WO1999062897A1

WO1999062897A1 - Hiv integrase inhibitors

Info

Publication number: WO1999062897A1
Application number: PCT/US1999/012094
Authority: WO
Inventors: Steven D. Young; John S. Wai; Mark W. Embrey; Thorsten E. Fisher
Original assignee: Merck & Co., Inc.
Priority date: 1998-06-03
Filing date: 1999-06-01
Publication date: 1999-12-09
Also published as: CA2333771A1; EP1086091A1; AU757409B2; AU4225599A; JP2002517390A; EP1086091A4

Abstract

Sulfur-containing heteroaryl dioxo-butyric acid derivatives are described as inhibitors of HIV integrase and inhibitors of HIV replication. These compounds are useful in the prevention or treatment of infection by HIV and the treatment of AIDS, either as compounds, pharmaceutically acceptable salts, pharmaceutical composition ingredients, whether or not in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of preventing or treating infection by HIV are also described.

Description

TITLE OF THE INVENTION HIV INTEGRASE INHIBITORS

CROSS-REFERENCE TO RELATED APPLICATIONS The present application claims priority of U.S. provisional application Serial No. 60/087,846, filed June 3, 1998.

BACKGROUND OF THE INVENTION

A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the insertion by virally-encoded integrase of proviral DNA into the host cell genome, a required step in HIV replication in human T-lymphoid and monocytoid cells. Integration is believed to be mediated by integrase in three steps: assembly of a stable nucleoprotein complex with viral DNA sequences; cleavage of two nucleotides from the 3' termini of the linear proviral DNA; covalent joining of the recessed 3' OH termini of the proviral DNA at a staggered cut made at the host target site. The fourth step in the process, repair synthesis of the resultant gap, may be accomplished by cellular enzymes. Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al., Nature, 313, 277(1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, integrase and an HIV protease [Toh, H. et al., EMBO J. 4, 1267 (1985); Power, M.D. et al., Science, 231, 1567 (1986); Pearl, L.H. et al., Nature, 329, 351 (1987)]. All three enzymes have been shown to be essential for the replication of HΓV.

It is known that some antiviral compounds which act as inhibitors of HIV replication are effective agents in the treatment of AIDS and similar diseases, e.g., azidothymidine or AZT. Applicants demonstrate that the compounds of this invention are inhibitors of HIV integrase and inhibitors of HIV replication. The applicants additionally demonstrate that inhibition of integrase in vitro and HIV replication in cells is a direct result of inhibiting the strand transfer reaction catalyzed by the recombinant integrase in vitro and integrase as a component of the preintegration complex in HIV infected cells. The particular advantage of the present invention is highly specific inhibition of HIV integrase and HIV replication. The compounds of the present invention inhibit integrases of closely related lentiviruses such as HIV 2 and SIV, but not integrases from more distantly related retroviruses, for example RSV. These compounds do not inhibit binding or catalysis of other nucleic acid binding proteins, including enzymatic reactions such as those catalyzed by HIV reverse transcriptase, HIV Rnase H, Influenza transcriptase, Hepatitis C polymerase, Yeast DNA polymerase, DNase I, Eco RI endonuclease, or mammalian polymerase II.

Zhao et al., (J. Med Chem. vol. 40, pp. 937-941 and 1186- 1194 (1997)) describe hydrazide and arylamide HIV integrase inhibitors. Bis-catechols useful for inhibiting HIV integrase are described in LaFemina et al. (Antimicrobial Agents & Chemotherapy, vol. 39, no. 2, pp. 320-324, February 1995).

U.S. Patents 4,377,258; 4,336,397; and 4,423,063 as well as Williams and Rooney (J. Med. Chem. vol 26, pp. 1196-1200, 1983) disclose 2,4-dioxo-4-substituted-l-butanoic acid derivatives useful intreating urinary tract calcium oxalate lithiasis. 4-substituted 2,4- dioxobutanoic acid compounds useful for inhibiting an influenza virus endonuclease are described in Tomassini et al. (Antimicrobial Agents & Chemotherapy, vol. 38, no. 12, pp. 2827-2837, December, 1994). Applicants have discovered that certain 5-membered sulfur containing heteroaromatic diketo acid derivatives are potent inhibitors of HIV integrase. These compounds are useful in the treatment of AIDS or HIV infection.

SUMMARY OF THE INVENTION Compounds of formula I, as herein defined, are disclosed. These compounds are useful in the inhibition of HIV integrase, the prevention of infection by HIV, the treatment of infection by HIV and in the treatment of AIDS and/or ARC, either as compounds, pharmaceutically acceptable salts or hydrates (when appropriate), pharmaceutical composition ingredients, whether or not in combination with other antivirals, anti-infectives, immunomodulators, antibiotics or vaccines. Methods of treating AIDS, methods of preventing infection by HIV, and methods of treating infection by HIV are also disclosed.

DETAILED DESCRIPTION OF THE INVENTION

This invention is concerned with compounds of formula I, combinations thereof, or pharmaceutically acceptable salts thereof, in the inhibition of HIV integrase, the prevention or treatment of infection by HIV and in the treatment of the resulting acquired immune deficiency syndrome (AIDS). Compounds of formula I are defined as follows:

(I) and tautomers or pharmaceutically acceptable salts thereof, wherein:

A is a five-membered heteroaromatic ring containing 1 sulfur atom and

1 2 8

0 or 1 nitrogen atoms and substituted on carbon by R ,R and R ; the heteroaromatic ring may optionally be fused with a phenyl ring or a C4.6 cycloalkyl ring, or with two six membered rings to form:

R is selected from:

(1) -H,

(2) -Cn.5 alkyl,

(3) -CFg,

(4) -halo,

(5) -N0₂,

(6) -N(R )(R⁵),

(7) -R6,

(8) -C₂_5 alkenyl-R ,

(9) -C₂_₅ alkynyl-R ,

(10) -0-R6,

(ID -O-Ci-6 alkyl, and

(12) -C(0)CH2C(0)C(0)OR7

2 R is selected from:

(1) -H,

(2) -R³,

(3) -Ci., alkyl, ,

(6) - -C^_Q alkyl-OR⁶,

(7) -S(0)n-R⁶,

(8) -C^e alkyl (OR⁶)(R⁴) ,

(9) -C₁ alkyl (OR⁴)(R⁶) , (10) -C₀_₆ alkyl-N(R⁴)(R⁶) ,

(11) -C₁ alkyl S(0)n-R⁶,

(12) -C₀^ alkyl C(0)-R⁶,

(13) -C₀.₆ alkyl C(S)-R⁶,

(14) -C₀_₆ alkyl NR⁴ C(0)-R⁶ , and (15) -C₀_₆ alkyl-C(0)N(R⁴)(R⁵); 3 each R is independently selected from:

(1) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, 2, 3, or 4 heteroatoms selected from oxygen, nitrogen and sulfur, unsubstituted or substituted on a nitrogen or carbon atom by 1 to 5 substituents selected from: (a) halogen,

(b) C_{l Q} alkyl,

(c) C_l alkyloxy-,

(d) phenyl,

(e) -CF₃,

(f⁾ -OCFg,

(g) -CN,

(h) hydroxy,

(i) phenyloxy, and

(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:

(i) halogen,

(ii) C^e alkyl,

(iii) -CF₃, and

(iv) hydroxy;

(2) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms selected from oxygen, nitrogen or sulfur, unsubstituted or substituted with 0 to 5 substituents selected from

(a) halogen,

(b) C_l alkyl,

(c) C-^g alkyloxy-,

(d) -CF₃,

(e) -OCFg,

(f) -CN,

(g) =0,

(h) hydroxy; (3) unsubstituted or substituted hexahydrothieno[3,4- d]imidazolyl with one or two substituents selected from: (a) oxo,

(b) halogen,

(0 C₁ alkyl,

(d) C-L.g alkyloxy-

(e) -CF₃,

(f) -OCFg,

(g) -CN, and

(h) hydroxy;

(4) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, or 2 heteroatoms selected from oxygen, nitrogen and sulfur, fused with a phenyl ring; wherein the ring system is unsubstituted or substituted on a nitrogen or carbon atom by 1 to 3 substituents selected from:

(a) -halogen,

(b) -C_l alkyl,

(c) -C^g alkyloxy-,

(d) "CFg,

(e) -OCFg,

(f) -CN, and

(g) -hydroxy;

(5) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms selected from oxygen, nitrogen or sulfur, fused with a phenyl ring, unsubstituted or substituted withl or 2 substituents selected from: (a) halogen,

(b) C_l alkyl,

(c) C_lmQ alkyloxy-,

(d) -CFg, (e) -OCFg,

(f) -CN,

(g) =0,

(h) hydroxy;

(6) a 5 to 6 membered ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, containing 2 or 3 double bonds, unsubstituted or substituted with 1 or 2 substituents selected from: (a) halogen,

(b) C^g alkyl,

(c) C^g alkyloxy-,

(d) -CFg,

(e) -OCFg,

(f) -CN,

(g) =o,

(h) hydroxy;

4

. is independently selected

(1) -H,

(2) -C_λ_₃ alkyl,

(3) -CF₃,

(4) -R³,

(5) -C₂.g alkenyl,

(6) -C^g alkyl-R³,

(7) -C₂.g alkenyl-R ,

(8) -S(0)_n-R³, and

(9) -C(0)-R³; g each R is independently selected from:

(1) -H,

(2) -C-L.3 alkyl, yO) - r g,

(4) -R³,

(5) -C .g alkenyl,

(6) -CLS alkyl-R³,

(7) -C₂.g alkenyl-R ,

(8) -S(0)_n-R³, and

(9) -C(0)-R³;

each R is independently selected from: (1) -C^g alkyl-R³, and

(2) -R³;

R7 is selected from: (1) -H, and (2) Ci-6 alkyl;

R8 is selected from:

(1) -H, and

(2) Ci-6 alkyl-oxy-; (3) Ci-6 alkyl-;

each n is independently selected from 0, 1 and 2, and each m is independently selected from 0, 1, and 2.

Particular compounds of structural formula I include:

(1)

(2) (3)

(4)

(5)

(6)

(7)

(8)

(9)

(10)

(ID

(12)

(13)

(14)

(15)

(16)

(17)

(18)

(19)

(20) (21)

(22)

(23)

(24)

(25)

(26)

(27)

(28)

(29)

(30)

(31)

(32)

(33) (34)

(35)

(36)

(37)

(38)

(39)

(40)

(41)

(42)

(43)

(44) (45)

(46)

(47)

(48)

(49) (50)

(51)

(55)

and tautomers and pharmaceutically acceptable salts thereof.

In one embodiment of the present invention, structural formula (I) is:

In another embodiment of the present invention, structural formula (I) is:

In still another embodiment of the present invention, structural formula (I) is:

In yet another embodiment of the present invention, structural formula (I) is;

In one class of compounds of the present invention, A is selected from: (1) thienyl,

(2) thiazolyl,

(3)

I en anoother class of compounds of the present invention, A is selected from:

(1) thienyl,

(2) thiazolyl,

(3)

(4)

In one class of compounds of the present invention, Rl is selected from: (1) -H, (2) -CHg,

(3) -CFg,

(4) -halo,

(5) -N0₂, (6) -N(R⁴)(R⁵),

(7) -phenyl,

(8) substituted phenyl substituted with 1 or 2 substituents independently selected from:

(a) halogen,

(b) C_l alkyl,

(c) C-^g alkyloxy-,

(d) phenyl,

(e) -CFg,

( ) "OCFg,

(g) -CN,

(h) hydroxy,

(i) phenyloxy, and

(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:

(i) halogen,

(ii) Ci__Q alkyl,

(iii) -CF₃, and

(iv) hydroxy;

(9) phenyl C^g alkyl-,

(10) substituted phenyl C_j.g alkyl- substituted with 1 or 2 substituents independently selected from:

(a) halogen,

(b) C^g alkyl,

(c) C₁.₆ alkyloxy-,

(d) phenyl,

(e) -CFg,

(f) "OCFg,

⁽ε⁾ -CN,

(h) hydroxy,

(i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C^g alkyl, (iii) -CF₃, and

(iv) hydroxy;

(11) -C₂_₅ alkenyl-R³,

(12) -C₂.₅ alkynyl-R³, and

(13) -C(0)CH2C(0)C(0)OR7. In another class of compounds of the present invention, Rl cted from:

(1) -H,

(2) -CHg,

(3) -CFg, (4) -halo,

(5) -N0₂,

(6) -N(R⁴)(R⁵),

(7) -phenyl,

(a) halo,

(b) methyl, and

(c) methoxy,

(9) phenyl C^g alkyl-, (10) substituted phenyl C^g alkyl- substituted with 1 or 2 substituents independently selected from:

(a) halo,

(b) methyl, and

(c) methoxy, and (11) -C₂.₅ alkenyl-R³.

In still another class of compounds of the present invention, ydrogen. In one class of compounds of the present invention, R2 is selected from:

(1) -H,

(2) -R³,

(3) -C-L.g alkyl, g

(4) -C^.g alkyl substituted with R ,

(5) -O-R⁶,

(6) -O-C^g alkyl-OR⁶,

(7) -S(0)n-R⁶,

(8) -C^g alkyl (OR⁶)(R⁴) ,

(9) -C^g alkyl (OR⁴)(R⁶) ,

(10) -C₀.₆ alkyl-N(R⁴)(R⁶) ,

(11) -C-L.g alkyl S(0)n-R⁶,

(12) -C₀.₆ alkyl C(0)-R⁶,

(13) -C₀.₆ alkyl C(S)-R⁶,

(14) -C₀.₆ alkyl NR⁴C(0)-R⁶, and

(15) -C₀_g alkyl-C(0)N(R⁴)(R⁵).

In another class of compounds of the present invention, R2 is selected from:

(1) -H,

(2) -R³,

(3) -C^g alkyl, g

(4) -C^. alkyl substituted with R ,

(5) -O-R⁶,

(6) -S(0)n-R⁶,

(7) -C^g alkyl (OR⁶)(R⁴) ,

(8) -C^_Q alkyl (OR⁴)(R⁶) ,

(9) -C₀.₆ alkyl-N(R⁴)(R⁶) ,

(10) -C^_Q alkyl S(0)n-R⁶,

(11) -C₀.₆ alkyl C(0)-R⁶,

(12) -Cn._fi alkyl NR⁴C(0)-R⁶, and (13) -C₀.₆ alkyl-C(0)N(R⁴)(R⁵).

In one class of compounds of the present invention, R3 is selected from:

(1) phenyl;

(2) substituted phenyl with 1, 2, or 3 substituents independently selected from:

(a) halogen,

(b) C-L.0 alkyl,

(0 C^ alkyloxy-,

(d) phenyl,

(e) -CFg,

(f⁾ -OCFg,

(g) -CN,

(h) hydroxy,

(i) phenyloxy, and

(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:

(i) halogen,

(ii) C₁ alkyl,

(iii) -CF₃, and

(iv) hydroxy;

(3) thienyl;

(4) substituted thienyl substituted on a carbon atom with one or two substituents independently selected from:

(a) halogen,

(b) C^g alkyl,

(c) C₁.g alkyloxy-,

(d) phenyl,

(e) -CFg,

(f) "OCFg,

(g) -CN,

(h) hydroxy, (i) phenyloxy, and

(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:

(i) halogen,

(ii) C^ alkyl,

(iii) -CF₃, and

(iv) hydroxy;

(5) pyridyl;

(6) substituted pyridyl substituted on a carbon atom with one or two substituents independently selected from:

(a) halogen,

(b) C^ alkyl,

(c) C^ alkyloxy-,

(d) phenyl,

(e) -CF₃,

(f) -OCFg,

(g) -CN,

(h) hydroxy,

(i) phenyloxy, and

(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:

(i) halogen,

(ii) Cι_g alkyl,

(iii) -CF₃, and

(iv) hydroxy;

(7) imi( iazolyl;

(8) substituted imidazolyl substituted on a carbon atom with one or two substituents independently selected from:

(a) halogen,

(b) Ci_₆ alkyl,

(c) Ci_₆ alkyloxy-,

(d) phenyl,

(e) -CF₃, ( ) "OCFg,

(g) -CN,

(h) hydroxy,

(i) phenyloxy, and

(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:

(i) halogen,

(ii) Cι_g alkyl,

(iii) -CF₃, and

(iv) hydroxy;

(9) pyrrolyl;

(10) substituted pyrrolyl substituted on a carbon atom with one or two substituents independently selected from:

(a) halogen,

(b) C _₆ alkyl,

(c) Ci_₆ alkyloxy-,

(d) phenyl,

(e) "CFg,

(f) -OCFg,

(g) -CN,

(h) hydroxy,

(i) phenyloxy, and

(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:

(i) halogen,

(ii) Ci_₆ alkyl,

(iii) -CF₃, and

(iv) hydroxy;

(ID pyrazolyl;

(12) substituted pyrazolyl substituted on a carbon atom with one or two substituents independently selected from:

(a) halogen,

(b) Ci_₆ alkyl, (0 Ci_₆ alkyloxy-,

(d) phenyl,

(e) -CFg,

(f) "OCFg,

(g) -CN,

(h) hydroxy,

(i) phenyloxy, and

(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:

(i) halogen,

(ii) Cι_g alkyl,

(iii) -CF₃, and

(iv) hydroxy;

(13) 3-6 cycloalkyl;

(14) substituted Cg.g cycloalkyl with 1 or 2 substituents independently selected from:

(a) halogen,

(b) Cι_g alkyl,

(c) Ci_₆ alkyloxy-,

(d) -CF₃,

(e) -OCFg,

(f) -CN,

(g) =0,and

(h) hydroxy;

(15) piperidinyl;

(16) substituted piperidinyl substituted on a carbon atom with one 1 or two substituents independently selected from:

(a) halogen,

(b) Ci_₆ alkyl,

(c) Ci_₆ alkyloxy-,

(d) "CFg,

(e) -OCFg, (f) -CN,

(g) =0, and

(h) hydroxy;

(17) morpholinyl;

(18) substituted morpholinyl substituted at a carbon or nitrogen atom with 1 or 2 independently selected from:

(a) halogen,

(b) Ci_₆ alkyl,

(c) C _₆ alkyloxy-,

(d) -CFg,

(e) -OCFg,

(f) -CN,

(g) =0, and

(h) hydroxy;

(19) naphthyl,

(20) substituted naphthyl with 1, 2, or 3 substituents independently selected from:

(a) -halogen,

(b) -Ci_₆ alkyl,

(0 -Ci_₆ alkyloxy-,

(d) -CFg,

(e) -OCFg,

(f) -CN, and

(g) -hydroxy;

(21) indolyl;

(22) substituted indolyl substituted on a carbon atom with one or two substituents independently selected from:

(a) -halogen,

(b) -Ci_₆ alkyl,

(c) -Ci_₆ alkyloxy-,

(d) "CFg,

(e) -OCFg,

(f) -CN, and (g) -hydroxy;

(23) C_3.g cycloalkyl fused with a phenyl ring

(24) substituted C₃.g cycloalkyl fused with a phenyl ring substituted on a carbon atom with one or two substituents independently selected from:

(a) halogen,

(b) Ci_₆ alkyl,

(c) Ci_₆ alkyloxy-,

(d) -CFg,

(e) -OCFg,

(f) -CN,

(g) =0, and

(h) hydroxy.

In another class of compounds of the present invention, R3 cted from:

(1) phenyl;

(a) halogen,

(b) Cι_g alkyl,

(c) C _₆ alkyloxy-,

(d) phenyl,

(e) -CFg,

(f) -OCFg,

(g) -CN,

(h) hydroxy,

(i) phenyloxy, and

(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:

(i) halogen,

(ii) Cι_g alkyl,

(iii) -CF₃, and

(iv) hydroxy; (3) thienyl; (4) substituted thienyl substituted on a carbon atom with one or two substituents independently selected from:

(a) halogen,

(b) Cι_g alkyl,

(c) Ci. alkyloxy-,

(d) phenyl,

(e) "CFg,

(f) -OCFg,

(g) -CN,

(h) hydroxy,

(i) phenyloxy, and

(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:

(i) halogen,

(ii) C₁ alkyl,

(iii) -CF₃, and

(iv) hydroxy;

(5) pyridyl;

(a) halogen,

(b) Ci. alkyl,

(c) C^ alkyloxy-,

(d) phenyl,

(e) -CFg,

(f> -OCFg,

(g) -CN,

(h) hydroxy,

(i) phenyloxy, and

(j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) Ci.g alkyl, (iii) -CF₃, and (iv) hydroxy; (7) imidazolyl; (8) pyrrolyl;

(9) pyrazolyl;

(10) Cg.₆ cycloalkyl,

(11) substituted Cg.g cycloalkyl with 1 or 2 substituents independently selected from: (a) halogen,

(b) Ci_.g alkyl,

(c) C^g alkyloxy-,

(d) -CFg,

(e) -OCFg, (f) -CN,

(g) =0, and (h) hydroxy;

(12) piperidinyl;

(13) substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from:

(a) halogen,

(b) Ci.6 alkyl,

(c) Ci.g alkyloxy-,

(d) -CFg, (e) -OCFg,

(f) -CN,

(g) =0, and (h) hydroxy;

(14) morpholinyl; (15) naphthyl;

(16) indolyl, and

(17) Cg.g cycloalkyl fused with a phenyl ring. In still another class of compounds of the present invention, R3 is selected from:

(1) phenyl,

(a) halogen selected from -F, -Cl, -Br„

(b) CHg,

(c) methoxy-,

(d) phenyl,

(e) -CF₃,

(f) -OCFg,

(g) -CN,

(h) hydroxy,

(i) phenyloxy, and

(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:

(i) halogen selected from -F, -Cl, -Br,

(ii) -CH₃,

(iii) -CFg, and

(iv) hydroxy;

(3) thienyl,

(5) pyridyl,

(7) imidazolyl,

(8) pyrrolyl,

(9) pyrazolyl,

(10) Cg_₆ cycloalkyl,

(12) piperidinyl,

(14) morpholinyl,

(15) naphthyl,

(16) indolyl, and

(17) Cg.g cycloalkyl fused with a phenyl ring.

In one class of compounds of the present invention, R4 is selected from: (1) -H,

(2) -Ci.g alkyl,

(3) -CFg,

(4) -R³,

(5) -C₂_g alkenyl,

(6) -C^g alkyl-R³,

(7) -C₂.g alkenyl-R ,

(8) -S(0)_n-R³, and

(9) -C(0)-R³. In another class of compounds of the present invention, R4 is selected from:

(1) -H,

(2) -Ci.3 alkyl,

(3) -CFg, (4) -R³,

(5) -C₂_3 alkenyl,

(6) -Ci.3 alkyl-R°, and ,3

(7) -S(0)_n-R^c

In one class of compounds of the present invention, R5 is selected from:

(1) -H,

(2) -Ci.3 alkyl,

(3) -CF₃,

(4) -R³,

(5) -C₂_g alkenyl,

(6) -Ci.3 alkyl-R³,

(7) -C₂_3 alkenyl-R ,

(8) -S(0)_n-R³, and

(9) -C(0)-R³. In another class of compounds of the present invention, R5 is selected from: (1) -H,

(2) -Ci.3 alkyl,

(3) -CFg,

(4) -R³,

(5) -C₂_3 alkenyl,

(6) -C^g alkyl-R³,

(7) -C₂_3 alkenyl-R and

(8) -S(0)_n-R³.

In one class of compounds of the present invention, R7 is hydrogen.

In one class of compounds of the present invention, Rδ is selected from: hydrogen, methyl and methoxy.

Also included within the present invention are pharmaceutical compositions useful for inhibiting HIV integrase, comprising an effective amount of a compound of this invention, and a pharmaceutically acceptable carrier. Pharmaceutical compositions useful for treating infection by HIV, or for treating AIDS or ARC, are also encompassed by the present invention, as well as a method of inhibiting HIV integrase, and a method of treating infection by HIV, or of treating AIDS or ARC. Additionally, the present invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention in combination with a therapeutically effective amount of an AIDS treatment agent selected from: (1) an AIDS antiviral agent,

(2) an anti-infective agent, and

(3) an immunomodulator.

The compounds of the present invention may have asymmetric centers and may occur, except when specifically noted, as mixtures of stereoisomers or as individual diastereomers, or enantiomers, with all isomeric forms being included in the present invention. As is recognized by one of ordinary skill in the art, the diketo-acid/ester compounds of the present invention exist as tautomers, and thus by using the phrase "and tautomers thereof in describing compounds of structural formula (I), Applicants also intend the following tautomeric forms of the same compound (la) and (lb):

(lb)

By naming or referring to compound (I) and tautomers thereof, it is understood for the purposes of the present application that the tautomers (la) and (lb) are also intended. Similarly, by referring to compound (la), it is understood for the purposes of the present application that the tautomers (I) and (lb) are also intended. The same holds true for references to tautomer (lb).

When any variable (e.g., R3, R4, etc.) occurs more than one time in any constituent or in formula I, 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 compounds of the present inventions are useful in the inhibition of HrV integrase, the prevention or treatment of infection by human immunodeficiency virus (HIV) and the treatment of consequent pathological conditions such as AIDS. Treating AIDS or preventing or treating infection by HFv⁷ is defined as including, but not limited to, treating a wide range of states of HIV infection: AIDS, ARC (AIDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV. For example, the compounds of this invention are useful in treating infection by HIV after suspected past exposure to HIV by e.g., blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery. The compounds of this invention are useful in the preparation and execution of screening assays for antiviral compounds. For example, the compounds of this invention are useful for isolating enzyme mutants, which are excellent screening tools for more powerful antiviral compounds. Furthermore, the compounds of this invention are useful in establishing or determining the binding site of other antivirals to HIV integrase, e.g., by competitive inhibition. Thus the compounds of this invention are commercial products to be sold for these purposes. The present invention also provides for the use of a compound of structural formula (I) to make a pharmaceutical composition useful for inhibiting HIV integrase and in the treatment of AIDS or ARC.

Compounds of structural formula (I) wherein A is thienyl may be made according to the procedures in Schemes Al, All, BI, Cl, CII, DI, El, FI, FII, and Fill. Compounds of structural formula (I) wherein A is thiazolyl may be prepared according to the procedures in Scheme GI.

AI ( 3 ) i. NaOH, MeOH-H₂0-THF

ii.HCl

AI(4

Scheme All

All (2a-e NaOEt, THF

All (3a-e

i. NaOH, MeOH-H₂0-THF

ii.HCl

All (4a-e)

Scheme BI

BF₃.Et₂0, Et₃SiH, CH₂C1₂

BI(3a-d)

n-BuLi, Et₂0, CH₃CONCH₃ (OCH₃ )

BI(4a-d]

BI (5a-d)

i. NaOH, MeOH-H₂0-THF

ii.HCl

BI (6a-d)

Scheme BII

O- SNa acetone

R

NaOEt, THF

O

BII(3)

i. NaOH, MeOH-H₂0-THF

ii.HCl

BII (4) Scheme Cl

BF₃.Et₂0, Et₃SiH(xs) , CH₂C1₂

Cl (3a-d:

n-BuLi, Et₂0, CH₃CONCH₃ (OCH₃ )

CI(4a-d!

Scheme Cl (continue^

Cl (5a-d)

i. NaOH, MeOH-H₂0-THF

ii.HCl

CI(6a-d: Scheme CII

₃CONCH₃ (OCH₃

i. NaOH, MeOH-H₂0-THF

ii.HCl

Scheme DI

BF₃.Et₂0, Et₃SiH, CH₂C1₂

DI(3a-c)

n-BuLi, Et₂0, CH₃CONCH₃ (OCH₃ )

DI (4a-c Scheme DI (continue!

DI (4a-c^'

DI (5a-c

i. NaOH, MeOH-H₂0-THF

ii.HCl

DI (6a-c Scheme El

BI(2d)

NaH, DMSO, RX

El (la-c!

n-BuLi, Et₂0, CH₃CONC

El (2a-c)

Scheme El (continue^'

El (4a-c)

i. NaOH, MeOH-H₂0-THF

ii.HCl

El (5a-c Scheme FI

i. H₂, Pt₂S/C, MeOH ii.HCl

RX, iPr₂NEt, MeCN or RX, Cs₂C0₃, DMF

R'= H, R

R = Bn, n-Pr, allyl, Me

NaOEt, THF

i. NaOH, MeOH-H₂0-THF

ii.HCl

Scheme FII

R

NH CS CO 3 ' DMF

R'

NaOEt, THF

i. NaOH, MeOH-H₂0-THF

ii.HCl

Scheme Fill

RS0₂C1, pyridine

NaHMDS, DMSO, R'X

NaOEt, THF

i. NaOH, MeOH-H₂0-THF

ii.HCl

Scheme GI

R

N-H

R'

R = Bn, R' = Bn S=C=N- hexane R = Bn, R' = H R = Bn, R' = CH₃ 11 c. HCl

NaOEt, THF

i. NaOH, MeOH-H₂0-THF

ii.HCl

Scheme Gil

R

N-H

R'

S=C=N- hexane

11 c HCl

NaOEt, THF

i. NaOH, MeOH-H₂0-THF

ii.HCl

The compounds of the present invention may be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" is intended to include all acceptable salts such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutamate, stearate, glycollylarsanilate, sulfate, hexylresorcinate, subacetate, hydrabamine, succinate, hydrobromide, tannate, hydrochloride, tartrate, hydroxynaphthoate, teoclate, iodide, tosylate, isothionate, triethiodide, lactate, panoate, valerate, and the like which can be used as a dosage form for modifying the solubility or hydrolysis characteristics or can be used in sustained release or pro- drug formulations. Depending on the particular functionality of the compound of the present invention, pharmaceutically acceptable salts of the compounds of this invention include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethyl enediamine, N-methyl- glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylene- diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethyl- amine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide. These salts may be prepared by standard procedures, e.g. by reacting a free acid with a suitable organic or inorganic base. Where a basic group is present, such as amino, an acidic salt, i.e. hydrochloride, hydrobromide, acetate, pamoate, and the like, can be used as the dosage form. Also, in the case of an acid (-COOH) or alcohol group being present, pharmaceutically acceptable esters can be employed, e.g. acetate, maleate, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.

For these purposes, the compounds of the present invention may be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectally, in dosage unit formulations containing conventional non-toxic pharmaceutically- acceptable carriers, adjuvants and vehicles.

The terms "administration of and or "administering a" compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment.

Thus, in accordance with the present invention there is further provided a method of treating and a pharmaceutical composition for treating HIV infection and AIDS. The treatment involves administering to a patient in need of such treatment a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically-effective amount of a compound of the present invention.

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 combination of the specified ingredients in the specified amounts.

By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. These pharmaceutical compositions may be in the form of orally-aclministrable suspensions or tablets, nasal sprays, sterile injectible preparations, for example, as sterile injectible aqueous or oleagenous suspensions or suppositories.

When administered orally as a suspension, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners/flavoring agents known in the art. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.

When administered by nasal aerosol or inhalation, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. The injectible solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally- acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.

When rectally administered in the form of suppositories, these compositions may be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.

The compounds of this invention can be administered orally to humans in a dosage range of 1 to 1000 mg/kg body weight in divided doses. One preferred dosage range is 0.1 to 200 mg/kg body weight orally in divided doses. Another preferred dosage range is 0.5 to 100 mg/kg body weight orally in divided doses. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. It will be understood, however, that 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.

The present invention is also directed to combinations of the HIV integrase inhibitor compounds with one or more agents useful in the treatment of AIDS. For example, the compounds of this invention may be effectively administered, whether at periods of pre-exposure and or post-exposure, in combination with effective amounts of the AIDS antivirals, imunomodulators, antiinfectives, or vaccines, such as those in the following table.

ANTIVIRALS

Drue Name M anuf actur er Indication

097 Hoechst/Bayer HIV infection, AIDS, ARC (non-nucleoside reverse transcriptase (RT) inhibitor)

Amprenivir Glaxo Wellcome HP7 infection,

141 W94 AIDS, ARC

GW141 (protease inhibitor)

Abacavir (1592U89) Glaxo Wellcome HIV infection, AIDS, ARC (RT inhibitor)

Acemannan Carrington Labs ARC (Irving, TX)

Acyclovir Burroughs Wellcome HIV infection, AIDS, ARC, in combination with AZT

AD-439 Tanox Bio systems HIV infection, AIDS, ARC

AD-519 Tanox Bio systems HIV infection, AIDS, ARC

Adefovir dipivoxil Gilead Sciences HIV infection

AL-721 Ethigen ARC, PGL

(Los Angeles, CA) HIV positive, AIDS

Alpha Interferon Glaxo Wellcome Kaposi's sarcoma, HIV in combination w/Retrovir Ansamycin Adria Laboratories ARC

LM 427 (Dublin, OH) Erbamont (Stamford, CT)

Antibody which Advanced Biotherapy AIDS, ARC neutralizes pH Concepts labile alpha aberrant (Rockville, MD)

Interferon

AR177 Aronex Pharm HΓV infection, AIDS, ARC beta-fluoro-ddA Nat'l Cancer Institute AIDS-associated diseases

BMS-232623 Bristol-Myers Squibb/ HΓV infection,

(CGP-73547) Novartis AIDS, ARC (protease inhibitor)

BMS-234475 Bristol-Myers Squibb/ HP/ infection,

(CGP-61755) Novartis AIDS, ARC (protease inhibitor)

CI-1012 Warner-Lambert HΓV-1 infection

Cidofovir Gilead Science CMV retinitis, herpes, papilloma virus

Curdlan sulfate AJI Pharma USA HΓV infection

Cytomegalovirus immune Medlmmune CMV retinitis globin

Cytovene Syntex sight threatening

Ganciclovir CMV peripheral CMV retinitis

Delaviridine Pharmacia-Upj ohn HΓV infection, AIDS, ARC (RT inhibitor)

Dextran Sulfate Ueno Fine Chem. AIDS, ARC, HIV

Ind. Ltd. (Osaka, positive asymptomatic

Japan) ddC Hoffman- La Roche HΓV infection, AIDS,

Dideoxycytidine ARC ddl Bristol-Myers Squibb HΓV infection, AIDS,

Dideoxyinosine ARC; combination with AZT/d4T

DMP-450 AVID HΓV infection, (Camden, NJ) AIDS, ARC (protease inhibitor)

Efavirenz DuPont Merck HΓV infection,

(DMP 266) AIDS, ARC

((-) 6-Chloro-4(S)- (non-nucleoside RT cyclopropylethynyl-4(S)- inhibitor) trifluoro -methyl -1,4- dihydro-2H-3,l- benzoxazin-2-one)

STOCRIN,

EL10 Elan Corp, PLC H infection (Gainesville, GA)

Famciclovir Smith Kline herpes zoster, herpes simplex

FTC Emory University HΓV infection,

AIDS, ARC

(reverse transcriptase inhibitor)

GS 840 Gilead HIV infection,

AIDS, ARC

(reverse transcriptase inhibitor)

HBY097 Hoechst Marion HΓV infection, Roussel AIDS, ARC

(non-nucleoside reverse transcriptase inhibitor) Hypericin VIMRx Pharm. HΓV infection, AIDS,

ARC

Recombinant Human Triton Biosciences AIDS, Kaposi's Interferon Beta (Almeda, CA) sarcoma, ARC Interferon alfa-n3 Interferon Sciences ARC, AIDS Indinavir Merck HIV infection, AIDS,

ARC, asymptomatic

HΓV positive, also in combination with

AZT/ddl/ddC

ISIS 2922 ISIS Pharmaceuticals CMV retinitis KNI-272 Nat'l Cancer Institute HIV-assoc. diseases

Lamivudine, 3TC Glaxo Wellcome HΓV infection,

AIDS, ARC

(reverse transcriptase inhibitor); also with

AZT

Lobucavir Bristol-Myers Squibb CMV infection Nelfϊnavir Agouron HΓV infection,

Pharmaceuticals AIDS, ARC

(protease inhibitor)

Nevirapine Boeheringer HΓV infection, Ingleheim AIDS, ARC

(RT inhibitor)

Novapren Novaferon Labs, Inc. HΓV inhibitor (Akron, OH)

Peptide T Peninsula Labs AIDS

Octapeptide (Belmont, CA)

Sequence

Trisodium Astra Pharm. CMV retinitis, HΓV

Phosphonoformate Products, Inc infection, other CMV infections PNU-140690 Pharmacia Upjohn HΓV infection, AIDS, ARC (protease inhibitor)

Probucol Vyrex HΓV infection, AIDS

RBC-CD4 Sheffield Med. Tech HΓV infection,

(Houston TX) AIDS, ARC

Ritonavir Abbott HΓV infection, AIDS, ARC (protease inhibitor)

Saquinavir Hoffmann-LaRoche HΓV infection, AIDS, ARC (protease inhibitor)

Stavudine; d4T Bristol-Myers Squibb HΓV infection, AIDS,

Didehydrodeoxy- ARC thymidine

Valaciclovir Glaxo Wellcome genital HSV & CMV infections

Virazole Viratek/ICN asymptomatic HP/

Ribavirin (Costa Mesa, CA) positive, LAS, ARC

VX-478 Vertex HΓV infection, AIDS, ARC

Zalcitabine Hoffmann-La Roche HΓV infection, AIDS, ARC, with AZT

Zidovudine; AZT Glaxo Wellcome HΓV infection, AIDS, ARC, Kaposi's sarcoma, in combination with other therapies

IMMUNO-MODULATORS

Drug Name Manufacturer Indication

AS-101 Wyeth-Ayerst AIDS Bropirimine Pharmacia Upjohn advanced AIDS

Acemannan Carrington Labs, Inc. AIDS, ARC (Irving, TX)

CL246,738 American Cyanamid AIDS, Kaposi's

Lederle Labs sarcoma

EL10 Elan Corp, PLC HΓV infection (Gainesville, GA)

FP-21399 Fuki ImmunoPharm blocks HΓV fusion with CD4+ cells

Gamma Interferon Genentech ARC, in combination w/TNF (tumor necrosis factor)

Granulocyte Genetics Institute AIDS

Macrophage Colony Sandoz

Stimulating

Factor

Granulocyte Hoeschst-Roussel AIDS

Macrophage Colony Immunex

Stimulating

Factor

Granulocyte Schering-Plough AIDS, combination

Macrophage Colony w/AZT

Stimulating Factor

HΓV Core Particle Rorer seropositive HD7

Immunostimulant

IL-2 Cetus AIDS, in combination

Interleukin-2 w/AZT

IL-2 Hoffman-La Roche AIDS, ARC, HΓV, in

Interleukin-2 Immunex combination w/AZT

IL-2 Chiron AIDS, increase in CD4

Interleukin-2 cell counts

(aldeslukin) Immune Globulin Cutter Biological pediatric AIDS, in Intravenous (Berkeley, CA) combination w/AZT (human) IMREG-1 Imreg AIDS, Kaposi's

(New Orleans, LA) sarcoma, ARC, PGL

IMREG-2 Imreg AIDS, Kaposi's

(New Orleans, LA) sarcoma, ARC, PGL

Imuthiol Diethyl Merieux Institute AIDS, ARC

Dithio Carbamate

Alpha-2 Schering Plough Kaposi's sarcoma

Interferon w/AZT, AIDS

Methionine- TNI Pharmaceutical AIDS, ARC

Enkephalin (Chicago, IL)

MTP-PE Ciba-Geigy Corp. Kaposi's sarcoma

Muramyl-Tripeptide

Granulocyte Amgen AIDS, in combination

Colony Stimulating w/AZT

Factor

Remune Immune Response immunotherapeutic

Corp. rCD4 Genentech AIDS, ARC

Recombinant

Soluble Human CD4 rCD4-IgG AIDS, ARC hybrids

Recombinant Biogen AIDS, ARC

Soluble Human CD4

Interferon Hoffman-La Roche Kaposi's sarcoma

Alfa 2a AIDS, ARC, in combination w/AZT

SK&F106528 Smith Kline HΓV infection Soluble T4 Thymopentin Immunobiology HΓV infection Research Institute (Annandale, NJ)

Tumor Necrosis Genentech ARC, in combination

Factor; TNF w/gamma Interferon

ANTI-INFECTIVES

Drug Name Manufacturer Indication

Clindamycin with Pharmacia Upjohn PCP

Primaquine

Fluconazole Pfizer cryptococcal meningitis, candidiasis

Pastille Squibb Corp. prevention of

Nystatin Pastille oral candidiasis

Ornidyl Merrell Dow PCP

Eflornithine

Pentamidine LyphoMed PCP treatment

Isethionate (IM & IV) (Rosemont, IL)

Trimethoprim antibacterial

Trimethoprim/sulfa antibacterial

Piritrexim Burroughs Wellcome PCP treatment

Pentamidine Fisons Corporation PCP prophylaxis isethionate for inhalation

Spiramycin Rhone-Poulenc cryptosporidial diarrhea

Intraconazole- Janssen Pharm. histoplasmosis;

R51211 cryptococcal meningitis

Trimetrexate Warner-Lambert PCP OTHER

Drug Name Manufacturer Indication Daunorubicin NeXstar, Sequus Karposi's sarcoma Recombinant Human Ortho Pharm. Corp. severe anemia Erythropoietin assoc. with AZT therapy

Recombinant Human Serono AIDS-related wasting, Growth Hormone cachexia Megestrol Acetate Bristol-Myers Squibb treatment of anorexia assoc. w/AIDS

Testosterone Alza, Smith Kline AIDS-related wasting Total Enteral Norwich Eaton diarrhea and Nutrition Pharmaceuticals malabsorption related to AIDS

It will be understood that the scope of combinations of the compounds of this invention with AIDS antivirals, immunomodulators, anti-infectives or vaccines is not limited to the list in the above Table, but includes in principle any combination with any pharmaceutical composition useful for the treatment of AIDS.

Preferred combinations are simultaneous or alternating treatments of with a compound of the present invention and an inhibitor of HΓ protease and/or a non-nucleoside inhibitor of HIV reverse transcriptase. An optional fourth component in the combination is a nucleoside inhibitor of HP/ reverse transcriptase, such as AZT, 3TC, ddC or ddl. A preferred inhibitor of HΓ protease is indinavir, which is the sulfate salt of N-(2(R)-hydroxy- l(S)-indanyl)-2(R)-phenylmethyl-4-(S)- hydroxy-5-(l-(4-(3-pyridyl-methyl)-2(S)-N'-(t-butylcarboxamido)- piperazinyl))-pentaneamide ethanolate, and is synthesized according to U.S. 5,413,999. Indinavir is generally administered at a dosage of 800 mg three times a day. Other preferred protease inhibitors are nelfinavir and ritonavir. Another preferred inhibitor of HP/ protease is saquinavir which is administered in a dosage of 600 or 1200 mg tid. Preferred non- nucleoside inhibitors of HP7 reverse transcriptase include efavirenz. The preparation of ddC, ddl and AZT are also described in EPO 0,484,071. These combinations may have unexpected effects on limiting the spread and degree of infection of HP7. Preferred combinations include those with the following (1) indinavir with efavirenz, and, optionally, AZT and/or 3TC and/or ddl and/or ddC; (2) indinavir, and any of AZT and/or ddl and/or ddC and/or 3TC, in particular, indinavir and AZT and 3TC; (3) stavudine and 3TC and/or zidovudine; (4) zidovudine and lamivudine and 141W94 and 1592U89; (5) zidovudine and lamivudine.

In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).

Indinavir is an inhibitor of HP7 protease and is the sulfate salt of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5- (l-(4-(3-pyridyl-methyl)-2(S)-N'-(t-butylcarboxamido)-piperazinyl))- pentaneamide ethanolate, and is synthesized according to U.S. 5,413,999. Indinavir is generally administered at a dosage of 800 mg three times a day.

The following examples are provided to further illustrate details for the perparation and use of the compounds of the present invention. The examples are not intended to be limitations on the scope of the instant invention in any way, and they should not be so construed. Furthermore, the compounds described in the following examples are not to be construed as forming the only genus that is considered as the invention, and any combination of the ocmpounds or their moieties may itself form a genus. Those skilled in the art will readily understand that known variatioons of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are in degrees Celsius unless noted otherwise.

Abbreviations: aq is aqueous; Ac represents acetyl; ACN is acetonitrile; Bn represents benzyl; DMF is dimethyl formamide; DMSO is dimethyl sulfoxide; Et represents ethyl; IPA is isopropyl alcohol; Me represents methyl; NaHMDS represents sodium hexamethyl disilamide; rt, RT both represent room temperature; sat represents saturated; THF is tetrahydrofuran; TLC is thin layer (Siθ2) chromatography.

EXAMPLE 1

2,4-dioxo-4-(5-phenethylthiophen-2-yl)butanoic acid

Step A: Preparation of ethyl 2,4-dioxo-4-(5-phenethynylthiophen-2- yl)butanoate AI(2)

A mixture of 2-acetyl-5-(phenylethynyl)thiophene (1.81 g, 8.02 mmol), diethyl oxalate (2.17 mL, 16 mmol), and sodium ethoxide (1.09 g, 16 mmol) in anhydrous THF (25 mL) was stirred at rt under an atmosphere of argon for 5 hr. The resultant mixture was diluted with dichloromethane, and washed successively with dilute HCl, and brine. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide yellow solid. Recrystallization of the solid from a mixture dichloromethane and hexane provided the title compound.

Step B: Preparation of ethyl 2,4-dioxo-4-(5-phenethylthiophen-2- yDbutanoate AI(3)

A mixture of ethyl 2,4-dioxo-4-(5-phenethynylthiophen-2-yl)butanoate (195 mg, 0.597 mmol), 10% Pd/C (95 mg), and THF (5 mL) in absolute ethanol (40 mL) was stirred under a balloon of hydrogen for 2 h. The resulting mixture was filtered through a pad of Celite™, diatomaceous earth. The filtrate was concentrated under vacuum to provide the title compound.

Step C: Preparation of 2,4-dioxo-4-(5-phenethylthiophen-2- yl)butanoic acid AI(4)

A solution of ethyl 2,4-dioxo-4-(5-phenethylthiophen-2-yl)butanoate (125 mg, 0.378 mmol), aqueous sodium hydroxide (1.2 mL, IM, 1.2 mmol), and THF (5 mL) in methanol (5 mL) was stirred at rt overnight. The resultant mixture was treated with aq HCl (1.3 mL. IM), and concentrated under vacuum. The residue was partitioned between brine and dichloromethane. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide off-white solid. Recrystallization of the solid from a mixture dichloromethane and hexane provided the title compound. lH NMR (CDCI3) δ 7.72 (d, J =3.1 Hz, 1H), 7.35-7.15 (m, 5H), 6.94 (s, 1H), 6.86 (d, J

=3.1 Hz, 1H), 3.22 (d, J =8.1 Hz, 2H), 3.03 (d, J =8.1 Hz, 2H).

EXAMPLE 2

2,4-dioxo-4-(5-benzyloxythiophen-2-yl)butanoic acid

Step A: Preparation of 2-acetyl-5-(benzyloxy)thiophene AII(2a)

A suspension of sodium hydride (538 mg, 22.4 mmol) in anhydrous DMSO (30 mL) was stirred at 60 °C under an atmosphere of argon for 1 hr. The resultant mixture was cooled to rt, benzyl alcohol (2.32 mL, 22.40 mmol) and 2-acetyl-5-chlorothiophene (3.01 g, 18.74 mmol) was added. The mixture was heated under an atmosphere of argon at 85 °C overnight. The product mixture was concentrated under vacuum, and the residue partitioned between ethyl acetate and dilute aqueous HCl. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 3% methanol in chloroform. Collection and concentration of appropriate fractions provided the title ketone.

Step B: Preparation of 2,4-dioxo-4-(5-benzyloxythiophen-2- yDbutanoic acid AII(4a)

The title compound was prepared using the protocol described in Example AI(4), Step A and C substituting 2-acetyl-5-(phenylethynyl)- thiophene with 2-acetyl-5-(benzyloxy)thiophene in Step A. lH NMR (CDCI3) δ 7.75 (d, J =4.6 Hz, 1H), 7.5-7.3 (m, 5H), 6.85 (s, 1H), 6.42 (d, J

=4.6 Hz, 1H), 5.21 (s, 2H).

EXAMPLE 3

2,4-dioxo-4-[5-(3-fluorobenzyloxy)thiophen-2-yl]butanoic acid

The title compound was prepared using the protocol described in Example AII(4a), Step A - B substituting benzyl alcohol with 3- fluorobenzyl alcohol in Step A. lH NMR (DMSO-cfø) δ 8.0 (br s IH), 7.5-

7.15 (m, 4H), 6.85 (brs, IH), 6.6 (br s, IH), 5.3 (br s, 2H).

EXAMPLE 4

2,4-dioxo-4-[5-(4-fluorobenzyloxy)thiophen-2-yl]butanoic acid

The title compound was prepared using the protocol described in Example AII(4a), Step A - B substituting benzyl alcohol with 4- fluorobenzyl alcohol in Step A. lH NMR (DMSO-dβ) δ 8.0 (br s IH), 7.54

(m, 2H), 7.25 (m, 2H), 6.85 (brs, IH), 6.6 (br s, IH), 5.3 (br s, 2H).

EXAMPLE 5

2,4-dioxo-4-[5-(3,4-difluorobenzyloxy)thiophen-2-yl]butanoic acid

The title compound was prepared using the protocol described in Example AII(4a), Step A - B substituting benzyl alcohol with 3,4- difluorobenzyl alcohol in Step A. lH NMR (CD3OD) δ 7.79 (d, J =4.4 Hz,

IH), 7.45-7.25 (m, 3H), 6.92 (s, IH), 6.53 (d, =4.4 Hz, IH), 5.24 (s, 2H). EXAMPLE 6

2,4-dioxo-4-[5-(pyridin-2-ylmethyloxy)thiophen-2-yl]butanoic acid

The title compound was prepared using the protocol described in Example AII(4a), Step A - B substituting benzyl alcohol with 2- pyridylcarbinol in Step A. lH NMR (DMSO-dβ) δ 8.60 (d, J =4.6 Hz, IH),

8.07 (d, J =4.6 Hz, IH), 7.87 (ddd, J =7.7, 7.7, 1.7 Hz, IH), 7.56 (d, J =7.7 Hz, IH), 7.40 (dd, J =7.7, 4.7 Hz, IH), 6.95 (s, IH), 6.67 (d, J =4.6 Hz, IH), 5.39 (s, 2H).

EXAMPLE 7

2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-2-yl]butanoic acid

Step A: Preparation of (5-bromothiophen-2-yl)-(3- fluorophenyDmethanol BI(2a)

To a cold (-78 ^*C) solution of n-butyl lithium (20.8 mL, 2.5 M in hexane, 52 mmol) in anhydrous diethyl ether (100 mL) under an atmosphere of argon, 2,5-dibromothiophene (5.63 mL, 50 mmol) was added dropwise over a period of 30 min. After the reaction mixture was stirred at -78 °C for an additional 90 min, 3-fluorobenzaldehyde (5.5 mL, 52 mmol) was added over a period of 15 min. The resultant mixture was allowed to warm to rt over a period of 2.5 h. The resultant solution was diluted with dichloromethane, and neutralized with dilute HCl. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the title compound as brown oil. The oil was used in the following step without further purification.

Step B: Preparation of 2-bromo-5-(3-fluorobenzyl)thiophene BI(3a)

To a cold (0 °C) solution of (5-bromothiophen-2-yl)-(3-fluorophenyl)- methanol (4.35 g, 15.2 mmol) and triethylsilane (3.60 mL, 22.7 mmol) in dichloromethane (30 mL), boron trifluoride etherate (2.90 mL, 22.9 mmol) was added. The resultant mixture was stirred at rt for 3 h, and treated with sat. aq. sodium bicarbonate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with hexane. Collection and concentration of appropriate fractions provide the title compound as clear colorless oil. The product was stored under argon in a freezer.

Step C: Preparation of 2-acetyl-5-(3-fluorobenzyl)thiophene BI(4a)

To a cold (-78 °C) solution of 2-bromo-5-(3-fluorobenzyl)thiophene (2.0 g, 7.38 mmol) in anhydrous diethyl ether (20 mL) under an atmosphere of argon, n-butyl lithium (4.8 mL, 1.6 M in hexane, 7.68 mmol) was added dropwise over a period of 15 min. After the reaction mixture was stirred at -78 °C for an additional 1 h, N-methoxy-N-methylacetamide (0.91 mL, 8.86 mmol) was added over a period of 10 min. The resultant mixture was allowed to warm to rt and stirred overnight. The resultant solution was diluted with ether, and neutralized with dilute HCl. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 20% ethyl acetate in hexane. Collection and concentration of appropriate fractions provide the title compound as clear pale yellow oil.

Step D: Preparation of ethyl 2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-

2-yl]butanoate BI(5a)

To a cold (-78 °C) solution of 2-acetyl-5-(3-fluorobenzyl)thiophene (315 mg, 1.34 mmol) in anhydrous THF (5 mL) under an atmosphere of argon, LDA (0.7 mL, 2 M in a mixture of heptane, THF and ethylbenzene, 1.40 mmol) was added dropwise over a period of 10 min. After the reaction mixture was stirred at -78 °C for an additional 40 min, diethyl oxalate (0.26 mL, 1.91 mmol) was added over a period of 5 min. The resultant mixture was allowed to warm to rt and stirred overnight. The resultant solution was diluted with ethyl acetate, and neutralized with dilute HCl. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was triturated with hexane. The precipitate was filtered to provide the title compound as yellow solid.

Step E: Preparation of 2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-2- yl]butanoic acid BI(6a)

The title compound was prepared using the protocol described in Example AI(4), Step C substituting ethyl 2,4-dioxo-4-(5- phenethylthiophen-2-yl)butanoate with ethyl 2,4-dioxo-4-[5-(3- fluorobenzyl)thiophen-2-yl]butanoate. The product was recrystallized from a mixture of ether and hexane. lH NMR (CDCI3) δ 7.75 (d, J =4.1

Hz, IH), 7.35-7.25 (m, 2H), 7.05-6.90 (m, 4H), 4.20 (s, 2H).

EXAMPLE 8

2,4-dioxo-4-[5-(4-fluorobenzyl)thiophen-2-yl]butanoic acid

The title compound was prepared using the protocol described in Example BI(6a), Step A - E substituting 3-fluorobenzaldehyde with 4- fluoro-benzaldehyde in Step A. lH NMR (CDCI3) δ 7.74 (d, J =3.8 Hz,

IH), 7.21 (m, 2H), 7.03 (m, 2H), 6.91 (m, 2H), 4.18 (s, 2H).

EXAMPLE 9

2,4-dioxo-4-[5-(3-chlorobenzyl)thiophen-2-yl]butanoic acid

The title compound was prepared using the protocol described in Example BI(6a), Step A - E substituting 3-fluorobenzaldehyde with 3- chloro-benzaldehyde in Step A. lH NMR (CDCI3) δ 7.74 (d, J =4.0 Hz,

IH), 7.3-7.2 (m, 3H), 7.14 (m, IH), 6.92 (m, 2H), 4.18 (s, 2H).

EXAMPLE 10

2,4-dioxo-4-(5-benzylthiophen-2-yl)butanoic acid

The title compound was prepared using the protocol described in Example BI(6a), Step A - E substituting 3-fluorobenzaldehyde with benzaldehyde in Step A. lH NMR (CDCI3) δ 7.74 (d, J =3.9 Hz, IH), 7.38-

7.22 (m, 5H), 6.91 (m, 2H), 4.21 (s, 2H).

EXAMPLE 11

2,4-dioxo-4-(5-phenylsulfanylthiophen-2-yl)butanoic acid

Step A: Preparation of 2-acetyl-5-phenylsufanylthiophene BII(2)

A mixture of thiophenol, sodium salt (718 mg, 5,43 mmol) and 2-acetyl-5- bromothiophene (1.0 g, 4.88 mmol) in acetone (10 mL) was stirred at rt under an atmosphere of argon overnight. The resultant mixture was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with chloroform. Collection and concentration of appropriate fractions provided the title ketone. Step B: Preparation of 2,4-dioxo-4-(5-phenylsulfanylthiophen-2- yDbutanoic acid BII(4)

The title compound was prepared using the protocol described in Example AI(4), Step A and C substituting 2-acetyl-5-(phenylethynyl)- thiophene with 2-acetyl-5-phenylsufanylthiophene in Step A. The product was recrystallized from a mixture of ether and hexane. lH NMR (CDCI3) δ 7.73 (d, J =4.0 Hz, IH), 7.48 (m, 2H), 7.38 (m, 3H), 7.08 (d, J =4.0 Hz, IH), 6.88 (s, IH).

EXAMPLE 12

2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-3-yl]butanoic acid

Step A: Preparation of (4-bromothiophen-2-yl)-(3- fluorophenyDmethanol CI(2a)

The title compound was prepared using the protocol described in Example BI(6a), Step A substituting 2,5-dibromothiophene with 2,4- dibromothiophene . Step B: Preparation of 4-bromo-2-(3-fluorobenzyl)thiophene CI(3a)

To a cold (0 °C) solution of (5-bromothiophen-2-yl)-(3-fluorophenyl)- methanol (3.78 g, 13.2 mmol) and triethylsilane (8.4 mL, 52.7 mmol) in dichloromethane (60 mL), boron trifluoride etherate (2.49 mL, 19.8 mmol) was added. The resultant mixture was stirred at rt for 2 h, and treated with sat. aq. sodium bicarbonate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with hexane. Collection and concentration of appropriate fractions provide the title compound as clear colorless oil. The product was stored under argon in a freezer.

Step C: Preparation of 2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-3- yl]butanoic acid CI(6a)

The title compound was prepared using the protocol described in Example BI(6a), Step C - E substituting 2-bromo-5-(3-fluorobenzyl)- thiophene with 4-bromo-2-(3-fluorobenzyl)thiophene in Step C. lH NMR (CDCI3) δ 8.08 (d, J =1.5 Hz, IH), 7.35-7.25 (m, 3H), 7.05-6.92 (m, 2H), 6.90

(s, IH), 4.15 (s, 2H).

EXAMPLE 13

2,4-dioxo-4-[5-(4-fluorobenzyl)thiophen-3-yl]butanoic acid

The title compound was prepared using the protocol described in Example CI(6a), Step A - C substituting 3-fluorobenzaldehyde with 4- fluoro-benzaldehyde in Step A. lH NMR (CDCI3) δ 8.07 (d, J =1.5 Hz, IH), 7.26-7.18 (m, 3H), 7.05-6.92 (m, 2H), 6.89 (s, IH), 4.13 (s, 2H).

EXAMPLE 14

2,4-dioxo-4-[5-(3-chlorobenzyl)thiophen-3-yl]butanoic acid

The title compound was prepared using the protocol described in Example CI(6a), Step A - C substituting 3-fluorobenzaldehyde with 3- chloro-benzaldehyde in Step A. lH NMR (CDCI3) δ 8.09 (br s, IH), 7.28-

7.22 (m, 4H), 7.14 (m, IH), 6.90 (s, IH), 4.13 (s, 2H).

EXAMPLE 15

2,4-dioxo-4-(5-benzylthiophen-3-yl)butanoic acid

The title compound was prepared using the protocol described in Example CI(6a), Step A - C substituting 3-fluorobenzaldehyde with benzaldehyde in Step A. lH NMR (CDCI3) δ 8.07 (d, J =1.3 Hz, IH), 7.36- 7.22 (m, 6H), 6.89 (s, IH), 4.16 (s, 2H).

EXAMPLE 16

2,4-dioxo-4-(2-phenylsulfanylthiophen-4-yl)butanoic acid

Step A: Preparation of 2-phenylsulfanyl-4-bromothiophene CII(l)

To a cold (-78 °C) solution of n-butyl lithium (10.4 mL, 2.5 M in hexane, 26 mmol) in anhydrous diethyl ether (100 mL) under an atmosphere of argon, 2,4-dibromothiophene (2.81 mL, 25 mmol) was added dropwise over a period of 15 min. After the reaction mixture was stirred at -78 °C for an additional 15 min, a solution of diphenyl disulfide (5.68 g, 52 mmol) in ether (50 mL) was added over a period of 15 min. The resultant mixture was allowed to warm to rt and stirred at rt overnight. The resultant solution was diluted with ether, and washed successively with aq. NaOH, and brine. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with hexane. Collection and concentration of appropriate fractions provided the title compound.

Step B: Preparation of 4-acetyl-2-phenylsulfanylthiophene CII(2)

To a cold (-78 °C) solution of 2-phenylsulfanyl-4-bromothiophene (2.28 g, 8.4 mmol) in anhydrous diethyl ether (20 mL) under an atmosphere of argon, n-butyl lithium (5.78 mL, 1.6 M in hexane, 9.25 mmol) was added dropwise over a period of 5 min. After the reaction mixture was stirred at -78 °C for an additional 1 h, N-methoxy-N-methylacetamide (1.03 mL, 10 mmol) was added over a period of 5 min. The resultant mixture was allowed to warm to rt and stirred overnight. The resultant solution was diluted with ether, and neutralized with dilute HCl. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 20% ethyl acetate in hexane. Collection and concentration of appropriate fractions provide the title compound as clear pale yellow oil.

Step C: 2,4-dioxo-4-(2-phenylsulfanylthiophen-4-yl)butanoic acid

CII(4)

The title compound was prepared using the protocol described in Example AI(4), Step A and C substituting 2-acetyl-5-(phenylethynyl)- thiophene with 4-acetyl-2-phenylsulfanylthiophene in Step A. The product was recrystallized from a mixture of ether and hexane. lH NMR (CDCI3) δ 8.27 (d, J =1.5 Hz, IH), 7.68 (d, J =1.5 Hz, IH), 7.34-7.24

(m, 5H), 6.93 (s, IH).

EXAMPLE 17

2,4-dioxo-4-[2-(3-fluorobenzyl)thiophen-3-yl]butanoic acid

The title compound was prepared using the protocol described in Example BI(6a), Step A - E substituting 2,5-dibromothiophene with 1,2- dibromothiophene in Step A. lH NMR (CDCI3) δ 7.42 (d, J =5.5 Hz, IH),

7.32-7.24 (m, IH), 7.20 (dd, J =5.5, 1.1 Hz, IH), 7.05 (br d, J =7.5 Hz, IH), 6.98-6.92 (m, 3H), 4.57 (s, 2H).

EXAMPLE 18

2,4-dioxo-4-[2-(4-fluorobenzyl)thiophen-3-yl]butanoic acid

The title compound was prepared using the protocol described in Example BI(6a), Step A - E substituting 2,5-dibromothiophene with 1,2- dibromothiophene, and 3-fluorobenzaldehyde with 4-fluorobenzaldehyde in Step A. lH NMR (DMSO-dβ) δ 7.62 (br d, IH), 7.47 (br d, IH), 7.35 (m,

2H), 7.15 (m, 2H), 6.83 (br s, IH), 4.55 (s, 2H).

EXAMPLE 19

2,4-dioxo-4-[2-(3-chlorobenzyl)thiophen-3-yl]butanoic acid

The title compound was prepared using the protocol described in Example BI(6a), Step A - E substituting 2,5-dibromothiophene with 1,2- dibromothiophene, and 3-fluorobenzaldehyde with 3-chlorobenzaldehyde in Step A. lH NMR (DMSO-^6) δ 7.42 (br d, IH), 7.3-7.1 (m, 5H), 6.92 (br s, IH), 4.55 (s, 2H).

EXAMPLE 20

2,4-dioxo-4-[5-(benzyloxy-phenylmethyl)thiophen-2-yl]butanoic acid

Step A: Preparation of (5-bromothiophen-2-yl)-(phenyl)methanol

CI(2d)

The title compound was prepared using the protocol described in Example BI(6a), Step A substituting 3-fluorobenzaldehyde with benzaldehyde. Without further purification, the alcohol was used in the following step.

Step B: Preparation of 5-(benzyloxy-phenylmethyl)-2- bromothiophene EΙ(la)

A suspension of sodium hydride (147 mg, 6 mmol) in anhydrous DMSO (20 mL) was stirred at 60 °C under an atmosphere of argon for 1 hr. The resultant mixture was cooled to rt, (5-bromothiophen-2-yl)-(phenyl)- methanol (1.5 g, 5.57 mmol) was added. After stirring for 10 min., benzyl bromide (0.8 mL, 6.68 mmol) was added. The mixture was stirred at rt under an atmosphere of argon overnight. The product mixture was concentrated under vacuum, and the residue partitioned between ethyl ether and dilute aqueous HCl. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 5% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title compound.

Step C: Preparation of 2,4-dioxo-4-[5-(benzyloxy- phenylmethyl)thiophen-2-yl]butanoic acid EI(5a)

The title compound was prepared using the protocol described in Example BI(6a), Step C - E substituting 2-bromo-5-(3-fluorobenzyl)- thiophene with 5-(benzyloxy-phenylmethyl)-2-bromothiophene in Step C. lH NMR (CDCI3) δ 7.71 (d, J =4.0 Hz, IH), 7.5-7.3 (m, 9H), 6.94 (s, IH), 6.86 (d, J =4.0 Hz, IH), 5.62 (s, 2H), 4.63 (d, J =12.1 Hz, IH), 4.53 (d, J =12.1 Hz, IH).

EXAMPLE 21

2,4-dioxo-4-[5-(phenoxy-phenylmethyl)thiophen-2-yl]butanoic acid The title compound was prepared using the protocol described in Example EI(5a), Step A - C substituting benzyl bromide with diphenyl iodonium chloride in Step B. lH NMR (CDCI3) δ 7.73 (d, J =4.0 Hz, IH),

7.5-7.2 (m, 7H), 7.01 (d, =4.0 Hz, IH), 6.94 (s, IH), 7.00-6.95 (m, 3H), 6.41 (s, IH).

EXAMPLE 22

2,4-dioxo-4-[5-(methoxy-phenylmethyl)thiophen-2-yl]butanoic acid

The title compound was prepared using the protocol described in Example EI(5a), Step A - C substituting benzyl bromide with methyl iodide in Step B. lH NMR (CDCI3) δ 7.71 (d, J =4.0 Hz, IH), 7.42 (m, 7H),

6.94 (s, IH), 6.92 (d, J =4.0 Hz, IH), 3.42 (s, 3H).

EXAMPLE 23 2,4-dioxo-4-(5-dibenzylaminothiophen-2-yl)butanoic acid

Step A: Preparation of 2-acetyl-5-aminothiophene hydrochloride

FI(2)

A mixture of 2-acetyl-5-nitrothiophene (5.00 g, 29.2 mmol), and 5% Pt2S/C (3 g) in methanol (120 mL) was stirred under a balloon of hydrogen overnight at rt. To the resulting mixture, an ethanolic solution of hydrogen chloride gas was added (final pH ~ 2), and the solution was filtered through a pad of Celite. The filtrate was concentrated under vacuum to provide the title compound.

Step B: Preparation of 2-acetyl-5-dibenzylaminothiophene FI(3a)

A mixture of 2-acetyl-5-aminothiophene hydrochloride (700 mg, 3.94 mmol), benzyl bromide (0.94 mL, 7.88 mmol), and diisopropylethylamine (2.4 mL, 13.8 mmol) in acetonitrile (15 mL) was stirred at 60 °C for 7 days. The resulting mixture was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with chloroform - chloroform saturated with ammonia gradient.

Collection and concentration of appropriate fractions provided the title compound as red oil.

Step C: Preparation of 2,4-dioxo-4-(5-dibenzylaminothiophen-2- yDbutanoic acid FI(5a)

The title compound was prepared using the protocol described in Example AI(4), Step A and C substituting 2-acetyl-5-(phenylethynyl)- thiophene with 2-acetyl-5-dibenzylaminothiophene in Step A. The product was purified by HPLC on C-18 stationary phase. lH NMR (DMSO-ctø) δ 7.93 (d, J =4.8 Hz, IH), 7.40-7.25 (m, 10H), 6.79 (s, IH), 6.27

(d, J =4.8 Hz, IH), 4.81 (s, 4H).

EXAMPLE 24

2,4-dioxo-4-(5-benzylaminothiophen-2-yl)butanoic acid

Step A: Preparation of 2-acetyl-5-benzylaminothiophene FI(3b)

A mixture of 2-acetyl-5-aminothiophene hydrochloride (700 mg, 3.94 mmol), benzyl bromide (0.47 mL, 3.94 mmol), and diisopropylethylamine (1.72 mL, 9.85 mmol) in acetonitrile (15 mL) was stirred at 60 °C for 4 days. The resulting mixture was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with chloroform - chloroform saturated with ammonia gradient.

Collection and concentration of appropriate fractions provided the title compound. Step B: Preparation of 2,4-dioxo-4-(5-benzylaminothiophen-2- yDbutanoic acid FI(5b)

The title compound was prepared using the protocol described in Example AI(4), Step A and C substituting 2-acetyl-5-(phenylethynyl)- thiophene with 2-acetyl-5-benzylaminothiophene in Step A. The product was purified by HPLC on C-18 stationary phase. lH NMR (CD3OD) δ 7.70

(d, J =4.6 Hz, IH), 7.40-7.25 (m, 5H), 6.79 (s, IH), 6.14 (d, J =4.6 Hz, IH), 4.86 (s, 2H).

EXAMPLE 25

2,4-dioxo-4-(5-diallylaminothiophen-2-yl)butanoic acid

Step A: Preparation of 2-acetyl-5-diallylaminothiophene FI(3c)

A mixture of 2-acetyl-5-aminothiophene hydrochloride (1.5 g, 8.44 mmol), allyl bromide (7.30 mL, 84.4 mmol), and diisopropylethylamine (6.5 mL, 37.3 mmol) in acetonitrile (10 mL) was stirred at 60 °C for 3 days. The resulting mixture was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 40% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title compound as orange oil. Step B: Preparation of 2,4-dioxo-4-(5-diallylaminothiophen-2- yl)butanoic acidFI(5c)

The title compound was prepared using the protocol described in Example AI(4), Step A and C substituting 2-acetyl-5-(phenylethynyl)- thiophene with 2-acetyl-5-diallylaminothiophene in Step A. The product was purified by HPLC on C-18 stationary phase. lH NMR (CDCI3) δ 7.67

(d, J =4.6 Hz, IH), 6.76 (s, IH), 6.06 (d, J =4.6 Hz, IH), 5.85 (m, 2H), 5.3 (m, 4H), 4.05 (m, 4H).

EXAMPLE 26

2,4-dioxo-4-(5-di-n-propylaminothiophen-2-yl)butanoic acid

Step A: Preparation of 2-acetyl-5-di-n-propylaminothiophene FI(3d)

A mixture of 2-acetyl-5-diallylaminothiophene (200 mg, 0.904 mmol) and 5% Pd C (200 mg) in methanol (10 mL) was stirred under a balloon of hydrogen for 3 h. The resulting mixture was filtered through a pad of of Celite™, diatomaceous earth. The filtrate was concentrated under vacuum to provide the title compound.

Step B: Preparation of 2,4-dioxo-4-(5-di-n-propylaminothiophen-2- yl)butanoic acid FI(5d)

The title compound was prepared using the protocol described in Example AI(4), Step A and C substituting 2-acetyl-5-(phenylethynyl)- thiophene with 2-acetyl-5-di-n-propylaminothiophene in Step A. The product was purified by HPLC on C-18 stationary phase. lH NMR (DMSO-d6) 7.95 (d, J =4.8 Hz, IH), 6.81 (s, IH), 6.19 (d, J =4.8 Hz, IH),

3.38 (t, J =7.5 Hz, 4H), 1.62 (h, J =7.5 Hz, 4H), 0.89 (d, J =7.5 Hz, 6H),

EXAMPLE 27

2,4-dioxo-4-[5-(di-4-fluorobenzylamino)thiophen-2-yl]butanoic acid

Step A: Preparation of 2-acetyl-5-(di-4-fluorobenzylamino)thiophene

FI(3e)

A mixture of 2-acetyl-5-aminothiophene hydrochloride (600 mg, 3.38 mmol), 4-fluorobenzyl bromide (0.92 mL, 7.43 mmol), and Cs₂C0₃ (2.42 g, 7.43 mmol) in DMF (10 mL) was stirred at rt for 2 days. The resulting mixture was concentrated under vacuum. The residue was treated with a mixture of chloroform and aq HCl. After stirring at rt for 1 h, the pH of the mixture was adjusted to ~8. The organic extract was washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 40% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title compound.

Step B: Preparation of 2,4-dioxo-4-[5-(di-4- fluorobenzylamino)thiophen-2-yl]butanoic acid FI(5e)

The title compound was prepared using the protocol described in Example AI(4), Step A and C substituting 2-acetyl-5-(phenylethynyl)- thiophene with 2-acetyl-5-(di-4-fluorobenzylamino)thiophene in Step A. lH NMR (CDCI3) δ 7.66 (d, J =4.6 Hz, IH), 7.2-7.0 (m, 8H), 6.78 (s, IH),

6.14 (d, J =4.6 Hz, IH), 4.59 (s, 4H).

EXAMPLE 28

2,4-dioxo-4-[5-(N-benzyl-N-methylamino)thiophen-2-yl]butanoic acid

Step A: Preparation of 2-acetyl-5-(N-benzyl-N- methylamino)thiophene FΙI(la)

A solution of cesium carbonate (3.25 g, 10 mmol), N-methyl-N- benzylamine (2.58 mL, 20 mmol) and 2-acetyl-5-chlorothiophene (1.61 g, 10 mmol) in DMF (20 mL) was stirred at 60 °C under an atmosphere of argon for 9 days. The product mixture was concentrated under vacuum, and the residue was treated with a mixture of ethyl ether and dilute aqueous HCl. After stirring at rt for 1 h, pH of the solution was adjusted to ~8 with sat. aq. NaHCθ3, and organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 30% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title ketone.

Step B: Preparation of 2,4-dioxo-4-[5-(N-benzyl-N- methylamino)thiophen-2-yl]butanoic acid FII(3a)

The title compound was prepared using the protocol described in Example AI(4), Step A and C substituting 2-acetyl-5-(phenylethynyl)- thiophene with 2-acetyl-5-(benzylmethylamino)thiophene in Step A. lH NMR (CDCI3) δ 7.70 (d, J =4.6 Hz, IH), 7.4-7.2 (m, 5H), 6.77 (br s, IH), 6.10 (d, J =4.6 Hz, IH), 4.62 (s, 2H), 3.15 (s, 3H).

EXAMPLE 29

2,4-dioxo-4-(5-piperidin-l-yl-thiophen-2-yl)butanoic acid

Step A: Preparation of 2-acetyl-5-piperidin-l-yl-thiophene FII(2b)

The title compound was prepared using the protocol described in Example FII(3a), Step A and C substituting N-methyl-N-benzylamine with piperidine in Step A, and using DMSO as solvent. Step B: Preparation of 2,4-dioxo-4-(5-piperidin-l-yl-thiophen-2- yDbutanoic acid FII(3b)

The title compound was prepared using the protocol described in Example AI(4), Step A and C substituting 2-acetyl-5-(phenylethynyl)- thiophene with 2-acetyl-5-piperidin-l-yl-thiophene in Step A. lH NMR (CDCI3) δ 7.70 (d, J =4.8 Hz, IH), 6.77 (br s, IH), 6.13 (d, J =4.6 Hz, IH),

3.41 (t, J =5.7 Hz, 4H), 1.7 (m, 6H).

EXAMPLE 30

2,4-dioxo-4-[5-(benzylbenzenesulfonylamino)thiophen-2-yl]butanoic acid

Step A: Preparation of 2-acetyl-5-(benzenesulfonylamino)thiophene

FIII(l)

A solution of 2-amino-5-acetylthiophene hydrochloride (0.75 g, 4.22 mmol), benzenesulfonyl chloride (0.7 mL, 5.49 mmol) in pyridine (15 mL) was stirred at 70 °C under an atmosphere of argon for 1.5 h. The product mixture was concentrated under vacuum, and the residue was partitioned between ethyl acetate and aq. HCl. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 50% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title sulfonamide.

Step B: Preparation of 2-acetyl-5-

(benzylbenzenesulfonylamino)thiophene FIII(2)

To a solution of 2-acetyl-5-(benzenesulfonylamino)thiophene (0.192 g, 0.682 mmol) in DMSO (11.5 mL), a solution of NaHMDS (0.72 mL, IM) in THF was added. The resultant deep red solution was stirred at rt for 2.5 h, and treated with benzyl bromide (89.2 μL, 0.75 mmol), and stirred at rt overnight. The product mixture was concentrated under vacuum, and the residue was partitioned between dichloromethane and aq. HCl. The organic extract was washed with brine, dried over anhydrous MgSθ4, filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 40% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title ketone.

Step C: Preparation of 2,4-dioxo-4-[5- (benzylbenzenesulfonylamino)thiophen-2-yl]butanoic acid

FIIK4)

The title compound was prepared using the protocol described in Example AI(4), Step A and C substituting 2-acetyl-5-(phenylethynyl)- thiophene with 2-acetyl-5-(benzylbenzenesulfonylamino)thiophene in Step A. IH NMR (CDCI3) δ 7.76 (d, J =4.5 Hz, IH), 7.7-7.5 (m, 5H), 7.3 (m,

5H), 6.83 (br s, IH), 6.82 (d, =4.5 Hz, IH), 4.83 (s, 4H).

EXAMPLE 31

2,4-dioxo-4-(2-dibenzylaminothiazol-5-yl)butanoic acid

Step A: Preparation of 1,1-dibenzylthiourea GΙ(la)

A mixture of dibenzylamine (9.6 mL, 50 mmol) and tert-butyl isothiocyanate (6.34 mL, 50 mmol) in hexane (50 mL) was stirred at rt overnight. The white precipitate was isolated by filtration, and was treated with concentrated hydrochloric acid (25 mL) at 100 °C for 1.5 h. The product mixture was concentrated under vacuum. The residue was treated with 10% aq. NaHCO . The white solid precipitated was obtained by filtration, and recrystallized from a mixture of chloroform and hexane. Filtration provided the title compound as white powder.

Step B: Preparation of l,l-dibenzyl-3- dimethylaminomethylenethiourea GI(2a)

A mixture of 1,1-dibenzylthiourea (4.0 g, 15.6 mmol) and N,N- dimethylformamide dimethyl acetal (20 mL) was heated at 100 °C for 1 h. The reaction mixture was concentrated, and the residue was recrystallized from a mixture of chloroform and hexane. Filtration of the white solid provide the title compound.

Step C: Preparation of 2-dibenzylamino-5-acetylthiazole GI(3a)

A solution of l,l-dibenzyl-3-dimethylaminomethylenethiourea (1.8 g, 5.78 mmol) and bromoacetone (0.93 g, 5.78 mmol) in acetone (25 mL) was stirred in the dark for 3 days. The resultant mixture was concentrated under vacuum, and the residue partitioned between toluene and aq. sodium bicarbonate. The organic extract was washed with brine, dried over Na2Sθ4, filtered and concentrated under vacuum. The residue was recrystallized from a mixture ethyl acetate and hexane to provide the title compound as light yellow solid.

Step D: Preparation of 2,4-dioxo-4-(2-dibenzylaminothiazol-5- yl)butanoic acid GI(5a)

The title compound was prepared using the protocol described in Example AI(4), Step A and C substituting 2-acetyl-5-(phenylethynyl)- thiophene with 2-dibenzylamino-5-acetylthiazole in Step A. The product was purified by recrystallization from toluene. lH NMR (CDCI3) δ 8.19

(s, IH), 7.40-7.20 (m, 10H), 6.81 (s, IH), 4.76 (s, 4H).

EXAMPLE 32

2,4-dioxo-4-(2-benzylaminothiazol-5-yl)butanoic acid

Step A: Preparation of l-benzyl-3-dimethylaminomethylenethiourea

GI(2b)

A mixture of 1-benzylthiourea (8.3 g, 50 mmol) and N,N-dimethyl- formamide dimethyl acetal (25 mL) was heated at 100 °C for 1 h. The reaction mixture was concentrated, and the residue was recrystallized from a mixture of chloroform and hexane. Filtration of the white solid provide the title compound.

Step B: Preparation of 2-benzylamino-5-acetylthiazole GI(3b)

A solution of l-benzyl-3-dimethylaminomethylenethiourea (4.0 g, 18 mmol) and bromoacetone (2.5 g, 18.3 mmol) in acetone (75 mL) was stirred in the dark for 3 days. The white precipitated was isolated by filtration and dissolved in chloroform. The organic solution was washed successively with aq. NaHCθ3, brine, dried over Na2Sθ4, filtered and concentrated under vacuum. The residue was recrystallized from a mixture dichloromethane and hexane to provide the title compound.

Step C: Preparation of 2,4-dioxo-4-(2-benzylaminothiazol-5- yl)butanoic acid GI(5b)

The title compound was prepared using the protocol described in Example AI(4), Step A and C substituting 2-acetyl-5-(phenylethynyl)- thiophene with 2-benzylamino-5-acetylthiazole in Step A. The product was purified by recrystallization from a mixture of THF and hexane. lH NMR (DMSO-cfø) δ 9.50 (br s, IH), 8.39 (s, IH), 7.40-7.20 (m, 5H), 6.88 (s, IH), 4.57 (d, =5.4 Hz, 2H).

EXAMPLE 33

2,4-dioxo-4-(2-N-benzyl-N-methylaminothiazol-5-yl)butanoic acid

Step A: Preparation of 2-N-benzyl-N-methylamino-5-acetylthiazole GI(3c)

The title compound was prepared using the protocol described in Example GI(5a), Step A - C substituting N,N-dibenzylamine with N- benzyl-N-methylamine in Step A.

Step B: Preparation of 2,4-dioxo-4-(2-N-benzyl-N- methylaminothiazol-5-yl)butanoic acid GI(5c)

The title compound was prepared using the protocol described in Example AI(4), Step A and C substituting 2-acetyl-5-(phenylethynyl)- thiophene with 2-N-benzyl-N-methylamino-5-acetylthiazole in Step A. The product was purified by recrystallization from toluene. lH NMR (CDCI3) δ 8.01 (s, IH), 7.40-7.20 (m, 5H), 6.78 (s, IH), 4.82 (s, 2H), 3.15 (s,

3H).

EXAMPLE 34

2,4-dioxo-4-(2-dibenzylaminothiazol-4-yl)butanoic acid

Step A: Preparation of 2-dibenzylamino-4-acetylthiazole GII(3)

A suspension of 1,1-dibenzylthiourea (3.05 g, 11.9 mmol) in absolute ethanol (40 mL) was treated with l-bromo-2,3-butanedione (2.06 g, 12.5 mmol). The mixture was heated under reflux for 2 h. The resultant mixture was cooled to 0 °C, and white solid precipitated. The white solid was dissolved in ethyl acetate, and washed with sat. aq. NaHCθ3. The organic extract was washed with brine, dried over Na2Sθ4, filtered and concentrated under vacuum. The residue solidified upon standing to provide the title compound.

Step D: Preparation of 2,4-dioxo-4-(2-dibenzylaminothiazol-4- yl)butanoic acid GII(5)

The title compound was prepared using the protocol described in Example AI(4), Step A and C substituting 2-acetyl-5-(phenylethynyl)- thiophene with 2-dibenzylamino-4-acetylthiazole in Step A. The product was purified by recrystallization from a mixture of ether and hexane as orange needles. lH NMR (CDCI3) δ 7.56 (s, IH), 7.40-7.20 (m, 11H), 4.70

(s, 4H).

EXAMPLE 35 HP7 Integrase Assay: Strand Transfer Catalyzed by Recombinant Integrase and Preintegration Complexes Assays for the strand transfer activity of integrase were conducted according to Wolfe, A.L. et al., J. Virol. 70, 1424 (1996), and Farnet, CM. and Bushman F.D. (1997) Cell; 88, 483 for recombinant integrase and preintegration complexes, respectively, hereby incorporated by reference for these purposes.

Representative compounds tested in the integrase assay demonstrated IC50's less than 1 micromolar. Further, representative compounds tested in the preintegration complex assay also demonstrated ICδO's of less than 1 micromolar.

EXAMPLE 36 Assay for inhibition of HP7 replication

Assays for the inhibition of acute HP7 infection of T- lymphoid cells was conducted according to Vacca, J.P.et al., (1994), Proc. Natl. Acad. Sci. USA 91, 4906, herein incorporated by reference for these purposes.

Representative compounds tested in the present assay demonstrated IC95S of less than 10 micromolar.

EXAMPLE 37 Oral Composition

As a specific embodiment of an oral composition of a compound of this invention, 50 mg of a compound of the present invention is formatted with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.

While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adoptions, or modifications, as come within the scope of the following claims and their equivalents.

Claims

WHAT IS CLAIMED:

1. A compound of structural formula (I):

(I) or tautomers or pharmaceutically acceptable salts thereof, wherein:

A is a five-membered heteroaromatic ring containing 1 sulfur atom and

1 8

0 or 1 nitrogen atoms and substituted on carbon by R , R and R ; the heteroaromatic ring may optionally be fused with a phenyl ring or a C4-6 cycloalkyl ring, or with two six membered rings to form:

R is selected from:

(1) -H,

(2) -C₁ 5 alkyl,

(3) -CFg,

(4) -halo,

(5) -N0₂,

(6) -N(R⁴)(R⁵),

(7) -R6,

(8) -C₂_5 alkenyl-R ,

(9) -C₂_₅ alkynyl-R ,

(10) -0-R6,

(11) -O-Ci-6 alkyl, and

(12) -C(0)CH2C(0)C(0)OR7; 2 R is selected from:

(2) -E³,

(3) -C₁ alkyl, g

(4) -CI__Q alkyl substituted with R ,

(5) -O-R⁶,

(6) -O-C^_Q alkyl-OR⁶,

(7) -S(0)n-R⁶,

(8) -C_╬╗_₆ alkyl (OR⁶)(R⁴) ,

(9) -C₁ alkyl (OR⁴)(R⁶) ,

(10) -C₀_₆ alkyl-N(R⁴)(R⁶) ,

(11) -C^e alkyl S(0)n-R⁶,

(12) -C₀.₆ alkyl C(0)-R⁶,

(13) -C₀_₆ alkyl C(S)-R⁶,

(14) -C₀.₆ alkyl NR⁴C(0)-R⁶, and

(15) -C₀_₆ alkyl-C(0)N(R⁴)(R⁵); g each R is independently selected from:

(b) C╧ç.₆ alkyl,

(c) C₁ alkyloxy-,

(d) phenyl,

(e) -CFg,

(f "OCFg,

(g) -CN,

(h) hydroxy,

(i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C₁ alkyl, (iii) -CF₃, and

(iv) hydroxy;

(2) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms selected from oxygen, nitrogen or sulfur, unsubstituted or substituted with 0 to 5 substituents selected from:

(a) halogen,

(b) C₁ alkyl,

(c) C^g alkyloxy-, (d) -CF₃,

(e) -OCFg,

(f) -CN,

(g) =0, and (h) hydroxy;

(3) unsubstituted or substituted hexahydrothieno[3,4- d]imidazolyl with one or two substituents selected from:

(a) oxo,

(b) halogen, (c) C^e alkyl,

(d) C^g alkyloxy-,

(e) -CF₃,

(f) "OCFg,

(g) -CN, and (h) hydroxy;

(4) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, or 2 heteroatoms selected from oxygen, nitrogen and sulfur, fused with a phenyl ring; wherein the ring system is unsubstituted or substituted on a nitrogen or carbon atom by 1 to 3 substituents selected from: (a) -halogen,

(b) -C_╬╗_₆ alkyl,

(0 -C_l alkyloxy-,

(d) -CFg,

(e) -OCFg,

(f) -CN, and

(g) -hydroxy;

(5) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms selected from oxygen, nitrogen or sulfur, fused with a phenyl ring, unsubstituted or substituted withl or 2 substituents selected from:

(a) halogen,

(b) C^_Q alkyl,

(c) C₁ alkyloxy-,

(d) "CFg,

(e) -OCFg,

(f) -CN,

(g) =0, and

(h) hydroxy;

(6) a 5 to 6 membered ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, containing 2 or 3 double bonds, unsubstituted or substituted with 1 or 2 substituents selected from: (a) halogen, (b) C₁ alkyl,

(c) C-^_Q alkyloxy-,

(d) -CFg,

(f) -CN,

(g) =0, and

(h) hydroxy:

^> i,⁴ i iss independently se

(1) -H,

(2) -C-L_.3 alkyl,

(3) -CFg 3,'

(4) -R³,

(5) -C₂.g alkenyl,

(6) -C^g alkyl-R³,

(7) -C₂.g alkenyl-R ,

(8) -S(0)_n-R³, and

(9) -C(0)-R³;

,5 . t is independently sele

(1) -H,

(2) -C┬▒_₃ alkyl,

(3) -CFg,

(4) -R³,

(5) -C₂.₃ alkenyl,

(6) -C^g alkyl-R³,

(7) -C .g alkenyl-R ,

(8) -S(0)_n-R³, and

(9) -C(0)-R³;

each R is independently selected from:

(1) -C^g alkyl-R³, and

(2) -R³;

R7 is selected from: (1) -H, and

(2) Ci-6 alkyl;

R8 is selected from: (1) -H, and

(2) Cl-6 alkyl-oxy-, and

(3) Ci-6 alkyl-;

2. The compound according to Claim 1, and tautomers and pharmaceutically acceptable salts thereof, wherein: A is selected from:

(1) thienyl,

(2) thiazolyl,

(3)

(4)

(5)

R is selected from:

(1) -H,

(2) -CHg,

(3) -CFg,

(4) -halo, (5) -N0₂

(6) -N(R⁴)(R⁵),

(7) -phenyl,

(a) halogen,

(b) C_╬╗_₆ alkyl,

(0 C^g alkyloxy-,

(d) phenyl,

(e) -C g,

(f) -OCFg,

(g) -CN,

(h) hydroxy,

(i) phenyloxy, and

(j) substituted phenyloxy with 1, 2, or 3 substituent selected from:

(i) halogen,

(ii) C₁ alkyl,

(iii) -CF₃, and

(iv) hydroxy;

(9) phenyl C^.g alkyl-,

(10) substituted phenyl C^ alkyl- substituted with 1 or 2 substituents independently selected from:

(a) halogen,

(b) C^_Q alkyl,

(c) C₁ alkyloxy-,

(d) phenyl,

(e) -CFg,

(f) "OCFg,

(g) -CN,

(h) hydroxy,

(i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen,

(ii) C₁ alkyl,

(iii) -CF₃, and

(iv) hydroxy;

(11) -C₂_5 alkenyl-R , g

(12) -C₂_ alkynyl-R , and

(13) -C(0)CH2C(0)C(0)OR7_;

select ed from:

(1) -H,

(2) -R³,

(3) -C_{l 6} alkyl, g

(4) -C-L_g alkyl substituted with R ,

(5) -O-R⁶,

(6) -O-C^_Q alkyl-OR⁶,

(7) -S(0)n-R⁶,

(8) -C₁ alkyl (OR⁶)(R⁴) ,

(9) -C₁ alkyl (OR⁴)(R⁶) ,

(10) -C₀.₆ alkyl-N(R⁴)(R⁶) ,

(ID -C^g alkyl S(0)n-R⁶,

(12) -C₀.₆ alkyl C(0)-R⁶,

(13) -C₀_₆ alkyl C(S)-R⁶,

(14) -C₀.₆ alkyl NR⁴C(0)-R⁶, and

(15) -C₀.₆ alkyl-C(0)N(R⁴)(R⁵); g each R is independently selected from: (1) phenyl; (2) substituted phenyl with 1, 2, or 3 substituents independently selected from: (a) halogen, (b) C-^g alkyl,

(0 C_{l Q} alkyloxy-,

(d) phenyl,

(e) -CFg,

(f) "OCFg,

(g) -CN,

(h) hydroxy,

(i) phenyloxy, and

(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:

(i) halogen,

(ii) C-^g alkyl,

(iii) -CF₃, and

(iv) hydroxy;

(3) thienyl;

(a) halogen,

(b) C₁ alkyl,

(c) C₁.₆ alkyloxy-,

(d) phenyl,

(e) -CFg,

(f) -OCFg,

(g) -CN,

(h) hydroxy,

(i) phenyloxy, and

(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:

(i) halogen,

(ii) C₁ alkyl,

(iii) -CF₃, and

(iv) hydroxy; (5) pyridyl;

(a) halogen, (b) C^g alkyl,

(c) C^g alkyloxy-,

(d) phenyl,

(e) -CF₃,

(f) -OCFg, (g) -CN,

(h) hydroxy, (i) phenyloxy, and

(j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen,

(ii) C^g alkyl, (iii) -CF₃, and (iv) hydroxy;

(7) imidazolyl; (8) substituted imidazolyl substituted on a carbon atom with one or two substituents independently selected from:

(a) halogen,

(b) C^g alkyl,

(c) C^g alkyloxy-, (d) phenyl,

(e) -CF₃,

(f) -OCFg,

(g) -CN, (h) hydroxy, (i) phenyloxy, and

(j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C^g alkyl,

(iii) -CF₃, and

(iv) hydroxy;

(9) pyrrolyl;

(a) halogen,

(b) C _₆ alkyl,

(c) C_j. alkyloxy-,

(d) phenyl,

(e) "CFg,

(f⁾ -OCFg,

(g) -CN,

(h) hydroxy,

(i) phenyloxy, and

(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:

(i) halogen,

(ii) C^g alkyl,

(iii) -CF₃, and

(iv) hydroxy;

(11) pyrazolyl;

(a) halogen,

(b) C₁ alkyl,

(c) C-^ alkyloxy-,

(d) phenyl,

(e) -CFg,

(f) "OCFg,

(g) -CN,

(h) hydroxy, (i) phenyloxy, and

(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:

(i) halogen,

(ii) C^g alkyl,

(iii) -CF₃, and

(iv) hydroxy;

(13) ^C3-6 cycloalkyl;

(a) halogen,

(b) C₁ alkyl,

(c) C-^g alkyloxy-,

(d) -CFg,

(e) "OCFg,

(f⁾ -CN,

(g) =0, and

(h) hydroxy;

(15) piperidinyl;

(16) substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from:

(a) halogen,

(b) C-L.g alkyl,

(c) C₁.₆ alkyloxy-,

(d) -CFg,

(e) -OCFg,

(f) -CN,

(g) =0, and

(h) hydroxy;

(17) morpholinyl;

(18) substituted morpholinyl substituted at a carbon or nitroge atom with 1 or 2 independently selected from: (a) halogen, (b) C^g alkyl,

(c) C-^g alkyloxy-,

(d) "CFg,

(e) -OCFg,

(f) -CN,

(g) =0, and

(h) hydroxy;

(19) naphthyl,

(a) -halogen,

(b) -Ci.g alkyl,

(c) -C-L.g alkyloxy-,

(d) -CFg,

(e) -OCFg,

(f) -CN, and

(g) -hydroxy;

(21) indolyl;

(a) -halogen,

(b) -C₁ alkyl,

(c) -C^g alkyloxy-,

(d) -CFg,

(e) -OCFg,

(f) -CN, and

(g) -hydroxy;

(23) ^C3-6 cycloalkyl fused with a phenyl ring

(24) substituted Co.c cycloalkyl fused with a phenyl ring substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, (b) C^g alkyl,

(c) C^g alkyloxy-,

(d) -CFg,

(e) -OCFg,

(f) -CN,

(g) =0, and

(h) hydroxy;

L. IS independently selected

(1) -H,

(2) -C-L.g alkyl,

(3) "CFg,

(4) -R³,

(5) -C₂.g alkenyl,

(6) -C^g alkyl-R³,

(7) -C₂.g alkenyl-R ,

(8) -S(0)_n-R³, and

(9) -C(0)-R³;

each R is independently selected from: i-) -n,

(2) -C-^ alkyl,

(3) "CFg,

(4) -R³,

(5) -C₂.₃ alkenyl,

(6) -C^g alkyl-R³,

(7) -C₂.g alkenyl-R ,

(8) -S(0)_n-R³, and

(9) -C(0)-R³;

each R is independently selected from: (1) -C^g alkyl-R⁰, and

(2) -R³;

R7 is H;

R╬┤ is selected from hydrogen, methyl and methoxy;

3. The compound according to Claim 2 , and tautomers and pharmaceutically acceptable salts thereof, wherein:

A is selected from:

(1) thienyl,

(2) thiazolyl,

(3)

(4)

R is selected from:

(1) -H,

(2) -CHg,

(3) -CFg,

(4) -halo,

(5) -N0₂,

(6) -N(R )(R⁵)

(7) -phenyl, (8) substituted phenyl substituted with 1 or 2 substituents independently selected from:

(a) halo,

(b) methyl, and (c) methoxy,

(9) phenyl C^g alkyl-,

(10) substituted phenyl C^_.g alkyl- substituted with 1 or 2 substituents independently selected from:

(a) halo, (b) methyl, and

(c) methoxy, and

(ID -C₂_5 alkenyl-R ;

R is selected from:

(1) -H,

(2) -R³,

(3) -C₁ alkyl,

(4) -C^.g alkyl substituted with B

(5) -O-R⁶,

(6) -S(0)n-R⁶,

(7) -C^g alkyl (OR⁶)(R⁴) ,

(8) -C₁ alkyl (OR⁴)(R⁶) ,

(9) -C₀_g alkyl-N(R⁴)(R⁶) ,

(10) -C^g alkyl S(0)n-R⁶,

(11) -C₀.₆ alkyl C(0)-R⁶,

(12) -C₀_g alkyl NR⁴C(0)-R⁶, and

(13) -C₀_g alkyl-C(0)N(R⁴)(R⁵); g each R is independently selected from: (1) phenyl;

(2) substituted phenyl with 1, 2, or 3 substituents independently selected from: (a) halogen,

(b) C╬╣_g alkyl,

(c) C-^g alkyloxy-,

(d) phenyl,

(e) -CFg,

(f) -OCFg,

(g) -CN,

(h) hydroxy,

(i) phenyloxy, and

(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:

(i) halogen,

(ii) Ci.g alkyl,

(iii) -CF₃, and

(iv) hydroxy;

(3) thienyl;

(a) halogen,

(b) C╬╣_g alkyl,

(c) C_j. alkyloxy-,

(d) phenyl,

(e) "CFg,

(f) -OCFg,

(g) -CN,

(h) hydroxy,

(i) phenyloxy, and

(ii) C_l alkyl, (iii) -CF₃, and (iv) hydroxy; (5) pyridyl;

(a) halogen, (b) C₁ alkyl,

(c) C^g alkyloxy-,

(d) phenyl,

(e) -CF₃,

(f) -OCFg, (g) -CN,

(h) hydroxy,

(i) phenyloxy, and

(ii) C₁ alkyl,

(iii) -CF₃, and

(iv) hydroxy;

(7) imidazolyl; (8) pyrrolyl;

(9) pyrazolyl;

(10) Cg.₆ cycloalkyl,

(b) C₁ alkyl,

(c) C^g alkyloxy-,

(d) -CFg,

(e) -OCFg, (f) -CN,

(g) =0, and (h) hydroxy;

(12) piperidinyl; (13) substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from:

(a) halogen,

(b) C^g alkyl, (c) C-L.g alkyloxy-,

(d) -CFg,

(e) -OCFg,

(f) -CN,

(g) =0, and (h) hydroxy;

(14) morpholinyl;

(15) naphthyl;

(16) indolyl; and

(17) Cg.g cycloalkyl fused with a phenyl ring;

4 each R is independently selected from:

(1) -H,

(2) -C-L.3 alkyl,

(3) -CFg,

(4) -R³,

(5) -C₂.g alkenyl,

(6) -C^g alkyl-R³, and

(7) -S(0)_n-R³; and

5 each R is independently selected from:

(1) -H,

(2) -C^g alkyl,

(3) -CFg,

(4) -R³, (5) -C₂_g alkenyl,

(6) -C^g alkyl-R³, g

(7) -C₂.g alkenyl-R , and

(8) -S(0)_n-R³;

each R is independently selected from:

(1) -C-L.3 alkyl-R³, and

(2) -R³;

R7 is H;

R8 is H; and

each n is independently selected from 0, 1 and 2.

4. The compound according to Claim 1 of structural formula:

and tautomers and pharmaceutically acceptable salts thereof, wherein:

2 R is selected from:

(1) -H,

(2) -R³,

(3) -C^g alkyl,

3

(4) -C-^g alkyl substituted with R

(5) -O-R⁶,

(6) -S(0)n-R⁶,

(7) -C₁ alkyl (OR⁶)(R⁴) ,

(8) -C^g alkyl (OR⁴)(R⁶) ,

(9) -C₀_g alkyl-N(R⁴)(R⁶) ,

(10) -C^g alkyl S(0)n-R⁶, (11) -C₀.₆ alkyl C(0)-R⁶,

(12) -C₀_g alkyl NR⁴ C(0)-R⁶ , and

(13) -C₀_g alkyl-C(0)N(R⁴)(R⁵); g each R is independently selected from:

(1) phenyl,

(a) halogen selected from -F, -Cl, -Br,

(b) CHg,

(c) methoxy-,

(d) phenyl,

(e) -CFg,

(f) -OCFg,

(g) -CN,

(h) hydroxy,

(i) phenyloxy, and

(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:

(i) halogen selected from -F, -Cl, -Br,

(ii) -CHg,

(iii) -CF₃, and

(iv) hydroxy;

(3) thienyl,

(5) pyridyl,

(7) imidazolyl,

(8) pyrrolyl,

(9) pyrazolyl,

(10) Cg.₆ cycloalkyl,

(12) piperidinyl,

(14) morpholinyl,

(15) naphthyl,

(16) indolyl, and (17) Cg.g cycloalkyl fused with a phenyl ring;

each R is independently selected from:

(1) -H, (2) -C ₃ alkyl,

(3) -CF₃,

(4) -E³,

(5) -C₂.₃ alkenyl,

(6) -C_j^.g alkyl-R , and

(7) -S(0)_n-R³,

each R is independently selected from:

(1) -H,

(2) -C-^g alkyl,

(3) -CFg,

(4) -R³,

(5) -C₂.g alkenyl,

(6) -C^g alkyl-R³,

(7) -C₂.g alkenyl-R , and

(8) -S(0)_n-R³,

each R is independently selected from:

(1) -Ci-3 alkyl-R , and

(2) -R ; and

each n is independently selected from 0, 1 and 2

5. The compound according to Claim 4 selected from:

(1)

(2)

(3)

(4)

(5)

(6)

(7)

(8)

(9)

(10)

(11)

(12)

(13)

(14)

(15)

(16)

(17)

(18)

(19)

(20)

(21)

(22)

(23)

(24)

(25) (26)

(27)

(28)

and tautomers and pharmaceutically acceptable salts thereof.

6. The compound according to Claim 1 of structural formula:

and tautomers and pharmaceutically acceptable salts thereof, wherein:

2 R is selected from:

(1) -H,

(2) -R³, (3) -C^g alkyl, g

(4) -C╬╣_g alkyl substituted with R ,

(5) -O-R⁶,

(6) -S(0)n-R⁶, (7) -C^g alkyl (OR⁶)(R⁴) ,

(8) -C^g alkyl (OR⁴)(R⁶) ,

(9) -C₀_g alkyl-N(R⁴)(R⁶) ,

(10) -C₁ alkyl S(0)n-R⁶,

(11) -C_0.6 alkyl C(0)-R⁶, (12) -C₀.₆ alkyl NR C(0)-R⁶, and

(13) -C₀.₆ alkyl-C(0)N(R⁴)(R⁵); g each R is independently selected from:

(1) phenyl; (2) substituted phenyl with 1, 2, or 3 substituents independently selected from:

(a) halogen selected from -F, -Cl, -Br,

(b) CHg,

(c) methoxy-, (d) phenyl,

(e) -CFg,

(f) "OCFg,

(g) -CN, (h) hydroxy, (i) phenyloxy, and

(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:

(i) halogen selected from -F, -Cl, -Br, (ii) -CH₃, (iii) -CF₃, and

(iv) hydroxy; (3) thienyl, (5) pyridyl,

(7) imidazolyl,

(8) pyrrolyl,

(9) pyrazolyl,

(10) C₃. cycloalkyl,

(12) piperidinyl,

(14) morpholinyl,

(15) naphthyl,

(16) indolyl, and

(17) Cg.g cycloalkyl fused with a phenyl ring;

4 each R is independently selected from:

(1) -H,

(2) -C-L.3 alkyl,

(3) -CF₃,

(4) -R³,

(5) -C₂_g alkenyl,

(6) -C╬╣_3 alkyl-R , and

(7) -S(0)_n-R³,

,5 . 1 is independently selected

(1) -H,

(2) -C^ alkyl,

(3) -CFg,

(4) -R³,

(5) -C₂-3 alkenyl,

(6) -C^g alkyl-R³,

3

(7) -C₂_3 alkenyl-R , and

(8) -S(0)_n-R³,

each R is independently selected from: (1) -C^g alkyl-R⁰, and

(2) -R³;

R8 is selected from methyl and hydrogen; and

each n is independently selected from 0, 1 and 2.

7. The compound according to Claim 6 selected from:

(1)

(2)

(3)

(4)

(5)

(6)

(7)

and tautomers and pharmaceutically acceptable salts thereof.

8. The compound according to Claim 1 of structural formula:

and tautomers and pharmaceutically acceptable salts thereof, wherein: R is selected from:

(1) -H, (2) -R³,

(3) -Ci.g alkyl,

(4) -C^g alkyl substituted with ╬ò

(5) -O-R⁶,

(6) -S(0)n-R⁶,

(7) -Ci.6 alkyl (OR⁶)(R⁴) ,

(8) -C^g alkyl (OR⁴)(R⁶) ,

(9) -C₀_g alkyl-N(R⁴)(R⁶) ,

(10) -C_lJ╬▓ alkyl S(0)n-R⁶, (11) -C_0.6 alkyl C(0)-R⁶,

(12) -C₀.g alkyl NR⁴C(0)-R⁶, and

(13) -C₀.₆ alkyl-C(0)N(R⁴)(R⁵);

each R is independently selected from:

(1) phenyl,

(a) halogen selected from -F, -Cl, -Br,

(b) CH₃,

(c) methoxy-,

(d) phenyl,

(e) -CF₃,

(f) -OCFg,

(g) -CN,

(h) hydroxy,

(i) phenyloxy, and

(j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen selected from -F, -Cl, -Br,

(╧ï) -CH₃,

(iii) -CFg, and

(iv) hydroxy;

(3) thienyl,

(5) pyridyl,

(7) imidazolyl,

(8) pyrrolyl,

(9) pyrazolyl,

(10) Cg.₆ cycloalkyl,

(12) piperidinyl,

(14) morpholinyl,

(15) naphthyl,

(16) indolyl, and (17) Cg_.g cycloalkyl fused with a phenyl ring;

4 each R is independently selected from:

(1) -H,

(2) -C-L.3 alkyl,

(3) -CFg,

(4) -R³,

(5) -C₂_g alkenyl,

(6) -C_]_.g alkyl-R , and

(7) -S(0)_n-R³,

, .5 i ΓÇós independently selected

(1) -H,

(2) -C-L.3 alkyl,

(3) -CFg,

(4) -R³,

(5) -C₂_g alkenyl,

(6) -C^g alkyl-R³, g

(7) -C₂.g alkenyl-R , and

(8) -S(0)_n-R³,

each R is independently selected from:

(1) -C^g alkyl-R³, and

(2) -R³; and

each n is independently selected from 0, 1 and 2.

9. The compound according to Claim 8 selected from:

(1)

(2)

(3)

(4)

(5)

and tautomers and pharmaceutically acceptable salts thereof.

10. The compound according to Claim 1 of structural formula:

(1) -H,

(2) -R³,

(3) -C-L.g alkyl,

(4) -C^.g alkyl substituted with E

(5) -O-R⁶,

(6) -S(0)n-R⁶,

(7) -C^g alkyl (OR⁶)(R⁴) ,

(8) -C^g alkyl (OR⁴)(R⁶) ,

(9) -C₀_g alkyl-N(R⁴)(R⁶) ,

(10) -C^g alkyl S(0)n-R⁶,

(11) -C₀.₆ alkyl C(0)-R⁶,

(12) -C₀.₆ alkyl NR⁴C(0)-R⁶, and

(13) -C₀_g alkyl-C(0)N(R⁴)(R⁵); g each R is independently selected from:

(1) phenyl,

(a) halogen selected from -F, -Cl, -Br, (b) CH₃,

(c) methoxy-,

(d) phenyl,

(e) -CF₃, (f) "OCFg,

(g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:

(i) halogen selected from -F, -Cl, -Br,

(ii) -CH₃,

(iii) -CFg, and (iv) hydroxy;

(3) thienyl,

(5) pyridyl,

(7) imidazolyl,

(8) pyrrolyl, (9) pyrazolyl,

(10) Cg.₆ cycloalkyl,

(12) piperidinyl,

(14) morpholinyl,

(15) naphthyl, (16) indolyl, and

(17) Cg.g cycloalkyl fused with a phenyl ring

4 each R is independently selected from:

(1) -H, (2) -C^g alkyl,

(3) -CFg,

(4) -R³,

(5) -C .g alkenyl,

(6) -C^g alk yyll-R^d, and (7) -S(0)_n-R

5 each R is independently selected from: (1) -H,

(2) -C^g alkyl,

(3) -CFg,

(4) -R³,

(5) -C₂_g alkenyl,

(6) -C^g alkyl-R³,

(7) -C₂.g alkenyl-R and

(8) -S(0)_n-R³,

each R is independently selected from:

(1) -C^g alkyl-R³, and

(2) -R³; and

each n is independently selected from 0, 1 and 2.

11. The compound according to Claim 10 selected from:

(1)

(2)

(3) (4)

(5)

(6)

(7)

and tautomers and pharmaceutically acceptable salts thereof.

12. The compound according to Claim 1 selected from:

(1)

(2)

(3)

(4)

(6)

and tautomers and pharmaceutically acceptable salts thereof.

13. The compound according to Claim 1 selected from:

(I) 2,4-dioxo-4-(5-phenethylthiophen-2-yl)butanoic acid, (2) ethyl 2,4-dioxo-4-(5-phenethylthiophen-2-yl)butanoate,

(3) 2,4-dioxo-4-(5-benzyloxythiophen-2-yl)butanoic acid,

(4) 2,4-dioxo-4-[5-(3-fluorobenzyloxy)thiophen-2-yl]butanoic acid,

(5) 2,4-dioxo-4-[5-(4-fluorobenzyloxy)thiophen-2-yl]butanoic acid,

(6) 2,4-dioxo-4-[5-(3,4-difluorobenzyloxy)thiophen-2-yl]butanoic acid,

(7) 2,4-dioxo-4-[5-(pyridin-2-ylmethyloxy)thiophen-2-yl]butanoic acid, (8) 2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-2-yl]butanoic acid,

(9) ethyl 2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-2-yl]butanoate,

(10) 2,4-dioxo-4-[5-(4-fluorobenzyl)thiophen-2-yl]butanoic acid,

(II) 2,4-dioxo-4-[5-(3-chlorobenzyl)thiophen-2-yl]butanoic acid, (12) 2,4-dioxo-4-(5-benzylthiophen-2-yl)butanoic acid, (13) 2,4-dioxo-4-(5-phenylsulfanylthiophen-2-yl)butanoic acid,

(14) 2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-3-yl]butanoic acid, (15 2,4-dioxo-4-[5-(4-fluorobenzyl)thiophen-3-yl]butanoic acid, (16 2,4-dioxo-4-[5-(3-chlorobenzyl)thiophen-3-yl]butanoic acid, (17 2,4-dioxo-4-(5-benzylthiophen-3-yl)butanoic acid, (18 2,4-dioxo-4-(2-phenylsulfanylthiophen-4-yl)butanoic acid, (19 2,4-dioxo-4-[2-(3-fluorobenzyl)thiophen-3-yl]butanoic acid, (20 2,4-dioxo-4-[2-(4-fluorobenzyl)thiophen-3-yl]butanoic acid, (21 2,4-dioxo-4-[2-(3-chlorobenzyl)thiophen-3-yl]butanoic acid, (22 2,4-dioxo-4-[5-(benzyloxy-phenylmethyl)thiophen-2- yl]butanoic acid,

(23 2,4-dioxo-4-[5-(phenoxy-phenylmethyl)thiophen-2- yl]butanoic acid,

(24; 2,4-dioxo-4-[5-(methoxy-phenylmethyl)thiophen-2- yl]butanoic acid,

(25 2,4-dioxo-4-(5-dibenzylaminothiophen-2-yl)butanoic acid, (26 2,4-dioxo-4-(5-benzylaminothiophen-2-yl)butanoic acid, (27 2,4-dioxo-4-(5-diallylaminothiophen-2-yl)butanoic acid, (28: 2,4-dioxo-4-(5-di-n-propylaminothiophen-2-yl)butanoic acid, (29 2,4-dioxo-4-[5-(di-4-fluorobenzylamino)thiophen-2- yl]butanoic acid,

(30 2,4-dioxo-4-[5-(N-benzyl-N-methylamino)thiophen-2- yl]butanoic acid,

(31 2,4-dioxo-4-(5-piperidin-l-yl-thiophen-2-yl)butanoic acid, (32 2,4-dioxo-4-[5-(benzylbenzenesulfonylamino)thiophen-2- yl]butanoic acid,

(33 2,4-dioxo-4-(2-dibenzylaminothiazol-5-yl)butanoic acid, (34; 2,4-dioxo-4-(2-benzylaminothiazol-5-yl)butanoic acid, (35 2,4-dioxo-4-(2-N-benzyl-N-methylaminothiazol-5-yl)butanoic acid,

(36) 2,4-dioxo-4-(2-dibenzylaminothiazol-4-yl)butanoic acid, and tautomers and pharmaceutically acceptable salts thereof.

14. The compound according to Claim 13 selected from:

(1) 2,4-dioxo-4-(5-phenethylthiophen-2-yl)butanoic acid,

(2) 2,4-dioxo-4-(5-benzyloxythiophen-2-yl)butanoic acid, (3) 2,4-dioxo-4-[5-(3-fluorobenzyloxy)thiophen-2-yl]butanoic acid,

(4) 2,4-dioxo-4-[5-(4-fluorobenzyloxy)thiophen-2-yl]butanoic acid, (5) 2,4-dioxo-4-[5-(3,4-difluorobenzyloxy)thiophen-2-yl]butanoic acid,

(6) 2,4-dioxo-4-[5-(pyridin-2-ylmethyloxy)thiophen-2-yl]butanoic acid,

(7) 2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-2-yl]butanoic acid, (8) 2,4-dioxo-4-[5-(4-fluorobenzyl)thiophen-2-yl]butanoic acid,

(9) 2,4-dioxo-4-[5-(3-chlorobenzyl)thiophen-2-yl]butanoic acid,

(10) 2,4-dioxo-4-(5-benzylthiophen-2-yl)butanoic acid,

(11) 2,4-dioxo-4-(5-phenylsulfanylthiophen-2-yl)butanoic acid,

(12) 2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-3-yl]butanoic acid, (13) 2,4-dioxo-4-[5-(4-fluorobenzyl)thiophen-3-yl]butanoic acid,

(14) 2,4-dioxo-4-[5-(3-chlorobenzyl)thiophen-3-yl]butanoic acid,

(15) 2,4-dioxo-4-(5-benzylthiophen-3-yl)butanoic acid,

(16) 2,4-dioxo-4-(2-phenylsulfanylthiophen-4-yl)butanoic acid,

(17) 2,4-dioxo-4-[2-(3-fluorobenzyl)thiophen-3-yl]butanoic acid, (18) 2,4-dioxo-4-[2-(4-fluorobenzyl)thiophen-3-yl]butanoic acid,

(19) 2,4-dioxo-4-[2-(3-chlorobenzyl)thiophen-3-yl]butanoic acid,

(20) 2,4-dioxo-4-[5-(benzyloxy-phenylmethyl)thiophen-2- yljbutanoic acid,

(21) 2,4-dioxo-4-[5-(phenoxy-phenylmethyl)thiophen-2- yl]butanoic acid,

(22) 2,4-dioxo-4-[5-(methoxy-phenylmethyl)thiophen-2- yl]butanoic acid,

(23) 2,4-dioxo-4-(5-dibenzylaminothiophen-2-yl)butanoic acid,

(24) 2,4-dioxo-4-(5-benzylaminothiophen-2-yl)butanoic acid, (25) 2,4-dioxo-4-(5-diallylaminothiophen-2-yl)butanoic acid,

(26) 2,4-dioxo-4-(5-di-n-propylaminothiophen-2-yl)butanoic acid,

(27) 2,4-dioxo-4-[5-(di-4-fluorobenzylamino)thiophen-2- yl]butanoic acid,

(28) 2,4-dioxo-4-[5-(N-benzyl-N-methylamino)thiophen-2- yl]butanoic acid, (29) 2,4-dioxo-4-(5-piperidin-l-yl-thiophen-2-yl)butanoic acid,

(30) 2,4-dioxo-4-[5-(benzylbenzenesulfonylamino)thiophen-2- yl]butanoic acid,

(31) 2,4-dioxo-4-(2-dibenzylaminothiazol-5-yl)butanoic acid,

(32) 2,4-dioxo-4-(2-benzylaminothiazol-5-yl)butanoic acid,

(33) 2,4-dioxo-4-(2-N-benzyl-N-methylaminothiazol-5-yl)butanoic acid,

(34) 2,4-dioxo-4-(2-dibenzylaminothiazol-4-yl)butanoic acid, and tautomers and pharmaceutically acceptable salts thereof.

15. The compound according to Claim 14 selected from:

(1) 2,4-dioxo-4-[5-(3-chlorobenzyl)thiophen-2-yl]butanoic acid,

(2) 2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-3-yl]butanoic acid,

(3) 2,4-dioxo-4-[5-(4-fluorobenzyl)thiophen-3-yl]butanoic acid, (4) 2,4-dioxo-4-[5-(3-chlorobenzyl)thiophen-3-yl]butanoic acid,

(5) 2,4-dioxo-4-(5-benzylthiophen-3-yl)butanoic acid,

(6) 2,4-dioxo-4-(2-phenylsulfanylthiophen-4-yl)butanoic acid, XII(4)

(7) 2,4-dioxo-4-[2-(3-chlorobenzyl)thiophen-3-yl]butanoic acid, (8) 2,4-dioxo-4-[5-(benzyloxy-phenylmethyl)thiophen-2- yl]butanoic acid,

(9) 2,4-dioxo-4-[5-(phenoxy-phenylmethyl)thiophen-2- yl]butanoic acid,

(10) 2,4-dioxo-4-(5-dibenzylaminothiophen-2-yl)butanoic acid, (11) 2,4-dioxo-4-(5-diallylaminothiophen-2-yl)butanoic acid,

(12) 2,4-dioxo-4-[5-(di-4-fluorobenzylamino)thiophen-2- yl]butanoic acid,

(13) 2,4-dioxo-4-[5-(N-benzyl-N-methylamino)thiophen-2- yl]butanoic acid, (14) 2,4-dioxo-4-(2-dibenzylaminothiazol-5-yl)butanoic acid, and

(15) 2,4-dioxo-4-(2-N-benzyl-N-methylaminothiazol-5-yl)butanoic acid, and tautomers and pharmaceutically acceptable salts thereof.

16. A pharmaceutical composition useful for inhibiting HIV integrase, comprising an effective amount of a compound according to Claim 1 and a pharmaceutically acceptable carrier.

17. The pharmaceutical composition of Claim 16, useful for treating infection by HIV, or for treating AIDS or ARC.

18. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Claim 1 in combination with a therapeutically effective amount of an AIDS treatment agent selected from

(1) an AIDS antiviral agent,

(2) an anti-infective agent, and

(3) an immunomodulator.

19. The composition of Claim 18 wherein the antiviral agent is an HIV protease inhibitor.

20. The composition of Claim 19 wherein the HIV protease inhibitor is N-(2(R)-hydroxy-l-(S)-indanyl)-2(R)-phenylmethyl- 4(S)-hydroxy-5-(l-(4-(3-pyridylmethyl)-2(S)-N'-(t-butylcarboxamido)- piperazinyl))-pentaneamide or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition made by combining the compound of Claim 1 and a pharmaceutically acceptable carrier.

22. A process for making a pharmaceutical composition comprising combining a compound of Claim 1 and a pharmaceutically acceptable carrier.

23. A method of inhibiting HIV integrase, comprising the administration to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1.

24. A method of treating infection by HIV, or of treating AIDS or ARC, comprising the administration to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1.