_H 2. Prepared by alkylating the appropriate monoalkyl compound.

GO VD I

3. Isolated as the dihydrochloride salt.

4. Preparation: a solution of 41.3 mg of Ex.3B was dissolved in a mixture of 10ml of ethanol and 1 ml of 1 N hydrochloric acid. Catalyst (20 mg of 10% palladium on carbon) was added, and the mixture was hydrogenated at atm pressure for 16 hours. A quantitative yield of Ex. 3K as isolated as the hydrochloride salt .

Table 2C

H rt-* o

3T RSSR 1-naphthylmethyl 1-naphthylmethyl ++ 231-233 607(85%)

I— ^• I

Table,,2C (continued)

cyclopropylmethyl cinnamyl

2,3,4,5, 6-penta- 2,3, 4,5, 6-penta- fluoro-benzyl fluoro-benzyl cyclopropylmethyl 2-naphthylmethyl cyclopentylmethyl 2-naphthylmethyl benzyl 2-naphthylmethyl cyclopropylmethyl 2-picolinyl benzyl 2-quinolinylmethyl

3-cyanobenzyl 3-cyanobenzyl

3-benzyloxybenzyl 3-benzyloxybenzyl

4-phenylbenzyl 4-phenylbenzyl

3-allyl 2-naphthylmethyl n-propyl 2-naphthylmethyl n-butyl 2-naphthylmethyl

H 2-naphthylmethyl 2-adamantylethyl 2-adamantylethyl

Table 2C (continued)

H cyclopropylmethyl ++

2-picolinyl 2-naphthylmethyl ++

4-ρicolinyl 2-naphthylmethyl +++

3-allyl H +

3-allyl cyclopentylmethyl +++

3-allyl 2-picolinyl ++

3-allyl 2-quinolinylmethyl +++

3-allyl 4-picolinyl ++

3-benzyloxybenzyl 3-benzyloxybenzyl ++

5T RSSR

„

5U RSSR

GΠ I

H if"

I

Table 2C (continued) m-CH3θ-C6H CH2- m-CH3θ-C6H4CH2~ 567.29

(CH3)2NCH2CH2~ (CH3)2NCH ₂ CH ₂ - 469.32 m,p-F2-C6H4CH2- m,p- 2-C6H4CH2- 579.23 P-CH3-C6H4CH2- p-CH ₃ -C ₆ H ₄ CH2- 535.30 p-Cl-C ₆ H ₄ CH2- P-CI-C6H4CH2- 575.19 ( ³⁵ C1)

6V RSSR P-F-C6H4CH2- 183.4 489.26

P-CF3-C6H4CH2- P-CF3-C6H4CH2- 643.24 m-Cl-C6H CH2 m-Cl-C6H4CH2 210.3 575.19

<» -J ( ³⁵ C )

I m-CF3-CgH4CH2 m-C 3-C6H4CH2 643.24 m-N02~C6H4CH2- 111-NO2-C6H4CH2- 248.3 597.23 m-CH3-C6H4CH2- m-CH3-C6H4CH2- 535.30

0-CH3O-C6H4CH2- 0-CH3O-C6H4CH2- 567.29 m,m-F2-C6H4CH2- ,m- 2-C6H4CH2- 167.9 579.23

Table 20. (continued)

7D RSSR 0-CI-C6H4CH2- 0-CI-C6H4CH2-

-Br-C6H4CH2- m-B -C6H CH2-

P-F-C6H4CH2- H

p-Br-C6H4CH2~ _p _ _Br _ _C6 H ₄ cH2-

7H RSSR m-Cl-C6H4CH2- -l

537.29

71 RSSR m- H2C6H CH2~ m-NH2C6H4CH2-(HCl) (HC1)

H *> 00

7J RSSR m,m-Cl2-C6H4CH2- m,m-Cl2-C6H4CH2- 231.1 642.10 ( ³⁵ C1) + 565.32

7K RSSR m-(NH2CH2)- m-(NH2CH2)- + C6H4CH2- C6H4CH2-

462.20

7L RSSR m- 02C6H4CH2" H

7M RSSR m- (NHCHO) - m- (NHCHO) -C6H4CH2- 593.28 C6H4CH2-

Table 2C (continued)

7N RSSR m-(NHC0CH3) m-(NHC0CH3)- 621.31 C6H4CH2- C6H4CH2-

7o RSSR m,p-(H0)2" m,p-(H0)2-C6H ₄ CH2- 571.24 C ₆ H ₄ CH ₂ -

All of the compounds of Table 2C were synthesized using procedure 5

Synthesis of compounds of the invention in Table 2d is described in further detail below.

Example K

To a solution of bis m-(HO-N=CH)-C ₆ H ₄ CH ₂ cyclic urea (0.297, 0.502mmol) in methanol (5ml) was added borane-pyridine complex (0.464g, 5.02mmol) at -10°C and the resultant mixture was stirred for 15 minutes. After treated with 4M HCl in dioxane (5ml) , the reaction mixture was allowed to stir to room temperature for additional 1.5 hours. The solution was neutralized with sat. NaHCθ ₃ to pH=8, washed with water and dried over MgSθ . After removal of solvents, the residue was purified on silica gel plate with ethyl acetate: dichloromethane : methanol ^" (50:50:2) to give 60mg of a solid, M.P. 214-216°C. ^• -_ NMR (CD ₃ OD) : δ

8.03(s, 1H), 7.46 - 7.06 (m, 18H) , 4.74 (d, J=13.9 Hz, 1H) , 4.73 (d -7=13.9Hz, 1H) , 3.92(s,2H), 3.62-3.59 (bs, 4H), 3.07-2.91(m,6H) ¹³ C NMR (CD ₃ OD) : 163.88, 149.70,

141.26, 141.23, 139.92, 139.39, 138.73, 134.91, 131.50, 131.41, 130.64, 130.00 129.72, 129.64, 129.57, 129.53, 128.47, 127.45 127.42, 127.31, 71.96, 71.92, 67.42, 67.11, 58.65, 57.09, 57.03, 33.62, 33.57, MS: 594 (100%) 595 (M+H,60%).

Example 9C

To a stirred solution of bis m-(HO-N=CH)-C ₆ H ₄ CH ₂ cyclic urea (257 mg, 0.434 mmol), sodium cyano- borohydride (290 g, 4.6mmol) and trace amount of methyl orange in methanol (10ml) at room temperature was added dropwise 2N HCl at a rate sufficient to maintain a pH of 3-4 over 3 hours. The methanol was removed by rotary evaporation. The residue was purified on a reverse phase TLC plate with 90% methanol

in water to give the product. -E NMR (CD ₃ OD) : δ 7.33-

7.09 (m, 18H), 4.75 (d, J=13.9Hz, 2H) , 3.93 (s,4H), 3.61- 3.56 (m, 4H) , 3.06- 2.94 (m, 6H) ; ¹³ C NMR (CD ₃ OD) : 162.42, 139.72, 137.88, 137.79, 129.92, 129.20, 128.31,

A 5 128.14, 128.06, 126.02, 70.36, 65.49, 57.40, 55.59,

* ^• 32.09.

Example 9E

10 A solution of Example 9C (30mg) in methanol was treated with 4M HCl in dioxane at room temperature. All solvents were removed under vacuum to give hydroxylamine hydrochloride. ¹ H NMR (CD ₃ OD) : δ 7.44-

7.23 (m,4H), 6.99 (d, J=6.2Hz, 4H) , 4.65 (d, 7=14.3 15 Hz,2H), 4.35(S, 4H) , 3.70-3.66 (m, 4H) , 3.12- 3.05 (m,4H), 2.89-2.85 (m,2H); ¹³ C NMR(CD ₃ OD) : 163.68, 141.13, 140.39, 123.09, 132.03, 131.06, 130.59, 130.50, 129.59, 127.48, 71.82, 68.23, 57.40, 56.12, 33.70.

20 Example 9B

An unpurified sample of example 9C was purified on TLC plate using acetic acid: ethyl acetate: dichloromethane (5: 50:45) to give the acetic acid 25 salt. --H NMR (CD ₃ OD) : δ 7.35-7.08 (m, 18H) , 4.73 (d,

J=10.6Hz, 2H) , 3.97 (s, 4H) , 3.62-3.53 (m, 4H) , 3.06- 2.88 (m, 6H) , 1.97 (s, 3H) .

Example 9D

30

A solution of bis (HV-CHO-C ₆ H ₄ CH ₂ ) cyclic urea (119 mg, 0.212 mml) and O-benzylhydroxylamine hydrochloride (203mg, 1.27mmol) in pyridine/ethanol (6ml 1:1) was refluxed for 3 hours. After removal of solvent, the 35 residue was purified on T.L.C. plate with 15% ethyl acetate in dichloromethane to give the product (164mg)

as a solid, M.P. 170.5-171°C. * ^■ _ NMR(CDC1 ₃ ) : δ 8.01 (s, 2H), 7.39- 7.07 (m, 28H) , 5.09 (s, 4H) , 4.81 (d, •7=14.3Hz, 2H), 3.59 (bs, 2H) , 3.52 (d, J-*_1.0Hz* 2H) , 3.07- 2.88 (m, 8H) ; ¹³ C NMR(CDC1 ₃ ) : 162.14, 148.55, 139.40, 138.62, 137.39, 132.50, 130.50, 129.43, 128.87, 128.62, 128.35, 128.27, 128.87, 127.57, 126.56, 126.46, 76.34, 71.32, 64.55, 55.57, 32.70; MS 790 (M+NH ₄ , 100%) .

Example 9F

By the procedure given above Example 9C, a solution of Example 9D (60mg, 0.078mmol), sodium cyanoborohydride (70mg, l.lmml), trace amounts of methyl orange in methanol was treated with 2N HCl (approx. 0.5 ml) . Purification on T.L.C. plate with 40% ethyl acetate in methylene chloride gave the product (30mg) . --R NMR (CDC1 ₃ ) : δ 8.05 (s,lH), 7.43- 7.06 (m,

28H), 5.13 (s, 24), 4.90 (d, J-=14.3Hz, 1H) , 4.87(d, J=14.3Hz, 1H), 4.61(s, 2H) , 3.98 (s, 2H) , 3.59-3.49 (m, 4H), 3.07- 2.95 (m, 6H) . ¹ C NMR(CDC1 ₃ ) : 161.98, 148.59, 139.48, 138.86, 138.32, 138.05, 137.74, 137.48, 132.56 130.61, 129.87, 129.51, 128.91, 128.67, 128.65, 128.44, 128.37, 128.11, 127.91, 127.86, 127.66, 126.59, 126.56, 126.40, 77.20, 76.41, 76.15, 71.52, 71.48, 64.33, 64.11, 56.26, 55.58, 55.57, 33.79, 32.47. MS: 792 (M+NH ₄ , 40%) 775 (M+H,100%) .

Example 9G

To a suspension solution of bis ( -(HO)-C ₆ H CH ₂ ) cyclic urea (280mg, 0.52 mmol) and CS ₂ CO ₃ (1.5g, 4.6mmol) in THF (4ml) was added methylchloroformate (122.9mg, 1.3mm) and the resulting mixture was stirred at room temperature overnight. The mixture was filtered through celite and concentrated to give a residue which was purified on T.L.C. plate with 15% ethyl acetate in

methylene chloride to give the product (220 mg) . as a solid, M.P. 146-147°C. ^ NMR (CD ₃ OD) : d 7.34-6.95 (m, 18m), 4.78 (d.7=14.3Hz, 2H) , 3.78 (s. 6H) , 3.68 (bs, 2H) , 3.61 (d, 7=11.4Hz, 2H) , 3.10- 2.83 (m, 6H) . ¹ C NMR 5 (CD ₃ OD) : 162.22, 154.08, 151.28 139.74, 129.28,.129.14 • 128.11, 126.52, 125.99, 121.63, 119.85, 70.44, 66.14, 55.46, 54.51, 32.22; MS: 655 (M+H, 100%) .

Example 9X 0

To a solution of Example 9S (lOO g) in tetrahydrofuran (1ml) was added methyl amine (0.4ml, 40% in water) and the resulting solution was stirred overnight. After concentration and purification on the 5 plate, the product was obtained in good yield.

Examples 9J and 9K

By the procedure described previously for 0 preparation of Example 9D, and substituting b- ethanolamine and trace amounts of molecular sieves (powder) in ethanol. The reaction mixture was filtered ° through Celite and concentrated to give a residue, which was purified on reverse phrase T.L.C. plate with 5 90% methanol in water to the desired compounds.

Example 9J: ¹ H NMR (CD ₃ OD) : δ 8.31 (s, 2H) , 7.67 (d, 7=7.7Hz, 2H) , 7.59 (s, 2H) , 7.43- 7.03 (m, 14H) , 4.74 (d, 7=14Hz, 2H) , 3.81-3.58 (m, 12H) , 3.10- 2.86 ( , 0 6H) ; ¹³ C NMR (CD ₃ OD) : 164.97, 163.73, 141.22, 140.14

137.66, 133.06, 130.65, 130.53, 130.06, 129.56, 128.50, 127.46, 71.93, 67.90, 64.26, 62.29, 57.20, 33.68, MS: 649 (M+H, 100%) .

5 Example 9K: ¹ H NMR (CD ₃ OD) : δ 8.31 (s,lH), 7.68- 7.03 (m, 18H), 5.33 (s, 1H) , 4.76 (d, 7= 13.9Hz, 1H) , 4.75

(d, 7= 14.3Hz, 1H) , 3.81- 3.55 (m, 10H) , 3.12- 2.7 (m, 8H) ; ¹³ C NMR (CD ₃ OD) : 164,97, 163.78, 141.29, 141.24, 140.18, 139.39, 137.63, 133.06, 130.67, 130.64, 130.53, 130.48, 130.05, 129.55, 129.50, 128.86, 128.49, 127.47, 127.45, 127.20, 104.35, 71.98, 67.90, 67.40, 64.25 62.39, 57.22, 57.11, 53.23, 33.67; M.S.: 649 (M+H, 100%) .

Example 9

To a solution of Example 51 (0.7g, 1.3 mmol) and triethylamine (0.263g, 2.6mmol) in THF (5ml) was added benzyl isocyanate (0.346g, 2.6mmol) and the resulting solution was stirred at room temperature overnight. After removal of all the volatiles, the residue was purified on T.L.C. plate to give 0.7g of a solid, M.P. 150°C (decompose). -41 NMR (CD ₃ OD) : δ 7.33- 6.83 (m,

28H) , 4.74 (d, 7= 13.9Hz, 2H) , 4.30 (s, 4H) , 3.64 (bs, 2H), 3.59 (d, -7=12.1 Hz, 2H) , 3.13- 2.91 (m, 6H) ; ¹³ C NMR (CD ₃ OD) : 162.54, 155.68, 151.33, 139.88, 139.30,

138.64, 129.29, 129.20, 128.24, 128.18, 127.02, 126.90, 126.13, 125.81, 122.44, 120.55, 70.44, 65.28, 55.20, 44.31, 32.28; M.S: 805 (M+H, 100%).

Example 9M

To a solution of Example 51 (lOO g, 0.186mmol) triethylamine (38mg. 0.39mmol) in THF (1 ml) was added methyl isocyanate (27mg. 0.47mmol) at room temperature and the resulting mixture was stirred overnight. After removal of all volatile reagents, a residue was purified on T.L.C. plate with 40% ethyl acetate in dichloromehane to give 51mgs of a solid, M.P. 150°C (decompose). ¹ H NMR (CD ₃ OD) δ 7.44-6.99 (m, 18H) , 4.82 (d, 7=14.2Hz, 2H) , 3.69- 3.65 (m, 4H) , 3.15-2.95

(m,6H), 2.84 (s, 6H) . ¹³ C NMR (CD ₃ OD) : 163.96, 157.56,

152.92, 141.31 140.83, 130.66, 130.55, 129.58, 127.46, 127.17, 123.70, 121.95, 71.88, 67.02, 56.67, 33.65, 27.57. M.S.: 670 (M+NH, 100%).

Examp e 9N

A solution of bis (m-bromobenzyl) cyclic urea (MEM-protected) (0.84g, 1 mmol), propargyl alcohol (0.224g, 4mmol) , tetrakis (triphenylphoshine) palladium (0.116g, O.lmmol), copper iodide (0.019g, O.lmmol) in triethylamine (5ml) was refluxed under nitrogen overnight. After evaporation of all volatiles, a residue was diluted with ether (20ml) and filtered through Celite. The filtrate was concentrated and purified on T.L.C. plate to give 400mg of MEM- protected-mono/coupling product. Deprotection of 170mg of the coupled product by the standard procedure gave 130 mg of the desired product. --H NMR (CD ₃ OD) : δ 7.50-

7.09 (m, 18H), 4.72 (d, 7=13.9Hz, IH) , 4.69 (d, 7=13.4Hz, IH) , 4.46 (s, 2H) , 3.75-3.68 (m, 4H) , 3.18- 2.86 (m, 6H) . ¹³ C NMR (CD ₃ OD) : 163.61, 141.99, 141.07, 139.73, 133.64, 133.54, 131.91, 131.76, 131.47, 130.57, 130.50, 129.81, 129.59, 129.19, 127.51, 124.69, 123.46, 89.28, 85.09, 71.93, 71.91, 68.12, 67.75, 57.07, 57.03, 51.15, 33.60, 33.59;; M.S.: 639/641 (M+H, 100%), 656/658 (M+NH ₄ , 100%) .

Examples 9o and 9P

A solution of bis (m-Br-CgH ₄ CH ₂ ) cyclic urea (425,mg, 0.64 mmol), 1-ethoxy-l-trimethylstannyl ethylene (833mg, 3.84mmol) and Pd(PPh ₃ ) (37mg, 0.032mmol) in THF (5ml) was refluxed under N ₂ overnight. After cooling to room temperature, the reaction mixture was diluted with ether (10ml) and filtered through

silica gel to give two products. Further purification on T.L.C. plate with 20% ethyl acetate in methylene chloride gave Example 9__ (107mg, M.P. 190-191°C) and Example 9P (225 mg, M.P. 158-159°C) .

Example 9o: _ NMR (CDC1 ₃ ) : δ 7.78 (d, 7=7.3Hz, IH) , 7.71 (s, IH) , 7.42- 7.02 (m, 16H) , 4.81 (d, 7= 13.9Hz, IH), 4.77 (d, 7=13.9H, IH) , 3.71 (bs, 2H) , 3.62-3.54 (m, 2H) , 3.20- 2.85(m, 8H) , 2.50 (s, 3H) ; ¹³ C NMR (CDCI ₃ ) : 198.27, 161.86, 140.38, 139.29, 139.22, 138.81, 137.22, 133.99, 132.36, 130.65, 130.09, 129.36, 129.32, 128.99, 128.86, 128.66, 127.70, 127.55, 126.61, 122.53, 71.38, 65.24, 65.12, 55.83, 55.59, 32.77, 26.58, M.S: 644/646 (M+NH ₄ , 100%) .

Example 9P: ^X H NMR (CDCI ₃ ) : δ 7.78- 7.03 (m, 18H) , 4.83

(d, 7=14.3Hz, 2H) , 3.73 (bs, 2H) , 3.60 (d, 7=10.6Hz, 2H), 3.17- 3.08 (m, 4H) , 2.92-2.89 (m, 2H) , 2.49 (s, 6H); ¹³ C NMR (CDCI ₃ ) : 198.03, 161.83, 139.40, 138.78, 137.12, 133.87, 129.29, 129.04, 128.74, 128.52, 127.36, 126.46, 71.25, 71.15, 65.32, 55.82, 30.73, 26.51; M.S.: 608 (M+NH ₄ , 100%) .

Example 90

A solution of Example 9P (84mg, 0.142mmol) and hydroxylamine hydrochloride (59.4mg, 0.854mmol) in pyridine /ethanol (6ml, 1:1) was refluxed overnight. Evaporation of all solvents under vacuum gave a residue which was purified on preparative T.L.C. plates with ethyl acetate: methylene chloride: methanol (50:50:2) to give 71mg of a solid, M.P. 200 202°C. --H NMR (CD ₃ OD) : δ 7.67- 7.07 (m, 18H) , 4.74 (d, 7=13.9Hz, 2H) , 3.64-

3.62 ( , 4H), 3.09- 2.89 (m, 6H) , 2.17 (s, 6H) ; ¹³ C NMR(CD ₃ OD) : 163.94, 155.43, 141.23, 139.46, 138.97, 130.77, 130.65, 129.69, 129.37, 128.10, 127.47, 126.32, 72.02, 67.16, 57.08, 33.62, 11.96; M.S.: 621, (M+H, > 5 100%) .

Table 2d

MS

Ex Stereo E ²² E ²³ HPLC I£90 m∑_r°C M+H Nθte-5

_____ 2-.3:4;5 fii (_±_H_)

9A RSSR m-(H0-N=CH)- m-(H0NMCH ₂ )- +++ +++ 214-216 595

C6H CH2- C6H4CH2-

9B RSSR m-(H0NHCH2)~ m-(H0NHCH2)- +++ +++ *

C6H4CH2- HOAc C6H4CH2- HOAc

9C RSSR m-(H0NHCH2)~ m-(H0NHCH2)- +++ +++ 610

C ₆ H ₄ CH2- C6H4CH2- .5- 790

9E RSSR m-(HONHCH2)~ m-(HONHCH2)- +++ +++ *

C6H4CH2- HCl C6H CH2- HCl

9F RSSR m- m- ++ +++ 775

(C6H ₅ CH ₂ ON=CH)- (C6H ₅ CH ₂ ON=CH)- (792)

C6H4CH2- C6H4CH2-

9G RSSR m-(CH3OC(=0) -O)- m-(CH3OC(=0)-0)- +++ +++ 146-147 655

C ₆ H ₄ CH ₂ C ₆ H ₄ CH ₂

9H RSSR m-(CH3CH(OH))- m- (CH ₃ CH(OH) ) 612

C6H4CH2- C6H4CH2-

91 RSSR m-(CH ₃ NHCH ₂ )- m-(CH ₃ NHCH ₂ ) - 593

C6H4CH2 C ₆ H ₄ CH ₂

9J RSSR m- m- +++ +++ 649

(H0CH2CH2N=CH)- (HOCH2CH2 =CH)-

C ₆ H ₄ CH ₂ - C ₆ H CH2-

9 RSSR m- m- +++ +++ 150 805

(C6H ₅ CH ₂ NHC(=0)- (C ₆ H ₅ CH2NHC(=0)- (dec)

C6H4CH2- 0)-C ₆ H CH ₂ -

I 9M RSSR m-(CH ₃ NHC(=0) )- m-(CH3NHC(=0) )- +++ +++ 150 670

H uπ

VD 0)-C ₆ H CH2- 0)-C ₆ H ₄ CH ₂ - (dec) I

9N RSSR m-(H0CH2CC)- m-Br-C6H4CH2- +++ +++ 639/641

C6H4CH2- (656/

658)

9o RSSR -(CH3C(=0) )- m-Br-C6H4CH2~ +++ +++ 190-191 644/646

C ₆ H ₄ CH ₂ -

9P RSSR m-(CH3C(=0) )- m-(CH3C(=0))- +++ +++ 158-159 608

C ₆ H ₄ CH ₂ - C ₆ H ₄ CH ₂ -

9Q RSSR -(CH3C(=N0H) )- m-(CH ₃ C(=N0H) )- +++ +++ 200-202 621

C ₆ H ₄ CH2- C ₆ H ₄ CH ₂ -

9R RSSR m-(CH3CH(OH))- m-Br-C6H4CH2- +++ +++ 629/631

C ₆ H ₄ CH ₂ -

9S RSSR

9T RSSR m-(5-tetrazolyl) m-(5-tetrazolyl) +++ + 159.4 643.2893

-C ₆ H4CH ₂ - C ₆ H ₄ CH ₂ -

9U RSSR m-(5-tetrazolyl) cyclopropyl- +++ +++ 171.6 539.2771

-C6H4CH2- methyl

10A RSSR m-(C0 ₂ H)- H +++ + 141-143 2

C ₆ H CH ₂ -

IOC RSSR m-(NC)- m-(0HC)-C6H4CH2- +++ +++ 189-191 560 4

C6H4CH2- (577)

10D RSSR m-(CH30N=CH)- m-(CH3θN=CH) ++ + 183-185 (638) 5

C ₆ H ₄ CH ₂ - C6H4CH2-

H 10E RSSR p-(CH3C(=0)0)- p-(HO)-C6H4CH2- +++ +++ 110-112 623 6 o C ₆ H ₄ CH ₂ -

10F RSSR m-(CH3C(=0)0)- m-(CH3C(=0)0)- ++ +++ 623 8

C ₆ H ₄ CH ₂ - C ₆ H ₄ CH ₂ -

10G RSSR -(NH ₂ C(=0) )- m-(NH ₂ C(=0))- +++ +++ (610) 7

C ₆ H CH ₂ - C ₆ H ₄ CH ₂ -

10H RSSR m-( H2C(=0) m-(NH2C(=0) +++ +++ NMR only

-CH2O)-C6H4CH2- -CH2θ)-C6H4CH2-

101 RSSR m-(HO)-C6H4CH2- H +++ +++ 193-194 433

10J RSSR m-(CH ₃ )-C6H4CH2- m-(HO)-C6H4CH2- +++ +++ 537

• * V „

10K RSSR 2-Naphthylmethyl m-(HO)-C6H4CH2- +++ +++ 137-138 573 3 10 RSSR p-(CH3C(=0)-0)- p-(CH ₃ C(=0)-0)- ++ +++ 623 8

C ₆ H CH ₂ - C ₆ H ₄ CH ₂ -

10M RSSR m-(NH2NHC(=0))- m-(NH NHC(=0) )- +++ +++ 205 623 7

C6H4CH2- C6H4CH2-

10N RSSR p-(NH ₂ NHC(=0))- p-(NH ₂ NHC(=0) )- +++ +++ 215-217 623 7

C ₆ H CH ₂ - C ₆ H ₄ CH ₂ -

10O RSSR p-(HOCH ₂ ) -(H0)-C6H4CH2- +++ ++ 141-144 553 3

-C ₆ H ₄ CH ₂ -

10P RSSR m-(NH2C(=0)- m-(NH2C(=0)- +++ +++ 301-303 5

NHN=CH)-C6H4CH2- NHN=CH)-C6H4CH2-

I 10Q RSSR 2-picolinyl- m- (HO) -C6H4CH2- ++ +++ 524 3

1- ¹ 1

10R RSSR m-(CH30NHC(=0))- m-(CH3ONHC(=0) )- +++ +++ 150-158 (670) 7

C6H4CH2- C ₆ H CH ₂ -

10S RSSR p-(CH3ONHC(=0) )- p-(CH ₃ ONHC(=0))- +++ +++ 186-189 653 7

C6H4CH2- C6H4CH2-

10T RSSR m-(H0CH ₂ CH(0H)- irH(H0CH ₂ CH (OH)- +++ +++ 113-115 9

CH ₂ 0)-C6H ₄ CH ₂ - CH ₂ 0)-C6H4CH2-

10U RSSR m-(adamantamido)- m-(adamantamido)- +++ +++ 183-184 893 8

C6H4CH2- C6H4CH2-

10V RSSR m-(HO)-C6H4CH2- m-(adamantamido)- + +++ 196-198 716 6

C6H4CH2-

10W RSSR m-(CH3CH2OC(*=0) ) m-(CH3CH20C(*=0)) +++ + 178-180 651 10

^' -C6H4CH2- -C6H4CH2-

10X RSSR m-(H0NHC(«0))- -(HONHC(=0) )- +++ +++ 139-143 11

C6H4CH2- C6H4CH2-

10Y RSSR m-(HOCH2CH2O)- m-(HOCH2CH2θ)- +++ +++ 245-247 627 12

CGH4CH2- C6H4CH2-

10Z SRRS p-(H0CH ₂ )CGH4CH ₂ p-(H0CH ₂ )C6H4CH ₂ + ++ 198-199 567 1

11A RSSR m-(NH ₂ C(=NH) )- m-(NH ₂ C(=NH) )- ++ + 224-226 591 13

C6H4CH2-HOAC C6H CH2-HOAC 11B RSSR (H0CH2~CH(0H))- (H0CH ₂ "CH(OH) )- +++ +++ 135-137 627 9

CGH4CH2- C ₆ H ₄ CH2- m, p, positions m, p, positions mixture mixture cn 11C RSSR m-(NH2C(-0) )- m-(NH2C(=NH) )- +++ +++ 229-231 4

C6H4CH2- C6H4CH2- HOAC

11D RSSR p-(HO)-C6H ₄ CH2- p-(HO)- -(HOCH2)- +++ ++ 178-180 14

C ₆ H ₃ CH ₂ -

11E RSSR p-(HO)-C6H4CH2- p-(HO)-m-(OHC)- +++ +++ 567 14

C ₆ H ₃ CH ₂ - 11F RSSR p-(CH ₃ CH20C(=0))- p-(CH ₃ CH OC(=0) )- ++ + 174-178 651 10

C ₆ H ₄ CH ₂ - C6H CH2-

11G RSSR m-(CH ₃ OC(=0))- m-(CH3NHC(=0) )- +++ +++ 158-161 622 4 C6H CH2- C6H4CH2- (639)

11H RSSR m-(CH3NHC(=0))- m-(CH3NHC(=0) )- +++ +++ 160-163 621 7

C ₆ H CH ₂ - C ₆ H ₄ CH ₂ -

-' • ^■ *> * n

111 RSSR benzyl - (HO)-C6H4CH2- +++ +++ 189-193 523 3

11J RSSR 2-Naphthylmethyl p- (HOCH2)-C6H4CH2 +++ +++ 199-201 587 3

•UK RSSR m-(HOCH2-CH(OH)) m-(HOCH2~CH(OH) ) +++ +++ 627 9

-C6H4CH2- -C ₆ H ₄ CH ₂ -

11L RSSR p-(HOCH -CH(OH)) p-(HOCH ₂ -CH(OH) ) +++ +++ 627 9

-C6H4CH2- -C6H4CH2-

11M RSSR m-(HOCH2) -(CH3NHC(=0) )- +++ +++ 107-109 (611) 4

-C6H4CH2- C6H4CH2- 594

UN RSSR p-(HOCH ₂ )- H +++ +++ 112-114 447 2

C ₆ H ₄ CH ₂ - llo RSSR m-((HO) ₂ B)- m-((H0) ₂ B)- +++ +++ 263-267 15

C6H4CH2- C6H4CH2-

I IIP RSSR -( 02)-C6H4CH ₂ - m-(C6H5CH2O)- + +++ 173-176 (675) 3

S C6H4CH2-

11Q RSSR m-(NH2)-C6H4CH2- m-(HO)-C6H4CH2 +++ +++ 116-120 538 3

11R RSSR m-(CH3CH ₂ NHC m-(CH3CH2NHC(=0) )-+++ +++ 135-138 649 7

(=0) )-C ₆ H CH ₂ - C6H4CH2- .

US RSSR m-((CH3)2N m-( (CH3)2NC(=0) )- +++ +++ 132-134 649 7

C(=0))-C6H ₄ CH ₂ - C6H4CH2-

11T RSSR m-(CH ₃ 0 ₂ C)- m-( (CH ₃ CH ₂ )2NC

C ₆ H ₄ CH ₂ (=0))-C ₆ H ₄ CH ₂ - +++ +++ (681) 4

11U RSSR m-(CH ₃ 02C)- m-(CH ₃ CH ₂ NHC +++ +++

C ₆ H ₄ CH ₂ - (=0) ) -C6H CH2- ( 653)

12A RSSR 6-amino-l-hexyl 6-amino-l-hexyl + + 525

633

415 503 569 641 626 584 425 16

439 16

481 16

635 (652)

491 523

811 hexyl hexyl

685

499

559

435

407 507 567

407 435

327 507 439 567

617

_* -

264-6 609 521

182-4 687

547

507 577 (594 )

685

541

458

543

I

I- ¹ 739 16

-J I

479 587 16

457 16

Notes (for Table 2d) :

(1) Prepared according to the general alkylation procedure.

(2) Monoalkyl compounds were prepared by following the procedure 5 under the title of synthesis of monoalkyl cyclic urea.

(3) Prepared by the alkylating the appropriate monoalkyl compound.

(4) Isolated as the side product due to the uncompletion reaction.

(5) Hydroxylamine hydrochloride (0.384 mmol) was added into appropriate bis (N-m-benzaldehyde) cyclic urea (0.064 mmol) in a mixture of 2mL pyridine and 2mL ethanol. The mixture was heated to reflux for 4 hr and the solvent was removed on a rotary evaporator. The residue was purified on silica gel (0.2:3:7 methanol:ethyl acetate:methylene chloride) .

(6) Preparation of monoalkyl compounds were favored by using one equivalent of alkylating agent.

(7) A solution of bis (N-m-benzoic acid) cyclic urea (1.56 mmol) in 1 : 1 benzene: methylene chloride containing 1 drop of DMF and pyridine (9.36 mmol) was treated with oxalyl chloride (2M in methylene chloride, 9.36 mmol) at zero degree and stirred at room temperature for overnight . The solvent removed on a rotary evaporator and the resulting residue was dried under pump for 2 hr. To the residue 20 mL methylene chloride was added followed by pyridine

(9.36 mmol) and methylamine (8.03M in ethanol, 9.36 mmol) . Stirred at room temperature for overnight. The mixture was extracted with EtOAc, dried over MgSθ4 and purified on silica gel (1:9 methanol chloroform) .

(8) A solution of bis (N-m-hydroxy-benzyl) cyclic urea (0.93 mmol) in methylene chloride was treated with triethylamine (1.67 mmol) at -20oC. Then a solution of 1-adamantyl isocyanate (1.4 mmol) in 5 mL methylene chloride was added dropwise. The mixture was stirred at -20oC for 10 min, OoC for 1 hr, room temperature for overnight and washed with cooled 5% HCl, sat'd NaHC03, water, and dried over MgS04. The residue was purified on silica gel (2:8 ethyl acetate: methylene chloride) .

(9) 2 drops of OSO ₄ (25% in t-BuOH) was added into the mixture of bis(N-m-allyloxy-benzyl) cyclic urea (0.19 mmol) and N-methyl-morpholine N-oxide (0.57 mmol) in 5 mL acetone. The mixture was stirred at RT for overnight. The solvent was removed on a totary evaporator and the residue was purified on silica gel (2:8 methanol:chloroform) .

(10) The ethyl ester was prepared by reflexing appropriate acid with 4M HCl (in dioxane) in ethanol.

(11) To the appropriate ethyl ester (0.21 mmol) and hydroxylamine hydrochloride (1.71 mmol) mixture (10 mL methanol was used as the solvent), a 5M (2.1 mmol) solution of potassium hydroxide in methanol was added dropwisely at room temperature. After stirring for 24 hr, methanol was evaporated and the solid residue acidified with acetic acid and

extracted with ethyl acetate which was purified on silica gel (0.1:3:7 acetic acid:methanol:ethyl acetate) .

(12) To the bis (N-m-allyloxy-benzyl) cyclic urea (0.16 mmol) in lOmL methanol, ozone was bubbled through for 10 min at -78°C. After warmed up to RT, sodium borohydride (1.6 mmol) was added and stirred at RT for overnight. The reaction was worked up by quenching with acetic acid, the solvent was removed on rotary evaporator and purified on silica gel (0.3:9.7 methanol:ethyl acetate) .

(13) A solution of the bis-cyano compound in absolute methanol was saturated with hydrochloric acid and left at zero degree for 3 hr followed by TLC until completed. After evaporation of the solvent, the resulting was solubilized in 2M ammonia in methanol. After one week stirring at room temperature, the solvent was removed under reduced pressure and the residue was purified on silica gel (by 0.2:1:9 acetic acid:methanol:ethyl acetate) to give a solid.

(14) To the bis (N-p-hydroxy-benzyl) cyclic urea

(1.11 mmol) in ethanol, NaOH (15.54 mmol) in 2 mL water was added dropwise. The mixture was heated up to 80°C for 1 hr, then 2 mL chloroform was added following additional heating at 80°C for overnight. The reaction was worked up by neutralizing with 5% cooled HCl, washed with sat'd sodium bicarbonate, water and dried over MgS04. The residue was purified on silica gel (1.5:8.5 methanol:chloroform) . To this solid, ethanol was added following by excess sodium borohydride . The mixture was heated up to reflux for 2 hr. The

reaction was worked up by quenching with acetic acid, the solvent was removed on rotary evaporator and the purified on silica gel (2:8 methanol:chloroform) .

(15) n-Butyllithium (1.6M in hexane, 5 mmol) was added dropwise to bis (N-m-bromo-benzyl) cyclic urea (1 mmol) in THF at -78°C. After stirring for 0.5 hr, trimethyl borate (5 mmol) was added. The mixture slowly warmed up to room temperature and remained stirring for 4 hr. The reaction mixture was decomposed by the addition of 5% HCl, diluted with ethyl acetate, washed 2 time with water and dried over MgSθ ₄ . The residue was purified on silica gel (0.1: 0.5:9.5 acetic acid:methanol:chloroform) .

(16) Required alkylating agents were prepared in a three step sequence: 1.) Asymmetric cyclopropanation [D. A. Evans et al. , J. Amer. Chem. Soc. 1991 , 113 , 726-728] . 2.) Reduction with lithium aluminum hydride. 3.) Conversion to the bromide with CBr ₄ , Ph3P, and imidazole.

Listed below are a representative list of data for compounds listed in Table 2d:

Example 12A: MS: 525 (M + 1) . NMR (CD3OD) : δ 7.30-7.10 ( , 10H) , 3.96-3.88 (m, 2H) , 3.58-3.42 (m, 4H), 3.37=3.28 (m, 4H) , 3.17-3.10 (m, 2H) , 2.94-2.78 (m, 6H) , 2.20-2.08 (m, 2H) , 1.72-1.10 (br , 14H) .

Example 12B: MS: 516 (M + 1, 100) . NMR (CD3OD) : δ 6.96-7.72 (br m, 15H) , 4.68 (d, IH) , 3.78-3.89

(m, IH) , 3.43-3.64 (m, 3H) , 3.28-3.34 (m, 2H) ,

3.10-3.19 (m, IH) , 2.81-3.02 (m, 6H) , 2.12-2.26 (m, IH), 1.10-1.84 (br m, 9H) .

Example 12C: MS: 427 (M + 1, 100) . NMR (CDCI3) : δ 7.16-7.36 (m, 10H) , 4.82 (d, IH) , 3.88-3.98 (m,

2H), 3.37-3.69 (m, 8H) , 3.04-3.19 (m, 3H) , 2.63- 2.77 (m, IH), 2.08-2.22 (m, IH) , 1.74-1.88 (m, 2H) , 1.10-1.64 (br m, 6H) .

Example 12D: MS: 527 (M + 1, 100) . NMR (CDCI3) : δ 7.17-7.38 (m, 10H) , 3.99 (s, 2H) , 3.45-3.75 (m,

8H) , 3.03-3.14 (m, 2H) , 2.89-3.01 (m, 2H) , 2.60- 2.68 (m, 2H) , 2.12-2.24 (m, 2H) , 1.12-1.62 (br m, 18H) .

Example 12E: MS: 481 (M + 1, 100) . NMR (CDCI3) : δ 7.17-7.37 (m, 10H) , 3.94-4.13 ( , 2H) , 3.61-3.75

(m, 2H) , 3.43-3.61 (m, 4H) , 3.05-3.20 (m, 3H) , 2.73-3.03 (m, 3H) , 2.10-2.23 (m, IH) , 1.98-2.08 (m, IH), 1.02-1.75 (br m, 9H) , 0.82-0.97 (m, IH) , 0.30- 0.47 (m, 2H) , 0.02-0.13 (m, 2H) .

Example 12F: MS: 471 (M + l, 100) . NMR (DMSO- d6) : δ 7.06-7.33 (m, 10H) , 5.25 (s, 2H) , 4.34 (t, 2H) , 3.71 (s, 2H), 3.44-3.58 (m, 2H) , 3.20-3.42 (m, 6H) , 2.96-3.06 (m, 2H) , 2.79-2.91 (m, 2H) , 1.83- 1.97 (m, 2H), 1.08-1.42 (br m, 8H) .

Example 12G: FABMS: 555 (M + 1, 100) . NMR (DMSO-d6) : δ 8.41 (s, 4H) , 7.06-7.33 (m, 10H) , 3.71

(s, 2H) , 3.33-3.50 (m, 5H) , 3.00-3.09 (m, 2H) , 2.75-2.88 (m, 2H) , 2.11-2.21 (m, 2H) , 2.03-2.11 (m, 3H), 1.90-2.03 (m, 2H) , 1.02-1.54 (br m, 10 H) .

Example 12H: MS: 583 (M + 1, 100) . NMR (CDCI3) : δ 7.12-7.35 (m, 10H) , 3.98 (s, 2H) , 3.61 (s, 6H) ,

3.60-3.74 (m, 2H) , 3.45-3.58 (m, 2H) , 3.03-3.13 ( , 2H) , 2.84-3.03 ( , 4H) , 2.07-2.28 (m, 6H) , 1.08- 1.81 (br , 12H) .

Example 121: MS: 555 (M - CH2 + 1, 100) . NMR (CDCI3) : δ 7.12-7.34 ( , 10H) , 3.98 (s, 2H) , 3.62

(s, 3H) , 3.45-3.76 (m, 6H) , 3.04-3.13 (m, 2H) , 2.85-2.99 (m, 3H) , 2.79 (s, IH) , 2.10-2.28 (m, 4H) , 1.08-1.64 (br m, 12H) .

Example 12J: MS: 759 (M + 1, 100), 633 (M - I + 1, 33), 507 (M - 21 + 1, 17) . NMR (CDCI3) : δ 7.00-

7.64 (br m, 18H) , 4.77 (d, 2H) , 3.70 (s, 2H) , 3.49- 3.57 ( , 2H) , 2.99-3.12 (m, 4H) , 2.81-2.93 (m, 2H) , 2.29 (s, 2H) .

Example 12K: MS: 583 (M + 1, 100) . NMR (CDCI3) : δ 7.15-7.35 (m, 10H) , 3.98 (s, 2H) , 3.44-3.74 (m,

8H) , 3.02-3.22 (m, 2H) , 2.88-3.02 (m, 2H) , 2.02- 2.20 (m, 2H), 0.94-1.92 (br m, 28H) .

Example 12L: MS: 495 (M+1,100) NMR (CDCI3) : δ 7.31 (m,10H) 4.22 (m. 4H) 3.76-4.05 (m. 6H) 3.60 (m, 2H) 3.03-3.37 (m, 6H) 1.89 (m, 2H) 0.95 (m, 2H) 0.80 (m, 2H) 0.45 (m, 2H) 0.30 (m, 2H) .

Example 12M: MS: 501 (M+1,100) NMR (CDCI3) : δ 7.05-7.38 (m, 15H) 4.84 (dd, IH) 4.04 (m, IH) 3.93 (m, IH) 3.49-3.75 (m. 3H) 3.05 (m, 6H) 1.74 (m, 2H) 0.70-0.98 (m, 2H) 0.40 (m, IH) 0.28 (m, IH) .

Example 12N: MS: 411 (M+l, 100) NMR (CDCI3) : δ 7.25 (m, 10H) 4.72 (bs, IH) 3.95 (m, 5H) 3.53 (m. 2H) 3.11 (m. 6H) 2.94 (t, IH) 2.76 ( . IH) 0.84 (m. 2H) 0.39 (m, IH) 0.24 (m. IH) .

Example 12o: MS: 441 (M + 1, 100) . NMR

(CDCI3) : δ 7.17-7.36 (m, 10H) , 4.70 (d, IH) , 3.90-

4.01 (m, 2H) , 3.53-3.68 ( , 4H) , 3.37-3.45 (m, IH) , 3.04-3.20 (m, 3H) , 2.78-3.03 (m, IH) , 2.68-2.77 (m, IH) , 2,09-2.24 (m, IH) , 1.10-1.95 (br m, 12H) .

Example 12P: MS: 555 (M + 1, 100) . NMR (CDCI3) : δ 7.13-7.37 ( , 10H), 3.98 (s, 2H) , 3.44-3.77 (m, 10H) , 3.03-3.14 (m, 2H) , 2.80-3.01 (m, 4H) , 2.06- 2.21 (m, 2H) , 1.00-1.75 (br m, 20H) .

Example 12Q: m. p. 185.7 ° C. FABMS: 655 (M + 1, 100), 613 (M - HNCNH + 1, 80) . NMR (DMSO-dδ) : δ

8.99 (br s, 8H) , 6.87-7.62 (br m, 18H) , 5.08-5.35 (m, 2H) , 4.44-4.62 (m, 2H) , 3.41-3.61 (m, 4H) , 2.96-3.18 (m, 4H) , 2.64-2.81 (m, 2H) . Reference: K. Takagi, Chemistry Letters (1985), pp. 1307-1308.

Example 12R: m. p. 169.3° C. MS: 599 (M + 1, 100) . NMR (CDCI3) : δ 6.90-7.40 (m, 18H) , 4.88 (d,

2H) , 3.63 (s, 2H), 3.49-3.58 (m, 2H) , 2.91-3.12 (m, 6H) , 2.42 (s, 6H), 2.22 (s, 2H) .

Example 12S: MS: 663 (M + 1), 680 (M + NH3 + 1) . NMR (CDCI3) : δ 6.93-7.83 (br m, 18H) , 4.78 (d, 2H) ,

3.71 (s, 2H) , 3.53-3.59 (m, 2H) , 3.19 (d, 2H) , 3.00-3.14 (m, 4H) , 2.98 (s, 6H) , 2.75-2.83 (m, 2H) .

Example 12T: MS: 415 (M + 1) . NMR (Acetone-dδ) : δ 7.15-7.30 (m, 10H) , 5.29 (s, IH) , 4.41 (s, IH) ,

4.25 (s, IH), 3.81-4.05 (m, 3H) , 3.63-3.78 (m, 2H) , 3.56-3.63 (m, 2H) , 3.37-3.47 (m, 5H) , 3.05-3.25 (m, 3H), 2.79-2.94 (m, IH) , 2.20 (br s, IH) .

Example 12U: MS: 503 (M + 1) . NMR (Acetone-dδ) : δ 7.15-7.28 (m, 10H) , 4.29 (s, IH) , 3.95-4.07 (m,

4H) , 3.49-3.66 (m, 8H) , 3.35-3.49 (m, 8H) , 3.14- 3.22 (m, 2H), 3.02-3.09 (m, 2H) , 2.08-2.21 (m, 3H) .

Example 12V: MS: 569 (M + 1) . NMR (CDCI3) : δ 7.14-7.34 (m, 10H) , 3.90-4.03 ( , 4H) , 3.42-3.74 (m, 8H) , 3.03-3.14 (m, 2H) , 2.86-3.01 (m, 2H) , 2.68-2.86 (m, 2H) , 2.05-2.23 (m, 2H) , 2.01 (s, 3H) , 0.98-1.75 (br m, 15 H) .

Example 12W: MS: 641 (M + 1), 584 (M - CONHCH2 + 1), 527 (M - 2CONHCH2 + 1) . NMR (CDCI3) : δ 7.10- 7.35 (m, 10H) , 4.77 (br s, 2H) , 3.89-4.12 (m, 6H) , 3.60-3.80 (m, 2H) , 3.35-3.47 ( , 2H) , 3.04-3.16 (m, 2H) , 2.87-3.01 (m, 2H) , 2.78 (d, 6H) , 2.01-2.16 (m, 2H), 0.98-1.80 (br m, 18H) .

Example 12X: MS: 626 (M + 1), 569 (M - CONHCH2 + 1) . NMR (CDCI3) : δ 7.09-7.35 (m, 10H) , 4.79 (br s,

IH) , 3.82-4.14 (m, 6H) , 3.38-3.81 (m, 4H) , 3.01- 3.22 (m, 2H) , 2.83-3.01 (m, 2H) , 2.79 (d, 3H) , 2.04-2.20 (m, 2H) , 2.01 (s, 3H) , 0.96-1.84 (br m, 18 H) .

Example 12Y: MS: 584 (M + 1), 527 (M - CONHCH2 + 1) . NMR (CDCI3) : δ 7.11-7.41 (m, 10H) , 4.81 (br s,

IH) , 3.87-4.10 (m, 4H) , 3.41-3.76 (m, 6H) , 3.02- 3.16 (m, 2H) , 2.81-3.02 (m, 2H) , 2.78 (d, 3H) , 2.00-2.21 ( , 2H) , 1.79 (br s, IH) , 0.95-1.63 (br m, 18H) .

Example 12Z: MS: 425 (M+l, 100) .

Example 13A: MS: 439 (M+l, 100) .

Example 13B: MS: 481 (M+l, 100) .

Example 13C: MS: 635 (M+l, 100) 652 (M+NH ₄ ) .

Example 13D : MS: 491 (M+1,100); NMR (CDCI3) : δ 7.24 (m, 10H), 5.68 (m, 2H) , 4.90 (m, 4H) , 3.98 (s,2H), 3.66 (m,2H), 3.50 (m, 2H) , 3.04 (m, 4H) , 2.19 (m,2H), 1.95 (m, 4H), 1.22 (m, 8H) .

Example 13E: MS: 523 (M+1,100); NMR (CDCI3) : δ 7.19 (m,10H), 3.98 (s,2H), 3.66 (m, 2H) , 3.53 (m,2H), 3.23 (s,2H), 3.14-2.66 (m, 8H) , 2.40 (m, 2H) ,

2.21 (m,2H), 1.55-1.23 (m, 12H) .

Example 13F: MS: 811 (M+1,100); NMR (CDCI3) : δ

7.22 (m,10H), 4.00 (m, 4H) , 3.77 (dd,2H), 3.56 (m, 6H), 3.13 (m, 4H) , 2.93 (m,2H), 2.23 (m,2H), 2.00 (m,2H), 1.65 ( , 2H) , 1.50-1.23 (m, 8H) .

Example 13G: MS: 685 (M+1,100); NMR (CDCI3) : δ

7.22 (m,10H), 4.01 (m, 2H) , 3.72-3.26 (m, 12H) , 3.14 (d,2H),2.96-2.70 (m, 6H) , 2.26 (m, 2H) , 1.43-1.18

(m, 8H) .

Example 13H: MS: 499 (M+1,100); NMR (CDCI3) : δ

7.23 (m,10H), 3.99 (s,2H), 3.54 (m, 8H) , 3.12 (m,2H), 2.94 (m, 4H) , 2.22 (m,2H), 1.47-1.20

(m, 12H) .

Example 131: MS: 559 (M+1,100); NMR (CDCI3/CD3OD) : δ 7.02 (m, 10H), 3.79 (s,2H), 3.69 (s,2H), 3.28 (m,6H), 3.13 (m, 4H) , 2.86 (m,2H), 2.67 (m,2H) , 1.95 (m,2H), 1.09-0.90 (m, 12H) .

Example 13J: MS: 435 (M+1,100); NMR (CDCI3) : δ 7.26 (m,10H), 4.15 (m,lH), 3.86 (m, IH) , 3.76 (m, IH) , 3.64 (m, IH) , 3.53 (m,2H), 3.23-2.97 (m, 4H) , 2.78 (m,2H), 2.16 (d,lH), 1.92 (m, IH) , 1.18 (m, IH) ,

0.88 (m, lH) , 0 .58 (m, 2H) , 0 .46 (m, 2H) , 0 .29 (d, IH) , 0.07 (d, lH) .

Example 13K: MS: 407 (M+1,100); NMR (CDCI3) : δ 7.23 (m,10H), 6.05 (m, IH) , 5.67 (m,IH) , 5.25

(m,2H), 5.05 (dd,2H), 4.17 (m,2H), 3.96 (m, IH) ,

3.83 (m,lH), 3.65 (m, IH) , 3.55 (m,IH) , 3.12-2.79 (m,5H), 2.59 (br s,lH), 2.35 (d, IH) .

Example 13L: MS: 507 (M+1,100); NMR (CDCI3) : δ 7.28 (m,18H), 6.91 (d,2H) , 4.10 (d,2H), 3.92 (d,lH), 3.58 (m,4H) , 3.18-2.63 (m,5H) .

Example 13M: MS: 567 (M+1,100); NMR (CDCI3) : δ 7.46-6.95 ( , 18H) , 4.90 (dd,2H), 4.67 (br d,4H) ,

3.84 (d,lH), 3.53 (m,4H) , 3.09-2.75 (m, 5H) , 2.44 (d,lH).

Example 13N: MS: 407 (M+1,100); NMR (CDCI3) : δ 7.24 (m,10H), 5.55 ( ,2H) , 5.14 (m, H) , 4.07 (dd,2H), 3.74 (m,2H), 3.27 (m,2H) , 3.12-2.84 (m,6H), 2.09 (s,2H) .

Example 13o: MS: 435 (M+1,100); NMR (CDCI3) : δ 7.26 (m,10H), 3.85 (s,2H), 3.41 (m,4H) , 3.01

(ddd,4H), 2.28 (dd,2H),2.19 (s,2H), 0.93 (m,2H), 0.50 (m,2H), 0.16 (m,2H) .

Example 13P: MS:327 (M+1,100); NMR (CDCI3) : δ 7.28 (m,10H), 4.25 ( ,2H) , 3.35 (m, 6H) , 2.81 (m,2H) , 2.65 (m,2H) .

Example 13Q: MS: 507 (M+1,100); NMR (CDCI3) : δ 7.24 (m,20H), 4.74 (d,2H) , 3.55 (m,4H) , 3.20 (m,2H), 2.96 (m,2H) , 2.77 (m,2H) .

Example 13R: MS: 439 (M+1,100); NMR (CDCI3) : δ

7.26 (m,10H), 3.75 (s,2H), 3.62 (m,2H), 3.20

(m,2H), 3.08 (m, 2H) , 2.84 (m,2H) , 2.38 (m,2H),

A 1.38-1.23 (m,8H), 0.90 (m, 6H) .

5

Example 13S: MS: 567 (M+1,100); NMR (CDCI3) : δ

7.34-7.07 (m, 18H), 4.68 (m, 6H) , 3.57 (m, 4H) , 3.17 (m,2H), 2.96 (m,2H) , 2.79 (m,2H) .

10 Example 13T: MS: 617 (M+H, 100%) ; NMR

(CDCI3,300MHz) : δ 7.3(m, 10H), 6.7 (m, H) ,

6.35(m,2H), 4.75(d,2H), 3.5(s,4H), 3.3(m,4H), 3.0(m,6H), 2.7 (m,4H) , 1.9 (m, 4H) .

15 Example 13U: m.p. 264-266 °C; MS: 609 (M+H, 100%) ; NMR (CDCI3,300MHz) : δ δ.6(d,2H), 7.95(d,2H),

7.8(d,2H), 7.6(d,2H), 7.3(m,14H), 5.1(d,2H), 3.7(m,4H), 3.2(m,6H) .

20 Example 13V: MS: 521 (M+H, 100%) ; NMR

(CDCI3,300MHz) : δ 8.8(s,2H), 7.2(m,12H),

4.15(s,2H), 3.8(t,2H), 3.6(m,4H), 2.9 (m,4H) .

Example 13W: m.p. 182-184 °C; MS: 687 (M+H, 100%) ; 25 NMR (CDCI3,300MHz) : δ 7.2(m,10H), 6.95(d,2H),

6.2(d,2H), 4.9(d,2H), 4.15(d,2H), 3.9(bs,2H), 3.7(d,2H), 3.0(m,6H), 1.45(s,18H) .

Example 13X: MS: 547 (M+H, 100%) ; NMR 30 (CDCI3,300MHz) : δ 7.2 (m, 10H) , 6.2(d,2H), 6.0(d,2H),

4.8(d,2H), 4.5(bs,2H), 3.8(s,2H), 3.5(d,2H), 3.1(m,6H) .

Example 13Y: MS: 507 (M+l, 100%); NMR 35 (CDCI3,300MHz) : δ 7.0-7.4 (m, 20H) , 4.7-4.8 (d,

2H) , 4 .5 (m, 2H) , 3 .45 (m, 4H) , 3 . 1 (m, 4H) , 2 . 9 (m, 2H) .

Example 13Z: MS: 577((M+H) ⁺ , 100%); 594((M + NH4) ⁺ , 80%) . NMR (CDCI3) : δ 8.08 (s IH) , 7.48 (dd,

IH, J = 8.4, 1.9 Hz), 7.25-7.38(m, 3H) ; 7.19(d, IH, J = 8.4 Hz), 7.00-7.03 (m, 2H) , 3.96(ABq, 2H) , 3.73(d, IH, J = 1.1 Hz), 3.50(dd, IH, J = 11.4, 1.1Hz), 3.23 (br.s., IH) , 2.98(ABx, 2H) .

Example 14A: NMR (CDCI3) : δ 8.27 (dd, IH, J - 4.9,

2.0 Hz), 7.66(dd, IH, J = 7.5, 2.0 Hz), 7.14- 7.27(m, 4H), 6.68(dd, 2H, J = 7.5, 3.6 Hz), 4.16(d, IH, J = 0.8 Hz) , 3.90 (ABq, 2H) , 3.72 (dd, IH, J = 11.3, 1.1Hz), 3.14 (br.s., IH) , 2.87 (ABx, 2H) .

Example 14B: MS: 685 ( (M+H) ⁺ , 100%) . NMR (CDCI3) : δ 8.34(dd, IH, J = 4.8, 1.9 Hz), 7.16-7.37(m, 4H) ,

6.93(dd, IH, J = 7.6, 4.8 Hz), 6.87(dd, 2H, J = 7.5, 1.7 Hz), 4.14(s, IH) , 3.90(ABq, 2H) , 3.68 (td,

IH, J =- 6.3, 0.7 Hz), 2.99(d, 2H, J = 6.3 Hz), 2.43 (br.s., IH) .

Example 14C: MS: 541( (M+H) ⁺ , 100%) . NMR (CD3OD) : δ 7.53(dd, IH, J = 9.5, 2.6 Hz), 7.15-7.26(m, 3H) ,

7.06(d _r IH, J = 2.6 Hz), 6.96-6.99(m, 2H) , 6.42(d, IH, J = 9.5 Hz), 3.80(s, IH) , 3.71(ABq, 2H) , 3.62(dd, IH, J = 11.7, 0.7 Hz), 2.92 (ABx, 2H) .

Example 14D : MS : 458 (M+H ⁺ , 100% ) .

Example 14E: MS: 543 (M+H ⁺ , 100%) NMR (CDCI3) : δ 7.4-7.l(m, 5H) , 4.42(d, J = 17.5 Hz, IH) , 4.10(s, IH) , 3.83(d, J = 10.6 Hz), 3.2-3.0 (m, 2H) , 2.82(d, J = 17.6 Hz, IH) , 2.36(s, IH) , 2.14 (m, 2H) , 1.5- 1.2(m, 6H) , 0.85(t, J = 7.0 Hz, 3H) .

Example 14F: MS: 739.5(M+H ⁺ ) NMR (CDCI3) : δ 7.4-7.0 (m, 15H) , 3.90(s, IH) , 3.3-3.1 (m, 2H) , 3.04(m, 2H) , 2.43(dd, J = 14.7, 5.7 Hz, IH) , 2.17(s _f IH) , 1.824(m, IH) , 1.26(t, J = 6.0 Hz, IH) , 1.02 (dd, J = 9.0, 5.1 Hz, IH)

Example 14G: MS: 479(M+H ⁺ , 100%) NMR (CDCI3) : δ 7.24(bs, 5H) , 7.15-6.9 (m, 3H) , 6.72(d, J = 7.5 Hz, 2H) , 4.15(s, IH) , 4.06(d, J = 10.5 Hz, IH) , 3.5- 3.2(m, 2H) , 2.98(s, IH) .

Example 14H: MS: 587 (M+H ⁺ , 100%) NMR (CDCI3) : δ 7.4-6.9 (m, 10H), 3.92(s, IH) , 3.8-3.6(m, 2H) , 3.03 (m, 2H), 2.50(bs, IH) , 2.19(dd, J = 14.3, 7.0 Hz, IH) , 1.57 (m, IH) , 1.0-0.7 (m, 2H) .

Example 141: MS: 457 (M+H ⁺ , 100%), 474 (M + NH4 ⁺ , 15%) NMR (CDCI3) : δ 7.4-6.9(m, 15H) , 4.69(d, J =

6.2 Hz, IH) , 3.95(m, 2H) , 3.77(m, 2H) , 3.37(m, IH) , 3.25-3.0 (m, 3H) , 2.15(b, IH) , 1.61 (m, 2H) , 1.24 (m, IH) , 1.0-0.7 (m, 2H) .

Example 14J: NMR (CDCI3) : δ 7.42(d, 2H, J = 7.3

Hz), 7.22-7.38(m, 6H) , 7.11(d, 2H, J = 6.6 Hz), 6.54(s, IH) , 6.35(s, IH) , 5.31(s, 2H) , 3.84(ABq, 2H), 3.72(s, IH) , 3.49(d, IH, J = 10.4 Hz), 2.90- 3.01 (m, 2H), 2.39(s, 3H) .

Example 14K: NMR ((CD3)2SO) : δ 7.00-7.33(m, 7H) ,

3.61(s, IH), 3.55(ABq, 2H) , 3.45(d, IH, J = 11.0 Hz), 2.95 (AB _X , 2H) , 2.09(s, 3H, ) .

The structures of the Examples below are shown in Table 2e.

Ketal formation: Preparation of Triacetonide (XXVIa) :

Lithium borohydride (1.2 gr, 56.2 mmol) was added in four portions to a suspension of L- mannonic-g-lactone (5 gr, 28.1 mmol) in methanol (250 mL) at 0 °C over 10 min. Ice bath was removed and reaction stirred at room temperature for 30 min. Reaction was quenched at 0 °C with 2N HCl. Solvent was evaporated and residue taken up in acetone (75 mL) to which 2,2-dimethoxyproρane (20 mL, 168.6 mmol) and camphorsulphonic acid (20 gr, 84.3 mmol) were added in four portions. Reaction becomes clear for a few minutes and then a precipitate forms . Reaction stirred at room temperature for 14 h. Solvent volume then reduced by 2/3 at reduced pressure and then poured into EtOAc, washed with saturated NaHC0 ₃ , dried (MgSθ4) and concentrated. Solid residue taken up in hexane and filtered thru a pad of silica gel. Filtrate concentrated to give triacetonide (XXVIa) as a yellowish solid (7.1 gr, 80%) . m.p. 72-74 °C; MS: 303 (M+H, 100%); NMR (CDCI3,300MHz) : 5 4.25 (m, 2H) , 4.15 (m, 2H) , 4.05

(m, 4H), 1.5 (s, 6H) , 1.45 (s, 6H) , 1.4 (s, 6H) .

Selective Acetonide Deprotection: Preparation of Tetraol (XXVIb) :

Compound (XXVIa) (14 gr) in 70% AcOH (200 mL) was stirred at 45 °C for 2 h. Solvent removed at reduced pressure with a bath temperature of 45 °C. Residue recrystalized from ether. Mother liquors concentrated and chromatographed (silica, 10% methanol in methylene chloride) to give the desired product as a white solid (8.2 gr, 80%) . m.p. 91-93 °C; [a] _D = -26.40 (c=3, H20) ; MS: 240 (M+NH , 100%) ; NMR (CDCI3, 300MHz) : δ 3.95 (m, 6H) , 3.75 (m, 4H) , 2.5 (bs, 2H), 1.4 (s,6H) .

Epoxide Formation: Preparation of Diepoxide (XXVIc) :

A solution of Compound (XXVIb) (1 g, 4.5 mmol) in pyridine (5 mL) was cooled to -20 °C and treated with p-toluenesulfonyl chloride (1.89 g, 10 mmol) . Stirring continued at -20 °C for 20 min, 0 °C for 20 min, and 23 °C for 20 min. The reaction was then diluted with methylene chloride and washed with 2N HCl and NaHC0 ₃ . The organic extract was dried over MgS0 ₄ and concentrated. The crude product was then taken up in methanol (14 mL) and cooled to 0 °C . Next, K2CO3 (3.11 g, 22 mmol) was added and the reaction stirred at room temperature for 30 min ^" . The methanol was then stripped off (do not evaporate to dryness, epoxide is volatile) and the crude was washed with water, extracted with ether, dried over MgSθ ₄ , filtered, and concentrated. The compound was purified on Siθ2 and eluted with 30-60% ether/petroleum ether to afford the diepoxide (0.63 g, 75%) as an oil. NMR (CDCI3,300MHz) : δ 3.81 (m,

2H), 3.10 ( , 2H), 2.80 (t, 2H) , 2.68 ( , 2H) , 1.40 (S, 6H, CH3) .

Opening of Epoxide: Prepepartion of Diol (XXVld) :

To a suspension of cuprous bromide-dimethyl sulfide complex (1.8 g, 8.7 mmol) in anhydrous THF (5 mL) at -20 °C was added 8.5 ml benzylmagnesium chloride (2M in THF, 17 mmol) . Reaction stirred at -20 °C for 30 min and at 0 °C for 1 h. Next, Compound (XXVIc) (0.54 g, 3 mmol) in THF (5 mL) was added, and the reaction stirred at 0 °C for 1 h. The excess reagent was quenched with saturated NH ₄ CI solution and allowed to warm to room temperature. The contents were then washed with water and brine, extracted with ether, dried over MgSθ ₄ , filtered, and concentrated. Crude material was then purified by flash chromatography (30-60% ether/petroleum ether) to yield 0.84 g (78%) of an oil. MS: 371 (M+H,66%); NMR (CDCI3, 300MHz) : δ 7.2-7.4 (m, 10H) ,

4.65 (s, 2H), 3.6-3.8 (m, 4H) , 2.6-3.0 (m, 4H) , 1.8- 2.2 (m, 4H), 1.4 (s, 6H) .

Hydroxyl Displacement: Preparation of Diazide

(XXVIe) :

To a solution of Compound (XXVId) (0.48 g, 1.3 mmol) and triphenyl phosphine (1.0 g, 3.9 mmol) in THF (5 mL) at 0 °C was added diethylazodicarbox late (0.61 mL, 3.9 mmol) and dipheylphosphorylazide (0.84 mL, 3.9 mmol) . Contents were allowed to warm to room temperature in the ice bath for 1 h. The excess reagents were quenched by the addition of methanol (0.2 mL, 5 mmol) at 0 °C. The mixture was then stirred at room temperature for 30 min and then concentrated to a small volume. Crude was then purified on Siθ2 using 1:40 ethyl acetate/hexane giving 0.245 g (45%) of an oil. MS: 438 (M+NH ₄ 8%); NMR (CDCI3,300MHz) : δ 7.2-7.4 (m, 10H) , 4.18 (s,

2H), 2.7-3.0 (m, 6H) , 2.0-2.3 (m, 4H) , 1.58 (s, 6H) .

Reduction of Diazide (XXVIe) :

To Compound (XXVIe) (0.245 g, 0.58 mmol) in ethanol (6 mL) under N2 was added 10% Pd/C (73.5 mg, 30%/weight) . Reaction stirred under H2 atmosphere at room temperature overnite. Crude was then filtered

-* 5 through celite and concentrated. 0.21 g (98%) of the diamine was collected as an oil and taken onto next step without further purification. MS: 369 (M+H, 100%) ; NMR (CDCI3, 300MHz) : δ 7.05-7.3 (m,

10H) , 3.9 (bs, 2H) , 3.05 (bs. 4H) , 2.8 (m, 2H) , 2.6 10 (m, 4H) , 1.7 (bs, 4H) , 1.35 (s, 6H) .

Cyclization of the Diamine: Formation of Cyclic Urea

(XXVIf) :

The diamine (0.21 g, 0.57 mmol) was dissolved in methylene chloride (50 mL) and carbonyldiimidazole 15 (0.102 g, 0.63 mmol) was added and the reaction stirred at 23 °C overnite. The solution was then concentrated and purified on Siθ ₂ using 75% ethyl acetate/hexane as elutent which gave 85mg (38%) of

(XXVIf) as a foam. MS: 395 (M+H, 100%) ; NMR 20 (CDCI3,300MHz) : δ 7.0-7.2 (m, 10H) , 3.6-4.0 (m, 4H) ,

3.6-2.7 (m, 4H) , 1.8-1.9 (m, 4H) , 1.3 (s, 6H) .

Alkylation of the Cyclic Urea (XXVIf) :

To Compound (XXVIf) (85mg, 0.22 mmol) in dry DMF (3 mL) was added 60% NaH (0.07 g, 1.7 mmol) . The

25 solution was stirred for 5 min at room temperature. Next, benzyl bromide (0.1 mL, 0.86 mmol) was added and the reaction stirred at 23 °C overnite. Reaction was then quenched with methanol (several drops) , washed with H2O, extracted with ether, dried

30 (MgSθ ₄ ) , and concentrated. Crude was then purified on silica gel using 1:1 hexane/ethyl acetate affording 0.03 g (25%) of the bis-alkylated urea as a foam. MS: 575 (M+H, 100%); NMR (CDCI3, 300MHz) : δ

7.1-7.4 (m, 20H), 5.1 (d, 2H) , 4.0 (d, 2H) , 3.75 (bs, 2H), 3.6 (m, 2H) , 2.7 (m, 2H) , 2.6 (m, 2H) , 1.9-2.0 (m, 4H) , 1.25 (s, 6H) .

Deprotection of Acetonide: Preparation of Example

16A:

To above prepared bis-alkylated cyclic urea (0.03 g, 0.05 mmol) in THF (2 mL) at room temperature was added several drops of concentrated HCl. Reaction stirred at room temperature for 2 h. Reaction was then washed with 1 N NaOH, extracted with ethyl acetate, dried ( gS0 ₄ ) , and concentrated.

Chromatography (silica, 1-5% methanol in methylenechloride) gave 0.024 g (85%) of example 16A as a foam. MS: 535 (M+H,100%); NMR (CDCI ₃ ,300MHz) : δ

7.1-7.3 (m, 20H), 5.15 (d, 2H) , 3.9 (d, 2H) , 3.5 (bs, 2H), 3.3-3.4 (m, 2H) , 2.7-2.8 (m, 2H) , 2.5-2.6 (m, 2H) , 2.0-2.1 (m, 6H) .

Table 2e

methyl methyl

Listed below are physical data for representative compounds of the invention,

Example 16A: MS: 535 (M+l, 100%); NMR (CDCI3,300MHz) : δ 7.1-7.3 (m, 20H) , 5.15 (d, 2H) ,

3.9 (d, 2H), 3.5 (bs, 2H) , 3.3-3.4 (m, 2H) , 2.7-2.8 (m, 2H) , 2.5-2.6 (m, 2H) , 2.0-2.1 (m, 6H) .

Example 16B: MS: 435 (M+l, 100%); NMR (CDCI3,300MHz) : δ 7.1-7.3 ( m, 10H) , 5.8 (m, 2H) , 5.15 (s, 2H) , 5.1 (d, 2H) , 4.5-4.6 (m, 2H) , 3.8 (s, 2H) , 3.3-3.5 (m, 4H) , 2.5-2.9 (m, 4H) , 2.2 (m, 2H) , 2.0 (m, 4H) .

Example 16C: MS: 312 (22, M + 2), 311 (100, M + 1), 267 (1) . HRMS: Calc. 311.2334. Found: 311.2330.

NMR (CDCI3) : δ 5.81 (m, 2H) , 5.2 (m, 4H) , 4.4 (m, 2H) ,

4.0(br s, 2H), 3.4 (m, 2H) , 3.1 (br s, 2H) , 3.0(m, 2H), 2.4 (m, 2H), 1.2 (d, 6H) , 0.9(d, 6H) .

Example 16D: MS: 341(4), 340 (25), 339 (100, M +

1), 321 (1), 295 (2), 256 (2) . HRMS: Calc. 339.2647. Found: 339.2652. NMR (CDCI3) : δ 4.2 (brs,

2H) , 3.65(m, 2H) , 3.20(m, 4H) , 2.6 (m, 4H) , 1.2(d, 6H) , 1.0(m, 2H), 0.9(d, 6H) , 0.5(m, 4H) , 0.2(m, 4H) .

Example 16E: MS: 256 (15, M + 2) , 255 (100, M + 1) . HRMS: Calc. 255.1706. Found: 255.1708.NMR (CDC1 ₃ ) δ 5.8 (m, 2H) , 5.2 (m, 4H) , 4.0(m, 2H) , 3.8 (br s, 2H), 3.65(m, 2H) , 3.4 (m, 2H) , 2.8 (m, 2H) , 1.2 (d, 6H) .

Example 16F: MS: 272 (16, M + 2) , 271 (100, M + 1) . HRMS: Calc. 271.2021. Found: 271.2036. NMR (CDCI3) : δ 5.8 (m, IH) , 5.2 (m, 2H) , 4.0 (m, 2H) ,

3.8 (br s, 2H) , 3.6-3.3 (3H) , 3.0 (m, 2H) , 2.45 (m, 2H) , 1.35 (m, 2H), 1.2 (d, 6H) , 0.9(m, 4H) .

Example 16G: MS: 356 (23, M + 2) , 355 (100, M + 1) . HRMS: Calc. 355.2021. Found: 355.2012. NMR (CDCI3) : δ 7.4-7.2 (m, 10H) , 4.9(d, 2H) , 4.2 (d, 2H) ,

3.6(br s, 2H), 3.3 (m, 2H) , 2.2 (m, 2H) , 1.2 (d, 6H) .

Example 16H: mp 236-238°C. MS: 456 (29, M + 2) , 455 (100, M + l), 315 (10), 158 (5) . HRMS:

455.2334. Found: 455.2333. NMR (CDCI3) : δ 7.9-7.8 (m,

8H), 7.6-7.45(m, 6H) , 5.0(d, 2H) , 4.4 (m, 2H) , 3.6(br s, 2H) , 3.4(m, 2H) , 1.9(m, 2H) , 1.2 (m, 2H) .

Example 161: MS 339 (100, M+l), 311 (4) . HRMS 339.265377 (calc. mass = 339.264768) . NMR (CDC1 ₃ ) : δ 5.91-5.79 (m), 5.29-5.18 (m, 4H) , 4.53-4.46 (m, 2H), 3.76 (s, 2H), 3.41-3.33 (m, 4H) , 2.13 (s, 2H) , 1.81-1.71 (m, 2H), 1.71-1.62 (m, 2H) , 1.45-1.35 (m, 2H) , 0. 90 (t, 12H) .

Example 16J: m.p . 137-139 °C . MS 367 (100, M+l) . HRMS 367.295357 (calc . mass = 367 .296068) . NMR (CDCI3) : δ 3.94 (s, 2H) , 3.82 (d, 2H) , 3 .77 (d, 2H) ,

3.48 (d, 2H) , 2. 91 (bs, 2H) , 2.63 (d, 2H) , 2 . 61 (d, 2H) , 1.99 (m, 2H) , 1.70-1. 61 (m, 2H) , 1 .43 (m, 2H) ,

1 .26 (s , 2H) , 1 . 07-0 . 98 (m, 2H) , 0 . 91 (t, 12H) , 0 . 52 (m, 2H) , 0 .22 (m, 2H) .

The structures of the Examples below are shown in Table 2f-h.

Synthesis of Thiourea (XXVIIa) :

Diaminodimem Compound (XXIb) (22.45g, 47.1 mmol) was dissolved in 200 mL of tetrahydrofuran and to this solution was added 9.23g (51.8 mmol) of thiocarbonyl diimidazole. After stirring the mixture for 18 hours at room temperature TLC (10:1:10 ethyl acetate: ethanol: hexane) indicated complete reaction. The reaction mixture was taken to dryness and the solid residue purified by flash chrmatography (silica gel, 250g, 1:1 ethyl acetate: hexane) to provide solid which was triturated with hexane to provide 17.8g (73% yield) of XXVIIa as a white solid.

Synthesis of Compound (XXVIIb) :

Compound (XXVIIa) (3.108g, 6mmol) was dissolved in 15ml acetonitrile and to this solution was added methyl iodide 1.5ml (24mmol) via syringe and stirred at room temperature for one hour. The contents were then taken to dryness . The residue was dissolved in 30ml dimethylformamide and to this solution, cooled in a 0°C ice bath, was added NaH (60% in oil) 720mg (18mmol) slowly (EVOLUTION!) . The contents were stirred at room temperature for 30 minutes. The mixture was cooled in a 0°C ice bath and benzyl bromide (2.052g, 12mmol) was added via syringe and stirred at room temperature for 18 hours. TLC (2:3 EtOAc:Hexane R _f =0.25) indicated a complete reaction. The reaction was worked up by

diluting with water (300ml) and extracting with diethyl ether (3x50ml) . The organic layer was dried over magnesium sulfate and the filtrate taken to dryness. The residue was purified on Siθ2 gel (200g; 2:3 EtOAc.Hexane) to provide 2.923g (78.2% yield) of XXVIIb as a colorless oil.

Synthesis of Compounds (XXVIIc) and (XXVIId) :

Compound (XXVIIb) (2.900g, 4.65mmol) was dissolved in 25ml pyridine and to this solution was added 742mg (4.65mmol) benzylhydroxylamine hydrochloride. The contents were refluxed in a 125°C oil bath for 18 hours. (Caution: Methyl mercaptan is a by-product and the reaction should be vented to a Clorox scrubber) . TLC indicated a complete reaction. The reaction was diluted with 150ml dichloromethane. The organic layer was washed with IN HCl (2x300ml) followed by sat. sodium bicarbonate solution (100ml) . It was separated and dried over magnesium sulfate and the filtrate taken to dryness. The residue was purified on Siθ2 gel(130g; using 1:3 EtOAc:Hexane) to provide 58 mg (18.0% yield) of Compound (XXVIIc) as a colorless oil.- 1:2 EtOAc:Hexane was used to provide 2.113g of a side product thiourea (XXVIId) .

Synthesis of Oxime (XXVIIe) :

Compound (XXVIIc) (584mg, 0.84mmmol) was dissolved in 5ml dimethylformamide and to this solution, cooled in a 0°C ice bath, was added NaH( 60% in oil) 80mg (2mmol) slowly (EVOLUTION!). The contents were stirred at room temperature for 30 minutes. The mixture was cooled in a 0°C ice bath and benzyl bromide (0.24ml, 2mmol) was added via syringe and stirred at room temperature for 18 hours. TLC (1:3 EtOAc:Hexane Rf=0.26) indicated a

complete reaction. The reaction was worked up by diluting with water (50ml) and extracting with diethyl ether (2x25ml) . The organic layer was dried over magnesium sulfate and the filtrate taken to dryness. The residue was purified on Siθ2 gel (33g; 1:3

EtOAc:Hexane) to provide 491mg (74.2% yield) of a colorless oil.

Example 18A

Compound (XXVIId) (450mg, 0.57mmol) was placed in a 25ml R.B. Flask and cooled in a 0°C ice bath. To this flask was added 4M HCl in dioxane (5ml, 20mmol) and the mixture stirred at room temperature for 18 hours. TLC (2:3 EtOAc:Hexane Rf=0.29) indicated a complete reaction. The mixture was worked up by quenching in sat.sodium bicarbonate solution (50ml) and extracting with dichloromethane (2x50ml) . The organic extracts were dried over magnesium sulfate and the filtrate taken to dryness. The residue was purified on Siθ2 gel(33g;

2:3 EtOAc:Hexane) to provide 246mg (70.5% yield) of Example 18A as a waxy solid.

Example 17A

Example 18A (160mg, 0.26mmol) was dissolved in 5ml ethanol. To this mixture was added 50mg of 10% palladium hydroxide on Carbon and the suspension stirred for 18 hours under hydrogen(1 atm) . TLC (10:1:10 EtOAc:EtOH: Hexane Rf=0.3) indicated a complete reaction. The suspension was filtered through a celite pad and the filtrate taken to dryness . The residue was purified on Siθ2 gel (33g; 10:1:10 EtOAc:EtOH:Hexane) to provide 97mg of Example 17A (69.5% yield) as a white solid.

Example 19 A

Compound (XXVIId) (500mg, 0.82mmol) was placed in a 25ml R.B. Flask and cooled in a 0°C ice bath. To this flask was added 4M HCl in dioxane (7.5ml, 30mmol) and the mixture stirred at room temperature for 18 hours. TLC (1:2 EtOAc:Hexane R _f =0.29) indicated a complete reaction. The mixture was worked up by quenching in sat.sodium bicarbonate solution (50ml) and extracting with dichloromethane (2x50ml) . The organic extracts were dried over magnesium sulfate and the filtrate taken to dryness. The residue was purified on Siθ ₂ gel (33g; 1:2 EtOAc:Hexane) to provide 181mg (51.1% yield) of Example 19A as a white solid.

Table 2f

Ex. No. HPLC _Z_o m.p.°C MS

ILL M±H

17A CH ₂ C ₆ H ₅ ++ 120.1 522.275

Table 2σ

tOCH ₂ Ph

N'

^R "N^N" ^R

Ex. NO. E HPLC _Z_ m.p.° MS

Ki M±_ 18A CH ₂ C ₆ H ₅ + 59.5 612.322

Table 2h

EX. NQ. E HPLC 1.90 m.p-°C MS ^• Ki M+H 19A CH2Ph +++ +++ 74.0

The structures of the Examples below are shown in'Table 2i.

Acetylation of Diol: Compound (XXVIIIa) :

Example IX (3.517g, 7.58mmol) was dissolved in 25ml pyridine and to this solution, cooled in a 0°C ice bath, was added 350mg 4-Dimethylaminopyridine and 7.16ml (75.85mmol) acetic anhydride. The contents were stirred at room temperature for 18

hours. TLC (1:4 EtOAc:Hexane Rf=0.3) indicated a complete reaction. The reaction was diluted with 250ml dichloromethane. The organic layer was washed with IN HCl (2x300ml) followed by sat. sodium bicarbonate solution (100ml) . It was separated and dried over magnesium sulfate and the filtrate taken to dryness. The residue was purified on Siθ ₂ gel (200g; 1:5 EtOAc:Hexane) to provide 2.632g (67.0%) of XXVIIIa as a white solid.

Nitration of Benzyl Group: Compound (XXVIIIb) and

(XXVIIIc) :

Compound (XXVIIIa) (518mg, lmmol) was dissolved in 4ml acetonitrile and to this solution, cooled in a -40°C dry ice-acetone bath, was added 4.4ml (2.2mmol) 0.5M Nitronium tetrafluoroborate in sulfolane. The contents were stored in a -40°C freezer for 18 hours. TLC indicated a complete reaction. The reaction was diluted with 100ml ether and washed with water (2x50ml) . The organic layer was dried over magnesium sulfate and the filtrate taken to dryness. The residue was purified on Siθ ₂ gel (75g; 1:3 EtOAC:Hexane for XXVIIIb, 1:2 EtOAc:Hexane for XXVIIIc) to provide

106mg (17.4% yield) of XXVIIIb as a white solid and 159mg(26.2% yield) of XXVIIIc as a white solid.

Example ?.0A

Compound (XXVIIIb) (106mg, 0.174mmol) was dissolved in 5ml methanol and to this solution was added 0.5ml 0.5M sodium methoxide in methanol via syringe. The contents were stirred at room temperature for 30 minutes. TLC indicated a complete reaction. The mixture was quenched by

adding 500mg of AG50 -X8 acid resin and stirring the suspension at room temperature for 5 minutes. The filtrate was taken to dryness and the residue purified on Siθ ₂ gel (33g; 1:2 EtOAc:Hexane) to provide 43mg (47.1% yield) of Example 20A as a white solid.

Example 2OB

Compound (XXVIIIc) (159mg, 0.261mmol) was dissolved in 5ml methanol and to this solution was added 0.5ml 0.5M sodium methoxide in methanol via syringe. The contents were stirred at room temperature for 30 minutes. A white precipitate started forming after 15 minutes. TLC indicated a complete reaction. The mixture was quenched by adding 500mg of AG50W-X8 acid resin and stirring the suspension at room temperature for 5 minutes. 10ml dichloromethane was then added to solubilize the solid. The filtrate was taken to dryness and the residue provided lllmg (81.1% yield) of Example 20B as a white solid.

Example 20E

Example 20A (lOOmg, 0.191mmol) was dissolved in 5ml ethanol. To this mixture was added 50mg of 5% palladium on Carbon and the suspension stirred for 18 hours under hydrogen(1 atm). TLC indicated a complete reaction. The suspension was filtered through a celite pad and the filtrate taken to dryness. The residue provided 47mg (53.0% yield) of Example 20E as a white solid.

Example 2OF

Example 20B (lOOmg, 0.191mmol) was suspended in 5ml ethanol. To this mixture was added 50mg of 5% palladium on Carbon and the suspension stirred for 18 hours under hydroge (1 atm) . The starting material went into solution as the reaction progressed. TLC indicated a complete reaction. The suspension was filtered through a celite pad and the filtrate taken to dryness. The residue provided 49mg (55.2% yield) of example 20F as a white solid.

Example 2QG

A. Synthesis of 4-Fluorobenzyl Cyclic Urea (XXXI) :

(XXXI)

The synthesis of 4-fluorobenzyl cyclic urea is outlined in Scheme 7. N-acetyl-D-4- fluorophenylalanine methyl ester (23.9 g, 0.1 mol), obtained using the procedure of M.J. Burk (J. Am. Chem. Soc. 1991, 113, 8518), was dissolved in 40 mL of acetic acid and treated with 100 mL of concentrated HCl, 40 mL of water and heated to reflux for 5 hrs. The solution was cooled to room temperature and then made basic (pH = 10) with 50% NaOH while cooling in an ice bath. Benzyl chloroformate (25 mL, 29 g, 0.17 mol) and NaOH are added in four portions and the solution is

maintained alkaline by the addition of NaOH. The mixture is then stirred at rt for 30 min. The alkaline solution is extracted with ether (2 X 500 mL) and the solution acidified with cone HCl to pH 1. The precipitate is extracted into methylene chloride and dried over MgS0 ₄ . The solution is filtered and concentrated to give 20 g of the N- Cbz-D-4-fluorophenylalanine as a white solid that is used without further purification. A solution of N,0-dimethylhydroxylamine hydrochloride (8.0 g, 0.082 mol) in DMF is prepared by gentle warming. The solution is allowed to cool slightly and treated with N-methylmorpholine (8.2 g, 0.082 mol) and diluted with THF to facilitate transfering of the resulting thick suspension.

A solution of N-Cbz-D-4-fluorophenylalanine (20 g, 0.063 mol) in THF is treated with N- methylmorpholine (9.0 g 0.09 mol) and cooled to 0°C in an ice bath. To the stirred cold solution is added isobutyl chloroformate (8.6 g, 0.063 mol) in small portions over a period of 10 mins. Then the solution of N,0-dimethylhydroxylamine in DMF prepared above is added and the reaction mixture is stirred for 20 mins. Most of the solvent is removed on a rotorary evaporator and the residue is partitioned between water and methylene chloride. The organic layer is washed successively with 1 N HCl, 1 N NaOH, water, brine and then dried over MgSθ ₄ . The solution is then filtered and concentrated and the residue chromatographed on silica gel (50% EtOAc/Hex) to give 16 g of the amide.

Using the procedure of by J-A. Fehrentz and B.

Castro (Synthesis, 1983, 676) 11 g (0.031 mol) of N-Cbz-D-4-fluorophenyl-alanine N,0- dimethylhydroxylamide was converted to 9.0 g of N-

Cbz-D-4-fluorophenylalaninal obtained as a thick oil that was used without further purification.

N-Cbz-D-4-fluorophenylalaninal (9.0 g , 0.031 mol) was converted, using procedure 1, to (2R,3S,4S, 5R)-2.5-bis(N-Cbz-amino)-3,4-dihydroxy- 1, 6-di(4-fluorophenyl)hexane (4 g) obtained as a white solid. MS: (Cl, NH ₃ ) (M+H) ⁺ = 605.

The (2R,3S,4S,5R)-2.5-bis (N-Cbz-amino)-3,4- dihydroxy-1, 6-di(4-fluorophenyl)hexane (4.0 g, 0.0066 mol) was converted, as described in procedure 4, to 1.3 g of the 4-fluorobenzyl cyclic urea (XXXI) obtained as a white solid. MS: (Cl, NH ₃ ) (M+H) ⁺ = 539.3

B. The 4-fluorobenzyl cyclic urea (XXXI) (270 mg, 0.5 mmol) was alkylated with 3-benzoxybenzyl chloride (350 mg, 1.5 mmol) according to general procedure 5. The resulting intermediate was dissolved in THF and hydrogenated for 12 hours (200 mg 10% Pd/C, 55 psi) to remove the benzyl protecting groups. The MEM group was then removed, according to general procedure 5, to give, after chromatography on HPLC (silica gel, 10% MeOH/CHCl ₃ ) , 140 mg of Example 20G as a white foam. MS: (Cl, NH ₃ ) (M+H) ⁺ = 575.2 (100%) .

Table 2i

The structures of the Examples below are shown in Table 2 j .

Example 21A

A. Synthesis of Aziridine Urea (XXXIIa) :

A solution of Example 1A (5.3 g, 0.016 mol) in pyridine was treated with acetic anhydride (3.3 g, 0.033 mol) and strirred at room temperature for 3 hrs. 10 mL of MeOH was added and the mixture was evaporated to dryness. The residue was extracted into methylene chloride and washed sequentially with water, 1 N HCl, brine, and dried over MgS0 ₄ .

The solution was filtered, concentrated and the residue chromatographed on silica gel (5%MeOH/CHCl ₃ ) to give 2.0 g of the corresponding monoacetate product as a white solid. The solid obtained was dissolved in methylene chloride and

cooled in an ice bath under nitrogen. To this was added DAST (0.875 g, 0.005 mol) via syringe and the solution stirred for 10 mins. The mixture was quenched with sat'd NaHCθ ₃ ^anς -- ^--- organic layer washed with water and brine. The solution is dried over MgS0 ₄ then filtered and concentrated to give

1.9 g of the acetate aziridine (XXXIIa) which is used without further purification.

B. The acetate aziridine (XXXIIa) (100 mg. 0.29 mmol) is dissolved in MeOH (2 mL) and treated with 1 N NaOH (0.5 ml) and stirred at rt for 30 min. The mixture is diluted with water (20 mL) and extracted into CH ₂ C1 ₂ . The extract is washed with water and brine, dried over MgS0 ₄ then filtered and concentrated to give 30 mg of Example 21A as a white solid. MS: (Cl, NH ₃ ) (M+H) ⁺ = 309.0

Example B and 2 C

The acetate aziridine (XXXIIa) (200 mg, 0.57 mmol) is alkylated with benzyl bromide (120 mg, 0.69 mmol) according to Procedure 5 to give a mixture of products. This was HPLC chromatographed on silica gel (50% EtOAc/Hex) to give first 50 mg of Example 21B as a white solid. MS: (Cl, NH ₃ ) (M+H) ⁺ = 309.0.

This was followed by 30 mg of Example 21C, obtained as a colorless oil. MS: (Cl, NH ₃ ) (M+H) ⁺ = 489.2.

Table 2j

E' 22 E

H H

The structures of the Examples below are shown in Table 2k.

Preparation of the Cyclic Urea (XXXIIIa)

A. Preparation of 4-Amino-2- (t-butoxycarbonylamino) 1, 5-diphenyl-3- (2-methoxyethoxymethyl)pentane.

15 A mixture of 595 mg (1.50 mmole) of 4-azido-2- (t-

* butoxycarbonylamino-1, 5-diphenyl-3-hydroxypentane (EP 0 ? 402 646 Al), 10 ml of dioxane, 0.2 ml (1.75 mmole) of MEM chloride, and 0.32 ml (1.83 mmole) of

diisopropylethylamine was heated at 80°C for 16 hrs. Evaporated the solvent and purified the residue by flash chromatography on silica gel with 85:15 hexane-ethyl acetate to give 0.64 g (88%) of an oil. Mass spec (M+H) ⁺ — 485.2. This was reduced to the title compound with hydrogen using 100 mg of 10 % Pd on carbon in 60 ml of ethyl acetate and 0.6 ml of acetic acid in 49% yield.

B. Preparation of 2,4-diamino-l,5-diphenyl-3- hydroxypentane.

The product from Part A (218 mg) was dissolved in 2 ml of ice cold 1:1 trifluoroacetic acid - dichloromethane. After 1 hr the solution was poured into a mixture of sodium bicarbonate solution and ethyl acetate. The ethyl acetate extract yielded 163 mg of the desired diamino compound.

C. Cyclization of the Diamine

The product from Part B (146 mg) , 75 mg of carbonyl diimidazole, and 0.15 ml of diisopropylethylamine were dissolved in 2.5 ml of anydrous THF and stirred at room temperature for 16 hrs. The solvent was evaporated. The residue was purified by preparative TLC on silica gel with 90:10 dichloromethane - methanol to give 108 mg (69 %) of the cyclic urea. Mass spec (M+H) ⁺ = 385.1.

N-Alkylation of the Cyclic Urea (XXXIIIa) :

D. The product from Part C (93 mg) was dissolved in 2.5 ml of anhydrous DMF, and 100 mg of 60% NaH in mineral oil was added. The mixture was stirred for one hr. m-Benzyloxbenzyl chloride (350 mg) was added, and the mixture was stirred for 16 hrs at room temperature.

Water and ethyl acetate were added. The ethyl acetate extract was washed with water, dried and evaporated . The residue was purified by prep TLC on silica gel with 60:40 hexane - ethyl acetate to give 105 mg (54%) of the desired bis-alkylated product . Mass spec (M+H) ⁺ = 777.5

Deprotection of Protecting Groups (Example 22A) :

The product from part D (103 mg) was dissolved in 4N HCl/dioxane for 16 hrs. The solution was evaporated and purified by prep TLC on silica gel with 60:40 hexane - ethyl acetate. Mass spec (M+H) ⁺ = 689.4. The purified material was hydrogenated for 16 hrs in the presence of 3 ml ethanol. 0.2 ml of acetic acid, and 35 mg of 10% Pd on carbon to give Example 22A. Mass spec (M+H) ⁺ = 509.25; calculated, 509.24.

MS EX NQ . E ²² R ²³ Ki ISgo -M±H

22A m- (HO) - m- (HO) - ++ 509 . 25

C6H4CH2- C6H4CH2-

Table 3

.23

= R' R ²² =

Table 3

125 126 127 128 129 130 131 132

133 134 135 136 137 138 139 140 141 142 143 144 145 146 147

148

149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 dimethylamino) phenylmethyl"

166 benzyl "3,3-dimethallyl" 167 1-pyrolylmethyl "3,3-dimethallyl" 168 1-pyrazolylmethyl "3,3-dimethallyl" 169 1-imidazolylmethyl "3,3-dimethallyl" 170 1-indolylmethyl "3,3-dimethallyl" 171 1-triazolylmethyl "3,3-dimethallyl" 172 1-tetrazolylmethyl "3,3-dimethallyl" 173 2-pyridylmethyl "3,3-dimethallyl" 174 3-pyridylmethyl "3,3-dimethallyl"

3/07128

Table 3

274 4-pyridylmethyl 2-propyl

275 cyclohexylmethyl 2-propyl

276 2-naphthylmethyl 2-propyl

277 3 -naphthylmethyl 2-propyl

278 2-thioρhenylmethyl 2-propyl

279 4- (1-methyl) piperidinyl- 2-propyl methyl

280 " (3, 4- 2-propyl raethylenedioxyphenyl) methyl"

281 2-thienylmethyl 2-propyl

282 4-biphenylmethyl 2-ρropyl

283 pyrimidinylmethyl 2-propyl

284 2-benzothiazolylmethyl 2-propyl

285 2-benzothiophenylmethyl 2-propyl

286 2-thiomethy lethyl 2-ρropyl

287 2-thiomethylmethyl 2-propyl

288 2-methylpropyl 2-propyl

289 2-methylbutyl 2-propyl

290 3-methylbutyl 2-propyl

291 cyclopropylmethyl 2-propyl

292 cyclobutylmethyl 2-propyl

293 cyclopentylmethyl 2-propyl

294 p-hydroxyphenylmethyl 2-propyl

295 p-nitrophenylmethyl 2-propyl

296 p-aminophenylmethyl 2-propyl

297 "4-(N,N- 2-propyl _d imethylamino) phenylmethyl"

298 benzyl cyclopropyl

299 1-pyrolylmethyl cyclopropyl

300 1-pyra zolylmet hy 1 cyclopropyl

301 1-imidazolylmethyl cyclopropyl

302 1-indolylmethyl cyclopropyl

303 1-triazolylmethyl cyclopropyl

304 1-tetrazolylmethyl cyclopropyl

305 2-pyridylmethyl cyclopropyl

306 3-pyridylmethyl cyclopropyl

307 4-ρyridylmethyl cyclopropyl

308 cyclohexylmethyl cyclopropyl

309 2-naρhthylmethyl cyclopropyl

310 3-naphthylmethyl cyclopropyl

311 2-thiophenylmethyl cyclopropyl

312 4- (1-methyl) piperidinyl- cyclopropyl methyl

313 ⁿ (3, 4- cyclopropyl methylenedioxyphenyl) methyl"

314 2-thienylmethyl cyclopropyl

315 4-biphenylmethyl cyclopropyl

316 pyrimidinylmethyl cyclopropyl

317 2-benzothiazolylmethyl cyclopropyl

318 2-benzothiophenylmethyl cyclopropyl

319 2-thiomethylethyl cyclopropyl

320 2-thiomethylmethyl cyclopropyl

321 2-methylpropyl cyclopropyl

322 2-methylbutyl cyclopropyl

Table 3

323 3-methylbutyl cyclopropyl 324 cyclopropylmethyl cyclopropyl 325 cyclobutylmethyl cyclopropyl 326 cyclopentylmethyl cyclopropyl 327 p-hydroxyphenylmethyl cyclopropyl 328 p-nitrophenylmethyl cyclopropyl 329 p-aminophenylmethyl cyclopropyl 330 "4-(N,N- cyclopropyl dimethylamino)phenylmethyl"

331 benzyl cyclopropylmethyl 332 1-ρyrolylmethyl cyclopropylmethyl 333 1-pyrazolylmethyl eyelopropylmethyl 334 1-imidazolylmethyl cyclopropylmethyl 335 1-indolylmethyl cyclopropylmethyl 336 1-triazolylmethyl cyclopropylmethyl 337 1-tetrazolylmethyl cyclopropylmethyl 338 2-pyridylmethyl cyclopropylmethyl 339 3-ρyridylmethyl cyclopropylmethyl 340 4-pyridylmethyl cyclopropylmethyl 341 cyclohexylmethyl cyclopropylmethyl 342 2-naphthylmethyl cyclopropylmethyl 343 3-naphthylmethyl cyclopropylmethyl 344 2-thiophenylmethyl cyclopropylmethyl 345 4-(1-methyl)ρiperidinyl- cyclopropylmethyl methyl

346 "(3,4- cyclopropylmethyl methylenedioxyphenyl)methyl"

347 2-thienylmethyl cyclopropylmethyl 348 4-biphenylmethyl cyclopropylmethyl 349 pyrimidinylmethyl cyclopropylmethyl 350 2-benzothiazolylmethyl cyclopropylmethyl 351 2-benzothiophenylmethyl cyclopropylmethyl 352 2-thiomethylethyl cyclopropylmethyl 353 2-thio ethylmethy1 cyclopropylmethyl 354 2-methylpropyl cyclopropylmethyl 355 2-methylbutyl cyclopropylmethyl 356 3-methylbutyl cyclopropylmethyl 357 cyclopropylmethyl cyclopropylmethyl 358 cyclobutylmethyl cyclopropylmethyl 359 cyclopentylmethyl cyclopropylmethyl 360 p-hydroxyphenylmethyl cyclopropylmethyl 361 p-nitrophenylmethyl cyclopropylmethyl 362 p-aminophenylmethyl cyclopropylmethyl 363 "4-(N,N- cyclopropylmethyl dimethylamino)phenylmethyl"

364 benzyl n-pentyl 365 1-pyrolylmethyl n-pentyl 366 1-pyrazolylmethyl n-pentyl 367 1-imidazolylmethyl n-pentyl 368 1-indolylmethyl n-pentyl 369 1-triazolylmethyl n-pentyl 370 1-tetrazolylmethyl n-pentyl 371 2-pyridylmethyl n-pentyl 372 3-pyridylmethyl n-pentyl

cyclobutyl cyclobutyl cyclobutyl cyclobutyl cyclobutyl cyclobutyl cyclobutyl cyclobutyl cyclobutyl cyclobutyl cyclobutyl cyclobutyl cyclobutyl cyclobutyl cyclobutyl cyclobutyl cyclobutyl cyclobutyl cyclobutyl cyclobutyl cyclobutyl cyclobutyl cyclobutyl cyclobutyl cyclobutylmethyl cyclobutylmethyl cyclobutylmethyl cyclobutylmethyl cyclobutylmethyl cyclobutylmethyl cyclobutylmethyl cyclobutylmethyl cyclobutylmethyl cyclobutylmethyl eyelobutylmeth 1 cyclobutylmethyl cyclobutylmethyl cyclobutylmethyl cyclobutylmethyl cyclobutylmethyl eyelobutylmethyl cyclobutylmethyl cyclobutylmethyl cyclobutylmethyl cyclobutylmethyl eyelobutylmeth 1 cyclobutylmethyl cyclobutylmethyl cyclobutylmethyl

Ta l 3

620 3-methylbutyl cyclobutylmethyl 621 cyclopropylmethyl cyclobutylmethyl 622 cyclobutylmethyl cyclobutylmethyl 623 cyclopentylmethyl cyclobutylmethyl 624 p-hydroxyphenylmethyl cyclobutylmethyl 625 p-nitrophenylmethyl cyclobutylmethyl 626 p-aminophenylmethyl cyclobutylmethyl 627 "4-(N,N- cyclobutylmethyl dimethylamino)phenylmethyl"

628 benzyl cyclopentyl 629 1-pyrolylmethyl cyclopentyl 630 1-pyrazolylmethyl cyclopentyl 631 1-imidazolylmethyl cyclopentyl 632 1-indolylmethyl cyclopentyl 633 1-triazolylmethyl cyclopentyl 634 1-tetrazolylmethyl cyclopentyl 635 2-pyridylmethyl cyclopentyl 636 3-pyridylmethyl cyclopentyl 637 4-pyridylmethyl cyclopentyl 638 cyclohexylmethyl cyclopentyl 639 2-naphthylmethy1 cyclopentyl 640 3-naphthylmethyl cyclopentyl 641 2-thiophenylmethyl cyclopentyl 642 4-(1-methyl)piperidinyl- cyclopentyl ethyl

643 "(3,4- cyclopentyl methylenedioxypheny1)methyl"

644 2-thienylmethyl cyclopentyl 645 4-biphenylmethyl cyclopentyl 646 pyrimidinylmethyl cyclopentyl 647 2-benzothiazolylmethyl cyclopentyl 648 2-benzothiophenylmethyl cyclopentyl 649 2-thiomethylethyl cyclopentyl 650 2-thiomethylmethyl cyclopentyl 651 2-methylpropyl cyclopentyl 652 2-methylbutyl cyclopentyl 653 3-methylbutyl cyclopentyl 654 cyclopropylmethyl cyclopentyl 655 cyclobutylmethyl cyclopentyl 656 cyclopentylmethyl cyclopentyl 657 p-hydroxyphenylmethyl cyclopentyl 658 p-nitrophenylmethyl cyclopentyl 659 p-aminophenylmethyl cyclopentyl 660 "4-(N,N- cyclopentyl dimethylamino)phenylmethyl"

661 benzyl cyclopentylmethyl 662 1-pyrolylmethyl cyclopentylmethyl 663 1-pyrazolylmethyl cyclopentylmethyl 664 1-imidazolylmethyl cyclopentylmethyl 665 1-indolylmethyl cyclopentylmethyl 666 1-triazolylmethyl cyclopentylmethyl 667 1-tetrazolylmethyl cyclopentylmethyl 668 2-pyridylmethyl cyclopentylmethyl 669 3-pyridylmethyl cyclopentylmethyl

Table 3 cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl eyelopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl eyelopentylmethyl cyclopentylmethyl cyclopentylmethyl eyelopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl

1-hexyl 1-hexyl 1-hexyl 1-hexyl 1-hexyl 1-hexyl 1-hexyl 1-hexyl 1-hexyl 1-hexyl 1-hexyl 1-hexyl 1-hexyl 1-hexyl 1-hexyl

1-hexyl

1-hexyl 1-hexyl 1-hexyl 1-hexyl 1-hexyl 1-hexyl 1-hexyl 1-hexyl 1-hexyl

Table 3

Table 3

917 3-methylbutyl 3-phenylρropyl 918 cyclopropylmethyl 3-phenylpropyl 919 cyclobutylmethyl 3-phenylpropyl 920 cyclopentylmethyl 3-phenylpropyl 921 p-hydroxyphenylmethyl 3-phenylρropyl 922 p-nitrophenylmethyl 3-phenylprop l 923 p-aminophenylmethyl 3-phenylρropyl 924 "4-(N,N- 3-phenylpropyl dimethylamino)phenylmethyl"

925 926 927 928 929 930 931 932 933 934 935 936 937 938 939

940

941 942 943 944 945 946 947 948 949 950 951 952 953 954 955 956 957

958 959 960 961 962 963 964 965 966

3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl

3-oxetanylmethyl

3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl

2- etrahydrofuranyl 2-tetrahydrofuranyl 2-tetrahydrofuranyl 2-tetrahydrofuranyl 2-tetrahydrofuranyl 2-tetrahydrofuranyl 2-tetrahydrofuranyl 2-tetrahydrofuranyl 2-tetrahydrofuranyl 2-tetrahydrofuranyl 2-tetrahydrofuranyl 2-tetrahydrofuranyl 2-te rahydrofurany1 2-tetrahydrofuranyl 2-tetrahydrofuranyl

2-tetrahydrofuranyl

2-tetrahydrofuranyl 2-tetrahydrofuranyl 2-tetrahydrofuranyl 2-tetrahydrofuranyl 2-tetrahydrofuranyl 2-tetrahydrofurany1 2-tetrahydrofuranyl 2-tetrahydrofuranyl 2-tetrahydrofuranyl

Table 3

1016 3-methylbutyl 2-tetrahydrofuranyl

1017 cyclopropylmethyl 2-tetrahydrofuranyl

1018 cyclobutylmethyl 2-tetrahydrofuranyl

1019 cyclopentylmethyl 2-tetrahydrofuranyl

1020 p-hydroxyphenylmethyl 2-tetrahydrofuranyl

1021 p-nitrophenylmethyl 2-tetrahydrofuranyl

1022 p-aminophenylmethyl 2-tetrahydrofuranyl

1023 "4- (N,N- 2-tetrahydrofuranyl dimethylamino) phenylmethyl"

1024 benzyl 2-methoxypropyl

1025 1-pyrolylmethyl 2-methoxypropyl 1026 1-pyrazolylmethyl 2-methoxypropyl

1027 1-imidazolylmethyl 2-methoxypropyl

1028 1-indolylmethyl 2-methoxypropyl

1029 1-triazolylmethyl 2-methoxypropyl

1030 1-tetrazolylmethyl 2-methoxypropyl

1031 2-pyridylmethyl 2-methoxyproρyl

1032 3-pyridylmethyl 2-methoxyρropyl

1033 4-pyridylmethyl 2-methoxypropyl

1034 cyclohexylmethyl 2-methoxypropyl

1035 2-naphthylmethyl 2-methoxypropyl

1036 3-naphthylmethyl 2-methoxypropyl

1037 2-thiophenylmethyl 2-methoxypropyl

1038 4- (1-methyl ) piperidinyl- 2-methoxypropyl methyl

1039 " (3, 4- 2-methoxypropyl methylenedioxyphenyl) methyl"

1040 2-thienylmethyl 2-methoxypropyl

1041 4-biphenylmethyl 2-methoxypropyl

1042 pyrimidinylmethyl 2-methoxypropyl

1043 2-benzothiazolylmethyl 2-methoxypropyl

1044 2-benzothiophenylmethyl 2-methoxypropyl

1045 2-thiomethylethyl 2-methoxypropyl 1046 2-thiomethylmethyl 2-methoxypropyl

1047 2-methylpropyl 2-methoxypropyl

1048 2-methylbutyl 2-methoxypropyl

10 9 3-methylbutyl 2-methoxypropyl

1050 cyclopropylmethyl 2-methoxypropyl

1051 cyclobutylmethyl 2-methoxyproρyl

1052 cyclopentylmethyl 2-methoxypropyl

1053 p-hydroxyphenylmethyl 2-methoxypropyl

1054 p-nitrophenylmethyl 2-methoxypropyl

1055 p-aminophenylmethyl 2-methoxypropyl

1056 "4- (N,N- 2-methoxypropyl dimethylamino) phenylmethyl"

1057 benzyl 2-ethoxyethyl

1058 1-pyrolylmethyl 2-ethoxyethyl

1059 1-pyrazolylmethyl 2-ethoxyethyl

1060 1-imidazolylmethyl 2-ethoxyethyl

1061 1-indolylmethyl 2-ethoxyethyl

1062 1-triazolylmethyl 2-ethoxyethyl

1063 1-tetrazolylmethyl 2-ethoxyethyl

1064 2-pyridylmethyl 2-ethoxyethyl

1065 3-pyridylmethyl 2-ethoxyethyl

2-ρyridylmethyl 2-pyridylmet yl 2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl

2-pyridylmethyl

2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl 2-py idylmethyl 2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl

2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2- hiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl

2-thiomethylethyl

2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl

Table 3

1214 3-methylbutyl 2-thiomethylethyl

1215 cyclopropylmethyl 2-thiomethylethyl

1216 cyclobutylmethyl 2-thiomethylethyl

1217 cyclopentylmethyl 2-thiomethylethyl

1218 p-hydroxyphenylmethyl 2-thiomethylethyl

1219 p-nitrophenylmethyl 2-thiomethylethyl

1220 p-aminophenylmethyl 2-thiomethylethyl

1221 "4- (N, N- 2-thiomethylethyl dimethylamino) phenylmethyl"

Table 4

TABLE 4

,22

= R ⁷ ;

Table 4

1302

1303

1304 1305 1306 1307 1308 1309 1310 1311 1312 1313 1314 1315 1316 1317 1318 1319 1320

1321 1322 1323 1324 1325 1326 1327 1328 1329 1330 1331 1332 1333 1334 1335

1336

1337 1338 1339 1340 1341 1342 1343 1344 1345 1346 1347 1348 1349 1350 1351 1352

Table 4

Table 4

1509 2-methylpropyl 2-propyl

1510 2-methylbutyl 2-propyl

1511 3-methylbutyl 2-propyl

1512 cyclopropylmethyl 2-propyl

1513 cyclobutylmethyl 2-propyl

1514 cyclopentylmethyl 2-propyl

1515 p-hydroxyphenylmethyl 2-propyl

1516 p-nitrophenylmethyl 2-proρyl

1517 p-aminophenylmethyl 2-propyl

1518 "4-(N,N- 2-propyl dimethylamino)phenylmethyl"

1519 benzyl cyclopropyl

1520 1-pyrolylmethyl cyclopropyl

1521 1-pyrazolylmethyl cyclopropyl

1522 1-imidazolylmethyl cyclopropyl

1523 1-indolylmethyl cyclopropyl

1524 1-triazolylmethyl cyclopropyl

1525 1-tetrazolylmethyl cyclopropyl

1526 2-pyridylmethyl cyclopropyl

1527 3-pyridylmethyl cyclopropyl

1528 4-pyridylmethyl cyclopropyl

1529 cyclohexylmethyl cyclopropyl

1530 2-naphthylmethyl cyclopropyl

1531 3-naphthylmethyl cyclopropyl

1532 2-thiophenylmethyl cyclopropyl

1533 4-(1-methyl) iperidinyl- cyclopropyl methyl

1534 "(3,4- cyclopropyl methylenedioxyphenyl)methyl"

1535 2-thienylmethyl cyclopropyl

1536 4-biphenylmethyl cyclopropyl

1537 pyrimidinylmethyl cyclopropyl

1538 2-benzothiazolylmethyl cyclopropyl

1539 2-benzothiophenylmethyl cyclopropyl

1540 2-thiomethylethyl cyclopropyl

1541 2-thiomethylmethyl cyclopropyl

1542 2-methylpropyl cyclopropyl

1543 2-methylbutyl cyclopropyl

1544 3-methylbutyl cyclopropyl

1545 cyclopropylmethyl cyclopropyl

1546 cyclobutylmethyl cyclopropyl

1547 cyclopentylmethyl cyclopropyl

1548 p-hydroxyphenylmethyl cyclopropyl

1549 p-nitrophenylmethyl cyclopropyl

1550 p-aminophenylmethyl cyclopropyl

1551 "4-(N,N- cyclopropyl dimethylainino)phenylmethyl"

1552 benzyl cyclopropylmethyl

1553 1-pyrolylmethyl cyclopropylmethyl

1554 1-pyrazolylmethyl eyelopropylmethy1

1555 1-imidazolylmethyl cyclopropylmethyl

1556 1-indolylmethyl cyclopropylmethyl

1557 1-triazolylmethyl cyclopropylmethyl

1558 1-tetrazolylmethyl cyclopropylmethyl

1559 2-pyridylmethyl cyclopropylmethyl

1560 3-pyridylmethyl cyclopropylmethyl

1561 4-pyridylmethyl eyelopropyImethyl

Table 4

1562 cyclohexylmethyl cyclopropylmethyl

1563 2-naphthylmethyl cyclopropylmethyl

1564 3-naphthylmethyl cyclopropylmethyl

1565 2-thiophenylmethyl cyclopropylmethyl

1566 4-(1-methyl)piperidinyl- cyclopropylmethyl methyl

1567 "(3,4- cyclopropylmethyl methylenedioxyphenyl)methyl"

1568 2-thienylmethyl cyclopropylmethyl

1569 4-biphenylmethyl cyclopropylmethyl

1570 pyrimidinylmethyl cyclopropylmethyl

1571 2-benzothiazolylmethyl cyclopropylmethyl

1572 2-benzothiophenylmethyl cyclopropylmethyl

1573 2-thiomethylethyl cyclopropylmethyl

1574 2-thiomethylmethyl cyclopropylmethyl

1575 2-methylpropyl cyclopropylmethyl

1576 2-methylbutyl cyclopropylmethyl

1577 3-methylbutyl cyclopropylmethyl

1578 cyclopropylmethyl cyclopropylmethyl

1579 cyclobutylmethyl cyclopropylmethyl

1580 cyclopentylmethyl eye1opropylmethyl

1581 p-hydroxyphenylmethyl cyclopropylmethyl

1582 p-nitrophenylmethyl cyclopropylmethyl

1583 p-aminophenylmethyl cyclopropylmethyl

1584 "4-(N,N- cyclopropylmethyl dimethylamino)phenylmethyl"

1585 benzyl n-pentyl

1586 1-pyrolylmethyl n-pentyl

1587 1-pyrazolylmethyl n-pentyl

1588 1-imidazolylmethyl n-pentyl

1589 1-indolylmethyl n-pentyl

1590 1-triazolylmethyl n-pentyl

1591 1-tetrazolylmethyl n-pentyl

1592 2-pyridylmethyl n-pentyl

1593 3-pyridylmethyl n-pentyl

1594 4-pyridylmethyl n-pentyl

1595 cyclohexylmethyl n-pentyl

1596 2-naphthylmethyl n-pentyl

1597 3-naphthylmethyl n-pentyl

1598 2-thiophenylmethyl n-pentyl

1599 4-(1-methyl)piperidinyl- n-pentyl methyl

1600 "(3,4- n-pentyl methylenedioxyphenyl)methyl"

1601 2-thienylmethyl n-pentyl

1602 4-biphenylmethyl n-pentyl

1603 pyrimidinylmethyl n-pentyl

1604 2-benzothiazolylmethyl n-pentyl

1605 2-benzothiophenylmethyl n-pentyl

1606 2-thiomethylethyl n-pentyl

1607 2-thiomethylmethyl n-pentyl

1608 2-methylpropyl n-pentyl

1609 2-methylbutyl n-pentyl

1610 3-methylbutyl n-pentyl

1611 cyclopropylmethyl n-pentyl

1612 cyclobutylmethyl n-pentyl

1613 cyclopentylmethyl n-pentyl

methyl

Table 4

1770 2-benzothiophenylmethyl propargyl

1771 2-thiomethylethyl propargyl

1772 2-thiomethylmethyl propargyl

1773 2-methylpropyl propargyl

1774 2-methylbutyl propargyl

1775 3-methylbutyl propargyl

1776 cyclopropylmethyl propargyl

1777 cyclobutylmethyl propargyl

1778 cyclopentylmethyl propargyl

1779 p-hydroxyphenylmethyl propargyl

1780 p-nitrophenylmethyl propargyl

1781 p-aminophenylmethyl propargyl

1782 "4- (N, N- propargyl dimethylamino) phenylmethyl"

1783 benzyl cyclobutyl

1784 1-pyrolylmethyl cyclobutyl

1785 1-pyrazolylmethyl cyclobutyl

1786 1-imidazolylmethyl cyclobutyl

1787 1-indolylmethyl cyclobutyl

1788 1-triazolylmethyl cyclobutyl

1789 1-tetrazolylmethyl cyclobutyl

1790 2-pyridylmethyl cyclobutyl

1791 3-pyridylmethyl cyclobutyl

1792 4-pyridylmethyl cyclobutyl

1793 cyclohexylmethyl cyclobutyl

179 2-naphthylmethy1 cyclobutyl

1795 3-naphthylmethyl cyclobutyl

1796 2-thiophenylmethy1 cyclobutyl

1797 4-(1-methyl)piperidinyl- cyclobutyl methyl

1798 "(3,4- cyclobutyl methylenedioxyphenyl)methyl"

1799 2-thienylmethyl cyclobutyl

1800 4-biphenylmethyl cyclobutyl

1801 pyrimidinylmethyl cyclobutyl

1802 2-benzothiazolylmethyl cyclobutyl

1803 2-benzothiophenylmethyl cyclobutyl

1804 2-thiomethylethyl cyclobutyl

1805 2-thiomethylmethyl cyclobutyl

1806 2-methylpropyl cyclobutyl

1807 2-methylbutyl cyclobutyl

1808 3-methylbutyl cyclobutyl

1809 cyclopropylmethyl cyclobutyl

1810 cyclobutylmethyl cyclobutyl

1811 cyclopentylmethyl cyclobutyl

1812 p-hydroxyphenylmethyl cyclobutyl

1813 p-nitrophenylmethyl cyclobutyl

1814 p-aminophenylmethyl cyclobutyl

1815 "4-(N,N- cyclobutyl dimethylamino)phenylmethyl"

1816 benzyl cyclobutylmethyl

1817 1-pyrolylmethyl cyclobutylmethyl

1818 1-pyrazolylmethyl cyclobutylmethyl

1819 1-imidazolylmethyl cyclobutylmethyl

1820 1-indolylmethyl cyclobutylmethyl

1821 1-triazolylmethyl cyclobutylmethyl

1822 1-tetrazolylmethyl cyclobutylmethyl

/07128

Table 4

1823 2-ρyridylmethyl cyclobutylmethyl

1824 3-pyridylmethyl cyclobutylmethyl

1825 4-pyridylmethyl cyclobutylmethyl

1826 cyclohexylmethyl cyclobutylmethyl

1827 2-naphthylmethyl cyclobutylmethyl

1828 3-naphthylmethyl cyclobutylmethyl

1829 2-thioρhenylmethyl cyclobutylmethyl

1830 4-(1-methyl)piperidinyl- cyclobutylmethyl methyl cyclobutylmethyl

1831 "(3,4- methylenedioxyphenyl)methyl"

1832 2-thienylmethyl cyclobutylmethyl

1833 4-biphenylmethyl cyclobutylmethyl

1834 pyrimidinylmethyl cyclobutylmethyl

1835 2-benzothiazolylmethyl cyclobutylmethyl

1836 2-benzothiophenylmethyl cyclobutylmethyl

1837 2-thiomethylethyl cyclobutylmethyl

1838 2-thiomethylmethyl cyclobutylmethyl

1839 2-methylpropyl cyclobutylmethyl

1840 2-methylbutyl cyclobutylmethyl

1841 3-methylbutyl cyclobutylmethyl

1842 cyclopropylmethyl cyclobutylmethyl

1843 cyclobutylmethyl cyclobutylmethyl

1844 cyclopentylmethyl cyclobutylmethyl

1845 p-hydroxyphenylmethyl cyclobutylmethyl

1846 p-nitrophenylmethyl cyclobutylmethyl

1847 p-aminophenylmethyl eyelobutylmethyl

1848 "4-(N,N- cyclobutylmethyl dimethylamino)phenylmethyl"

1849 benzyl cyclopentyl

1850 1-pyrolylmethyl cyclopentyl

1851 1-pyrazolylmethyl cyclopentyl

1852 1-imidazolylmethyl cyclopentyl

1853 1-indolylmethyl cyclopentyl

1854 1-triazolylmethyl cyclopentyl

1855 1-tetrazolylmethyl cyclopentyl

1856 2-pyridylmethyl cyclopentyl

1857 3-pyridylmethyl cyclopentyl

1858 4-pyridylmethyl cyclopentyl

1859 cyclohexylmethyl cyclopentyl

1860 2-naphthylmethyl cyclopentyl

1861 3-naphthylmethyl cyclopentyl

1862 2-thiophenylmethyl cyclopentyl

1863 4-(1-methyl)piperidinyl- cyclopentyl methyl

1864 "(3,4- cyclopentyl methylenedioxyphenyl)methyl"

1865 2-thienylmethyl cyclopentyl

1866 4-biphenylmethyl cyclopentyl 1867 pyrimidinylmethyl cyclopentyl

1868 2-benzothiazolylmethyl cyclopentyl

1869 2-benzothiophenylmethyl cyclopentyl

1870 2-thiomethylethyl cyclopentyl

1871 2-thiomethylmethyl cyclopentyl

1872 2-methylpropyl cyclopentyl

1873 2-methylbutyl cyclopentyl

1874 3-methylbutyl cyclopentyl

cyclopentyl cyclopentyl cyclopentyl cyclopentyl cyclopentyl cyclopentyl cyclopentyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl eyelopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl cyclopentylmethyl

1-hexyl 1-hexyl 1-hexyl 1-hexyl 1-hexyl 1-hexyl 1-hexyl 1-hexyl 1-hexyl 1-hexyl 1-hexyl 1-hexyl 1-hexyl

Table 4

3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl

3-oxetanylmethyl

3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl 3-oxetanylmethyl

2-tetrahydrofuranyl 2-tetrahydrofuranyl 2-tetrahydrofuranyl 2-tetrahydrofurany1 2-tetrahydrofurany1 2-tetrahydrofuranyl 2-tetrahydrofuranyl 2-tetrahydrofuranyl 2-tetrahydrofuranyl 2-tetrahydrofurany1 2-tetrahydrofuranyl 2-tetrahydrofuranyl 2-tetrahydrofuranyl 2-tetrahydrofuranyl 2-tetrahydrofuranyl

2-tetrahydrofuranyl

2-tetrahydrofuranyl 2-tetrahydrofuranyl 2-tetrahydrofuranyl 2-tetrahydrofuranyl 2-tetrahydrofuranyl 2-tetrahydrofuranyl 2-tetrahydrofuranyl 2-tetrahydrofuranyl 2-tetrahydrofuranyl 2-tetrahydrofuranyl 2-tetrahydrofuranyl 2-tetrahydrofuranyl 2-tetrahydrofuranyl

Table 4

2-tetrahydrofuranyl 2-tetrahydrofuranyl 2-tetrahydrofuranyl 2-tetrahydrofuranyl

2-methoxypropyl 2-methoxypropyl 2-methoxypropyl 2-methoxypropyl 2-methoxypropyl 2-methoxypropyl 2-methoxypropyl 2-methoxypropyl 2-methoxypropyl 2-methoxyρropyl 2-methoxypropyl 2-methoxypropyl 2-methoxypropyl 2-methoxypropyl 2-methoxypropyl

2-methoxypropyl

2-methoxypropyl 2-methoxypropyl 2-methoxypropyl 2-methoxypropyl 2-methoxypropyl 2-methoxypropyl 2-methoxypropyl 2-methoxyproρyl 2-methoxypropyl 2-methoxypropyl 2-methoxypropyl 2-methoxypropyl 2-methoxyρropyl 2-methoxypropyl 2-methoxypropyl 2-methoxypropyl 2-methoxypropyl

2-ethoxyethyl 2-ethoxyethyl 2-ethoxyethy1 2-ethoxyethyl 2-ethoxyethyl 2-ethoxyethyl 2-ethoxyethyl 2-ethoxyethyl 2-ethoxyethyl 2-ethoxyethyl 2-ethoxyethyl 2-ethoxyethyl 2-ethoxyethyl 2-ethoxyethyl 2-ethoxyethyl

2-(1-imidazolyl)ethyl 2-(1-imidazolyl)ethyl 2-(1-imidazolyl)ethyl 2-(1-imidazolyl)ethyl 2-(1-imidazolyl)ethyl 2-(1-imidazolyl)ethyl 2-(1-imidazolyl)ethyl 2-(1-imidazolyl)ethyl 2-(1-imidazolyl)ethyl 2-(1-imidazolyl)ethyl 2-(1-imidazolyl)ethyl 2-(1-imidazolyl)ethyl 2-(1-imidazolyl)ethyl 2-(1-imidazolyl)ethyl

2-(1-imidazolyl)ethyl

2-(1-imidazolyl)ethyl 2-(1-imidazolyl)ethyl 2-(1-imidazolyl)ethyl 2-(1-imidazolyl)ethyl 2-(1-imidazolyl)ethyl 2-(1-imidazolyl)ethyl 2-(1-imidazolyl)ethyl 2-(1-imidazolyl)ethyl 2-(1-imidazolyl)ethyl 2-(1-imidazolyl)ethyl 2-(1-imidazolyl)ethyl 2-(1-imidazolyl)ethyl 2-(1-imidazolyl)ethyl 2-(1-imidazolyl)ethyl 2-(1-imidazolyl)ethyl 2-(1-imidazolyl)ethyl 2-(1-imidazolyl)ethyl

2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl

2-pyridylmethyl

2-pyridylmethyl 2-pyridylmethyl 2-ρyridylmethyl 2-pyridylmethyl

Table 4

2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl 2-pyridylmethyl

2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl

2-thiomethylethyl

2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl 2-thiomethylethyl

Table 5

TABLE 5

.23

R ²² =

Example Ei S R22 = R23

Number

2443 benzyl "4-(N,N- allyl dimethylamino) henyl¬ methyl"

Tabl e 5

2464 2-thiomethylethyl 2-benzothiophenyl- allyl methyl

2465 2-thiomethylmethyl 2-thiomethylethyl allyl

2466 2-methylpropyl 2-thiomethylmethyl allyl

2467 2-methylbutyl 2-methylpropyl allyl

2468 3-methylbutyl 2-methylbutyl allyl

2469 cyclopropylmethyl 3-methylbutyl allyl

2470 cyclobutylmethyl cyclopropylmethyl allyl

2471 cyclopentylmethyl cyclobutylmethyl allyl

2472 p-hydroxyphenyl-methyl cyclopentylmethyl allyl

2473 p-nitrophenylmethyl p-hydroxyphenyl-methyl allyl

2474 p-aminopheny1-methyl p-nitrophenylmethyl allyl

2475 "4-(N,N-dimethylam¬ p-aminophenyl-methyl allyl ino)phenylmethyl"

2476 benzyl "4-(N,N-dimethyl- propyl amino)-pheny1-methyl"

2477 1-pyrolylmethyl benzyl propyl

2478 1-pyrazolylmethyl 1-pyrolylmethyl propyl

2479 1-imidazolylmethyl 1-pyrazolylmethyl propyl

2480 1-indolylmethyl 1-imidazolylmethyl propyl

2481 1-triazolylmethyl 1-indolylmethyl propyl

2482 1-tetrazolylmethyl 1-triazolylmethyl propyl

2483 2-pyridylmethyl 1-tetrazolylmethyl propyl

2484 3-pyridylmethyl 2-pyridylmethyl propyl

2485 4-pyridylmethyl 3-pyridylmethyl propyl

2486 cyclohexylmethyl 4-pyridylmethyl propyl

2487 2-naphthylmethyl cyclohexylmethyl propyl

2488 3-naphthylmethyl 2-naphthylmethyl propyl

2489 2-thiophenylmethyl 3-naphthylmethyl propyl

2490 4-(1-methyl)- 2-thiophenylmethyl propyl piperidinyl-methyl

2491 "(3,4-methylene- 4-(1-methyl)- propyl dioxyphenyl)methyl" piperidinyl-methyl

2492 2-thienylmethyl " (3,4-methylene- propyl dioxyphenyl)methyl"

Table 5

1-pyrazolylmethyl n-butyl

1-imidazolylmethyl n-butyl

1-indolylmethyl n-butyl

1-triazolylmethyl n-butyl

1-tetrazolylmethyl n-butyl

2-pyridylmethyl n-butyl

3-pyridylmethyl n-butyl

4-pyridylmethyl n-butyl cyclohexylmethyl n-butyl

2-naphthylmethyl n-butyl

3-naphthylmethyl n-butyl

2-thiophenylmethyl n-butyl

4-(1-methyl)- n-butyl piperidinyl-methyl

" (3,4-methylene- n-butyl dioxyphenyl) ethyl"

piperidinyl-methyl 2557 "(3,4- methylenedioxyphenyl)m ethyl"

Table 5

2558 2-thienylmethyl " (3,4-methylene- isobutyl dioxyphenyl)methyl"

2559 4-biρhenylmethyl 2-thienylmethyl isobutyl 2560 pyrimidinylmethyl 4-biphenylmethyl isobutyl 2561 2-benzothiazolylmethyl pyrimidinylmethyl isobutyl 2562 2- 2-benzothiazolylmethyl isobutyl benzothiophenylmethyl

2563 2-thiomethylethyl 2- isobutyl benzothiophenylmethyl

2564 2-thiomethylmethyl 2-thiomethylethyl isobutyl 2565 2-methylpropyl 2-thiomethylmethyl isobutyl 2566 2-methylbutyl 2-methylpropyl isobutyl 2567 3-methylbutyl 2-methylbutyl isobutyl 2568 cyclopropylmethyl 3-methylbutyl isobutyl 2569 cyclobutylmethyl cyclopropylmethyl isobutyl 2570 cyclopentylmethyl cyclobutylmethyl isobutyl 2571 p-hydroxyphenyl-methyl cyclopentylmethyl isobutyl 2572 p-nitrophenylmethyl p-hydroxyphenyl-methyl isobutyl 2573 p-aminophenyl-methyl p-nitrophenylmethyl isobutyl 2574 "4-(N,N-dimethyl¬ p-aminophenyl-methyl isobutyl amino)-phenylmethyl"

2575 benzyl "4-(N,N-dimethyl- 2-butyl amino)-phenylmethyl"

2576 1-pyrolylmethyl benzyl 2-butyl 2577 1-pyrazolylmethyl 1-pyrolylmethyl 2-butyl 2578 1-imidazolylmethyl 1-pyrazolylmethyl 2-butyl 2579 1-indolylmethyl 1-imidazolylmethyl 2-butyl 2580 1-triazolylmethyl 1-indolylmethyl 2-butyl 2581 1-tetrazolylmethyl 1-triazolylmethyl 2-butyl 2582 2-pyridylmethyl 1-tetrazolylmethyl 2-butyl 2583 3-pyridylmethyl 2-pyridylmethyl 2-butyl 2584 4-pyridylmethyl 3-pyridylmethyl 2-butyl 2585 cyclohexylmethyl 4-pyridylmethyl 2-butyl 2586 2-naphthylmethyl cyclohexylmethyl 2-butyl 2587 3-naphthylmethyl 2-naphthylmethyl 2-butyl 2588 2-thiophenylmethyl 3-naphthylmethyl 2-butyl 2589 4-(1-methyl)- 2-thiophenylmethyl 2-butyl piperidinyl-methyl

2590 " (3,4-methylene¬ 4-(1-methyl)- 2-butyl dioxyphenyl)methyl" piperidinyl-methyl

2591 2-thienylmethyl "(3,4-methylene- 2-butyl dioxyphenyl)methyl"

Table 5

2634 cyclopropylmethyl 3-methylbutyl "3,3- dimethallyl" 2635 cyclobutylmethyl cyclopropylmethyl "3,3- dimethallyl" 2636 cyclopentylmethyl cyclobutylmethyl "3,3- dimethallyl" 2637 p-hydroxyphenyl-methyl cyclopentylmethyl "3,3- dimethallyl" 2638 p-nitrophenylmethyl p-hydroxyphenyl-methyl "3,3- dimethallyl" 2639 p-aminophenyl-methyl p-nitrophenylmethyl "3,3- dimethallyl" 2640 "4-(N,N- p-aminophenyl-methyl "3,3- dimethylamino)phenyl e dimethallyl" thyl"

2641 benzyl "4-(N,N- 3-methallyl dimethylamino)-phenyl¬ methyl"

2642 1-pyrolylmethyl benzyl 3-methallyl 2643 1-pyrazolylmethyl 1-pyrolylmethyl 3-methallyl 2644 1-imidazolylmethyl 1-pyrazolylmethyl 3-methallyl 2645 1-indolylmethyl 1-imidazolylmethyl 3-methallyl 2646 1-triazolylmethyl 1-indolylmethyl 3-methallyl 2647 1-tetrazolylmethyl 1-triazolylmethyl 3-methallyl 2648 2-pyridylmethyl 1-tetrazolylmethyl 3-methallyl 2649 3-pyridylmethyl 2-pyridylmethyl 3-methallyl 2650 4-pyridylmethyl 3-pyridylmethyl 3-methallyl 2651 cyclohexylmethyl 4-pyridylmethyl 3-methallyl 2652 2-naphthylmethyl cyclohexylmethyl 3-methallyl 2653 3-naphthylmethy1 2-naphthylmethyl 3-methallyl 2654 2-thiophenylmethyl 3-naphthylmethyl 3-methallyl 2655 4-(1-methyl)- 2-thiophenylmethyl 3-methallyl piperidinyl-methyl

2656 "(3,4- 4-(l- 3-methallyl methylenedioxypheny1)m methyl)piperidinyl- ethyl" methyl

2657 2-thienylmethyl " (3,4-methylene¬ 3-methallyl dioxyphenyl)methyl"

2658 4-biphenylmethyl 2-thienylmethyl 3-methallyl 2659 pyrimidinylmethyl 4-biphenylmethyl 3-methallyl 2660 2-benzothiazolylmethyl pyrimidinylmethyl 3-methallyl 2661 2- 2-benzothiazolylmethyl 3-methallyl benzothiophenylmethyl

2662 2-thiomethylethyl 2- 3-methallyl benzothiophenylmethyl

2663 2-thiomethylmethyl 2-thiomethylethyl 3-methallyl 2664 2-methylpropyl 2-thiomethylmethyl 3-methallyl 2665 2-methylbutyl 2-methylpropyl 3-methallyl 2666 3-methylbutyl 2-methylbutyl 3-methallyl 2667 cyclopropylmethyl 3-methylbutyl 3-methallyl 2668 cyclobutylmethyl cyclopropylmethyl 3-methallyl 2669 cyclopentylmethyl cyclobutylmethyl 3-methallyl 2670 p-hydroxyphenyl-methyl cyclopentylmethyl 3-methallyl 2671 p-nitrophenylmethyl p-hydroxyphenyl-methyl 3-methallyl 2672 p-aminophenyl-methyl p-nitrophenylmethyl 3-methallyl 2673 "4-(N,N-dimethyl¬ p-aminophenyl-methyl 3-methallyl amino)-phenyl-methyl"

Table 5

Table 5

2831 3-methylbutyl 2-methylbutyl n-pentyl

2832 cyclopropylmethyl 3-methylbutyl n-pentyl

2833 cyclobutylmethyl cyclopropylmethyl n-pentyl

2834 cyclopentylmethyl cyclobutylmethyl n-pentyl

2835 p-hydroxyphenyl-methyl cyclopentylmethyl n-pentyl

2836 p-nitrophenylmethyl p-hydroxyphenyl-methyl n-pentyl

2837 p-aminophenyl-methyl p-nitrophenylmethyl n-pentyl

2838 "4-(N,N- p-aminophenyl-methyl n-pentyl dimethylamino)phenylme thyl"

2839 benzyl "4-(N,N- 2-pentyl dimethylamino)phenylme thyl"

2840 1-pyrolylmethyl benzyl 2-pentyl

2841 1-pyrazolylmethyl 1-pyrolylmethyl 2-pentyl

2842 1-imidazolylmethyl 1-pyrazolylmethyl 2-pentyl

2843 1-indolylmethyl 1-imidazolylmethyl 2-pentyl

2844 1-triazolylmethyl 1-indolylmethyl 2-pentyl

2845 1-tetrazolylmethyl 1-triazolylmethyl 2-pentyl

2846 2-pyridylmethyl 1-tetrazolylmethyl 2-pentyl

2847 3-pyridylmethyl 2-pyridylmethyl 2-pentyl

2848 4-py idylmethyl 3-pyridylmethyl 2-pentyl

2849 cyclohexylmethyl 4-pyridylmethyl 2-pentyl

2850 2-naphthylmethyl cyclohexylmethyl 2-pentyl

2851 3-naphthylmethyl 2-naphthylmethyl 2-pentyl

2852 2-thiophenylmethyl 3-naphthylmethyl 2-pentyl

2853 4-(l- 2-thiophenylmethyl 2-pentyl methyl) iperidinyl- methyl

2854 "(3,4- 4-(l- 2-pentyl methylenedioxyphenyl)m methyl)piperidinyl- ethyl" methyl

2855 2-thienylmethyl "(3,4- 2-pentyl methylenedioxyphenyl)m ethyl"

2856 4-biphenylmethyl 2-thienylmethyl 2-pentyl

2857 pyrimidinylmethyl 4-biphenylmethyl 2-pentyl

2858 2-benzothiazolylmethyl pyrimidinylmethyl 2-ρentyl

2859 2- 2-benzothiazolylmethyl 2-pentyl benzothiophenylmethyl

2860 2-thiomethylethyl 2- 2-pentyl benzothiophenylmethyl

2861 2-thiomethylmethyl 2-thiomethylethyl 2-pentyl

2862 2-methylpropyl 2-thiomethylmethyl 2-pentyl

2863 2-methylbutyl 2-methylpropyl 2-pentyl

2864 3-methylbutyl 2-methylbutyl 2-pentyl

2865 cyclopropylmethyl 3-methylbutyl 2-pentyl

2866 cyclobutylmethyl cyclopropylmethyl 2-pentyl

2867 cyclopentylmethyl cyclobutylmethyl 2-pentyl

2868 p-hydroxyphenyl-methyl cyclopentylmethyl 2-pentyl

2869 p-nitrophenylmethyl p-hydroxyphenyl-methyl 2-pentyl

2870 p-aminophenyl-methyl p-nitrophenylmethyl 2-pentyl

2871 "4-(N,N- p-aminophenyl-methyl 2-pentyl dimethylamino)phenylme thyl"

2872 benzyl "4-(N,N- 3-pentyl dimethylamino)phenylme thyl"

Table 5

2873 1-pyrolylmethyl benzyl 3-pentyl 2874 1-pyrazolylmethyl 1-pyrolylmethyl 3-pentyl 2875 1-imidazolylmethyl 1-pyrazolylmethyl 3-pentyl 2876 1-indolylmethyl 1-imidazolylmethyl 3-pentyl 2877 1-triazolylmethyl 1-indolylmethyl 3-pentyl 2878 1-tetrazolylmethyl 1-triazolylmethyl 3-pentyl 2879 2-pyridylmethyl 1-tetrazolylmethyl 3-ρentyl 2880 3-pyridylmethyl 2-pyridylmethyl 3-pentyl 2881 4-pyridylmethyl 3-pyridylmethyl 3-pentyl 2882 cyclohexylmethyl 4-pyridylmethyl 3-pentyl 2883 2-naphthylmethyl cyclohexylmethyl 3-pentyl 2884 3-naphthylmethyl 2-naphthylmethyl 3-pentyl 2885 2-thiophenylmethyl 3-naphthylmethyl 3-pentyl 2886 4-(l- 2-thiophenylmethyl 3-pentyl methyl)piperidinyl- methyl

2887 "(3,4- 4-(l- 3-pentyl methylenedioxyphenyl)m methyl)piperidinyl- ethyl" methyl

2888 2-thienylmethyl "(3,4- 3-pentyl methylenedioxyphenyl)m ethyl"

2889 4-biphenylmethyl 2-thienylmethyl 3-pentyl 2890 pyrimidinylmethyl 4-biphenylmethyl 3-pentyl 2891 2-benzothiazolylmethyl pyrimidinylmethyl 3-pentyl 2892 2- 2-benzothiazolylmethyl 3-pentyl benzothiophenylmethyl

2893 2-thiomethylethyl 2- 3-pentyl benzothiophenylmethyl

2894 2-thiomethylmethyl 2-thiomethylethyl 3-pentyl 2895 2-methylpropyl 2-thiomethylmethyl 3-pentyl 2896 2-meth lbu yl 2-methylpropyl 3-pentyl 2897 3-methylbutyl 2-methylbutyl 3-pentyl 2898 cyclopropylmethyl 3-methylbutyl 3-pentyl 2899 cyclobutylmethyl cyclopropylmethyl ^• 3-pentyl 2900 cyclopentylmethyl cyclobutylmethyl ^" 3-pentyl 2901 p-hydroxyphenyl-methyl cyclopentylmethyl 3-pentyl 2902 p-nitrophenylmethyl p-hydroxyphenyl-methyl 3-pentyl 2903 p-aminophenyl-methyl p-nitrophenylmethyl 3-pentyl 2904 "4-(N,N- p-aminophenyl-methyl 3-pentyl dimethylamino)phenylme thyl"

2905 benzyl "4-(N,N- 3-methylbutyl dimethylamino)phenylme thyl"

2906 1-pyrolylmethyl benzyl 3-methylbutyl 2907 1-pyrazolylmethyl 1-pyrolylmethyl 3-methylbutyl 2908 1-imidazolylmethyl 1-pyrazolylmethyl 3-methylbutyl 2909 1-indolylmethyl 1-imidazolylmethyl 3-methylbutyl 2910 1-triazolylmethyl 1-indolylmethyl 3-methylbutyl 2911 1-tetrazolylmethyl 1-triazolylmethyl 3-methylbutyl 2912 2-pyridylmethyl 1-tetrazolylmethyl 3-methylbutyl 2913 3-pyridylmethyl 2-pyridylmethyl 3-methylbutyl 2914 4-pyridylmethyl 3-pyridylmethyl 3-methylbutyl 2915 cyclohexylmethyl 4-pyridylmethyl 3-methylbutyl 2916 2-naphthylmethyl cyclohexylmethyl 3-methylbutyl 2917 3-naρhthylmethyl 2-naphthylmethyl 3-methylbutyl 2918 2-thiophenylmethyl 3-naphthylmethyl 3-methylbutyl

Table 5

Table 5

2958 2- 2-benzothiazolylmethyl 2-methylbutyl benzothiophenylmethyl

2959 2-thiomethylethyl 2- 2-methylbutyl benzothiophenylmethyl

2960 2-thiomethylmethyl 2-thiomethylethyl 2-methylbutyl 2961 2-methylpropyl 2-thiomethylmethyl 2-methylbutyl 2962 2-methylbutyl 2-methylpropyl 2-methylbutyl 2963 3-methylbutyl 2-methylbutyl 2-methylbutyl 2964 cyclopropylmethyl 3-methylbutyl 2-methylbutyl 2965 cyclobutylmethyl cyclopropylmethyl 2-methylbutyl 2966 cyclopentylmethyl cyclobutylmethyl 2-methylbutyl 2967 p-hydroxyphenyl-methyl cyclopentylmethyl 2-methylbutyl 2968 p-nitrophenylmethyl p-hydroxyphenyl-methyl 2-methylbutyl 2969 p-aminophenyl-methyl p-nitrophenylmethyl 2-methylbutyl 2970 "4-(N,N- p-aminophenyl-methyl 2-methylbutyl dimethylamino)phenylme thyl"

2971 benzyl "4-(N,N- propargyl dimethylamino)phenylme thyl"

______ p-nitrophenylmethyl propargyl p-aminophenyl-methyl propargyl

"4-(N,N- cyclobutyl dimethylamino)phenylme thyl"

3005 1-pyrolylmethyl benzyl cyclobutyl

3006 1-pyrazolylmethyl 1-ρyrolylmethyl cyclobutyl

3007 1-imidazolylmethyl 1-pyrazolylmethyl cyclobutyl

3008 1-indolylmethyl 1-imidazolylmethyl cyclobutyl

3009 1-triazolylmethyl 1-indolylmethyl cyclobutyl

3010 1-tetrazolylmethyl 1-triazolylmethyl cyclobutyl

3011 2-pyridylmethyl 1-tetrazolylmethyl cyclobutyl

3012 3-pyridylmethyl 2-pyridylmethyl cyclobutyl

3013 4-ρyridylmethyl 3-pyridylmethyl cyclobutyl

301 cyclohexylmethyl 4-pyrid lmeth l cyclobutyl

3015 2-naphthylmethyl eyelohexylmethyl cyclobutyl

3016 3-naphthylmethyl 2-naphthylmethyl cyclobutyl

3017 2-thiophenylmethyl 3-naphthylmethyl cyclobutyl

3018 4-(l- 2-thiophenylmethyl cyclobutyl ethyl)piperidinyl- methyl

3019 "(3,4- 4-(l- cyclobutyl methylenedioxyphenyl) methyl)piperidinyl- ethyl" methyl

3020 2-thienylmethyl "(3,4- cyclobutyl methylenedioxyphenyl)m ethyl"

3021 4-biphenylmethyl 2-thienylmethyl cyclobutyl

3022 pyrimidinylmethyl 4-biphenylmethyl cyclobutyl

3023 2-benzothiazolylmethyl pyrimidinylmethyl cyclobutyl

3024 2- 2-benzothiazolylmethyl cyclobutyl benzothiophenylmethyl

3025 2-thiomethylethyl 2- cyclobutyl benzothiophenylmethyl

3026 2-thiomethylmethyl 2-thiomethylethyl cyclobutyl

3027 2-methylρropyl 2-thiomethylmethyl cyclobutyl

3028 2-methylbutyl 2-methylpropyl cyclobutyl

3029 3-methylbutyl 2-methylbutyl cyclobutyl

3030 cyclopropylmethyl 3-methylbutyl cyclobutyl

3031 cyclobutylmethyl cyclopropylmethyl cyclobutyl

3032 cyclopentylmethyl cyclobutylmethyl cyclobutyl

3033 p-hydroxyphenyl-methyl cyclopentylmethyl cyclobutyl

3034 p-nitrophenylmethyl p-hydroxyphenyl-methyl cyclobutyl

3035 p-aminophenyl-methyl p-nitrophenylmethyl cyclobutyl

3036 "4-(N,N- p-aminophenyl-methyl cyclobutyl dimethylamino)phenylme thyl"

3037 benzyl "4-(N,N- cyclobutylmeth dimethylamino)phenylme yi thyl"

3038 1-pyrolylmethyl benzyl cyclobutylmeth yi

3039 1-pyrazolylmethyl 1-pyrolylmethyl cyclobutylmeth yi

3040 1-imidazolylmethyl 1-pyrazolylmethyl cyclobutylmeth yi

Table 5

1-imidazolylmethyl cyclobutylmeth yi

1-indolylmethyl cyclobutylmeth yl ^■

1-triazolylmethyl cyclobutylmeth yi

1-tetrazolylmethyl cyclobutylmeth yi

2-pyridylmethyl cyclobutylmeth yi

3-pyridylmethyl cyclobutylmeth y

4-pyridylmethyl cyclobutylmeth yi cyclohexylmethyl cyclobutylmeth yi

2-naphthylmethyl cyclobutylmeth y

3-naphthylmethyl cyclobutylmeth y

2-thiophenylmethyl cyclobutylmeth yi 4-(l- cyclobutylmeth methylenedioxyphenyl)m methyl)piperidinyl- yi ethyl" methyl

3053 2-thienylmethyl "(3,4- cyclobutylmeth methylenedioxyphenyl)m yi ethyl"

3054 4-biphenylmethyl 2-thienylmethyl cyclobutylmeth yi 3055 pyrimidinylmethyl 4-biphenylmethyl cyclobutylmeth yi 3056 2-benzothiazolylmethyl pyrimidinylmethyl cyclobutylmeth yi 3057 2- 2-benzothiazolylmethyl cyclobutylmeth benzothiophenylmethyl y 3058 2-thiomethylethyl 2- cyclobutylmeth benzothiophenylmethyl yi 3059 2-thiomethylmethyl 2-thiomethylethyl cyclobutylmeth yi 3060 2-methylpropyl 2-thiomethylmethyl cyclobutylmeth yi 3061 2-methylbutyl 2-methylpropyl cyclobutylmeth yi 3062 3-methylbutyl 2-methylbutyl cyclobutylmeth y 3063 cyclopropylmethyl 3-methylbutyl cyclobutylmeth yi 3064 cyclobutylmethyl cyclopropylmethyl cyclobutylmeth yi 3065 cyclopentylmethyl cyclobutylmethyl cyclobutylmeth yi 3066 p-hydroxyphenyl-methyl cyclopentylmethyl cyclobutylmeth yi 3067 p-nitrophenylmethyl p-hydroxyphenyl-methyl cyclobutylmeth yi

Table 5

3068 p-aminophenyl-methyl p-nitrophenylmethyl cyclobutylmeth yi 3069 "4-(N,N- p-aminophenyl-methyl cyclobutylmeth dimethylamino)phenylme yi thyl"

3070 benzyl "4-(N,N- cyclopentyl dimethylamino)phenylme thyl"

3071 1-pyrolylmethyl benzyl cyclopentyl 3072 1-ρyrazolylmethyl 1-pyrolylmethyl cyclopentyl 3073 1-imidazolylmethyl 1-pyrazolylmethyl cyclopentyl 3074 1-indolylmethyl 1-imidazolylmethyl cyclopentyl 3075 1-triazolylmethyl 1-indolylmethyl cyclopentyl 3076 1-tetrazolylmethyl 1-triazolylmethyl cyclopentyl 3077 2-pyridylmethyl 1-tetrazolylmethyl cyclopentyl 3078 3-pyridylmethyl 2-pyridylmethyl cyclopentyl 3079 4-pyridylmethyl 3-pyridylmethyl cyclopentyl 3080 cyclohexylmethyl 4-pyridylmethyl cyclopentyl 3081 2-naphthylmethyl cyclohexylmethyl cyclopentyl 3082 3-naphthylmethyl 2-naphthylmethyl cyclopentyl 3083 2-thiophenylmethyl 3-naphthylmethyl cyclopentyl 3084 4-(l- 2-thiophenylmethyl cyclopentyl methyl) iperidinyl- methyl

3085 "(3,4- 4-(l- cyclopentyl methylenedioxyphenyl) methyl)piperidinyl- ethyl" methyl

3086 2-thienylmethyl "(3,4- cyclopentyl methylenedioxyphenyl)m ethyl"

3087 4-biphenylmethyl 2-thienylmethyl cyclopentyl 3088 pyrimidinylmethyl 4-biphenylmethyl cyclopentyl 3089 2-benzothiazolylmethyl pyrimidinylmethyl cyclopentyl 3090 2- 2-benzothiazolylmethyl cyclopentyl benzothiophenylmethyl

3091 2-thiomethylethyl 2- cyclopentyl benzothiophenylmethyl

3092 2-thiomethylmethyl 2-thiomethylethyl cyclopentyl 3093 2-methylpropyl 2-thiomethylmethyl cyclopentyl 3094 2-methylbutyl 2-methylpropyl cyclopentyl 3095 3-methylbutyl 2-methylbutyl cyclopentyl 3096 cyclopropylmethyl 3-methylbutyl cyclopentyl 3097 cyclobutylmethyl cyclopropylmethyl cyclopentyl 3098 cyclopentylmethyl cyclobutylmethyl cyclopentyl 3099 p-hydroxyphenyl-methyl eyelopentylmethy1 cyclopentyl 3100 p-nitrophenylmethyl p-hydroxyphenyl-methyl cyclopentyl 3101 p-aminophenyl-methyl p-nitrophenylmethyl cyclopentyl 3102 "4-(N,N- p-aminophenyl-methyl cyclopentyl dimethylamino)phenylme thyl"

3103 benzyl "4-(N,N- cyclopentylmet dimethylamino)phenylme hyl thyl"

3104 1-pyrolylmethyl benzyl cyclopentylmet hyl 3105 1-pyrazolylmethyl 1-pyrolylmethyl cyclopentylmet hyl

Table 5

1-pyrazolylmethyl cyclopentylmet hyl

1-imidazolylmethyl cyclopentylmet hyl

1-indolylmethyl cyclopentylmet hyl

1-triazolylmethyl cyclopentylmet hyl

1-tetrazolylmethyl cyclopentylmet hyl

2-ρyridylmethyl cyclopentylmet hyl

3-pyridylmethyl cyclopentylmet hyl

4-ρyridylmethyl cyclopentylmet hyl cyclohexylmethyl cyclopentylmet hyl

2-naphthylmethyl cyclopentylmet hyl

3-naphthylmethyl cyclopentylmet hyl

2-thiophenylmethyl cyclopentylmet hyl 4-(l- cyclopentylmet methylenedioxyphenyl) methyl)piperidinyl- hyl ethyl" methyl

3119 2-thienylmethyl "(3,4- cyclopentylmet methylenedioxyphenyl)m hyl ethyl"

3120 4-biphenylmethyl 2-thienylmethyl cyclopentylmet hyl 3121 pyrimidinylmethyl 4-biphenylmethyl cyclopentylmet hyl 3122 2-benzothiazolylmethyl pyrimidinylmethyl cyclopentylmet hyl 3123 2- 2-benzothiazolylmethyl cyclopentylmet benzothiophenylmethyl hyl 3124 2-thiomethylethyl 2- cyclopentylmet benzothiophenylmethyl hyl 3125 2-thiomethylmethyl 2-thiomethylethyl cyclopentylmet hyl 3126 2-methylpropyl 2-thiomethylmethyl cyclopentylmet hyl 3127 2-methylbutyl 2-methylpropyl cyclopentylmet hyl 3128 3-methylbutyl 2-methylbutyl cyclopentylmet hyl 3129 cyclopropylmethyl 3-methylbutyl cyclopentylmet hyl 3130 cyclobutylmethyl cyclopropylmethyl cyclopentylmet hyl 3131 cyclopentylmethyl cyclobutylmethyl cyclopentylmet hyl 3132 p-hydroxyphenyl-methyl cyclopentylmethyl cyclopentylmet hyl

Table 5

3133 p-nitrophenylmethyl p-hydroxyphenyl-methyl cyclopentylmet hyl 3134 p-aminophenyl-methyl p-nitrophenylmethyl cyclopentylmet hyl 3135 "4-(N,N- p-aminophenyl-methyl cyclopentylmet dimethylamino)phenylme hyl thyl"

3136 benzyl "4-(N,N- 1-hexyl dimethylamino)phenylme thyl"

Table 5

3173 1-indolylmethyl 1-imidazolylmethyl 4-methylpentyl 3174 1-triazolylmethyl 1-indolylmethyl 4-methylpentyl 3175 1-tetrazolylmethyl 1-triazolylmethyl 4-methylpentyl 3176 2-pyridylmethyl 1-tetrazolylmethyl 4-methylpentyl 3177 3-pyridylmethyl 2-pyridylmethyl 4-methylpentyl 3178 4-pyridylmethyl 3-pyridylmethyl 4-methylpentyl 3179 cyclohexylmethyl 4-pyridylmethyl 4-methylpentyl 3180 2-naphthylmethyl cyclohexylmethyl 4-methylpentyl 3181 3-naphthylmethyl 2-naphthylmethyl 4-methylpentyl 3182 2-thiophenylmethyl 3-naphthylmethyl 4-methylpentyl 3183 4-(l- 2-thiophenylmethyl 4-methylpentyl methyl)piperidinyl- methyl

3184 "(3,4- 4-(l- 4-methylpentyl methylenedioxyphenyl)m methyl)piperidinyl- ethyl" methyl

3185 2-thienylmethyl "(3,4- 4-methylpentyl methylenedioxyphenyl)m ethyl"

3186 4-biphenylmethyl 2-thienylmethyl 4-methylpentyl 3187 pyrimidinylmethyl 4-biphenylmethyl 4-methylpentyl 3188 2-benzothiazolylmethyl pyrimidinylmethyl 4-methylpentyl 3189 2- 2-benzothiazolylmethyl 4-methylpentyl benzothiophenylmethyl

3190 2-thiomethylethyl 2- 4-methylpentyl benzothiophenylmethyl

3191 2-thiomethylmethyl 2-thiomethylethyl 4-methylpentyl 3192 2-methylpropyl 2-thiomethylmethyl 4-methylpentyl 3193 2-methylbutyl 2-methylpropyl 4-methylpentyl 3194 3-methylbutyl 2-methylbutyl 4-methylpentyl 3195 cyclopropylmethyl 3-methylbutyl ' 4-methylpentyl 3196 cyclobutylmethyl cyclopropylmethyl 4-methylpentyl 3197 cyclopentylmethyl cyclobutylmethyl 4-methylpentyl 3198 p-hydroxyphenyl-methyl cyclopentylmethyl 4-methylpentyl 3199 p-nitrophenylmethyl p-hydroxyphenyl-methyl 4-methylpentyl 3200 p-aminophenyl-methyl p-nitrophenylmethyl 4-methylpentyl 3201 "4-(N,N- p-aminophenyl-methyl 4-methylpentyl dimethylamino)phenylme thyl"

3202 benzyl "4-(N,N- 3-methylpentyl dimethylamino)phenylme thyl"

3203 1-pyrolylmethyl benzyl 3-methylpentyl 3204 1-pyrazolylmethyl 1-pyrolylmethyl 3-methylpentyl 3205 1-imidazolylmethyl 1-pyrazolylmethyl 3-methylpentyl 3206 1-indolylmethyl 1-imidazolylmethyl 3-methylpentyl 3207 1-triazolylmethyl 1-indolylmethyl 3-methylpentyl 3208 1-tetrazolylmethyl 1-triazolylmethyl 3-methylpentyl 3209 2-pyridylmethyl 1-tetrazolylmethyl 3-methylpentyl 3210 3-pyridylmethyl 2-pyridylmethyl 3-methylpentyl 3211 4-pyridylmethyl 3-pyridylmethyl 3-methylpentyl 3212 cyclohexylmethyl 4-pyridylmethyl 3-methylpentyl 3213 2-naphthylmethyl cyclohexylmethyl 3-methylpentyl 3214 3-naphthylmethyl 2-naphthylmethyl 3-methylpentyl 3215 2-thiophenylmethyl 3-naphthylmethyl 3-methylpentyl 3216 4-(l- 2-thiophenylmethyl 3-methylpentyl methyl)piperidinyl- methyl

benzothiophenylmethyl

Table 5

3257 2-thiomethylmethyl 2-thiomethylethyl isopropyl 3258 2-methylpropyl 2-thiomethylmethy1 isopropyl 3259 2-methylbutyl 2-methylpropyl isopropyl 3260 3-methylbutyl 2-methylbutyl isopropyl 3261 cyclopropylmethyl 3-methylbutyl isopropyl 3262 cyclobutylmethyl cyclopropylmethyl isopropyl 3263 cyclopentylmethyl cyclobutylmethyl isopropyl 3264 p-hydroxyphenyl-methyl cyclopentylmethyl isopropyl 3265 p-nitrophenylmethyl p-hydroxyphenyl-methyl isopropyl 3266 p-aminophenyl-methyl p-nitrophenylmethyl isopropyl 3267 "4-(N,N- p-aminophenyl-methyl isopropyl dimethylamino)phenylme thyl"

3268 benzyl "4-(N,N- 3-methylbutyl dimethylamino)phenylme thyl"

3269 1-pyrolylmethyl benzyl 3-methylbutyl 3270 1-pyrazolylmethyl 1-pyrolylmethyl 3-methylbuty1 3271 1-imidazolylmethyl 1-pyrazolylmethyl 3-methylbutyl 3272 1-indolylmethyl 1-imidazolylmethyl 3-methylbutyl 3273 1-triazolylmethyl 1-indolylmethyl 3-methylbutyl 3274 1-tetrazolylmethyl 1-triazolylmethyl 3-methylbutyl 3275 2-pyridylmethyl 1-tetrazolylmethyl 3-methylbutyl 3276 3-pyridylmethyl 2-pyridylmethyl 3-methylbutyl 3277 4-pyridylmethyl 3-pyridylmethyl 3-methylbuty1 3278 cyclohexylmethyl 4-pyridylmethyl 3-methylbutyl 3279 2-naphthylmethyl cyclohexylmethyl 3-methylbutyl 3280 3-naphthylmethyl 2-naphthylmethyl 3-methylbutyl 3281 2-thiophenylmethyl 3-naphthylmethyl 3-methylbutyl 3282 4-(l- 2-thiophenylmethyl 3-methylbutyl ethyl)piperidinyl- methyl

3283 "(3,4- 4-(l- 3-methylbutyl methylenedioxyphenyl)m methyl)piperidinyl- ethyl" methyi

3284 2-thienylmethyl "(3,4- 3-methylbutyl methylenedioxyphenyl)m ethyl"

2-thienylmethyl 3-methylbutyl

4-biphenylmethyl 3-methylbutyl pyrimidinylmethyl 3-methylbutyl

2-benzothiazolylmethyl 3-methylbutyl

2- 3-methylbutyl benzothiophenylmethyl

2-thiomethylethyl 3-methylbutyl

2-thiomethylmethyl 3-methylbutyl

2-methylpropyl 3-methylbutyl

2-methylbutyl 3-methylbutyl

3-methylbutyl 3-methylbutyl cyclopropylmethyl 3-methylbutyl cyclobutylmethyl 3-methylbutyl cyclopentylmethyl 3-methylbutyl p-hydroxyphenyl-methyl 3-methylbutyl p-nitrophenylmethyl 3-methylbutyl p-aminophenyl-methyl 3-methylbutyl

Table 5

3301 benzyl "4-(N,N- 2-phenylethyl dimethylamino)phenylme thyl"

3302 1-p rolylm thyl benzyl 2-phenylethyl

3303 1-pyrazolylmethyl 1-pyrolylmethy1 2-phenylethyl

3304 1-imidazolylmethyl 1-pyrazolylmethyl 2-phenylethyl

3305 1-indolylmethyl 1-imidazolylmethyl 2-phenylethyl

3306- 1-triazolylmethyl 1-indolylmethyl 2-phenylethyl

3307 1-tetrazolylmethyl 1-triazolylmethyl 2-phenylethyl

3308 2-pyridylmethyl 1-tetrazolylmethyl 2-phenylethyl

3309 3-pyridylmethyl 2-pyridylmethyl 2-phenylethyl

3310 4-pyridylmethyl 3-pyridylmethyl 2-phenylethyl

3311 cyclohexylmethyl 4-pyridylmethyl 2-phenylethyl

3312 2-naphthylmethyl cyclohexylmethyl 2-phenylethyl

3313 3-naphthylmethyl 2-naphthylmethyl 2-phenylethyl

3314 2-thioρhenylmethyl 3-naph hylmethyl 2-phenylethyl

3315 4-(l- 2-thiophenylmethyl 2-phenylethyl methyl)piperidinyl- methyl

3316 "(3,4- 4-(l- 2-phenylethyl methylenedioxyphenyl)m methyl)piperidinyl- ethyl" methyl

3317 2-thienylmethyl "(3,4- 2-phenylethyl methylenedioxyphenyl)m ethyl"

3318 4-biphenylmethyl 2-thienylmethyl 2-phenylethyl 3319 pyrimidinylmethyl 4-biphenylmethyl 2-phenylethyl 3320 2-benzothiazolylmethyl pyrimidinylmethyl 2-phenylethyl 3321 2- 2-benzothiazolylmethyl 2-phenylethyl benzothiophenylmethyl

3322 2-thiomethylethyl 2- 2-phenylethyl benzothiophenylmethyl

3323 2-thiomethylmethyl 2-thiomethylethyl 2-phenylethyl 3324 2-methylpropyl 2-thiomethylmethyl 2-phenylethyl 3325 2-methylbutyl 2-methylpropyl 2-phenylethyl 3326 3-methylbutyl 2-methylbutyl 2-phenylethyl 3327 cyclopropylmethyl 3-methylbutyl 2-phenylethyl 3328 cyclobutylmethyl cyclopropylmethyl 2-phenylethyl 3329 cyclopentylmethyl cyclobutylmethyl 2-phenylethyl 3330 p-hydroxyphenyl-methyl cyclopentylmethyl 2-phenylethyl 3331 •p-nitrophenylmethyl p-hydroxyphenyl-methyl 2-phenylethyl 3332 p-aminophenyl-methyl p-nitrophenylmethyl 2-phenylethyl 3333 "4-(N,N- p-aminophenyl-methyl 2-ρhenylethyl dimethylamino)phenylme thyl"

3334 benzyl "4-(N,N- 3-phenylpropyl dimethylamino)phenylme thyl"

3335 1-pyrolylmethyl benzyl 3-phenylpropyl 3336 1-pyrazolylmethyl 1-p rolylmethyl 3-phenylpropyl 3337 1-imidazolylmethyl 1-pyrazolylmethyl 3-phenylpropyl 3338 1-indolylmethyl 1-imidazolylmethyl 3-phenylpropyl 3339 1-triazolylmethyl 1-indolylmethyl 3-phenylpropyl 3340 1-tetrazolylmethyl 1-triazolylmethyl 3-phenylpropyl 3341 2-pyridylmethyl 1-tetrazolylmethyl 3-phenylpropyl 3342 3-pyridylmethyl 2-pyridylmethyl 3-phenylpropyl 3343 4-pyridylmethyl 3-pyridylmethyl 3-phenylpropyl 3344 cyclohexylmethyl 4-pyridylmethyl 3-phenylpropyl

3-phenylpropyl 3-phenylpropyl 3-phenylpropyl 3-phenylpropyl

3349 "(3,4- 4-<l- 3-phenylpropyl methylenedioxyphenyl)m methyl)piperidinyl- ethyl" methyl

3350 2-thienylmethyl "(3,4- 3-phenylpropyl methylenedioxyphenyl)m ethyl"

3351 4-biphenylmethyl 2-thienylmethyl 3-phenylpropyl

3352 pyrimidinylmethyl 4-biphenylmethyl 3-phenylpropyl

3353 2-benzothiazolylmethyl pyrimidinylmethyl 3-phenylpropyl

3354 2- 2-benzothiazolylmethyl 3-phenylpropyl benzothiophenylmethyl

3355 2-thiomethylethyl 2- 3-phenylpropyl benzothiophenylmethyl

3356 2-thiomethylmethyl 2-thiomethylethyl 3-phenylpropyl

3357 2-methylpropyl 2-thiomethylmethyl 3-phenylpropyl

3358 2-methylbutyl 2-methylpropyl 3-phenylpropy1

3359 3-methylbutyl 2-methylbutyl 3-phenylpropyl

3360 cyclopropylmethyl 3-methylbutyl 3-phenylpropyl

3361 cyclobutylmethyl cyclopropylmethyl 3-phenylpropyl

3362 cyclopentylmethyl cyclobutylmethyl 3-phenylpropyl

3363 p-hydroxyphenyl-methyl cyclopentylmethyl 3-phenylpropyl

3364 p-nitrophenylmethyl p-hydroxyphenyl-methyl 3-phenylpropyl

3365 p-aminophenyl-methyl p-nitrophenylmethyl 3-phenylpropyl

3366 "4-(N,N- p-aminophenyl-methyl 3-phenylpropyl dimethylamino)phenylme thyl"

3367 benzyl "4-(N,N- "2-(N,N- dimethylamino)phenylme dimethylamino) thyl" ethyl"

3368 1-pyrolylmethyl benzyl "2-(N,N- dimethylamino) ethyl"

3369 1-pyrazolylmethyl 1-pyrolylmethyl "2-(N,N- dimethylamino) ethyl"

3370 1-imidazolylmethyl 1-pyrazolylmethyl "2-(N,N- dimethylamino) ethyl"

3371 1-indolylmethyl 1-imidazolylmethyl "2-(N,N- dimethylamino) ethyl"

3372 1-triazolylmethyl 1-indolylmethyl "2-(N,N- dimethylamino) ethyl"

3373 1-tetrazolylmethyl 1-triazolylmethyl "2-(N,N- dimethylamino) ethyl"

3374 2-pyridylmethyl 1-tetrazolylmethyl "2-(N,N- dimethylamino) ethyl"

Table 5

3375 3-pyridylmethyl 2-pyridylmethyl "2-(N,N- dimethylamino) ethyl"

3376 4-pyridylmethyl 3-pyridylmethyl "2-(N,N- dimethylamino) ethyl"

3377 cyclohexylmethyl 4-pyridylmethyl "2-(N,N- di ethylamino) ethyl"

3378 2-naphthylmethyl cyclohexylmethyl "2-(N,N- dimethylamino) ethyl"

3379 3-naphthylmethyl 2-naphthylmethyl "2-(N,N- dimethylamino) ethyl"

3380 2-thiophenylmethyl 3-naphthylme hyl "2-(N,N- dimethylamino) ethyl"

3381 4-(l- 2-thiophenylmethyl "2-(N,N- methyl)piperidinyl- dimethylamino) methyl ethyl"

3382 "(3,4- 4-(l- "2-(N,N- methylenedioxyphenyl)m methyl)piperidinyl- dimethylamino) ethyl" methyl ethyl"

3383 2-thienylmethyl "(3,4- "2-(N,N- methylenedioxyphenyl)m dimethylamino) ethyl" ethyl"

3384 4-biphenylmethyl 2-thienylmethyl "2-(N,N- dimethylamino) ethyl"

3385 pyrimidinylmethyl 4-biphenylmethyl "2-(N,N- dimethylamino) ethyl"

3386 2-benzothiazolylmethyl pyrimidinylmethyl "2-(N,N- dimethylamino) ethyl"

3387 2- 2-benzothiazolylmethyl "2-(N,N- benzothiophenylmethyl dimet ylamino) ethyl"

3388 2-thiomethylethyl 2- "2-(N,N- benzothiophenylmethyl dimethylamino) ethyl"

3389 2-thiomethylmethyl 2-thiomethylethyl "2-{N,N- dimethylamino) ethyl"

3390 2-methylpropyl 2-thiomethylmethyl "2-(N,N- dimethylamino) ethyl"

3391 2-methylbutyl 2-methylpropyl "2-(N,N- dimethylamino) ethyl"

3392 3-methylbutyl 2-methylbutyl "2-(N,N- dime hylamino) ethyl"

3393 cyclopropylmethyl 3-methylbutyl "2-(N,N- dimeth lamino) ethyl"

Table 5

Table 5

3418 pyrimidinylmethyl 4-biphenylmethyl 3- oxetanylmethyl

3419 2-benzothiazolylmethyl pyrimidinylmethyl 3- oxetanylmethyl

3420 2- 2-benzothiazolylmethyl 3- benzothiophenylmethyl oxetanylmethyl

3421 2-thiomethylethyl 2- 3- benzothiophenylmethyl oxetanylmethyl

3422 2-thiomethylmethyl 2-thiomethylethyl 3- oxetanylmethyl

3423 2-methylpropyl 2-thiomethylmethyl 3- oxetanylmethyl

3424 2-methylbutyl 2-methylpropyl 3- oxetanylmethyl

3425 3-methylbutyl 2-methylbutyl 3- oxetanylmethyl

3426 cyclopropylmethyl 3-methylbutyl 3- oxetanylmethyl

3427 cyclobutylmethyl cyclopropylmethyl 3- oxetan lmethyl

3428 cyclopentylmethyl cyclobutylmethyl 3- oxetanylmethy1

3429 p-hydroxyphenyl-methyl cyclopentylmethyl 3- oxetanylmethyl

3430 p-nitrophenylmethyl p-hydroxyphenyl-methyl 3- oxetanylmethyl

3431 p-aminophenyl-methyl p-nitrophenylmethyl 3- oxetanylmethyl

3432 "4-(N,N- p-aminophenyl-methyl 3- dimethylamino)phenylme oxetanylmethyl thyl"

3433 benzyl "4-(N,N- 2- dimethylamino)phenylme tetrahydrofura thyl" nyl

3434 1-pyrolylmethyl benzyl 2- tetrahydrofura nyl

3435 1-pyrazolylmethyl 1-pyrolylmethyl 2- tetrahydrofura nyl

3436 1-imidazolylmethyl 1-pyrazolylmethyl 2- tetrahydrofura nyl

3437 1-indolylmethyl 1-imidazolylmethyl 2- tetrahydrofura nyl

3438 1-triazolylmethyl 1-indolylmethyl 2- tetrahydrofura nyl

3439 1-tetrazolylmethyl 1-triazolylmethyl 2- tetrahydrofura nyl

3440 2-pyridylmethyl 1-tetrazolylmethyl 2- tetrahydrofura nyl

3441 3-pyridylmethyl 2-pyridylmethyl 2- tetrahydrofura nyl

Tahl e 5

3442 4-pyridylmethyl 3-pyridylmethyl 2- tetrahydrofura nyl 3443 cyclohexylmethyl 4-pyridylmethyl 2- tetrahydrofura nyl 3444 2-naphthylmethyl cyclohexylmethyl 2- tetrahydrofura nyl 3445 3-naphthylmethyl 2-naphthylmethyl 2- tetrahydrofura nyl 3446 2-thiophenylmethyl 3-naphthylmethyl 2- tetrahydrofura nyl 3447 4-(l- 2-thiophenylmethyl 2- methyl)piperidinyl- tetrahydrofura methyl nyl 3448 "(3,4- 4-(l- 2- methylenedioxyphenyl)m methyl)piperidinyl- tetrahydrofura ethyl" methyl nyl 3449 2-thienylmethyl "(3,4- 2- methylenedioxyphenyl)m tetrahydrofura ethyl" nyl 3450 4-biphenylmethyl 2-thienylmethyl 2- tetrahydrofura nyl 3451 pyrimidinylmethyl 4-biphenylmethyl 2- tetrahydrofura nyl 3452 2-benzothiazolylmethyl pyrimidinylmethyl 2- tetrahydrofura nyl 3453 2- 2-benzothiazolylmethyl 2- benzothiophenylmethyl tetrahydrofura nyl

2- 2- benzothiophenylmethyl tetrahydrofura nyl

2-thiomethylethyl 2- tetrahydrofura nyl

2-thiomethylmethyl 2- tetrahydrofura nyl

2-methylpropyl 2- tetrahydrofura nyl 2-methylbutyl 2- tetrahydrofura nyl

3459 cyclopropylmethyl 3-methylbutyl 2- tetrahydrofura nyl

3460 cyclobutylmethyl cyclopropylmethyl 2- tetrahydrofura nyl

Table 5

Table 5

Table 5

Table 5

3550 pyrimidinylmethyl 4-biphenylmethyl 2-(l- pyrolyl)ethyl 3551 2-benzothiazolylmethyl pyrimidinylmethyl 2-(l- pyrolyl)ethyl 3552 2- 2-benzothiazolylmethyl 2-U- benzothiophenylmethyl pyrolyl)ethyl 3553 2-thiomethylethy1 2- 2-(l- benzothiophenylmethyl pyrolyl)ethyl 3554 2-thiomethylmethyl 2-thiomethylethyl 2-(l- pyrolyl)ethyl 3555 2-methylpropyl 2-thiomethylmethyl 2-(l- pyrolyl)ethyl 3556 2-methylbutyl 2-methylpropyl 2-(l- pyrolyl)ethyl 3557 3-methylbutyl 2-methylbutyl 2-(l- pyrolyl)ethyl 3558 cyclopropylmethyl 3-methylbutyl 2-(l- pyrolyl)ethyl 3559 cyclobutylmethyl cyclopropylmethyl 2-(l- pyrolyl)ethyl 3560 cyclopentylmethyl cyclobutylmethyl 2-(l- pyrolyl)ethyl 3561 p-hydroxyphenyl-methyl cyclopentylmethyl 2-(l- pyrolyl)ethyl 3562 p-nitrophenylmethyl p-hydroxyphenyl-methyl 2-(l- pyrolyl)ethyl 3563 p-aminophenyl-methyl p-nitrophenylmethyl 2-(l- pyrolyl)ethyl 3564 "4-(N,N- p-aminophenyl-methyl 2-(l- dimethylamino)phenylme pyrolyl)ethyl thyl"

3565 benzyl "4-(N,N- 2-(l- dimethylamino)phenylme imidazolyl)eth thyl" y

3566 1-pyrolylmet yl benzyl 2-(l- imidazolyl)eth yi

3567 1-pyrazolylmethyl 1-pyrolylmethyl 2-(l- imidazolyl)eth yi

3568 1-imidazolylmethyl 1-pyrazolylmethyl 2-(l- imidazolyl)eth yi

3569 1-indolylmethyl 1-imidazolylmethyl 2-(l- imidazolyl)eth yi

3570 1-triazolylmethyl 1-indolylmethyl 2-(l- imidazolyl)eth y

3571 1-tetrazolylmethyl 1-triazolylmethyl 2-(l- imidazolyl)eth yi

3572 2-pyridylmethyl 1-tetrazolylmethyl 2-{l- imidazolyl)eth yi

3573 3-pyridylmethyl 2-pyridylmethyl 2-U- imidazolyl)eth y

Table 5

3574

3575

3576

3577

3578

3579

3580

3581

3582

3583

3584

3585

3586

3587

3588

3589

3590

3591

3592

Table 5

Table 5

3617 2-benzothiazolylmethyl pyrimidinylmethyl 2- pyrid lmethyl

3618 2- 2-benzothiazolylmeth l 2- benzothiophenylmethyl pyridylmethyl

3619 2-thiomethylethyl 2- 2- benzothiophenylmethyl pyrid lmethyl

3620 2-thiomethylmethyl 2-thiomethylethyl 2- pyridylmethyl

3621 2-methylpropyl 2-thiomethylmethyl 2- pyridylmethyl

3622 2-methylbutyl 2-methylproρyl 2- pyridylmethyl

3623 3-methylbutyl 2-methylbutyl 2- pyridylmethyl

3624 cyclopropylmethyl 3-methylbutyl 2- pyrid lmethyl

3625 cyclobutylmethyl cyclopropylmethyl 2- pyridylmethyl

3626 cyclopentylmethyl cyclobutylmethyl 2- pyridylmethyl

3627 p-hydroxyphenyl-methyl cyclopentylmethyl 2- pyridylmethyl

3628 p-nitrophenylmethyl p-hydroxyphenyl-methyl 2- pyridylmethyl

3629 p-aminophenyl-methyl p-nitrophenylmethyl 2- pyridylmethyl

3630 "4-(N,N- p-aminophenyl-methyl 2- dimethylamino)phenylme pyridylmethyl thyl"

3631 benzyl "4-(N,N- 2- dimethylamino)phenylme thiomethylethy thyl" 1

3632 1-pyrolylmethyl benzyl 2- thiomethylethy

1

3633 1-pyrazolylmethyl 1-pyrolylmethyl 2- thiomethylethy

1

3634 1-imidazolylmethyl 1-pyrazolylmethyl 2- thiomethylethy

1

3635 1-indolylmethyl 1-imidazolylmethyl 2- thiomethylethy

1

3636 1- riazolylmethyl 1-indolylmethyl 2- thiomethylethy

1

3637 1-tetrazolylmethyl 1-triazolylmethyl 2- thiomethylethy

1

3638 2-pyridylmethyl 1-tetrazolylmethyl 2- thiomethylethy

1

3639 3-pyridylmethyl 2-pyridylmeth l 2- thiomethylethy

1

Table 5

3640 4-pyridylmethyl 3-pyridylmethyl

3641

3642

3643

3644

3645

3646

3647

3648

3649

3650

3651

3652

3653

3654

3655

3656

3657

3658

__a__l____L

3659 cyclopentylmethyl cyclobutylmethyl 2- thiomethylethy 1

3660 p-hydroxyphenyl-methyl cyclopentylmethyl 2- thiomethylethy 1

3661 p-nitrophenylmethyl p-hydroxyphenyl-methyl 2- thiomethylethy 1

3662 p-aminophenyl-methyl p-nitrophenylmethyl 2- thiomethylethy 1

3663 "4-{N,N- p-aminophenyl-methyl 2- dimethylamino)phenylme thiomethylethy thyl" 1

3664 "4-(N,N- dimethylamino) henylme thyl"

Table 6

TABLE 6

Table 6

3676 2- cyclohexylmethyl allyl naphthylmethyl thiomethyleth 3677 3- 2-naphthylmethyl allyl 2- naphthylmethyl thiomethyleth 3678 2- 3-naphthylmethyl allyl 2- thiophenylmeth thiomethyleth yl

3679 4-U- 2- allyl 2- methyl)piper— thiophenylmethyl thiomethyleth idinylmethyl

3680 "(3,4- 4-(l- allyl 2- methylenedioxy methyl)piperi¬ thiomethylethy dinyl-methyl phenyl)methyl" 3681 2- "(3,4- allyl 2- thienylmethyl methylenedioxy¬ thiomethylethy phenyl)methyl"

3682 4- 2-thienylmethyl allyl 2- biphenylmethyl thiomethylethy 3683 pyrimidinylmet 4-biphenylmethyl allyl 2- hyl thiomethylethy 3684 2- pyrimidinylmethy allyl 2- benzothiazolyl 1 thiomethylethy

-methyl

3685 2- 2- allyl 2- benzothiopheny benzothiazolyl- thiometh lethy

1-methyl methyl

3686 2- 2- allyl 2- thiomethylethy benzothiophenyl- thiomethylethy

1 methyl

3687 2- 2- allyl 2- thiomethylmeth thiomethylethyl thiomethylethy yi

3688 2-methylpropyl 2- allyl 2- thiomethylmethyl thiomethylethy 3689 2-methylbutyl 2-methylpropyl allyl 2- thiomethylethy 3690 3-methylbutyl 2-methylbutyl allyl 2- thiomethylethy 3691 cyclopropylmet 3-methylbut l allyl 2- hyl thiomethylethy 3692 cyclobutylmeth cyclopropylmethy allyl 2- yi 1 thiomethylethy 3693 cyclopentylmet eyelobutylmeth 1 allyl 2- hyl thiomethylethy 3694 p- cyclopentylmethy allyl 2- hydroxyphenyl- 1 thiomethylethy methyl

3695 p- p-hydroxyphenyl¬ allyl 2- rxitrophenylmet methyl thiomethylethyl hyl

3696 p-aminophenyl¬ P- allyl 2- methyl nitrophenylmethy thiomethylethyl

1

2- thiomethyleth

allyl

allyl allyl

allyl

allyl allyl

allyl

allyl allyl allyl allyl allyl allyl allyl

allyl

allyl

allyl

allyl allyl allyl

allyl

n-butyl n-butyl n-butyl n-butyl n-butyl

n-butyl

n-butyl

n-butyl

isobutyl

isobutyl isobutyl

isobutyl

isobutyl isobutyl

isobutyl

isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl

isobutyl

Table 6

3858 cyclopentylmet eyelobutylmethyl "3,3- 2-butyl hyl dimethallyl"

3859 p- cyclopentylmethy "3,3- 2-butyl hydroxyphenyl- 1 dimethallyl" methyl

3860 p- p-hydroxyphenyl¬ "3,3- 2-butyl nitrophenylmet methyl dimethallyl" hyl

3861 p-aminophenyl¬ p- "3,3- 2-butyl methyl nitrophenylmethy dimethallyl" 1

3862 "4-(N,N- p-aminophenyl¬ "3,3- 2-butyl dimethylamino) methyl dimethallyl" phenylmethyl"

3863 benzyl "4-(N,N- 3-methallyl "3,3- dimethylamino)ph dimethallyl" enylmethyl"

3864 1- benzyl 3-methallyl "3,3- pyrolylmethyl dimethallyl"

3865 1- 1-pyrolylmethyl 3-methallyl "3,3- pyrazolylmethy dimethallyl" 1

3866 1- 1- 3-methallyl "3,3- imidazolylmeth pyrazolylmethyl dimethallyl" y

3867 1- 1- 3-methallyl "3,3- indolylmethyl imidazolylmethy1 dimethallyl"

3868 1- 1-indolylmethyl 3-methallyl "3,3- triazolylmethy dimethallyl" 1

3869 1- 1- 3-methallyl "3,3- tetrazolylmeth triazolylmethyl dimethallyl" yi

3870 2- 1- 3-methallyl "3,3- pyridylmethyl tetrazolylmethyl dimethallyl"

3871 3- 2-pyridylmethyl 3-methallyl "3,3- pyridylmethyl dimethallyl"

3872 4- 3-pyrid lmethyl 3-methallyl "3,3- pyridylmethyl dimethallyl"

3873 cyclohexylmeth 4-pyridylmethyl 3-methallyl "3,3- yi dimethallyl"

3874 2- cyclohexylmethyl 3-methallyl "3,3- naphthylmethyl dimethallyl"

3875 3- 2-naphthylmethyl 3-methallyl "3,3- naphthylmethyl dimethallyl"

3876 2- 3-naphthylmethyl 3-methallyl "3,3- thiophenylmeth dimethallyl" yi

3877 4-(l- 2- 3-methallyl "3,3- methyl)piperid thiophenylmethyl dimethallyl" iny1-methyl

3878 "(3,4- 4-(l- 3-methallyl "3,3- methylenedioxy methyl)piperidin dimethallyl" phenyl) ethyl" yl-methyl

3879 2- "(3,4- 3-methallyl "3,3- thienylmethyl methylenedioxyph dimethallyl" enyl)methyl"

Table 6

Table 6

4142 "(3,4- 4-(l- 3-methylbutyl 3-pentyl methylenedioxy methyl)piperidin phenyl)methyl" yl-methyl

4143 2- "(3,4- 3-methylbutyl 3-pentyl thienylmethyl methylenedioxyph enyl)methyl"

4144 4- 2-thienylmet yl 3-methylbutyl 3-pentyl biphenylmethyl

4145 pyrimidinylmet 4-biphenylmethyl 3-methylbutyl 3-pentyl hyl

4146 2- pyrimidinylmethy 3-methylbutyl 3-pentyl benzothiazolyl 1 methyl

4147 2- 2- 3-methylbutyl 3-pentyl benzothiopheny benzothiazolylme lmethyl thyl

4148 2- 2- 3-methylbutyl 3-pentyl thiomethylethy benzothiophenylm 1 ethyl

4149 2- 2- 3-methylbutyl 3-pentyl thiomethylmeth thiomethylethyl yi

4150 2-methylpropyl 2- 3-methylbutyl 3-pentyl thiomethylmethyl

4151 2-methylbutyl 2-methylpropyl 3-methylbutyl 3-ρentyl

4152 3-methylbutyl 2-methylbutyl 3-methylbutyl 3-pentyl

4153 cyclopropylmet 3-methylbutyl 3-methylbutyl 3-pentyl hyl

4154 cyclobutylmeth cyclopropylmethy 3-methylbutyl 3-pentyl y 1

4155 cyclopentylmet cyclobutylmethyl 3-methylbutyl 3-pentyl hyl

4156 p- cyclopentylmethy 3-methylbutyl 3-pentyl hydroxyphenyl- 1 methyl

4157 p- p-hydroxyphenyl¬ 3-methylbutyl 3-pentyl nitrophenylmet methyl hyl

4158 p-aminophenyl¬ P- 3-methylbutyl 3-pentyl methyl nitrophenylmethy 1

4159 "4-(N,N- p-aminophenyl¬ 3-methylbutyl 3-pentyl dimethylamino) methyl phenylmethyl"

4160 benzyl "4-(N,N- 2-methylbutyl 3-methylbutyl dimethylamino)ph enylmethyl"

4161 1- benzyl 2-methylbutyl 3-methylbutyl pyrolylmethyl

4162 1- 1-pyrolylmethyl 2-methylbutyl 3-methylbutyl pyrazolylmethy 1

4163 1- 1- 2-methylbutyl 3-methylbutyl imidazolylmeth pyrazolylmethyl yi

4164 1- 1- 2-methylbutyl 3-methylbutyl indolylmethyl imidazolylmethyl

Table 6

4189 p- cyclopentylmethy 2-methylbutyl 3-methylbutyl hydroxyphenyl- 1 methyl

4190 p- p-hydroxyphenyl¬ 2-methylbutyl 3-methylbutyl nitrophenylmet methyl hyl

4191 p-aminophenyl¬ p- 2-methylbutyl 3-methylbutyl methyl nitrophenylmethy 1

4192 "4-(N,N- p-aminophenyl¬ 2-methylbutyl 3-methylbutyl dimethylamino) methyl phenylmethyl"

4193 benzyl "4-(N,N- propargyl 2-methylbutyl dimethylamino)ph enylmethyl"

4194 1- benzyl propargyl 2-methylbutyl pyrolylmethyl

4195 1- 1-pyrolylmethyl propargyl 2-methylbutyl pyrazolylmethy 1

4196 1- 1- propargyl 2-methylbutyl imidazolylmeth pyrazol lmethyl yi

4197 1- 1- propargyl 2-methylbutyl indolylmethyl imidazol lmethyl

4198 1- 1-indolylmethyl propargyl 2-methylbutyl triazolylmethy 1

4199 1- 1- propargyl 2-methylbutyl tetrazolylmeth triazolylmethyl y

4200 2- 1- propargyl 2-methylbutyl pyridylmethyl tetrazolylmethyl

4201 3- 2-pyridylmethyl propargyl 2-methylbutyl pyridylmethyl

4202 4- 3-pyridylmethyl propargyl 2-methylbutyl pyridylmethyl

4203 cyclohexylmeth 4-py idylmeth l propargyl 2-methylbutyl yi

4204 2- cyclohexylmethyl propargyl 2-methylbutyl naphthylmethyl

4205 3- 2-naphthylmethyl propargyl 2-methylbutyl naphthylmethyl

4206 2- 3-naphthylmethyl propargyl 2-methylbutyl thiophenylmeth yi

4207 4-(1- 2- propargyl 2-methylbutyl methyl)piperid thiophenylmethyl inyl-methyl

4208 "(3,4- 4-(l- propargyl 2-methylbuty1 methylenedioxy methyl)piperidin phenyl)methyl" yl-methyl

4209 2- "(3,4- propargyl 2-methylbutyl thienylmethyl methylenedioxyph enyl)methyl"

4210 4- 2-thienylmethyl propargyl 2-methylbutyl biphenylmethyl

Table 6

Table 6

4371 2- 3-naphthylmethyl 1-hexyl cyclopentylmeth thiophenylmeth yi yi

4372 4-α- 2- 1-hexyl cyclopentylmeth methyl)piperid thiophenylmethyl yi inyl-methyl

4373 "(3,4- 4-(l- 1-hexyl cyclopentylmeth methylenedioxy methyl)piperidin yi phenyl)methyl" yl-methyl

4374 2- "(3,4- 1-hexyl cyclopentylmeth thienylmethyl methylenedioxyph yi enyl)methyl"

4375 4- 2-thienylmethyl 1-hexyl cyclopentylmeth biphenylmethyl yi 4376 pyrimidinylmet 4-biphenylmethyl 1-hexyl eyelopentylmeth hyl yi 4377 2- pyrimidin lmethy 1-hexyl cyclopentylmeth benzothiazolyl 1 yi methyl

4378 2- 2- 1-hexyl cyclopentylmeth benzothiopheny benzothiazolylme yi lmethyl thyl

4379 2- 2- 1-hexyl cyclopentylmeth thiomethylethy benzothiophenylm yi

1 ethyl

4380 2- 2- 1-hexyl cyclopentylmeth thio ethylmeth thiomethylethyl yi yi

4381 2-methylpropyl 2- 1-hexyl cyclopentylmeth thiomethylmethyl yi 4382 2-methylbutyl 2-methylpropyl 1-hexyl cyclopentylmeth yi 4383 3-methylbutyl 2-methylbutyl 1-hexyl eyelopentylmeth yi 4384 cyclopropylmet 3-methylbutyl 1-hexyl cyclopentylmeth hyl y 4385 cyclobutylmeth cyclopropylmethy 1-hexyl cyclopentylmeth yi 1 yi 4386 cyclopentylmet cyclobutylmethyl 1-hexyl cyclopentylmeth hyl yi 4387 P- cyclopentylmethy 1-hexyl cyclopentylmeth hydroxyphenyl- 1 yi methyl

4388 P- p-hydroxyphenyl¬ 1-hexyl cyclopentylmeth nitrophenylmet methyl yi hyl

4389 p-aminophenyl¬ p- 1-hexyl eyelopentylmeth methyl nitrophenylmethy yi 1

4390 "4-(N,N- p-aminophenyl¬ 1-hexyl cyclopentylmeth dimethylamino) methyl yi phenylmethyl"

4391 benzyl "4-(N,N- 4-methylpentyl 1-hexyl dimethylamino)ph enylmethyl"

4392 1- benzyl 4-methylpentyl 1-hexyl pyrolylmethyl

4-methylpentyl 1-hexyl

4-methylpentyl 1-hexyl

4-methylpentyl 1-hexyl

4-methylpentyl 1-hexyl

4-methylpentyl 1-hexyl

4-methylpentyl 1-hexyl

4-methylpentyl 1-hexyl

4-methylpentyl 1-hexyl

4-methylpentyl 1-hexyl

4-methylpentyl 1-hexyl

4-methylpentyl 1-hexyl

4-methylpentyl 1-hexyl

4-methylpentyl 1-hexyl

4-methylpentyl 1-hexyl

4-methylpentyl 1-hexyl

4-methylpentyl 1-hexyl

4-methylpentyl 1-hexyl

4-methylpentyl 1-hexyl

4-methylpentyl 1-hexyl

4-methylpentyl 1-hexyl

4-methylpentyl 1-hexyl

4-methylpentyl 1-hexyl 4-methylpentyl 1-hexyl

Table 6

4416 3-methylbutyl 2-methylbutyl 4-methylpentyl 1-hexyl 4417 cyclopropylmet 3-methylbutyl 4-methylpentyl 1-hexyl hyl

4418 cyclobutylmeth cyclopropylmethy 4-methylpentyl 1-hexyl yi 1

4419 cyclopentylmet cyclobutylmethyl 4-methylpentyl 1-hexyl hyl

4420 P- cyclopentylmethy 4-methylpentyl 1-hexyl hydroxyphenyl- 1 methyl

4421 P- p-hydroxyphenyl- 4-methylpentyl 1-hexyl nitrophenylmet methyl hyl

4422 p-aminophenyl¬ p-nitrophenyl¬ 4-methylpentyl 1-hexyl methyl methyl 4423 "4-(N,N- p-aminophenyl¬ 4-methylpentyl 1-hexyl dimethylamino) methyl phenylmethyl"

4424 benzyl "4-(N,N- 3-methylpentyl 4-methylpentyl dimethyl-amino)— phenylmethyl"

4425 1-pyrolyl¬ benzyl 3-methylpentyl 4-methylpentyl methyl

4426 1-pyrazolyl¬ 1-pyrolylmethyl 3-methylpentyl 4-methylpentyl methyl

4427 1-imidazolyl¬ 1- 3-methylpentyl 4-methylpentyl methyl pyrazolylmethyl

4428 1-indolyl¬ 1- 3-methylpentyl 4-methylpentyl methyl imidazolylmethyl

4429 1-triazolyl¬ 1-indolylmethyl 3-methylpentyl 4-methylpentyl methyl

4430 1-tetrazolyl¬ 1- 3-methylpentyl 4-methylpentyl methyl triazolylmethyl

4431 2-ρyridyl- 1- 3-methylpenty1 4-methylpentyl methyl tetrazolylmethyl

4432 3- 2-pyridylmethyl 3-methylpentyl 4-methylpentyl pyridylmethyl

4433 4- 3-pyridylmethyl 3-methylpentyl 4-methylpentyl pyridylmethyl

4434 cyclohexylmeth 4-pyridylmethyl 3-methylpentyl 4-methylpentyl yi

4435 2- cyclohexylmethyl 3-methylpentyl 4-methylpentyl naphthylmethyl

4436 3- 2-naphthylmethyl 3-methylpentyl 4-methylpentyl naphthylmethyl

4437 2-thiophenyl¬ 3-naphthylmethyl 3-methylρentyl 4-methylpentyl methyl

4438 4-(l- 2- 3-methylpentyl 4-methylpentyl methyl)piperid thiophenylmethyl inyl-methyl

4439 "(3,4- 4-(l- 3-methylpentyl 4-methylpentyl methylenedioxy methyl)piperidin phenyl)methyl" yl-methyl

4440 2- "(3,4- 3-methylpentyl 4-methylpentyl thienylmethyl methylenedioxyph enyl)methyl"

Table 6

4441 4- 2-thienylmethyl 3-methylpentyl 4-methylpentyl biphenylmethyl 4442 pyrimidinylmet 4-biphenylmethyl 3-methylpentyl 4-methylpentyl hyl- 4443 2- pyrimidinylmethy 3-methylρentyl 4-methylpentyl benzothiazolyl 1 methyl

4444 2- 2- 3-methylpentyl 4-methylpentyl benzothiopheny benzothiazolylme lmethyl thyl

4445 2- 2- 3-methylpentyl 4-methylpentyl thiomethylethy benzothiophenylm

1 ethyl

4446 2- 2- 3-methylpentyl 4-methylpentyl thiomethylmeth thiomethylethyl yi

4447 2-methylpropyl 2- 3-methylpentyl 4-methylpentyl thiomethylmethyl

4448 2-methylbutyl 2-methylpropyl 3-methylpentyl 4-methylpentyl 4449 3-methylbutyl 2-methylbutyl 3-methylpentyl 4-methylpentyl 4450 cyclopropylmet 3-methylbutyl 3-methylpentyl 4-methylpentyl hyl

4451 cyclobutylmeth cyclopropylmethy 3-methylpentyl 4-methylpentyl yi 1

4452 cyclopentylmet cyclobutylmethyl 3-methylpentyl 4-methylpentyl hyl

4453 P- cyclopentylmethy 3-methylpentyl 4-methylpentyl hydroxyphenyl- 1 ethyl

4454 p- p-hydroxyphenyl¬ 3-methylρentyl 4-methylpentyl nitrophenylmet methyl hyl

4455 p-aminophenyl¬ p- 3-methylpentyl 4-methylpentyl methyl nitrophenylmethy 1

4456 "4-(N,N- p-aminophenyl¬ 3-methylpentyl 4-methylpentyl dimethylamino) methyl phenylmethyl"

4457 benzyl "4-(N,N- isopropyl 3-methylpentyl dimethylamino)ph enylmethy1"

4458 1- benzyl isopropyl 3-methylpentyl pyrolylmethyl 4459 1- 1-pyrolylmethyl isopropyl 3-methylpentyl pyrazolylmethy

1

4460 1- 1- isopropyl 3-methylpentyl imidazolylmeth pyrazolylmethyl yi

4461 1- 1- isopropyl 3-methylpentyl indolylmethyl imidazolylmethyl 4462 1- 1-indolylmethyl isopropyl 3-methylpentyl triazolylmethy

1

4463 1- 1- isopropyl 3-methylpentyl tetrazolylmeth triazolylmethyl yi

Table 6

Table 6

4511 2- 2- 3-methylbutyl isopropyl thiomethylethy benzothiophenylm

1 ethyl

4512 2- 2- 3-methylbutyl isopropyl thiomethylmeth thiomethylethyl yi

4513 2-methylpropyl 2- 3-methylbuty1 isopropyl thiomethylmethyl

4514 2-methylbutyl 2-methylpropyl 3-methylbu l isopropyl 4515 3-methylbutyl 2-methylbutyl 3-methylbutyl isopropyl 4516 cyclopropylmethyl 3-methylbutyl 3-methylbutyl isopropyl 4517 cyclobutylmethyl cyclopropylmethyl 3-methylbutyl isopropyl 4518 cyclopentylmethyl cyclobutylmethyl 3-methylbutyl isopropyl 4519 p- cyclopentylme 3-methylbutyl isopropyl hydroxyphenyl thyl

-methyl

4520 p- p- 3-methylbutyl isopropyl nitrophenylme hydroxyphenyl thyl -methyl 4521 p- p- 3-methylbutyl isopropyl aminophenyl- nitrophenylme methyl thyl 4522 "4-(N,N- p- 3-methylbutyl isopropyl dimethylamino aminophenyl- ) henylmethyl methyl

4523 benzyl "4-(N,N- 2-phenylethyl 3-methylbutyl dimethylamino )phenylmethyl

4524 1- benzyl 2-phenylethyl 3-methylbutyl pyrol lmethyl 4525 1- 1- 2-phenylethyl 3-methylbutyl pyrazolylmeth pyrolylmethyl y

4526 1- 1- 2-ρhenylethyl 3-methylbutyl imidazolylmet pyrazolylmeth hyl yl

4527 1- 1- 2-phenylethyl 3-methylbutyl indolylmethyl imidazolylmet hyl

4528 1- 1- 2-phenylethyl 3-methylbutyl triazolylmeth indolylmethyl yi

4529 1- 1- 2-phenylethyl 3-methylbutyl tetrazolylmet triazolylmeth hyl yl

4530 2- 1- 2-phenylethyl 3-methylbutyl pyridylmethyl tetrazolylmet hyl

4531 3- 2- 2-phenylethyl 3-methylbutyl pyridylmethyl pyridylmethyl 4532 4- 3- 2-phenylethyl 3-methylbutyl pyridylmethyl pyridylmethyl 4533 cyclohexylmet 4- 2-phenylethyl 3-methylbutyl hyl pyridylmethyl

2-phenylethyl 3-methylbutyl

2-phenylethyl 3-methylbutyl

2-phenylethyl 3-methylbutyl

2-phenylethyl 3-methylbutyl

2-phenylethyl 3-methylbutyl

2-phenylethyl 3-methylbutyl

2-phenylethyl 3-methylbutyl

2-phenylethyl 3-methylbutyl

2-phenylethyl 3-methylbutyl

2-phenylethyl 3-methylbutyl

2-phenylethyl 3-methylbutyl

2-phenylethyl 3-methylbutyl

2-phenylethyl 3-methylbutyl

2-phenylethyl 3-methylbutyl

2-phenylethyl 3-methylbutyl

2-phenylethyl 3-methylbutyl

2-phenylethyl 3-methylbutyl

2-phenylethyl 3-methylbutyl

2-phenylethyl 3-methylbutyl

2-phenylethyl 3-methylbutyl

4554 2-phenylethyl 3-methylbutyl

4555 2-phenylethyl 3-methylbutyl dimethylamino aminophenyl- )phenylmethyl methyl

4556

4557 4558

4559

4560

4561

4562

4563

4564 4565 4566 4567

4568

4569

4570

4571

4572

1"

4589 benzyl "4-(N,N- "2-(N,N- 3- dimethylamino dimethylamino phenylpropyl )phenylmethyl )ethyl"

4590

4591

4592

4593 "2-(N,N- 3- dimethylamino phenylpropyl )ethyl"

4594 "2-(N,N- 3- dimethylamino phenylpropyl )ethyl"

4595 "2-(N,N- 3- dimethylamino phenylpropyl )ethyl"

4596 "2-(N,N- 3- dimethylamino phenylpropyl )ethyl"

4597 "2-(N,N- 3- dimethylamino phenylpropyl )ethyl"

4598 4- 3- "2-(N,N- 3- pyridylmethyl pyridylmethyl dimethylamino phenylpropyl )ethyl"

4599 cyclohexylmet 4- "2-(N,N- 3- hyl pyridylmethyl dimethylamino phenylpropyl )ethyl"

4600 "2-(N,N- 3- dimethylamino phenylpropyl )ethyl"

4601 "2-(N,N- 3- dimethylamino phenylpropyl )ethyl"

4602 "2-(N,N- 3- dimethylamino phenylpropyl )ethyl"

4603 "2-(N,N- 3- dimethylamino phenylpropyl )ethyl"

4604 "2-(N,N- 3- dimethylamino phenylpropyl )ethyl"

4605 "2-(N,N- 3- dimethylamino phenylpropyl )ethyl"

4606 "2-(N,N- 3- dimethylamino phenylpropyl )ethyl"

4607 "2-(N _r N- 3- dimethylamino phenylpropyl )ethyl"

4608 "2-(N,N- 3- dimethylamino phenylpropyl )ethyl"

4609 "2-(N,N- 3- dimethylamino phenylpropyl )ethyl"

4610 "2-(N,N- 3- dimethylamino phenylpropyl )ethyl"

4611

4612

4613

4614

4615

4616

4617

4618

4619 nitrophenylme hydroxyphenyl dimethylamino phenylpropyl thyl -methyl )ethyl"

4620 p- P- "2-(N,N- 3- aminophenyl- nitrophenylme dimethylamino phenylpropyl methyl thyl )ethyl"

4621 "4-(N,N- P- "2-(N,N- 3- dimethylamino aminophenyl- dimethylamino phenylpropyl )phenylmethyl methyl )ethyl"

4622

4623

4624

4625

4626

4627

4628

4629

4630

4631

4632

4633

4634

4635

4636

4637

4638

4639

4640

4641

4642

4643

4644

4645

4646

4647

4648

4649

4650

4651

4652

4653

4654

4655 benzyl

4656

4657

4658

4659

4660

4661

4662

4663

4664

4665

4666

4667

4668

4669

4670

4671

4672

4673

4674

4675

4676

4677

4678

4679

4680

4681

4682

4683

4684

4685

4686

4687

4688 benzyl

Table 6

4701 2- 3- 2- 2- thiophenylmet naphthylmethy methoxypropyl tetrahydrofur hyl 1 anyl

4702 4-(l- 2- 2- 2- methyl)piperi thiophenylmet methoxypropyl tetrahydrofur dinyl-methyl hyl anyl

4703 "(3,4- 4-(l- 2- 2- meth lenediox methyl)piperi methoxypropyl tetrahydrofur yphenyl)methy dinyl-methyl anyl

1"

4704 2- "(3,4- 2- 2- thienylmethyl methylenediox methoxypropyl tetrahydrofur yphenyl)methy anyl

1"

4705 4- 2- 2- 2- biphenylmethy thienylmethyl methoxypropyl tetrahydrofur

1 anyl

4706 pyrimidinylme 4- 2- 2- thyl biphenylmethy methoxypropyl tetrahydrofur

1 anyl

4707 2- pyrimidinylme 2- 2- benzothiazoly thyl methoxypropyl tetrahydrofur lmethyl anyl

4708 2- 2- 2- 2- benzothiophen benzothiazoly methoxypropyl tetrahydrofur ylmethyl lmethyl anyl

4709 2- 2- 2- 2- thiomethyleth benzothiophen methoxypropyl tetrahydrofur y ylmethyl anyl

4710 2- 2- 2- 2- thiomethylmet thiomethyleth methoxypropyl tetrahydrofur hyl yi anyl

4711 2- 2- 2- 2- methylpropyl thiomethylmet methoxypropyl tetrahydrofur hyl anyl

4712 2-methylbutyl 2- 2- 2- methylpropyl methoxypropyl tetrahydrofur anyl

4713 3-methylbutyl 2-methylbutyl 2- 2- methoxypropyl tetrahydrofur anyl

4714 cyclopropylme 3-methylbutyl 2- 2- thyl methoxypropyl tetrahydrofur anyl

4715 cyclobutylmet cyclopropylme 2- 2- hyl thyl methoxypropyl tetrahydrofur anyl

4716 cyclopentylme cyclobutylmet 2- 2- thyl hyl methoxypropyl tetrahydrofur anyl

4717 P- cyclopentylme 2- 2- hydroxyphenyl thyl methoxypropy1 tetrahydrofur

-methyl anyl

4718 p- p- 2- 2- nitrophenylme hydroxyphenyl methoxypropyl tetrahydrofur thyl -methyl anyl

4754 benzyl "4-(N,N- 2-(1- 2-ethoxyethyl dimethylamino pyrolyl)ethyl )phenylmethyl

4755 4756

4757

Table 6

4778 2-methylbutyl 2- 2-(l- 2-ethoxyethyl methylpropyl pyrolyl)ethyl 4779 3-methylbutyl 2-methylbutyl 2-<l- 2-ethoxyethyl pyrolyl)ethyl 4780 cyclopropyl¬ 3-methylbut l 2-(l- 2-ethoxyethyl methyl pyrolyl)ethyl 4781 cyclobutyl¬ cyclopropylme 2-(l- 2-ethoxyethyl methyl thyl pyrolyl)ethyl 4782 cyclopentyl¬ cyclobutylmet 2-(l- 2-ethoxyethyl methyl hyl pyrolyl)ethyl 4783 P- cyclopentylme 2-(l- 2-ethoxyethyl hydroxyphenyl thyl pyrolyl)ethyl

-methyl

4784 P- P- 2-(l- 2-ethoxyethyl nitrophenylme hydroxyphenyl pyrolyl)ethyl thyl -methyl

4785 P- P- 2-(l- 2-ethoxyethyl aminophenyl- nitrophenylme pyrolyl)ethyl methyl thyl

4786 "4-(N,N- P- 2-(l- 2-ethoxyethyl dimethylamino aminophenyl- pyrolyl)ethyl

)phenylmethyl methyl n

4787 benzyl "4-(N,N- 2-(l- 2-(l- dimethylamino imidazolyl)et pyrolyl)ethyl )phenylmethyl hyl

4788 1- benzyl 2-(l- 2-(l- pyrolylmethyl imidazolyl)et pyrolyl)ethyl hyl 4789 1- 1- 2-(l- 2-(l- pyrazolylmeth pyrolylmethyl imidazolyD et pyrolyl)ethyl yi hyl 4790 1- 1- 2- (l- 2- (l- imidazolylmet pyrazolylmeth imidazolyl)et j yrolyl) ethyl hyl yi hyl 4791 1- 1- 2-(l- 2-(l- indolylmethyl imidazolylmet imidazolyl)et pyrolyl)ethyl hyl hyl 4792 1- 1- 2-(l- 2-(l- triazolylmeth indolylmethyl imidazolyl)et pyrolyl)ethyl yi hyl 4793 1- 1- 2-(l- 2-(l- tetrazolylmet triazolylmeth imidazolyl)et pyrolyl)ethyl hyl yi hyl 4794 2- 1- 2-(l- 2-(l- pyridylmethyl tetrazolylmet imidazolyl)et pyrolyl)ethyl hyl hyl 4795 3- 2- 2-(l- 2-(l- pyridylmethyl pyridylmethyl imidazolyl)et pyrolyl)ethyl hyl 4796 4- 3- 2-(l- 2-(l- pyridylmethyl pyridylmethyl imidazolyDet pyrolyl)ethyl hyl 4797 cyclohexylmet 4- 2-(l- 2-(l- hyl pyridylmethyl imidazolyl)et pyrolyl)ethyl hyl

Table 6

Table 6

4816

4817

4818

4819

4820 benzyl "4-(N,N- 2- 2-(l- dimethylamino pyridylmethyl imidazolyl)et )phenylmethyl hyl

4834

4835

4836

4837

4838

4839

4840

4841

4842

4843

4844

4845

4846

4847

4848

4849

4850

4851

Table 6

4852 "4-(N,N- p- 2- 2-(l- dimethylamino aminophenyl- pyridylmethyl imidazolyl)et ) henylmethyl methyl hyl

4853 benzyl "4-(N,N- 2- 2- dimethylamino thiomethyleth pyridylmethyl )phenylmethyl yl

1"

Table 6

4869

4870

4871

4872

4873

4874

4875

4876

4877

4878

4879

4880

4881

4882

4883

4884

4885

Table 7

TABLE 7

Table 8

TABLE 8

Table 9

5098 (3,4- 2- cyclobutylmethy cyclobutylme methylenedioxyp thiophenylmethy 1 1 henyl)methyl 1

5099 2-thienylmethyl (3,4- cyclopropylmeth cyclopropylm methylenedioxyp yi yi henyl)methyl

5100 4- 2-thienylmethyl isobutyl isobutyl biphenylmethyl

5101 2- 4- n-butyl n-butyl thiomethylethyl biphenylmethyl

5102 p- 2- n-pentyl n-pentyl hydroxyphenylme thiomethylethyl thyl

5103 p- P- propyl propyl nitrophenylmeth hydroxyphenylme yi thyl

5104 benzyl P- 2-methallyl 2-methallyl nitrophenylmeth yi benzyl 4-methylpentyl 4-methylpent 1-pyrolylmethyl 3-methallyl 3-methallyl

1- 3-methylbutyl 3-methylbuty pyrazolylmethyl 1- 3-methylpentyl 3-methylpent imidazolylmethy

1

1-indolylmethyl 3-pentyl 3-pentyl

2-ρyridylmethyl 4-methylpentyl 4-methylpent

3-pyridylmethyl 3,3-dimethallyl 3,3-dimethall

4-pyridylmethyl 3,3- 3,3- dimethylbutyl dimethylbutyl cyclohexylmethy allyl allyl

1

2- cyclobutylmethy cyclobutylmet thiophenylmethy 1 1 1 (3,4- cyclopropylmeth cyclopropylme methylenedioxyp yi yi henyl)methyl

5116 4- 2-thienylmethyl isobutyl isobutyl biphenylmethyl

5117 2- 4- n-butyl n-butyl thiomethylethyl biphenylmethyl

5118 p- 2- n-pentyl n-pentyl hydroxyphenylme thiomethylethyl thyl

5119 p- p- propyl propyl nitrophenylmeth hydroxyphenylme yi thyl

5120 benzyl p- 2-methallyl propyl nitrophenylme h yi

5121 1-pyrolylmethyl benzyl 4-methylpentyl 2-methallyl

Table 9

Table 1Q

TABLE 10

_R 24

-24 H, CH ₃ , or C ₂ H ₅

Table 10

Table 11

Table 11

Table 12

TABLE 12

a l 13

TABLE 13

Table 13

5418 (3,4- 2- cyclobutylmethy cyclobutylmeth methylenedioxyp thiophenylmethy 1 1 henyl)methyl 1

5419 2-thienylmethyl (3,4- cyclopropylmeth cyclopropylmet methylenedioxyp yi yi henyl)methyl

5420 4- 2-thienylmethyl isobutyl isobutyl biphenylmethyl

5421 2- 4- n-butyl n-butyl thiomethylethyl biphenylmethyl

5422 p- 2- n-pentyl n-pentyl hydroxyphenylme thiomethylethyl thyl

5423 p- p- propyl propyl nitrophenylmeth hydroxyphen lme yi thyl

5424 benzyl p- 2-methallyl 2-methallyl nitrophenylmeth yi benzyl 4-methylpentyl 4-methylpentyl 1-pyrolylmethyl 3-methallyl 3-methallyl

1- 3-methylbutyl 3-methylbutyl pyrazolylmethyl 1- 3-methylpentyl 3-methylpentyl imidazolylmethy

1

1-indolylmethyl 3-pentyl 3-pentyl

2-pyridylmethyl 4-methylpentyl 4-methylpentyl

3-pyridylmethyl 3,3-dimethallyl 3,3-dimethallyl

4-pyridylmethyl 3,3- 3,3- dimethylbutyl dimethylbutyl cyclohexylmethy allyl allyl

1

2- cyclobutylmethy cyclobutylmethy thiophenylmethy 1 1 1 (3,4- cyclopropylmeth cyclopropylmeth methylenedioxyp yi yi henyl)methyl

5436 4- 2-thienylmethyl isobutyl isobutyl biphenylmethyl

5437 2- 4- n-butyl n-butyl thiomethylethyl biphenylmethyl

5438 p- 2- n-pentyl n-pentyl hydroxyphen lme thiomethylethyl thyl

5439 p- P- propyl propyl nitrophenylmeth hydroxyphenylme y thyl

5440 benzyl P- 2-methallyl propyl nitrophenylmeth yi

5441 1-pyrolylmethyl benzyl 4-methylpentyl 2-methallyl

Table 14

TABLE 14

imidazolylmethyl

Table 15

TABLE 15

imidazolylmethyl

Table 16

TABLE 16

Table 1 7

23 ⁴

m-tetrazolyl)benzyl (p-fluoro)benzyl m-tetrazolyl)benzyl (p-fluoro)benzyl m-tetrazolyl)benzyl (p-fluoro)benzyl m-tetrazolyl)benzyl (p-fluoro)benzyl m-tetrazolyl)benzyl (p-fluoro)benzyl m-tetrazolyl)benzyl (p-fluoro)benzyl

m-imidazolyl)benzyl (p-fluoro)benzyl m-imidazolyl)benzyl (p-fluoro)benzyl m-imidazolyl)benzyl (p-fluoro)benzyl

5641 (p-hydroxy)benzyl (m-imidazolyl)benzyl (p-fluoro)benzyl

5642 (m-carboxamido)benzyl (m-imidazolyl)benzyl (p-fluoro)benzyl

5643 (m-(N-met yl (m-imidazolyl)benzyl (p-fluoro)benzyl carboxamido))benzyl

5644 (m-carboxy)benzyl

5645 (m-carboxy)benzyl

5646 (m-carboxy)benzyl

5647 (m-carboxy)benzyl

5648 (m-carboxy)benzyl

5649 (m-carboxy)benzyl

5650 (m-carboxy)benzyl

5651 (m-carboxy)benzyl

5652 (m-carboxy)benzyl

5653 (m-carboxy)benzyl

5654 (m-carboxamido)benzyl

5655 (m-carboxamido)benzyl

5656 (m-carboxamido)benzyl

5657 (m-carboxamido)benzyl

5658 (m-carboxamido)benzyl

5659 (m-carboxamido)benzyl

5660 (m-carboxamido)benzyl

5661 (m-carboxamido)benzyl

5662 (m-carboxamido)benzyl

5663 (m-carboxamido)benzyl

5664 (m-(N-methyl (m-hydroxy)benzyl benzyl carboxamido) )benzyl

5665 (m-(N-methyl (p-hydroxy)benzyl benzyl carboxamido) )benzyl

5666 (m-(N-methyl carboxamido) )benzyl

5667 (m-(N-methyl carboxamido) )benzyl

5668 (m-(N-methyl carboxamido) )benzyl

5669 (m-(N-methyl carboxamido))benzyl

5670 (m-(N-methyl carboxamido) )benzyl

5671 (m-(N-methyl (m-glycolyl)benzyl benzyl carboxamido) )benzyl

5672 (m-(N-methyl carboxamido) )benzyl

5673 (m-(N-methyl carboxamido) )benzyl

5674 (m-sulfonamido)benzyl

5675 (m-sulfonamido)benzyl

5676 (m-sulfonamido)benzyl

5677 (m-sulfonamido)benzyl

5678 (m-sulfonamido)benzyl

5679 (m-sulfonamido)benzyl

5680 (m-sulfonamido)benzyl

5681 (m-sulfonamido)benzyl

5682 (m-sulfonamido)benzyl

5683 (m-sulfonamido)benzyl

-fluoro)benzyl -fluoro)benzyl -fluoro)benzyl

-fluoro)benzyl

-fluoro)benzyl

-fluoro)benzyl

-fluoro)benzyl -fluoro)benzyl -fluoro)benzyl

-fluoro)benzyl

-fluoro)benzyl -fluoro)benzyl -fluoro)benzyl

-fluoro)benzyl

-fluoro)benzyl

-fluoro)benzyl

-fluoro)benzyl -fluoro)benzyl -fluoro)benzyl

- luoro)benzyl

-fluoro)benzyl

-fluoro)benzyl carboxamido) )benzyl

5726 ( -(N-methyl (m-hydroxymethyl) (p-fluoro)benzyl carboxamido))benzyl benzyl

5727 (m-(N-methyl (p-hydroxymethyl) (p-fluoro)benzyl carboxamido))benzyl benzyl

5728 (m-(N-methyl (m-carboxamido) (p-fluoro)benzyl carboxamido) )benzyl benzyl

5729 (m-(N-methyl (m-(N-methyl (p-fluoro)benzyl carboxamido) )benzyl carboxamido) )benzyl

5730 (m-(N-methyl (m-acetyl)benzyl (p-fluoro)benzyl carboxamido) )benzyl

5731 (m-(N-methyl (m-glycolyl)benzyl (p-fluoro)benzyl carboxamido))benzyl

5732 (m-(N-methyl (m-sulfonamido) (p-fluoro)benzyl carboxamido) )benzyl benzyl

5733 (m-(N-methyl (m-(N-methylamino) (p-fluoro)benzyl carboxamido) )benzyl benzyl

5734 (m-sulfonamido)benzyl (m-hydroxy)benzyl (p-fluoro)benzyl

5735 (m-sulfonamido)benzyl (p-hydroxy)benzyl (p-fluoro)benzyl

5736 (m-sulfonamido)benzyl (m-hydroxymethyl) (p-fluoro)benzyl benzyl

5737 (m-sulfonamido)benzyl (p-hydroxymethyl) (p-fluoro)benzyl benzyl

5738 (m-sulfonamido)benzyl (m-carboxamido) (p-fluoro)benzyl benzyl

5739 (m-sulfonamido)benzyl (m-(N-methyl (p-fluoro)benzyl carboxamido) )benzyl

5740 (m-sulfonamido)benzyl (m-acetyl)benzyl (p-fluoro)benzyl

5741 (m-sulfonamido)benzyl (m-glycolyl)benzyl (p-fluoro)benzyl

5742 (m-sulfonamido)benzyl (m-sulfonamido) (p-fluoro)benzyl benzyl

5743 (m-sulfonamido)benzyl (m-(N-methylamino) (p-fluoro)benzyl benzyl

5744 m-(N-ethylcarboxamido) (m-hydroxy)benzyl (p-fluoro)benzyl benzyl

5745 m-(N-ethylcarboxamido) (p-hydroxy)benzyl (p-fluoro)benzyl benzyl

(m-hydroxymethyl) (p-fluoro)benzyl benzyl

(p-hydroxymethyl) (p-fluoro)benzyl benzyl

(m-carboxamido) (p-fluoro) enzyl benzyl (m-(N-methyl (p-fluoro)benzyl carboxamido) )benzyl (m-acetyl)benzyl (p-fluoro)benzyl

(m-glycolyl)benzyl (p-fluoro)benzyl

(m-sulfonamido) (p-fluoro)benzyl benzyl

(m-(N-methylamino) (p-fluoro)benzyl benzyl

(m-hydroxy)benzyl (p-fluoro)benzyl (p-hydroxy)benzyl (p-fluoro)benzyl (m-hydroxymethyl) (p-fluoro)benzyl benzyl

5757 3-pyridylmethyl (p-hydroxymethyl) (p-fluoro)benzyl benzyl

5758 3-pyridylmethyl (m-carboxamido) (p-fluoro)benzyl benzyl

5759 3-pyridylmethyl (m-(N-methyl (p-fluoro)benzyl carboxamido) )benzyl

5760 3-pyridylmethyl (m-acetyl)benzyl (p-fluoro)benzyl

5761 3-pyridylmethyl (m-glycolyl)benzyl (p-fluoro)benzyl

5762 3-pyridylmethyl (m-sulfonamido) (p-fluoro)benzyl benzyl

5763 3-ρyridylmethyl (m-(N-methylamino) (p-fluoro)benzyl benzyl