AU757409B2 - Hiv integrase inhibitors - Google Patents
Hiv integrase inhibitors Download PDFInfo
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- AU757409B2 AU757409B2 AU42255/99A AU4225599A AU757409B2 AU 757409 B2 AU757409 B2 AU 757409B2 AU 42255/99 A AU42255/99 A AU 42255/99A AU 4225599 A AU4225599 A AU 4225599A AU 757409 B2 AU757409 B2 AU 757409B2
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- substituted
- hydroxy
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/32—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/34—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/36—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D333/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/74—Naphthothiophenes
Description
1 TITLE OF THE INVENTION HIV INTEGRASE INHIBITORS 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 15 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 HIV.
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, azidothymidine'or AZT. Applicants WO 99/62897 PCT/US99/12094 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., 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 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 2,4dioxobutanoic 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 -2- 3 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.
According to a first embodiment, the present invention provides compound of structural formula R
O
0R2 OH R O O and tautomers and pharmaceutically acceptable salts thereof, wherein: A is selected from: thienyl, i* thiazolyl,
S
and /m R' is selected from:
-H,
-CH
3
-CF
3 -halo,
-NO
2
-N(R
4
)(R
5 -phenyl, [I:\DayLib\LIBHI529782speci.doc:aak substituted phenyl substituted with I or 2 substituents independently selected from: halogen, (b C 1 6 alkyl,
C
1 6 alkyloxy-, phenyl,
-CF
3
-OCF
3
-CN,
hydroxy, 0I) phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected fror Wi halogen, 00i C 1 6 alkyl, (iii) -CF 3 and (iv) hydroxy; phenyl CI- 3 alkyl-, substituted phenyl C 1 3 alkyl- substituted with 1 or 2 substituents independently selected from: halogen,
CI-
6 alkyl, Mc CI- 6 alkyloxy-, phenyl,
-CF
3
-OCF
3
-CN,
Nh hydroxy, Wi phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, 0ii) C 1 6 alkyl, (iii) -CF 3 and (i v) hydroxy; 3 ilkenyl-R (11)
-C
2 5 (12)
-C
2 5 alkynyl-R 3, and (13) -C(O)CH2C(O)C(O)0R7; R Is selected from:
-H,
-R3
-C
1 6 alkyl,
-C
1 6 alkyl substituted with R3 6 -0-R -0-CI- 6 alkyl-OR 6 6 -S(0)n-R
-C
1 6 alkyl (OR
-C
6 akl(OR )(R
-CO
0 6 alkyl-N(R 15 6 156 011) -C 1 6 alkylIS(O)n-R 6 (12)
-CO
0 6 alkyl C(O)-R 0*0 (13 6
-CO
0 6 alkyl C(S)-R %000- (14)
-CO
0 6 alkyl NR 4C(O)-R 6, and 4
-C
0 6 alkyl-C(O)N(R 0 each R is independently selected from: phenyl; substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen, C 1 6 alkyl,
C
1 6 alkyloxy-, phenyl,
-CF
3
-OCF
3
-CN,
hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C-6 alkyl, (iii) -CF 3 and (iv) hydroxy; thienyl; substituted thienyl substituted on a carbon atom with one or two substituents independently selected from: halogen, CI-6 alkyl, C1- 6 alkyloxy-, phenyl,
-CF
3
-OCF
3
-CN,
hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) CI- 6 alkyl, (iii) -CF 3 and S. (iv) hydroxy; pyridyl; substituted pyridyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1- 6 alkyl,
C
1 -6 alkyloxy-, phenyl,
-CF
3
-OCF
3
-CN,
hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) CI- 6 alkyl, (iii) -CF 3 and (iv) hydroxy; imidazolyl; substituted imidazolyl substituted on a carbon atom with one or two substituents independently selected from: halogen,
CI-
6 alkyl,
CI-
6 alkyloxy-, phenyl,
-CF
3
-OCF
3
-CN,
hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: So halogen, (ii) C 1 6 alkyl, (iii) -CF 3 and S. hydroxy; pyrrolyl; substituted pyrrolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C1- 6 alkyl, C1- 6 alkyloxy-, phenyl,
-CF
3
-OCF
3
-CN,
hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii0 C 1 6 alkyl, (iii) -CE 3 and (1iv) hydroxy; (11) pyrazolyl; (12) substituted pyrazolyl substituted on a carbon atom with one or two substituents independently selected from: halogen,
C-
6 alkyl,
CI-
6 alkyloxy-, phenyl, 0:
-CF
3 0
-OCF
3
-CN,
hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: 0 halogen, 0:.:25 (ii) C 1 6 alkyl, 0 6. (Iii) -CF 3 and 0 (iv) hydroxy; (13) C 3 6 cycloalkyl; (14) substituted C 3 6 cycloalkyl with 1 or 2 substituents independently selected from: halogen, C 1 6 alkyl,
CI-
6 alkyloxy-,
-CF
3
-OCF
3
-CN,
and hydroxy; (15) piperidinyl; (16) substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from: halogen,
CI-
6 alkyl,
C
1 6 alkyloxy-,
-CF
3
-OCF
3
-CN,
and hydroxy; (17) morpholinyl; (18) substituted morpholinyl substituted at a carbon or nitrogen atom with I or 2 substituents independently selected from: halogen, Cjj.
6 alkyl,
C
1 6 alkyloxy-,
-CF
3
-OCF
3
-CN,
and hydroxy; naphthyl, substituted naphthyl with 1, 2, or 3 substituents independently selected from: -halogen, -C 1 6 alkyl,
C
1 6 alkyloxy-,
-CF
3
-OCF
3 -CN, and -hydrox (21) indolyl; (22) substituted indolyl substituted on a carbon atom with one or two substituents independently selected from: -halogen, -C 1 6 alkyl, C 1 6 alkyloxy-,
-CF
3
-OCF
3 -CN, and -hydroxy; (23) C 3 6 cycloalkyl fused with a phenvl ing substituted C 3 6 cycloalkyl fused with a phenyl fing substituted on a :15 carbon atom with one or two substituents independently selected from: halogen,
C
1 6 alkyl,
CI-
6 alkyloxy-,
-CF
3
-OCF
3
-CN,
and hydroxy; each R is independently selected from:
-H,
-CI-
3 alkyl,
-CF
3 3
-R,
-C
2 3 alkenyl, 3
-CI-
3 alkyl-R 3
-C
2 3 alkenyl-R 3 -S(O)n-R ,and
-C(O)-R
each R is independently selected from:
-H,
-C 1 3 alkyl,
-CF
3 .3
-R,
-C
2 3 alkenyl,
-CI-
3 alkyl-R 3 3
-C
2 3 alkenyl-R S 3 -S(O)n-R ,and -C(O)-R3 each R 6 is independently selected from:
-C
1 3 alkyl-R 3 and
-R
3 R' s H.
R
8 is selected from hydrogen, methyl and methoxy; eahni neednl eetdfo ,1ad2 n each n is independently selected from 0, 1, and 2;n (A wh ah sineeentlyiselectedl fro 0, 1,y and 2i Ho C16akl hnRI when A -ipth eny tilylad s- r- lyte ii 3i when A is thienyl or thiazolyl and R 2 is -R 3 wherein R 3 is unsubstituted phenyl, then R' is not -H or
-CH
3 when A is thienyl and R 2 is -H or -C1-6 alkyl, then R' is not -halo,
-NO
2 or
-N(R
4
)(R
5 when R 4 and R 5 are both and when A is thienyl and R 2 is -R 3 wherein R 3 is imidiazolyl or (17) morpholinyl, then R' is not
-H,
-CH
3 -halo, •o -NO 2 or is1
-N(R
4
)(R
5 when R 4 and R 5 are both -H.
0* Detailed Description of the Invention This invention discloses 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:
R
1
R
2
OR
7 S8 I I R 0 O
(I)
and tautomers or pharmaceutically acceptable salts thereof, wherein: A is a five-membered heteroaromatic ring containing 1 sulfur atom and 0 or 1 nitrogen atoms and substituted on carbon by R 1
R
2 and R 8 the heteroaromatic ring may optionally be fused with a phenyl ring or a C 4 -6 cycloalkyl ring, or with two six membered rings to form: or or S or or [I:\DayLib\LIBH]529782speci.doc:aak WO 99/62897 WO 9962897PCT/US99/1 2094 R 1is R is selected from:
-H,
-C
1 5 alkyl,
-CF
3 -halo,
-NO
2 -N(R )R -R6, 3
-C
2 5 alkenyl-R 3
-C
2 5 alkynyl-R -0-R6, (11) -0-Cl.-6 alkyl, and (12) -C(O)CH2C(O)C(O)0R7; selected from:
-H,
33
-C
1 6 alkyl. substituted withR 66 -0Cl..
6 alkyl-O 46 -Cl-6 alkyl (OR 6), (10) -C 0 6 alkyl-N(R (11)
-C
1 6 alkyl S(O)n-R6 6 (12) -C 0 -6 alkyl. C(O)-R (13) -C 0 6 alkyl C(S)-Rt6 (14) -CO 0 6 alkyl NR C(O)-R 6 and -4- WO 99/62897 PCT/US99/12094 each R 3 is independently selected from: 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: halogen,
C
1 -6 alkyl,
C
1 -6 alkyloxy-, phenyl,
-CF
3
-OCF
3
-CN,
hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 -6 alkyl, (iii) -CF 3 and (iv) hydroxy; 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: halogen,
C
1 6 alkyl,
C
1 -6 alkyloxy-,
-CF
3
-OCF
3
-CN,
=0, hydroxy; WO 99/62897 PCT/US99/12094 unsubstituted or substituted hexahydrothieno[3,4d]imidazolyl with one or two substituents selected from: oxo, halogen, C1 6 alkyl,
C
1 6 alkyloxy-,
-CF
3
-OCF
3 -CN, and hydroxy; 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: -halogen,
-C
1 6 alkyl,
-C
1 -6 alkyloxy-,
-CF
3
-OCF
3 -CN, and -hydroxy; 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: halogen,
C
1 6 alkyl, C1- 6 alkyloxy-,
-CF
3 WO 99/62897 WO 9962897PCTIUS99/12094
-OCF
3
-CN,
=0, hydroxy; 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: halogen, C 1 6 alkyl,
C
1 6 alkyloxy-,
-CF
3
-OCF
3
-CN,
=0, hydroxy; each IF 4 i (1) (2) independently selected from:
-H,
-C 1-.3 alkyl,
-CF
3
-R,
-C
2 3 alkenyl, 3
-C
1 -3 alkyl-R 3
-C
2 3 alkenyl-R 3 -S(O)n-R ,and -C(0)-R 3 each R5is independently selected from:
-H,
-C 1 3 alkyl, -7- WO 99/62897 PCT/US99/12094
-CF
3
-R
3
-C
2 3 alkenyl,
-C
1 3 alkyl-R 3
-C
2 3 alkenyl-R 3 -S(O)n-R 3 and
-C(O)-R
3 each R 6 is independently selected from:
-C
1 3 alkyl-R 3 and -R3;
R
7 is selected from: and C1-6 alkyl;
R
8 is selected from: and C1-6 alkyl-oxy-; C1-6 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) S OH OSO 0 0 (2) -8- WO 99/62897 WO 9962897PCTIUS99/1 2094 S2
OH
0 0 (3) S
OH
O 0
F
(4) F- IP S OH 0 0 F-W S OH 0 0
F
(6) CN 0 S
OH
(7) (8) 0O -9- WO 99/62897 WO 9962897PCTIUS99/12094 (9) S OH (12) 100 s
OH
WO 99/62897 WO 9962897PCTIUS99/1 2094 N~I OH 0 0 (16) 0 H S OH 0 0 (17) 0
OH
0 0
OH
0 0 (19) F N~I0 S
OH
0 0
F
-11- WO 99/62897 WO 9962897PCT/US99/1 2094 (21) (22) 0
H
3 0' OH 0 0
OH
0 0 0 025'S OH b0 0 ,Sl
OH
(23) (24) C -j 0 0 (26) Hi~ S
OH
S 0 0 SOD OH 12- WO 99/62897 WO 9962897PCTIUS99/12094 (27) 0~ 0 S OH 0 0 (28) S 0
OH
O 0 100 F (32) (33) 13 WO 99/62897 WO 9962897PCTIUS99/1 2094 (34) 0
OH
0 0 c (36)
F
(37) 100 (38) 14- WO 99/62897 WO 9962897PCTIUS99/1 2094 (39) (41) CI 0 0 0 S OH 000 N0 H S r
OH
0 0 (42) (43)
HC
0 0 (44) 15 WO 99/62897 WO 9962897PCTIUS99/1 2094
C
(46) (47)
N
H Sl) OH 0 0
N
/N N-'
H
3 C S WOH 0 0
N-<\I
N lyliOH N N-<\I N3W
OH
00D (48) (49) 16- WO 99/62897 WO 9962897PCTIUS99/12094 s 0
OH
cc0 0 0 S 0
OH
CIs o 00 (51) s s 0
OH
00 F0 0 (52) S 0
OH
0 0 (53) 0 Qs
OH
0 0 (54) qI
OH
S 0 0 ,and 17 WO 99/62897 PCT/US99/12094 O O and tautomers and pharmaceutically acceptable salts thereof.
In one embodiment of the present invention, structural formula is: R
OH
O O In another embodiment of the present invention, structural formula is:
R
8 S 0 R2OH O O In still another embodiment of the present invention, structural formula is: S0
OH
R
2 0 0 In yet another embodiment of the present invention, structural formula is; N j 0 R2 S OH O O In one class of compounds of the present invention, A is selected from: -18- WO 99/62897 PCT/US99/12094 thienyl, thiazolyl,
S
selected fror (1) (2) (3) (4) selected fron (1) (2) (3) (4) Sand In another class of compounds of the present invention, A is n: thienyl, thiazolyl, S and
S
In one class of compounds of the present invention, R1 is n:
-H,
-CH
3 -CF3, -halo,
-NO
2 -19- WO 99/62897 PCT/US99/12094
-N(R
4
)(R
5 -phenyl, substituted phenyl substituted with 1 or 2 substituents independently selected from: halogen,
C
1 -6 alkyl, C1- 6 alkyloxy-, phenyl,
-CF
3
-OCF
3
-CN,
hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 .6 alkyl, (iii) -CF 3 and (iv) hydroxy; phenyl C 1 -3 alkyl-, substituted phenyl CI.
3 alkyl- substituted with 1 or 2 substituents independently selected from: halogen, C1-6 alkyl, C1- 6 alkyloxy-, phenyl,
-CF
3
-OCF
3
-CN,
hydroxy, phenyloxy, and WO 99/62897 PCT/US99/12094 substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 6 alkyl, (iii) -CF 3 and (iv) hydroxy; (11) -C 2 5 alkenyl-R 3 (12) -C2 5 alkynyl-R 3 and (13) -C(O)CH2C(O)C(O)OR7.
In another class of compounds of the present invention, R1 is selected from:
-H,
-CH
3 -CF3, -halo,
-NO
2 -phenyl, substituted phenyl substituted with 1 or 2 substituents independently selected from: halo, methyl, and methoxy, phenyl C 1 -3 alkyl-, substituted phenyl C1- 3 alkyl- substituted with 1 or 2 substituents independently selected from: halo, methyl, and methoxy, and (11) -C 2 5 alkenyl-R 3 In still another class of compounds of the present invention, R1 is hydrogen.
-21- WO 99/62897 WO 9962897PCTIUS99/1 2094 In one class of compounds of the present invention, R 2 is selected from:
-H,
3
-R,
-C 1 6 alkyl,
-C
1 6 alkyl substituted with R, 6
-O-R
6 -0-Cl..
6 alkyl-OR -S(O)n-R 6
-C
1 6 alkyl(O6 R
-C
1 6 alkyl (OR 6),
-C
0 6 alkyl-N(R 6 (11) -C 1 6 alkyl S(O)n-R 6 (12) -C 0 -6 alkyl C(O)-R 6 (13) -C 0 6 alkyl C(S)-R (14) -C 0 -6 alkyl NR C(O)-R and In another class of compounds of the present invention, R 2 is selected from:
-H,
3
-R,
-C
1 6 alkyl,
-C
1 6 alkyl substituted with R, 6
-O-R
-S(O)n-R 6
-C
1 6 alkyl (OR 6), 46
-C
1 6 alkyl 46
-C
1 6 alkyl S(O)-R (12) -C 0 6 alkyl NR C(O)-R 6 and 22- WO 99/62897 PCT/US99/12094 (13) -Co 0 6 In one class of compounds of the present invention, R 3 is selected from: phenyl; substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen, C1.
6 alkyl,
C
1 -6 alkyloxy-, phenyl,
-CF
3
-OCF
3
-CN,
hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 6 alkyl, (iii) -CF 3 and (iv) hydroxy; thienyl; substituted thienyl substituted on a carbon atom with one or two substituents independently selected from: halogen,
C
1 -6 alkyl,
C
1 -6 alkyloxy-, phenyl,
-CF
3
-OCF
3
-CN,
hydroxy, -23- WO 99/62897 PCT/US99/12094 phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C1- 6 alkyl, (iii) -CF 3 and (iv) hydroxy; pyridyl; substituted pyridyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C1.6 alkyl,
C
1 -6 alkyloxy-, phenyl, -CF3,
-OCF
3
-CN,
hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C.-6 alkyl, (iii) -CF 3 and (iv) hydroxy; imidazolyl; substituted imidazolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C1-6 alkyl,
C
1 -6 alkyloxy-, phenyl,
-CF
3 -24- WO 99/62897 PCT/US99/12094
-OCF
3
-CN,
hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 -6 alkyl, (iii) -CF 3 and (iv) hydroxy; pyrrolyl; substituted pyrrolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C1- 6 alkyl, C1-6 alkyloxy-, phenyl,
-CF
3
-OCF
3
-CN,
hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) CI-6 alkyl, (iii) -CF 3 and (iv) hydroxy; (11) pyrazolyl; (12) substituted pyrazolyl substituted on a carbon atom with one or two substituents independently selected.from: halogen, C1.
6 alkyl, WO 99/62897 PCT/US99/12094
C
1 -6 alkyloxy-, phenyl,
-CF
3
-OCF
3
-CN,
hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 -6 alkyl, (iii) -CF 3 and (iv) hydroxy; (13) C 3 .6 cycloalkyl; (14) substituted C3- 6 cycloalkyl with 1 or 2 substituents independently selected from: halogen,
C
1 .6 alkyl,
C
1 -6 alkyloxy-,
-CF
3
-OCF
3
-CN,
=O,and hydroxy; (15) piperidinyl; (16) substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from: halogen,
CI_
6 alkyl,
C
1 -6 alkyloxy-,
-CF
3
-OCF
3 -26- WO 99/62897 PCT/US99/12094
-CN,
and hydroxy; (17) morpholinyl; (18) substituted morpholinyl substituted at a carbon or nitrogen atom with 1 or 2 independently selected from: halogen, C1- 6 alkyl, C1- 6 alkyloxy-,
-CF
3
-OCF
3
-CN,
and hydroxy; (19) naphthyl, substituted naphthyl with 1, 2, or 3 substituents independently selected from: -halogen,
-C
1 -6 alkyl,
-C
1 -6 alkyloxy-,
-CF
3
-OCF
3 -CN, and -hydroxy; (21) indolyl; (22) substituted indolyl substituted on a carbon atom with one or two substituents independently selected from: -halogen, -CI-6 alkyl,
-C
1 -6 alkyloxy-,
-CF
3
-OCF
3 -CN, and -27- WO 99/62897 PCT/US99/12094 -hydroxy; (23) C 3 -6 cycloalkyl fused with a phenyl ring (24) substituted C 3 -6 cycloalkyl fused with a phenyl ring substituted on a carbon atom with one or two substituents independently selected from: halogen,..
C1- 6 alkyl,
C
1 -6 alkyloxy-,
-CF
3
-OCF
3
-CN,
and hydroxy.
In another class of compounds of the present invention, R3 is selected from: phenyl; substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen,
C
1 -6 alkyl, C16 alkyloxy-, phenyl,
-CF
3
-OCF
3
-CN,
hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen,
C
1 6 alkyl, (iii) -CF 3 and (iv) hydroxy; -28- WO 99/62897 PCT/US99/12094 thienyl; substituted thienyl substituted on a carbon atom with one or two substituents independently selected from: halogen,
C
1 6 alkyl,
C
1 -6 alkyloxy-, phenyl,
-CF
3
-OCF
3
-CN,
hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 -6 alkyl, (iii) -CF 3 and (iv) hydroxy; pyridyl; substituted pyridyl substituted on a carbon atom with one or two substituents independently selected from: halogen,
C
1 6 alkyl,
C
1 -6 alkyloxy-, phenyl,
-CF
3
-OCF
3
-CN,
hydroxy, phenyloxy, and substituted phenyloxy with 1, 2.,,or 3. substituents selected from: halogen, -29- WO 99/62897 PCT/US99/12094 (ii) C 1 .6 alkyl, (iii) -CF 3 and (iv) hydroxy; imidazolyl; pyrrolyl; pyrazolyl;
C
3 6 cycloalkyl, (11) substituted C 3 -6 cycloalkyl with 1 or 2 substituents independently selected from: halogen, CI-6 alkyl,
C
1 -6 alkyloxy-,
-CF
3
-OCF
3
-CN,
and hydroxy; (12) piperidinyl; (13) substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from: halogen,
C
1 -6 alkyl,
C
1 -6 alkyloxy-,
-CF
3
-OCF
3
-CN,
and hydroxy; (14) morpholinyl; (15) naphthyl; (16) indolyl, and (17) C 3 6 cycloalkyl fused with a phenyl ring.
WO 99/62897 PCT/US99/12094 In still another class of compounds of the present invention, R3 is selected from: phenyl, substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen selected from -Cl, -Br,,
CH
3 methoxy-, phenyl,
-CF
3
-OCF
3
-CN,
hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen selected from -Cl, -Br, (ii) -CH 3 (iii) -CF 3 and (iv) hydroxy; thienyl, pyridyl, imidazolyl, pyrrolyl, pyrazolyl,
C
3 -6 cycloalkyl, (12) piperidinyl, (14) morpholinyl, naphthyl, (16) indolyl, and (17) C3- 6 cycloalkyl fused with a phenyl ring.
In one class of compounds of the present invention, R4 is selected from: -31- WO 99/62897 WO 9962897PCTIUS99/1 2094 (1) (2) (3) (4) (6) (7) (8) (9) is selected (1) (2) (3) (4) (6) (7)
-H,
-C
1 3 alkyl,
-CF
3
-R
3
-C
2 3 alkenyl,
-C
1 3 alkyl-R 3 3
-C
2 3 alkenyl-R 3 -S(O)n-R ,and
-C(O)-R
3 In another class of compounds of the present invention, R 4 from:
-H,
-C
1 3 alkyl,
-CF
3
-C
2 3 alkenyl, 3 -C 1 3 alkyl-R ,and 3 -S(O)n-R In one class of compounds of the present invention, R5 is selected frc (1) (2) (3) (4) (5) (6) (7) (8) (9) is selected
-H,
-C
1 3 alkyl,
-C
2 3 aknl 33 -C2-.
3 alkeylR 3
-C
2 3 alkenyl-R and 3 In another class of compounds of the present invention, from: 32- WO 99/62897 PCT/US99/12094
-H,
-C1- 3 alkyl,
-CF
3 3
-R
3
-C
2 3 alkenyl, -C1.
3 alkyl-R 3
-C
2 .3 alkenyl-R 3 and -S(O)n-R.
In one class of compounds of the present invention, R 7 is hydrogen.
In one class of compounds of the present invention, R8 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: an AIDS antiviral agent, an anti-infective agent, and 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.
-33- WO 99/62897 PCT/US99/12094 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 Applicants also intend the following tautomeric forms of the same compound (Ia) and (Ib): R1 R1
R
2
OR
7 R
OR
R
8 O O
R
8 O OH (la) R1 0 R m OR 7
R
8 OH O (Ib) By naming or referring to compound and tautomers thereof, it is understood for the purposes of the present application that the tautomers (Ia) and (Ib) are also intended. Similarly, by referring to compound (Ia), it is understood for the purposes of the present application that the tautomers and (Ib) are also intended. The same holds true for references to tautomer (Ib).
When any variable R3, R 4 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 HIV 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 HIV is defined as including, but not limited to, treating a wide range of states of HIV infection: AIDS, ARC (AIDS -34- WO 99/62897 PCT/US99/12094 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 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, 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 to make a pharmaceutical composition useful for inhibiting HIV integrase and in the treatment of AIDS or ARC.
Compounds of structural formula wherein A is thienyl may be made according to the procedures in Schemes AI, All, BI, CI, CII, DI, EI, FI, FII, and FIII. Compounds of structural formula (I) wherein A is thiazolyl may be prepared according to the procedures in Scheme GI.
S OEt 0 0 AI (3) WO 99/62897 WO 9962897PCTIUS99/1 2094 i. NaCH, MeOH-H 2 0-THF ii .HC1 0 S OH 0 0 AI(4) Scheme All
CI-
S
0 AI 1 (1) X= CH, N R H, F, F 2 X OH NaH, X 0-I s All (2a-e) 36- WO 99/62897 WO 9962897PCTIUS99/1 2094 0 EtO,,, 0 NaQEt, THF x 0
I
S- GEt R 0 0 AIl (3a-e) i. NaCH, MeOH-H 2 0-THF ii .HC1 7 x 0- S OH, R 0 0 AII (4a-e) -37 WO 99/62897 WO 9962897PCTIUS99/1 2094 Scheme BI Br/ S Br EI (1) n-BuLi, Et 2 0, R 0 HO0 BI (2a-d)
BF
3 .Et 2 O, EL 3 SiH, CH 2 C1 2 38- WO 99/62897 WO 9962897PCTIUS99/1 2094 Br BI (3a-d) n-BuLi, Et 2 O, CH 3
CONCH
3
(OCH
3
S
130 BI (4a-d) 0 EtO, t 0 LDA, THE 39- WO 99/62897 WO 9962897PCTJUS99/1 2094
R
BI i. NaGH, MeOH-H 2 0-THF i i.HC 1 0 0 BI (6a-d) Scheme BI Br/ 0 BIT1 (1)
R
7 SNa acetone WO 99/62897 WO 9962897PCT[US99/1 2094
S--
S~
0 BIT1 (2) EtO G Et 0 NaQEt, THE SEt R 0 0 BIT1 (3) iNaOH, MeOH-H 2 0-THF ii. HC1 S-0 S-
OH
0 BIT (4) -41- WO 99/62897 WO 9962897PCTIUS99/1 2094 Scheme CI
S
Br \0Br CI (1) n-BuLi, HO S Br Et 2 O, 04 R ~H CI (2a-d)
BF
3 .Et 2
O,
Et 3 SiH(xs), CH 2 C1 2 -42- WO 99/62897 WO 9962897PCTIUS99/1 2094
S
Br CI (3a-d) n-BuLi, Et 2 O, CH 3
CONCH
3
(OCH
3 CI (4a-d) -43- WO 99/62897 WO 9962897PCT/US 99/12094 Scheme CI (cont inue) CI (4a-d) 0 EtCA 0 LDA, THF CI i. NaOH, M~eOH-H 2
O-THF
ii.HC1 0'.0 CI (6a-d) -44- WO 99/62897 WO 9962897PCTIUS99/1 2094 Scheme CII
S
Br \0 Br C 1(1) n-BuLi, Et 2
O,
R/
S
S
-Br Ci 1 (1) n-BuLi, Et 2 O, CH 3
CONCH-
3
(OCH
3
S
0y CII (2) 0 EtOIf, 0 LDA, THF WO 99/62897 WO 9962897PCTIUJS99/1 2094 S0 OEt CII (3) i. NaOH, MeOH-H 2 0-THF ii .HC1 -0--rOH R 0 0 CII (4) Scheme DI s Br DI (1) n-BuLi, Et 2
O,
Rj 0 -46- WO 99/62897 WO 9962897PCTIUS99/1 2094
S
Br
OH
DI (2a-c)
BE
3 .Et 2
O,
Et 3 SiH, CH 2 C1 2 DI (Ba-c) n-BuLi, Et 2 O, CH 3
CONCH
3
(OCH
3 DI (4a-c) -47 WO 99/62897 WO 9962897PCT/US99/1 2094 Scheme DI (continue) DI (4a-c) 0 EtOr) t 0 LDA, THF s 0 OEt 0 0 R DI NaOH, MeOH-H 2 0-THF ii.HC1 0 0 DI (6a-c) -48- WO 99/62897 WO 9962897PCTIUS99/1 2094 Scheme El BrBr BI (1) n-BuLi, Et 2
O,
R C- H0 BI (2d) NaH, DMSO, RX -49- WO 99/62897 WO 9962897PCTIUS99/I 2094 R =Bn, Ph, Me
RO
S Br EI (la-c) n-BuLi, Et 2 O, CH 3
CONC
EI (2a-c) WO 99/62897 WO 9962897PCTIUS99/1 2094 Scheme EI (continue) El (Ba-c) 0 EtC C -Et 0 LDA, THF
RO
EI (4a-c) i. NaCH, NeOH-H 2 0--THF ii.HC1 El -51- WO 99/62897 WO 9962897PCTIUS99/12094 Scheme FI 0 2Nl SalI 0 i.I H2 ii.HC
HCI.H
2
N/
S
0
RX,
RX,
Fl (1) Pt 2 S/C, MeOH Fl (2) iPr 2 NEt, MeCN or
CS
2
CO
3
DMF
52 WO 99/62897 WO 9962897PCT/US99/12094
R
R Bn, n-Pr, allyl, Me FT (3a-e) 0 EtOA t 0 R' S OEt 0 0 i. NaOH, Me( NaQEt, THF FT (4a-e)
OH-H
2 0-THF ii.HC1 FT 53- WO 99/62897 WO 9962897PCTIUS99/12094 Scheme FIT Cl 0
R
NH Cs
R
0 All (1) 2)CO31 DMF FIT (la-b) 54- WO 99/62897 WO 9962897PCTIUS99/1 2094 0 EtO 0Et 0 NaQEt, THE /N 0 S OEt 0 0 FIT (2a-b) i. NaOH, IveOH-H 2 0-THF ii.HC1 R 0 S OH 0 0 FII (3a-b) Scheme FIll
HCI.H
2
N/
S
a FI (2)
RSO
2 C1, pyridine WO 99/62897 WO 9962897PCTJUS99/1 2094 RS0 2
HN/
0 NaH
RSO
2 R'N
I
0 FIIl (1) 4DS, DMSO, R'X FIIl (2) 0 EtOrJ t 0 NaQEt, THF RS0 2 R'N 0 S OEt 0 0 FIll (3) 1. NaOH, MeOH-H 2 0-THF ii .HC1
RSO
2 R'N 0 Sy
OH
0 0 FIT (4) 56- WO 99/62897 WO 9962897PCTIUS99/1 2094 Scheme GI
/N-H
R Bn, R I Bn R Bn, R' H R Bn, R' =CH 3 R,
NH
2 R" S S=CN ,hexane c. HC1 GI (la-c)
CH
3 0 CH 3
>N
CH
3 0 CH 3 R, CH3 Rl S GI (2a-c) Br 0 R% N 0 GI (3a-c) 57 WO 99/62897 WO 9962897PCT/US99/12094 0 EtOYJ 0 NaQEt, THE
RN
R' S3 CEt 0 0 GI (4a-c) i. NaQH, MeOH-H 2 0-THF ii.HCi R N
/N-KI
R'S3I
OH
0 0 GI Scheme GII
N-H
11.
S=C=N
hexane c. HC1 58- WO 99/62897 WO 9962897PCTIUS99/1 2094
R
R'
S
GJI (1)
NH
2 Br 0 0 R'
N'
0 GIl1 (3) 0 EtO,,, 0 NaOEt, THF NlGEt 0 0 GIl1 (4) i. NaOH, MeOH-H 2 0-THF ii .HC1 59- WO 99/62897 PCT/US99/12094 R, S R' Ny OH O O 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 prodrug 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, ethylenediamine, N-methylglutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, 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.
WO 99/62897 PCT/US99/12094 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 pharmaceuticallyacceptable 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-administrable 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 -61- WO 99/62897 PCT/US99/12094 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, parenterallyacceptable 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 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 -62- WO 99/62897 PCT/US99/12094 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.
-63- WO 99/62897 PCT/US99/12094
ANTIVIRALS
Drug Name 097 Amprenivir 141 W94 GW141 Abacavir (1592U89) Acemannan Acyclovir Manufacturer Hoechst/Bayer Glaxo Wellcome Glaxo Wellcome Carrington Labs (Irving, TX) Burroughs Wellcome Indication HIV infection, AIDS, ARC (non-nucleoside reverse transcriptase (RT) inhibitor) HIV infection, AIDS, ARC (protease inhibitor) HIV infection, AIDS, ARC (RT inhibitor)
ARC
HIV infection, AIDS, ARC, in combination with
AZT
HIV infection, AIDS,
ARC
HIV infection, AIDS,
ARC
HIV infection ARC, PGL HIV positive, AIDS Kaposi's sarcoma, HIV in combination w/Retrovir AD-439 AD-519 Tanox Biosystems Tanox Biosystems Gilead Sciences Ethigen (Los Angeles, CA) Glaxo Wellcome Adefovir dipivoxil AL-721 Alpha Interferon -64- WO 99/62897 PCT/US99/12094 Ansamycin LM 427 Antibody which neutralizes pH labile alpha aberrant Interferon AR177 beta-fluoro-ddA BMS-232623 (CGP-73547) BMS-234475 (CGP-61755) CI-1012 Cidofovir Curdlan sulfate Cytomegalovirus immune globin Cytovene Ganciclovir Adria Laboratories (Dublin, OH) Erbamont (Stamford, CT) Advanced Biotherapy Concepts (Rockville, MD) Aronex Pharm Nat'l Cancer Institute Bristol-Myers Squibb/ Novartis Bristol-Myers Squibb/ Novartis Warner-Lambert Gilead Science AJI Pharma USA Medlmmune AIDS, ARC
ARC
HIV infection, AIDS,
ARC
AIDS-associated diseases HIV infection, AIDS, ARC (protease inhibitor) HIV infection, AIDS, ARC (protease inhibitor) HIV-1 infection CMV retinitis, herpes, papillomavirus HIV infection CMV retinitis sight threatening
CMV
peripheral CMV retinitis HIV infection, AIDS, ARC (RT inhibitor) AIDS, ARC, HIV positive asymptomatic Syntex Delaviridine Dextran Sulfate Pharmacia-Upjohn Ueno Fine Chem.
Ind. Ltd. (Osaka, Japan) WO 99/62897 PCT/US99/12094 ddC Dideoxycytidine ddl Dideoxyinosine Hoffman-La Roche Bristol-Myers Squibb DMP-450 AVID (Camden, NJ) Efavirenz (DMP 266) 6-Chloro-4(S)cyclopropylethynyl-4(S)trifluoro-methyl-1,4dihydro-2H-3,1benzoxazin-2-one)
STOCRIN,
Famciclovir
FTC
GS 840 HBY097 DuPont Merck Elan Corp, PLC (Gainesville, GA) Smith Kline Emory University Gilead Hoechst Marion Roussel HIV infection, AIDS,
ARC
HIV infection, AIDS, ARC; combination with AZT/d4T HIV infection, AIDS, ARC (protease inhibitor) HIV infection, AIDS, ARC (non-nucleoside RT inhibitor) HIV infection herpes zoster, herpes simplex HIV infection, AIDS, ARC (reverse transcriptase inhibitor) HIV infection, AIDS, ARC (reverse transcriptase inhibitor) HIV infection, AIDS, ARC (non-nucleoside reverse transcriptase inhibitor) -66- WO 99/62897 PCT/US99/12094 Hypericin Recombinant Human Interferon Beta Interferon alfa-n3 Indinavir ISIS 2922 KNI-272 Lamivudine, 3TC Lobucavir Nelfinavir Nevirapine Novapren Peptide T Octapeptide Sequence Trisodium Phosphonoformate VIMRx Pharm.
Triton Biosciences (Almeda, CA) Interferon Sciences Merck ISIS Pharmaceuticals Nat'l Cancer Institute Glaxo Wellcome Bristol-Myers Squibb Agouron Pharmaceuticals Boeheringer Ingleheim Novaferon Labs, Inc.
(Akron, OH) Peninsula Labs (Belmont, CA) Astra Pharm.
Products, Inc HIV infection, AIDS,
ARC
AIDS, Kaposi's sarcoma, ARC ARC, AIDS HIV infection, AIDS, ARC, asymptomatic HIV positive, also in combination with AZT/ddI/ddC CMV retinitis HIV-assoc.
diseases HIV infection, AIDS, ARC (reverse transcriptase inhibitor); also with
AZT
CMV infection HIV infection, AIDS, ARC (protease inhibitor) HIV infection, AIDS, ARC (RT inhibitor) HIV inhibitor
AIDS
CMV retinitis, HIV infection, other CMV infections -67- WO 99/62897 PCT/US99/12094 PNU-140690 Pharmacia Upjohn Probucol RBC-CD4 Ritonavir Vyrex Sheffield Med. Tech (Houston TX).
Abbott Saquinavir Stavudine; d4T Didehydrodeoxythymidine Valaciclovir Virazole Ribavirin VX-478 Zalcitabine Zidovudine; AZT Hoffmann-LaRoche Bristol-Myers Squibb Glaxo Wellcome Viratek/ICN (Costa Mesa, CA) Vertex Hoffmann-La Roche Glaxo Wellcome HIV infection, AIDS, ARC (protease inhibitor) HIV infection, AIDS HIV infection, AIDS, ARC HIV infection, AIDS, ARC (protease inhibitor) HIV infection, AIDS, ARC (protease inhibitor) HIV infection, AIDS,
ARC
genital HSV CMV infections asymptomatic HIV positive, LAS, ARC HIV infection, AIDS,
ARC
HIV infection, AIDS, ARC, with AZT HIV infection, AIDS, ARC, Kaposi's sarcoma, in combination with other therapies
IMMUNO-MODULATORS
Drug Name AS-101 Manufacturer Wyeth-Ayerst Indication
AIDS
-68- WO 99/62897 PCT/US99/12094 Bropirimine Acemannan CL246,738 FP-21399 Gamma Interferon Granulocyte Macrophage Colony Stimulating Factor Granulocyte Macrophage Colony Stimulating Factor Granulocyte Macrophage Colony Stimulating Factor HIV Core Particle Immunostimulant IL-2 Interleukin-2 IL-2 Interleukin-2 IL-2 Interleukin-2 (aldeslukin) Pharmacia Upjohn Carrington Labs, Inc.
(Irving, TX) American Cyanamid Lederle Labs Elan Corp, PLC (Gainesville, GA) Fuki ImmunoPharm Genentech Genetics Institute Sandoz Hoeschst-Roussel Immunex Schering-Plough Rorer Cetus Hoffman-La Roche Immunex Chiron advanced AIDS AIDS, ARC AIDS, Kaposi's sarcoma HIV infection blocks HIV fusion with CD4+ cells ARC, in combination w/TNF (tumor necrosis factor)
AIDS
AIDS
AIDS, combination w/AZT seropositive HIV AIDS, in combination w/AZT AIDS, ARC, HIV, in combination w/AZT AIDS, increase in CD4 cell counts -69- WO 99/62897 PCT/US99/12094 Immune Globulin Intravenous (human) IMREG-1 IMREG-2 Imuthiol Diethyl Dithio Carbamate Alpha-2 Interferon Methionine- Enkephalin
MTP-PE
Muramyl-Tripeptide Granulocyte Colony Stimulating Factor Remune rCD4 Recombinant Soluble Human CD4 rCD4-IgG hybrids Recombinant Soluble Human CD4 Interferon Alfa 2a SK&F106528 Soluble T4 Cutter Biological (Berkeley, CA) Imreg (New Orleans, LA) Imreg (New Orleans, LA) Merieux Institute Schering Plough TNI Pharmaceutical (Chicago, IL) Ciba-Geigy Corp.
Amgen Immune Response Corp.
Genentech Biogen Hoffman-La Roche Smith Kline pediatric AIDS, in combination w/AZT AIDS, Kaposi's sarcoma, ARC, PGL AIDS, Kaposi's sarcoma, ARC, PGL AIDS, ARC Kaposi's sarcoma w/AZT, AIDS AIDS, ARC Kaposi's sarcoma AIDS, in combination w/AZT immunotherapeutic AIDS, ARC AIDS, ARC AIDS, ARC Kaposi's sarcoma AIDS, ARC, in combination w/AZT HIV infection WO 99/62897 WO 9962897PCT/US99/1 2094 Thymopentin Tumor Necrosis Factor; TNF Immunobiology Research Institute (Annandale, NJ) Genentech HJV infection ARC, in combination w/gamma Interferon Drua Name Clindamycin with Primaquine Fluconazole Pastille Nystatin Pastille Ornidyl Eflornithine Pentamidine Isetbionate (JM IV) Triinethoprim Trimethoprim/sulfa Piritrexim Pentamidine isethionate for inhalation Spiramycin Intraconazole- 12 11 Trimetrexate ANTI-INFECTIVE S Manufacturer Pharmacia Upjohn Pfizer Squibb Corp.
Merrell Dow Indication
PCP
cryptococcal meningitis, candidiasis prevention of oral candidiasis
PCP
LyphoMed (Rosemont, IL) Burroughs Wellcome Fisons Corporation Rhone-Poulenc Janssen Pharm.
Warner-Lambert PCP treatment antibacterial antibacterial PCP treatment PCP prophylaxis cryptosporidial diarrhea histoplasmosis; cryptococcal meningitis
PCP
-71- WO 99/62897 PCT/US99/12094
OTHER
Drug Name Daunorubicin Recombinant Human Erythropoietin Recombinant Human Growth Hormone Megestrol Acetate Testosterone Total Enteral Nutrition Manufacturer NeXstar, Sequus Ortho Pharm. Corp.
Serono Bristol-Myers Squibb Alza, Smith Kline Norwich Eaton Pharmaceuticals Indication Karposi's sarcoma severe anemia assoc. with AZT therapy AIDS-related wasting, cachexia treatment of anorexia assoc.
w/AIDS AIDS-related wasting diarrhea and 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 HIV protease and/or a non-nucleoside inhibitor of HIV reverse transcriptase. An optional fourth component in the combination is a nucleoside inhibitor of HIV reverse transcriptase, such as AZT, 3TC, ddC or ddl. A preferred inhibitor of HIV protease is indinavir, which is the sulfate salt of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4-(S)hydroxy-5-(1-(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 HIV protease is saquinavir which is administered in a dosage of 600 or 1200 mg tid. Preferred non- -72- WO 99/62897 PCT/US99/12094 nucleoside inhibitors of HIV 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 HIV. Preferred combinations include those with the following indinavir with efavirenz, and, optionally, AZT and/or 3TC and/or ddl and/or ddC; indinavir, and any of AZT and/or ddl and/or ddC and/or 3TC, in particular, indinavir and AZT and 3TC; stavudine and 3TC and/or zidovudine; (4) zidovudine and lamivudine and 141W94 and 1592U89; 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).
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.
Indinavir is an inhibitor of HIV protease and is the sulfate salt of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5- (1-(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 -73- WO 99/62897 PCT/US99/12094 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 (SiO2) chromatography.
EXAMPLE 1 2,4-dioxo-4-(5-phenethylthiophen-2-yl)butanoic acid Step A: Preparation of ethyl 2,4-dioxo-4-(5-phenethynylthiophen-2yl)butanoate AI(2) S OEt O O 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 HC1, 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-2yl)butanoate AI(3) -74- WO 99/62897 PCT/US99/12094 S OEt 0 0 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
TM
diatomaceous earth. The filtrate was concentrated under vacuum to provide the title compound.
Step C: Preparation of 2,4-dioxo-4-(5-phenethylthiophen-2yl)butanoic acid AI(4) S
OH
O O A solution of ethyl 2,4-dioxo-4-(5-phenethylthiophen-2-yl)butanoate (125 mg, 0.378 mmol), aqueous sodium hydroxide (1.2 mL, 1M, 1.2 mmol), and THF (5 mL) in methanol (5 mL) was stirred at rt overnight. The resultant mixture was treated with aq HCI (1.3 mL. 1M), 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. 1H NMR (CDC13) 6 7.72 J =3.1 Hz, 1H), 7.35-7.15 5H), 6.94 1H), 6.86 J =3.1 Hz, 1H), 3.22 J =8.1 Hz, 2H), 3.03 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) WO 99/62897 PCT/US99/12094
O
0 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 HC1.
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-2yl)butanoic acid AII(4a) S OH 0 0 The title compound was prepared using the protocol described in Example AI(4), Step A and C substituting thiophene with 2-acetyl-5-(benzyloxy)thiophene in Step A. 1H NMR (CDC13) 6 7.75 J =4.6 Hz, 1H), 7.5-7.3 5H), 6.85 1H), 6.42 J =4.6 Hz, 1H), 5.21 2H).
EXAMPLE 3 2,4-dioxo-4-[5-(3-fluorobenzyloxy)thiophen-2-yl]butanoic acid -76- WO 99/62897 WO 9962897PCTIUS 99/12094 I O 0 0
F
The title compound was prepared using the protocol described in Example AII(4a), Step A B substituting benzyl alcohol with 3fluorobenzyl alcohol in Step A. 1H NMR (DMSO-d6) 8 8.0 (hr s 1H), 7.15 (in, 4H), 6.85 (brs, 1H), 6.6 (br s, 1H), 5.3 (hr s, 2H).
EXAMPLE 4 2,4-dioxo-4-[5-(4-fluorobenzyloxy)thiophen-2-yllbutanoic acid 0 0 The title compound was prepared using the protocol described in Example AII(4a), Step A B substituting benzyl alcohol with 4fluorobenzyl alcohol in Step A. 1H NMR (DMSO-d6) 8 8.0 (hr s 1H), 7.54 (in, 2H), 7.25 (in, 2H), 6.85 (brs, 1H), 6.6 (hr s, 1H), 5.3 (hr s, 2H).
EXAMPLE 2 ,4-dioxo-4-[5-(3 ,4-difluorobenzyloxy)thiophen-2-yllbutanoic acid
OH
0 0 The title compound was prepared using the protocol described in Example- AJJ(4a), Step A B substituting benzyl alcohol with 3,4difluorobenzyl alcohol in Step A. 1H NMR (CD3OD) 6 7.79 J =4.4 Hz, 1H), 7.45-7.25 (mn, 3H), 6.92 1H), 6.53 J =4.4 Hz, 1H), 5.24 2H).
77 WO 99/62897 PCT/US99/12094 EXAMPLE 6 2,4-dioxo-4-[5-(pyridin-2-ylmethyloxy)thiophen-2-yl]butanoic acid N o-
OH
S OH O O The title compound was prepared using the protocol described in Example AII(4a), Step A B substituting benzyl alcohol with 2pyridylcarbinol in Step A. 1H NMR (DMSO-d6) 6 8.60 J =4.6 Hz, 1H), 8.07 J =4.6 Hz, 1H), 7.87 (ddd, J 7.7, 1.7 Hz, 1H), 7.56 J =7.7 Hz, 1H), 7.40 (dd, J 4.7 Hz, 1H), 6.95 1H), 6.67 J =4.6 Hz, 1H), 5.39 2H).
EXAMPLE 7 2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-2-yl]butanoic acid Step A: Preparation of (5-bromothiophen-2-yl)-(3fluorophenyl)methanol BI(2a)
HO
S Br
F
To a cold (-78 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 -78- WO 99/62897 PCT/US99/12094 dichloromethane, and neutralized with dilute HC1. 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) S Br To a cold (0 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) 0 0 To a cold (-78 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, -79- WO 99/62897 PCT/US99/12094 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 HC1. 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 F-C S 0 0OEt To a cold (-78 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 HC1.
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-2yl]butanoic acid BI(6a) WO 99/62897 WO 9962897PCT/US99/12094 The title compound was prepared using the protocol described in Example Step C substituting ethyl'2,4-dioxo-4-(5phenethylthiophen-2-yl)butanoate with ethyl 2 ,4-dioxo-4-[5-(3fluorobenzyl)thiophen-2-yllbutanoate. The product was recrystallized from a mixture of ether and hexane. 1H NMR (CDCl3) 8 7.75 J =4.1 Hz, 1H), 7.35-7.25 (in, 2H), 7.05-6.90 (in, 4H), 4.20 2H).
EXAMPLE 8 2,4-dioxo-4-[5-(4-fluorobenzyl )thiophen-2-yllbutanoic acid
F
The title compound was prepared using the protocol described in Example BI(6a), Step A E substituting 3-fluorobenzaldehyde, with 4fluoro-benzaldehyde in Step A. 1H NMR (CDCl3) 8 7.74 J =3.8 Hz, 1H), 7.21 (mn, 2H), 7.03 (in, 2H), 6.91 (mn, 2H), 4.18 2H).
EXAMPLE 9 2 ,4-dioxo-4-[5-(3-chlorobenzyl)thiophen-2-yllbutanoic acid S
OH
CI- -81- WO 99/62897 PCT/US99/12094 The title compound was prepared using the protocol described in Example BI(6a), Step A E substituting 3-fluorobenzaldehyde with 3chloro-benzaldehyde in Step A. 1H NMR (CDC13) 5 7.74 J =4.0 Hz, 1H), 7.3-7.2 3H), 7.14 1H), 6.92 2H), 4.18 2H).
EXAMPLE 2,4-dioxo-4-(5-benzylthiophen-2-yl)butanoic acid S OH The title compound was prepared using the protocol described in Example BI(6a), Step A E substituting 3-fluorobenzaldehyde with benzaldehyde in Step A. 1H NMR (CDC13) 6 7.74 J =3.9 Hz, 1H), 7.38- 7.22 5H), 6.91 2H), 4.21 2H).
EXAMPLE 11 2,4-dioxo-4-(5-phenylsulfanylthiophen-2-yl)butanoic acid Step A: Preparation of 2-acetyl-5-phenylsufanylthiophene BII(2)
S
A mixture of thiophenol, sodium salt (718 mg, 5,43 mmol) and 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.
-82- WO 99/62897 WO 9962897PCTIUS99/I 2094 Step B: Preparation of 2 ,4-dioxo-4-(5-phenylsulfanylthiophen-2yl)butanoic acid BII(4) S I
OH
0 0 The title compound was prepared using the protocol described in Example AJ(4), Step A and C substituting thiophene with 2-acetyl-.5-phenylsufanylthiophene in Step A. The product was recrystallized from a mixture of ether and hexane. 1H NMRn (CDC13) 6 7.73 J =4.0 Hz, 1H), 7.48 (in, 2H), 7.38 (in, 3H), 7.08 (d, J =4.0 Hz, 1H), 6.88 1H).
EXAMPLE 12 2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-3-yllbutanoic acid 15F600, Step A: Preparation of (4-bromothiophen-2-yl)-(3fluorophenyl)methanol CI(2a) HO S I Br Fd The title compound was prepared using the protocol described in Example BJ(6a), Step A substituting 2,5-dibromothiophene with 2,4dibromothiophene.
83- WO 99/62897 PCT/US99/12094 Step B: Preparation of 4-bromo-2-(3-fluorobenzyl)thiophene CI(3a)
S
Br
F
To a cold (0 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-3yl]butanoic acid CI(6a)
F
0 0 O OH 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. 1H NMR (CDC13) 5 8.08 J =1.5 Hz, 1H), 7.35-7.25 3H), 7.05-6.92 2H), 6.90 1H), 4.15 2H).
EXAMPLE 13 2,4-dioxo-4-[5-(4-fluorobenzyl)thiophen-3-yl]butanoic acid -84- WO 99/62897 PCT/US99/12094 Y T OH 0 0
F
The title compound was prepared using the protocol described in Example CI(6a), Step A C substituting 3-fluorobenzaldehyde with 4fluoro-benzaldehyde in Step A. 1H NMR (CDC13) 6 8.07 J =1.5 Hz, 1H), 7.26-7.18 3H), 7.05-6.92 2H), 6.89 1H), 4.13 2H).
EXAMPLE 14 2,4-dioxo-4-[5-(3-chlorobenzyl)thiophen-3-yl]butanoic acid S O
OH
The title compound was prepared using the protocol described in Example CI(6a), Step A C substituting 3-fluorobenzaldehyde with 3chloro-benzaldehyde in Step A. 1H NMR (CDC13) 5 8.09 (br s, 1H), 7.28- 7.22 4H), 7.14 1H), 6.90 1H), 4.13 2H).
EXAMPLE 2,4-dioxo-4-(5-benzylthiophen-3-yl)butanoic acid S O or OH The title compound was prepared using the protocol described in Example CI(6a), Step A C substituting 3-fluorobenzaldehyde with WO 99/62897 PCT/US99/12094 benzaldehyde in Step A. 1H NMR (CDC13) 5 8.07 J =1.3 Hz, 1H), 7.36- 7.22 6H), 6.89 1H), 4.16 2H).
EXAMPLE 16 2,4-dioxo-4-(2-phenylsulfanylthiophen-4-yl)butanoic acid Step A: Preparation of 2-phenylsulfanyl-4-bromothiophene CII(1)
S
S
S Br To a cold (-78 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)
S
S
-86- WO 99/62897 PCT/US99/12094 To a cold (-78 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, 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 HC1. 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) S O0 0
T-OH
The title compound was prepared using the protocol described in Example AI(4), Step A and C substituting thiophene with 4-acetyl-2-phenylsulfanylthiophene in Step A. The product was recrystallized from a mixture of ether and hexane. 1H NMR (CDC13) 8 8.27 J =1.5 Hz, 1H), 7.68 J =1.5 Hz, 1H), 7.34-7.24 5H), 6.93 1H).
EXAMPLE 17 2,4-dioxo-4-[2-(3-fluorobenzyl)thiophen-3-yl]butanoic acid -87- WO 99/62897 WO 9962897PCT/US99/12094 y Y -OH 0 0
F
The title compound was prepared using the protocol described in Example BJ(6a), Step A E substituting 2,5-dibromothiophene with 1,2dibromothiophene in Step A. 1H NMR (CDCl3) 6 7.42 J =5.5 Hz, 1H), 7.32-7.24 (in, 1H), 7.20 (dd, J 1.1 Hz, 1H), 7.05 (hr d, J =7.5 Hz, 1H), 6.98-6.92 (in, 3H), 4.57 2H).
EXAMPLE 18 2 ,4-dioxo-4-12-(4-fluorobenzyl)thiophen-3-yllbutanoic acid The title compound was prepared using the protocol described in Example BI(6a), Step A E substituting 2,5-dibromothiophene with 1,2dibromothiophene, and 3-fluorobenzaldehyde with 4-fluorobenzaldehyde in Step A. 1H NMR (DMSO-d6) 5 7.62 (hr d, 1H), 7.47 (hr d, 1H), 7.35 (in, 2H), 7.15 (mn, 2H), 6.83 (hr s, 1H), 4.55 2H).
EXAMPLE 19 2,4-dioxo-4-[2-(3-chlorobenzyl)thiophen-3-yllbutanoic acid 88- WO 99/62897 PCT/US99/12094 Y Y
OH
O0 Cl The title compound was prepared using the protocol described in Example BI(6a), Step A E substituting 2,5-dibromothiophene with 1,2dibromothiophene, and 3-fluorobenzaldehyde with 3-chlorobenzaldehyde in Step A. 1H NMR (DMSO-d6) 8 7.42 (br d, 1H), 7.3-7.1 5H), 6.92 (br s, 1H), 4.55 2H).
EXAMPLE 2,4-dioxo-4-[5-(benzyloxy-phenylmethyl)thiophen-2-yl]butanoic acid Step A: Preparation of (5-bromothiophen-2-yl)-(phenyl)methanol CI(2d)
HO
S Br 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)-2bromothiophene EI(la) -89- WO 99/62897 PCT/US99/12094 O Br A suspension of sodium hydride (147 mg, 6 mmol) in anhydrous DMSO 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 HC1. 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-(benzyloxyphenylmethyl)thiophen-2-yl]butanoic acid o 0 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.
WO 99/62897 WO 9962897PCTJIUS99/1 2094 1H NMR (CDC13) 8 7.71 J =4.0 Hz, 1H), 7.5-7.3 (in, 9H), 6.94 1H), 6.86 J =4.0 Hz, 1H), 5.62 2H), 4.63 J =12.1 Hz, 1H), 4.53 J 12.1 Hz, 1H).
EXAMPLE 21 2,4-dioxo-4-[5-(phenoxy-phenylmethyl )thiophen-2-yllbutanoic acid The title compound was prepared using the protocol described in Example EJ(5a), Step A C substituting benzyl bromide with diphenyl iodonium chloride in Step B. 1H NMR (CDCl3) 5 7.73 J =4.0 Hz, 1H), 7.5-7.2 (in, 7H), 7.01 J =4.0 Hz, 1H), 6.94 1H), 7.00-6.95 (in, 3H), 6.41 1H).
EXAMPLE 22 2 ,4-dioxo-4-[5-(methoxy-phenylmethyl)thiophen-2-yllbutanoic acid The title compound was prepared using the protocol described in Example EJ(5a), Step A C substituting benzyl bromide with methyl iodide in Step B. 1H. NMR (CDCl3) 6 7.71 J =4.0 Hz, 1H), 7.42 7H), 6.94 1H), 6.92 J =4.0 Hz, 1H), 3.42 3H).
EXAMPLE 23 -91 WO 99/62897 PCT/US99/12094 2,4-dioxo-4-(5-dibenzylaminothiophen-2-yl)butanoic acid Step A: Preparation of 2-acetyl-5-aminothiophene hydrochloride FI(2)
HCI.H
2
N-
Sa
O
A mixture of 2-acetyl-5-nitrothiophene (5.00 g, 29.2 mmol), and 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 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)
S
0 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-2yl)butanoic acid -92- WO 99/62897 PCT/US99/12094 N1 0 S- OH NO O 0 0 The title compound was prepared using the protocol described in Example AI(4), Step A and C substituting thiophene with 2-acetyl-5-dibenzylaminothiophene in Step A. The product was purified by HPLC on C-18 stationary phase. 1H NMR (DMSO-d6) 6 7.93 J =4.8 Hz, 1H), 7.40-7.25 10H), 6.79 1H), 6.27 J =4.8 Hz, 1H), 4.81 4H).
EXAMPLE 24 2,4-dioxo-4-(5-benzylaminothiophen-2-yl)butanoic acid Step A: Preparation of 2-acetyl-5-benzylaminothiophene FI(3b)
N
H S 0 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.
-93- WO 99/62897 PCT/US99/12094 Step B: Preparation of 2,4-dioxo-4-(5-benzylaminothiophen-2yl)butanoic acid H S OH 0 0 The title compound was prepared using the protocol described in Example AI(4), Step A and C substituting thiophene with 2-acetyl-5-benzylaminothiophene in Step A. The product was purified by HPLC on C-18 stationary phase. 1H NMR (CD3OD) 6 7.70 J =4.6 Hz, 1H), 7.40-7.25 5H), 6.79 1H), 6.14 J =4.6 Hz, 1H), 4.86 2H).
EXAMPLE 2,4-dioxo-4-(5-diallylaminothiophen-2-yl)butanoic acid Step A: Preparation of 2-acetyl-5-diallylaminothiophene FI(3c)
N
O
A mixture of 2-acetyl-5-aminothiophene hydrochloride (1.5 g, 8.44 mmol), allyl bromide (7.30 mL, 84.4 mmol), and diisopropylethylamine 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.
-94- WO 99/62897 WO 9962897PCTIUS99/1 2094 Step B: Preparation of 2 ,4-dioxo-4-(5-diallylaminothiophen-2yl)butanoic The title compound was prepared using the protocol described in Example AJ(4), Step A and C substituting thiophene with 2-acetyl-5-diallylaminothiophene in Step A. The product was purified by HPLC on C-18 stationary phase. 1H NMR (CDCl3) 867.67 J =4.6 Hz, 1H), 6.76 1H), 6.06 J =4.6 Hz, 1H), 5.85 (in, 2H), 5.3 (in, 4H1), 4.05 (mn, 4H).
EXAMPLE 26 2 ,4-dioxo-4-(5-di-n-propylaminothiophen-2-yl)butaloic acid Step A: Preparation of 2-acetyl-5-di-n-propylaminothiophene FI( 3d) A mixture of 2-acetyl-5-diallylaminothiophene (200 mng, 0.904 mmnol) and Pd/C (200 mng) 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 TM1, 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 WO 99/62897 PCT/US99/12094 0 0 The title compound was prepared using the protocol described in Example AI(4), Step A and C substituting thiophene with 2-acetyl-5-di-n-propylaminothiophene in Step A. The product was purified by HPLC on C-18 stationary phase. 1H NMR (DMSO-d6) 6 7.95 J =4.8 Hz, 1H), 6.81 1H), 6.19 J =4.8 Hz, 1H), 3.38 J =7.5 Hz, 4H), 1.62 J =7.5 Hz, 4H), 0.89 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)
F
S
0
F
A mixture of 2-acetyl-5-aminothiophene hydrochloride (600 mg, 3.38 mmol), 4-fluorobenzyl bromide (0.92 mL, 7.43 mmol), and Cs 2 CO, (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 HC1. After stirring at rt for 1 h, the pH of the mixture was adjusted to The organic extract was washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was subjected to column chromatography on -96- WO 99/62897 PCT/US99/1 2094 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-4fluorobenzylamino)thiophen-2-yl]butanoic acid F- N \I S
OH
0 0
F
The title compound was prepared using the protocol described in Example AI(4), Step A and C substituting thiophene with 2-acetyl-5-(di-4-fluorobenzylamino)thiophene in Step A.
1H NMR (CDCl3) 6 7.66 J =4.6 Hz, 1H), 7.2-7.0 8H), 6.78 1H), 6.14 J =4.6 Hz, 1H), 4.59 4H).
EXAMPLE 28 2,4-dioxo-4-[5-(N-benzyl-N-methylamino)thiophen-2-yl]butanoic acid Step A: Preparation of methylamino)thiophene FII(la)
H
3 C
S
O
A solution of cesium carbonate (3.25 g, 10 mmol), N-methyl-Nbenzylamine (2.58 mL, 20 mmol) and 2-acetyl-5-chlorothiophene (1.61 g, 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 -97- WO 99/62897 PCT/US99/12094 aqueous HC1. After stirring at rt for 1 h, pH of the solution was adjusted to -8 with sat. aq. NaHC03, 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-Nmethylamino)thiophen-2-yl]butanoic acid FII(3a)
H
3 C S OH 0 0 The title compound was prepared using the protocol described in Example AI(4), Step A and C substituting thiophene with 2-acetyl-5-(benzylmethylamino)thiophene in Step A. 1H NMR (CDC13) 5 7.70 J =4.6 Hz, 1H), 7.4-7.2 5H), 6.77 (br s, 1H), 6.10 J =4.6 Hz, 1H), 4.62 2H), 3.15 3H).
EXAMPLE 29 2,4-dioxo-4-(5-piperidin-1-yl-thiophen-2-yl)butanoic acid Step A: Preparation of 2-acetyl-5-piperidin-1-yl-thiophene FII(2b)
N
S
0 O 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.
-98- WO 99/62897 PCT/US99/12094 Step B: Preparation of 2,4-dioxo-4-(5-piperidin-l-yl-thiophen-2yl)butanoic acid FII(3b) S OH O O The title compound was prepared using the protocol described in Example AI(4), Step A and C substituting thiophene with 2-acetyl-5-piperidin-1-yl-thiophene in Step A. 1H NMR (CDC13) 5 7.70 J =4.8 Hz, 1H), 6.77 (br s, 1H), 6.13 J =4.6 Hz, 1H), 3.41 J =5.7 Hz, 4H), 1.7 6H).
EXAMPLE 2,4-dioxo-4-[5-(benzylbenzenesulfonylamino)thiophen-2-yl]butanoic acid Step A: Preparation of FIII(1)
H
N'I
02
S
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. HC1. 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.
-99- WO 99/62897 PCT/US99/12094 Collection and concentration of appropriate fractions provided the title sulfonamide.
Step B: Preparation of (benzylbenzenesulfonylamino)thiophene FIII(2) 0 2 S S b 0 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, 1M) in THF was added. The resultant deep red solution was stirred at rt for h, and treated with benzyl bromide (89.2 pL, 0.75 mmol), and stirred at rt overnight. The product mixture was concentrated under vacuum, and the residue was partitioned between dichloromethane and aq. HC1. The organic extract was washed with brine, dried over anhydrous MgSO4, 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 FIII(4) 0 2 S\ S OH -100- WO 99/62897 PCT/US99/12094 The title compound was prepared using the protocol described in Example AI(4), Step A and C substituting thiophene with 2-acetyl-5-(benzylbenzenesulfonylamino)thiophene in Step A. 1H NMR (CDC13) 8 7.76 J =4.5 Hz, 1H), 7.7-7.5 5H), 7.3 (m, 5H), 6.83 (br s, 1H), 6.82 J =4.5 Hz, 1H), 4.83 4H).
EXAMPLE 31 2,4-dioxo-4-(2-dibenzylaminothiazol-5-yl)butanoic acid Step A: Preparation of 1,1-dibenzylthiourea GI(la)
NH
2
N
S
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. NaHC03. 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 1,1-dibenzyl-3dimethylaminomethylenethiourea GI(2a) -101- WO 99/62897 PCT/US99/12094
N-
S
A mixture of 1,1-dibenzylthiourea (4.0 g, 15.6 mmol) and N,Ndimethylformamide 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)
N
S
A solution of 1,1-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 Na2SO4, 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-5yl)butanoic acid -102- WO 99/62897 PCT/US99/12094 N OH bly- OH 0 0 The title compound was prepared using the protocol described in Example AI(4), Step A and C substituting thiophene with 2-dibenzylamino-5-acetylthiazole in Step A. The product was purified by recrystallization from toluene. 1H NMR (CDC13) 6 8.19 1H), 7.40-7.20 10H), 6.81 1H), 4.76 4H).
EXAMPLE 32 2,4-dioxo-4-(2-benzylaminothiazol-5-yl)butanoic acid Step A: Preparation of 1-benzyl-3-dimethylaminomethylenethiourea GI(2b)
N-
07N H S A mixture of 1-benzylthiourea (8.3 g, 50 mmol) and N,N-dimethylformamide 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) -103- WO 99/62897 PCT/US99/12094
N
N-
I
H S A solution..of 1-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. NaHCO3, brine, dried over Na2SO4, 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-5yl)butanoic acid N
O
H S3 OH 0 0 The title compound was prepared using the protocol described in Example AI(4), Step A and C substituting thiophene with 2-benzylamino-5-acetylthiazole in Step A. The product was purified by recrystallization from a mixture of THF and hexane. 1H NMR (DMSO-d6) 8 9.50 (br s, 1H), 8.39 1H), 7.40-7.20 5H), 6.88 (s, 1H), 4.57 J=5.4 Hz, 2H).
EXAMPLE 33 2,4-dioxo-4-(2-N-benzyl-N-methylaminothiazol-5-yl)butanoic acid Step A: Preparation of GI(3c) -104- WO 99/62897 WO 9962897PCT/US99/1 2094
N
H
3 0 S y 0 The title compound was prepared using the protocol described in Example GI(5a), Step A C substituting N,N-dibenzylamine with Nbenzyl-N-methylamine in Step A.
Step B: Preparation of 2,4-dioxo-4-(2-N-benzyl-Nacid N0
N-<
H
3 C/ S) OH 0 0 The title compound was prepared using the protocol described in Example AI(4), Step A and C substituting thiophene with 2-N-benzyl-N-methylamino-5-acetylthiazole in Step A.
The product was purified by recrystallization from tolluene. 1H NMR (CDCl3) 8 8.01 1H), 7.40-7.20 (in, 5H1), 6.78 1H), 4.82 2H), 3.15 (s, 3H).
EXAMPLE 34 2 ,4-dioxo-4-( 2-dibenzylaininothiazol-4-yl )butanoic acid Step A: Preparation of 2-dibenzylamino-4-acetylthiazole GJI(3) 105 WO 99/62897 PCT/US99/12094
S
N
0 A suspension of 1,1-dibenzylthiourea (3.05 g, 11.9 mmol) in absolute ethanol (40 mL) was treated with 1-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 and white solid precipitated. The white solid was dissolved in ethyl acetate, and washed with sat. aq. NaHCO3. The organic extract was washed with brine, dried over Na2SO4, 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-4yl)butanoid acid N "r
OH
0 0 The title compound was prepared using the protocol described in Example AI(4), Step A and C substituting 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. 1H NMR (CDC13) 5 7.56 1H), 7.40-7.20 11H), 4.70 4H).
EXAMPLE HIV Integrase Assay: Strand Transfer Catalyzed by Recombinant Integrase and Preintegration Complexes -106- WO 99/62897 PCT/US99/12094 Assays for the strand transfer activity of integrase were conducted according to Wolfe, A.L. et al., J. Virol. 70, 1424 (1996), and Farnet, C.M. 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 IC50's of less than 1 micromolar.
EXAMPLE 36 Assay for inhibition of HIV replication Assays for the inhibition of acute HIV infection of Tlymphoid 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.
-107-
Claims (4)
1. The compound of structural formula R1 R2 A OH R 8 0 0 (I) and tautomers and pharmaceutically acceptable salts thereof, wherein: A is selected from: thienyl, thiazolyl, (3) S (4) S ,and 1 R is selected from: -H, -CH 3 -CF 3 -halo, -NO 2 4 -N(R -phenyl,
108- A-MENDS SHEET 20235YPCT/US 99/12094 IPENJUS SO MAY 2000 substituted phenyl substituted with 1 or 2 substituents independently selected from: halogen, C 1 6 alkyl, C 1 6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 6 alkyl, (iii) -CF 3 and (iv) hydroxy; phenyl CI- 3 alkyl-, substituted phenyl Cl 1 3 alkyl- substituted with 1 or 2 substituents independently selected from: halogen, C 1 6 alkyl, C 1 6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, 00i C- 6 alkyl, (iii) -CF 3 and (iv) hydroxy; 3 (11) -C 2 5 alkenyl-R 109 AMENDED SHEET 20235Y IPEA/US 3 MAY 2000 3 (12) -C 2 5 alkynyl-R and (13) -C(O)CH2C(O)C(O)0R 7 2 R is selected from: -H, 3 -R, -C 1 6 alkyl, 3 -C 1 6 alkyl substituted with R 6 -O-R -0-Cl- 6 alkyl-OR 6 -S(O)n-R 6 4 -C 1 6 alkyl (OR 4 6 -C 1 6 alkyl (OR 4 6 -CO 0 6 alkyl-N(R 6 011) -C 1 6 alkyl S(O)n-R 6 (12) -CO. 6 alkyl C(O)-R -CO 0 6 alkyl C(S)-R, 4 6 (14) -C 0 6 alkyl NR C(O)-R ,and 4 -C 0 6 alkyl-C(O)N(R 3 each R is independently selected from: phenyl; substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen, C 1 6 alkyl, CI- 6 alkyloxy-, phenyl, AMENDED %WE 20235Y POT/US 99112094 IPEA/US SO MvAY 2000 -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) CI- 6 alkyl, (iii) ,-CF 3 and (iv) hydroxy; thienyl; substituted thienyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C1- 6 alkyl, C1- 6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C1-6 alkyl, (iii) -CF 3 and (iv) hydroxy; pyridyl; substituted pyridyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C1- 6 alkyl, C1- 6 alkyloxy-, phenyl, 111 AMENDED SHEET 0235Y PCTIUS 99f 12094 IPEA/US 0 MAY 2000 -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C1- 6 alkyl, (iii) -CF 3 and (iv) hydroxy; imidazolyl; substituted imidazolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C1- 6 alkyl, C1- 6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C1- 6 alkyl, (iii) -CF 3 and (iv) hydroxy; pyrrolyl; substituted pyrrolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 -6 alkyl, C1- 6 alkyloxy-, phenyl, -112- AMENDED Si*JE 20235Y PCTIU'S 9,7 /i209 4 IPEA/US 3 O0MAY 2000 -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (iii) -CF 3 and (iv) hydroxy; (11) pyrazolyl; (12) substituted pyrazolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 6 alkyl, CI- 6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 6 alkyl, (iii) -CF 3 and (iv) hydroxy; (13) C 3 6 cycloalkyl; (14) substituted C 3 6 cycloalkyl with 1 or 2 substituents independently selected from: halogen, C 1 6 alkyl, C 1 6 alkyloxy-, -CF 3 1 1 3 AMENDED SHEET 20235Y IPEA/US 30 MAY 2000 -OCF 3 -CN, and hydroxy; (15) piperidinyl; (16) substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C1- 6 alkyl, C1- 6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; (17) morpholinyl; (18) substituted morpholinyl substituted at a carbon or nitrogen atom with 1 or 2 substituents independently selected from: halogen, C1- 6 alkyl, C1- 6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; (19) naphthyl, substituted naphthyl with 1, 2, or 3 substituents independently selected from: -halogen, -C1- 6 alkyl, CI-6 alkyloxy-, -CF 3 -OCF 3 F_ -114- AMLNODlW SH*E' 20235Y POT/US 9 /12094 IPEAUS 30 MAY 2000 -CN, and -hydroxy; (21) indolyl; (22) substituted indolyl substituted on a carbon atom with one or two substituents independently selected from: -halogen, -C1- 6 alkyl, C1- 6 alkyloxy-, -CF 3 -OCF 3 -CN, and -hydroxy; (23) C 3 -6 cycloalkyl fused with a phenyl ring (24) substituted C 3 -6 cycloalkyl fused with a phenyl ring substituted on a carbon atom with one or two substituents independently selected from: halogen, C1- 6 alkyl, C1- 6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; 4 each R is independently selected from: -H, -C 1 3 alkyl, -CF 3 3 -R -C 2 3 alkenyl, 3 -C1- 3 alkyl-R 3 -C 2 3 alkenyl-R -115- \jF )AMENDED SHEET 116 3 -S(O)n-R ,and 3 each R is independently selected from: -H, -C1- 3 alkyl, -CF 3 3 -R -C 2 3 alkenyl, 3 -C1- 3 alkyl-R 3 -C 2 3 alkenyl-R -S(O)n-R ,and 3 -C(O)-R 15 each R 6 is independently selected from: -CI- 3 alkyl-R 3 and -R 3 7 is H. R 8 is selected from hydrogen, methyl and methoxy; each n is independently selected fom and 2, and each m is independently selected from 0, 1 and 2, and .i and provided that when A is thienyl or thiazolyl and R 2 is -H or 6 alkyl, then R1 is not -H, -CH 3 or -phenyl; o2025Y PCT/US 9 9 12094 IPENUS MAY 2000 when A is thienyl or thiazolyl and R 2 is -R 3 wherein R 3 is unsubstituted phenyl, then RI is not -H or -CH 3 when A is thienyl and R 2 is -H or -C 1 -6 alkyl, then R1 is not -halo, -NO 2 or -N(R 4 when R 4 and R 5 are both and when A is thienyl and R 2 is -R 3 wherein R 3 is imidiazolyl or (17) morpholinyl, then R1 is not -H, -CH 3 -halo, -NO 2 or -N(R 4 when R 4 and R5 are both -H. 2. The compound according to Claim 1, and tautomers and pharmaceutically acceptable salts thereof, wherein: A is selected from: thienyl, thiazolyl, (3) S and (4) S 1 R is selected from: -H, -CH 3 -CF 3 -117- AMENDED SHEET 2023 P T/US rf 1209 IPEA JS 3 0 MAY -halo, -NO 2 4 -N(R -phenyl, substituted phenyl substituted with 1 or 2 substituents independently selected from: halo, methyl, and methoxy, phenyl C 1 3 alkyl-, substituted phenyl C1- 3 alkyl- substituted with 1 or 2 substituents independently selected from: halo, methyl, and methoxy, and 3 (11) -C 2 5 alkenyl-R 2 R is selected from: -H, 3 -R -C1- 6 alkyl, 3 -C1- 6 alkyl substituted with R 6 -O-R 6 -S(O)n-R 6 4 -C1- 6 alkyl (OR 4 6 -C1- 6 alkyl (OR 4 6 -CO- 6 alkyl-N(R 6 -C 1 6 alkyl S(O)n-R 6 (11) -CO- 6 alkyl C(O)-R
118- AMEN SGMES 20235YP T/US /12094 IPEA/US 30 MAY 2000 4 6 (12) -CO- 6 alkyl NR C(O)-R and 4 (13) -CO- 6 alkyl-C(O)N(R 3 each R is independently selected from: phenyl; substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen, C1- 6 alkyl, C1- 6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C1-6 alkyl, (iii) -CF 3 and (iv) hydroxy; thienyl; substituted thienyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C1- 6 alkyl, C1- 6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and -119 AMENDED SHEET 20235Y rwiju5 I 1/ 12094 IPEA/US SOU MAY 2000 substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, 00i CI- 6 alkyl, (iii) -CF 3 and (iv) hydroxy; pyridyl; substituted pyridyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 6 alkyl, C1- 6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 6 alkyl, (iii) -CF 3 and (iv) hydroxy; imidazolyl; pyrrolyl; pyrazolyl; C 3 6 cycloalkyl, (11) substituted C 3 6 cycloalkyl with 1 or 2 substituents independently selected from: halogen, Cl- 6 alkyl, C 1 6 alkyloxy-, -CF 3 -OCF 3 -CN, -120- 20235Y PCT/US 9 /12094 IPEA/US 3 0 MAY 2000 and hydroxy; (12) piperidinyl; (13) substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C1- 6 alkyl, C1- 6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; (14) morpholinyl; (15) naphthyl; (16) indolyl; and (17) C 3 -6 cycloalkyl fused with a phenyl ring; 4 each R is independently selected from: -H, -C1- 3 alkyl, -CF 3 3 -R -C 2 3 aikenyl, 3 -C1- 3 alkyl-R and 3 -S(O)n-R and each R is independently selected from: -H, -C1- 3 alkyl, -CF 3 3 -R 121 S1 i' AMENDED SIHET 20235Y PCTAJs 12 09 4 IPEAIUS u MA ~IY 2000 -C 2 3 alkenyl, 3 -C 1 3 alkyl-R 3 -C 2 3 alkenyl-R and 3 -S(O)n-R 6 each R is independently selected from: 3 -CI- 3 alkyl-R ,and 3 -R; R8 is H; and each n is independently selected from 0, 1 and 2; and provided that when A is thienyl or thiazolyl and R 2 is -H or -Cl- 6 alkyl, then RI is not -H, -CH 3 or -phenyl; when A is thienyl or thiazolyl. and R 2 is -R 3 wherein R 3 is unsubstituted phenyl, then RI is not -H or -CH 3 and when A is thienyl and R 2 is -H or -C 1 6 alkyl, then R 1 is not (D) or (17) morpholinyl, -halo, -NO 2 or -N(R 4 when R 4 and R 5 are both and when A is thienyl and R 2 is -R 3 wherein R 3 is imidiazolyl then R I is not -H, -CH 3 -halo, -NO 2 or 122 AMENDED SHM~ SPCTUS 9/1209 4 IPEA/US U MAY 2000 -N(R 4 when R 4 and R5 are both -H. 3. The compound according to Claim 1 of structural formula: R S OH O O and tautomers and pharmaceutically acceptable salts thereof, wherein: 2 R is selected from: 3 -R 3 -C1- 6 alkyl substituted with R 6 -O-R, 6 -S(O)n-R 6 4 -C1- 6 alkyl (OR 4 6 -C1- 6 alkyl (OR 4 6 -CO- 6 alkyl-N(R 6 -C 1 6 alkyl S(O)n-R 6 -CO- 6 alkyl C(O)-R 4 6 -CO- 6 alkyl NR C(O)-R and 4 (11) -CO- 6 alkyl-C(O)N(R 3 each R is independently selected from: phenyl, substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen selected from -Cl, and -Br, CH 3 123 AMErNDW SHW' Or'%IUS9V/12094 IPENUS bU MAY 2000 methoxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen selected from -Cl, and -Br, (ii) -CH 3 (iii) -CF 3 and (iv) hydroxy; thienyl, pyridyl, imidazolyl, pyrrolyl, pyrazolyl, C 3 6 cycloalkyl, piperidinyl, (10) morpholinyl, (11) naphthyl, (12) indolyl, and (13) C 3 6 cycloalkyl fused with a phenyl ring; 4 each R is independently selected from: -H, -CI- 3 alkyl, -CF 3 3 -R, -C 2 3 alkenyl, 3 -C 1 3 alkyl-R ,and 3 -S(O)n-R -124- 'viENOW SHEE PCT/US 99/12094 IPEA/US 6 0 MAY 2000 each R is independently selected from: -H, -C1- 3 alkyl, -CF 3 3 -R, -C 2 -3 alkenyl, 3 -C1-3 alkyl-R 3 -C 2 3 alkenyl-R and 3 -S(O)n-R 6 each R is independently selected from: 3 -C1- 3 alkyl-R and 3 -R and each n is independently selected from 0, 1 and 2; and provided that when R 2 is -R then R 3 is not unsubstituted phenyl, unsubstituted imidazolyl, or unsubstituted morpholinyl. 4. The compound according to Claim 3 selected from: (1) O O 0 0 -125- AdMENJOD SHI*O' 20235Y POT/US 't/12O9' IPEAUS ;j u MAY 2000 o~I 0 S OH s0 0 F F-C S. OH ,w Sl, OH 0 0 F SO OH 0 0 -126- AMENDED SWE 20235Y PCT/US 1209 4 IPEA/US U MAY 2000 1 0 S OH 0 0 0 S OH 0 s OH 6.1 0 0r" (11) s I 0 S OH 0 0 O 127 AMENDED SHEET 20235Y PMTUM 99i/12094 IPEA/US 3o MAY 2000 (12) (13) 'OH (14) S0 0 128 -,MvINOED Wl 20235Y POT/"US 99/12094' IPENIUS 3 0 MAY 2000 (16) 0 0 H s OH 0 (17) (18) (19) 'OH 129 K ic~ I, AMENDED S1HM 20235Y POT/US 12094 IPENUS 3 0 MAY 2000 0 H 0 c S OH 0 (21) Sj, OH 0 0 (22) 0 025'S OH 0-0 0 (23) s~I 0 OH Q-1s 0 0 (24) 0 -i 0 0 130 AMEfNDO SHM 20235Y POT/US Y/ 12094 IPEA/US S U MAY 2000 (26) (27) o~0 0 0~ Oand (28) S OH 0 0 Cl and tautomers and pharmaceutically acceptable salts thereof. The compound according to Claim 1 of structural formula: 131 A AMNDED SHE 20235Y K /S )Y 2 9 IPEAIUS S Uj MvAY 2000 R 8 R OH 0 0 and tautomers; and pharmaceutically acceptable salts thereof, wherein: 2 R is selected from: 3 -R, 3 -Cl 1 6 alkyl substituted with R 6 -0-R 6 -S(O)n-R 6 4 -C 1 6 alkyl (OR 4 6 -Cl 1 6 alkyl (OR 4 6 -C- 6 alkyl-N(R 6 -CI-6 alkyl S(O)n-R 6 -CO 0 6 alkyl C(O)-R 4 6 -CO 0 6 alkyl NR C(O)-R ,and 4 (11) -CO 0 6 alkyl-C(O)N(R 3 each R is independently selected from: phenyl, substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen selected from -Cl, and -Br, CH 3 methoxy-, phenyl, -CF 3 132 (4AMENE SN~ 20235YPCT/US 9 I12O9J, IPEA/US MA w,.Y 2000 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen selected from -Cl, and -Br, (ii) -CH 3 (iii) -CF 3 and (iv) hydroxy; thienyl, pyridyl, imidazolyl, pyrrolyl, pyrazolyl, C 3 6 cycloalkyl, piperidinyl, morpholinyl, (11) naphthyl, (12) indolyl, and (13) C 3 6 cycloalkyl fused with a phenyl ring; 4 each R is independently selected from: -H, -C 1 3 alkyl, -CF 3 3 -R, -C 2 3 alkenyl, 3 -C 1 3 alkyl-R ,and 3 -S(O)n-R each R is independently selected from: -H, -Cl- 3 alkyl, 133 'EDD 20235Y PCT/US 99/12094 IPEA/US U MAY 2000 -CF 3 3 -R -C 2 3 alkenyl, 3 -C1- 3 alkyl-R 3 -C 2 3 alkenyl-R and 3 -S(O)n-R 6 each R is independently selected from: 3 -C1- 3 alkyl-R and 3 -R R8 is selected from methyl and hydrogen; and each n is independently selected from 0, 1 and 2; and provided that when R 2 is -R 3 then R 3 is not unsubstituted phenyl, unsubstituted imidazolyl, or unsubstituted morpholinyl. 6. The compound according to Claim 5 selected from: (1) S 0 OH O -134- I /;AltV D SHMK 20235Y PCTUS P/I2094 IpEA/US 30 MAY 2000 OH 0 0 F (4) 0 OH 0000 ,and va 135 A,'vIENDED SUET 20235Y PCT/US /i 120 9 IPEA/US 30MAY201 9 and tautomers and pharmaceutically acceptable salts thereof. 7. The compound according to Claim 1 of structural formula: SY OH R 2 0 0 and tautomers and pharmaceutically acceptable salts thereof, wherein: 2 R is selected from: 3 -R 3 -C1- 6 alkyl substituted with R 6 -O-R 6 -S(O)n-R 6 4 -C1- 6 alkyl (OR 4 6 -C1- 6 alkyl (OR 4 6 -CO- 6 alkyl-N(R 6 -C1- 6 alkyl S(O)n-R 6 -CO- 6 alkyl C(O)-R 4 6 -CO- 6 alkyl NR C(O)-R and 4 (11) -CO- 6 alkyl-C(O)N(R 3 each R is independently selected from: phenyl, substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen selected from -Cl, and -Br, CH 3 methoxy-, -136- A,-3 j'N 20235Y PCT/US /12094 IPEAUS 30 MAY 2000 phenyl, -CF 3 -OCF 3 -CN, hydroxy, phcnyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen selected from -Cl, and -Br, (ii) -CH 3 (iii) -CF 3 and (iv) hydroxy; thienyl, pyridyl, imidazolyl, pyrrolyl, pyrazolyl, C 3 -6 cycloalkyl, piperidinyl, morpholinyl, (11) naphthyl, (12) indolyl, and (13) C 3 -6 cycloalkyl fused with a phenyl ring; 4 each R is independently selected from: -H, -C1- 3 alkyl, -CF 3 3 -R, -C 2 3 alkenyl, 3 -C 1 3 alkyl-R and 3 -S(O)n-R each R is independently selected from: -137- ",^ES 20235Ymr%'PCT/US V 1/12O 9J. IPEAIUS 3 0 MAY 2000 -H, -CI- 3 alkyl, -CF 3 3 -R, -C 2 3 alkenyl, 3 -C 1 3 alkyl-R 3 -C 2 3 alkenyl-R ,and 3 -S(O)n-R 6 each R is independently selected from: 3 -CI- 3 alkyl-R ,and 3 -R and each n is independently selected from 0, 1 and 2; 2 3 3 and provided that when R is -R then R is not unsubstituted phenyl, unsubstituted imidazolyl, or unsubstituted morpholinyl. 8. The compound according to Claim 7 selected from: (1) F 138 AMNDW SWT 20235Y pcT/US 99/12094 IpEAJIS 3 0 MAY Z000 0 S CI 00OH and tautomers and pharmaceutically acceptable salts thereof. 9. The compound according to Claim 1 of structural formula: N 0W S2 OH 0 0 139 '2' 'I U ,12)) W4OW SD ET 20235Y 2 PGTIUS I Vl IL u' 4 IPEA/US 30 MAY 2000 and tautomers and pharmaceutically acceptable salts thereof, wherein: 2 R is selected from: 3 -R 3 -C1- 6 alkyl substituted with R 6 -O-R, 6 -S(O)n-R 6 4 -C1- 6 alkyl (OR 4 6 -C1- 6 alkyl (OR 4 6 -CO- 6 alkyl-N(R 6 -CI- 6 alkyl S(O)n-R 6 -CO- 6 alkyl C(O)-R 4 6 -CO- 6 alkyl NR C(O)-R and 4 (11) -CO- 6 alkyl-C(O)N(R 3 each R is independently selected from: phenyl, substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen selected from -Cl, and -Br, CH 3 methoxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: -140- 14ENOWE SNEVO I 20235Y POT/US v /12O09 4 IPENUS us MvAY 2000 halogen selected from -Cl, and -Br, (ii) -CH 3 S-CF 3 and (iv) hydroxy; thienyl, pyridyl, imidazolyl, pyrrolyl, pyrazolyl, C 3 6 cycloalkyl, piperidinyl, morpholinyl, (11) naphthyl, (12) indolyl, and (13) C 3 6 cycloalkyl fused with a phenyl ring; 4 each R is independently selected from: -H, -Cl- 3 alkyl, -CF 3 3 -R, -C 2 3 alkenyl, 3 -C 1 3 alkyl-R ,and 3 -S(O)n-R each R is independently selected from: -H, -CI- 3 alkyl, -CF 3 3 -R, -C 2 3 alkenyl, 3 -Cl 1 3 alkyl-R 141 AMNE 'HW el 20235Y PCT/US 99/12094 IPEA/US 0 MAY 2000 3 -C 2 3 alkenyl-R and 3 -S(O)n-R 6 each R is independently selected from: 3 -C1- 3 alkyl-R and 3 -R and each n is independently selected from 0, 1 and 2; and provided that when R 2 is -R 3 then R 3 is not unsubstituted phenyl. The compound according to Claim 9 selected from: (1) /N O S OH 0 (2) H "OH 0 0 -142- 7 ,J C 20235Y POT/US 99112094 IPENUS S U MAY 2000 N 0 H,C Sly y OH 0 0 H -OH ,and 0 0 -143- AMIEhED S 20235Y PMr/Us 99f 12094 IPEIS. 30MALY ZOOO S 0 OH 0 and tautomers and pharmaceutically acceptable salts thereof. 11. The compound according to Claim 1 selected from: (1) 0 OH 0 0 S OH CI 0 0 -144- AMENDED WO 20235Y POT/US 99fJ209* IPEA/VS 3 0 MAY 2000 S 0 OH .0000 -OH O0H OH and 0 0 and tautomers and pharmaceutically acceptable salts thereof. 145 'ii. AMiENDED MY~ POTUS 9 9f/12O09 4 IPEN/US 3 0 MAY 2000 12. The compound according to Claim 1 selected from: 2,4-dioxo-4-(5-phenethylthiophen-2-yl)butanoic acid, ethyl 2,4-dioxo-4-(5-phenethylthiophen-2-yl)butanoate, 2,4-dioxo-4-(5-benzyloxythiophen-2-yl)butanoic acid, 2,4-dioxo-4-[5-(3-fluorobenzyloxy)thiophen-2-yl]butanoic acid, 2,4-dioxo-4-[5-(4-fluorobenzyloxy)thiophen-2-yllbutanoic acid, 2,4-dioxo-4-[5-(3 ,4-difluorobenzyloxy)thiophen-2-yllbutanoic acid, 2,4-dioxo-4-[5-(pyridin-2-ylmethyloxy)thiophen-2-yl Ibutanoic acid, 2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-2-yl]butanoic acid, ethyl 2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-2-yllbutanoate, 2,4-dioxo-4- [5-(4-fluorobenzyl)thiophen-2-yllbutanoic acid, (11) 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-yI )butanoic acid, (14) 2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-3-yl]butanoic acid, 2,4-dioxo-4-[5-(4-fluorobenzyl)thiophen-3-yl]butanoic acid, (16) 2,4-dioxo-4-[5-(3-chlorobenzyl)thiophen-3-y ]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, 2,4-dioxo-4-[2-(4-fluorobenzyl)thiophen-3-yllbutanoic acid, (21) 2,4-dioxo-4- [2-(3-chlorobenzyl)thiophen-3-yllbutanoic acid, (22) 2,4-dioxo-4-[5-(benzyloxy-phenylmethyl)thiophen-2-y] butanoic acid, (23) 2,4-dioxo-4-[5-(phenoxy-phenylmethyl)thiophen 2-yllbutanoic acid, (24) 2,4-dioxo-4-[5-(methoxy-phenylmethyl)thiophen-2-yllbutanoic 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-di oxo-4-(5 -di all ylami nothiophen-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, 2,4-dioxo-4- [5-(N-benzyl-N-methylamino)thiophen-2-yllbutanoic acid, (31) 2,4-dioxo-4-(5-piperi din-I1 -yl-thiophen-2-yl)butanoic acid, 146 9 iW NDED SHF 20235YPCT/US 99/12094 IPEA/US 3 0 MAY 2001 (32) 2,4-dioxo-4-[5-(benzylbenzenesulfonylamino)thiophen-2-yllbutanoic 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. 13. The compound according to Claim 12 selected from: 2,4-dioxo-4-(5-phenethylthiophen-2-yl)butanoic acid, 2,4-dioxo-4-(5-benzyloxythiophen-2-yl)butanoic acid, 2,4-dioxo-4-[5-(3-fluorobenzyloxy)thiophen-2-yl]butanoic acid, 2,4-dioxo-5-(4-fluorobenzyloxy)thiophen-2-yllbutanoic acid, 2,4-dioxo-4-[5-(3,4-difluorobenzyloxy)thiophen-2-yl ]butanoic acid, 2,4-dioxo-4-[5-(pyridin-2-ylmethyloxy)thiophen-2-yl ]butanoic acid, 2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-2-yl]butanoic acid, 2,4-dioxo-4-[5-(4-fluorobenzyl)thiophen-2-yl]butanoic acid, 2,4-dioxo-4-[5-(3-chlorobenzyl)thiophen-2-yl]butanoic acid, 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, (1)24doo4[-3clrbnzltipe-/lbtni cd (14) 2,4-dioxo-4-[5-(3-chlobezlthiophen-3-yl~butanoic acid, 2,4-dioxo-4-(5-beniuylthiophen--yl)butanoic acid, (16) 2,4-dioxo-4-(2-henlulfabnzylthiophen--ylbutanoic acid, 2,4-dioxo-4-[2-(3-fluorobenzyl)thiophen-3-yl]butanoic acid, (18) 2,4-dioxo-4- [2-(4-florobenzyl)thiophen-3-yl]butanoic acid, (19) 2,4-dioxo-4- [2-(3-chlooben letyl)thiophen-lbutanoic acid, 30(20) 2,4-dioxo-4-[5-(benyoxy-phenylmethyl)thiophen-2-ylbutanoic acid, 30(21) 2,4-dioxo-4-[5-(phoxy-phenylmethyl)thiophen-2-yl ]butanoic acid, (22) 2,4-dioxo-4- [5-(mbenoy-phnylhlthiophen-2-yl ]butanoic acid, (23) 2,4-dioxo-4-(5-dbenzylaminothiophen-2-yl)butanoic acid, (24) 2, 4 -dioxo-4-(5-benzlylaminothiophen-2-yl)butanoic acid, 147 I AMENDED SHUTJ 20235YPO-T/US 99112094 IPEN/US 3 0 MAY 2000 (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- 1-yl-thiophen-2-yl)butanoic acid, 2,4-dioxo-4- [5-(benzylbenzenesulfonylam-ino)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. 14. The compound according to Claim 13 selected from: 2,4-dioxo-4-[5-(3-chlorobenzyl)thiophen-2-yllbutanoic acid, 2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-3-yllbutanoic acid, 2,4-dioxo-4-[5-(4-fluorobenzyl)thiophen-3-yl]butanoic acid, 2,4-dioxo-4-[5-(3-chlorobenzyl)thiophen-3-yl]butanoic acid, 2,4-dioxo-4-(5-benzylthiophen-3-yl)butanoic acid, 2,4-dioxo-4-(2-phenylsulfanylthiophen-4-yl)butanoic acid, CII(4) 2,4-dioxo-4-[2-(3-chlorobenzyl)thiophen-3-yl]butanoic acid, 2,4-dioxo-4-[5-(benzyloxy-phenylmethyl)thiophen-2-yllbutanoic acid, 2,4-dioxo-4-[5-(phenoxy-phenylmethyl)thiophen-2-yllbutanoic acid, 2,4-dioxo-4-(5-dibenzylaminothiophen-2-yl)butanoic acid, (11) 2,4-dioxo-4-(5-diallylaminothiophen-2-yl )butanoic acid, (12) 2,4-di oxo-4-[5-(di-4-fluorobenzylamino)thiophen-2-yl]butanoic acid, (13) 2,4-dioxo-4-[5-(N-benzyl-N-methylamino)thiophen-2-yi]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. -148- ~"AMENDED SHM 20235YU IPEA/US 30 MAY 2000 A pharmaceutical composition useful for inhibiting HIV integrase, comprising an effective amount of a compound according to Claim I and a pharmaceutically acceptable carrier. 16. The pharmaceutical composition of Claim 15, useful for treating infection by HIV, or for treating AIDS or ARC. 17. A pharmaceutical composition comprising a therapeutically effective amount of a compound of structural formula R R .R AOR 7 R 8 O O (I) or tautomers or pharmaceutically acceptable salts thereof, in combination with a therapeutically effective amount of an AIDS treatment agent selected from an AIDS antiviral agent, an anti-infective agent, and an immunomodulator; wherein A is a five-membered heteroaromatic ring containing 1 sulfur atom and 0 or 1 1 2 8 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: S-or- or R is selected from: -H, -C1- 5 alkyl, -CF 3 -halo, -NO 2
149- "AMENDED SW r 20235YPCT/US 99/12094 IPEN/US 3 0 MAY 2000 4 -N(R -R 6 3 -C 2 5 alkenyl-R 3 -C 2 5 alkynyl-R (10) -O-R 6 (11) -0-Cl-6 alkyl, and (12) -C(O)CH2C(O)C(O)0R 7 2 R is selected from: -H, 3 -R, -CI- 6 alkyl, 3 -CI- 6 alkyl substituted with R. 6 -O-R 6 -0-CI-6 alkyl-OR 6 -S(O)n-R 6 4 -C 1 6 alkyl (OR 4 6 -CO 1 6 alkyl(R 46 20(10) -C 1 6 alkyl-N(R 6 20(11) -C 1 6 alkylS(O)n-R 6 (12) -CO 0 6 alkyl C(O)-R 4 6 (14) -CO 0 6 alkyl NR C(O)-R ,and 4 -CO. 6 alkyl-C(O)N(R 3 each R is independently selected from: 150 CIE *C. r ullo U/ 1/UY4 IPEA/US 30 MAY 2000 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 substituents selected from: halogen, C1- 6 alkyl, C1- 6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C1-6 alkyl, (iii) -CF 3 and (iv) hydroxy; 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: halogen, C1- 6 alkyl, C1- 6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; unsubstituted or substituted hexahydrothieno[3,4-d]imidazolyl with one or two substituents selected from: oxo, -151- t',NOED SWI 152 halogen, C1- 6 alkyl, CI- 6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; 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: -halogen, S(b) -C- 6 alkyl, 15 -C1- 6 alkyloxy-, -CF3, -OCF 3 -CN, and -hydroxy; 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: halogen, C 1-6 alkyl, CI-6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; 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: 153 halogen, C 1 6 alkyl, C 1 6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; 4 each R is independently selected from: -H, -C 1 3 alkyl, -CF 3 3 -R, -C 2 3 alkenyl, 3 -CI- 3 alkyl-R 3 -C 2 3 alkenyl-R 3 -S(O)n-R ,and 3 -C(0)-R each R is independently selected from: -H, -CI- 3 alkyl, -CF 3 3 -R, -C 2 3 alkenyl, 3 -C 1 3 alkyl-R -C 2 3 alkenyl-R3 3 -S(O)n-R ,and 3 -C(0)-R 154 6 *each R is independent-y selected from: -Cl- 3 alkyl-R and -R; R 7 is selected from: and C1-6 alkyl; R 8 is selected from: and CI-6 alkyl-oxy-, and S(3) C1-6 alkyl-; Seach n is independently selected from 0, 1 and 2, and each m is independently selected from 0, 1, and 2. 18. The composition of Claim 17 wherein the antiviral agent is an HIV protease inhibitor. S19. The composition of Claim 18 wherein the HIV protease inhibitor is N-(2(R)-hydroxy-l-(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(l- 4 3 -pyridy:methyl)-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide or a *pharmaceutically acceptable salt thereof. .i 20. A pharmaceutical composition made by combining the compound of Claim 1 and a pharmaceutically acceptable carrier. 21. A process for making a pharmaceutical composition comprising combining a compound of Claim 1 and a pharmaceutically acceptable carrier. \n i i o s -2 R y r x -l i d n l p e yl e h l4 S -y r x -l h y 2 s -N-tbtycroamd)ppeaiy))pnaealer 155 22. 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 structural formula R A RV OR 7 R 8 O O (I) or tautomers or pharmaceutically acceptable salts thereof, wherein: A is a five-membered heteroaromatic ring containing 1 sulfur atom and 0 or 1 nitrogen atoms and substituted on carbon by R 1 R2 and R; the heteroaromatic ring may optionally be fused with a phenyl ring or a C4-6 cycloalkyl ring, or with two six S. 10 membered rings to form: ror o R is selected from: -H, -C 1 5 alkyl, 15 -CF 3 S(7) -R 6 -C2- 5 alkenyl-R -C 2 5 alkynyl-R -O-R 6 (11) -O-C 1- 6 alkyl, and (12) -C(O)CH2C(O)C(O)OR7; 156 R is selected from: -H, 3 -R, -C 1 6 alkyl, -C 1 6 alkyl substituted with R 3 6 -O-R -0-CI- 6 alkyl-OR 6 -S(O)n-R 46 -CO 1 6 alkyl(R 46 -CI- 6 alkyl (OR)(-R 4 6* 15 (14 46y N n -C 0 6 alkyl-N(R a-5or 6 aembeyl a()roaiorhtrao irigcnanng01,2 (13) -C h 6 alylg(S)- -c 0 a aklkylO-, n 25(15) -C lkl(o)N( (d phnl 3 e C3 haogen, 157 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) CI-6 alkyl, (iii) -CF 3 and (iv) hydroxy; a 3 to 6 membered saturated ring containing 0 or I heteroatoms selected from oxygen, nitrogen or sulfur, unsubstituted or substituted with 0 to 5 substituents selected from: halogen, C 1 6 alkyl, 15 CI- 6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; unsubstituted or substituted hexahydrothieno[3,4-d]imidazolyl with one or two substituents selected from: oxo, halogen, C 1 6 alkyl, C 1 -6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, or 2 heteroatoms selected from oxygen, nitrogen and sulfur, fused with a -1' 158 phenyl ring; wherein the ring system is unsubstituted or substituted on a nitrogen or carbon atom by 1 to 3 substituents selected from:* -halogen, -C1- 6 alkyl, -C 1 -6 alkyloxy-, -CF 3 -OCF 3 -CN, and -hydroxy; 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: halogen, S: 15 C1-6 alkyl, -CF 3 -OCF 3 -CN, and S(h) hydroxy; a 5 to 6 membered ring containing 0, 1 or 2 heteroatoms selected from Soxygen, nitrogen or sulfur, containing 2 or 3 double bonds, 25 unsubstituted or substituted with 1 or 2 substituents selected from: halogen, C 1 -6 alkyl, C 1 -6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; 159 each R 4is independently selected from: -CI- 3 alkyl, -CF 3 -R 3, -C 2 3 alkenyl, -CI- 3 alkyl-R3 -C 2 3 alkenyl-R3 3 each R is independently selected from: -H, -CI- 3 alkyl, -CF 3 3 -R, -C 2 3 alkenyl, 3 -CI- 3 alkyl-R -C 2 3 alkenyl-R -S(O)n-R ,and 3 -C(O)-R 9 6 each R is independently selected from: 3 -CI- 3 alkyl-R ,and -R; R 7 is selected from: and C 1-6 a]lkyl; 160 R 8 is selected from: and C1-6 alkyl-oxy-, and C1-6 alkyl-; each n is independently selected from 0, 1 and 2, and each m is independently selected from 0, 1, and 2. 23. 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 structural formula R 8 0 0 O O or tautomers or pharmaceutically acceptable salts thereof, wherein: A is a five-membered heteroaromatic ring containing 1 sulfur atom and 0 or 1 nitrogen atoms and substituted on carbon by R 1 R and R; the heteroaromatic ring *may optionally be fused with a phenyl ring or a C4-6 cycloalkyl ring, or with two six 20 membered rings to form: ,0or or i R is selected from: -H, -Cl-5 alkyl, -CF3, -halo, -NO2, SI nstbto ma pinal efse ihaphn-rn o 4 ccoly rno it w i 0@ 0 0 0O 0 0 0* *0 0 a OSO 0O S 9@ *0 0 *5 0 0* @0 0 6 @000 0 *000 0* 0 S 0 0 *00000 0 0 0 90 0 0 0@ 0@ S @0 00 -N(R -R 6 C2-5alkeylR3, -C 2 5 alknyl-R3 -0-R 6 (11) -O-C 1-6 alkyl, and (12) -C(O)CH2C(O)C(O)0R7; 2 R is selected from: -H, 3 -R, -CI- 6 alkyl, -Cp-6 alkyl substituted with R 3 -O-R -0-CI- 6 alkyl-OR 6 6 -S(O)n-R -CI- 6 alkyl (OR 6)(R 4), -CI- 6 alkyl (OR 4)(R 6), -CO 0 6 alkyl-N(R 4)(R 6), 6 (11) -C 1 6 alkyl S(O)n-R (12) -CO. 6 alkyl C(O)-R 6 (13) -CO. 6 -alkyl C(S)-R6, (14) -CO 0 6 alkyl NR4C(O)-R 6, and -CO 0 6 alkyl-C(O)N(R 4)(R each R 3is independently selected from: a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, 2, 3, or 4 heteroatoms selected from oxygen, nitrogen and sulfur, 162 unsubstituted or substituted on a nitrogen or carbon atom by 1 to substituents selected from: halogen, C1- 6 alkyl, Cl- 6 alkyloxy-, phenyl, -CF3, -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C1- 6 alkyl, (iii) -CF 3 and hydroxy; 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: halogen, C1- 6 alkyl, C1- 6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; unsubstituted or substituted hexahydrothieno[3,4-d]imidazolyl with one or two substituents selected from: oxo, halogen, C1- 6 alkyl, 163 C 1 -6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; 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: -halogen, -C 1 -6 alkyl, -Cl-6 alkyloxy-, -CF 3 15 -OCF 3 S(f) -CN, and -hydroxy; 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 withi or 2 substituents selected from: halogen, CI-6 alkyl, C 1 -6 alkyloxy-, -CF 3 -OCF 3 S(f) -CN, and hydroxy; 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: halogen, C- 6 alkyl, C 1 6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; 4 each R Is independently selected from: -H, -C 1 3 alkyl, -CF 3 3 -R, -C 2 -3 alkenyl, C 1 3 alyl3 3 -C 2 -3 alkenyl-R 3 -S(O)n-R ,and 3 -C(0)-R each 25 R is independently selected from: -H, -CI- 3 alkyl, -CF 3 3 -R, -C 2 3 alkenyl, -I-3 akyl 3 -C2- 3 alkeyl-R 3 -C 2 3 n- alknd 3 -C(0)-R 165 each R 6 is independently selected from: -C 1 3 alkyl-R 3 and -R 3 R 7 is selected from: and C1 6 alkyl; R 8is selected from: and C 1 6 alkyl-oxy-, and C 1 6 alkyl-; each n is independently selected from 0, 1 and 2, and each mn is independently selected from 0, 1, and 2. 24. A compound of formula Ri 0 R 2 A OH R8 0 0 I) 15i and tautomers and pharmaceutically acceptable salts thereof, wherein: A is selected from: thienyl, thiazolyl, a s 20 ,and R1 is selected from: -H, -CH 3 -CF 3 -halo, -NO 2 -N(R 4 )(R 5 ()-phenyl, [1:\DayLib\LIBH]529782speci.doc:aak substituted phenyl substituted with I or 2 substituents independently selected from: halogen, C 1 6 a]lkyl, CI-6alkyloxy-, phenyl, -CF 3 Mf -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, Ci C 1 6 alkyl, (iii) -CF 3 and hydroxy; phenyl CI- 3 alkyl-, substituted phenyl C 1 3 alkyl- substituted with 1 or 2 substituents independently selected from: halogen, (b CI- 6 alkyl, CI- 6 alkyloxy-, phenyl, -CF 3 (f)J -OCF 3 -CN, (N hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: 0i) halogen, 00i C 1 6 alkyl, (ill) -CF 3 and (iv) hydroxy; (11) -C 2 5 alkenyl-R 167 (12) -C 2 5 alkynyl-R 3, and (13) -C(O)CH2C(O)C(O)0R7; R is selected from: -H, 3 -R, -CI- 6 alkyl, -C 1 6 alkyl substituted with R 3 -O-R -0-CI- 6 alkyl-OR6 6 -S(O)n-R 4 -C 1 6 alkyl (OR alkyl (OR 4)(R 6) *4 *6 -CO 0 6 alkyl-N(R 6 (11) -C 1 6 alkyl S(O)n-R 6 (12) -CO 0 6 alkyl C(O)-R -CO 0 6 alkyl C(S)-R6 (14) -CO 0 6 alkyl NR 4C(O)-R 6 and -CO 06 alkyl-C(O)N(R 4)(R 3 :each R is independently selected from: phenyl; substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen, CI- 6 alkyl, CI-6 alkyloxy-, phenyl, 168 -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents'selected from: halogen, (ii) C 1 6 alkyl, (iii) -CF 3 and (1iV) hydroxy; thienyl; substituted thienyl substituted on a carbon atom with one or two substituents independently selected from: halogen, 150 C- 6 alkyl, 09 0(c) C 1 6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: see*:(i) halogen, GOi C 1 6 alkyl, (iii) -CF 3 and Lee0 (iv) hydroxy; pyridyl; substituted pyridyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 6 alkyl, C 1 6 alkyloxy-, phenyl, 169 -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 6 alkyl, (HOi -CF 3 and (iV) hydroxy; imi dazolyl; substituted im-idazolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, (b C 1 6 alkyl, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, 00i C 1 6 alkyl, (iii) -CF 3 and (iv) hydroxy; pyrrolyl; substituted pyrrolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 6 al kyl, C 1 6 alkyloxy-, phenyl, 170 -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituent6 selected from: halogen, C 1 6 alkyl, ii) -CF 3 and (i v) hydroxy; (11) pyrazolyl; (12) substituted pyrazolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 6 alkyl, V(c) CI- 6 alkyloxy-, phenyl, V(e) -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 6 alkyl, (iii) -CF 3 and hydroxy; (13) C 3 6 cycloalkyl; (14) substituted C 3 6 cycloalkyl with I or 2 substituents independently selected from: halogen, C 1 6 alkyl, C 1 6 alkyloxy-, -CF 3 171 -OCF 3 -CN and hydroxy; (15) piperidinyl; (16) substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 6 alkyl, C 1 6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; morpholinyl; substituted morpholinyl substituted at a carbon or nitrogen atom with I 00 or 2 substituents independently selected from: halogen, 90:20 CI- 6 alkyl, C 1 6 alkyloxy-, -CF 3 -OCF 3 -CN, 025 and hydroxy; 0 5 (19) naphthyl, S.(20) substituted naphthyl with 1, 2, or 3 substituents independently selected from: -halogen, -C 1 6 alkyl, C 1 6 alkyloxy-, -CF 3 -OCF 3 -CN, and -hydroxy; (21) indolyl; (22) substituted indolyl substituwed on a carbon atom with one or two substituents Independently selected from: -halogen, -Cr- 6 alkyl, C 1 6 alkyloxy-, -CF 3 -OCF 3 Mf -CN, and -hydroxy; (23) C 3 6 cycloalkyl fused with a phenvl ring (24) substituted C 3 6 cycloalkyl fused with a phenyl ring substituted on a 015 carbon atom with one or two substituents independently selected from: halogen, C 16 alkyl, C 1 6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; 0 4 25 each R is independently selected from: -H, -CI- 3 alkyl, -CF 3 3 -R, -C 2 3 alkenyl, 3 -CI- 3 alkyl-R 3 -C 2 3 alkenyl-R LL' 173 3 -S(O)n-R and each R 5Is independently selected from: -H, -C 1 3 alkyl, -CF 3 3 -R, -C 2 3 alkenyl, -CI- 3 alkyl-R 3 3 -C 2 3 alkenyl-R 3 -S(O)n-R ,and -C(O)-R3 each R 6 is independently selected from: -C 1 3 alkyl-R 3 and -R 3 R' s H. R 8 is selected from hydrogen, methyl and methoxy; each n is independently selected from 0, 1 and 2, and ***each m is independently selected from 0, 1, and 2; and provided that when A is thienyl or thiazolyl and R 2 is -H or -C 1 6 alkyl, then Rl Is not -H, -CH 3 or -phenyl; 174 when A is thienyl or thiazolyl and R 2 is -R 3 wherein R 3 is unsubstituted phenyl, then R' is not -H or -CH 3 when A is thienyl and R 2 is -H or -C1- 6 alkyl, then R' is not -halo, -NO 2 or -N(R 4 )(R 5 when R 4 and R 5 are both and when A is thienyl and R 2 is -R 3 wherein R 3 is imidiazolyl or (17) morpholinyl, then R' is not -H, -CH 3 -halo, -NO 2 or -N(R 4 )(R 5 when R 4 and R 5 are both -H. said compound being substantially as hereinbefore described with reference to any one of the examples. A process for preparing a compound of formula R1 O R24OH R8 O 20 and tautomers and pharmaceutically acceptable salts thereof, wherein: A is selected from: thienyl, thiazolyl, ?S ,and R' is selected from: -CH 3 S -CF 3 -halo, [I:\DayLib\LIBH]529782speci.doc:aak (6) (7) (8) from: -NO 2 -phenyl, substituted phenyl substituted with 1 or 2 substituents independently selected halogen, (b C 1 6 alkyl, C 1 6 alkoxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, 00i C 1 6 alkyl, (iii) -CF 3 and (iv) hydroxy; phenyl Ci. 3 alkyl-, substituted phenyl C 1 3 alkyl- substituted with 1 or 2 substituents independently selected from: halogen, C 1 6 alkyl, C 1 6 alkoxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 6 alkyl, (Ili) -CF 3 and (iv) hydroxy; -C 2 5 alkenyl-R a a a a. a a. a a. a. [1:\DayLib\LIBH]529782speci .doc:aak (12) (13) -C 2 5 alkynyl-R 3, and -C(O)CH2C(O)C(O)0R7; 9 9 9 9 *9 .9 9 *9*9 9 9 R Is selected from: -H, -R,3 -C 1 6 a]lkyl, -C 1 6 alkyl substituted with R 3 -O-R -0-CI- 6 alkyl-OR 6 6 -S(O)n-R -CI- 6 alkyl (OR 6)(R 4), -CI- 6 alkyl (OR 4)(R 6), -CO 0 6 alkyl-N(R 4)(R 6), 6 (11) -C 1 6 alkyl S(O)n-R (12) -CO- alkl C()R6, (12) -CO 0 6 alkyl C(O)-R 6 (14) -CO. 6 alkyl NR 4C(O)-R 6 and (15) -C 0 6 alkyl-C(O)N(R 4)(R each R 3is independently selected from: phenyl; substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen, C 1 6 alkyl, C 1 6 alkyloxy-, phenyl, a a a a a. a -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituenti selected from: halogen, C 1 6 alkyl, 0ii0 -CF 3 and (i v) hydroxy; thienyl; substituted thienyl substituted on a carbon atom with one or two substituents Independently selected from: halogen, C 1 6 alkyl, C 1 6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, Wi phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, -CF 3 and (iv) hydroxy; pyridyl; substituted pyridyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 6 alkyl, C 1 6 alkyloxy-, pheny), a. a .a 178 -CF 3 -OCF3, -CN, hydroxy, i) phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituent selected from: halogen, 00i C 1 6 alkyl, (iii0 -CF 3 and (i v) hydroxy; imidazolyl; substituted imidazolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 6 alkyl, C 1 6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, ni henvloxyan substituted phenyloxy with 1, 2, or 3 substituents selected from: 0 halogen, 0 25 0ii) C 1 6 alkyl, (iii) -CF 3 and hydroxy; oo*0. pyrrolyl; substituted pyrrolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 6 alkyl, CI- 6 alkyloxy-, phenyl, -CF 3 (M -OCF 3 -CN, Nh hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituentg selected from: halogen, Cii C 1 6 alkyl, -CE 3 and (iv) hydroxy; pyrazolyl; (12) substituted pyrazolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C- 6 alkyl, C 1 6 alkyloxy-, phenyl, -C F 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (iii) -CF 3 and (13) (14) (iv) hydroxy; C 3 6 cycloalkyl; substituted C 3 6 cycloalkyl with I or 2 substituents independently selected from: halogen, C 1 6 alkyl, C 1 6 alkyloxy-, -CF 3 180 -OCF 3 -CN, and hydroxy; (15) piperidinyl; (16) substituted piper-idinyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 6 alkyl, C. 1 6 alkyloxy-, -CF 3 -OCF 3 -CN, and 0:15 hydroxy; (17) morpholinyl; (18) substituted morpholinyl substituted at a carbon or nitrogen atom with 1 or 2 substituents independently selected from: halogen, C- 6 alkyl, C 1 6 alkyloxy-, -CF 3 0000(e) -OCF 3 -CM =0an hydroxy; 19) naphthyl, substituted naphthyl with 1, 2, or 3 substituents independently selected from: -halogen, -C 1 6 al kyl, C 1 6 alkyloxy-, -CF 3 -OCF 3 181 -CN, and -hydroxy; (21) indolyl; (22) substituted indolyl substituted on a carbon atom with one or two subst-ituents independently selected from: -halogen, -C 1 6 a]lkyl, C 1 6 alkyloxy-, -CF 3 -OCF 3 -CN, and -hydroxy; (23) C 3 6 cycloalkyl fused with a phenvI ring (24) substituted C 3 6 cycloalkyl fused with a phenyl ring substituted on a 15 carbon atom with one or two substituents independently selected from: halogen, C 1 6 alkyl, C 1 6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; 4 each R is independently selected from: -H, -CI- 3 alkyl, -CF 3 3 -R, -C 2 3 alkenyl, -C 1 3 alkyl-R3 -C 2 3 alkenyl-R3 182 -S(O)n-R and 3 each R is independently selected from: -H, -CI- 3 alkyl, -CF 3 .3 -R, -C 2 3 alkenyl, -CI- 3 alkyl-R 3 -C 2 3 alkenyl-R -S(O)n-R ,and 3 -C(O)-R each R 6 is independently selected from: -C 1 3 alkyl-R 3 and -R 3 R7 s H. R 8 is selected from hydrogen, methyl and methoxy; each nis independently selected from 0, 1 and 2, and each m is independently selected from 0, 1, and 2; and provided that when A is thienyl or thiazolyl and R 2 is -H or -C 1 6 alkyl, then Ri Is not -H, -CH 3 or -phenyl; 183 when A is thienyl or thiazolyl and R 2 is -R 3 wherein R 3 is unsubstituted phenyl, then R' is not -Hor -CH 3 when A is thienyl and R 2 is -H or -CI-6 alkyl, then R' is not -halo, -NO 2 or -N(R 4 )(R 5 when R 4 and R 5 are both and when A is thienyl and R 2 is -R 3 wherein R 3 is imidiazolyl or (17) morpholinyl, then R' is not -H, -CH 3 -halo, -NO 2 or 15 -N(R 4 )(R 5 when R 4 and R 5 are both said processi being .substantially as hereinbefore described with reference to any one of the examples. 26. A pharmaceutical composition when prepared by the process of claim 21. 27. Use of a therapeutically effective amount of a compound according to claim 1 for the manufacture of a medicament for inhibiting HIV integrase in a mammal in need of 20 such treatment. 28. Use of a therapeutically effective amount of a compound according to claim 1 for the manufacture of a medicament for treating infection by HIV, or of treating AIDS or SARC in a mammal in need of such treatment. 29. A therapeutically effective amount of a compound according to claim 1 when used for inhibiting HIV integrase in a mammal in need of such treatment. A therapeutically effective amount of a compound according to claim 1 when used for treating infection by HIV, or for treating AIDS or ARC in a mammal in need of such treatment. 31. A compound of structural formula R 1 R1 O SR2 OH I. 8 R O O and tautomers and pharmaceutically acceptable salts thereof, wherein: SA is selected from: [I:\DayLib\LIBH]529782speci.doc:aak 184 thienyl, thiazolyl, nS S ,and R' is selected from: -H, -CH 3 -CF 3 -halo, 5(5) -NO 2 -N(R 4 5 -phenyl, substituted phenyl substituted with 1 or 2 substituents independently selected 5 from: halogen, S(b) C 1 6 alkyl, C 16 alkyloxy-, phenyl, 0. 20 -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 16 alkyl, 1 (iii) -CF 3 and (iv) hydroxy; F0 phenyl C 1 3 alkyl-, [I:\DayLib\LIBH]529782speci.doc:aak 0 185 substituted phenyl C 1 -3 alkyl-substituted with 1 or 2 substituents independently selected from: halogen, C 1 6 alkyl, C 1 6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, 0ii) C 1 6 alkyl, (iii) -CF 3 and (iv) hydroxy; (11) -C 2 5 alkenyl-R (12) -C 2 5 alkynyl-R 3 and (13) -C(O)CH 2 C(O)C(0)0R 7 R 2is selected from: -R -C 1 6 alkyl substituted with R -O-R 6 -0-C 1.-6 alkyl-0R -C 1 6 alkyl (OR 6 -C 1 6 alkyl (0R 4 6 -C 0 6 alkyl-N(R 4 6 -C 1 6 alkyl S (0)n-R 6 -C 0 6 allyl C(O)-R (11) -C 0 6 alkyl C(S)-R 6 (12) -C 0 6 alkyl NR 4 C(0)-R 6 and (13) -C 0 6 alkyl-C(O)N(R 4 5 each R 3 isindependently selected from: phenyl; [I:\DayLib\LIBH]529782speci.doc:aak 186 substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen, C 1 6 alkyl, CI- 6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, to phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C-6 alkyl, (iii) -CF 3 and 15 (iv) hydroxy; thienyl; substituted thienyl substituted on a carbon atom with one or two substituents independently selected from: halogen, 20 C 1 6 alkyl, C 1 6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C1-6 alkyl, (iii) -CF 3 and (iv) hydroxy; pyridyl; substituted pyridyl substituted on a carbon atom with one or two.substituents 5 dependently selected from: [I:\DayLib\LIBH]529782speci.doc:aak 187 halogen, C1- 6 alkyl, CI- 6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C-6 alkyl, (iii) -CF 3 and (iv) hydroxy; 15 substituted imidazolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 -6 alkyl, C- 6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C- 6 alkyl, (iii) -CF 3 and (iv) hydroxy; pyrrolyl; substituted pyrrolyl substituted on a carbof atom with one or two substituents independently selected from: halogen, Cl- 6 alkyl, [I:\DayLib\LIBH]529782speci.doc:aak C 16 alkyloxy-, phenyl, -CE 3 Mf -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii1) C1 6 alkyl, (ili) -CF 3 and (iv) hydroxy; (10) pyrazolyl; (11) substituted pyrazolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 16 alkyl, C 1 6 alkyloxy-, phenyl, 20 -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, 0ii) C 1 6 al kyI, (ill) -CF 3 and (iv) hydroxy; (12) C 3 6 cycloalkyl; (13) substituted C 3 6 cycloalkyl with 1 or 2 substituents independently selected from: halogen, C 1 -6 alkyl, 35(C) C 1 6 alkyloxy-, [1:\DayLib\LIBH]529782speci.doc:aak -CF 3 -OCF 3 -CN, and hydroxy; (14) piperidinyl; substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 16 al kyl, C 1 6 alkyloxy-, -CF 3 -OCF 3 -CN, i and hydroxy; (16) substituted morpholinyl substituted at a carbon or nitrogen atom with I or 2 substituents independently selected from: halogen, 20 C1 6 alkyl, C 1 6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; (17) naphthyl, (18) substituted naphthyl with 1, 2, or 3 substituents independently selected from: halogen, C 1 6 alkyl, C- 6 alkyloxy-, -CE 3 A RA(e) -OCF 3 -CN, -hydroxy; [1:\DayLib\LIBHI529782spcci.docaak 190 (19) indolyl; substituted indolyl substituted on a carbon atom with one or two substituents independently selected from: halogen., C 1 6 alkyl, C 1 6 alkyloxy-, -CF 3 -OCF 3 -CN, -hydroxy; (21) C 3 6 cycloalkyl fused with a phenyl ring; (22) substituted C 3 6 cycloalkyl fused with a phenyl ring substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1-6alkyl, C 1 6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; each R7i independently selected from: -H -C 1 3 alkyl-, -C 2 3 alkenyl-, 3 and 3 each R 5 isindependently selected from: /OM 1) -H, 2) -C 1.-3 alkyl, [1:\DayLib\LIBH529782specidocaak 191 -CF 3 -R 3 C 2 3 alkenyl, -C1- 3 alkyl-R 3 -C 2 3 alkenyl-R 3 -S(O)n-R 3 and -C(O)-R 3 each R 6 is independently selected from: -C 3 alkyl-R 3 and -R 3 R 7 is H; R is selected from hydrogen, methyl and methoxy; each n is independently selected from 0, 1 and 2, and S*each m is independently selected from 0, 1, and 2; and provided that when A is thienyl or thiazolyl and R 2 is -R 3 wherein R 3 is unsubstituted phenyl, then R' is not -H or -CH 3 32. The compound according to claim 31, and tautomers and pharmaceutically 20 acceptable salts thereof, wherein each R 3 is independently selected from: i. substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen, C- 6 alkyl, C 1 6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 -6alkyl, (iii) -CF 3 and 3 (iv) hydroxy; [1:\DayLib\LIBH]529782speci.doc:aak 192 thienyl; substituted thienyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C1- 6 alkyl, C-6 alkyloxy-, phenyl, -CF 3 -OCF 3 io -CN, hydroxy, phenyloxy, and i.i substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, is (ii) C 1 -6 alkyl, (iii) -CF 3 and (iv) hydroxy; pyridyl; substituted pyridyl substituted on a carbon atom with one or two substituents 20 independently selected from: halogen, C 16 alkyl, C 16 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 6 alkyl, (iii) -CF 3 and (iv) hydroxy; [I:\DayLib\LIBH]529782speci.doc:aak 193 substituted imidazolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 16 alkyl, C 1 6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, 0 hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 16 alkyl, (iii) -CF 3 and (iv) hydroxy; pyrrolyl; substituted pyrrolyl substituted on a carbon atom with one or two substituents 0:0. :independently selected from: 00* 20 halogen, C 1 6 alkyl, C 1 6 alkyloxy-, 000(d) phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 6 alkyl, (iii) -CF 3 and (iv) hydroxy; pyrazolyl; [1:\DayLib\LIBH]529782speci.doc:aak substituted pyrazolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 6 alkyl, C 1 6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, 0 1i) C 16 a]lkyl, (iii) -CF 3 and S(iv) hydroxy; (11) C 3 6 cycloalkyl; (12) substituted C 3 6 cycloalkyl with I or 2 substituents independently selected from: halogen, C 16 alkyl, C 16 alkyloxy-, S S -CF 3 -OCF 3 -CN, and hydroxy; (13) piperidinyl; (14) substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 16 alkyl, M CI. 6 alkyloxy-, -CF 3 n~ 3n5 -OCF 3 1:\DayLib\LIB H j529782speci.docaak 195 -CN, and hydroxy; substituted morpholinyl substituted at a carbon or nitrogen atom with 1 or 2 s substituents independently selected from: halogen, C 1 -6 alkyl, C-6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; naphthyl, 15 (17) substituted naphthyl with 1, 2, or 3 substituents independently selected from: halogen, C1- 6 alkyl, C-6 alkyloxy-, -CF 3 20 -OCF 3 -CN, and -hydroxy; (18) indolyl; (19) substituted indolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C-6 alkyl, C- 6 alkyloxy-, -CF 3 -OCF 3 -CN, -hydroxy; C 3 -6 cycloalkyl fused with a phenyl ring; substituted C 3 6 cycloalkyl fused with a phenyl ring substituted on a carbon Stn with one or two substituents independently selected from: [1:\DayLib\LIBH]529782speci.docaak halogen, C- 6 alkyl, C-6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy. 33. The compound according to claim 32, and tautomers and pharmaceutically 0o acceptable salts thereof, wherein A is selected from: thienyl, thiazolyl, S ,and (4) R 1 is selected from: -H, -CH 3 -CF 3 -halo, -NO 2 -N(R 4 )(R 5 -phenyl, substituted phenyl substituted with 1 or 2 substituents independently selected from: halo, methyl, and methoxy, phenyl C 1 -3 alkyl-, substituted phenyl C 1 3 alkyl-substituted with 1 or 2 substituents. tly selected from: (9) [I:\DayLib\LIBH]529782spci.doc:aak halo, methyl, and methoxy, and (11) -C 2 5 alkenyl-R 3 ~R 2is selected from: -C 1 6 alkyl substituted with R -O-R 1 -R, -C 1 6 alkyl (OR 6 -C 1 -6 alkyl (OR 4 6 -C 0 6 alkyl-N(R 4 6 -C 1 6 alkyl -C 0 6 alkyl C(O)-R 6 (10) -C 0 6 alkyl NIR C(O) -R 6 and -C 0 6 alkyl-C(O)N(R 4 0% 0 each R 3 is independently selected from: phenyl; substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen, C 1 6 alkyl, C 1 6 alkyloxy-, 0 phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 6 alkyl, (iii) -CF 3 and (iv) hydroxy; Ldoc:aak 198 substituted thienyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 6 alkyl, C 1 -6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) Ci.6alkyl, 15 (iii) -CF 3 and (iv) hydroxy; pyridyl; substituted pyridyl substituted on a carbon atom with one or two substituents independently selected from: halogen, Cl-6alkyl, Ci- 6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 -6 alkyl, (iii) -CF 3 and (iv) hydroxy; R pyrrolyl; pyrazolyl; [I:\DayLib\LIBH]529782speci.doc:aak 199 C3-6 cycloalkyl, substituted C 3 6 cycloalkyl with 1 or 2 substituents independently selected from: halogen, C 1 6 alkyl, C 1 6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; piperidinyl; (12) substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from: a) halogen, C 1 6 alkyl, C 1 6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; (13) naphthyl; indolyl; and (15) C 3 6 cycloalkyl fused with a phenyl ring; each R 4 is independently selected from: -H, -C 1 3 alkyl, -CF 3 3 -R C 2 3 alkenyl, 3 alkyl-R 3 and -S(0)n-R 3 and each R 5 is independently selected from: -H, [1:\DayLib\LIBH]529782speci.doc:aak 200 -C 1 3 alkyl, -CF 3 -R 3 C 2 3 alkenyl, -Ci. 3 alkyl-R 3 -C 2 3 alkenyl-R 3 and -S(O)n-R 3 each R 6 is independently selected from: -Ci. 3 alkyl-R 3 and 1o -R 3 R 8 is H; and each n is independently selected from 0, 1 and 2; and provided that when A is thienyl or thiazolyl and R 2 is -R 3 wherein R 3 is unsubstituted phenyl, then R' is not -H or S 15 -CH 3 34. The compound according to claim 33, and tautomers and pharmaceutically acceptable salts thereof, wherein each R is independently selected from: substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen, 20 C1- 6 alkyl, C 1 6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 6 alkyl, (iii) -CF 3 and (iv) hydroxy; thienyl; substituted thienyl substituted on a carbon atom with one or two substituents .s b tt e t 0 00 0 independently selected from: halogen, (b C 1 6 alkyl, C- 6 alkyloxy-, (d phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C1- 6 alkyl, (Ili) -CF 3 and (iv) hydroxy; pyridyl; substituted pyridyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 16 alkyl, C 1 6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 6 alkyl, (iii) -CF 3 and (iv) hydroxy; pyrrolyl; S(7) pyrazolyl; I I[ vr,1\DayLib\L B H] 529782speci.doc:aak 202 C 3 6 cycloalkyl, substituted C 3 6 cycloalkyl with 1 or 2 substituents independently selected from: halogen, C 16 alkyl, C 16 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; piperidinyl; substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from: halogen, OLS C 16 alkyl, 000: C 16 alkyloxy-, -CF 3 -OCF 3 -CN, sot* and 0(h) hydroxy; (12) naphthyl; 60: (13) indolyl; and (14) C 3 6 cycloalkyl fused with a phenyl ring. The compound according to claim 31 of structural formnula: S OH 0 0 and tautomers and pharmaceutically acceptable salts thereof, wherein: R 2 is selected from: -R 16 alkyl substituted with R 6 :S(O)ngR 6, (1:\DayLib\LIBH]529782speci.docaak 203 -C 16 alkyl (OR 6 )(R 4 -C 16 alkyl (OR 4 6 -CO 0 6 alkyl-N(R 4 6 5(9) -C 1 6 alkyl 6 -CO 0 6 alkyl NR 4 C(O)-R 6, and (11) -CO 0 6 alkyl-C(O)N(R 4 each R 3 is independently selected from: phenyl, substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen selected from -Cl, and -Br, CH 3 methoxy, phenyl, -CF 3 -OCF 3 see:(g) -CN, hydroxy, 20(i) phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: 0 00 0(i) halogen selected from -Cl, and -Br, 0 0:(ii) -CH 3 (iii) -CF 3 and hydroxy; thienyl, pyridyl, pyrrolyl, pyrazolyl, C 36 cycloalkyl, piperidinyl, naphthyl, indolyl, and (11) C 3 6 cycloalkyl fused with a phenyl ring; each R 4 is independently selected from: P3 54' -H, [I:\DayLib\LIBH]529782speci.doc:aak 204 -Ci- 3 alkyl, -CF 3 -R 3 -C 2 3 alkenyl, s -C1- 3 alkyl-R 3 and -S(O)n-R 3 each R 5 is independently selected from: -H, -C 1 3 alkyl, 1o -CF 3 -R 3 -C 2 3 alkenyl, S -Ci.3 alkyl-R 3 -C 2 3 alkenyl-R 3 and 1. 5 -S(0)n-R 3 each R 6 is independently selected from: -C 1 -3 alkyl-R 3 and -R 3 and each n is independently selected from 0, 1 and 2; and provided that when R 2 is -R 3 3 20 then R 3 is not unsubstituted phenyl. 36. The compound according to claim 35, and tautomers and pharmaceutically acceptable salts thereof, wherein each R 3 is independently selected from: substituted phenyl with 1, 2, or 3 substituents independently selected from: a) halogen selected from -Cl, and -Br, CH 3 methoxy, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen selected from -Cl, and -Br, (ii) -CH 3 (iii) -CF 3 and (iv) hydroxy; thienyl, pyridyl, pyrrolyl, pyrazolyl, C 3 6 cycloalkyl, piperidinyl, naphthyl, indolyl, and C 3 6 cycloalkyl fused with a phenyl ring. The compound according to claim 31 of structural formula: .S 0 OH 0 0 and tautomers and pharmaceutically acceptable salts thereof, wherein: R i 1S selected from: -C 1 6 alkyl substituted with R 3 -O-R 6 -S(O)n-R 6 -C 1 6 alkyl (OR )(R 4 -C 1.-6 alkyl (OR 4 6 -C 0 6 alkyl-N(R 4 6 -C 1 6 alkyl S(O)n-R 6 6 -C 0 6 alkyl NR 4 C(O)-R 6 and (11) -C 0 6 alkyl-C(O)N(R 4 5 each R 3 is independently selected from: phenyl, substituted phenyl with 1, 2, or 3 substituents independently selected from: A11%_7a) halogen selected from -Cl, and -Br, [I:\DayLib\LIBH]529782speci.docaak 206 CH 3 methoxy, phenyl, -CF 3 Mf -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen selected from and -Br, (ii) -CH 3 (ili) -CF 3 and hydroxy; thienyl, 15 pyridyl, pyrrolyl, pyrazolyl, C 3 6 cycloalkyl, piperidinyl, 20 naphthyl, indolyl, and G11) C 3 6 cycloalkyl fused with a phenyl ring; ***each R 4 isindependently selected from: -H, -C 1 3 alkyl, -CF 3 -R -C 2 3 alkenyl, -C 1 3 alkyl-R 3 and each R 5 IS independently selected from: -H, C 1 -3 alkyl, -CF 3 1529782speci.doc:aak -C2- 3 alkenyl, -C1- 3 alkyl-R 3 -C 2 3 alkenyl-R 3 and -S(O)n-R 3 each R 6 is independently selected from: -C1- 3 alkyl-R 3 and -R 3 ;and R is selected from methyl and hydrogen; and each n is independently selected from 0, 1 and 2; and provided that when R 2 is -R 3 0o then R 3 is not unsubstituted phenyl. 38. The compound according to claim 37, and tautomers and pharmaceutically acceptable salts thereof, wherein each R 3 is independently selected from: substituted phenyl with 1, 2, or 3 substituents independently selected from: a) halogen selected from -Cl, and -Br, 15 CH 3 methoxy, phenyl, -CF 3 S 20(f) -OCF 3 20 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen selected from -Cl, and -Br, (ii) -CH 3 (iii) -CF 3 and (iv) hydroxy; thienyl, pyridyl, pyrrolyl, pyrazolyl, C 3 6 cycloalkyl, piperidinyl, naphthyl, indolyl, and 208 C 3 6 cycloalkyl fused with a phenyl ring. 39. The compound according to claim 31 of structural formula: 0 OH R 2 0 0 and tautomers and pharmaceutically acceptable salts thereof, wherein: R 2is selected from: -R -C 1 6 alkyl substituted with R 3 -O-R -C 1 6 a] kyl (OR 6 4 6 alkyl (OR 4 )(R 6 -CO 0 6 alkyl-N(R )(R 6 -C 1 6 alkyl 6 -C 0 6 alkyl C(O)-R 6 (10) -C 0 6 alkyl NR 4 and (11) -CO 0 6 alkyl-C(O)N(R 4 5 !!each R 3i independently selected from: phenyl, substituted phenyl with 1, 2, or 3 substituents independently selected from: a) halogen selected from -Cl, and -Br, CH 3 methoxy, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen selected from -Cl, and -Br, (ii) -CH 3 (iii) -CF 3 and [:\DayLib\LIB H5297 82speci.doc:aak 209 (iv) hydroxy; thienyl, pyridyl, pyrrolyl, pyrazolyl, C 3 -6 cycloalkyl, piperidinyl, naphthyl, indolyl, and (11) C 3 -6 cycloalkyl fused with a phenyl ring; each R 4 is independently selected from: -H, -C1- 3 alkyl, -CF 3 15s -R 3 -C 2 -3 alkenyl, 3 -CI- 3 alkyl-R and -S(O)n-R 3 each R 5 is independently selected from: 20 -H, -C1-3 alkyl, -CF 3 -R 3 -C 2 3 alkenyl, e• -C1- 3 alkyl-R 3 -C 2 3 alkenyl-R 3 and -S(O)n-R 3 each R 6 is independently selected from: -CI- 3 alkyl-R 3 and -R 3 and each n is independently selected from 0, 1 and 2; and provided that when R 2 is -R 3 then R 3 is not unsubstituted phenyl. The compound according to claim 39, and tautomers and pharmaceutically cceptable salts thereof, wherein each R 3 is independently selected from: [I:\DayLib\LIBH]529782speci.doc:aak 210 substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen selected from -Cl, and -Br, CH 3 methoxy, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen selected from -Cl, and -Br, (ii) -CH 3 (iii) -CF 3 and (iv) hydroxy; thienyl, pyridyl, pyrrolyl, pyrazolyl, C 3 -6 cycloalkyl, piperidinyl, naphthyl, indolyl, and C 3 6 cycloalkyl fused with a phenyl ring. 41. The compound according to claim 31 of structural formula: N 0 0 0 and tautomers and pharmaceutically acceptable salts thereof, wherein: R 2 is selected from: -R 3 -C1-6 alkyl substituted with R 3 -O-R 6 -S(O)n-R 6 -C 16 alkyl (OR 6 )(R 4 [1:\DayLib\LIBH]529782speci.doc:aak 211 -C 16 alkyl (0R, 4 )(R 6 -CO 0 6 alkyl-N(R 4 6 6 -CO 0 6 alkyl C(O)-R, -CO 0 6 alkyl NR 4 C(O)-R 6 and -CO 0 6 alkyl-C(O)N(R 4 5 each R 3 is independently selected from: substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen selected from -Cl, and -Br, CH 3 methoxy, phenyl, -CF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen selected from -Cl, and -Br, (ii) -CH 3 (iii) -CF 3 and (iv) hydroxy; thienyl, pyridyl, iniidazolyl, pyrrolyl, pyrazolyl, C 3 6 cycloalkyl, piperidinyl, morpholinyl, naphthyl, (11) indolyl, and (12) C 3 6 cycloalkyl fused with a phenyl ring; each R 4 is independently selected from: 35T (1)-H [1:\DayLib\LIBH]529782speci.doc:aak 212 -C 13 alkyl, -CF 3 -C 2 3 alkenyl, -C 1 3 alkyl-R each R 5 is independently selected from: -H, -C 1 3 alkyl, -CF 3 -R -C 2 3 alkenyl, -C 13 alkyl-R add,(7) -C 2 3 alkenyl-R, and od 6 i each R 6 i independently selected from: -C 1 3 alkyl-R 3 and S3 R; and each n is independently selected from 0, 1 and 2. add 20 Dated 27 November, 2002 Merck Co., Inc. a:***:Patent Attorneys for the Applicant/Nominated Person '%godSPRUSON FERGUSON d. ad [I:\DayLib\LIBH]529782speci.doc:aak
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US8784698P | 1998-06-03 | 1998-06-03 | |
| US60/087846 | 1998-06-03 | ||
| GB9814925 | 1998-07-09 | ||
| GBGB9814925.5A GB9814925D0 (en) | 1998-07-09 | 1998-07-09 | HIV integrase inhibitors |
| PCT/US1999/012094 WO1999062897A1 (en) | 1998-06-03 | 1999-06-01 | Hiv integrase inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU4225599A AU4225599A (en) | 1999-12-20 |
| AU757409B2 true AU757409B2 (en) | 2003-02-20 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU42255/99A Ceased AU757409B2 (en) | 1998-06-03 | 1999-06-01 | Hiv integrase inhibitors |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1086091A4 (en) |
| JP (1) | JP2002517390A (en) |
| AU (1) | AU757409B2 (en) |
| CA (1) | CA2333771A1 (en) |
| WO (1) | WO1999062897A1 (en) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2217421C2 (en) | 1998-03-26 | 2003-11-27 | Шионоги & Ко., Лтд. | Derivatives of indole eliciting antiviral activity |
| ES2244204T3 (en) | 1998-07-27 | 2005-12-01 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. | DERIVATIVES OF DICETOACIDES AS POLYMERASE INHIBITORS |
| JP3929244B2 (en) | 1998-12-25 | 2007-06-13 | 塩野義製薬株式会社 | Aromatic heterocyclic derivatives having HIV integrase inhibitory activity |
| ATE411292T1 (en) | 2001-03-01 | 2008-10-15 | Shionogi & Co | NITROGEN-CONTAINING HETEROARYL COMPOUNDS WITH HIV INTEGRASE INHIBITING EFFECT |
| KR100977701B1 (en) | 2001-08-10 | 2010-08-24 | 시오노기세이야쿠가부시키가이샤 | Antiviral agent |
| CN1700918B (en) | 2001-10-26 | 2011-06-08 | P·安杰莱蒂分子生物学研究所 | N-substituted hydroxypyrimidinone carboxamide inhibitors of HIV integrase |
| ATE355064T1 (en) * | 2001-10-26 | 2006-03-15 | Angeletti P Ist Richerche Bio | DIHYDROXYPYRIMIDINE CARBONIC ACID RAMIDE INHIBITORS OF HIV INTEGRASE |
| AU2003220170B2 (en) | 2002-03-15 | 2008-12-11 | Merck Sharp & Dohme Corp. | N-(Substituted benzyl)-8-hydroxy-1,6-naphthyridine-7- carboxamides useful as HIV integrase inhibitors |
| DE60322920D1 (en) | 2002-08-13 | 2008-09-25 | Shionogi & Co | HETEROCYCLIC COMPOUNDS WITH HIV INTEGRATE-INHIBITOR EFFECT |
| US7776883B2 (en) | 2004-03-10 | 2010-08-17 | The United States Of America As Represented By The Department Of Health And Human Services | Quinolin-4-ones as inhibitors of retroviral integrase for the treatment of HIV, AIDS and AIDS related complex (ARC) |
| AU2007275805A1 (en) | 2006-07-19 | 2008-01-24 | University Of Georgia Research Foundation, Inc. | Pyridinone diketo acids: Inhibitors of HIV replication in combination therapy |
| US8664255B2 (en) | 2008-10-20 | 2014-03-04 | The Texas A&M University System | Inhibitors of mycobacterium tuberculosis malate synthase, methods of making and uses thereof |
| MX2012006485A (en) | 2009-12-07 | 2012-08-23 | Univ Georgia | Pyridinone hydroxycyclopentyl carboxamides: hiv integrase inhibitors with therapeutic applications. |
| SI3523287T1 (en) | 2016-10-04 | 2021-11-30 | Merck Sharp & Dohme Corp. | Benzo(b)thiophene compounds as sting agonists |
| WO2019027857A1 (en) | 2017-08-04 | 2019-02-07 | Merck Sharp & Dohme Corp. | COMBINATIONS OF PD-1 ANTAGONISTS AND BENZO[b]THIOPHENE STING AGONISTS FOR CANCER TREATMENT |
| CA3071538A1 (en) | 2017-08-04 | 2019-02-07 | Merck Sharp & Dohme Corp. | Benzo[b]thiophene sting agonists for cancer treatment |
| EP3774765A4 (en) | 2018-04-03 | 2021-12-29 | Merck Sharp & Dohme Corp. | Aza-benzothiophene compounds as sting agonists |
| EP3774764A1 (en) | 2018-04-03 | 2021-02-17 | Merck Sharp&Dohme Corp. | Benzothiophenes and related compounds as sting agonists |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS56100784A (en) * | 1980-01-16 | 1981-08-12 | Yoshitomi Pharmaceut Ind Ltd | Indolizine derivative |
| US4336397A (en) * | 1980-12-29 | 1982-06-22 | Merck & Co., Inc. | 2,4-Dioxo-4-substituted-1-butanoic acid derivatives useful in treating urinary tract calcium oxalate lithiasis |
| US5475109A (en) * | 1994-10-17 | 1995-12-12 | Merck & Co., Inc. | Dioxobutanoic acid derivatives as inhibitors of influenza endonuclease |
| US5470862A (en) * | 1995-02-03 | 1995-11-28 | Ohmeda Pharmaceutical Products Division Inc. | Substituted pyrazolyl compounds and methods employing such compounds |
| RU2217421C2 (en) * | 1998-03-26 | 2003-11-27 | Шионоги & Ко., Лтд. | Derivatives of indole eliciting antiviral activity |
-
1999
- 1999-06-01 CA CA002333771A patent/CA2333771A1/en not_active Abandoned
- 1999-06-01 JP JP2000552109A patent/JP2002517390A/en not_active Withdrawn
- 1999-06-01 AU AU42255/99A patent/AU757409B2/en not_active Ceased
- 1999-06-01 WO PCT/US1999/012094 patent/WO1999062897A1/en not_active Application Discontinuation
- 1999-06-01 EP EP99926095A patent/EP1086091A4/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| EP1086091A4 (en) | 2001-10-10 |
| CA2333771A1 (en) | 1999-12-09 |
| WO1999062897A1 (en) | 1999-12-09 |
| JP2002517390A (en) | 2002-06-18 |
| EP1086091A1 (en) | 2001-03-28 |
| AU4225599A (en) | 1999-12-20 |
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