HIV REVERSE TRANSCRIPTASE INHIBITORS

This application claims the benefit of U.S. Provisional Application No. 60/614,635, filed September 30, 2004, the disclosure of which is herein incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention is directed to certain thiocarbamate, carbamate, urea, and diamide compounds and their pharmaceutically acceptable salts and their use for the inhibition of HIV reverse transcriptase, the prophylaxis and treatment of HIV infection and HIV replication, and the prophylaxis, delay in the onset of and treatment of AID S .

BACKGROUND OF THE INVENTION

The retrovirus designated human immunodeficiency virus (HTV), particularly the strains known as HTV type-1 (HTV-I) and type-2 (HTV-2) viruses, have been etiologically linked to the immunosuppressive disease known as acquired immunodeficiency syndrome (AIDS). HTV 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 prophylaxis 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 HIV 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 HTV strains.

The following references are of interest as background: JP06065186 and JP 09001767 disclose certain phenyl and pyridylcarbamate amides that are useful as pest control agents and herbicides.

WO 2004/024679 discloses certain [(phenyl)ureidojcarboxamide compounds as inhibitors of factor Xa and other serine proteases involved in the coagulation cascade.

SUMMARY OF THE INVENTION

The present invention is directed to certain thiocarbamate, carbamate, urea, and diamide compounds and their use in the inhibition of HTV reverse transcriptase, the prophylaxis of infection by HTV, the treatment of infection by HTV ₅ and the prophylaxis, treatment, and delay in the onset of AIDS and/or ARC. More particularly, the present invention includes compounds of Foπnula I and pharmaceutically acceptable salts thereof:

wherein:

T is O or S ;

U is:

(1) O,

(2) S,

(3) N(R4), or (4) a direct bond 1 inking V to the C(=T) moiety;

V is C i_6 alkylene, which is optionally substituted with -OH, -O-Ci-6 alkyl, -CN, -N(RC)RD _; -C(O)N(RC)RD ₅ -C(O)RA, -CO2RA, -SRA, -S(O)RA, -SO2RA, -SO2N(RC)RD ₅ -N(RA)C(O)RB, -N(RA)CO2RB, -N(RA)SO2RB, -N(RA)RK ₅ -C(O)N(RA)RK ₅ -C(O)RK ₅ -CO2RK or -N(RA)C(O)RK _;

W is C(O)N(R^) or a direct bond linking V to R3, with the proviso that U and W are not both direct bonds;

Rl is aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

R2 is H, OH, O-Ci-6 alkyl, CN ₅ C\-β alkyl, Ci_6 haloalkyl, C3_s cycloalkyl, or Q-6 alkyl substituted with C3-8 cycloalkyl;

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

R4 is:

(1) H,

(2) Ci-6 alkyl,

(3) C 1-6 haloalkyl, (4) C 1 _6 alkyl substituted with -OH, -0-C 1 _6 alkyl, -0-C 1 _6 haloalkyl, " ^CN _> - ^N °2,

-N(RC)RD ₅ -C(O)N(RC)RD ₅ -C(O)RA, -CO2RA, -SRA, -S(O)RA, -SO2RA, -Sθ2N(RC)RD ₅ -N(RA)C(O)RB, -N(RA)CO2RB, -N(RA)Sθ2RB, -N(RA)SO2N(RC)RD ₅ -OC(O)N(RC)RD _{5 O} r -N(RA)C(O)N(RC)RD ₅

(5) C l_6 alkyl substituted with: (a) aryl

(b) substituted aryl

(c) heteroaryl,

(d) substituted heteroaryl,

(e) C3-8 cycloalkyl, or (f) substituted C3-8 cycloalkyl,

(6) C3_8 cycloalkyl, or

(7) substituted C3-8 cycloalkyl;

R5 is:

(1) H,

(2) C 1-6 alky 1,

(3) C i_6 alkyl substituted with:

(a) aryl

(b) substituted aryl

(c) heteroaryl,

(d) substituted heteroaryl,

(e) C3.8 cycloalkyl, or

(f) substituted C3.8 cycloalkyl,

(4) aryl,

(5) substituted aryl,

(6) heteroaryl,

(7) substituted heteroaryl,

(8) C3-8 cycloalkyl, or

(9) substituted C3.8 cycloalkyl;

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 substituted with from 1 to 7 substituents, wherein:

(i) from zero to 7 substituents are each independently:

(1) -C 1-6 alkyl optionally substituted with -OH, -O-Ci-6 alkyl, -O-Ci-6 haloalkyl, -CN, -NO2, -N(RC)RD, -C(O)N(RC)RD ₃ -C(O)RA, -CO2RA, -SRA, -S(O)RA, -SO2RA, -SO2N(RC)RD, -N(RA)C(O)RB, -N(RA)Cθ2RB, -N(RA)Sθ2RB,

-N(RA)SO2N(RC)RD, -OC(O)N(RC)RD, or -N(RA)C(O)N(RC)RD _;

(2) -O-Ci_6 alkyl,

(3) -C i-6 haloalkyl,

(4) -0-C i_6 haloalkyl, (5) -OH,

(6) halogen,

(7) -CN,

(5) -NO ₂ ,

(9) -N(RC)RD,

(10) -C(O)N(RC)RD,

(H) -C(O)RA,

(12) -C(O)N(RA)-C 1-6 alkylene-N(RC)RD, _an d

(13) -CO2RA,

(14) -SRA,

(15) -S(O)RA,

(16) -SO2RA

(20) -N(RA)SO2N(RC)RD,

(21) -N(RA)C(O)RB,

(22) -N(RA)C(O)-C(O)N(RC)RD, or

(ϋ) from zero to 2 substituents are each independently:

(1) AryA,

(2) HetA,

(3) -C3.8 cycloalkyl,

(4) -C 1-6 alkyl substituted with AryA, HetA, or -C3.8 cycloalkyl,

(5) -Sθ2N(RA)-AryA,

(6) -Sθ2N(RA)-HetA,

(7) -C(O)-AryA, or

(S) -C(O)-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 (U) 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(O)2;

each substituted heteroaryl is independently heteroaryl as defined above substituted with from 1 to 7 substituents, wherein:

(i) from zero to 7 substituents are each independently:

I 1 ) -C i -6 alkyl optionally substituted with -OH, -O-C i _6 alkyl, -O-C i _g haloalkyl, -CN, -NO2, -N(RC)RD, -C(O)N(RC)RD ₅ -C(O)RA, -Cθ2R ^A , -SRA, -S(O)RA, -SO2RA, -S02N(RC)RD _; -N(RA)C(O)RB, -N(RA)CO2RB, -N(RA)SO ₂ RB, -N(RA)SO2N(RC)RD, -OC(O)N(RC)RD, or -N(RA)C(O)N(RC)RD, (2) -C 1-6 haloalkyl,

(3) -O-C i_6 alkyl,

(4) -O-C 1-6 haloalkyl,

(5) -OH,

(6) 0x0, (7) halogen,

(8) -CN,

(9) -NO ₂ ,

(10) -N(RC)RD,

(I I) -C(O)N(RC)RD, (12) -C(O)RA,

(13) -CO2RA,

(14) -SRA,

(15) -S(O)RA

(16) -SO2RA,

( 18) -SO ₂ N(RA)C(O)RB, and (ii) from zero to 2 substituents are each independently:

(1) AryA,

(2) HetA, (3) -C3-8 cycloalkyl,

(4) -C 1-6 alkyl substituted with AryA, HetA, or -C3-8 cycloalkyl,

(5) -Sθ2N(RA)-AryA,

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

each substituted C3-8 cycloalkyl is independently C3-8 cycloalkyl substituted with from 1 to 6 substituents, wherein (i) from zero to 6 substituents are each independently -Ci_6 alkyl, -OH, -O-Ci-6 alkyl, or -Ci -6 haloalkyl, and (ii) zero or 1 substituent is AryA;

each RA is independently H or C].6 allcyl;

each RB is independently H or C\.β alkyl;

each RC and RD are independently H or Q -6 alkyl, or together with the nitrogen to which they are attached form a 5- or 6-membered saturated heterocyclic ring optionally containing a heteroatom in addition to the nitrogen attached to RC and RD selected from N, O, and S, where the S is optionally oxidized to S(O) or S(O)2, and wherein the saturated heterocyclic ring is optionally substituted with 1 or 2 C 1-6 alkyl groups;

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, -C \.β alkyl, -Ci_6 haloalkyl, -OH, -O-Ci-6 alkyl, -O-Ci-6 haloalkyl, -C(O)N(RC)RD ₅ -C(O)RA, -CO2RA, -SRA, -S(O)RA, -SO2RA, -Sθ2N(RC)RD, or -SO2N(RA)C(O)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, -Cμg alkyl, -Ci -6 haloalkyl, -O-Ci-6 alkyl, -O-Q-g haloalkyl, -OH, -C(O)N(RC)RD, -C(O)RA, -CO2RA, -SRA, -S(O)RA, -SO2RA, -SO2N(RC)RD, _or -Sθ2N(RA)C(O)RB;

and provided that:

(A) when U is O, V is CEfc, W is C(0)N(R5), R2 is H or CH3, R5 is H or CH3, and

Rl is phenyl or pyridin-2-yl where the phenyl or pyridin-2-yl is unsubstituted or substituted with Cl, F, CF3, CH3, or OCH3, then R3 is not phenyl or pyridin-2-yl where the phenyl or pyridin-2-yl is unsubstituted or substituted with Cl, F, CF3, CH3, orOOT?; and

(B) when T is O, U is N(R4), W is C(O)N(RS), R2 is H or CH3, R5 is H, and Rl is 4-chlorophenyl, 4-fluorophenyl, or 5-chloro-pyridiny-2-yl, then R3 is not:

(i) phenyl which is (a) substituted in the 4-position with (2-sulfamoyl)phenyl or

(2-methanesulfonyl)phenyl and (b) optionally substituted in the 2-position with F, CF3, or CH3,

(ii) phenyl which is (a) substituted in the 4-position with (2-hydroxy)pyridin-l-yl (or equivalently 2-oxo-2H-pyridin-l-yl), pyrazol-1-yl, (5-methyl)pyrazol-l-yl, (3-methyl)- pyrazol-1-yl, (3,5-dimethyl)pyrazol-l-yl, or (2-methyl)imidazol-l-yl and (b) optionally substituted in the 2-position with F, or (iii) pyridin-2-yl which is substituted in the 5-position with (2-sulfamoyl)phenyl or

(2-methanesulfonyl)phenyl.

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

HIV 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-I reverse transcriptase. Based upon the testing of representative compounds of the invention in the assay set forth in Example 43 below, it is known that compounds of Formula I inhibit the RNA-dependent DNA polymerase activity of HTV-I reverse transcriptase. Certain compounds of the present invention also exhibit actuary against one or more drug resistant forms of HTV (e.g., mutant strains of HTV in which reverse transcriptase has a mutation at lysine 103 → asparagine (K 103N) or at tyrosine 181 → cysteine (Yl 81C) or has both mutations), and thus can exhibit decreased cross-resistance against currently approved antiviral therapies. A first embodiment of the present invention is a compound of Formula I (alternatively and more simply referred to herein as "Compound I"), or a pharmaceutically acceptable salt thereof, wherein each of the variables is as originally defined (i.e., as defined in the Summary of the Invention); and provided that:

(A) when U is O, V is unsubstituted Ci.6 alkylene, W is C(O)N(R5), R2 is H or Ci-6 alkyl, R5 is H or Ci_6 alkyl, and Rl is phenyl or pyridin-2-yl where the phenyl or pyridin-2-yl is unsubstituted or substituted with halogen, C\s alkyl, O-Ci-g alkyl, or Ci-6 haloalkyl, then R^ is not phenyl or pyridin-2-yl where the phenyl or pyridin-2-yl is unsubstituted or substituted with halogen, C\-β alkyl, O-Ci_6 alkyl, or C\.β haloalkyl; and

(B) when T is O, U is N(R4), W is C(O)N(R5), R2 is H or C\.β alkyl, R5 is H or C 1-6 alkyl, and Rl is phenyl substituted with halogen or pyridinyl substituted with halogen, then R ³ is not:

(i) phenyl which is (a) substituted with phenyl that is substituted with sulfarnoyl or methanesulfonyl and (b) optionally substituted with halogen, C 1-6 alkyl, Cj. ζ haloalkyl, or O-C 1-6 alkyl,

(ii) phenyl which is (a) substituted with hydroxypyridinyl, pyrazolyl optionally substituted with one or two Ci_6 alkyl groups, or imidazolyl substituted with C\.β alkyl, and (b) optionally substituted with halogen, or (iii) pyridinyl which is substituted with phenyl substituted with sulfamoyl or methanesulfonyl.

Additional embodiments of the present invention include those in which the compound of Formula I is as originally set forth above, except that one or more of the original definitions of the variables is(are) replaced by variable definition(s) (i) to (xiv) as follows: (i-a) T is O; or (i-b) T is S; (ii-a) U is O, S, NH, N(C 1.4 alkyl), or a direct bond linking V to the C(=T) moiety, with the proviso that U and W are not both direct bonds; (ii-b) U is O, S, NH, N(CH3), or a direct bond linking V to the C(=T) moiety, with the proviso that U and W are not both direct bonds; or

(ii-c) U is S;

(iii-a) V is Cl_6 alkylene;

(iii-b) V is C 1-4 alkylene; (iii-c) V is (CH2)l-3;

(iii-d) V is CH2, CH(CH3), or CH2CH2;

(iii-e) V is CH2 or CH2CH2; or

(iii-f) V is CH2 when U is O, S, NH or N(CH3), and V is CH2CH2 when U is a direct bond linking V to the C(=0) moiety; (iv-a) W is C(O)NH, C(O)N(CM alkyl), or a direct bond linking V to R3, with the proviso that U and W are not both direct bonds;

(iv-b) W is C(O)NH or C(O)N(CM alkyl); (iv-c) W is C(O)NH or C(0)N(CH3); or (iv-d) W is C(O)NH;

(v-a) R ¹ 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 1.4 alkyl, -O-C1.4 alkyl, -C 1.4 haloalkyl, -O-C1.4 haloalkyl, -OH, halogen, -CN, -NCh, -NH2, -NH-Ci-4 alkyl, -N(Ci -4 alkyl)2, -C(0)NH2, -C(O)NH-CM alkyl, -C(O)N(C 1.4 alkyl)2, -C(O)-C 1.4 alkyl, -C(O)NH-(CH ₂ )l-3-N(Ci.4 alkyl) ₂ , -C(O)N(C M alkylV(CH2)l-3-N(Ci_4 alkyltø, -C(O)NH-(CH2)l-3Q (where

Q is 4-morpholinyl, 4-thiomorpholinyl, 1-piperidinyl, I- piperazinyl optionally substituted with C 1.4 alkyl, or 1- pyrrolidinyl), -CO2-C1.4 alkyl, -S-C 1.4 alkyl, -S(O)-Ci -4 alkyl, -Sθ2-Cj_4 alkyl, -SO ₂ NH ₂ , -SO ₂ NH-C 1.4 alkyl, -SO ₂ N(CM alkyl)2, -SO ₂ NHC(O)-CM alkyl, -SO ₂ N(CM alkyl)C(0)-Ci_4 alkyl, NHC(O)-C 1-4 alkyl, or N(CM alkyl)C(OVCi-4 alkyl, and

(b) optionally substituted with:

(1) AryA, (2) CH ₂ -AryA,

(3) HetA,

(4) CH2-HetA,

(5) -SO ₂ NH-HetA, or

(6) -Sθ2N(C 1.4 alky l)-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 (a) optionally substituted with from 1 to 3 substituents each of which is independently -C 1.4 alkyl, -CM haloalkyl, -O-C1-4 alkyl, -O-C1-4 haloalkyl, halogen, -CN, -C(O)-Ci -4 alkyl, °r -CO2-C1-4 alkyl, and (b) optionally substituted with AryA,

(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 (a) optionally substituted with from 1 to 3 substituents each of which is independently -Ci -4 alkyl, -C 1.4 haloalkyl, -O-C1.4 alkyl, -0-C].4 haloalkyl, halogen, -CN, -C(O)-Ci -4 alkyl, or -CO2-Cj_4 alkyl, and (b) optionally substituted with AryA, 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 where the bicyclic heteroaromatic ring is (a) optionally substituted with from 1 to 3 substituents each of which is independently -Cl-4 alkyl, -C 1.4 haloalkyl,

-OC I-4 alkyl, -O-C1-.4 haloalkyl, halogen, -CN, -C(O)-CM alkyl, or -Cθ2-Ci_4 alkyl, and (b) optionally substituted with AryA;

(v-b) Rl is phenyl or naphthyl, wherein the phenyl or naphthyl is: (a) optionally substituted with from 1 to 5 substituents each of which is independently -C 1.4 alkyl, -0-Cj .4 alkyl, -Ci .4. haloalkyl, -O-C1-4 haloalkyl, -OH, halogen, -CN, -NO2, -NH2, -NH-Ci .4 alkyl, -N(C 1.4 alkyl)2, -C(O)NH2, -C(O)NH-CM alkyl, -C(O)N(CM alkyl)2, -C(O)-C M ^al M= -CO2-C1-4 alkyl, -S-C M ^al M> -S(O)-C M alkyl, -SO2-C1-4 alkyl, -SO2NH2, -SO2NH-CM alkyl, -S02N(CM alkyl)2,

-SO2NHC(O)-Ci_4 alkyl, -Sθ2N(Ci_4 alkyl)C(0)-Ci_4 alkyl, NHC(O)-CM alkyl, or N(CM alkyl)C(0)-Ci-4 alkyl, and (b) optionally substituted with AryA, (v-c) R ¹ is:

wherein j is an integer equal to zero, 1, 2 or 3; and each X is independently selected from the group consisting of -C j_4 alkyl, -O-C1.4 alkyl, -C 1.4 haloalkyl, -O-C1.4 haloalkyl, -OH, halogen, -CN, -NO2, -NH2, -NH-Ci-4 alkyl, -N(C 1-4 alkyltø, -C(O)NBk -C(O)NH-C M alkyl, -C(O)N(C 1.4 alkyl)2, -C(O)-C 1.4 alkyl, -CO2-C 1.4 alkyl, -S-C 1.4 alkyl,

-S(O)-C 1-4 alkyl, -SO2-C1.4 alkyl, -SO2NH2, -SOoNH-C 1.4 alkyl, -Sθ2N(Ci_ 4 alky 1)2, -Sθ2NHC(O)-Ci_4 alkyl, -Sθ2N(Ci_4 alkyl)C(0)-Ci_4 alkyl, NHC(O)-C 1.4 alkyl, N(C 1.4 alky I)C(O)-C 1.4 alkyl, and 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-C1.4 alkyl, -C 1.4 haloalkyl, or -O-Ci-4 haloalkyl; with the proviso that no more than one X substituent is optionally substituted phenyl;

(v-d) Rl is as defined in (v-c), except that j is an integer equal to 1, 2 or 3; and an X substituent is in the 2-position of the phenyl ring to which the 1 to 3 X substituents are attached; (v-e) Rl is as defined in (v-d), except that the phenyl ring to which the 1 to 3 X substituents are attached is 2-substituted, 2,3-disubstituted, 2,4-disubstituted, 2,5-disubstituted, 2,6- disubstituted, or 2,4,6-trisubstituted;

(v-f) Rl is as defined in any one of (v-c) to (v-e), except that each X is independently selected from the group consisting of CH3, OCH3, CF3, OCF3, Cl, Br, F, NO2, C(0)NH2, C(0)NH(CH3), C(O)N(CH3)2, C(O)CH3, SO2CH3, SO2NH2, Sθ2NH(CH3), and SO2N(CH3)2;

(v-g) Rl is as defined in (v-f), except that each X is independently selected from the group consisting of CH3, Cl, Br, and F;

(v-h) Rl is as defined in (v-f), except that each X is independently selected from the group consisting of CH3 and Cl; (v-i) Rl is 1-naphthyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl,

2,5-dichlorophenyl, 2,6-dichlorophenyl, 2-methylphenyl, 2,6-dimethylphenyl, 2,4,6-trimethylphenyl (mesityl), 2-methyl-3-chlorophenyl, 2-methyl-4-chlorophenyl, 2-bromophenyl, 2-chloro~6-methylphenyl, 2,4,6-trichlorophenyl, 2-bromo-4-methylphenyl, 2-methyl-3-fluorophenyl, 2-fluoro-3-chlorophenyl, 2- methyl-4-fluorophenyl, 2,5-difluorophenyl, or 2,6-dimethyl-4-bromophenyl; (v-j) Rl is 1-naphthyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl,

2,5-dichlorophenyl, 2,6-dichlorophenyl, 2-methylphenyl, 2,6-dimethylphenyl, 2,4,6-trimethylphenyl (mesityl), 2-methyl-3-chlorophenyl, or 2-methyl-4-chlorophenyl; or (v-k) Rl is 1-naphthyl or 2,4,6-trimethylphenyl; (vi-a) R2 is H or C 1-4 alkyl;

(vi-b) R2 is H or CH3; (vi-c) R2 is C 1-3 alkyl; or (vi-d) R2 is CH3;

(vii-a) R3 independently has the same definition as set forth for Rl in (v-a); (vii-b) R3 is:

(i) phenyl or naphthyl, wherein the phenyl or naphthyl is:

(a) optionally substituted with from 1 to 5 substituents each of which is independently -Ci .4 alkyl, -O-C1.4 alkyl, -C 1.4 haloalkyl, -OCi .4 haloalkyl, -OH, halogen, -CN, -NO2, -NH2, -NH-C 1.4 alkyl, -N(C 1.4 alkyl)2, -C(0)NH2, -C(O)NH-C 1.4 alkyl, -C(O)N(C 1.4 alkyl)2, -C(O)-C 1.4 alkyl, -C(O)N(H)-(CH ₂ ) 1-3-N(C 1.4 alkyl) ₂ , -C(O)N(C M alkyl)-(CH2)l-3-N(Ci_4 alkyl)2, -C(O)N(H)-(CH ₂ ) 1-3 Q (where

Q is 4-morpholinyl, 4-thiomorpholinyl, 1-piperidinyl, 1- piperazinyl optionally substituted with Cj .4 alkyl, or 1- pyrrolidinyl), -CO2-C1-4 alkyl, -S-C1-4 alkyl, -S(0)-Ci_4 alkyl, -SO2-C1-4 alkyl, -SO2NH2, -SO2NH-C1-4 alkyl, -SO ₂ N(Ci -4 alkyl)2, -Sθ2NHC(O)-Ci-4 alkyl, -Sθ2N(Ci_4 alkyl)C(0)-Ci-4 alkyl, NHC(O)-C M alkyl, or N(CM alkyl)C(0)-Ci_4 alkyl, and

(b) optionally substituted with:

(1) AryA,

(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, -Ci .4 alkyl, -Ci .4 haloalkyl, -O-Cj-4 alkyl, -O-Ci-4 haloalkyl, -CN, -C(O)-Ci -4 alkyl, or -CO2-Ci_4 alkyl; (vii-c) R3 is:

k is an integer equal to zero, 1, 2 or 3; and each Y is independently selected from the group consisting of -C 1.4 alkyl, -O-C1-4 alkyl, -C 1.4 haloalkyl, -O-C1.4 haloalkyl, -OH, halogen, -CN, -NO2, -NH2, -NH-Ci-4 alkyl, -N(CM alkyl)2, -C(O)NH ₂ , -C(O)NH-CM alkyl, -C(O)N(C 1.4 alky 1)2, -C(O)-C 1.4 alkyl, -C(O)N(C 1.4 alky I)- (CH2)1-3-N(C M alkyl)2, -C(O)N(H)-(CHi) 1-3 Q (where Q is 4-morpholinyl, 4- thiomorpholinyl, 1-piperidinyl, 1-piperazinyl optionally substituted in the A- position with Ci-4 alkyl, or 1-pyrrolidinyl), -CO2-C1-.4 alkyl, -S-C M alkyl, -S(O)-C 1.4 alkyl, -SO2-C 1.4 alkyl, -SO2NH2, -SO2NH-C 1.4 alkyl, -Sθ2N(C 1 -

4 alkyl)2, -Sθ2NHC(O)-Ci-4 alkyl, -S02N(CM alkyl)C(0)-Ci-4 alkyl, NHC(O)-C 1-4 alkyl, N(C 1.4 alkyl)C(0)-Ci_4 alkyl, and phenyl, wherein the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently halogen, -CN, -NO2, -C 1.4 alkyl, -O-Q-4 alkyl, -C 1.4 haloalkyl, or -0-C i-4 haloalkyl; with the proviso that no more than one Y substituent is optionally substituted phenyl;

(vii-d) R.3 is as defined in (vii-c), except that k is an integer equal to 1, 2 or 3; and a Y substituent is in the 2-position of the phenyl ring to which the 1 to 3 Y substituents are attached;

(vii-e) Rβ is as defined in (vii-d), except that k is an integer equal to 1 or 2; and the phenyl ring to which the 1 to 2 Y substituents are attached is 2-substituted or 2,4-disubstituted;

(vii-f) R3 is as defined in any one of (vii-c) to (vii-e), except that each Y is independently selected from the group consisting of CH3, OCH3, CF3, OCF3, Cl, Br, F, NO2, C(O)NH2,

C(O)NH(CH ₃ ), C(O)N(CH ₃ )2, C(0)CH3, C(O)NH-(CH ₂ )2N(CH ₃ )2, C(O)NH-(CH ₂ )3N(CH ₃ ) _2; SO2CH3, SO2NH2, Sθ2NH(CH3), Sθ2N(CH3)2,

(vii-g) R.3 is as defined in (vii-f), except that each Y is independently selected from the group consisting of CH3, Cl, NO2, C(O)NH(CH3), C<O)NH2, C(O)NH-(CH2)2N(CH3)2, SO2NH2, and

(vii-h) R3 is 2-chlorophenyl, 2-nitrophenyl, 2-chloro-4-(aminocarbonyl)phenyl, 2- chloro-4-(arninosulfbnyl)phenyl, 2-methyl-4-(aminosulfonyl)phenyl, 2-chloro-4-( { [3- (dirnethylamino)propyl]amino}carbonyl)phenyl, 2-chloro-4-{[(3-morpholin-4- ylpropyl)amino]carbonyl}phenyl, 2-chloro-4-[(methylamino)carbonyl]phenyl, or 2-chloro-4-({[2- (dirnethylamino)ethyl]amino} carbonyl)phenyl; or

(vii-i) R3 is 2-nitrophenyl;

(viii-a) R4 is H or C 1.4 alkyl; (viii-b) R^ is H or CH3; or

(viii-b) R4 is CH3;

(ix-a) R5 is H or C 1.4 alkyl;

(ix-b) R5 is H or CH3; or

(ix-c) R5 is H; (x-a) AryA is phenyl which is optionally substituted with from 1 to 3 substituents each of which is independently halogen, CN, -NCb, -Ci .4 alkyl, -C 1.4 haloalkyl, -OH, -O-C1.4 alkyl, -OCi .4 haloalkyl, -C(0)NH2, -C(O)NH-C M alkyl, -C(O)N(CM alkyltø, -C(O)-Ci -4 alkyl, -CO2-C1.4 alkyl, -S-Ci.4 alkyl, -S(O)-C 1.4 alkyl, -SO2-C1-4 alM. -SO2NH2, -SO2NH-C1.4 alkyl, -Sθ2N(Ci_4 alky 1)2, -SO2NHC(O)-Ci_4 alkyl, -S02N(CM alkyl)C(0)-Ci-4 alkyl; or

(x-b) AryA is phenyl, which 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-Ci .4 haloalkyl;

(xi-a) 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, -C 1.4 alkyl, -C 1-4 haloalkyl, -OCi .4 alkyl, or -O-CI-4 haloalkyl; or

(xi-b) each HetA is independently a heteroaromatic ring selected from the group consisting of pyridinyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, furanyl, thienyl, 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, -C 1.4 alkyl, -C 1.4 haloalkyl, -O-C1.4 alkyl, or-O-Ci-4 haloalkyl;

(xii-a) each RA is independently H or C 1.4 alkyl; or (xii-b) each RA is independently H or methyl;

(xiii-a) each RB is independently H or C 1.4 alkyl; or

(xiii-b) each RB is independently H or CH3; and

(xiv-a) each RC and RP are independently H or C 1.4 alkyl, or together with the nitrogen to which they are attached form 4-morpholinyl, 4-thiomorpholinyl, 1-piperidinyl, 1-piperazinyl optionally substituted with Cj_4 alkyl, or 1-pyrrolidinyl; or

(xiv-b) each R.C and RP are independently H or CH3, or together with the nitrogen to which they are attached form 4-morpholinyl, 4-thiomorpholinyl, 1-piρeridinyl, 1-piperazinyl optionally substituted with Ci -4 alkyl, or 1-pyrrolidinyl.

It is of course understood that the foregoing embodiments defined by the various combinations of one or more of items (i) to (xiv) are each accompanied as necessary by provisos (A) and (B) analogous to those originally set forth above. An analogous set of embodiments is defined by the various combinations of one or more of items (i) to (xiv) plus provisos (A) and (B) analogous to those set forth in the first embodiment.

Compound embodiments of particular interest herein are referred to as compound classes.

A first class of the present invention includes compounds of Formula I, and pharmaceutically acceptable salts thereof, wherein T is O or S; U is O, S, NH, N(C i_4 alkyl), or a direct bond linking V to the C(=T) moiety; V is Ci.6 alkylene; W is C(O)NH ₅ C(O)N(C 1.4 alkyl), or a direct bond linking V to R3, with the proviso that U and V are not both direct bonds; Rl is as defined in item

(v-a) above; R2 is H or C 1.4 alkyl; R3 is as defined in item (vii-a) above; AryA is as defined in item (x- a) above; and HetA is as defined in item (xi-a) above; and provided that:

(A) when U is O, V is CH2, W is C(O)N(H) or C(O)N(CH3), and R2 is H or CH3, and Rl is phenyl or pyridin-2-yl where the phenyl or pyridin-2-yl is unsubstituted or substituted with Cl, F, CF3, CH3, or OCH3, then R3 is not phenyl or pyridin-2-yl where the phenyl or pyridin-2-yl is unsubstituted or substituted with Cl, F, CF3, CH3, or OCH3; and

(B) when T is O, U is N(H) or N(C 1.4 alkyl), W is C(O)N(H), R2 is H or CH3, and Rl is 4-chlorophenyl, 4-fluorophenyl, or 5-chloro-pyridiny-2-yl, then R3 is not:

(i) phenyl which is (a) substituted in the 4-position with (2-sulfamoyl)phenyl or (2-methanesulfonyl)phenyl and (b) optionally substituted in the 2-position with F, CF3, or CH3,

(ii) phenyl which is (a) substituted in the 4-position with pyrazol-1-yl, (5-methyl)pyrazol-l- yl, (3-methyl)-pyrazol-l-yl, (3,5-dimethyl)pyrazol-l-yl, or (2-methyl)imidazol-l-yl and (b) optionally substituted in the 2-position with F, or (iii) pyridin-2-yl which is substituted in the 5-position with (2-sulfamoyl)phenyl or

(2-methanesulfonyl)phenyl.

A second class of the present invention includes compounds of Formula I, and pharmaceutically acceptable salts thereof, wherein T is O or S; U is O, S, NH, N(Ci .4 alkyl), or a direct bond linking V to the C(=T) moiety; V is C].6 alkylene; W is C(O)NH, C(O)N(Ci -4 alkyl), or a direct bond linking V to R^, with the proviso that U and W are not both direct bonds; Rl is as defined in item (v-b) above; R2 is H or Ci_4 alkyl; R3 is as defined in item (vii-b) above; AryA is a defined in item (x-b) above; and HetA is as defined in item (xi-b) above; and provided that:

(A) when U is O, V is CH2, W is C(O)N(H) or C(0)N(CH3), R2 is H or CH3, and Rl is phenyl or phenyl substituted with Cl, F, CF3, CH3, or OCH3, then R3 is not phenyl or pyridiny-2- yl where the phenyl or pyridin-2-yl is unsubstituted or substituted with Cl, F, CF3, CH3, or OCH3;

(B) when T is O, U is N(H) or N(CM alkyl), W is C(O)N(H), R2 is H or CH3, and Rl is 4-chlorophenyl or 4-fluorophenyl, then R^ is not phenyl which is (a) substituted in the 4-position with pyrazol-1-yl, (5-methyl)pyrazol-l-yl, (3-methyl)-pyrazol-l-yl, (3,5-dimethyl)pyrazol-l-yl, or (2- methyl)imidazol-l-yl and (b) optionally substituted in the 2-position with F.

A third class of the present invention includes compounds of Formula I, and pharmaceutically acceptable salts thereof, wherein T is O or S; U is: (1) O, (2) S, (3) N(H) or N(Ci-4 alkyl), or (4) a direct bond linking V to the C(=T) moiety; V is Cl .4 alkylene; W is C(O)NH or

C(O)N(Cj-4 alkyl); R* is as defined in item (v-c) above; R ² is H or C1.4 alkyl; and R3 is as defined in item (vii-c) above; and provided that (A) when U is O, V is CH2, W is C(O)N(H) or C(O)N(CH3), R ² is

H or CH3, J is zero or 1, and X is Cl, F, CF3, CH3, or OCH3, then k is not zero and k is not 1 when Y is Cl, F ₅ CF3, CH3, or OCH3.

A fourth class of the present invention includes compounds of Formula I, and pharmaceutically acceptable salts thereof, wherein T is O; either: (i) U is S, O, NH or N(CH3), and V is CH2; or (ii) U is a direct bond linking V to the C(=0) moiety and V is CH2CH2; W is C(O)NH; Rl is as defined in item (v-c) above; R ² is C 1.3 alkyl; and R3 is as defined in item (vii-c) above; and provided

that (A) when U is O and V is CH2, R ¹ i s: , j is zero or 1, and X is Cl, F, CF3, CH3, or

OCH3, then k is not zero and k is not 1 when Y is Cl, F, CF3, CH3, or OCH3. A sub-class of the fourth class is identical to the fourth class as just described, except that R2 is CH3.

A fifth class of the present invention includes compounds of Formula I, and pharmaceutically acceptable salts thereof, wherein T is O or S; U is: (1) O, (2) S, (3) N(H) or N(Ci_4 alkyl), or (4) a direct bond linking V to the C(=T) moiety; V is C1-4 alkylene; W is C(O)NH or C(O)N(C 1-4 alkyl); Rl is as defined in item (v-d) above; R ² is H or C 1.4 alkyl; and R3 is as defined in item (vii-d) above; and provided that (A) when U is O, V is CH2, W is C(O)N(H) or C(0)N(CH3), R ² is

is 1, and X is Cl, F, CF3, CH3, or OCH3, then k is not 1 when Y is Cl, F, CF3, CH3, or

OCH3.

A sixth class of the present invention includes compounds of Formula I, and pharmaceutically acceptable salts thereof, wherein T is O or S; U is: (1) O, (2) S, (3) N(H) or N(Ci-4 alkyl), or (4) a direct bond linking V to the C(=T) moiety; V is Ci -4 alkylene; W is C(O)NH or

C(O)N(Ci-4 alkyl); Rl is as defined in item (v-e) above; R ² is H or C1.4 alkyl; and R3 is as defined in

item (vii-e) above; and provided that (A) when U is O, V is CH2, W is C(O)N(H) or C(O)N(CH3) ₅ R ² is H or CH3, Rl is:

, j is 1, and X is Cl, F, CF3, CH3, or OCH3, then k is not 1 when Y is Cl, F, CF3, CH3, or

OCH3.

A seventh class of the present invention includes compounds of Formula I, and pharmaceutically acceptable salts thereof, wherein T is O; either: (i) U is S, O, NH or N(CH3), and V is CH2; or (ii) U is a direct bond linking V to the C(=0) moiety and V is CH2CH2; W is C(O)NH;

Rl is:

R2 is CH3;

R3 is:

j is an integer equal to 1, 2 or 3; k is an integer equal to 1 or 2; the phenyl ring to which the 1 to 3 X substituents are attached is 2-substituted, 2,3-disubstituted, 2,4-disubstituted, 2,5-disubstituted, 2,6- disubstituted, or 2,4,6-trisubstituted; and the phenyl ring to which the 1 to 2 Y substituents are attached is 2-substituted or 2,4-disubstituted;

each X is independently selected from the group consisting of CH3, OCH3, CF3, OCF3, Cl, Br, F, NO2, C(0)NH2, C(0)NH(CH3), C(O)N(CH3)2, C(0)CH3, SO2CH3, SO2NH2, Sθ2NH(CH3), and Sθ2N(CH3)2; and

each Y is independently selected from the group consisting of CH3, OCH3, CF3, OCF3, Cl, Br, F, NCb, C(O)NH2, C(O)NH(CH3), C(O)N(CH3)2, C(O)CH3, C(O)NH-(CH ₂ ) ₂ N(CH3) ₂ , C(O)NH-(CH2)3N(CH3)2, SO ₂ CH ₃ , SO ₂ NH ₂ , SO ₂ NHtCH ₃ ), SO ₂ N(CH ₃ )O,

and provided that (A) when U is O, V is CH ₂ , Rl is:

, j is 1, and X is Cl ₅ F, CF ₃ , CH ₃ , or OCH ₃ , then k is not 1 when Y is Cl, F, CF ₃ , CH ₃ , or OCH ₃ .

An eighth class of the present invention includes compounds of Formula I, and pharmaceutically acceptable salts thereof, wherein each of the variables is as defined in the seventh class, except that each X is independently selected from the group consisting of CH ₃ , Cl, Br and F; and each Y is independently selected from the group consisting of CH3, Cl, NO ₂ , C(0)NH(CH3), C(O)NH2, C(O)NH-(CH2)3N(CH3) ₂ , SO ₂ NH ₂ , and

and provided that (A) when U is O, V is CH ₂ , Rl is:

, j is 1, then k is not 1 when Y is Cl or CH3. A sub-class of the eighth class is identical to the eighth class as just described, except that each X is independently selected from the group consisting of CH3 and Cl.

A ninth class of the present invention includes compounds of Formula I, and pharmaceutically acceptable salts thereof, wherein T is O; either: (i) U is S, O, NH or N(CH3), and V is CH2; or (ii) U is a direct bond linking V to the C(=0) moiety and V is CH2CH2; W is C(O)NH; Rl is 1- naphthyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6- dichlorophenyl, 2-methylphenyl, 2,6-dimethylphenyl, 2,4,6-trimethylphenyl (mesityl), 2-methyl-3- chlorophenyl, 2-methyl-4-chlorophenyl, 2-bromophenyl, 2-chloro-6-methylphenyl, 2,4,6-trichlorophenyl, 2-bromo-4-methylphenyl, 2-methyl-3-fluorophenyl, 2-fluoro-3-chlorophenyl, 2-methyl-4-fluorophenyl, 2,5-difluorophenyl, or 2,6-dimethyl-4-bromophenyl; R^ is CH3; and R3 is 2-chlorophenyl, 2-nitrophenyl,

2-chloro-4-(aminocarbonyl)phenyl, 2-chloro-4-(aminosulfonyl)phenyl, 2-methyl-4- (aminosulfonyl)phenyl, 2-chloro-4-( { [3-(dimethylamino)propyl]amino} carbonyl)phenyl, 2-chloro-4- { [(3- morpholin-4-ylpropyl)amino]carbonyl}phenyl, 2-chloro-4-[(methylamino)carbonyl]phenyl, or 2-chloro- 4-({[2-(dimethylamino)ethyl]amino}carbonyl)phenyl; and with the proviso that (A) when U is O, V is CH2, and Rl is 2-chlorophenyl or 2-methylphenyl, then R3 is not 2-chlorophenyl. A sub-class of the ninth class is identical to the ninth class as just described, except that Rl is 1-naphthyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 2-methylphenyl, 2,6-dimethylphenyl, 2,4,6-trimethylphenyl (mesityl), 2-methyl-3-chlorophenyl, or 2-methyl-4- chlorophenyl.

A tenth class of the present invention includes compounds of Formula I, and pharmaceutically acceptable salts thereof, wherein each of the variables is as defined in the ninth class, except that Rl is 1-naphthyl or 2,4,6-trimethylphenyl.

An eleventh class of the present invention includes compounds of Formula I, and pharmaceutically acceptable salts thereof, wherein each of the variables is as defined in the ninth class, except that R^ is 2-nitrophenyl.

A sub-class of each of the foregoing classes includes compounds of Formula I, and pharmaceutically acceptable salts thereof, as defined in the class, in which the provisos (A) and (B) are analogous to those set forth in the first embodiment. Another sub-class of each of the foregoing classes includes compounds of Formula I, and pharmaceutically acceptable salts thereof, wherein U is S.

Another embodiment of the present invention is a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the compounds set forth in Examples 1 to 41 below. Another embodiment of the present invention is a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the compounds set forth in Examples 1 to 26 below. Still another embodiment of the present invention is a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the compounds set forth in Examples 27 to 41 below.

Another embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, as originally defined or as defined in any of the foregoing embodiments, classes, sub-classes, aspects, or features of Formula I, wherein the compound or its salt is substantially pure. As used herein "substantially pure" means that the compound or its salt is present (e.g., in a product isolated from a chemical reaction or a metabolic process) in an amount of at least about 90 wt. % (e.g., from about 95 wt.% to 100 wt.%), preferably at least about 95 wt.% (e.g., from about 98 wt.% to 100 wt.%), more preferably at least about 99 wt.%, and most preferably 100 wt.%. The level of purity of the compounds and salts can be determined using standard methods of analysis. A compound or salt of 100% purity can alternatively be described as one which is free of detectable impurities as determined by one or more standard methods of analysis. With respect to a compound of the invention which has one or more asymmetric centers and can occur as mixtures of stereoisomers, a substantially pure compound can be either a substantially pure mixture of the stereoisomers or a substantially pure individual diastereomer or enantiomer.

Other embodiments of the present invention include the following: (a) A pharmaceutical composition comprising an effective amount of Compound I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

(b) A pharmaceutical composition which comprises the product prepared by combining (e.g., mixing) an effective amount of Compound I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. (c) The pharmaceutical composition of (a) or (b), further comprising an effective amount of an anti-HTV agent selected from the group consisting of HTV antiviral agents, immunomodulators, and anti-infective agents.

(d) The pharmaceutical composition of (c), wherein the anti-HTV agent is an antiviral selected from the group consisting of HTV protease inhibitors, HTV reverse transcriptase inhibitors other than a compound of Formula I ₅ and HTV integrase inhibitors.

(e) A pharmaceutical combination which is (i) a compound of Formula I, or a pharmaceutically acceptable salt thereof, and (ii) an anti-HTV agent selected from the group consisting of HTV antiviral agents, immunomodulators, and anti-infective agents; wherein the compound of Formula I and the anti-HTV agent are each employed in an amount that renders the combination effective for inhibiting HTV reverse transcriptase, for treating or prophylaxis of infection by HTV, or for treating, prophylaxis of, or delaying the onset of ADDS.

(f) The combination of (e), wherein the anti-HTV 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.

Additional embodiments of the invention include the pharmaceutical compositions and combinations set forth in (a)-(f) above, wherein the compound of the present invention employed therein is a compound defined in one of the embodiments, classes, or sub-classes described above. In all of these embodiments, classes, and sub-classes, the compound can optionally be used in the form of a pharmaceutically acceptable salt.

The present invention also includes a method for inhibiting EDV reverse transcriptase, for treating or prophylaxis of HTV infection, or for treating, prophylaxis of, or delaying the onset of ADDS, 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 Formula I is as originally set forth and defined above, except that the accompanying provisos (A) and (B) are not applied (i.e., the provisos are absent). In other words, compounds suitable for use in the method of the present invention include the compounds embraced by Formula I when the provisos are applied (i.e., the compounds of the present invention as defined and described above ^" ) and the compounds embraced by Formula I that fall within the scope of provisos (A) and (B). Embodiments of the method of the present invention include those in which the compound of Formula I administered to the subject is as defined in the compound embodiments, classes and sub-classes set forth above, except that the provisos (A) and (B) are not applied. In sub- embodiments of each of these embodiments, provisos (A) and (B) are included in the definition of the compound. The present invention also includes a compound of Formula I, or a pharmaceutically acceptable salt thereof, (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) treating or prophylaxis of infection by HTV, or (c) treating, prophylaxis of, or delaying the onset of ADDS. In these uses, the compound of Formula I is as originally set forth and defined above, except that the accompanying provisos (A) and (B) are not applied (i.e., the provisos are absent). In these uses, the compounds of the present invention can optionally be employed in combination with one or more anti-HIV agents selected from HTV antiviral agents, anti-infective agents, and itnmunomodulators. Embodiments of the uses of the present invention include those in which the compound of Formula I is as defined in the compound embodiments, classes and sub-classes set forth above, except that the provisos (A) and (B) included therein are not applied. In sub-embodiments of these embodiments, provisos (A) and (B) are included in the definition of the compound.

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, "Ci -β alkyl" (or "C\-Cβ alkyl") refers to any 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, "C 1-4 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, "-Ci -6 alkylene-" refers to any of the Ci to Cβ linear or branched alkylenes. A class of alkylenes of particular interest with respect to the invention is -(CH2)l-6- ₅ and sub-classes of particular interest include -(CH2)i-4-, -(CH2)l-3-, -(CH2)l-2-, and -CH2-- Another class of particular interest includes alkylenes selected from the group consisting of -CH2-, -CH(CHs)-, ^aI *d -C(CH3)2-. A sub-class of this class that is of interest is the alkylene -CH(CH3)-. The term "cycloalkyl" refers to any cyclic ring of an alkane having a number of carbon atoms in the specified range. Thus, for example, "C3.8 cycloalkyl" (or "C3-C8 cycloalkyl") refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 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, Cl, Br and/or I). Thus, for example, "Ci_6 haloalkyl" (or "C1-C6 haloalkyl") refers to a Ci 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-proρyl, etc.). Fluoroalkyls of particular interest include CF3, CH2CF3, CH2CH2CF3, CF2CF3, and CH2CF2CF3.

The terms "sulfamoyl" and "aminosulfonyl" each refer to H2NSO2-.

The term "C(O)" appearing in the definition of a functional group (e.g., "C(O)RA") refers to carbonyl. The term "S(O)2" or "SO2" appearing in the definition of a functional group refers to sulfonyl, the term "S(O)" refers to sulfinyl, and the teπns "C(O)O" and "CO2" both refer to carboxyl.

The symbol " * " at the end of a bond each refer to the point of attachment of a functional group or other chemical moiety to the rest of the molecule of which it is a part.

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(O)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., OΛ 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, thienyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, and oxadiazolyl.

Any of the 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 expressly stated to the contrary, 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 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 2 to 4 heteroatoms, 3 to 4 heteroatoms, 1 to 3 heteroatoms, 2 to 3 heteroatoms, 1 to 2 heteroatoms, 1 heteroatom, 2 heteroatoms, 3 heteroatoms, and 4 heteroatoms. As another example, an aryl described as optionally substituted with "from 1 to 5 substituents" is intended to include as aspects thereof, an aryl optionally substituted with 1 to 4 substituents, 1 to 3 substituents, 1 to 2 substituents, 2 to 5 substituents, 2 to 4 substituents, 2 to 3 substituents, 3 to 5 substituents, 3 to 4 substituents, 4 to 5 substituents, 1 substituent, 2 substituents, 3 substituents, 4 substituents, and 5 substituents.

T C

- -

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.

The term "substituted" (e.g., as in "is optionally substituted with from 1 to 5 substituents ...") includes mono- and poly-substitution by a named substituent to the extent such single and multiple substitution (including multiple substitution at the same site) is chemically allowed. Unless expressly stated to the contrary, substitution by a named substituent is permitted on any atom in a ring (e.g., cycloalkyl, aryl, or heteroaryl) provided such ring substitution is chemically allowed and results in a stable compound. Ring substituents can be attached to the ring atom which is attached to the rest of the molecule, provided a stable compound results.

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 of the 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 foπn (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 alloλv use of the compound for the purposes 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 Foπnula I in the inhibition of HIV reverse transcriptase, the prophylaxis or treatment of infection by human immunodeficiency virus (HTV) and the prophylaxis, treatment or the delay in the onset of consequent pathological conditions such as AIDS. Prophylaxis of ADDS, treating AIDS, delaying the onset of AIDS, or treating or prophylaxis of infection by HTV is defined as including, but not limited to, treatment of a wide range of states of HIV infection: AIDS, ARC (AIDS 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 HIV-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 (-C00H) 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 prophylaxis of HIV 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.

When the agents of a combination are administered at the same time, they can be administered together in a single composition or they can be administered separately.

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 form (i.e., the non-salt form) of the compound. In the method of the present invention (i.e., inhibiting HTV reverse transcriptase, treating or prophylaxis of HTV infection or treating, prophylaxis of, or delaying the onset of AIDS), the compounds 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 of the 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 of the compounds of Formula I in combination λvith one or more agents useful in the treatment of HTV infection or ADDS. 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 antiviral agents, imunomodulators, antiinfectives, or vaccines useful for treating HTV infection or ADDS, such as those disclosed in Table 1 of WO 01/38332 or in the Table in WO 02/30930. Suitable HTV antiviral agents 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 HIV 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. The following Table A lists certain HTV antiviral agents with which the compounds of the invention can be used in combination:

Table A

FI = fusion inhibitor; PI = protease inhibitor; nRTI = nucleoside reverse transcriptase inhibitor; nnRTI = non-nucleoside reverse transcriptase inhibitor. Some of the drugs listed in the table are used in a salt form; e.g., indinavir sulfate, atazanvir sulfate, nelfinvavir mesylate.

It will be understood that the scope of combinations of compounds of Formula I with HIV antiviral agents, 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 FHV infection or AIDS. The FHV antiviral agents 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 ₅ 2003. The dosage ranges for a compound of Formula I in these combinations are the same as those set forth above. All agents can optionally be used in the form of pharmaceutically acceptable salts.

Abbreviations used in the instant specification, particularly the Schemes and Examples, include the following: AEDS = acquired immunodeficiency syndrome; ARC = ADDS related complex; DCM = dichloromethane; DMAP = dimethylaminopyridine; DMF = dimethylformamide; DMSO = dimethylsulfoxide; dGTP = deoxyguanosine triphosphate; dNTP = deoxynucleoside triphosphate; EDTA = ethylenediaminetetracetic acid; EGTA = ethylene glycol bis(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid; ES = electrospray; Et = ethyl; EtOAc = ethyl acetate; EtOH = ethanol; HTV = human immunodeficiency virus; HPLC = high performance liquid chromatography; Me = methyl; MeOH = methanol; MS = mass spectroscopy; NMR = nuclear magnetic resonance; RP-HPLC = reverse phase HPLC; t-Bu = tert-butyl; 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, hi 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.

A general synthetic method for preparing thiocarbamate compounds of the present invention is shown in Scheme I ₅ Parts A and B. In Part A, amine JUl is chloroformylated with triphosgene and the chlorine substituted with a thiol-substituted carboxylic ester in the presence of an appropriate base (e.g., pyridine) and solvent at elevated temperature (e.g., about 65 ⁰ C), to afford thiocarbamate JU2. The thiocarbamate can then be hydrolyzed with a base (e.g., NaOH or LiOH) to carboxylic acid JU3, which can be activated (e.g., with oxalyl chloride in DCM) and coupled with amine 1-4 to afford the desired thiocarbamate JU5. Alternatively, the activation and coupling can be conducted as discrete steps, wherein acid JU3 can first be converted to an acid halide (e.g., by reaction with thionyl chloride, phosphorus trichloride, or oxalyl chloride) and the resulting acid halide intermediate can then be coupled with amine JU4. The compounds JU5 can contain functional groups suitable for further elaboration, such as esters which can be hydrolyzed to the corresponding acids and then coupled with a suitable amine to form an amide, or amines which can be converted to amides, sulfonamides, ureas or carbamates. Part B is a modification of Part A, wherein amine JUl is chloroformylated with triphosgene or phosgene and the chlorine substituted with a thiol-substituted carboxyamide generated in situ from intermediate 1-17 treated with a suitable base in a suitable solvent (e.g., a metal alkoxide or thioalkoxide such as sodium thiomethoxide in an alkyl alcohol such as methanol) at room temperature, to afford directly the desired product JU5. The intermediate product 1-17 can be obtained by coupling

amine JU4 with a suitable acid chloride to afford amide 1-16, and then treating the amide with potassium thioacetate.

Scheme 1

PART A

hydrolysis

Et)

"

PART B

Amines of formula 1-1 can be prepared using the methods described in Richard Larock, Comprehensive Organic Transformations. VCH Publishers Inc, 1989, pp 385-438, or routine variations thereof. Suitable monomethylated amines can be prepared, for example, by first acylating a primary amine (e.g., with foπnic acid) and then reducing the resulting formamide using a hydride-donor reducing agent (e.g., a borane-THF adduct or a borane-Me2S adduct). Some amines of formula \Λ are also commercially available.

Scheme 2 provides a synthetic method for preparing diamide compounds of the present invention, wherein amine IA is acylated with a suitable cyclic anhydride in the presence of a base in aprotic solvent (e.g., DMAP in DMF at room temperature) to afford acid 1^6. The acid 1^6 can then be activated (e.g., with oxalyl chloride) and coupled with amine JU4 to obtain the desired product 1-7.

Scheme 2

ling

Scheme 3 depicts a method for preparing ureido-substituted alkylamide compounds of the present invention, wherein amine hΛ is treated first with triphosgene, and then with an amine of formula 1^8 and a base at elevated temperature (e.g., pyridine at 65°C) to obtain urea JU9. The ester group in urea 1^9 is converted to carboxylic acid 1-10 by treatment with an acid (e.g., TFA). Carboxylic acid 1-10 is in turn be activated (e.g., by treating with oxalyl chloride) and coupled with amine 1^4 to afford the desired compound 1-11.

Scheme 3

Scheme 4 depicts a general method for preparing carbamate compounds of the present invention, wherein amine 1^1 is treated first with triphosgene, and then with freshly prepared hydroxy ester salt 1-12 (e.g., Na salt) in an aprotic solvent at elevated temperature (e.g., THF at 55 ⁰ C) to obtain the carbamate intermediate 1-13. The ester group in 1-13 can be hydrolyzed with a base (LiOH) to carboxylic acid 1-14, which is in turn activated (e.g., by treating with oxalyl chloride) and coupled with amine U4 to afford the the desired compound 1-15.

Scheme 4

1-12

The present invention also includes a process for preparing a compound of Formula II:

which comprises reacting an amine of Formula DLI:

R ³ ,NH

R ⁵ (DI)

with a carboxylic acid of Formula IV:

in a solvent and in the presence of an activating agent and a base to obtain a compound of Formula π (alternatively and more simply referred to herein as "Compound EH); λvherein T, U, V, Rl, R2, R3 _; and R5 are as originally defined or as defined in any of the foregoing embodiments, classes, and subclasses. The solvent can be any organic substance which under the conditions employed is in the liquid phase, is chemically inert, and will dissolve, suspend, and/or disperse carboxylic acid IV and amine HI so as to bring them into contact and permit their reaction. Suitable solvents include haloalkanes (i.e., linear and branched alkanes substituted with one or more halogens), halocycloalkanes (i.e., cycloalkanes substituted with one or more halogens), dialkyl ethers, and cyclic ethers and diethers. The solvent can suitably be selected from the group consisting of Cl_4 haloalkanes, di-Ci.4 alkyl ethers, and C5.6 ethers and diethers. The solvent can, for example, be selected from the group consisting of dichloromethane, 1,2- dichloroethane, chloroform, bromoform, diethyl ether, THF ₅ and dioxane. A class of solvents particularly suitable for use in the process consists of dichloromethane, diethyl ether, and TfIF. Dichloromethane is a preferred solvent.

The activating agent can be a dicarboxylic acid halide (e.g., a diacid chloride) or an inorganic acid halide (e.g., a choride or bromide). The activating agent can suitably be selected from the group consisting of oxalyl chloride, thionyl chloride, PCI3, PBr3, PCI5, PBrs, and POCI3. Oxalyl chloride is a preferred activating agent.

The base can be a tertiary amine, such as a tri-C J -.4 alkyl amine. The base can suitably be selected from the group consisting of trimethyl amine, triethylamine, triisopropylamine, diisopropylethylamine, and diethylisopropylamine. Triethylamine is a preferred base.

The reaction can be conducted at any temperature at which the reaction (amine coupling) forming Compound II can be detected. The reaction can suitably be conducted at a temperature in a range of from about -15 ⁰ C to about SO ⁰ C, and is typically conducted at a temperature in a range of from about -5 ⁰ C to about 6O ⁰ C (e.g., from about O ⁰ C to about 4O ⁰ C). The amine reactant m, the base, and the activating agent can each be employed in any proportion with respect to the carboxylic reactant IV that will result in the formation of at least some of Compound π, but they are typically employed in amounts that can optimize conversion of carboxylic acid rv and formation of Compound EL For example, amine Ed, base and activating agent can each be employed in an amount of at least about 1 molar equivalent per molar equivalent of carboxylic acid EV. As another example, the reaction can suitably be conducted employing equimolar amounts of carboxylic acid, amine, base, and activating agent.

The present invention also includes a process for preparing a compound of Formula V:

which comprises reacting a haloformylated amine of Formula VI:

with a thioacetate of Formula VII:

in a solvent and in the presence of a base to obtain a compound of Formula V (alternatively and more simply referred to herein as "Compound V"); wherein Z is halogen; and V ₅ Rl, R2, R3, and R^ are as originally defined or as defined in any of the foregoing embodiments, classes, and subclasses. While not wishing to be bound by any particular theory, it is believed that thioacetate VII is deacetylated by the base resulting in the in situ formation of a thiol which is acylated by haloformylamine VI to afford Compound V. The solvent employed in the process can be any organic substance which in the liquid phase, is chemically inert, and will dissolve, suspend, and/or disperse haloformylamine VI, base and thioacetate VII so as to permit the reaction to proceed. Suitable solvents include alcohols such as the C i_6 alkyl alcohols (e.g., methanol or ethanol). Suitable bases include metal alkoxides. A suitable class of metal alkoxides includes the alkali metal alkoxides of C\.β alcohols and Cμg thioalcOhols, such as sodium methoxide, sodium thiomethoxide, sodium ethoxide, and sodium thioethoxide.

The process can be conducted at any temperature at which the reaction forming Compound V can be detected. The reaction can suitably be conducted at a temperature in a range of from about -1O ⁰ C to about 6O ⁰ C, and is typically conducted at a temperature in a range of from about -O ⁰ C to about 5O ⁰ C.

The haloformylamine reactant VI and the base can each be employed in any proportion with respect to the thioacetate reactant VII that will result in the formation of at least some of Compound V, but they are typically employed in amounts that can optimize conversion of haloformylamine VI and formation of Compound V. For example, reactant VI and base can each be employed in an amount of at

least about 1 molar equivalent per molar equivalent of thioacetate VII. As another example, the reaction can suitably be conducted employing equimolar amounts of haloformylamine VI, thioacetate VII, and base.

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 l S-(2-{[2-Chlorophenyl]amino}-2-oxoethyl) mesityl(methyl)thiocarbamate

Step 1: Mesityl(methyl)amine

To formic acid (87 eq.) was added dropwise acetic anhydride (19 eq.). After 10 minutes at O ⁰ C the mixture was stirred for 1 hour at room temperature. To the mixture was then added dropwise 2,4,6-trimethylaniline (1 eq.). After 1 hour the solvents were removed under vacuum and the residue was left under high vacuum for 3 hours. The solid obtained was suspended in dry THF at 0 ⁰ C. 2.5 eq. of borane-dimethylsulfide solution in THF (2 M) were added slowly and the mixture was stirred for 5 minutes at O ⁰ C and for 3 hours at 55 ⁰ C. The reaction was cooled to room temperature and quenched with MeOH. The mixture was partitioned between sat. aq. NaHCO3 and EtOAc. The organic phase was again extracted with water and the combined organic phases were dried over Na2SO4, filtered and concentrated to dryness under vacuum. MS m/s: 150 (M+H) ⁺ .

Step 2; Methyl ({[mesityl(methyl)amino]carbonyl}thio)acetate

To a solution of bis(trichloromethyl)carbonate (0.35 eq.) in anhydrous dichloromethane at -78°C was added pyridine (1 eq.) and then dropwise mesityl-(methyl)amine over 10 minutes. The reaction mixture was stirred for 1 hour at room temperature and was quenched with IN HCl. The mixture was extracted with dichloromethane and the organic phase was dried over Na2SO4, filtered and concentrated to dryness under vacuum. The residue was dissolved in dry pyridine. Methyl-thioglycolate (1 eq) was added and the mixture was stirred and warmed to 65°C for 16 hours. The mixture was cooled to room temperature and concentrated under vacuum. The residue λvas partitioned between

dichloromethane and IN HCI. The organic phase was dried over Na2SO4, filtered and concentrated to dryness under vacuum. MS m/z: 282 (M+H) ⁺ .

Step 3: ({[Mesityl(methyl)araino]carbonyl}thio)acetic acid

({[Mesityl(methyl)amino]carbonyl}thio)acetate was dissolved in a MeOH/water mixture (2:1). LiOH hydrate (1 eq.) was added and the mixture was stirred at 5°C for 16 hours. The mixture was partitioned between dichloromethane and IN NaOH. The aqueous phase was acidified with IN HCl and extracted with EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated to dryness under vacuum. The title compound was obtained as beige solid. lH NMR (300 MHz, DMSO-dβ): δ 12.51 (bs, IH), 6.98 (s, 2H), 3.50 (s, 2H), 3.07 (s, 3H), 2.25 (s, 3H),

2.13 (s, 6H). MS (EI+) 268 (M+H) ⁺ . MS (ES-) 266 (M+e)\

Step 4: S-(2-{[2-chlorophenyl]amino}-2-oxoethyl) mesityl(methyl)thiocarbamate ({[Mesityl(methyl)amino]carbonyl}thio)acetic acid was dissolved in anhydrous dichloromethane at 0 ⁰ C. Oxalyl chloride (1 eq., 2M in dichloromethane) was added followed by a small quantity of DMF. The mixture was stirred at O ⁰ C for 30 minutes. Then a solution of 2-chloroaniline (1 eq.) and triethylamine (1 eq.) in anhydrous dichloromethane was added. After 40 minutes the solvent was removed under vacuum. The product was isolated by preparative RP-HPLC, using water (0.1 % TFA) and acetonitrile (0.1 % TFA) as eluants (column: C 18). The pooled product fractions were lyophilized to afford the title compound as a light yellow solid. IH-NMR (300 MHz, CD3CN) δ: 8.82 (s, IH), 8.17 (m, IH), 7.45 (m, IH), 7.38 (m, IH), 7.31 (m, IH),

7.00 (s, 2H), 3.61 (s, 2H), 3.18 (s, 3H), 2.30 (s, 3H) ₅ 2.17 (s, 6H). MS m/z: 377 (M+H) ⁺

EXAMPLE 2

S-(2- { [2-Nitrophenyl]amino} -2-oxoethyl) mesityl(methyl)thiocarbamate

The title compound was prepared from ({[mesityl(methyl)amino]carbonyl}thio)acetic acid (see Example 1, Steps 1-3) and 2-nitroaniline in the manner described in Example 1, Step 4.

lH-NMR (300 MHz, DMSO-de) δ: 10.37 (s, IH), 8.48 (m, IH), 8.15 (m, IH), 7.67(m, IH), 7.27 (m, IH), 7.01 (s, 2H), 3.66 (s, 2H), 3,17 (s, 3H), 2,30 (s, 3H), 2.18 (s, 6H). MS 777/j: 388 (M+H) ⁺ .

EXAMPLE 3 S-(2-{[4-(Aminocarbonyl)-2-chlorophenyl]amino}-2-oxoethyl)me sityl(methyl) thiocarbamate

Step 1 : Potassium 4-amino-3-chlorobenzoate

A mixture of methyl 4-amino-3-chlorobenzoate, MeOH and IN KOH in water (1 eq.), was stirred at reflux for 2 hours. The title compound was obtained as a creamy white precipitate, that was filtered, washed with diethyl ether and dried under vacuum. MS (EI+) 172 (M+H) ⁺ . MS (ES-) 170 (M+e)\

Step 2: 3 -chloro-4- { [( { [mesity l(methyl)amino] carbonyl } thio)acetyl] -amino} benzoic acid

({[Mesityl(methyl)amino]carbonyl}thio)acetic acid prepared as described in Example 1 Steps 1-3 was dissolved in anhydrous dichloromethane at O ⁰ C. Oxalyl chloride (1 eq., 2M in dichloromethane) was added followed by a small quantity of DMF. The mixture was stirred at 0 ⁰ C for 30 minutes. Then a solution of potassium 4-amino-3-chlorobenzoate (1 eq.) and triethylamine (1 eq.) in anhydrous dichloromethane was added. After 40 minutes the solvent was removed under vacuum. The product was isolated by preparative RP-HPLC, using water (0.1 % TFA) and acetonitrile (0.1 % TFA) as eluants (column: CIS). The pooled product fractions were lyophilized to afford the title compound as a light yellow solid. lH NMR (300 MHz, DMSO-d6): δ 13.13 (bs, IH), 9.62 (s, IH), 8.10 (d, J= 8 Hz, IH), 7.95 (d, J= 2 Hz,

IH), 7.80 (dd, J ₁ = 8 Hz, J ₂ = 2 Hz, IH), 6.99 (s, 2H), 3.72 (s, 2H), 3.10 (s, 3H), 2.26 (s, 3H), 2.15 (s, 6H) . MS (EI+) 421 (M+H) ⁺ . MS (ES-) 419 (M+e)\

Step 3: S-(2-{[4-(aminocarbonyl)-2-chlorophenyl]amino}-2-oxoethyl) mesityl(methyl)thiocarbamate

3-chloro-4-{[({[mesityl(methyl)amino]carbonyl}thio)acetyl ]-amino}benzoic acid was dissolved in dioxane, then pyridine (0.6 eq.), di-tert-butyl dicarbonate (1.3 eq.) and ammonium hydrogen carbonate (1.3 eq.) were added. The mixture was stirred at room temperature for 6 hours. The solvent was removed under vacuum. The product was isolated by preparative RP-HPLC, using water (0.1 % TFA) and acetonitrile (0.1 % TFA) as eluants (column: C 18). The pooled product fractions were lyophilized to afford the title compound as a white solid. 1 H-NMR (300 MHz, DMSO-d6) δ: 9.58 (s, IH), 8.00 (m, 3H) ₅ 7.82 (d, J = 8.4 Hz, IH), 7.43 (s, IHD, 7.00 (s, 2H), 3.76 (s, 2H), 3.11 (s, 3H), 2.27 (s, 3H), 2.16 (s, 6H). MS m/z: 420 (M+H) ⁺ .

EXAMPLE 4 S-(2- { [4-(Aminosulfonyl)-2-chlorophenyl]amino } -2-oxoethyl) mesityl(methyl)thiocarbamate

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. lH NMR (300 MHz, DMSO-dβ) δ: 9.71 (s, IH), 8.06-7.97 (m, IH), 7.87 (d, J = 2.0 Hz, IH), 7.73 (dd, Ji

= 2.0 Hz, J2 = 8.6 Hz ₅ IH) ₅ 7.74 (s, 2H), 2.15 (s, 3H). MS m/z: 249 (M+H) ⁺ .

Step 2: 4-Amino-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 ⁰ C under nitrogen for 1 hour. After cooling to room temperature, the mixture was quenched with saturated NaHCθ3 and extracted with EtOAc. The organic phase was dried over Na2SO4, 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, Ji = 2.0 Hz, J2 = 8.6 Hz, IH) ₅ 6.87 (d, J = 8.6 Hz, IH), 5.45 (bs, 2H), 5.08 (bs, 2H). MS m/z: 207 (M+H)+.

Step 3: S-(2- { [4-(aminosulfonyl)-2-chlorophenyl]amino} -2-oxoethyl) mesityl(methyl)thiocarbamate

The title compound was prepared from ({[mesityl(methyl)amino]carbonyl}thio)acetic acid (see Example 1, Steps 1-3) and 4-amino-3-chlorobenzenesulfonamide in the manner described in Example 1, Step 4. lH-NMR (300 MHz, DMSO-d6) δ: 9.70 (s, IH), 8.10 (d, J = 8.6, IH), 7.88 (m, IH), 7.75 (m, IH), 7.44 (m, 2H), 7.00 (s, 2H), 3.77 (s, 2H) ₅ 3.11 (s, 3H) ₅ 2.27 (s, 3H) ₅ 2.15 (s, 6H). MS 777/5: 456 (M+H) ⁺ .

EXAMPLE 5 S-(2-{[4-(Aminosulfonyl)-2-methylphenyl]amino}-2-oxoethyl) mesityl (methyl) thiocarbamate

To a stirred suspension of ({[mesityl(methyl)amino]carbonyl}thio)acetic acid (see

Example I ₅ Steps 1-3) in dichloromethane at 0 ⁰ C was added a solution of oxalyl chloride in dichloromethane (2M ₅ 1.2 eq.) and a few drops of DMF. The mixture was stirred for 15 minutes at 0 ⁰ C and then a solution of 4-amino-3-methylbenzenesulfonamide (1.2 eq) and triethylamine (1.3 eq) in DMF/dichloromethane was added at once at O ⁰ C. The mixture was stirred for 2 hours at 0 ⁰ C and 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: CI S), by lyophilization of the pooled product fractions. lH NMR (300 MHz, DMSO-d6): δ 9.50 (bs, IH) ₅ 7.72-7.57 (m, 3H), 7.22 (s, 2H), 6.99 (s, 2H) ₅ 3.72 (s,

2H) ₅ 3.09 (s, 3H) ₅ 2.28-2.50 (m, 6H), 2.14 (s, 6H). MS (EI+) 436 (M+H) ⁺ . MS (ES-) 434 (M+e)\

EXAMPLE 6

S-(2-{[2-Chloro-4-({[3-(dimethylamino)propyl]amino}carbon yl)phenyl]amino} -2-oxoethyl) mesityl(methyl)thiocarbamate

A mixture of 3 -chloro-4- { [( { [mesityl(methyl)amino]carbonyl } thio)acetyl]- amino}benzoic acid prepared as described in Example 3, Steps 1-2, 3-dimethylaminopropylamine (1.1 eq.), HATU (1.2 eq) and diisopropylethylamine (2.0 eq.) was stirred at room temperature in DMF for 1 hour. After evaporation of the solvent, the product was isolated by preparative RP-HPLC, using water (0.1 % TFA) and acetonitrile (0.1 % TFA) as eluants (column: CIS). The pooled product fractions were lyophilized to afford the title compound. lH NMR (300 MHz, DMSO-d6): δ 9.60 (bs, IH), 9.29 (bs, IH), 8.65-8.60 (m, IH), 8.02 (d, J= 9 Hz,

IH), 7.95 (s, IH), 7.79 (d, J= 9 Hz, IH), 6.99 (s, 2H), 3.75 (s, 2H), 3.35-3.26 (m, 2H), 3.15-3.02 (m, 5H), 2.80-2.73 (m, 6H), 2.26 (s, 3H), 2.14 (s, 6H), 1.92-1.81 (m, 2H). MS (EI+) 505 (M+H) ⁺ .

EXAMPLE 7

S-{2-[(2-Chloro-4-{[(3-morpholin-4-ylpropyl)amino]carbony l}phenyl)amino]-2-oxoethyl} mesityl(methyl)thiocarbamate

The title compound was prepared from 3-chloro-4-{[({[mesityl(methyl)amino]- carbonyl}thio)acetyl]-amino}benzoic acid prepared as described in Example 3, Steps 1-2 and 3- morpholin-4-ylpropan-l -amine in the manner described in Example 6. lH NMR (300 MHz, DMSO-d6): δ 9.61 (bs, 2H), 8.67 (bt, J = 6 Hz, IH) ₅ 8.02 (d, J = 9 Hz, IH), 7.95 (d,

J = 2 Hz, IH), 7.80 (dd, J, = 9Hz, J ₂ = 2 Hz ₅ IH) ₅ 6.99 (s, 2H), 4.15-3.90 (m partially hidden under water, 2H), 3.75 (s, 2H), 3.69-3.56 (m, 2H), 3.48-3.38 (m, 2H) ₅ 3.37-3.27 (m, 2H), 3.20-3.00 (m, 7H), 2.26 (s, 3H), 2.14 (s, 6H) ₅ 1.96-1.84 (m ₅ 2H). MS (EI+) 547 (M+H) ⁺ . MS (ES-) 545 (M+e)\

EXAMPLE 8

S-(2- { [2-Chlorophenyl] amino } -2-oxoethy 1) methyl( 1 -naphthy l)thiocarbamate

Step 1: 1 -Naphthy l(methyl)amine

The title compound was prepared from 1-naphthylamine as described in Example 1, Step 1. MS m/z: 158 (MMH*)

Step 2: Methyl ({[l-naphthyl(methyl)amino]carbonyl}thio)acetate

The title compound was prepared from l-naphthyl(methyl)amine in the manner described in Example 1, Step 2. MS m/z: 312 (MH-H ⁺ ).

Step 3: ({[l-naphthyl(methyl)amino]carbonyl}thio)acetic acid

The title compound was prepared from methyl ({[1- naphthyl(methyl)amino]carbonyl}thio)acetate in the manner described in Example 1, Step 3.

1 H-NMR (300 MHz, DMSO-d6) δ: 12.55 (s, IH), 8.12-7.95 (m, 2H)., 7.83-7.71 (m, IH), 7.68-7.53 (m, 4H), 3.53 (s, 2H), 3.40-3.25 (m, 3H). MS m/z: 298 (M+H) ⁺ .

Step 4: S-(2-{[2-chlorophenyl]amino}-2-oxoethyl) methyl(l -naphthy l)thiocarbamate

The title compound was prepared from ({[l-naphthyl(methyl)amino]carbonyl}thio)acetic acid and 2-chloroaniline in the manner described in Example 1, Step 5. iH-NMR (300 MHz, CD3CN) δ: 8.81 (s, IH), 8.16 (m, IH), 8.02 (m, 2H), 7.82 (m, IH), 7.63-7.52 (m,

4H) ₅ 7.45 (m, IH), 7.31(m, IH), 7.12 (m, IH), 3.60 (s, 2H), 3,43 (s, 3H). MS m/z: 385 (M+H) ⁺ .

EXAMPLE 9 S-(2-{[2-Nitrophenyl]amino}-2-oxoethyl) methyl(l -naphthy l)thiocarbamate

The title compound was prepared from ({[l-naphthyl(methyl)amino]carbonyl}thio)acetic acid (see Example 8, Steps 1-3) and 2-nitroaniline in the manner described in Example 1, Step 4 lH-NMR (300 MHz, CD3CN) δ: 10.48 (s, IH), 8.51 (m, IH) ₅ 8.19 (m, IH), 8.03 (m, 2H), 7.85 (m, IH),

7.75-7.52 (m, 5H), 7.28 (m, IH), 3.64 (s, 2H), 3,42 (s, 3H). MS m/∑: 396 (M+H) ⁺ .

EXAMPLE 10 S-(2- { [4-(Aminosulfonyl)-2-chlorophenyl]amino} -2-oxoethyl) methyl( 1 -naphthyl)thiocarbamate

The title compound was prepared from ({[l-naphthyl(methyl)amino]carbonyl}thio)acetic acid (see Example 8, Steps 1-3) and 4-amino-3-chlorobenzenesulfonamide (see Example 4, Steps 1-2) in the manner described in Example 1, Step 4. lH-NMR (300 MHz, CD3CN) δ: 9.11 (s, IH), 8.44 (m, IH), 8.10-8.00 (m, 2H), 7.94 (m, IH), 7.86-7.76

(m, 2H), 7.65-7.50 (m, 4H), 5.69 (s, 2H), 3.64 (s, 2H), 3,44 (s, 3H). MS m/z: 464 (M+H) ⁺ .

EXAMPLE I l

S-[2-({2-Chloro-4-[(methylamino)carbonyl]phenyl}amino)-2- oxoethyl] methyl(l-naphthyl)thiocarbamate

Step 1 : 3-chloro-4-{[({[l-naphthyl(methyl)amino]carbonyl}thio)acetyl ]-amino}benzoic acid

The title compound was prepared from ({[l-naphthyl(methyl)amino]carbonyl}thio)acetic acid (see Example 8, Steps 1-3) coupled with the appropriate amine following the procedure described in Example 3, Step 2. MS m/z: 429 (M+H ¹ )

Step 2: S-[2-({2-chloro-4-[(methylamino)carbonyl]phenyl}amino)-2-oxo ethyl] methyl(l- naphthyl)thiocarbamate

The title compound was prepared from 3-chloro-4-{[({[l- naphthyl(methyl)amino]carbonyl}thio)acetyl]-amino}benzoic acid and methylamine hydrochloride in the manner described in Example 6. lH-NMR (300 MHz, CD3CN) δ: 8.99 (s, IH), 8.31 (m, IH), 8.08-7.96 (m, 2H), 7.91 (m, IH), 7.80 (m, IH), 7.68 (m, IH), 7.65-7.50 (m, 4H), 7.01 (s, IH), 3.62 (s, 2H), 3.44 (s, 3H), 2.86 (d, J = 4.65 Hz, 3H). MS w/z: 442 (MH-H) ⁺ .

EXAMPLE 12

S-(2- { [2-Chloro-4-( { [2-(dimethylamino)ethyl]amino} carbonyl) phenyljamino} -2-oxoethyl) methyl( 1 - naphthyl)thiocarbamate,

The title compound was prepared from 3-chloro-4-{[({[l-naphthyl

(methyl)amino]carbonylthio)acetyl]-amino} benzoic acid (Example 8, Steps 1-3) and N,N-dimethyl- ethylene diamine in the manner described in Example 6. 1 H-NMR (300 MHz, CD3CN) δ: 10.30 (bs, IH), 9.02 (s, IH), 8.33 (m, IH), 8.18-7.93 (m, 4H), 7.88-7.75

(m, 2H), 7.65-7.50 (m, 4H), 3.71 (m, 2H), 3.63 (s, 2H), 3.44 (s, 3H), 3.28 (m, 2H), 2.85 (s, 6H). MS m/z: 499 (M+H) ⁺ .

EXAMPLE 13 S-{2-[(2-Chlorophenyl)amino]-2-oxoethyl} (3-chloro-2-methylphenyl)methylthio-carbamate

Step 1 : (3-chloro-2-methylphenyl)rnethylamine

The title compound was prepared from (3-chloro-2-methylphenyl)amine according to the procedure described in Example 1, Step 1. MS m/z: 156 (M+H) ⁺ .

_2: Methyl ({[(3-chloro-2-methylphenyl)(methyl)amino]-carbonyl}thio)ace tate

The title compound was prepared from (3-chloro-2-methylphenyl)methylamine according to the procedure described in Example 1, Step 2. MS m/z: 288 (M+H) ⁺ .

Step 3: ({[(3-chloro-2-methylphenyl)(methyl)amino]carboπyl}thio)ace tic acid

Methyl ({[(3-chloro-2-methylphenyI)(methyl)amino]carbonyl}thio)acet ate was dissolved in MeOH and 2N NaOH (2 eq.). The mixture was stirred at room temperature for 1 hour. The mixture was partitioned between dichloromethane and IN NaOH. The aqueous phase was acidified with 6N HCl and extracted with dichloromethane; the organic phase was dried over Na2SO4, filtered and evaporated to dryness under vacuum. The title compound was obtained as solid.

1 H-NMR (300 MHz, DMSO-d6) δ: 12.6 (bs, IH), 7.60-7.51 (m, IH), 7.40-7.29 (m, 2H), 3.64-3.49 (m,

2H), 3.16 (s, 3H), 2.24 (s, 3H). MS m/z: 374 (M+H) ⁺ .

Step 4: S-{2-[(2-chlorophenyl)amino]-2~oxoethyl} (3-chloro-2-methylphenyl)~ methylthiocarbamate

The title compound was prepared from ({[(3-chloro-2- methylphenyl)(methyl)amino]carbonyl}thio)acetic acid and 2-chloro-aniline in the manner described in Example 1, Step 4. lH NMR (300 MHz, DMSO-d6) δ: 9.54 (bs, IH), 7.83-7.75 (m, IH), 7.60-7.53 (m, IH), 7.52-7.46 (m, IH), 7.40-7.28 (m, 3H), 7.22-7.14 (m, IH), 3.85-3.70 (m, 2H), 3.19 (s, 3H), 2.25 (s, 3H). MS m/z: 383 (M+H) ⁺ .

EXAMPLE 14 8-{2-[(2-Nitrophenyl)amino]-2-oxoethyl} (3-chloro-2-methylphenyl)methylthiocarb-amate

The title compound was prepared from ({[(3-chloro-2- methylphenyl)(methyl)amino]carbonyl}thio)acetic acid (see Example 13, Steps 1-3) and 2-nitroaniline in the manner described in Example 1, Step 4.

lH NMR (300 MHz ₅ DMSO-ctø) δ: 10.48 (bs, IH), 8.04-7.98 (m, IH), 7.90-7.83 (m, IH), 1.16-1.6% (m, IH), 7.61-7.53 (m, IH), 7.41-7.32 (m, 3H), 3.81-3.68 (m, 2H), 3.18 (s, 3H), 2.25 (s, 3H). MS m/z: 394 (MH-H) ⁺ .

EXAMPLE 15

S-(2-{[4-(Aminosulfonyl)-2-chlorophenyl]amino}-2-oxoethyl ) (3-chloro-2- methylphenyl)methylthiocarbamate

The title compound was prepared from ({[(3-chloro-2- methylphenyl)(methyl)amino]carbonyl}thio)acetic acid (see Example 13, Steps 1-3) and 2-chloro-4- aminosulfonylaniline (see Example 4, Steps 1-2) in the manner described in Example 1, Step 4. lH NMR (300 MHz, DMSO-d6) δ: 9.77 (bs, IH), 8.08 (d, J = 8.6 Hz, IH), 7.89 (d, J = 2 Hz, IH), 7.75

(dd, J, = 8.6 Hz, J ₂ = 2 Hz, IH), 7.61-7.53 (m, IH), 7.47-7.41 (bs, 2H), 7.40-7.36 (m, 2H), 3.90-3.76 (m, 2H), 3.19 (s, 3H), 2.25 (s, 3H). MS m/z: 460 (M+H) ⁺ .

EXAMPLE 16 S- {2-[(2-Nitrophenyl)amino]-2-oxoethyl } (2,5-dichlorophenyl)methylthiocarbamate

Step 1 : (2,5-dichlorophenyl)methylamine

To formic acid (87 eq.) was added dropwise acetic anhydride (19 eq.). After 10 minutes at O ⁰ C the mixture was stirred for 1 hour at room temperature. To the mixture was then added dropwise 2,5-dichloroaniline. After 1 hour the solvents were removed under vacuum and the residue was left under high vacuum for 3 hours. The solid obtained was suspended in dry THF at 0 ⁰ C, borane IM in THF (3.0 eq.) was added slowly and the mixture was stirred, for 2 hours at room temperature. The reaction was quenched with a solution 10% of citric acid. THF was evaporated and EtOAc was added. The organic

phase was separated and dried over Na2SO4, filtered and concentrated to dryness under vacuum. The title compound was obtained as a white solid. MS m/z: 176 (M+H) ⁺ .

Step 2: Methyl ({[(2,5-dichlorophenyl)(methyl)amino]carbonyl}thio)acetate The compound was prepared from (2,5-dichlorophenyl)methylamine in the manner described in Example 1, Step 2 MS m/z: 308 (M+H) ⁺ .

Step 3: ({[(2 _! 5-dichlorophenyl)(methyl)amino]carbonyl}thio)acetic acid. The compound was prepared from methyl ({[(2,5-dichlorophenyl)(methyl)amino]- carbonyl}thio)acetate in the manner described in Example 13, Step 3. MS m/z: 294 (M+H) ⁺ .

Step 4: S-{2-[(2-nitrophenyl)amino]-2-oxoethyl} (2,5-dichlorophenyl) methylthiocarbamate.

The title compound was prepared from ({[(2,5-dichlorophenyl)(methyl)amino]- carbonyl}thio)acetic acid and 2-nitroaniline in the manner described in Example 1, Step 4. iH-NMR (300 MHz, DMSO-d6) δ: 10.51 (s, IH), 8.22 (dd, J, = 8.22, J ₂ = 1.15 Hz, IH), 7.89-7.68 (m,

3H), 7.66-7.48 (m, 2H), 7.41-7-33 (m, IH), 3.78 (s, 2H), 3.19 (s, 3H). MS m/z: 414 (M+H) ⁺ .

EXAMPLE 17 S-{2-[(2-Chlorophenyl)amino]-2-oxoethyl} (2,5-dichlorophenyl)methylthiocarbamate

The title compound was prepared fiiOm ({[(2,5- dichlorophenyl)(methyl)amino]carbonyl}-thio)acetic acid (see Example 16, Steps 1-3) and 2- chloroaniline in the manner described in Example 1, Step 4. 1 H-NMR (300 MHz, DMSO-d6) δ: 9.56 (s, IH), 7.85-7.74 (m, 2H), 7.65-7.45 (m, 3H), 7.36-7.27 (m,

IH), 7.23-7.13 (m, IH), 3.81 (s, 2H), 3.20 (s, 3H). MS m/z: 403 (M+H) ⁺ .

EXAMPLE 18 S-(2-{[4-(Aminosulfonyl)-2-chlorophenyl]amino}-2-oxoethyl) (2,5-dichlorophenyl) methylthiocarbamate

The title compound was prepared from ({[(2,5- dichlorophenyl)(methyl)arnino]carbonyl}-thio)acetic acid (see Example 16, Steps 1-3) and 2-chloro-4- aminosulfonylaniline (see Example 4, Steps 1-2) in the manner described in Example 1, Step 4. IH-NMR (300 MHz ₅ DMSO-d6) δ: 9.78 (s, IH), 8.11-8.04 (m, IH), 7.92-7.86 (m, IH), 7.84-7.79 (m,

2H), 7.66-7.40 (m, 4H), 3.86 (s, 2H), 3.20 (s, 3H). MS m/z: 482 (M+H) ⁺ .

EXAMPLE 19 S-{2-[(2-Nitrophenyl)amino]-2-oxoethyl} (2,3-dichlorophenyl)methylthiocarbamate

Step 1 : (2,3-dichlorophenyl)methylamine.

The compound was prepared from the 2,3-dichloroaniline in the manner described in Example 1 , Step 1. MS m/z: 176 (M+H) ⁺ .

Step 2: Methyl ({[(2,3-dichlorophenyl)(methyl)amino]carbonyl}thio)acetate.

The compound was prepared from (2,3-dichlorophenyl)methylamine in the manner described in Example 1, Step 2. MS m/z: 308 (M+H) ⁺ .

Step 3: ({[(2,3-dichlorophenyl)(methyl)amino]carbonyl}thio)acetic acid.

The compound was prepared from methyl ({[(2,3-dichlorophenyl) (methyl)amino]- carbonyl}thio)acetate in the manner described in Example 13, Step 3. MS m/z: 294 (M+H) ⁺ .

Step 4: S-{2-[(2-nitrophenyl)amino]-2-oxoethyl} (2,3-dichlorophenyl) methylthiocarbamate

The title compound was prepared from ({[(2,3-dichlorophenyl)(methyl)amino]- carbonyl}thio)acetic acid and 2-nitroaniline in the manner described in Example 1, Step 4. lH-NMR (300 MHz, DMSO-dδ) δ: 10.52 (s, IH), 8.22 (dd, Jj = 8.22, J ₂ = 1.33 Hz, IH), 7.89-7.78 (m,

2H), 7.76-7.57 (m, 3 H), 7.41-7-33 (m, IH), 3.78 (s, 2 H), 3.18 (s, 3H). MS m/z: 414 (M+H) ⁺ .

EXAMPLE 20 S- {2-[(2-Chlorophenyl)amino]-2-oxoethyl} (2,3-dichlorophenyl) methylthiocarbamate

The title compound was prepared from ({[(2,3- dichlorophenyl)(methyl)amino]carbonyl}-thio)acetic acid (see Example 19, Step 1-3) and 2-chloro- aniline in the manner described in Example 1 Step 4. iH-NMR (300 MHz, DMSOdβ) δ: 9.57 (s, IH), 7.85-7.56 (m, 4H), 7.49 (dd, Ji = 8.00, J ₂ = 1.12 Hz,

IH), 7.37-7.28 (m, IH), 7.23-7.13 (m, IH), 3.81 (s, 2H), 3.19 (s, 3H). MS m/z: 403 (M+H) ⁺ .

EXAMPLE 21

S-(2-{[4-(Aminosulfonyl)-2-chlorophenyl]amino}-2-oxoethyl ) (2,3-dichlorophenyl)methylthiocarbamate.

The title compound was prepared from ({[(2,3- dichlorophenyl)(methyl)amino]carbonyl}-thio)acetic acid (see Example 19, Steps 1-3) and 2-chloro-4- aminosulfonylaniline (see Example 4, Steps 1-2) in the manner described in Example 1, Step 4.

IH-NMR (300 MHz, DMSO-d6) δ: 9.78 (s, IH) ₅ 8.12-8.04 (m, IH), 7.92 (m, 5H), 7.43 (s, 2H), 3.S7 (s,

+

2H), 3.19 (s, 3H). MS m/z: 482 (M+H) ⁺ .

EXMlPLE 22 N-Mesityl-N-methyl-iV-(2-nitrophenyl)succinamide

Step 1 : 4-[Mesityl(methyl)amino]-4-oxobutanoic acid.

Mesityl(methyl)amine (1 eq., see Example 1, Step 1) succinic anhydride (3 eqs.) and DMAP (catalytic) were stirred in DMF at room temperature for 6 hours. The mixture was partitioned between IN HCl and EtOAc. The organic phase was again extracted with water and the combined organic phases were dried over Na2SO4, filtered and concentrated to dryness under vacuum.

MS m/z: 250 (M+H) ⁺ .

Step 2: N-Mesityl-N-methyl-N'-(2-nitrophenyl)succinamide

The title compound was prepared from 4-[mesityl(methyl)amino]-4-oxobutanoic acid and 2-nitroaniline in the manner described in Example 1, Step 4 . iH-ΝMR (300 MHz, CD3CΝ) δ: 9.84 (s, IH), 8.38-S.32 (m, IH), 8.10-8.05 (m, IH), 7.66-7.58 (m, IH),

7.24-7.16 (m, IH), 6.95 (s, 2H), 3.05 (s, 4H), 2.60 (t, J = 6.2 Hz, 2H), 2.28 (s, 3H), 2.17-2.10 (m, 8H). MS m/z: 370 (M+H) ⁺ .

EXAMPLE 23 2-[(2-Nitrophenyl)amino]-2-oxoethyl mesityl(methyl)carbamate

Step 1: Methyl ({[mesityl(methyl)amino]carbonyl}oxy)acetate.

To a solution of bis(trichloromethyl)carbonate (0.35 eq.) in anhydrous dichloromethane at -78°C was added pyridine (1 eq.) and then dropwise mesityl-(methyl)amine (see Example 1, Step 1) over 10 minutes. The reaction mixture was stirred for 1 hour at room temperature and was quenched with IN HCl. The mixture was extracted with dichloromethane and the organic phase was dried over Na2SO4, filtered and concentrated to dryness under vacuum. The residue was dissolved in dry THF and added to

sodium 2-methoxy-2-oxoethanolate. The mixture was warmed to 55°C and stirred for 3 hours. The mixture was cooled to room temperature and partitioned between IN HCl and DCM. The organic phase was again extracted with water and the combined organic phases were dried over Na2SC>4, filtered and concentrated to dryness under vacuum. MS m/z: 266 (M+H) ⁺ .

Steg_2: ({[Mesityl(methyl)amino]carbonyl}oxy)acetic acid

The title compound was prepared from methyl ({[mesityl(methyl)amino]carbonyl}oxy)- acetate in the manner described in Example I ₅ Step 3. MS m/z: 252 (M+H) ⁺ .

Step 3: 2-[(2-Nitrophenyl)amino]-2-oxoethyl mesityl(methyl)carbamate

The title compound was prepared from ({[mesityl(methyl)amino]carbonyl}oxy)acetic acid and 2-nitroaniline in the manner described in Example 1 , Step 4. 1 H-NMR (300 MHz, CD3CN) δ: 10.70 (bs, 0.5 H), 9.8 (m, 0.5 H), 8.69-8.62 (m, 0.5 H), 8.41-8.33 (m,

0.5 H), 8.23-8.06 (m, 1 H), 7.76-7.61 (m, 1 H), 7.32-7.20 (m, IH), 6.93-6.87 (m, 2H), 4.7 (s, IH), 4.6 (s, IH), 3.32 (s, 2H), 2.28-2.07 (m, 10 H). MS m/z: 372 (M+H) ⁺ .

EXAMPLE 24 N2- { [Mesityl(methyl)amino]carbony] } -Nl -(2-nitrophenyl)glycinarnide

Step 1: to"/-Butyl N-{[mesityl(methyl)amino]carbonyl}glycinate

To a solution of bis(trichloromethyl)carbonate (0.35 eq.) in anhydrous dichloromethane at -78 ⁰ C was added pyridine (1 eq.) and then dropwise mesityl-(methyl)amine (see Example 1, Step 1) over 10 minutes. The reaction mixture was stirred for 1 hour at room temperature and was quenched with IN HCl. The mixture was extracted with dichloromethane and the organic phase was dried over ΝaoSO.]., filtered and concentrated to dryness under vacuum. The residue was dissolved in dry pyridine and tert- butyl glycinate hydrochloride was added. The mixture was warmed to 65 ⁰ C and stirred for 16 hours. The mixture was cooled to room temperature and partitioned between IN HCl and EtOAc. The organic phase

was again extracted with water and the combined organic phases were dried over Na2SO4, filtered and concentrated to dryness under vacuum. MS m/z\ 307 (M+H) ⁺ .

Step 2: N- { [Mesityl(methyl)amino]carbonyl} glycine tert-Butyl N-{[mesityl(methyl)amino]carbonyl}glycinate was dissolved in a mixture of

DCM and TFA (1:1). After 30 minutes mixture was evaporated and the residue partitioned between IM NaOH and DCM. The organic phase was again extracted with IN NaOH and the combined aqueous phase acidified with 6Ν HCl. The aqueous phase was extracted with EtOAc and the organic phases were dried over Na2SO4, filtered and concentrated to dryness under vacuum. MS m/z: 251 (M+H) ⁺ .

Step 3: Λ ⁷ 2-{[Mesityl(methyl)amino]carbonyl}-Nl-(2-nitrophenyl)g lycinamide

The title compound was prepared from N- {[mesityl(methyl)amino]carbonyl} glycine and 2-nitroaniline in the manner described in Example 1, Step 4. lH-ΝMR (330 MHz, DMSO-d6) δ: 10.19 (bs, IH), 8.21-8.11 (bs, IH), 8.09-8.02 (m, IH), 7.75-7.67 (m, IH), 7.37-7.27 (m, IH), 6.95 (s, 2H), 5.65 (bs, IH), 3.87-3.80 (s, 2H), 3.02 (s, 3H), 2.25 (s, 3H) ₅ 2.15 (s, 6 H). MS /π/z: 371 (M+H) ⁺ .

EXAMPLE 25 N2-{[Mesityl(methyl)amino]carbonyl}-N2-methyl-Nl-(2-nitrophe nyl)gIycinamide

Step 1: /(?r/-Butyl Λ ^/' -{[mesiryl(methy])amino]carbon)i}-N-methy]glycinate

To a solution of bis(trichloromethyl)carbonate (0.35 eq.) in anhydrous dichloromethane at -78 ⁰ C was added pyridine (1 eq.) and then dropwise mesityl-(methyl)amine (see Example 1, Step 1) over 10 minutes. The reaction mixture was stirred for 1 hour at room temperature and was quenched with IN HCI. The mixture was extracted with dichloromethane and the organic phase was dried over Νa2Sθ4, filtered and concentrated to dryness under vacuum. The residue was dissolved in dry pyridine and tert- butyl N-methylglycinate was added. The mixture was warmed to 65 ⁰ C and stirred for 16 hours. The mixture was cooled to room temperature and partitioned between IN HCl and EtOAc. The organic phase

was again extracted with water and the combined organic phases were dried over Na2SO4, filtered and concentrated to dryness under vacuum. MS m/∑: 321 (M+H) ⁺ .

Step 2: N-{[Mesityl(methyl)amino]carbonyl}-N-methylglycine The title compound was prepared from te/"/-butyl N-{[mesityl(methyl)amino]carbonyl}-

N-methylglycinate in the manner described in Step 2 of Example 24. MS m/z: 265 (M+H) ⁺ .

Step 3: N2-{[Mesityl(methyl)amino]carbonyl}-N2-methyl-Nl-(2-nitrophe nyl)glycinamide

The title compound was prepared from N-{[mesityl(methyl)amino]carbonyl}-N- methylglycine and 2-nitroaniline in the manner described in Step 4 of Example 1. lH-ΝMR (300 MHz ₅ CD3CN) δ: 10.02 (bs, IH), 8.45-8.35 (m, IH) ₅ 8.09-8.17 (m, IH) ₅ 7.69-7.58 (m,

IH) ₅ 7.24-7.15 (m, IH) ₅ 6.70 (s, 2H), 3.73 (s, 2H) ₅ 2.94 (s, 3H), 2.60 (s, 3H) ₅ 2.13 (s, 6H), 2.08 (s, 3H). MS m/z: 385 (M+H) ⁺ .

EXAMPLE 26 N'-(2-Chlorophenyl)-N-mesityl-N-methylsuccinamide

The title compound was prepared from 4-[mesityl(methyl)amino]-4-oxobutanoic acid (see Example 22, Step 1) and 2-chloroaniline in the manner described in Example I ₅ Step 4 . 1 H-NMR (300 MHz, CD3CN) δ: 8.28 (bs, IH), 8.04-7.96 (m, IH) ₅ 7.41-7.34 (m, IH) ₅ 7.28-7.19 (m, IH) ₅

7.09-7.01 (m, IH), 6.95 (s, 2H), 3.02 (s, 3H) ₅ 2.57 (t, J = 6.4 Hz ₅ 2H) ₅ 2.24 (s, 3H) ₅ 2.16-2.09 (m, 8H). MS m/z: 370 (M+H) ⁺ .

EXAMPLE 27 S-{2-[(2-nitrophenyl)amino]-2-oxoethyl}(2-bromo-4-methylphen yl) methyl thiocarbamate

Step 1: (2-bromo-4-methylphenyl)methylcarbamic chloride

A mixture of 2-bromo-4-methyl-N-methylaniline and triethylamine (2 eq.) in dry toluene was added at -20 ⁰ C to phosgene (20% solution in toluene). After 1 hour the organic mixture was filtered and the filtrate was evaporated at reduced pressure to afford crude title product. MS (EI+) 262 (M+H) ⁺ .

Step 2: 2-chloro-N-(2-nitrophenyl)acetamide

Chloroacetyl chloride (2 eq.) was added to a mixture of 2-nitroaniline and triethylamine (2 eq.) in DCM at 0 ⁰ C. After 2 hours stirring at room temperature, the organic mixture was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was filtered over a silica pad, eluting with DCM, the solvent was evaporated and the residue crystallized from EtOH/H2θ. lH NMR (300 MHz, CDCI3): δ 11.34 (bs, IH), S.75 (10 (d, J= 8 Hz, IH), 8.24 (dd, Ji = 1 Hz, J2 = 8 Hz, IH), 7.72-7.62 (m, IH), 7.30-7.20 (m, IH), 4.23 (s, 2H). MS (EI+) 215 (M+H) ⁺ . MS (ES-) 213 (M+e)-.

Step 3: S-{2-[(2-nitrophenyl)amino]-2-oxoethyl} ethanethioate

A mixture of 2-chloro-TSF-(2-nitrophenyl)acetamide and potassium thiolacetate (1.1 eq.) in MeOH Avas stirred at 80 ⁰ C for 1 hour. After evaporation of MeOH at reduced pressure, the residue was taken into EtOAc, washed with brine, dried and evaporated at reduced pressure. The crude product was stored at -20 ⁰ C for later use. MS (EI+) 255 (M+H) ⁺ .

Step 4: S-{2-[(2-nitrophenyl)amino]-2-oxoethyl}(2-bromo-4-methylphen yl) methyl thiocarbamate

To a mixture of crude S-{2-[(2-nitrophenyl)amino]-2-oxoethyl} ethanethioate in degassed MeOH at room temperature, a mixture of sodium thiomethoxide (1 eq.) in degassed MeOH was added. After 10 min stirring at room temperature a mixture of crude 2-bromo-4- methylphenyl)methylcarbamic chloride in acetonitrile was added in one portion and stirring at room temperature was continued for 1 hour. After evaporation of solvent, the product was isolated by

preparative RP-HPLC, using water (0.1 % TFA) and acetonitrile (0.1 % TFA) as eluants (column: C 18). The pooled product fractions were evaporated to afford the title compound.

1 H-NMR (300 MHz, DMSO-d6) δ 10.50 (s, IH), 8.00 (dd, Jj = 1 Hz, J2 = 8 Hz ₅ IH), 7.S6 (d, J= 8 Hz, IH), 7.77-7.67 (m, IH), 7.63 (s, IH), 7.44 (d, J = 8 Hz, IH), 7.40-7.29 (m, IH) ₅ 3.73 (dd, AB system, , Ji = 15 Hz ₅ J2 = 20 Hz, 2H), 3.14 (s, 3H), 2.35 (s, 3H). MS (EI+) 438 (M+H)+. MS (ES-) 436 (M+β)-.

EXAMPLES 28-41

The compounds in Table B below were prepared using a procedure similar to that employed in Example 27 (see also Scheme 1, Part B).

Table B

EXAMPLE 42 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 the title compound of Example 1 , 150 mg of lactose, 50 mg of cellulose, and 3 mg of stearic acid. Encapsulated oral compositions containing any one of the title compounds of Examples 2 to 41 can be similarly prepared.

EXAMPLE 43 Assay for Inhibition of HTV Reverse Transcriptase

Assays to determine the in vitro inhibition of HIV reverse transcriptase by compounds of the present invention were conducted as follows: HTV-I 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 mJVl

KCl, 0.2% polyethylene glycol 8000, 0.1 mM EGTA), and the mixture preincubated for 30 minutes 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 uM [ ³ H]-dGTP). The heterodimeric nucleic acid substrate was generated by annealing the DNA primer pD500 (described in Shaw-Reid et al., J. Biol. Chem., 278: 2777-2780; obtained from Integrated DNA Technologies) to t500, a 500 nucleotide RNA template created by in vitro transcription (see Shaw-Reid et al., J. Biol. Chem., 278: 2777-2780). After 1 hour incubation at 37 ⁰ 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 ⁰ 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 title compounds set forth above in Examples 1 to 41 were tested in the assay and all were found to have Kj values (K ₁ is the dissociation constant for binding to the enzyme) less than 25 micromolar.

EXAMPLE 44

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 Examples 1 to 21 and 27 to 41 were found to have IC95's of less than 30 micromolar in the assay. The compounds of Examples 22 to 26 were also tested in the spread assay up to 1 micromolar, but specific IC95 values were not obtained; i.e., the IC95 values for these compounds are greater than 1 micromolar.

EXA3MPLE 45

Cytotoxicity

Cytotoxicity was determined by microscopic examination of the cells in each well in the spread assay, wherein a trained analyst observed each culture for any of the following morphological changes as compared to the control cultures: pH imbalance, cell abnormality, cytostatic, cytopathic, or

crystallization (i.e., the compound is not soluble or forms crystals in the well). The toxicity value assigned to a given compound is the lowest concentration of the compound at which one of the above changes is observed. Representative compounds of the present invention that were tested in the spread assay (see Example 44) were examined for cytotoxicity. For those compounds for which an IC95 value was determined in the spread assay, no cytotoxicity was exhibited at the IC95 concentration; i.e., their toxicity value is greater than their IC95 value. In particular, the compounds set forth in Examples 1 to 21 and 27 to 41 exhibited no cytotoxicity at their IC95 concentrations. The compounds in Examples 22 to 26 exhibited no cytotoxicity at concentrations up to 1 micromolar.

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.