WO2005115147A2 - Hiv reverse transcriptase inhibitors - Google Patents

Abstract

Tetrazolyl derivatives of Formula (I): are HIV reverse transcriptase inhibitors, wherein U is O, S(O)n where n is an integer equal to zero, 1 or 2, or N(R4); V is optionally substituted C1-8 alkylene; W is C(O)N(R2) or a direct bond linking V to R3; and R1, R2, R3 and R4 are defined herein. The derivatives of Formula I are useful in the inhibition of HIV reverse transcriptase, the prevention and treatment of infection by HIV and in the prevention, delay in the onset, and treatment of AIDS. The derivatives are employed against HIV infection and AIDS as compounds per se or in the form of pharmaceutically acceptable salts. The derivatives and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines.

Description

TITLE OF THE INVENTION

HIV REVERSE TRANSCRIPTASE INHIBrrORS

FIELD OF THE INVENTION The present invention is directed to the use of certain tetrazole derivatives and their pharmaceutically acceptable salts for the inhibition of HTV reverse transcriptase, the prevention and treatment of HIV infection and HTV replication, and the prevention, delay in the onset of and treatment of AIDS. The present invention is also directed to tetrazole derivatives per se, their pharmaceutically acceptable salts, and their preparation.

BACKGROUND OF THE INVENTION The retrovirus designated human immunodeficiency virus (HTV), particularly the strains known as HTV type-1 (HTV-1) and type-2 (PHV-2) viruses, have been etiologically linked to the immunosuppressive disease known as acquired immunodeficiency syndrome (AIDS). HIV seropositive individuals are initially asymptomatic but typically develop AIDS related complex (ARC) followed by AIDS. Affected individuals exhibit severe immunosuppression which makes them highly susceptible to debilitating and ultimately fatal opportunistic infections. Replication of HTV by a host cell requires integration of the viral genome into the host cell's DNA. Since HTV is a retrovirus, the HTV replication cycle requires transcription of the viral RNA genome into DNA via an enzyme know as reverse transcriptase (RT). Reverse transcriptase has three known enzymatic functions: The enzyme acts as an RNA-dependent DNA polymerase, as a ribonuclease, and as a DNA- dependent DNA polymerase. In its role as an RNA-dependent DNA polymerase, RT transcribes a single-stranded DNA copy of the viral RNA. As a ribonuclease, RT destroys the original viral RNA and frees the DNA just produced from the original RNA. And as a DNA-dependent DNA polymerase, RT makes a second, complementary DNA strand using the first DNA strand as a template. The two strands form double-stranded DNA, which is integrated into the host cell's genome by the integrase enzyme. It is known that compounds that inhibit enzymatic functions of HTV RT will inhibit HTV replication in infected cells. These compounds are useful in the prevention or treatment of HTV infection in humans. Among the compounds approved for use in treating HTV infection and AIDS are the RT inhibitors 3'-azido- 3'-deoxythymidine (AZT), 2',3'-dideoxyinosine (ddl), 2',3'- dideoxycytidine (ddC), d4T, 3TC, nevirapine, delavirdine, efavirenz and abacavir. While each of the foregoing drugs is effective in treating HTV infection and AIDS, there remains a need to develop additional HTV antiviral drugs including additional RT inhibitors. A particular problem is the development of mutant HTV strains that are resistant to the known inhibitors. The use of RT inhibitors to treat AIDS often leads to viruses that are less sensitive to the inhibitors. This resistance is typically the result of mutations that occur in the reverse transcriptase segment of the pol gene. The continued use of antiviral compounds to prevent HTV infection will inevitably result in the emergence of new resistant strains of HTV. Accordingly, there is a particular need for new RT inhibitors that are effective against mutant HIV strains. The following references are of interest as background: US4372953, US4540703, US4663323, and US4766120 disclose certain tetrazole derivatives that are useful for treating ulcers. US5939462 and US6245817 B 1 disclose certain imidazole, triazole, and tetrazole derivatives as NPY5 receptor antagonists. EP785193 Al discloses certain arylthiadiazole derivatives and salts thereof having antiviral activity. WO 2004/030611 A2 discloses the use of certain carbonyl amide compounds containing a 5- or 6-membered heterocyclic ring (particularly imidazole or triazole) as non-nucleoside reverse transcriptase inhibitors.

SUMMARY OF THE INVENTION The present invention is directed to tetrazole compounds and their use in the inhibition of HTV reverse transcriptase, the prevention of infection by HTV, the treatment of infection by HTV, and the prevention, treatment, and delay in the onset of AIDS and/or ARC. More particularly, the present invention includes a method for inhibiting HTV reverse transcriptase, for treating or preventing HTV infection, or for preventing, treating or delaying the onset of AIDS, which comprises administering to a subject in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof:

wherein:

U is: (1) O, (2) S(O)_n where n is an integer equal to zero, 1 or 2, or (3) N(R4);

V is Ci-8 alkylene, which is optionally substituted with -OH, -O-Ci-6 alkyl, -CN, -N(RA)RB_; -C(O)N(RA)RB, -C(0)RA -CO2RA, -SRA, -S(0)RA, -S02RA, -Sθ2N(RA)RB, -N(RA)C(0)RB,

-N(RA)C02R^B, -N(RA)S02R^B, -N(RA)RK -C(0)N(RA)RK -C(0)RK, -Cθ2 ^κ, or -N(RA)C(0)RK_;

W is C(0)N(R2) or a direct bond linking V to R3;

Rl is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, with the proviso that Rl is not unsubstituted phenyl;

R is: (1) H, (2) Cl-6 alkyl, (3) Ci-6 alkyl substituted with: (a) aryl (b) substituted aryl (c) heteroaryl, (d) substituted heteroaryl, (e) C3_8 cydoalkyl, or (f) substituted C3-8 cydoalkyl, (3) C3-8 cydoalkyl, or (4) substituted C3-8 cydoalkyl;

R3 is aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

R4 is: (1) H, (2) C1-6 alkyl, (3) Ci-6 haloalkyl, (4) Ci-6 alkyl substituted with -OH, -O-Cι_6 alkyl, -O-Ci-6 haloalkyl, -CN, -NO2, -N(RA)RB, -C(0)N(RA)RB, -C(0)RA, -CO2RA, -SRA, -S(0)RA, -SO2RA -Sθ2N(RA)RB_? -N(RA)C(0)RB, -N(RA)Cθ2RB, -N(RA)Sθ2RB, -N(RA)Sθ2N(RA)RB_; -OC(0)N(RA)RB, or -N(RA)C(0)N(RA)RB, (5) Ci-6 alkyl substituted with: (a) aryl (b) substituted aryl (c) heteroaryl, (d) substituted heteroaryl, (e) C3_8 cydoalkyl, or (f) substituted C3.. cydoalkyl, (6) C3-8 cydoalkyl, or (7) substituted C3_8 cydoalkyl;

each aryl is independently (i) phenyl or (ii) a 9- or 10-membered bicyclic, fused carbocylic ring system in which at least one ring is aromatic;

each substituted aryl is independently aryl as defined above which has at least one substituent and is: (i) substituted with from zero to 5 substituents each of which is independently: (1) -C1 -6 alkyl optionally substituted with -OH, -O-Ci-6 alkyl, -O-Ci -6 haloalkyl, -CN, -NO2, -N(RA)RB, -C(0)N(RA)RB, -C(0)RA -CO2 A, -SRA -S(0)RA -Sθ2R^A, -Sθ2N(RA)RB, -N(RA)C(0)RB, -N(RA)Cθ2R^B, -N(RA)S02R^B, -N(RA)S02N(RA)RB, -OC(0)N(RA)RB_; or -N(RA)C(0)N(RA)RB, (2) -O-Ci-6 alkyl, (3) -Ci-6 haloalkyl, (4) -O-Ci-6 haloalkyl, (5) -OH, (6) halogen, (7) -CN, (8) -NO2, (9) -N(RA)RB, (10) -C(O)N(RA)RB, (11) -C(O)RA,

(13) -SRA (14) -S(0)RA, (15) -Sθ2R^A,

(18) -N(RA)S02RB, (19) -N(RA)S02N(RA)RB, (20) -N(RA)C(0)RB, (21) -N(RA)C(0)-C(0)N(RA)RB_; or (22) -N(RA)C02RB, and (ϋ) substituted with from zero to 2 substituents each of which is independently (1) AryA, (2) HetA, (3) -C3-8 cydoalkyl, (4) -Ci-6 alkyl substituted with AryA, HetA, or -C3_8 cydoalkyl,

(7) -C(0)-AryA, or (8) -C(0)-HetA;

each heteroaryl is independently (i) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein each N is optionally in the form of an oxide, or (ii) a 9- or 10-membered bicyclic, fused ring system containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein either one or both of the rings contain a heteroatom, at least one ring is aromatic, each N is optionally in the form of an oxide, and each S in a ring which is not aromatic is optionally S(O) or S(0)2;

each substituted heteroaryl is independently heteroaryl as defined above which has at least one substituent and is: (i) substituted with from zero to 6 substituents each of which is independently: (1) -Cι _6 alkyl optionally substituted with -OH, -O-Ci-6 alkyl, -O-Ci-6 haloalkyl, -CN, -NO2, -N(RA)RB, -C(0)N(RA)RB, -C(0)RA -CO2RA, -SRA -S(0)RA -SO2RA, -Sθ2N(RA)RB, -N(RA)C(0)RB, -N(RA)Cθ2RB, -N(RA)S02RB, -N(RA)S02N(RA)RB, -OC(0)N(RA)RB, or -N(RA)C(O)N(RA)RB, (2) -Ci-6 haloalkyl, (3) -O-Ci-6 alkyl, (4) -O-Ci-6 haloalkyl, (5) -OH, (6) oxo, (7) halogen, (8) -CN, (9) -NO2, (10) -N(RA)RB₅ (11) -C(0)N(RA)RB, (12) -C(0)RA (13) -CO₂RA, (14) -SRA, (15) -S(0)RA (16) -SO₂RA

(18) -S02N(RA)C(0)RB, and (ϋ) substituted with from zero to 2 substituents each of which is independently: (1) AryA, (2) HetA, (3) -C3-8 cydoalkyl, (4) -Cι_6 alkyl substituted with AryA, HetA, or -C3..8 cydoalkyl,

(7) -C(0)-AryA, or (8) -C(0)-HetA;

each substituted C3_8 cydoalkyl is independently C3_8 cydoalkyl which has at least one substituent and is (i) substituted with from zero to 6 substituents each of which is independently -Cι_6 alkyl, -OH, -O-Ci-6 alkyl, or -Ci-6 haloalkyl, and (ii) substituted with zero or 1 AryA;

each R is independently H or Cl-6 alkyl;

each RB is independently H or Ci-g alkyl;

each RK is independently aryl, substituted aryl, heteroaryl, or substituted heteroaryl; each AryA is independently an aromatic carbocycle selected from the group consisting of phenyl, naphthyl, and indenyl, wherein the aromatic carbocycle is optionally substituted with from 1 to 4 substituents each of which is independently halogen, CN, Nθ2, -Ci-6 alkyl, -Cl-6 haloalkyl, -OH, -O-Ci-6 alkyl, -O-Ci-6 haloalkyl, -C(0)N(RA)RB, -C(0)RA -CO2RA, -SRA -S(0)RA -SO2RA, -Sθ2N(RA)RB, or -Sθ2N(RA)C(0)RB; and

each HetA is independently a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein each N is optionally in the form of an oxide, and wherein the heteroaromatic ring is optionally substituted with from 1 to 4 substituents each of which is independently halogen, -C1 -6 alkyl, -Cχ-6 haloalkyl, -O-Ci-6 alkyl, -0-Cι_g haloalkyl, -OH, -C(0)N(RA)RB, -C(O)RA -CO2RA -SRA -S(0)RA -SO2RA -Sθ2N(RA)RB₅ or

Other embodiments, aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples and appended claims.

DETAILED DESCRIPTION OF THE INVENTION The compounds of Formula I above, and pharmaceutically acceptable salts thereof, are HTV reverse transcriptase inhibitors. The compounds are useful for inhibiting HTV reverse transcriptase and for inhibiting HTV replication in vitro and in vivo. More particularly, the compounds of Formula I inhibit the polymerase function of HTV-1 reverse transcriptase. Based upon the testing of representative compounds of the invention in the assay set forth in Example 21 below, it is known that the compounds of Formula I inhibit the RNA-dependent DNA polymerase activity of HTV-1 reverse transcriptase. A first embodiment of the present invention is a method as set forth above in the

Summary of the Invention, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, U is O, S, S(O), S(0)2, NH, or N(Ci-4 alkyl); and all other variables are as originally defined

(i.e., as defined in the Summary of the Invention). The definition of U in this embodiment can equivalently and alternatively be expressed as being O, S, S(O), S(0)2, or N(R4), wherein R4 is H or C1 _ 4 alkyl. A second embodiment of the present invention is a method as set forth above, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, U is S, S(O), or S(0)2; and all other variables are as originally defined. A third embodiment of the present invention is a method as set forth above, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, U is S; and all other variables are as originally defined. A fourth embodiment of the present invention is a method as set forth above, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, V is Ci_6 alkylene; and all other variables are as originally defined or as defined in any one of the preceding embodiments. A fifth embodiment of the present invention is a method as set forth above, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, V is (CH2)i_2, CH(CH3), C(CH₃)2, CH(CH₃)CH₂, CH₂CH(CH₃), CH(CH₃)CH(CH₃), C(CH₃)2CH₂, CH₂C(CH₃)2, C(CH3)2CH(CH3), CH(CH3)C(CH3)₂, or C(CH3)2C(CH3)2; and all other variables are as originally defined or as defined in any one of the preceding embodiments. A sixth embodiment of the present invention is a method as set forth above, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, V is CH2, CH(CH3), or CH2CH2; and all other variables are as originally defined or as defined in any one of the preceding embodiments. A seventh embodiment of the present invention is a method as set forth above, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, V is CH2; and all other variables are as originally defined or as defined in any one of the preceding embodiments. An eighth embodiment of the present invention is a method as set forth above, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, W is C(0)N(R2); and all other variables are as originally defined or as defined in any one of the preceding embodiments. A ninth embodiment of the present invention is a method as set forth above, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, W is a direct bond linking V to R3; and all other variables are as originally defined or as defined in any one of the preceding embodiments. A tenth embodiment of the present invention is a method as set forth above, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, W is C(0)NH, C(0)N(Cι_4 alkyl), or a direct bond linking V to R ; and all other variables are as originally defined or as defined in any one of the preceding embodiments. The definition of W in this embodiment can equivalently and alternatively be expressed as being C(0)N(R2) or a direct bond linking V to R3, wherein R is H or Ci .4 alkyl. In an aspect of this embodiment, W is C(0)NH or C(0)N(Cι_4 alkyl). An eleventh embodiment of the present invention is a method as set forth above, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, W is C(0)NH, C(O)N(CH3), or a direct bond linking V to R3; and all other variables are as originally defined or as defined in any one of the preceding embodiments. A twelfth embodiment of the present invention is a method as set forth above, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, W is C(0)NH or C(O)N(CH3); and all other variables are as originally defined or as defined in any one of the preceding embodiments. In an aspect of this embodiment, W is C(0)NH. A thirteenth embodiment of the present invention is a method as set forth above, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, Rl is: (i) aryl selected from the group consisting of phenyl and naphthyl, wherein the aryl is: (a) optionally substituted with from 1 to 5 substituents each of which is independently -Cχ-4 alkyl, -O-Ci-4 alkyl, -Ci-4 haloalkyl, -O-C1.4 haloalkyl, -OH, halogen, -CN, -NO2, -NH2, -NH-C1 -4 alkyl, -N(Cι .4 alkyl)2, -C(0)NH2, -C(0)NH-Ci-4 alkyl, -C(0)N(Ci-4 alkyl)2, -C(O)-Cι_4 alkyl, -CO2-C1.4 alkyl, -S-C1-4 alkyl, -S(O)-Cj_.-4 alkyl, -SO2-C1-4 alkyl, -SO2NH2, -SO2NH-C1.4 alkyl, -SO2N(Ci_4 alkyl)2, -Sθ2NHC(0)-Cι_4 alkyl, -Sθ2N(Cι_4 alkyl)C(O)-Cι_4 alkyl, NHC(0)-Cι_4 alkyl, or N(Cι_4 alkyl)C(0)-Cι_4 alkyl, and (b) optionally substituted with: (1) phenyl, which is optionally substituted with from 1 to 3 substituents each of which is independently halogen, -CN, -NO2, -C1.4 alkyl, -O-C1- 4 alkyl, -C1-4 haloalkyl, or -O-C1.4 haloalkyl, (2) CH2-phenyl, where the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently halogen, -CN, -NO2, -C1.4 alkyl, -O-Ci-4 alkyl, -Cl-4 haloalkyl, or -O-C1.4 haloalkyl, (3) HetA, (4) CH2-HetA, (5) -Sθ2NH-HetA, or (6) -Sθ2N(C 1 _4 alkyl)-HetA, or (ii) heteroaryl, which is: (a) a 5-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from 1 to 4 N atoms, zero or 1 O atom, and zero or 1 S atom, where each N is optionally in the form of an oxide, and where the heteroaromatic ring is optionally substituted with from 1 to 3 substituents each of which is independently halogen, -Cι_4 alkyl, -Cl-4 haloalkyl, -O-Ci -4 alkyl, -O-C1.4 haloalkyl, -C(0)-Cι _4 alkyl, -CO2-C1-4 alkyl, or -CN, (b) a 6-membered heteroaromatic ring containing 1 or 2 N atoms, where each N is optionally in the form of an oxide, and where the heteroaromatic ring is optionally fused with a benzene ring, and where the optionally fused heteroaromatic ring is optionally substituted with from 1 to 3 substituents each of which is independently halogen, -C1 -4 alkyl, -Cχ-4 haloalkyl, -O-Ci-4 alkyl, -O-C1-4 haloalkyl, -C(0)-Cι_4 alkyl, -Cθ2-Cι_4 alkyl, or -CN, or (c) a bicyclic heteroaromatic ring which is a benzene ring fused with a 5- or 6- membered saturated heterocyclic ring containing from 1 to 3 heteroatoms independently selected from N and O, wherein the saturated heterocyclic ring is optionally substituted with 1 or 2 oxo groups; with the proviso that Rl is not unsubstituted phenyl; and all other variables are as originally defined or as defined in any one of the preceding embodiments. A fourteenth embodiment of the present invention is a method as set forth above, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, Rl is: (i) naphthyl, (ii) substituted aryl selected from the group consisting of substituted phenyl and substituted naphthyl, wherein the substituted aryl has from 1 to 6 substituents wherein: (a) from zero to 5 substituents are independently selected from the group consisting of -Cl-4 alkyl, -O-Ci-4 alkyl, -Cl-4 haloalkyl, -O-Ci-4 haloalkyl, -OH, halogen, -CN, -NO2, -NH2, -NH-C1-4 alkyl, -N(Cι_4 alkyl)2, -C(0)NH2, -C(0)NH-Cι_4 alkyl, -C(O)N(Cι_4 alkyl)2, -C(0)-Cι_4 alkyl, -CO2-C1.4 alkyl, -S-Ci-4 alkyl, -S(0)-Ci-4 alkyl, -SO2-C1-4 alkyl, -SO2NH2, -SO2NH-C1-4 alkyl, -Sθ2N(Cι . 4 alkyl)2, -Sθ2NHC(0)-Cι_4 alkyl, and -Sθ2N(Cι_4 alkyl)C(0)-Cι _4 alkyl, and (b) an optional substituent is phenyl (i.e., the substituted aryl contains either no phenyl substituent or 1 phenyl substituent), wherein the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently halogen, -CN, -NO2, -Ci-4 alkyl, -O-C1 -4 alkyl, -C1.4 haloalkyl, or -O-C1.4 haloalkyl, or (iii) heteroaryl selected from the group consisting of quinolinyl, isoquinolinyl, benzo-1,3- dioxolyl, and 2,3-dihydrobenzo-l,4-dioxinyl, where the heteroaryl is optionally substituted with from 1 to 3 substituents each of which is independently halogen, -Cl-4 alkyl, -Ci-4 haloalkyl, -O-Ci-4 alkyl, or-O-Ci-4 haloalkyl; and all other variables are as originally defined or as defined in any one of the preceding embodiments. A fifteenth embodiment of the present invention is a method as set forth above, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, Rl is naphthyl, quinolinyl, isoquinolinyl, benzo-l,3-dioxolyl, or 2,3-dihydrobenzo-l,4-dioxinyl, substituted phenyl, or substituted naphthyl, wherein the substituted phenyl or substituted naphthyl has from 1 to 4 substituents wherein: (i) from zero to 3 substituents are independently selected from the group consisting of -C1.4 alkyl, -O-Ci-4 alkyl, -C1- haloalkyl, -O-C1.4 haloalkyl, -OH, halogen, -CN, -NO2, -NH2, -NH-Ci-4 alkyl, -N(Ci-4 alkyl)2, -C(0)NH2, -C(0)NH-Cι_4 alkyl, -C(0)N(Cι_4 alkyl)2, -C(0)-Cι_4 alkyl, -Cθ2-Cι_4 alkyl, -S-C1.4 alkyl, -S(0)-Cι_4 alkyl, -SO2-C1.4 alkyl, -SO2NH2, -SO2NH-C1-4 alkyl, -Sθ2N(Cι _4 alkyl)2, -Sθ2NHC(0)-Ci-4 alkyl, and -SO2N(Ci _4 alkyl)C(0)-Cι_4 alkyl; and (ii) an optional substituent is phenyl; and and all other variables are as originally defined or as defined in any one of the preceding embodiments. A sixteenth embodiment of the present invention is a method as set forth above, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, Rl is: (1) phenyl substituted with from 1 to 3 substituents each of which is independently halogen, -CN, -NO2, -C1-3 alkyl, -O-C1-3 alkyl, -C(0)-Cι.₃ alkyl, -N(Ci-3 alkyl)₂, (2) phenyl substituted with phenyl, (3) 1-naphthyl optionally substituted with -N(Cι_3 alkyl)2, (4) quinolinyl, (5) isoquinolinyl, (6) 1,3-benzodioxolyl, or (7) 2,3-dihydro-l ,4-benzodioxinyl; and all other variables are as originally defined or as defined in any one of the preceding embodiments. A seventeenth embodiment of the present invention is a method as set forth above, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, Rl is (1) 2- halophenyl, (2) 2,3-dihalophenyl, (3) 2,5-dihalophenyl, (4) 2,6-dihalophenyl, (5) 2-halo-6-(Cl-4 alkyl)phenyl, (6) 2-(Cι_4 alkyl)phenyl, (7) 2,6-di-(Ci-4 alkyl)phenyl, (8) 2,4,6-tri-(Cι_4 alkyl)phenyl, (9) l,l'-biphenyl-2-yl, (10) 1-naphthyl, (11) 4-dimethylamino- 1-naphthyl, (12) 5- or 6- or 7- or 8-quinolinyl, or (13) 5- or 6- or 7- or 8-isoquinolinyl; and all other variables are as originally defined or as defined in any one of the preceding embodiments. An eighteenth embodiment of the present invention is a method as set forth above, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, Rl is selected from the group consisting of 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 2,3- dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 2-chloro-6-methylphenyl, 2,6-dimethyl-4- bromophenyl, 1-naphthyl, 4-dimethylamino-l-naphthyl, 4-ethoxyphenyl, 2-methylphenyl, 4-methylphenyl, 3,4-dimethylphenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 2,4,6-trimethylphenyl (alternatively referred to as 1-mesityl), 4-dimethylaminophenyl, 2-nitro-4-methylphenyl, 3-cyanophenyl, 2-isopropylphenyl, 2-phenylphenyl (alternatively referred to as l,l'-biphenyl-2-yl),l-isoquinolin-5-yl, l,3-benzodioxol-5-yl, and 2,3-dihydro-l,4-benzodioxin-6-yl; and all other variables are as originally defined or as defined in any one of the preceding embodiments. A nineteenth embodiment of the present invention is a method as set forth above, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, Rl is 2-chlorophenyl, 2-bromophenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 2-chloro-6- methylphenyl, 2-methylphenyl, 2,6-dimethylphenyl, 2,4,6-trimethylphenyl, l,l'-biphenyl-2-yl, 1- naphthyl, 4-dimethylamino-l-naphthyl, or 5-isoquinolinyl; and all other variables are as originally defined or as defined in any one of the preceding embodiments. In an aspect of this embodiment, Rl is 2-chlorophenyl, 2-bromophenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 2,6-dimethylphenyl, 2,4,6-trimethylphenyl, 1-naphthyl, 4-dimethylamino-l-naphthyl, or 5-isoquinolinyl. hi another aspect of this embodiment, Rl is 2-bromophenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, 2,6- dichlorophenyl, 2,6-dimethylphenyl, 2,4,6-trimethylphenyl, 1-naphthyl, 4-dimethylamino-l-naphthyl, or 5-isoquinolinyl. In still another aspect of this embodiment, Rl is 2,4,6-trimethylphenyl. A twentieth embodiment of the present invention is a method as set forth above, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, R (i) aryl selected from the group consisting of phenyl and naphthyl, wherein the aryl is: (a) optionally substituted with from 1 to 5 substituents each of which is independently -Cχ-4 alkyl, -O-Ci-4 alkyl, -Ci-4 haloalkyl, -0-Cχ _4 haloalkyl, -OH, halogen, -CN, -NO2, -NH2, -NH-C1.4 alkyl, -N(Ci-4 alkyl)2, -C(0)NH2, -C(O)NH-Ci-4 alkyl, -C(0)N(Ci-4 alkyl)2, -C(0)-Cι_4 alkyl, -CO2-C1-4 alkyl, -S-C1-4 alkyl, -S(0)-Cι_4 alkyl, -SO2-C1. alkyl, -SO2NH2, -SO2NH-C1.4 alkyl, -Sθ2N(Cι _4 alkyl)2, -Sθ2NHC(0)-Cι_4 alkyl, -Sθ2N(Cι_4 alkyl)C(O)-Cι_4 alkyl, NHC(O)-Cι_4 alkyl, or N(Cι_4 alkyl)C(0)-Ci-4 alkyl, and (b) optionally substituted with: (1) phenyl, which is optionally substituted with from 1 to 3 substituents each of which is independently halogen, -CN, -NO2, -Cχ_4 alkyl, -0-Cι_ 4 alkyl, -Cl-4 haloalkyl, or -O-C1-4 haloalkyl, (2) CH2-phenyl, where the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently halogen, -CN, -NO2, -Ci_4 alkyl, -O-Cχ-4 alkyl, -Cχ-4 haloalkyl, or -O-Ci-4 haloalkyl, (3) HetA, (4) CH2-HetA, (5) -Sθ2NH-HetA, or (6) -SO2N(Ci_4 alkyl)-HetA, or (ii) heteroaryl, which is: (a) a 5-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from 1 to 4 N atoms, zero or 1 O atom, and zero or 1 S atom, where each N is optionally in the form of an oxide, and where the heteroaromatic ring is optionally substituted with from 1 to 3 substituents each of which is independently halogen, -Cl_4 alkyl, -Cι_4 haloalkyl, -O-Cχ-4 alkyl, -0-Cχ_4 haloalkyl, -C(0)-Cχ_4 alkyl, -CO2-CX.4 alkyl, or -CN, (b) a 6-membered heteroaromatic ring containing 1 or 2 N atoms, where each N is optionally in the form of an oxide, and where the heteroaromatic ring is optionally fused with a benzene ring, and where the optionally fused heteroaromatic ring is optionally substituted with from 1 to 3 substituents each of which is independently halogen, -Cχ_4 alkyl, -Cχ_4 haloalkyl, -O-Cχ-4 alkyl, -O-Cχ-4 haloalkyl, -C(0)-Cχ_4 alkyl, -CO2-CX.4 alkyl, or -CN, or (c) a bicyclic heteroaromatic ring which is a benzene ring fused with a 5- or 6- membered saturated heterocyclic ring containing from 1 to 3 heteroatoms independently selected from N and O, wherein the saturated heterocyclic ring is optionally substituted with 1 or 2 oxo groups; and all other variables are as originally defined or as defined in any one of the preceding embodiments. A twenty-first embodiment of the present invention is a method as set forth above, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, R3 is: (i) aryl selected from the group consisting of phenyl and naphthyl, wherein the aryl is: (a) optionally substituted with from 1 to 5 substituents each of which is independently -Cχ. alkyl, -O-Cχ-4 alkyl, -Cχ-4 haloalkyl, -0-Cχ_4 haloalkyl, -OH, halogen, -CN, -NO2, -NH2, -NH-Cχ.4 alkyl, -N(Cχ-4 alkyl)2, -C(O)NH2, -C(0)NH-Cχ_4 alkyl, -C(0)N(Cχ-4 alkyl)2, -C(0)-Cχ_4 alkyl, -Cθ2-C _4 alkyl, -S-Cχ-4 alkyl, -S(0)-Cχ_4 alkyl, -SO2-CX.4 alkyl, -SO2NH2, -SO2NH-CX.4 alkyl, -Sθ2N(Cχ_4 alkyl)2, -Sθ2NHC(0)-Cχ-4 alkyl, -Sθ2N(Cχ-4 alkyl)C(0)-Cχ_4 alkyl, NHC(O)-Cχ-4 alkyl, or N(Cχ_4 alkyl)C(O)-Cχ_4 alkyl , and (b) optionally substituted with: (1) phenyl, which is optionally substituted with from 1 to 3 substituents each of which is independently halogen, -CN, -NO2, -Cχ.4 alkyl, -0-Cχ_ 4 alkyl, -Cχ-4 haloalkyl, -O-Cχ-4 haloalkyl, (2) HetA, or (3) -Sθ2NH-HetA, or (ii) heteroaryl selected from the group consisting of thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyridinyl N-oxide, pyrimidinyl, quinolinyl, isoquinolinyl, 2,3-dihydrobenzo-l,4-dioxinyl, benzo-l,3-dioxolyl, and 2,3- dihydro-lH-isoindolyl optionally substituted with 1 or 2 oxo groups; wherein the heteroaryl is optionally substituted with from 1 to 3 substituents each of which is independently halogen, -C _4 alkyl, -Cχ_4 haloalkyl, -O-Cχ.4 alkyl, -O-Cχ.4 haloalkyl, -CN, -C(0)-Cχ_4 alkyl, or -Cθ2-Cχ_4 alkyl; and all other variables are as originally defined or as defined in any one of the preceding embodiments. A twenty-second embodiment of the present invention is a method as set forth above, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, R is phenyl, thienyl, isoxazoyl, pyridinyl, quinolinyl, isoquinolinyl, or 2,3-dihydro-lH-isoindolyl optionally substituted with 1 or 2 oxo groups, wherein: (i) the phenyl is: (a) optionally substituted with from 1 to 3 substituents each of which is independently -Cχ.4 alkyl, -O-Cχ-4 alkyl, -Cχ-4 haloalkyl, -O-Cχ.4 haloalkyl, -OH, halogen, -CN, -NO2, -NH2, -NH-Cχ-4 alkyl, -N(Cχ_4 alkyl)2, -C(O)NH2, -C(0)NH-Cχ_4 alkyl, -C(0)N(Cχ_4 alkyltø, -C(0)-Cχ_4 alkyl, -CO2-CX.4 alkyl, -S-C1.4 alkyl, -S(0)-Cχ_4 alkyl, -Sθ2-Cχ_4 alkyl, -SO2NH2, -SO2NH-CX.4 alkyl, -Sθ2N(Cχ_4 alkyl)2, -Sθ2NHC(0)-Cχ-4 alkyl, -Sθ2N(Cχ_4 alkyl)C(0)-Cχ_4 alkyl, NHC(0)-Cχ_4 alkyl, or N(Cχ_4 alkyl)C(O)-Cχ-4 alkyl; and (b) optionally substituted with phenyl, pyrazolyl, or -Sθ2NH-oxazolyl where the oxazolyl is optionally substituted with 1 or 2 -Cχ-4 alkyl, (ii) the pyridinyl or the isoxazolyl is optionally substituted with 1 to 3 substituents each of which is independently -Cχ.4 alkyl, -0-Cχ_4 alkyl or halogen, and (iii) the thienyl is optionally substituted with 1 to 3 substituents each of which is independently -Cχ_4 alkyl, halogen, CN, -Cθ2-Cχ_4 alkyl, or -C(0)-Cχ_4 alkyl; and all other variables are as originally defined or as defined in any one of the preceding embodiments. A twenty-third embodiment of the present invention is a method as set forth above, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, R is: (1) phenyl substituted with 1 or 2 substituents each of which is independently -Cχ-3 alkyl, -O-Cχ-3 alkyl, -Cχ.3 fluoroalkyl, -0-Cχ_3 fluoroal yl, halogen, -CN, -NO2, -NH2, -NH-Cχ-3 alkyl, -N(Cι _3 alkyl)2, -C(O)NH2, -C(O)-Cχ_3 alkyl, -Cθ2-Cχ_3 alkyl, -SO2NH2, or -NHC(0)-Cχ_3 alkyl, (2) phenyl substituted with pyrazolyl or -Sθ2NH-oxazolyl where the oxazolyl is optionally substituted with 1 or 2 -Cχ_3 alkyl, (3) isoxazolyl optionally substituted with 1 or 2 -Cχ_3 alkyl, (4) pyridinyl optionally substituted with 1 or 2 substituents each of which is independently halogen, -Cχ_3 alkyl, or -O-Cχ.3 alkyl, (5) thienyl optionally substituted with 1 or 2 substituents each of which is independently -Cχ-4 alkyl, CN, -Cθ2-Cχ_4 alkyl, or -C(0)-Cχ₇4 alkyl, (6) quinolinyl, (7) isoquinolinyl, or (8) l,3-dioxo-2,3-dihydro-lH-isoindolyl; and all other variables are as originally defined or as defined in any one of the preceding embodiments. A twenty-fourth embodiment of the present invention is a method as set forth above, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, R3 is: (1) phenyl substituted with 1 or 2 substituents each of which is independently -Cχ_3 alkyl, -O-Cχ-3 alkyl, -Cχ_3 fluoroalkyl, -O-Cχ.3 fluoroalkyl, halogen, -CN, -NO2, -NH2, -NH-Cχ-3 alkyl, -N(Cχ_3 alkyl)2, -C(O)NH2, -C(0)-Cχ_3 alkyl, -Cθ2-Cχ_3 alkyl, -SO2NH2, or -NHC(0)-Cχ_3 alkyl, wherein one substituent is in the 2-position of the phenyl ring, (2) 5- or 6- or 7- or 8-quinolinyl, (3) 5- or 6- or 7- or 8-isoquinolinyl, (4) 2-pyridinyl, optionally substituted with 1 or 2 substituents each of which is independently halogen, -Cχ_3 alkyl, or -O-Cχ_3 alkyl, or (5) 3-pyridinyl substituted with 1 or 2 substituents each of which is independently halogen, -Cχ_3 alkyl, or -0-Cχ_3 alkyl, wherein one substituent is in the 2-position of the pyridinyl ring; and all other variables are as originally defined or as defined in any one of the preceding embodiments. A twenty-fifth embodiment of the present invention is a method as set forth above, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, R3 is selected from the group consisting of phenyl, 2-acetylphenyl, 4-acetylphenyl, 2-(aminocarbonyl)phenyl, 4- (aminosulfonyl)phenyl, 2-aminophenyl, 2-bromophenyl, 2-bromo-4-fluorophenyl, 2-bromo-4- methylphenyl, 2-chlorophenyl, 2-chloro-4-cyanophenyl, 2-chloro-4-fluorophenyl, 2-chloro-4- (aminocarbonyl)phenyl, 2-chloro-4-(aminosulfonyl)phenyl, 2-chloro-4-(methoxycarbonyl)phenyl, 2- chloro-4-methylphenyl, 2-chloro-5-methylphenyl, 2-chloro-5-(acetylamino)phenyl, 2-chloro-4- nitrophenyl, 2-chloro-5-nitrophenyl, 2-cyanophenyl, 4-cyanophenyl, 2-cyano-3-fluorophenyl, 2-cyano-3- chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichorophenyl, 2-(difluoromethoxy)phenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,3-dimethylphenyl, 2-fluorophenyl, 2- fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2-fluoro-4-chlorophenyl, 2-iodophenyl, 2- methoxyphenyl, 2-(methoxycarbonyl)phenyl, 2-methoxy-4-nitrophenyl, 2-methylphenyl, 2-methyl-4- (aminosulfonyl)phenyl, 2-methyl-3-fluorophenyl, 2-methyl-4-fluorophenyl, 2-methyl-3- (methoxycarbonyl)phenyl, 2-methyl-4-methoxyphenyl, 2-methyl-4-(methoxycarbonyl)phenyl, 2-methyl- 4-nitrophenyl, 2-nitrophenyl, 3-nitrophenyl, 3-nitro-4-methylphenyl, 2-nitro-4-chlorophenyl, 2-nitro-4- fluorophenyl, 2-nitro-4-methoxyphenyl, 4-{ [(4,5-dimethyl-l,3-oxazol-2-yl)amino]sulfonyl}phenyl, 2-(trifluoromethyl)phenyl, 4-(lH-pyrazol-l-yl)phenyl, 2-pyridinyl, 2-(6-bromopyridinyl), 2-(5- chloropyridinyl), 3-(2-chloropyridinyl), 3-(2-bromopyridinyl), 3-(2,6-dichloropyridinyl), 3-(2- methoxypyridinyl), 3-(5-methylisoxazolyl), 3-(2-acetylthienyl), 2-(3-cyanothienyl), 3-[2-

(methoxycarbonyl)thienyl], 4-(l,3-dioxo-2,3-dihydro-lH-isoindolyl), 5-quinolinyl, and 8-quinolinyl; and all other variables are as originally defined or as defined in any one ofthe preceding embodiments. A twenty-sixth embodiment of the present invention is a method as set forth above, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, R is 2- nitrophenyl, 2-chlorophenyl, 3-(2-chloro)pyridinyl, 2-methyl-4-(aminosulfonyl)phenyl, 2-chloro-4~ fluorophenyl, 2-chloro-4-(methoxycarbonyl)phenyl, 8-quinolinyl, 2-nitro-4-methoxyphenyl, 2-chloro-4- (aminosulfonyl)phenyl, or 2-chloro-4-(aminocarbonyl)phenyl; and all other variables are as originally defined or as defined in any one of the preceding embodiments. A twenty-seventh embodiment of the present invention is a method as set forth above, wherein the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from the group consisting ofthe compounds listed in Table 3 below. In an aspect of this embodiment, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of compounds 5, 6, 10, 11, 31, 44, 47, 53, 54, 58, 61-63, 73, 75, 81 and 108-110 in Table 3. A twenty-eighth embodiment of the present invention is a method as set forth above, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, U is O, S, S(O), S(O)2, NH, or N(Cχ_4 alkyl); V is Cχ_6 alkylene; W is C(0)NH, C(0)N(Cχ_4 alkyl), or a direct bond linking V to R3; Rl is as defined above in the thirteenth embodiment; and R3 is as defined above in the twentieth embodiment. In an aspect of this embodiment, each HetA in the definition of Rl and R is independently a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from zero to 4 N atoms, zero or 1 O atom, and zero or 1 S atom, wherein each N atom is optionally in the form of an oxide, and wherein the heteroaromatic ring is optionally substituted with from 1 to 3 substituents each of which is independently halogen, -Cχ_4 alkyl, -Cχ-4 haloalkyl, -0-Cχ_4 alkyl, or -O-Cχ.4 haloalkyl. A twenty-ninth embodiment of the present invention is a method as set forth above, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, U is O, S, S(O), S(0)2, NH, or N(Cχ_4 alkyl); V is Cχ_6 alkylene; W is C(0)NH, C(0)N(Cχ_4 alkyl), or a direct bond linking V to R3; Rl is as defined above in the fourteenth embodiment; and R is as defined above in the twenty-first embodiment. In an aspect of this embodiment, HetA in the definition of R is HetA is a heteroaromatic ring selected from the group consisting of pyridinyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, and oxadiazolyl, wherein the heteroaromatic ring is optionally substituted with from 1 to 3 substituents each of which is independently halogen, -Cχ. alkyl, -Cχ-4 haloalkyl, -O-Cχ.4 alkyl, or-O-Cχ-4 haloalkyl. A thirtieth embodiment of the present invention is a method as set forth above, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, U is S, S(O) or S(0)2", V is CH2, CH(CH3), or CH2CH2; W is C(0)NH, C(0)N(Cχ_4 alkyl), or a direct bond linking V to R3; and Rl and R3 are each as defined in the twenty-ninth embodiment. A thirty-first embodiment of the present invention is a method as set forth above, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, U is S; V is CH2; W is C(O)NH, C(0)N(CH3), or a direct bond linking V to R3; Rl is as defined above in the fifteenth embodiment; and R3 is as defined above in the twenty-second embodiment. A thirty-second embodiment of the present invention is a method as set forth above, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, U is S; V is CH2; W is C(O)NH or C(0)N(CH3); Rl is as defined above in the sixteenth embodiment; and R3 is as defined above in the twenty-third embodiment. In an aspect of this embodiment, Rl is 2-bromophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 2,6-dimethylphenyl, 2,4,6- trimethylphenyl, 1-naphthyl, 4-dimethylamino-l-naphthyl, or 5-isoquinolinyl. A thirty-third embodiment of the present invention is a method as set forth above, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, U is S; V is CH2; W is C(0)NH or C(0)N(CH3); Rl is as defined above in the sixteenth embodiment; and R is as defined above in the twenty-fourth embodiment, i an aspect of this embodiment, R3 is 2-nitrophenyl, 2-chloroρhenyl, 3-(2-chloro)pyridinyl, 2-methyl-4-(aminosulfonyl)phenyl, 2-chloro-4-fluorophenyl, 2- chloro-4-(methoxycarbonyl)phenyl, 8-quinolinyl, 2-nitro-4-methoxyphenyl, 2-chloro-4- (aminosulfonyl)phenyl, or 2-chloro-4-(aminocarbonyl)phenyl. In the method of the invention as originally described in the Summary of the Invention or as described in any of the foregoing embodiments, or aspects thereof, the compound of Formula I, or a pharmaceutically acceptable salt thereof, can be administered per se or as an active ingredient of a pharmaceutical composition comprising a pharmaceutically acceptable carrier. The present invention also includes certain compounds of Formula I and their pharmaceutically acceptable salts. In particular, a thirty-fourth embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein V is Cχ_6 alkylene; Rl is: (1) 2-halophenyl, (2) 2,3-dihalophenyl, (3) 2,5-dihalophenyl, (4) 2,6-dihalophenyl, (5) 2-halo-6-(Cχ_4 alkyl)phenyl, (6) 2-(Cχ_4 alkyl)phenyl, (7) 2,6-di-(Cχ_4 alkyl)phenyl, (8) 2,4,6-tri-(Cχ_4 alkyl)phenyl, (9) l,l'-biphenyl-2-yl, (10) 1-naphthyl, (11) 4-dimethylamino-l-naphthyl, (12) 5- or 6- or 7- or 8-quinolinyl, or (13) 5- or 6- or 7- or 8-isoquinolinyl; and U, W and R3 are each as originally defined or as defined in any one of the preceding embodiments; and with the proviso that the compound is not one of the compounds listed in Table 1. hi an aspect of this embodiment, Rl is: (1) 2-chlorophenyl, (2) 2- bromophenyl, (3) 2,3-dichlorophenyl, (4) 2,5-dichlorophenyl, (5) 2,6-dichlorophenyl, (6) 2-chloro-6- methylphenyl, (7) 2-methylphenyl, (8) 2,6-dimethylphenyl, (9) 2,4,6-trimethylphenyl, (10) l,l'-biphenyl- 2-yl, (11) 1-naphthyl, (12) 4-dimethylamino-l-naphthyl, or (13) 5-isoquinolinyl.

Table 1 Compound (l) N-(2-chlorophenyl)-2-[(l-mesityl-lH-tetrazol-5-yl)thio]acetamide, (2) N-(5-bromo-8-quinolinyl)-2-[(l-mesityl-lH-tetrazol-5-yl)thio]acetamide, (3) N-[4-(chlorodifluoromethoxy)phenyl]-2-[(l-mesityl-lH-tetrazol-5-yl)thio]acetamide, (4) N-[4-(trifluoromethoxy)phenyll-2-[(l-mesityl-lH-tefrazol-5-yl)thio]acetamide, (5) N-[4-(ethoxycarbonyl)phenyl]-2-[(l-mesityl-lH-tetrazol-5-yl)thio]acetamide, (6) N-mesityl-2-[(l-mesityl-lH-tetrazol-5-yl)thio]acetamide, (7) N-(3-chloro-4-methoxyphenyl)-2-[(l-mesityl-lH-tetrazol-5-yl)thio]acetamide, (8) N-[(2-methoxycarbonyl)phenyl]-2-[(l-(l-naphthyl)-lH-tetrazol-5-yl)thio]acetamide, (9) N-(4-fluorophenyl)-2-[(l-(l-naphthyl)-lH-tetrazol-5-yl)thio]acetamide, (10) N-(4-isopropylphenyl)-2-[(l-(l-nap thyl)-lH-tetrazol-5-yl)thio]acetamide, (ll) N-(4-ethoxyphenyl)-2-[(l-(l-naphthyl)-lH-tetrazol-5-yl)thio]acetamide, (12) N-phenyl-2-[(l-(l-naphthyl)-lH-tetrazol-5-yl)thio]acetamide, (13) N-(4-ethylphenyl)-2-[(l-(l-naphthyl)-lH-tetrazol-5-yl)thio]acetamide, (14) N-(2,3-dimethylphenyl)-2-[(l-(l-naphthyl)-lH-tetrazol-5-yl)thio]acetamide,

(15) N-mesityl-2-[(l-(l-naphthyl)-lH-tetrazol-5-yl)thio]acetamide,

(16) N-(2-fluorophenyl)-2-[(l-(l-naphthyl)-lH-tetrazol-5-yl)thio]acetamide,

(17) N-((2-nitrophenyl)-2-[(l-(l-naphthyl)-lH-tetrazol-5-yl)thio]acetamide,

(18) N-[2-methyl-3-phenyl-4-(ethoxycarbonyl)mien-5-yl]-2-[(l-(2-methylphenyl)-lH-tetrazol-5- yl)thio] acetamide, (19) N-(3-nitro-4-fluorophenyl)-2-[(l-(2-methylphenyl)-lH-tetrazol-5-yl)thio]acetamide, (20) N-(2-nitro-4-ethoxyphenyl)-2-[(l-(2-methylphenyl)-lH-tetrazol-5-yl)thio]acetamide, (21) N-{2-chloro-5-[(N^,-phenyl-N'-ethyl)aminosulfonyl]phenyl}-2-[(l-(2-methylphenyl)-lH- tetrazol-5-yl)mio]acetamide, (22) N-phenyl-N-isopropyl-2-[(l-(2-methylphenyl)-lH-tetrazol-5-yl)thio]acetaιnide, (23) N-(2-tjifluoromethyl-4-chlorophenyl)-2-[(l-(2-methylphenyl)-lH-tetrazol-5- yl)thio] acetamide, (24) N-[4-(trifluoromethoxy)phenyl]-2-[(l-(2,6-dimethylphenyl)-lH-tetrazol-5- yl)thio]acetamide, (25) N-(l,3-benzodioxol-5-yl)-2-[(l-(2,6-dimethylphenyl)-lH-tetrazol-5-yl)thio]acetamide, (26) N-[4-(ethoxycarbonyl)phenyl]-2-[(l-(2,6-dimethylphenyl)-lH-tetrazol-5-yl)thio]acetamide, (27) N-[4-(chlorodifluoromethoxy)phenyl]-2-[(l-(2-chlorophenyl)-lH-tetrazol-5- yl)thio]acetamide, (28) N-(4-bromophenyl)-2-[(l-(2-chlorophenyl)-lH-tetrazol-5-yl)thio]acetamide, (29) N-(2,3-dihydro-l,4-benzodioxin-6-yl)-2-[(l-(2-chlorophenyl)-lH-tetrazol-5- yl)thio] acetamide, (30) N-[4-(methoxycarbonyl)phenyl]-2-[(l-(2-chlorophenyl)-lH-tetrazol-5-yl)thio]acetamide, (31) N-[2,3-dimethyl-4-(ethoxycarbonyl)mien-5-yl]-2-[(l-(2-fluorophenyl)-lH-tetrazol-5- y l)thio] acetamide, (32) N-[2-acetyl-3-methyl-4-(ethoxycarbonyl)thien-5-yl]-2-[(l-(2-fluorophenyl)-lH-tetrazol-5- yl)thio] acetamide, (33) N-[4-(acetylamino)phenyl]-2-[(l-(2-fluorophenyl)-lH-tetrazol-5-yl)thio]acetamide,

(34) N-(2-methoxyphenyl)-2-[(l-(2-fluorophenyl)-lH-tetrazol-5-yl)thio]acetamide,

(35) N-(2,5-dimethoxyphenyl)-2-[( l-(2-fluorophenyl)- lH-tetrazol-5-yl)thio]acetamide, (36) N-(3,4-dimethoxyphenyl)-2-[(l-(2-fluorophenyl)-lH-tetrazol-5-yl)thio]acetarnide, (37) N-[3-(acetylamino)phenyl]-2-[(l-(2-fluorophenyl)-lH-tetrazol-5-yl)thio]acetamide, (38) N-(2,4-dimethoxyphenyl)-2-[(l-(2-fluorophenyl)-lH-tetrazol-5-yl)thio]acetamide, (39) N-(2,3-dimethylphenyl)-2-[(l-(2-fluorophenyl)-lH-tetrazol-5-yl)thio]acetamide, (40) N-(4-methoxyphenyl)-2-[(l-(2-fluorophenyl)-lH-tetrazol-5-yl)thio]acetamide, (41) N-{3-(ethoxycarbonyl)-4,5,6,7-tetrahydrobenzo[b]thien-2-yl}-2-[(l-(2-fluorophenyl)-lH- tetrazol-5-yl)thio]acetamide, (42) N-(2-methylpyridin-6-yl)-2-[(l-(2-fluorophenyl)-lH-tetrazol-5-yl)thio]acetamide, (43) N-[4-(metlιoxycarbonyl)phenyl]-2-[(l-(2-chlorophenyl)-lH-tetrazol-5-yl)thio]acetamide, (44) N-(2-fluorophenyl)-2-[(l-(2-fluorophenyl)-lH-tetrazol-5-yl)thio]acetamide, (45) N-[4-(n-butoxycarbonyl)phenyl]-2-[(l-(2-fluorophenyl)-lH-tetrazol-5-yl)thio]acetamide, (46) N-(l,3-benzodioxol-5-yl)-2-[(l-(2-fluorophenyl)-lH-tetrazol-5-yl)thio]acetamide, (47) N-[3-methyl-4-(propanoylamino)phenyl]-2-[(l-(2-fluorophenyl)-lH-tetrazol-5- yl)thio] acetamide, (48) N-[2,3-dimethyl-4-(methoxycarbonyl)thien-5-yl]-2-[(l-(2-fluorophenyl)-lH-tetrazol-5- yl)thio] acetamide, (49) N-[2-(ethoxycarbonyl)phenyl]-2-[(l-(2-fluorophenyl)-lH-tetrazol-5-yl)thio]acetamide, (49) N-[2-(methoxycarbonyl)phenyl]-2-[(l-(2-fluorophenyl)-lH-tetrazol-5-yl)thio]acetamide, (50) N-(2,3-dihydro-l,4-benzodioxin-6-yl)-2-[(l-(2-fϊuorophenyl)-lH-tetrazol-5- yl)thio] acetamide, (51) N-(3,4-dimethylphenyl)-2-[(l-(2-fluorophenyl)-lH-tetrazol-5-yl)thiolacetamide, (52) N-(2-ethoxyphenyl)-2-[(l-(2-fluorophenyl)-lH-tetrazol-5-yl)thio]acetamide,

(53) N-[4-(isopropoxycarbonyl)phenyl]-2-[(l-(2-fluorophenyl)-lH-tetrazol-5-yl)thio]acetamide,

(54) N-[5-methylisoxazol-3-yl]-2-[(l-(2-fluorophenyl)-lH-tetrazol-5-yl)thio]acetamide, (55) N-methyl-N-(2-methylphenyl)-2-[(l-(2,5-dichlorophenyl)-lH-tetrazol-5-yl)oxy]acetamide, or (56) N-methyl-N-(2-methylphenyl)-2-[(l-(2-chloro-6-methylphenyl)-lH-tetrazol-5- yl)oxy] acetamide.

A thirty-fifth embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein U is S, S(O) or S(0)2; V is CH2, CH(CH3), or CH2CH2; W is C(0)NH or C(0)N(Cχ_4 alkyl); Rl is as defined in the thirty-fourth embodiment; and R is as defined in the twenty-first embodiment; and with the proviso that the compound is not one of compounds (1)-(17), (19), (20), (22)-(40), and (42)-(54) as listed in Table 1 above. A thirty-sixth embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein U is S; V is CH2; W is C(0)NH; Rl is 2-bromophenyl,

2,3-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 2,6-dimethylphenyl, 2,4,6-trimethylphenyl, 1-naphthyl, 4-dimethylamino-l-naphthyl, or 5-isoquinolinyl; and R3 is as defined in the twenty-first embodiment; and with the proviso that the compound is not one of compounds (1)-(17) and (24)-(26) as listed in Table 1 above. In an aspect of this embodiment, Rl is 2,4,6-trimethylphenyl, and with the proviso that the compound is not one of compounds (l)-(7) as listed in Table 1 above. A thirty-seventh embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, selected from the group consisting of compounds 7-11 , 15-23 and 25-110 as listed in Table 3 below. A thirty-eighth embodiment ofthe present invention is a method for inhibiting HTV reverse transcriptase, for treating or preventing HTV infection, or for preventing, treating or delaying the onset of AIDS, which comprises administering to a subject in need thereof an effective amount of a compound of Formula I as defined in any one of the thirty-fourth, thirty-fifth, thirty-sixth, and thirty- seventh embodiments, or a pharmaceutically acceptable salt thereof. In an aspect of this embodiment, the compound is administered per se. In another aspect of this embodiment, the compound is administered as an active ingredient of a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier. Other embodiments of the present invention include the following: (39) A pharmaceutical composition comprising an effective amount of a compound of Formula I as defined in any one of the thirty-fourth, thirty-fifth, thirty-sixth, and thirty-seventh embodiments, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. (40) A pharmaceutical composition which comprises the product prepared by combining (e.g., mixing) an effective amount of a compound of Formula I as defined in any one of the thirty-fourth, thirty-fifth, thirty-sixth, and thirty-seventh embodiments, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. (41) The pharmaceutical composition of (39) or (40), further comprising an effective amount of an HTV infection/AIDS treatment/prophylaxis agent selected from the group consisting of HTV/AIDS antiviral agents, immunomodulators, and anti-infective agents. (42) The pharmaceutical composition of (41), wherein the HTV infection AIDS agent is an antiviral selected from the group consisting of HTV protease inhibitors, HTV reverse transcriptase inhibitors other than a compound of Formula I, and HTV integrase inhibitors. (43) A pharmaceutical combination which is (i) a compound of Formula I as defined in any one of the thirty-fourth, thirty-fifth, thirty-sixth, and thirty-seventh embodiments, or a pharmaceutically acceptable salt thereof, and (ii) an HTV infection AIDS treatment/prophylaxis agent selected from the group consisting of HTV/AIDS antiviral agents, immunomodulators, and anti-infective agents; wherein the compound of Formula I and the HTV infection/ DDS treatment agent are each employed in an amount that renders the combination effective for inhibiting HTV integrase, for treating or preventing infection by HTV, or for preventing, treating or delaying the onset of AIDS. (44) The combination of (43), wherein the HTV infection/AIDS agent is an antiviral selected from the group consisting of HTV protease inhibitors, HTV reverse transcriptase inhibitors other than a compound of Formula I, and HTV integrase inhibitors. Still other embodiments of the present invention include the following: (45) A method for inhibiting HTV reverse transcriptase, for treating or preventing

HTV infection, or for preventing, treating or delaying the onset of AIDS, which comprises administering to a subject in need thereof a compound of Formula I as originally defined above, or a pharmaceutically acceptable salt thereof, in combination with another HTV infection/AIDS treatment/prophylaxis agent selected from the group consisting of HTV/AIDS antiviral agents, immunomodulators, and anti-infective agents; wherein the compound of Formula I and the HTV infection/AIDS agent are each employed in an amount that renders the combination effective for inhibiting HTV reverse transcriptase, for treating or preventing infection by HTV, or for preventing, treating or delaying the onset of AIDS. (46) The method of (45), wherein the other HTV infection/AIDS agent is selected from the group consisting of HTV protease inhibitors, HTV reverse transcriptase inhibitors other than a compound of Formula I, and HTV integrase inhibitors. (47) A method for inhibiting HTV reverse transcriptase, for treating or preventing HTV infection, or for preventing, treating or delaying the onset of AIDS, which comprises administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of a compound of Formula I as originally defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. (48) A method for inhibiting HTV reverse transcriptase, for treating or preventing HTV infection, or for preventing, treating or delaying the onset of AIDS, which comprises administering to a subject in need thereof a combination of (i) a pharmaceutical composition comprising a compound of Formula I as originally defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and (ii) another HTV infection/ATDS treatment/prophylaxis agent selected from the group consisting of HTV/AIDS antiviral agents, immunomodulators, and anti-infective agents; wherein the compound of Formula I and the HTV infection JDS agent are each employed in an amount that renders the combination effective for inhibiting HTV reverse transcriptase, for treating or preventing infection by HTV, or for preventing, treating or delaying the onset of AIDS. Additional embodiments of he invention include the methods set forth in embodiments (45)-(48) above, wherein the compound of Formula I employed therein is a compound as defined above in the earlier-described embodiments (and aspects thereof) ofthe method of the present invention. In the methods of the present invention involving a combination of active compounds

(e.g., a compound of Formula I and another HTV antiviral agent), it is understood that the active compounds can be administered separately or together, and when administered separately, the active compounds can be given concurrently or at different times (e.g., alternately). When the active compounds are administered together (either per se or more typically in a pharmaceutical composition), they can both be part of a single composition (e.g., an admixture of the compounds optionally including one or more excipients) or they can be in separate compositions (e.g., encapsulated compositions respectively containing one of the active compounds and optionally one or more excipients) that can be packaged together or separately. The present invention also includes a compound of Formula I (i) for use in, (ii) for use as a medicament for, or (iii) for use in the preparation of a medicament for: (a) inhibiting HTV reverse transcriptase, (b) preventing or treating infection by HTV, or (c) preventing, treating or delaying the onset of AIDS, these uses, the compounds ofthe present invention can optionally be employed in combination with one or more HTV/AIDS treatment/prophylaxis agents selected from HTV/AIDS antiviral agents, anti-infective agents, and immunomodulators. Additional embodiments of the invention include the uses set forth in the preceding paragraph, wherein the compound of Formula I employed therein is a compound as defined in the earlier- described embodiments (and aspects thereof) of the method of the present invention. In all of these embodiments, the compound can optionally be used in the form of a pharmaceutically acceptable salt and can be employed per se or as an active ingredient in a pharmaceutical composition comprising a pharmaceutically acceptable carrier. The present invention also includes a pharmaceutical composition or combination as set forth in any one of embodiments (39) to (44) (i) for use in, (ii) for use as a medicament for, or (iii) for use in the preparation of a medicament for: (a) inhibiting HTV reverse transcriptase, (b) preventing or treating infection by HTV, or (c) preventing, treating or delaying the onset of AIDS. In these uses, the compounds of the present invention can optionally be employed in combination with one or more HTV/AIDS treatment/prophylaxis agents selected from HTV/AIDS antiviral agents, anti-infective agents, and immunomodulators. As used herein, the term "alkyl" refers to any linear or branched chain alkyl group having a number of carbon atoms in the specified range. Thus, for example, "Cχ-6 alkyl" (or "Cχ-C6 alkyl") refers to all of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. As another example, "Cχ_4 alkyl" refers to n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. The term "alkylene" refers to any linear or branched chain alkylene group (or alternatively "alkanediyl") having a number of carbon atoms in the specified range. Thus, for example, "-Cχ_6 alkylene-" refers to any of the Cx to Cfi linear or branched alkylenes. A class of alkylenes of particular interest with respect to the invention is -(CH2)l-6-_> and sub-classes of particular interest include -(CH2)l-4-, -(CH2)χ_3-, -(CH2)χ_2-, and -CH2-. Also of interest is the alkylene -CH(CH3)-. The term "cydoalkyl" refers to any cyclic ring of an alkane having a number of carbon atoms in the specified range. Thus, for example, "C3.8 cydoalkyl" (or "C3-C8 cydoalkyl") refers to cyclopropyl, cyclobutyl, cyclopentyl, cydohexyl, cycloheptyl, and cyclooctyl. The term "halogen" (or "halo") refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro, chloro, bromo, and iodo). The term "haloalkyl" refers to an alkyl group as defined above in which one or more of the hydrogen atoms has been replaced with a halogen (i.e., F, CI, Br and/or I). Thus, for example, "Cχ_6 haloalkyl" (or "Cχ-C6 haloalkyl") refers to a Cx to C6 linear or branched alkyl group as defined above with one or more halogen substituents. The term "fluoroalkyl" has an analogous meaning except that the halogen substituents are restricted to fluoro. Suitable fluoroalkyls include the series (CH2)θ-4CF3 (i.e., trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-n-propyl, etc.). The term "aryl" refers to (i) phenyl or (ii) a 9- or 10-membered bicyclic, fused carbocylic ring system in which at least one ring is aromatic. A class of aryls suitable for use in the present invention is phenyl, naphthyl, and indenyl. Another class of suitable aryls is phenyl and naphthyl. A particularly suitable aryl is phenyl. The term "heteroaryl" refers to (i) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein each N is optionally in the form of an oxide, or (ii) a 9- or 10-membered bicyclic, fused ring system containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein either one or both of the rings contain a heteroatom, at least one ring is aromatic, each N is optionally in the form of an oxide, and each S in a ring which is not aromatic is optionally S(O) or S(0)2- Suitable heteroaryls include, for example, pyridinyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzodioxolyl, benzopiperidinyl, benzisoxazolyl, benzoxazolyl, chromenyl, chromanyl, isochromanyl, cinnolinyl, quinazolinyl, benzothienyl, benzofuranyl, imidazo[l,2-a]pyridinyl, benzotriazolyl, dihydroindolyl, dihydroisoindolyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl, quinazolinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo-l,4-

dioxinyl (i.e., Q° O) ), and benzo-l,3-dioxolyl (i.e.,

). A class of heteroaryls suitable for use in the present invention consists of 5- or 6- membered heteroaromatic rings containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein each N is optionally in the form of an oxide. Another class of suitable heteroaryls consists of 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from zero to 4 N atoms, zero or 1 O atom, and zero or 1 S atom, wherein each N atom is optionally in the form of an oxide. Heteroaryls belonging to this class include pyridinyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, and oxadiazolyl. Unless a contrary meaning is clear in a given context, any ofthe various aryl and heteroaryl groups defined herein are attached to the rest of the compound at any ring atom (i.e., any carbon atom or any heteroatom) provided that a stable compound results. Unless a contrary meaning is clear in a given context, all ranges cited herein are inclusive. For example, a heterocyclic ring described as containing from " 1 to 4 heteroatoms" means the ring can contain 1, 2, 3 or 4 heteroatoms. It is also to be understood that any range cited herein includes within its scope all of the sub-ranges within that range. Thus, for example, a heterocyclic ring described as containing from " 1 to 4 heteroatoms" is intended to include as aspects thereof, heterocyclic rings containing 1 to 4 heteroatoms, 2 to 4 heteroatoms, 3 or 4 heteroatoms, 1 to 3 heteroatoms, 2 or 3 heteroatoms, 1 or 2 heteroatoms, 1 heteroatom, 2 heteroatoms, 3 heteroatoms, or 4 heteroatoms. When any variable (e.g., RA, RB₎ AryA and HetA) occurs more than one time in any constituent or in Formula I or in any other formula depicting and describing compounds employed in the invention, 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. Mono- and poly-substitution by a named substituent (e.g., as in "is optionally substituted with from 1 to 5 substituents ...") is permitted to the extent such single and multiple substitution

(including multiple substitution at the same site) is chemically allowed. Unless a contrary meaning is clear in a given context, substitution by a named substituent is permitted on any atom in a ring (e.g., cydoalkyl, aryl, or heteroaryl) provided such ring substitution is chemically allowed and results in a stable compound. In instances where a hydroxy (-OH) substituent(s) is (are) permitted on a heteroaromatic ring and keto-enol tautomerism is possible, it is understood that the substituent might in fact be present, in whole or in part, in the keto form, as exemplified here for a hydroxypyridinyl substituent:

Compounds ofthe present invention having a hydroxy substituent on a carbon atom of a heteroaromatic ring are understood to include compounds in which only the hydroxy is present, compounds in which only the tautomeric keto form (i.e., an oxo substitutent) is present, and compounds in which the keto and enol forms are both present. In addition to the presence of oxo substituents due to keto-enol tautomerism as described in the preceding paragraph, oxo substituents are also permitted on saturated ring atoms present in a heteroaryl group (e.g., the saturated ring carbon atoms in 2,3-dihydro-lH-isoindolyl). A "stable" compound is a compound which can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the puφoses described herein (e.g., therapeutic or prophylactic administration to a subject). As a result of the selection of substituents and substituent patterns, certain of the compounds employed in the present invention can have asymmetric centers (e.g., when V is CH(CH3)) and can occur as mixtures of stereoisomers, or as individual diastereomers, or enantiomers. All isomeric forms of these compounds, whether individually or in mixtures, are within the scope of the present invention. The method of the present invention involves the use of compounds of Formula I in the inhibition of HTV reverse transcriptase, the prevention or treatment of infection by human immunodeficiency virus (HTV) and the prevention, treatment or the delay in the onset of consequent pathological conditions such as AIDS. Preventing AIDS, treating AIDS, delaying the onset of AIDS, or preventing or treating infection by HTV is defined as including, but not limited to, treatment of a wide range of states of HTV infection: AIDS, ARC (ADDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HTV. For example, the present invention can be employed to treat infection by HTV after suspected past exposure to HTV by such means as blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery. As another example, the present invention can also be employed to prevent transmission of HTV from a pregnant female infected with HTV to her unborn child or from an HTV-infected female who is nursing (i.e., breast feeding) a child to the child via administration of an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. The compounds of Formula I can be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a salt which possesses the effectiveness of the parent compound and which is not biologically or otherwise undesirable (e.g., is neither toxic nor otherwise deleterious to the recipient thereof). Suitable salts include acid addition salts which may, for example, be formed by mixing a solution of the compound of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid. Certain of the compounds employed in the present invention carry an acidic moiety (e.g., -COOH or a phenolic group), in which case suitable pharmaceutically acceptable salts thereof can include alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and salts formed with suitable organic ligands such as quaternary ammonium salts. Also, in the case of an acid (-COOH) or alcohol group being present, pharmaceutically acceptable esters can be employed to modify the solubility or hydrolysis characteristics of the compound. The term "administration" and variants thereof (e.g., "administering" a compound) in reference to a compound of Formula I mean providing the compound or a prodrug of the compound to the individual in need of treatment or prophylaxis. When a compound of the invention or a prodrug thereof is provided in combination with one or more other active agents (e.g., antiviral agents useful for treating or preventing HTV infection or AIDS), "administration" and its variants are each understood to include provision of the compound or prodrug and other agents at the same time or at different times. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combining the specified ingredients in the specified amounts. By "pharmaceutically acceptable" is meant that the ingredients of the pharmaceutical composition must be compatible with each other and not deleterious to the recipient thereof. The term "subject" as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. The term "effective amount" as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. In one embodiment, the effective amount is a "therapeutically effective amount" for the alleviation of the symptoms of the disease or condition being treated. In another embodiment, the effective amount is a "prophylactically effective amount" for prophylaxis of the symptoms of the disease or condition being prevented. The term also includes herein the amount of active compound sufficient to inhibit HTV reverse transcriptase and thereby elicit the response being sought (i.e., an "inhibition effective amount"). When the active compound (i.e., active ingredient) is administered as the salt, references to the amount of active ingredient are to the free acid or free base form of the compound. hi the method of the present invention (i.e., inhibiting HIV reverse transcriptase, preventing or treating HTV infection or preventing, treating or delaying the onset of ADDS), the compound of Formula I, optionally in the form of a salt, can be administered by any means that produces contact of the active agent with the agent's site of action. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but typically are administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. The compounds of the invention can, for example, be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectally, in the form of a unit dosage of a pharmaceutical composition containing an effective amount of the compound and conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles. Liquid preparations suitable for oral administration (e.g., suspensions, syrups, elixirs and the like) can be prepared according to techniques known in the art and can employ any of the usual media such as water, glycols, oils, alcohols and the like. Solid preparations suitable for oral administration (e.g., powders, pills, capsules and tablets) can be prepared according to techniques known in the art and can employ such solid excipients as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like. Parenteral compositions can be prepared according to techniques known in the art and typically employ sterile water as a carrier and optionally other ingredients, such as a solubility aid. Injectable solutions can be prepared according to methods known in the art wherein the carrier comprises a saline solution, a glucose solution or a solution containing a mixture of saline and glucose. Further description of methods suitable for use in preparing pharmaceutical compositions for use in the present invention and of ingredients suitable for use in said compositions is provided in Remington's Pharmaceutical Sciences. 18^th edition, edited by A. R. Gennaro, Mack Publishing Co., 1990. The compounds of Formula I can be administered orally in a dosage range of 0.001 to

1000 mg/kg of mammal (e.g., human) body weight per day in a single dose or in divided doses. One preferred dosage range is 0.01 to 500 mg/kg body weight per day orally in a single dose or in divided doses. Another preferred dosage range is 0.1 to 100 mg/kg body weight per day orally in single or divided doses. For oral administration, the compositions can be provided in the form of tablets or capsules containing 1.0 to 500 milligrams of the active ingredient, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, and 500 milligrams, ofthe active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. As noted above, the present invention is also directed to the use ofthe compounds of Formula I in combination with one or more agents useful in the treatment of HTV infection or AIDS. For example, the compounds of Formula I can be effectively administered, whether at periods of pre- exposure and/or post-exposure, in combination with effective amounts of one or more HTV/AIDS antivirals, imunomodulators, antiinfectives, or vaccines useful for treating HTV infection or AIDS, such as those disclosed in Table 1 of WO 01/38332 or in the Table in WO 02/30930. Suitable HTV/AIDS antivirals for use in combination with the compounds of Formula I include, for example, HTV protease inhibitors (e.g., indinavir, atazanavir, lopinavir optionally with ritonavir, saquinavir, or nelfinavir), nucleoside HTV reverse transcriptase inhibitors (e.g., abacavir, lamivudine (3TC), zidovudine (AZT), or tenofovir), non-nucleoside HTV reverse transcriptase inhibitors (e.g., efavirenz or nevirapine), and HTV integrase inhibitors such as those described in WO 02/30930, WO 03/35076, and WO 03/35077. It will be understood that the scope of combinations of compounds of Formula I with HTV/AIDS antivirals, immunomodulators, anti-infectives or vaccines is not limited to the foreogoing substances or to the list in the above-referenced Tables in WO 01/38332 and WO 02/30930, but includes in principle any combination with any pharmaceutical composition useful for the treatment of ADDS. The HTV/AIDS antivirals and other agents will typically be employed in these combinations in their conventional dosage ranges and regimens as reported in the art, including, for example, the dosages described in the Physicians' Desk Reference, 57^th edition, Thomson PDR, 2003. The dosage ranges for a compound of Formula I in these combinations are the same as those set forth above. Abbreviations used in the instant specification, particularly the Schemes and Examples, include the following: AIDS = acquired immunodeficiency syndrome ARC = AIDS related complex DCM = dichloromethane DEAD = diethylazodicarboxylate DMAP = dimethylaminopyridine DMF = dimethylformamide DMSO = dimethylsulfoxide dGTP = deoxyguanosine triphosphate dNTP = deoxynucleoside triphosphate EDC or EDAC = l-ethyl-3-(3-dimethylaminopropyl) carbodiimide EDTA = ethylenediaminetetracetic acid EGTA = ethylene glycol bis(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid Et = ethyl EtOAc = ethyl acetate EtOH = ethanol HIV = human immunodeficiency virus HOBT or HOBt = 1 -hydroxy benzotriazole hydrate HPLC = high performance liquid chromatography MCPBA = meta-chloroperbenzoic acid MS = mass spectroscopy NMR = nuclear magnetic resonance Ph = phenyl TBAB = tetrabutylammonium bromide TEA = triethylamine TEMPO = 2,2,6,6-tetramethyl-l- piperidinyloxy TFA = trifluoroacetic acid THF = tetrahydrofuran The compounds of Formula I employed in the present invention can be readily prepared according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Furthermore, other methods for preparing compounds of Formula I will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above. General synthetic methods for preparing compounds of Formula I are shown in Schemes 1 to 5. In Scheme 1, the desired aniline or amino-heterocyclic compound 1-1 is converted to the corresponding isothiocyanate 1-2, which is then condensed with azide to provide the desired 5- thiotetrazole 1-3. Alkylation with the appropriate halo acid 1-4 gives the thioether compounds 1-5. Coupling with an amine 1-6 yields the desired inhibitors 1-8. Alternatively, these inhibitors may be prepared by alkylation of the 5-thiotetrazoles 1-3 with the desired halo amide 1-7.

Scheme 1 CSCI₂, H₂0/DCM or DMAP/DCM ,'^{, C 0} -^N<*, NaN₃, H₂0 N-N heat R¹-NH₂ R¹ -N=C= N " v N SM 1-1 1-2 1-3 pΛ [M= H, Na]

Treatment of the primary amine 1-1 with either thiophosgene or with bis-2- pyridylthiocarbamate in the presence of 4-dimethylaminopyridine (DMAP) provides the isothiocyanate 1-2." Heating 1-2 in the presence of sodium azide or an equivalent reagent gives rise to the 5-thiotetrazole 1-3 either as the sodium salt or the corresponding free thiol. Alkylation of the thio group in 1-3 to give the acid 1-5 can be carried out by treatment with a reagent such as chloroacetic acid and a base such as aqueous NaOH, or with ethyl bromoacetate or an equivalent reagent using a base such as K2C03. When the alkylation is carried out using a haloester, saponifϊcation with sodium hydroxide or an equivalent reagent affords the acid 1-5. Standard peptide coupling methods can be used to carry out the reaction of the amine 1-6 with the acid 1-5 to give the inhibitor 1-8 (eg, EDC/HOBT/TEA in DMF). In the alternative route, the preformed haloamide 1-7 can be used to alkylate thiotetrazole 1-3 using similar conditions for the conversion of 1-3 to 1-5. The amino compounds of formula 1-1 shown in Scheme 1 may be obtained commercially or prepared by established chemical processes such as reduction of the corresponding nitro compounds, Curtius rearrangement of the corresponding acyl azides (see Jerry March, Advanced Organic Chemistry, 4th Ed, John Wiley & Sons 1992, p. 1091) or heterocyclic syntheses that yield the amines directly (cf. Gompper, Chem. Ber. 1959, 92: pp. 1944, 1948; or Watanabe et al., Heterocycles 1980, 14 (3):_pp. 287-290.). Representative examples of the treatment of isothiocyanates to give the mercaptotetrazoles can be found in Shin et al.; Bioorg. Med. Chem. Lett. 2000, 10 (13): pp. 1421 - 1425. Scheme 2 outlines the one step conversion of the desired 5-thio or 5-hydroxy tetrazoles 2-1 to the desired tetrazole inhibitors 2-2. This transformation can be carried out by alkylation, or in the case where Y = OH via the Mitsunobu reaction (cf. Shi et al., Tetrahedron Letters 2003, 44 (18): pp. 3609-3611).

Scheme 2 R³-V-X [X = CI, Br] N-N heat + base N-N ^N'' or 1 YH R³-V-OH | Rl Mitsunobu Rx Ri (e.g., PPh₃, DEAD) ₂_₂ [Y = O or S] 2-1 In the case where Y = O or S, the alkylation of 2-1 can be carried out by treatment with a halide or an equivalent reagent using a base such as K2CO3 to give the inhibitor 2-2. hi the case where

Y = O, an alternative Mitsunobu method can be used that utilizes an alcohol (R3-V-OH) in the presence of a phosphine such as PI13P and a diazodicarboxylate such as DEAD to provide the inhibitor 2-2. Scheme 3 outlines the preparation of 5-aminotetrazole derivatives of formula 3-3. The isothiocyanate 1-2 is reacted with the amino t-butyl ester 3-4 to generate the thiourea derivative 3-1, which can be converted to the corresponding 5-aminotetrazole 3-2 by reaction with sodium azide. Deprotection of the ester moiety of 3-2 and coupling with the amine 1-6 will afford the desired 5- aminotetrazole derivative 3-3. Scheme 3 if R⁵ = alkyl, then heating by microwave if R⁵ = H, ambient temperature (e.g., OtBu 20-25°C) NaN_3> HgCI₂, DMF

1-2 3-1

Isothiocyanates 1-2 prepared as described in Scheme 1 can be reacted in a suitable solvent (e.g., a polar solvent such as DCM) with the amino tertbutylester 3-4 alone or, if 3-4 is in the form of a salt, in the presence of a base such as triethyl amine to give the desired thiourea 3-1. Thiourea 3-1 can then be reacted with sodium azide in presence of HgCl2 in DMF to generate the 5-aminotetrazole intermediate 3-2. The reaction can be also conducted in a microwave reactor using the same reagents. The final compound can be obtained by deprotection of tertbutylester 3-2 with an acid (e.g., TFA) followed by coupling with amine 1-6. A representative synthesis of aminotetrazoles can be found in Batey et al., Org. Lett. 2000, 2(20): pp. 3227-3234. The general scheme for preparation of 5-oxotetrazoles derivative 4-4 is shown in Scheme 4. 5-thiotetrazole 1-3 is methylated and oxidized to the methylsulfonyl derivative 5-1 that is displaced with diols 4-5 to give the 5-oxotetrazole derivative 4-2. Oxidation of the free alcohol affords the acid 4-3 that is coupled with the amine 1-6 to give the desired product 4-4.

Scheme 4 N N

1-3 4-1

The thiotetrazoles of formula 1-3, prepared as described in Scheme 1, are methylated with Mel in presence of a base (e.g., NaOH) and a phase transfer catalyst (e.g., TBAB). Oxidation with MCPBA in DCM to the methyl-sulfone 4-1, followed by treatment of 4-1 with an excess of diol 4-5 in the presence of an appropriate base such NaOH gives intermediate 4-2. Oxidation of the free hydroxyl group of 4-2 leads to the carboxylic acid 4-3. The oxidation can be accomplished (i) in two steps by first conducting a Swern oxidation to obtain an aldehyde intermediate than oxidizing the aldehyde with NaClθ2/H θ2 or (ii) in one step using TEMPO/NaClO in acetone-water. The carboxylic acid intermediate 4-3 can then be coupled with amine 1-6 to form a final amide 4-4 in the manner described for carboxylic acid intermediate 1-8 in Scheme 1. Representative examples of the synthesis of O- alkylated 5-oxotetrazoles from methylsulfonyl-tetrazoles can be found in Kharbash et al., Russ. J. Org. Chem. 2002, 38(9): pp. 1356-1359. In Scheme 5, the halo or sulfonyl tetrazoles 5-1 are treated with an appropriate amine 5-2 to give the desired inhibitors 5-3. Alternatively, the appropriately substituted thioureas 5-4 can be treated with sodium azide in the presence of mercuric chloride to afford 5-3. Scheme 5

5-3 [X = halogen, S0₂-alkyl]

Treatment of the 5-halo or 5-sulfonyltetrazoles 5-1 with an appropriately substituted amino compound 5-2 in the presence of a base such as triethylamine using a solvent such as THF or

DMF gives rise to the desired inhibitors 5-3. (for further description of this chemistry, see also, e.g., Ding et al., J. Med. Chem. 1999, 42 (25): 5241). Alternatively, the inhibitors 5-3 may be prepared by treatment of an appropriately substituted thiourea 5-4 with sodium azide and mercuric chloride in the presence of a base such as triethylamine or Hunig's base in a solvent such as DMF or DMA. (see also, e.g., Batey et al., Org. Lett. 2000, 2 (20): 3237).

The following examples serve only to illustrate the invention and its practice. The examples are not to be construed as limitations on the scope or spirit of the invention. EXAMPLE 1

N-(2-chloropyridin-3-yl)-2-[(l-mesityl-lH-tetrazol-5-yl)thio]acetamide

Step 1: l-mesityl-lH-tetrazole-5-thiol To a suspension of 2,4,6-trimethylphenyl isothiocyanate in water, sodium azide (1.5 eq) was added. The mixture was vigorously stirred at reflux for 20 hours. After cooling to room temperature, the solution was washed with diethyl ether and acidified with HCl (6 Ν). A colorless oil separated, which solidified upon vigorous stirring at 0°C. The title compound was collected by filtration as white solid and dried under high vacuum.

IH ΝMR (300 MHz, DMSO-d6) δ: 7.10 (s, 2H), 2.33 (s, 3H), 1.95 (s, 6H). 13C-ΝMR (75 MHz, DMSO-d6) δ: 165.0, 140.9, 136.1, 129.5, 21.1, 17.4. MS m/z: 221 (M+H)+.

Step 2: [(l-mesityl-lH-tetrazol-5-yl)thio]acetic acid To a suspension of l-mesityl-lH-tetrazole-5-thiol in water, chloroacetic acid (1 eq) and aqueous NaOH (2M, 2 eq) were added. The mixture was vigorously stirred at reflux for 2 hours. After cooling to room temperature, the mixture was acidified with aqueous HCl (6M). The title compound was collected by filtration as white solid and dried under high vacuum. lH NMR (300 MHz, DMSO-d6) δ: 12.89 (bs, IH), 7.18 (s, 2H), 4.23 (s, 2H), 2.35 (s, 3H), 1.88 (s, 6H). 13C NMR (75 MHz, DMSO-dδ) δ: 169.0, 155.7, 141.7, 135.6, 129.9, 128.5, 34.6, 21.1, 17.0. MS m/z: 279 (M+H)+.

Step 3: iV-(2-chloropyridin-3-yl)-2-[(l-mesityl-lH-tetrazol-5-yl)thio]acetamide To a stirred suspension of [(l-mesityl-lH-tetrazol-5-yl)thio]acetic acid and 2-chloro-3- aminopyridine (1 eq.) in a mixture of chloroform and toluene (2:1) at room temperature was added phosphorus pentachloride (1.2 eq.). The mixture was stirred at room temperature for 3.5 hours and then for 1 hour at 70°C. After cooling to room temperature, dichloromethane was added and the mixture was washed with water. The organic phase was dried over Na2Sθ4, filtered and concentrated to dryness under reduced pressure. The product was purified by preparative RP-HPLC, using water (0.1 % TFA) and acetonitrile (0.1 % TFA) as eluents (column: C18). The product was obtained after lyophilization of the pooled product fractions as a white solid. lH NMR (300 MHz, DMSO-d6) δ: 10.16 (s, IH), 8.22 (dd, Iχ = 4.6 Hz, J2 = 1.5 Hz, IH), 8.16 (dd, lχ = 8.0 Hz, J2 = 1.5 Hz, IH), 7.45 (dd, lχ = 4.6, J2 = 8.0 Hz, IH), 7.18 (s, 2H), 4.50 (s, 2H), 2.35 (s, 3H),

1.89 (s, 6H).

13C NMR (75 MHz, DMSO-d6) δ: 165.9, 155.2, 145.6, 141.3, 135.2, 133.6, 131.5, 129.5, 128.1, 123.5, 36.4, 20.7, 16.6.

MS m/z: 389 (M+H)+.

EXAMPLES 2-11 The compounds in Table 2 below were prepared in accordance with the procedures set forth in Example 1, Step 3 using either [(l-mesityl-lH-tetrazol-5-yl)thio]acetic acid (prepared as described in Example 1, Steps 2 and 3) or the appropriate counterpart and the appropriate amine in place of 2-chloro-3-aminopyridine.

EXAMPLE 12 2-( { 1 -[4-(dimethylamino)- 1 -naphthyl]- lH-tetrazol-5-yl } thio)-N-(2-nitrophenyl)acetamide

Step 1: 1 -[4-(dimethylamino)- 1 -naphthyl] - lH-tetrazole-5-thiol The title compound was prepared from from 4-dimethylamino-l-naphthyl isothiocyanate, according to the procedure described in Example 1, Step 1 with the following modification: The crude compound was isolated by extraction in CH2CI2 after acidification with HCl. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. The title compound was obtained as a brown foam, which was used without further purification. lH NMR (300 MHz, DMSO-d6) δ: 8.25 (d, J = 8.2 Hz, IH), 7.65-7.51 (m, 3H), 7.29 (d, J = 8.0 Hz, IH), 7.21 (d, J = 8.2 Hz, IH), 2.93 (s, 6H). 13CNMR (75 MHz, DMSO-d6) δ: 153.0, 129.9, 128.0, 127.4, 127.1, 125.9, 124.7, 123.8, 122.6, 112.9, 44.6.

MS m/z 272 (M+H)+.

Step 2: ({ l-[4-(dimethylamino)-l-naphthyl]-lH-tetrazol-5-yl}thio)acetic acid The title compound was prepared from -[4-(dimethylamino)-l-naphthyl]-lH-tetrazole-5- thiol, according to the procedure described in Example 1, Step 2 with the following modifications: The crude compound was isolated by extraction in CH2CI2 after acidification with HCl. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. The title compound was used without further purification. MS m/z 330 (M+H)+. Step 3: 2-({ l-[4-(dimethylamino)-l-naphthyl]-lH-tetrazol-5-yl}thio)-N-(2- nitrophenyl)acetamide The title compound was prepared from l-[4-(dimethylamino)-l-naphthyl]-lH-tetrazol-5- yl}thio)acetic acid and 2-nitroaniline, according to the procedure described in Example 1, Step 3. lH NMR (300 MHz, DMSO-d6) δ: 10.73 (s, IH), 8.28 (d, J = 8.2 Hz, IH), 7.97 (d, J = 8.2 Hz, IH), 7.77-7.53 (m, 5H), 7.44-7.35 (m, IH), 7.23 (d, J = 8.2 Hz, IH), 7.11 (d, J = 8.2 Hz, IH), 4.38 (s, 2H), 2.95 (s, 6H). MS m/z: 450 (M+H)+. EXAMPLE 13

N-[4-(aminosulf onyl)-2-chlorophenyl] -2-[( 1 -mesityl- 1 H-tetrazol-5-yl)thio] acetamide

Step 1: 4-Acetamido-3-chlorobenzenesulfonamide To a mixture of THF and concentrated aqueous ammonia (2: 1) was added 4-acetamido- 3-chlorobenzensulfonyl chloride. The mixture was stirred for 20 minutes at room temperature and the solvents were removed under reduced pressure. The residue was triturated with cold water. The obtained solid was collected by filtration and dried under high vacuum.

1HΝMR (300 MHz, DMSO-d6) δ: 9.71 (s, IH), 8.06-7.97 (m, IH), 7.87 (d, J = 2.0 Hz, IH), 7.73 (dd, l

= 2.0 Hz, J2 = 8.6 Hz, IH), 7.74 (s, 2H), 2.15 (s, 3H). MS m/z 249 (M+H)+.

Step 2: 4-a ino-3-chlorobenzenesulfonamide 4-Acetamido-3-chlorobenzenesulfonamide was suspended in a mixture of water, EtOH and concentrated aqueous HCl (0.06: 1 : 0.4). The suspension was stirred and heated to 85°C under nitrogen for 1 hour. After cooling to room temperature, the mixture was quenched with saturated ΝaHC03 and extracted with EtOAc. The organic phase was dried over Na2Sθ4, filtered and concentrated to dryness under reduced pressure. lH NMR (300 MHz, CD3CN) δ: 7.70 (d, J = 2.0 Hz, IH), 7.52 (dd, J = 2.0 Hz, J2 = 8.6 Hz, IH), 6.87

(d, J = 8.6 Hz, IH), 5.45 (bs, 2H), 5.08 (bs, 2H). MS m/z: 207 (M+H)+.

Step3: N-[4-(aminosulfonyl)-2-chlorophenyl]-2-[(l-mesityl-lH-tetrazol-5-yl)thio]acetamide The title compound was prepared from [(l-mesityl-lH-tetrazol-5-yl)thio]acetic acid (obtained as described in Example 1, Steps 1-2) and 4-amino-3-chlorobenzenesulfonamide according to the procedure described in Example 1, Step 3. lH NMR (300 MHz, DMSO-d6) δ: 10.19 (s, exchangeable proton, <1H), 8.05-7.96 (m, IH), 7.90 (d, J = 2.0 Hz, IH), 7.76 (dd, Jx = 2.0 Hz, J2 = 8.6 Hz, IH), 7.45 (s, exchangeable proton, < 2H), 4.52 (s, 2H), 2.35 (s, 3H), 1.89 (s, 6H). MS m/z 267 (M+H)+.

EXAMPLE 14 3 -chloro-4-( { [( 1 -mesityl- lH-tetrazol-5 -y l)thio] acetyl } amino)benzamide

Step 1: 4-amino-3-chlorobenzamide To methyl 4-amino-3-chlorobenzoate was added concentrated aqueous ammonia. The mixture was stirred overnight at 70°C, then solvent was removed under reduced pressure. The resulting white solid contained 4-amino-3-chlorobenzoic acid but was without further purification. MS m/z 11 (M+H)+.

Step 2: 3-chloro-4-({[(l-mesityl-lH-tetrazol-5-yl)thio]acetyl}amino)benzamide To a stirred suspension of [(l-mesityl-lH-tetrazol-5-yl)thio]acetic acid in DCM at 0°C was added a solution of oxalyl chloride in DCM (2M,1 eq.) and a few drops of DMF. The mixture was stirred for 15 minutes at 0°C and then added to a solution of crude 4-amino-3-chlorobenzamide (1 eq) and Et3N (1 eq) in DCM at 0°C. The mixture was stirred for 2 hours at 0°C, after which the solvent was evaporated under reduced pressure. The product was purified by preparative RP-HPLC, using water (0.1 % TFA) and acetonitrile (0.1 % TFA) as eluants (column: C18). After lyophilization of the pooled product fractions the title compound was obtained as a white solid. lH NMR (400 MHz, DMSO-d6) δ: 10.08 (s, IH), 8.02 (s, IH), 8.00 (d, J= 1.8 Hz, IH), 7.89 (d, J= 8.6, IH), 7.82 (dd, Jχ= 8.6 Hz, J2= 1.8 Hz, IH), 7.45 (s, IH), 7.18 (s, 2H), 4.51 (s, 2H), 2.35 (s, 3H), 1.90 (s, 6H). MS ??ι z: 431 (M+H)+

EXAMPLE 15 N-[4-(aminosulfonyl)-2-chlorophenyl]-2-{[l-(2,5-dichlorophenyl)-lH-tetrazol-5-yl]thio}acetamide

Stepl: l-(2,5-dichlorophenyl)-lH-tetrazole-5-thiol The title compound was prepared from 2,5-dichlorophenyl isothiocyanate, according to the procedure described in Example 1, Step 1. MS m/z 247 (M+H)+.

Step 2: {[l-(2,5-dichlorophenyl)-lH-tetrazol-5-yl]thio}acetic acid The title compound was prepared from l-(2,5-dichlorophenyl)-lH-tetrazole-5-thiol according to the procedure described in Example 1, Step 2. lH NMR (300 MHz, DMSO-d6) δ: 13.16 (bs, IH), 8.09 (d, J = 2.2 Hz, IH), 7.94-7.83 (m, 2H), 4.22 (s,

2H). MS m/z 305 (M+H)+.

Step 3: N-[4-(anainosulfonyl)-2-chlorophenyl]-2-{[l-(2,5-dichlorophenyl)-lH-tetrazol-5- yl]thio } acetamide. The title compound was prepared from {[l-(2,5-dichlorophenyl)-lH-tetrazol-5- yl]thioj acetic acid and and 4-amino-3-chlorobenzenesulfonamide according to the procedure described in Example 14, Step 2. lH NMR (300 MHz, DMSO-d6) δ: 10.18 bs, (exchangeable proton, <1H), 8.11 (d, J = 2.0 Hz, IH), 8.00 (d, J = 8.4 Hz, IH), 7.95-7.84 (m, 3H), 7.76 (dd, Iχ = 8.4 Hz, J2 = 2.0 Hz, IH), 4.50 (s, 2H). MS m/z 493 (M+H)+.

EXAMPLE 16 N-(2-Chlorophenyl)-2-[(l-isoquinolin-5-yl-lH-tetrazol-5-yl)thio]-acetamide

Step 1: 5-Isothiocyanatoisoquinoline A solution of isoquinoline-5-amine (1 eq.), C>,C>, -dipyridin-2-yl thiocarbonate (1.3 eq.), and N, N-dimethylpyridin-4-amine (0.25 eq.) in CH2CI2 was stirred for 6 hours under anhydrous conditions. Silica gel was added to the reaction mixture, then concentrated under reduced pressure. The residual solid was filtered through a pad of silica gel eluting with 25 % EtOAc in hexanes. The filtrate was concentrated under reduced pressure to give the title compound. iHΝMR (400 MHz, CDCI3) δ : 9.31 (d, IH, J=l); 8.67 (d, IH, J=6); 7.94 (d, IH, J=l); 7.91 (d, IH,

J=l); 7.56-7.64 (m, 2H). ES MS M+l = 187.

Step 2: N-(2-Chlorophenyl)-2-[(l-isoquinolin-5-yl-lH-tetrazol-5-yl)thio]acetamide. A solution of 5-isothiocyanatoisoquinoline (1 eq.), sodium azide (0.026 g, 0.403 mmol) and 2-chloro-N-(2-chlorophenyl)acetamide ( 1.5 eq.) in water was refluxed for 0.5 hour. The reaction mixture was cooled, then acetone and K2CO3 were added. After stirring overnight at room temperature, the solids were filtered, washed with water, and then concentrated under reduced pressure to give the title compound. iHNMR (400 MHz, DMSO-d6) δ: 10.00 (br s, IH); 9.57 (s, IH); 8.61 (d, IH, J=6); 8.53 (d, IH, J=8);

8.18 (d, IH, J=7); 7.96 (t, IH, J=8); 7.68 (dd, IH, J=l, 8); 7.50 (dd, IH, J=l, 7); 7.33 (t, IH, J=7); 7.26 (d, IH, J=6); 7.21 (t, IH, J=7); 4.45 (s, 2H). ES MS M+l = 398

EXAMPLE 17

N-(2-Chlorophenyl)-2-[(l-mesityl-lH-tetrazol-5-yl)thio]-acetamide To a solution of [(l-mesityl-lH-tetrazol-5-yl)thio]acetic acid (1 eq.) in DMF was added

2-chloroaniline (1.2 eq.), l-hydroxy-7-azabenzotriazole (1 eq.), and l-[3-(dimethylamino)propyl]-3- ethylcarbodiimide hydrochloride (1.3 eq.). After stirring overnight at room temperature, additional 2- chloroaniline (1.1 eq.) was added. The reaction was concentrated under reduced pressure. The residual material was purified using reverse phase HPLC on a C18 stationary phase eluting with 5 % - 95 % acetonitrile (0.1 % TFA) in H2O (0.1 % TFA) to afford the title compound. iHNMR (400 MHz, DMSO-de) δ 10.00 (s, IH), 7.70 (d, 7=12 Hz, IH), 7.51 (d, 7=12 Hz, IH), 7.7.33 (t, 7=12 Hz, IH), 7.22 (d, 7=12 Hz, IH), 7.18 (s, 2H), 4.47 (s, 2H), 2.35 (s, 3H), 1.89 (s, 6H) ppm.

ES MS M+l = 388.

EXAMPLE 18 2-[(l-mesityl-lH-tetrazol-5-yl)thio]-N-(2-nitrophenyl)acetamide To a solution 2-bromo-N-(2-nitrophenyl)acetamide (1.1 eq.) in THF was added 1- mesityl-lH-tetrazole-5-thiol (1 eq.) and cesium carbonate (2 eq.). After stirring for 2 minutes., the reaction mixture was concentrated under reduced pressure. The residual solid was diluted in water and IN HCl, then filtered. The solid was concentrated under reduced pressure to afford the title compound as a bright yellow solid. iHΝMR (400 MHz, DMSO-d6) δ 10.76 (s, IH), 7.97 (m, IH), 7.72 (m, 2H), 7.40 (m IH), 7.18 (m, 2H),

4.42 (s, 2H), 2.35 (s, 3H), 1.89 (s, 6H) ppm. ES MS M+l = 399.

EXAMPLE 19 2-{ [l-(l-Νaphthyl)-lH-tetrazol-5-yl]thio}-N-(2-nitrophenyl)acetamide To a solution 2-bromo-N-(2-nitrophenyl)acetamide ( 1 eq.) in anhydrous THF (3 mL) was added l-(l-naphthyl)-lH-tetrazole-5-thiol (1 eq.). After stirring, cesium carbonate (2 eq.) was added to the reaction mixture. After 2 minutes., the reaction was concentrated under reduced pressure. Water and IN HCl was added to the crude material, then filtered and washed with water. The solid was concentrated under reduced pressure to give the title compound. IHNMR (400 MHz, DMSO-d<s) δ 10.76 (s, IH), 8.32 (d, 7=12 Hz, IH), 8.18 (d, 7=12 Hz, IH), 7.98 (d,

7=12 Hz, IH), 7.85 (d, 7=12 Hz, IH), 7.71 (m, 5H), 7.41 (m, IH), 7.25 (d, 7=12 Hz, IH), 4.41 (s, 2H) ppm.

ES MS M+l = 407.

Table 3 below lists compounds employed in the present invention. The table provides the structure and name of each compound, the mass of its molecular ion plus 1 (M+) or molecular ion minus 1 (M^~) as determined via ES, and a reference to the preparative example or scheme that is, or is representative of, the procedure employed to prepare the compound. Compounds in the table for which no preparative example/scheme and no molecular ion data is given were obtained from a commercial source.

Table 3

N-(2,3-dimethylphenyl)-2-{[l-(l- 389.482 naphthyl)-lH-tetrazol-5- yl]thio}acetamide

N-(2-nitrophenyl)-2-[(l-(4- 370.392 methylphenyl)-lH-tetrazol-5- yl)thio]acetamide

7V-(2-nitrophenyl)-2-{ [1-(1- 1 407 406.426 naphthyl)-177-tetrazol-5- (Ex. 19) yl]thio}acetamide

N-(2-chlorophenyl)-2-[(l-mesityl- 1 388 387.894 lH-tetrazol-5-yl)thio]acetamide (Ex. 17)

N-(2-chlorophenyl)-2-{ [l-(3- 380 380.258 chlorophenyl)-lH-tetrazol-5- yl]thio}acetamide

N-(2-chlorophenyl)-2-{ [1-(1- 396 395.873 naphthyl)- lH-tetrazol-5- yl]thio}acetamide

N-(2-chlorophenyl)-2-{ [l-(2- 380 380.258 chlorophenyl)- lH-tetrazol-5- yl]thio}acetamide

N-(2-chlorophenyl)-2-[( 1- 1 398 396.861 isoquinolin-5-yl- lH-tetrazol-5- (Ex. 16) yl)thio] acetamide

2-[(l-mesityl-lH-tetrazol-5- 1 399 398.447 yl)thio]-N-(2- (Ex. 18) nitrophenyl)acetamide

2-{[l-(l,3-benzodioxol-5-yl)-lH- 389.823 tetrazol-5-yl]thio)-N-(2- chlorophenyl)acetamide

N-(2-chlorophenyl)-2-{ [l-(4- 359.84 methylphenyl)-lH-tetrazol-5- yl]thiojacetamide

N-(2,4-difluorophenyl)-2-[(l- 390 389.43 mesityl- lH-tetrazol-5- yl)thio]acetamide

N-(2-chloropyridin-3-yl)-2-[(l- 1 389 388.882 mesityl- lH-tetrazol-5- (Ex. 1) yl)thio]acetamide

2-[(l-mesityl-lH-tetrazol-5- 415 414.446 yl)sulfmyl]-N-(2- nitrophenyl)acetamide

N-(2,5-difluorophenyl)-2-[(l- 390 389.43 mesityl- lH-tetrazol-5- yl)thio] acetamide

N- [4-(aminosulfonyl)-2- 447 446.554 methylphenyl]-2-[(l-mesityl-lH- (Ex. 2) tetrazol-5-yl)thio]acetamide

N-(2-chlorophenyl)-2-{ [l-(2,6- 1 414 414.703 dichlorophenyl)-lH-tetrazol-5- (Ex. 8) yl]thio}acetamide

2-{[l-(2-chloro-6-methylphenyl)- 405 404.837 lH-tetrazol-5-yl]thio }-N-(2- nitrophenyl)acetamide

2- { [ 1 -(2-chloro-6-methylphenyl)- 394 394.285 lH-tetrazol-5-yl]thio}-N-(2- chlorophenyl)acetamide

2-{ [l-(2-bromophenyl)-lH- 435 435.261 tetrazol-5-yl]thio}-N-(2- nitrophenyl)acetamide

2-{ [l-(2-bromophenyl)-lH- 1 424 424.709 tetrazol-5-yl]thio }-N-(2- (Ex. 9) chlorophenyl)acetamide

2-{ [l-(2-isopropylphenyl)-lH- 399 398.447 tetrazol-5-yl]thio}-N-(2- nitrophenyl)acetamide

N-(2-chlorophenyl)-2-{ [l-(2- 388 387.894 isopropylphenyl)-lH-tetrazol-5- yl]thio} acetamide

EXAMPLE 20 Encapsulated Oral Compositions A capsule formulation suitable for use in the present invention can be prepared by filling standard two-piece gelatin capsules each with 100 mg of compound 1 in Table 3, 150 mg of lactose, 50 mg of cellulose, and 3 mg of stearic acid. Encapsulated oral compositions containing any one of the compounds listed in Table 3 can be similarly prepared.

EXAMPLE 21 Assay for Inhibition of HIV Reverse Transcriptase Assays to determine the in vitro inhibition of HTV reverse transcriptase by compounds of the present invention were conducted as follows: HTV-1 RT enzyme (1 nM) was combined with inhibitor or DMSO (5%) in assay buffer (50 mM Tris-HCl, pH 7.8, 1 mM dithiothreitol, 6 mM MgCl2, 80 mM KCI, 0.2% polyethylene glycol 8000, 0.1 mM EGTA), and the mixture preincubated for 30 min at room temperature in microtiter Optiplates (Packard). 100 μl reaction mixtures were initiated with a combination of primer-template substrate (10 nM final concentration) and dNTPs (0.6 μM dNTPs, 0.75 μM [³H]-dGTP). The heterodimeric nucleic acid substrate was generated by annealing the DNA primer pD500 (described in Shaw-Reid et al., 7. Biol. Chem., 228: 2777-2780; obtained from Integrated DNA Technologies) to t500, a 500 nucleotide RNA template created by in vitro transcription (see Shaw-Reid et al., 7. Biol. Chem., 278: 2777-2780). After 1 hour incubation at 37°C, reactions were quenched by 10 μL streptavidin scintillation proximity assay beads (10 mg/ml, from Amersham Biosciences) in 0.5 M EDTA, pH 8. Microtiter plates were incubated an additional 10 minutes at 37°C prior to quantification via Topcount (Packard). Representative compounds of the present invention exhibit inhibition of the reverse transcriptase enzyme in this assay. For example, the compounds set forth above in Table 3 were tested in the assay and all were found to have ICso's less than 2 micromolar. EXAMPLE 22

Assay for inhibition of HTV replication Assays for the inhibition of acute HTV infection of T-lymphoid cells were conducted in accordance with Vacca, J.P. et al., Proc. Natl. Acad. Sci. USA 1994, 91: 4096. Representative compounds of the present invention exhibit inhibition of HTV replication in this assay. For example, the compounds set forth in Table 3 were found to have IC95's of less than 10 micromolar in the assay.

While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, the practice of the invention encompasses all of the usual variations, adaptations and/or modifications that come within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:

1. A method for inhibiting HTV reverse transcriptase, for treating or preventing

HTV infection, or for preventing, treating or delaying the onset of AIDS, which comprises administering to a subject in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof:

wherein:

U is: (1) O, (2) S(0)_n where n is an integer equal to zero, 1 or 2, or (3) N(R4);

V is Cχ_8 alkylene, which is optionally substituted with -OH, -O-Cχ.6 alkyl, -CN, -N(RA)RB_;

-C(0)N(RA)RB, -C(0)RA -CO2RA, -SRA -S(0)RA -SO2RA, -Sθ2N(RA)RB, -N(RA)C(0)RB, -N(RA)C02R^B, -N(RA)Sθ2R^B, -N(RA)RK -C(0)N(RA)RK -C(0)RK, -Cθ2R^κ, or -N(RA)C(0)RK_;

W is C(O)N(R2) or a direct bond linking V to R3;

Rl is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, with the proviso that Rl is not unsubstituted phenyl;

R is: (1) H, (2) Cχ_6 alkyl, (3) Cχ-6 alkyl substituted with: (a) aryl (b) substituted aryl (c) heteroaryl, (d) substituted heteroaryl, (e) C3-8 cydoalkyl, or (f) substituted C3-8 cydoalkyl, (3) C3-8 cydoalkyl, or (4) substituted C3-8 cydoalkyl;

R3 is aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

R4 is: (1) H, (2) Cχ_6 alkyl, (3) Cχ_6 haloalkyl, (4) Cχ_6 alkyl substituted with -OH, -O-Cχ-6 alkyl, -O-Cχ-6 haloalkyl, -CN, -NO2, -N(RA)RB, -C(0)N(RA)RB, -C(0)RA, -CO2RA, -SRA, -S(0)RA -SO2RA, -Sθ2N(RA)RB, -N(RA)C(0)RB, -N(RA)C02R , -N(RA)S02R^B, -N(RA)S02N(RA)RB, -OC(0)N(RA)RB, or -N(RA)C(0)N(RA)RB, (5) Cχ-6 alkyl substituted with: (a) aryl (b) substituted aryl (c) heteroaryl, (d) substituted heteroaryl, (e) C3-8 cydoalkyl, or (f) substituted C3-8 cydoalkyl, (6) C3-8 cydoalkyl, or (7) substituted C3-8 cydoalkyl;

each aryl is independently (i) phenyl or (ii) a 9- or 10-membered bicyclic, fused carbocylic ring system in which at least one ring is aromatic;

each substituted aryl is independently aryl as defined above which has at least one substituent and is: (i) substituted with from zero to 5 substituents each of which is independently: (1) -Cχ-6 alkyl optionally substituted with -OH, -0-Cχ_6 alkyl, -0-Cχ_6 haloalkyl, -CN, -NO2, -N(RA)RB, -C(0)N(RA)RB, -C(0)RA -CO2RA, -SRA -S(0)RA -SO2RA, -Sθ2N(RA)RB, -N(RA)C(0)RB, -N(RA)C02R^B, -N(RA)S02R^B, -N(RA)S02N(RA)RB_J -OC(0)N(RA)RB_j or -N(RA)C(0)N(RA)RB_J (2) -O-Cχ.6 alkyl, (3) -Cχ_6 haloalkyl, (4) -0-Cχ_6 haloalkyl, (5) -OH, (6) halogen, (7) -CN, (8) -NO2, (9) -N(RA)RB, (10) -C(O)N(RA)RB, (11) -C(0)RA (12) -CO₂RA, (13) -SRA, (14) -S(0)RA, (15) -SO₂RA,

(18) -N(RA)S02R^B, (19) -N(RA)S02N(RA)RB, (20) -N(RA)C(0)RB, (21) -N(RA)C(0)-C(0)N(RA)RB_{5 or} (22) -N(RA)C02R^B, and

(ϋ) substituted with from zero to 2 substituents each of which is independently: (1) AryA, (2) HetA, (3) -C3_ cydoalkyl, (4) -Cχ_6 alkyl substituted with AryA, HetA, or -C3.8 cydoalkyl,

(7) -C(0)-AryA, or (8) -C(0)-HetA; each heteroaryl is independently (i) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein each N is optionally in the form of an oxide, or (ii) a 9- or 10-membered bicyclic, fused ring system containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein either one or both of the rings contain a heteroatom, at least one ring is aromatic, each N is optionally in the form of an oxide, and each S in a ring which is not aromatic is optionally S(O) or S(0)2;

each substituted heteroaryl is independently heteroaryl as defined above which has at least one substituent and is: (i) substituted with from zero to 6 substituents each of which is independently: (I) -Cχ-6 alkyl optionally substituted with -OH, -0-Cχ_6 alkyl, -O-Cχ-6 haloalkyl, -CN, -N02, -N(RA)RB, -C(0)N(RA)RB_Ϊ -C(0)RA, -Cθ2 ^A, -SRA -S(0)RA -SO2RA, -S02N(RA)RB, -N(RA)C(0)RB, -N(RA)Cθ2R^B, -N(RA)Sθ2R^B, -N(RA)S02N(RA)RB, -0C(0)N(RA)RB, or -N(RA)C(0)N(RA)RB_; (2) -Cχ-6 haloalkyl, (3) -O-Cχ-6 alkyl, (4) -O-Cχ-6 haloalkyl, (5) -OH, (6) oxo, (7) halogen, (8) -CN, (9) -NO2, (X0) -N(RA)RB, (II) -C(0)N(RA)RB, (12) -C(0)RA (13) -CO2RA, (14) -SRA (15) -S(0)RA

(18) -Sθ2N(RA)C(0)RB, and (ii) substituted with from zero to 2 substituents each of which is independently: (1) AryA, (2) HetA, (3) -C3-8 cydoalkyl, (4) -Cχ-6 alkyl substituted with AryA, HetA, or -C3.8 cydoalkyl,

(7) -C(0)-AryA, or (8) -C(0)-HetA;

each substituted C3_8 cydoalkyl is independently C3-8 cydoalkyl which has at least one substituent and is (i) substituted with from zero to 6 substituents each of which is independently -Cχ_6 alkyl, -OH, -O-Cχ-6 alkyl, or -Cχ-6 haloalkyl, and (ii) substituted with zero or 1 AryA;

each RA is independently H or Cχ-6 alkyl;

each R^B is independently H or Cχ_6 alkyl;

each RK is independently aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

each AryA is independently an aromatic carbocycle selected from the group consisting of phenyl, naphthyl, and indenyl, wherein the aromatic carbocycle is optionally substituted with from 1 to 4 substituents each of which is independently halogen, CN, NO2, -Cχ_6 alkyl, -Cχ_6 haloalkyl, -OH, -O-Cχ-6 alkyl, -O-Cχ-6 haloalkyl, -C(0)N(RA)RB, -C(O)RA -CO2RA -SRA -S(0)RA -SO2RA -Sθ2N(RA)RB, or -Sθ2N(RA)C(0)R^B; and

each HetA is independently a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein each N is optionally in the form of an oxide, and wherein the heteroaromatic ring is optionally substituted with from 1 to 4 substituents each of which is independently halogen, -Cχ_6 alkyl, -Cχ_6 haloalkyl, -0-Cχ_g alkyl, -O-Cχ. haloalkyl, -OH, -C(0)N(RA)RB, -C(0)RA -CO2RA, -SRA -S(0)RA -SO2RA, -Sθ2N(RA)RB, or

2. The method according to claim 1, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof:

U is O, S, S(O), S(0)2, NH, or N(Cχ_4 alkyl); V is Cχ_6 alkylene;

W is C(0)NH, C(0)N(Cχ_4 alkyl), or a direct bond linking V to R3;

Rl and R3 are each independently: (i) aryl selected from the group consisting of phenyl and naphthyl, wherein the aryl is: (a) optionally substituted with from 1 to 5 substituents each of which is independently -Cχ.4 alkyl, -O-Cχ-4 alkyl, -Cχ.4 haloalkyl, -0-Cχ_4 haloalkyl, -OH, halogen, -CN, -NO2, -NH2, -NH-Cχ.4 alkyl, -N(Cχ-4 alkyl)₂, -C(0)NH2, -C(0)NH-Cχ_4 alkyl, -C(0)N(Cχ_4 alkyl)₂, -C(0)-Cχ_4 alkyl, -Cθ2-Cχ_4 alkyl, -S-Cχ-4 alkyl, -S(0)-Cχ_4 alkyl, -Sθ2-Cχ_4 alkyl, -SO2NH2, -SO2NH-CX-4 alkyl, -Sθ2N(Cχ_4 alkyl)2, -Sθ2NHC(0)-Cχ_4 alkyl, -Sθ2N(Cχ_4 alkyl)C(0)-Cχ_4 alkyl, NHC(O)-Cχ_4 alkyl, or N(Cχ_4 alkyl)C(0)-Cχ_4 alkyl, and (b) optionally substituted with: (1) phenyl, which is optionally substituted with from 1 to 3 substituents each of which is independently halogen, -CN, -NO2, -Cχ_4 alkyl, -0-Cχ. 4 alkyl, -Cχ.4 haloalkyl, or -O-Cχ.4 haloalkyl, (2) CH2-phenyl, where the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently halogen, -CN, -NO2, -Cχ_4 alkyl, -O-Cχ-4 alkyl, -Cχ-4 haloalkyl, or -0-Cχ_4 haloalkyl, (3) HetA, (4) CH2-HetA, (5) -S02NH-HetA, or (6) -Sθ2N(Cχ_4 alkyl)-HetA, or (ii) heteroaryl, which is: (a) a 5-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from 1 to 4 N atoms, zero or 1 O atom, and zero or 1 S atom, where each N is optionally in the form of an oxide, and where the heteroaromatic ring is optionally substituted with from 1 to 3 substituents each of which is independently halogen, -Cχ_4 alkyl, -Cχ_4 haloalkyl, -0-Cχ_4 alkyl, -O-Cχ-4 haloalkyl, -C(0)-Cχ_4 alkyl, -CO2-C -4 alkyl, or -CN, (b) a 6-membered heteroaromatic ring containing 1 or 2 N atoms, where each N is optionally in the form of an oxide, and where the heteroaromatic ring is optionally fused with a benzene ring, and where the optionally fused heteroaromatic ring is optionally substituted with from 1 to 3 substituents each of which is independently halogen, -Cχ_4 alkyl, -Cχ.4 haloalkyl, -0-Cχ_4 alkyl, -0-Cχ_4 haloalkyl, -C(0)-Cχ_4 alkyl, -CO2-CX-4 alkyl, or -CN, or (c) a bicyclic heteroaromatic ring which is a benzene ring fused with a 5- or 6- membered saturated heterocyclic ring containing from 1 to 3 heteroatoms independently selected from N and O, wherein the saturated heterocyclic ring is optionally substituted with 1 or 2 oxo groups;

with the proviso that R is not unsubstituted phenyl; and

each HetA is independently a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from zero to 4 N atoms, zero or 1 O atom, and zero or 1 S atom, wherein each N atom is optionally in the form of an oxide, and wherein the heteroaromatic ring is optionally substituted with from 1 to 3 substituents each of which is independently halogen, -Cχ.4 alkyl, -Cχ-4 haloalkyl, -O-Cχ-4 alkyl, or -O-Cχ.4 haloalkyl. 3. The method according to claim 2, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof:

Rl is: (i) naphthyl, (ii) substituted aryl selected from the group consisting of substituted phenyl and substituted naphthyl, wherein the substituted aryl has from 1 to 6 substituents wherein: (a) from zero to 5 substituents are independently selected from the group consisting of -Cχ-4 alkyl, -O-Cχ-4 alkyl, -Cχ_4 haloalkyl, -O-Cχ.4 haloalkyl, -OH, halogen, -CN, -NO2, -NH2, -NH-Cχ-4 alkyl, -N(Cχ_4 alkyl)2, -C(0)NH2, -C(0)NH-Cχ_4 alkyl, -C(0)N(Cχ_4 alkyl)2, -C(0)-Cχ_4 alkyl, -Cθ2-Cχ_4 alkyl, -S-Cχ.4 alkyl, -S(0)-Cχ_4 alkyl, -Sθ2-Cχ_4 alkyl, -SO2NH2, -SO2NH-CX.4 alkyl, -Sθ2N(Cχ. 4 alkyl)2, -Sθ2NHC(0)-Cχ_4 alkyl, and -Sθ2N(Cχ_4 alkyl)C(0)-Cχ_4 alkyl, and (b) an optional substituent is phenyl, wherein the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently halogen, -CN, -NO2, -Ci-4 alkyl, -O-Cχ-4 alkyl, -Cχ.4 haloalkyl, or -O-Cχ.4 haloalkyl, or (ii) heteroaryl selected from the group consisting of quinolinyl, isoquinolinyl, benzo-1,3- dioxolyl, and 2,3-dihydrobenzo-l,4-dioxinyl, where the heteroaryl is optionally substituted with from 1 to 3 substituents each of which is independently halogen, -Cχ-4 alkyl, -Cχ.4 haloalkyl, -O-Cχ-4 alkyl, or-O-Cχ.4 haloalkyl;

R3 is: (i) aryl selected from the group consisting of phenyl and naphthyl, wherein the aryl is: (a) optionally substituted with from 1 to 5 substituents each of which is independently -C .4 alkyl, -O-Cχ-4 alkyl, -Cχ_4 haloalkyl, -O-Cχ-4 haloalkyl, -OH, halogen, -CN, -NO2, -NEfc, -NH-Cχ.4 alkyl, -N(Cχ_4 alkyl)2, -C(0)NH2, -C(0)NH-Cχ_4 alkyl, -C(0)N(Cχ-4 alkyl)2, -C(0)-Cχ_4 alkyl, -CO2-C -4 alkyl, -S-Cχ-4 alkyl, -S(0)-Cχ_4 alkyl, -Sθ2-Cχ_4 alkyl, -SO2NH2, -Sθ2NH-Cχ-4 alkyl, -Sθ2N(Cχ_4 alkyl)2, -Sθ2NΗC(0)-Cχ_4 alkyl, -Sθ2N(Cχ_4 alkyl)C(0)-Cχ_4 alkyl, NHC(0)-Cχ_4 alkyl, or N(Cχ_4 alkyl)C(0)-Cχ-4 alkyl , and (b) optionally substituted with: (1) phenyl, which is optionally substituted with from 1 to 3 substituents each of which is independently halogen, -CN, -NO2, -Cχ.4 alkyl, -0-Cχ_ 4 alkyl, -Cχ_4 haloalkyl, -O-Cχ.4 haloalkyl, (2) HetA, or (3) -Sθ2NH-HetA, or (ii) heteroaryl selected from the group consisting of thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyridinyl N-oxide, pyrimidinyl, quinolinyl, isoquinolinyl, 2,3-dihydrobenzo-l,4-dioxinyl, benzo-l,3-dioxolyl, and 2,

3- dihydro-lH-isoindolyl optionally substituted with 1 or 2 oxo groups; wherein the heteroaryl is optionally substituted with from 1 to 3 substituents each of which is independently halogen, -Cχ_4 alkyl, -Cχ_4 haloalkyl, -O-Cχ.4 alkyl, -O-Cχ-4 haloalkyl, -CN, -C(0)-Cχ_4 alkyl, or -CO2-CX.4 alkyl; and

HetA is a heteroaromatic ring selected from the group consisting of pyridinyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, and oxadiazolyl, wherein the heteroaromatic ring is optionally substituted with from 1 to 3 substituents each of which is independently halogen, -Cχ-4 alkyl, -Cχ-4 haloalkyl, -O-Cχ-4 alkyl, or-O-Cχ-4 haloalkyl.

4. The method according to claim 3, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof:

U is S, S(0) or S(O)2; and

V is CH2, CH(CH3), or CH2CH2.

5. The method according to claim 4, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof:

U is S;

V is CH2;

W is C(O)NH, C(O)N(CH3), or a direct bond linking V to R3;

Rl is naphthyl, quinolinyl, isoquinolinyl, benzo-l,3-dioxolyl, or 2,3-dihydrobenzo-l,4-dioxinyl, substituted phenyl, or substituted naphthyl, wherein the substituted phenyl or substituted naphthyl has from 1 to 4 substituents wherein: (i) from zero to 3 substituents are independently selected from the group consisting of -Cχ-4 alkyl, -O-Cχ.4 alkyl, -Cχ-4 haloalkyl, -0-Cχ_4 haloalkyl, -OH, halogen, -CN, -NO2, -NH2, -NH-Cχ-4 alkyl, -N(Cχ_4 alkyl)2, -C(0)NH2, -C(0)NH-Cχ_4 alkyl, -C(0)N(Cχ_4 alkyl)2, -C(0)-Cχ_4 alkyl, -CO2-CX-4 alkyl, -S-Cχ.4 alkyl, -S(0)-Cχ_4 alkyl, -Sθ2-Cχ_4 alkyl, -SO2NH2, -SO2NH-CX.4 alkyl, -Sθ2N(Cχ_4 alkyl)2, -Sθ2NHC(0)-Cχ_4 alkyl, and -Sθ2N(Cχ_4 alkyl)C(0)-Cχ_4 alkyl; and (ii) an optional substituent is phenyl; and

R3 is phenyl, thienyl, isoxazoyl, pyridinyl, quinolinyl, isoquinolinyl,or 2,3-dihydro-lH-isoindolyl optionally substituted with 1 or 2 oxo groups, wherein: (i) the phenyl is: (a) optionally substituted with from 1 to 3 substituents each of which is independently -Cχ_4 alkyl, -O-Cχ-4 alkyl, -Cχ_4 haloalkyl, -O-Cχ-4 haloalkyl, -OH, halogen, -CN, -NO2, -NH2, -NH-Cχ.4 alkyl, -N(Cχ_4 alkyl)2, -C(O)NH2, -C(0)NH-Cχ_4 alkyl, -C(0)N(Cχ-4 alkyl)2, -C(0)-Cχ_4 alkyl, -Cθ2-Cχ_4 alkyl, -S-Cχ-4 alkyl, -S(0)-Cχ_4 alkyl, -SO2-CX-4 alkyl, -SO2NH2, -SO2NH-CX-4 alkyl, -Sθ2N(Cχ_4 alkyl)2, -Sθ2NHC(0)-Cχ-4 alkyl, -Sθ2N(Cχ_4 alkyl)C(0)-Cχ_4 alkyl, NHC(0)-Cχ_4 alkyl, or N(Cχ_4 alkyl)C(0)-C _4 alkyl; and (b) optionally substituted with phenyl, pyrazolyl, or -Sθ2NH-oxazolyl where the oxazolyl is optionally substituted with 1 or 2 -Cχ.4 alkyl, (ii) the pyridinyl or the isoxazolyl is optionally substituted with 1 to 3 substituents each of which is independently -Cχ_4 alkyl, -O-C -4 alkyl or halogen, and (iii) the thienyl is optionally substituted with 1 to 3 substituents each of which is independently -Cχ.4 alkyl, halogen, CN, -CO2-CX-4 alkyl, or -C(0)-Cχ_4 alkyl.

6. The method according to claim 5, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof:

W is C(0)NH or C(0)N(CH3);

Rl is: (1) phenyl substituted with from 1 to 3 substituents each of which is independently halogen, -CN, -NO2, -Cχ-3 alkyl, -O-Cχ.3 alkyl, -C(0)-Cχ_3 alkyl, -N(Cχ„₃ alkyl)₂, (2) phenyl substituted with phenyl, (3) 1-naphthyl optionally substituted with -N(Cχ_3 alkyl)2, (4) quinolinyl, (5) isoquinolinyl, (6) 1,3-benzodioxolyl, or (7) 2,3-dihydro-l,4-benzodioxinyl; and

R3 i is: (1) phenyl substituted with 1 or 2 substituents each of which is independently -C _3 alkyl, -O-Cχ-3 alkyl, -Cχ.3 fluoroalkyl, -O-Cχ.3 fluoroalkyl, halogen, -CN, -NO2, -NH2, -NH-Cχ-3 alkyl, -N(Cχ_3 al yl)2, -C(0)NH2, -C(0)-Cχ_3 alkyl, -CO2-CX.3 alkyl, -SO2NH2, or -NHC(0)-Cχ_3 alkyl, (2) phenyl substituted with pyrazolyl or -Sθ2NH-oxazolyl where the oxazolyl is optionally substituted with 1 or 2 -Cχ_3 alkyl, (3) isoxazolyl optionally substituted with 1 or 2 -Cχ_3 alkyl, (4) pyridinyl optionally substituted with 1 or 2 substituents each of which is independently halogen, -Cχ.3 alkyl, or -0-Cχ_3 alkyl, (5) thienyl optionally substituted with 1 or 2 substituents each of which is independently -Cχ-4 alkyl, CN, -Cθ2-Cχ_4 alkyl, or -C(0)-Cχ_4 alkyl, (6) quinolinyl, (7) isoquinolinyl, or (8) l,3-dioxo-2,3-dihydro-lH-isoindolyl.

7. The method according to claim 6, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, Rl is 2-bromophenyl, 2-chlorophenyl, 2,3-dichlorophenyl,

2,5-dichlorophenyl, 2,6-dichlorophenyl, 2,6-dimethylphenyl, 2,4,6-trimethylphenyl, 1-naphthyl, 4-dimethylamino-l-naphthyl, or 5-isoquinolinyl.

8. The method according to claim 6, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, R is: (1) phenyl substituted with 1 or 2 substituents each of which is independently -Cχ_3 alkyl, -O-Cχ-3 alkyl, -Cχ_3 fluoroalkyl, -O-Cχ-3 fluoroalkyl, halogen, -CN, -NO2, -NH2, -NH-Cχ-3 alkyl, -N(Cχ_3 alkyl)2, -C(0)NEΪ2, -C(0)-Cχ_3 alkyl, -Cθ2-Cχ_3 alkyl, -SO2NH2, or -NHC(0)-Cχ-3 alkyl, wherein one substituent is in the 2-position of the phenyl ring, (2) 5- or 6- or 7- or 8-quinolinyl, (3) 5- or 6- or 7- or 8-isoquinolinyl, (4) 2-pyridinyl, optionally substituted with 1 or 2 substituents each of which is independently halogen, -Cχ_3 alkyl, or -O-Cχ.3 alkyl, or (5) 3-pyridinyl substituted with 1 or 2 substituents each of which is independently halogen, -Cχ_3 alkyl, or -0-Cχ_3 alkyl, wherein one substituent is in the 2-position of the pyridinyl ring.

9. The method according to claim 8, wherein in the compound of Formula II, or a pharmaceutically acceptable salt thereof, R is 2-nitrophenyl, 2-chlorophenyl, 3-(2-chloro)pyridinyl, 2- methyl-4-(aminosulfonyl)phenyl, 2-chloro-4-fluorophenyl, 2-chloro-4-(methoxycarbonyl)phenyl, 8- quinolinyl, 2-nitro-4-methoxyphenyl, 2-chloro-4-(aminosulfonyl)phenyl, or 2-chloro-4- (aminocarbonyl)phenyl.

10. The method according to claim 1, wherein the compound of Formula I is a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of compounds listed in Table 3 in the specification.

11. The method according to claim 10, wherein the compound of Formula I is a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of compounds 5, 6, 10, 11, 31, 44, 47, 53, 54, 58, 61-63, 73, 75, 81 and 108-110 in Table 3 in the specification.

12. A compound of Formula I, or a pharmaceutically acceptable salt thereof:

wherein

V is Cχ_6 alkylene;

Rl is: (1) 2-halophenyl, (2) 2,3-dihalophenyl, (3) 2,5-dihalophenyl, (4) 2,6-dihalophenyl, (5) 2-halo-6-(Cχ_4 alkyl)phenyl, (6) 2-(Cχ-4 alkyl)phenyl, (7) 2,6-di-(Cχ_4 alkyl)phenyl, (8) 2,4,6-tri-(Cχ-4 alkyl)phenyl, (9) l,l'-biphenyl-2-yl, (10) 1-naphthyl, (11) 4-dimethylamino- 1 -naphthyl, (12) 5- or 6- or 7- or 8-quinolinyl, or (13) 5- or 6- or 7- or 8-isoquinolinyl; and

U, W and R3 are each as defined in claim 1;

and with the proviso that the compound is not a compound listed in Table 1 in the specification.

13. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein:

U is S, S(O) or S(0)2;

V is CH2, CH(CH3), or CH2CH2;

W is C(0)NH or C(0)N(Cχ_4 alkyl); and

R3 is: (i) aryl selected from the group consisting of phenyl and naphthyl, wherein the aryl is: (a) optionally substituted with from 1 to 5 substituents each of which is independently -Cχ.4 alkyl, -O-Cχ-4 alkyl, -Cχ-4 haloalkyl, -0-Cχ_4 haloalkyl, -OH, halogen, -CN, -NO2, -NH2, -NH-Cχ-4 alkyl, -N(Cχ_4 alkyl)2, -C(0)NH2, -C(0)NH-Cχ_4 alkyl, -C(0)N(Cχ_4 alkyl)2, -C(0)-Cχ_4 alkyl, -Cθ2-Cχ_4 alkyl, -S-Cχ-4 alkyl, -S(0)-Cχ_4 alkyl, -Sθ2-Cχ_4 alkyl, -SO2NH2, -SO2NH-CX.4 alkyl, -Sθ2N(Cχ_4 alkyl)2, -Sθ2NHC(0)-Cχ_4 alkyl, -Sθ2N(Cχ_4 alkyl)C(0)-Cχ_4 alkyl, NHC(0)-Cχ_4 alkyl, or N(Cχ_4 alkyl)C(0)-Cχ_4 alkyl, and (b) optionally substituted with: (1) phenyl, which is optionally substituted with from 1 to 3 substituents each of which is independently halogen, -CN, -NO2, -Cχ_4 alkyl, -0-Cχ_ 4 alkyl, -Cχ_4 haloalkyl, -O-Cχ-4 haloalkyl, (2) HetA, or (3) -Sθ2NH-HetA, or (ii) heteroaryl selected from the group consisting of thienyl, oxazolyl, isoxazolyl, pyridinyl, pyridinyl N-oxide, quinolinyl, isoquinolinyl, 2,3-dihydrobenzo-l,4-dioxinyl, benzo-1,3- dioxolyl, and 2,3-dihydro-lH-isoindolyl optionally substituted with 1 or 2 oxo groups; wherein the heteroaryl is optionally substituted with from 1 to 3 substituents each of which is independently halogen, -Cχ_4 alkyl, -Cχ_4 haloalkyl, -O-Cχ-4 alkyl, -0-Cχ_4 haloalkyl, -CN, -C(0)-Cχ_4 alkyl, or -Cθ2-Cχ_4 alkyl;

and with the proviso that the compound is not one of compounds (1)-(17), (19), (20), (22)-(40), and (42)- (54) listed in Table 1 in the specification.

14. The compound according to claim 13, or a pharmaceutically acceptable salt thereof, wherein

U is S;

V is CH2;

W is C(O)NH; and

Rl is 2-bromophenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 2,6-dimethylphenyl, 2,4,6-trimethylphenyl, 1-naphthyl, 4-dimethylamino-l-naphthyl, or 5-isoquinolinyl;

and with the proviso that the compound is not one of compounds (1)-(17) and (24)-(26) listed in Table 1 in the specification.

15. The compound according to claim 14, or a pharmaceutically acceptable salt thereof, wherein Rl is 2,4,6-trimethylphenyl; and with the proviso that the compound is not one of compounds (l)-(7) listed in Table 1 in the specification.

16. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of compounds 7-11, 15-23 and 25-110 as listed in Table 3 in the specification.

17. Use of a compound of Formula I, or a pharmaceutically acceptable salt thereof:

R¹ (I), wherein U, V, W, Rl and R in Formula I are as defined in claim 1, for inhibiting HTV reverse transcriptase, for preventing or treating HTV infection, or for preventing, treating or delaying the onset of AIDS, in a subject in need thereof.

18. A compound of Formula I, or a pharmaceutically acceptable salt thereof:

wherein U, V, W, Rl and R3 in Formula I are as defined in claim 1, for use in the preparation of a medicament for inhibiting HTV reverse transcriptase, for preventing or treating HTV infection, or for preventing, treating or delaying the onset of AIDS, in a subject in need thereof.

19. A pharmaceutical composition comprising: (i) a compound of Formula I, or a pharmaceutically acceptable salt thereof:

wherein U, V, W, Rl and R3 in Formula I are as defined in claim 1, in an amount effective for inhibiting HTV reverse transcriptase, for preventing or treating HTV infection, or for preventing, treating or delaying the onset of AIDS; and (ii) a pharmaceutically acceptable carrier.

20. Use of a pharmaceutical composition according to claim 19 for inhibiting HTV reverse transcriptase, for preventing or treating HTV infection, or for preventing, treating or delaying the onset of in a subject in need thereof.

21. A pharmaceutical composition according to claim 19, for use in the preparation of a medicament for inhibiting HT reverse transcriptase, for preventing or treating HTV infection, or for preventing, treating or delaying the onset of ADDS, in a subject in need thereof.

22. A pharmaceutical combination which is (i) a compound of Formula I, or a pharmaceutically acceptable salt thereof:

wherein U, V, W, Rl and R3 in Formula I are as defined in claim 1; and (ii) an HTV infection/AIDS antiviral agent selected from the group consisting of HTV protease inhibitors, HTV integrase inhibitors, and HTV reverse transcriptase inhibitors other than those represented by Formula I; wherein the compound of Formula I and the HTV infections/AIDS antiviral agent are each employed in an amount that renders the combination effective for inhibiting HTV reverse transcriptase, for preventing or treating HTV infection, or for preventing, treating or delaying the onset of AIDS.

23. Use of a pharmaceutical combination according to claim 22 for inhibiting HTV reverse transcriptase, for preventing or treating HTV infection, or for preventing, treating or delaying the onset of AIDS, in a subject in need thereof.

24. A pharmaceutical combination according to claim 22, for use in the preparation of a medicament for inhibiting HTV reverse transcriptase, for preventing or treating HTV infection, or for preventing, treating or delaying the onset of AIDS, in a subject in need thereof.