AU4225599A - Hiv integrase inhibitors - Google Patents
Hiv integrase inhibitors Download PDFInfo
- Publication number
- AU4225599A AU4225599A AU42255/99A AU4225599A AU4225599A AU 4225599 A AU4225599 A AU 4225599A AU 42255/99 A AU42255/99 A AU 42255/99A AU 4225599 A AU4225599 A AU 4225599A AU 4225599 A AU4225599 A AU 4225599A
- Authority
- AU
- Australia
- Prior art keywords
- alkyl
- dioxo
- butanoic acid
- substituted
- independently selected
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- 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
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Immunology (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Virology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Tropical Medicine & Parasitology (AREA)
- Communicable Diseases (AREA)
- AIDS & HIV (AREA)
- Molecular Biology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
WO 99/62897 PCT/US99/12094 TITLE OF THE INVENTION HIV INTEGRASE INHIBITORS CROSS-REFERENCE TO RELATED APPLICATIONS 5 The present application claims priority of U.S. provisional application Serial No. 60/087,846, filed June 3, 1998. BACKGROUND OF THE INVENTION A retrovirus designated human immunodeficiency virus 10 (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 15 replication is the insertion by virally-encoded integrase of proviral DNA into the host cell genome, a required step in HIV replication in human T-lymphoid and monocytoid cells. Integration is believed to be mediated by integrase in three steps: assembly of a stable nucleoprotein complex with viral DNA sequences; cleavage of two 20 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. 25 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., 30 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 35 AIDS and similar diseases, e.g., azidothymidine or AZT. Applicants - 1- 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 5 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 10 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 15 transcriptase, Hepatitis C polymerase, Yeast DNA polymerase, DNase I, Eco RI endonuclease, or mammalian polymerase II. Zhao et al., (J. Med Chem. vol. 40, pp. 937-941 and 1186 1194 (1997)) describe hydrazide and arylamide HIV integrase inhibitors. Bis-catechols useful for inhibiting HIV integrase are 20 described in LaFemina et al. (Antimicrobial Agents & Chemotherapy, vol. 39, no. 2, pp. 320-324, February 1995). U.S. Patents 4,377,258; 4,336,397; and 4,423,063 as well as Williams and Rooney (J. Med. Chem. vol 26, pp. 1196-1200, 1983) disclose 2,4-dioxo-4-substituted-1-butanoic acid derivatives useful 25 intreating urinary tract calcium oxalate lithiasis. 4-substituted 2,4 dioxobutanoic acid compounds useful for inhibiting an influenza virus endonuclease are described in Tomassini et al. (Antimicrobial Agents & Chemotherapy, vol. 38, no. 12, pp. 2827-2837, December, 1994). 30 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. 35 SUMMARY OF THE INVENTION -2- WO 99/62897 PCT/US99/12094 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, 5 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. 10 DETAILED DESCRIPTION OF THE INVENTION This invention is concerned with compounds of formula I, combinations thereof, or pharmaceutically acceptable salts thereof, in the inhibition of HIV integrase, the prevention or treatment of infection 15 by HIV and in the treatment of the resulting acquired immune deficiency syndrome (AIDS). Compounds of formula I are defined as follows: R2~R7 R AOR 7
R
8 0 0 (I) and tautomers or pharmaceutically acceptable salts thereof, 20 wherein: A is a five-membered heteroaromatic ring containing 1 sulfur atom and 1 2 8 0 or 1 nitrogen atoms and substituted on carbon by R ,R and R8; 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: or or/\ 25
-S
WO 99/62897 PCT/US99/12094 R is selected from: (1) -H, (2) -C 1
-
5 alkyl, (3)
-CF
3 ' 5 (4) -halo, (5)
-NO
2 , (6) -N(R )(R 5), (7) -R6, 3 (8) -C 2
-
5 alkenyl-R3 3 10 (9) -C 2
-
5 alkynyl-R3 (10) -O-R6, (11) -0-C1-6 alkyl, and (12) -C(O)CH2C(O)C(O)OR7; 15 R is selected from: (1) -H, (2) -R3, (3) -C 1
-
6 alkyl, (4) -C 1
-
6 alkyl substituted with R 20 (5) -O-R 6 (6) -0-C 1
-
6 alkyl-OR (7) -S(O)n-R 6 (8) -C1- 6 alkyl (OR6)(Re) (9) -C 1
-
6 alkyl (OR )(R6), 25 (10) -C 0
-
6 alkyl-N(R 4)(R 6), (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)-R (14) -C 0
-
6 alkyl NR C(O)-R , and 30 (15) -C 0
-
6 alkyl-C(O)N(R )(R5); -4.- WO 99/62897 PCT/US99/12094 each R 3 is independently selected from: (1) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, 2, 3, or 4 heteroatoms selected from oxygen, nitrogen and sulfur, unsubstituted or substituted on a 5 nitrogen or carbon atom by 1 to 5 substituents selected from: (a) halogen, (b) C 1
-
6 alkyl, (c) C 1
-
6 alkyloxy-, (d) phenyl, 10 (e) -CF 3 , (f)
-OCF
3 ' (g) -CN, (h) hydroxy, (i) phenyloxy, and 15 (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C 1
-
6 alkyl, (iii) -CF 3 , and 20 (iv) hydroxy; (2) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms selected from oxygen, nitrogen or sulfur, unsubstituted or substituted with 0 to 5 substituents selected 25 from: (a) halogen, (b) C 1
-
6 alkyl, (c) C 1
-
6 alkyloxy-, (d)
-CF
3 , 30 (e) -OCF 3 ' (f) -CN, (g) =0, (h) hydroxy; -5- WO 99/62897 PCT/US99/12094 (3) unsubstituted or substituted hexahydrothieno[3,4 d]imidazolyl with one or two substituents selected from: (a) oxo, 5 (b) halogen, (c) C 1
-
6 alkyl, (d) C 1
-
6 alkyloxy-, (e)
-CF
3 , (f)
-OCF
3 ' 10 (g) -CN, and (h) hydroxy; (4) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, or 2 heteroatoms selected from oxygen, 15 nitrogen and sulfur, fused with a phenyl ring; wherein the ring system is unsubstituted or substituted on a nitrogen or carbon atom by 1 to 3 substituents selected from: (a) -halogen, (b) -C1- 6 alkyl, 20 (c) -C 1
-
6 alkyloxy-, (d)
-CF
3 , (e)
-OCF
3 ' (f) -CN, and (g) -hydroxy; 25 (5) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms selected from oxygen, nitrogen or sulfur, fused with a phenyl ring, unsubstituted or substituted with or 2 substituents selected from: 30 (a) halogen, (b) C 1
-
6 alkyl, (c) C 1
-
6 alkyloxy-, (d)
-CF
3 , -6- WO 99/62897 PCTIUS99/12094 (e)
-OCF
3 ' (f) -CN, (g) =0, (h) hydroxy; 5 (6) a 5 to 6 membered ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, containing 2 or 3 double bonds, unsubstituted or substituted with 1 or 2 substituents selected from: 10 (a) halogen, (b) C 1
-
6 alkyl, (c) C 1
-
6 alkyloxy-, (d) -CF 3 , (e)
-OCF
3 ' 15 (f) -CN, (g) =0, (h) hydroxy; each R4 is independently selected from: 20 (1) -H, (2) -C 1
-
3 alkyl, (3)
-CF
3 , (4) -R3, (5) -C 2
-
3 alkenyl, 25 (6) -C1- 3 alkyl-R3 3 (7) -C 2
-
3 alkenyl-R 3 (8) -S(O)n-R, and (9) -C(O)-R 30 each R5 is independently selected from: (1) -H, (2) -C1- 3 alkyl, -7- WO 99/62897 PCTIUS99/12094 (3)
-CF
3 , (4) -R3 (5) -C 2
-
3 alkenyl, 3 (6) -C 1
-
3 alkyl-R 3 5 (7) -C 2
-
3 alkenyl-R (8) -S(O)n-R 3, and (9) -C(O)-R each R6 is independently selected from: 10 (1) -C 1
-
3 alkyl-R 3, and (2) -R R7 is selected from: (1) -H, and 15 (2) C1-6 alkyl; R8 is selected from: (1) -H, and (2) C1-6 alkyl-oxy-; 20 (3) 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: 25 (1) 0 OH 0 0 (2) -8- WO 99/62897 PCTIUS99/12094 j sOH 0 0 (3) S OH F (4) F S OH 5 0 0 (5) F S OH 0 0 F (6) S OH 0 0 10 (7) F- OH (8) s OH F -9- WO 99/62897 PCT/US99/12094 (9) (10) 5 (11) 00 SS OH 0 0 (12) (13) 10O (14) H OH -0 WO 99/62897 PCT/US99/12094 (15) S OH 0 0 (16) H OH 0 0 5 (17) N O OH 0 0 (18) OH (19) F NO - N-\ I 0 O OH 0 0 10 F (20) -11- WO 99/62897 PCT/US99/12094
H
3 C SOH 0 0 (21) S OH 0 0 (22) 02N OH 5~ 0 0 5 (23) OH 0 0 (24) 0 O OH 0 0 10 (25) S OH - 0 0 0 (26) O OH -12- WO 99/62897 PCT/US99/12094 (27) 0
-
l 0 S S OH 0 0 (28) S 0 OH 0 0 Cl 5 (29) OH O O (30) F OH (31) OH 10 F (32) CI OH (33) - 13- WO 99/62897 PCT/US99/12094 -Y OH (34) S OH 0 0 (35) OH 0 0 5 CI (36) OH F (37) 10F (38) OH -14- WO 99/62897 PCT/US99/12094 (39) (40) OH 5 (41) N N OH 000 (42) N H S OH 0 0 (43) N - N-</ H S O OH 10 0 0 (44) - 15 - WO 99/62897 PCT/US99/12094 N S OH 00 (45) N - N-<'I H Slj OH O 0 (46) 0
--
\ N / N-</!
H
3 N S OH 5 0 0 (47) N N-<\ N O OH 0 0 (48) - N-< \I NN OH 0 0 10 (49) -16- WO 99/62897 PCT/US99/12094 S 0 OH O 00 (50) S 0 OH CI o 0 (51) s s 0 OH 0 00 5 F (52) S 0 OH 0 0 (53) 0 s OH 0 0 10 (54) O H , and S 0 0 ,and (55) -17- WO 99/62897 PCT/US99/12094 S 0 OH 0 0 and tautomers and pharmaceutically acceptable salts thereof. In one embodiment of the present invention, structural formula (I) is: 0 R2 OH 5 0 0 In another embodiment of the present invention, structural formula (I) is: R 0
R
2 OH O 0 In still another embodiment of the present invention, 10 structural formula (I) is: S 0 S- OH
R
2 0 0 In yet another embodiment of the present invention, structural formula (I) is; N 0 S OH 0 0 15 In one class of compounds of the present invention, A is selected from: -18- WO 99/62897 PCT/US99/12094 (1) thienyl, (2) thiazolyl, (3) S 5 (4) / / \ S and (5) S In another class of compounds of the present invention, A is 10 selected from: (1) thienyl, (2) thiazolyl, (3) S ,and 15 (4) / / \ S In one class of compounds of the present invention, R1 is selected from: (1) -H, 20 (2) -CH3, (3)
-CF
3 ' (4) -halo, (5)
-NO
2 , -19- WO 99/62897 PCT/US99/12094 (6) -N(R )(R5 (7) -phenyl, (8) substituted phenyl substituted with 1 or 2 substituents independently selected from: 5 (a) halogen, (b) C1- 6 alkyl, (c) C 1
-
6 alkyloxy-, (d) phenyl, (e)
-CF
3 , 10 (f) -OCF 3 , (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents 15 selected from: (i) halogen, (ii) C 1
-
6 alkyl, (iii) -CF3, and (iv) hydroxy; 20 (9) phenyl C 1
-
3 alkyl-, (10) substituted phenyl C 1
-
3 alkyl- substituted with 1 or 2 substituents independently selected from: (a) halogen, (b) C 1
-
6 alkyl, 25 (c) C 1
-
6 alkyloxy-, (d) phenyl, (e)
-CF
3 ' (f)
-OCF
3 ' (g) -CN, 30 (h) hydroxy, (i) phenyloxy, and 20- WO 99/62897 PCT/US99/12094 (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C 1
-
6 alkyl, 5 (iii) -CF 3 , and (iv) hydroxy; 3 (11) -C 2
-
5 alkenyl-R3 3 (12) -C 2
-
5 alkynyl-R , and (13) -C(O)CH2C(O)C(O)OR7. 10 In another class of compounds of the present invention, R1 is selected from: (1) -H, (2)
-CH
3 , (3)
-CF
3 ' 15 (4) -halo, (5)
-NO
2 , (6) -N(R4)(R 5), (7) -phenyl, (8) substituted phenyl substituted with 1 or 2 substituents 20 independently selected from: (a) halo, (b) methyl, and (c) methoxy, (9) phenyl C 1
-
3 alkyl-, 25 (10) substituted phenyl C 1
-
3 alkyl- substituted with 1 or 2 substituents independently selected from: (a) halo, (b) methyl, and (c) methoxy, and 3 30 (11) -C 2
-
5 alkenyl-R In still another class of compounds of the present invention, R1 is hydrogen. -21- WO 99/62897 PCT/US99/12094 In one class of compounds of the present invention, R 2 is selected from: (1) -H, (2) -R3 5 (3) -C1- 6 alkyl, (4) -C 1
-
6 alkyl substituted with R (5) -O-R 6 (6) -0-C 1
-
6 alkyl-OR (7) -S(O)n-R 6 10 (8) -C1-6 alkyl (OR6)(R ) , (9) -C 1
-
6 alkyl (OR )(R 6), (10) -C- 6 alkyl-N(R4)(R6), 46 (11) -C1- 6 alkyl S(0)n-R6 (12)
-C
1
-
6 alkyl C(O)-R6 15 (13)
-C
0
-
6 alkyl C(S)-R6 (14) -C 0
-
6 alkyl NR C(O)-R , and (15) -C 0
-
6 alkyl-C(O)N(R )(R5 ). In another class of compounds of the present invention, R 2 is selected from: 20 (1) -H, 3 (2) -R3 (3) -C 1
-
6 alkyl, (4) -C 1
-
6 alkyl substituted with R 3 6 (5) -O-R 25 (6) -S(O)n-R 6 (7) -C 1
-
6 alkyl (OR 6)(R ), (8) -C 1
-
6 alkyl (OR4 )(R 6), (9) -C 0
-
6 alkyl-N(R4)(R6, 6 (10) -C 1
-
6 alkyl S(O)n-R 30 (11) -C 0
-
6 alkyl C(O)-R6 (12) -C 0
-
6 alkyl NR C(O)-R 6, and - 22- WO 99/62897 PCT/US99/12094 (13) -C 0
-
6 alkyl-C(O)N(R )(R ). In one class of compounds of the present invention, R 3 is selected from: (1) phenyl; 5 (2) substituted phenyl with 1, 2, or 3 substituents independently selected from: (a) halogen, (b) C 1
-
6 alkyl, (c) C 1
-
6 alkyloxy-, 10 (d) phenyl, (e)
-CF
3 , (f)
-OCF
3 ' (g) -CN, (h) hydroxy, 15 (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C 1
-
6 alkyl, 20 (iii) -CF 3 , and (iv) hydroxy; (3) thienyl; (4) substituted thienyl substituted on a carbon atom with one or two substituents independently selected from: 25 (a) halogen, (b) C 1
-
6 alkyl, (c) C 1
-
6 alkyloxy-, (d) phenyl, (e)
-CF
3 > 30 (f) -OCF 3 > (g) -CN, (h) hydroxy, -23- WO 99/62897 PCT/US99/12094 (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, 5 (ii) C 1
-
6 alkyl, (iii) -CF 3 , and (iv) hydroxy; (5) pyridyl; (6) substituted pyridyl substituted on a carbon atom with one or 10 two substituents independently selected from: (a) halogen, (b) C 1
-
6 alkyl, (c) C 1
-
6 alkyloxy-, (d) phenyl, 15 (e) -CF 3 , (f)
-OCF
3 , (g) -CN, (h) hydroxy, (i) phenyloxy, and 20 (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C1-6 alkyl, (iii) -CF 3 , and 25 (iv) hydroxy; (7) imidazolyl; (8) substituted imidazolyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, 30 (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e)
-CF
3 , -24- WO 99/62897 PCT/US99/12094 (f)
-OCF
3 , (g) -CN, (h) hydroxy, (i) phenyloxy, and 5 (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C 1
-
6 alkyl, (iii) -CF3, and 10 (iv) hydroxy; (9) pyrrolyl; (10) substituted pyrrolyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, 15 (b) C 1
-
6 alkyl, (c) C 1
-
6 alkyloxy-, (d) phenyl, (e)
-CF
3 , (f)
-OCF
3 ' 20 (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: 25 (i) halogen, (ii) C 1
-
6 alkyl, (iii) -CF 3 , and (iv) hydroxy; (11) pyrazolyl; 30 (12) substituted pyrazolyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, (b) C 1
-
6 alkyl, -25- WO 99/62897 PCT/US99/12094 (c) C 1
-
6 alkyloxy-, (d) phenyl, (e)
-CF
3 ' (f)
-OCF
3 > 5 (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: 10 (i) halogen, (ii) C 1
-
6 alkyl, (iii) -CF 3 , and (iv) hydroxy; (13) C 3
-
6 cycloalkyl; 15 (14) substituted C 3
-
6 cycloalkyl with 1 or 2 substituents independently selected from: (a) halogen, (b) C 1
-
6 alkyl, (c) C 1
-
6 alkyloxy-, 20 (d) -CF 3 ' (e)
-OCF
3 ' (f) -CN, (g) =O,and (h) hydroxy; 25 (15) piperidinyl; (16) substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, (b) C 1
-
6 alkyl, 30 (c) C 1
-
6 alkyloxy-, (d)
-CF
3 > (e) -OCF 3 > - 26- WO 99/62897 PCT/US99/12094 (f) -CN, (g) =0, and (h) hydroxy; (17) morpholinyl; 5 (18) substituted morpholinyl substituted at a carbon or nitrogen atom with 1 or 2 independently selected from: (a) halogen, (b) C 1
-
6 alkyl, (c) C 1
-
6 alkyloxy-, 10 (d) -CF 3 , (e)
-OCF
3 , (f) -CN, (g) =0, and (h) hydroxy; 15 (19) naphthyl, (20) substituted naphthyl with 1, 2, or 3 substituents independently selected from: (a) -halogen, (b) -C 1
-
6 alkyl, 20 (c) -C 1
-
6 alkyloxy-, (d)
-CF
3 , (e)
-OCF
3 ' (f) -CN, and (g) -hydroxy; 25 (21) indolyl; (22) substituted indolyl substituted on a carbon atom with one or two substituents independently selected from: (a) -halogen, (b) -C1- 6 alkyl, 30 (c) -C 1
-
6 alkyloxy-, (d)
-CF
3 , (e)
-OCF
3 , (f) -CN, and -27- WO 99/62897 PCT/US99/12094 (g) -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 5 independently selected from: (a) halogen, (b) C 1
-
6 alkyl, (c) C 1
-
6 alkyloxy-, (d)
-CF
3 , 10 (e) -OCF 3 ' (f) -CN, (g) =0, and (h) hydroxy. In another class of compounds of the present invention, R 3 15 is selected from: (1) phenyl; (2) substituted phenyl with 1, 2, or 3 substituents independently selected from: (a) halogen, 20 (b) C 1
-
6 alkyl, (c) C 1
-
6 alkyloxy-, (d) phenyl, (e)
-CF
3 , (f)
-OCF
3 ' 25 (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: 30 (i) halogen, (ii) C 1
-
6 alkyl, (iii) -CF 3 , and (iv) hydroxy; -28- WO 99/62897 PCT/US99/12094 (3) thienyl; (4) substituted thienyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, 5 (b) C 1
-
6 alkyl, (c) C 1
-
6 alkyloxy-, (d) phenyl, (e)
-CF
3 , (f)
-OCF
3 ' 10 (g) -CN, (h) hydroxy, (i) phenyloxy, and () substituted phenyloxy with 1, 2, or 3 substituents selected from: 15 (i) halogen, (ii) C 1
-
6 alkyl, (iii) -CF3, and (iv) hydroxy; (5) pyridyl; 20 (6) substituted pyridyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, (b) C 1
-
6 alkyl, (c) C 1
-
6 alkyloxy-, 25 (d) phenyl, (e)
-CF
3 , (f)
-OCF
3 ' (g) -CN, (h) hydroxy, 30 (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, -29- WO 99/62897 PCT/US99/12094 (ii) C 1
-
6 alkyl, (iii) -CF3, and (iv) hydroxy; (7) imidazolyl; 5 (8) pyrrolyl; (9) pyrazolyl; (10) C 3
-
6 cycloalkyl, (11) substituted C 3
-
6 cycloalkyl with 1 or 2 substituents independently selected from: 10 (a) halogen, (b) C 1
-
6 alkyl, (c) C 1
-
6 alkyloxy-, (d)
-CF
3 ' (e)
-OCF
3 , 15 (f) -CN, (g) =0, and (h) hydroxy; (12) piperidinyl; (13) substituted piperidinyl substituted on a carbon atom with 20 one or two substituents independently selected from: (a) halogen, (b) C 1
-
6 alkyl, (c) C 1
-
6 alkyloxy-, (d)
-CF
3 ' 25 (e) -OCF 3 ' (f) -CN, (g) =0, and (h) hydroxy; (14) morpholinyl; 30 (15) naphthyl; (16) indolyl, and (17) C 3
-
6 cycloalkyl fused with a phenyl ring. -30 - WO 99/62897 PCT/US99/12094 In still another class of compounds of the present invention,
R
3 is selected from: (1) phenyl, (2) substituted phenyl with 1, 2, or 3 substituents independently 5 selected from: (a) halogen selected from -F, -Cl, -Br,, (b)
CH
3 , (c) methoxy-, (d) phenyl, 10 (e) -CF 3 ' (f)
-OCF
3 , (g) -CN, (h) hydroxy, (i) phenyloxy, and 15 (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen selected from -F, -Cl, -Br, (ii)
-CH
3 ' (iii) -CF 3 , and 20 (iv) hydroxy; (3) thienyl, (5) pyridyl, (7) imidazolyl, (8) pyrrolyl, 25 (9) pyrazolyl, (10) C 3
-
6 cycloalkyl, (12) piperidinyl, (14) morpholinyl, (15) naphthyl, 30 (16) indolyl, and (17) C 3
-
6 cycloalkyl fused with a phenyl ring. In one class of compounds of the present invention, R 4 is selected from: -31- WO 99/62897 PCT/US99/12094 (1) -H, (2) -C 1
-
3 alkyl, (3)
-CF
3 , (4) -R3 5 (5) -C 2
-
3 alkenyl, 3 (6) -C 1
-
3 alkyl-R (7) -C 2
-
3 alkenyl-R3 3 (8) -S(O)n-R, and (9) -C(O)-R 3 10 In another class of compounds of the present invention, R 4 is selected from: (1) -H, (2) -C1- 3 alkyl, (3)
-CF
3 ' 15 (4) -R3, (5) -C 2
-
3 alkenyl, 3 (6) -C 1
-
3 alkyl-R3, and (7) -S(O)n-R 3 In one class of compounds of the present invention, R5 is 20 selected from: (1) -H, (2) -C 1
-
3 alkyl, (3)
-CF
3 , (4) -R3 25 (5) -C 2
-
3 alkenyl, 3 (6) -C 1
-
3 alkyl-R (7) -C 2
-
3 alkenyl-R3 3 (8) -S(O)n-R, and (9) -C(O)-R 3 30 In another class of compounds of the present invention, R5 is selected from: - 32- WO 99/62897 PCT/US99/12094 (1) -H, (2) -C 1
-
3 alkyl, (3)
-CF
3 , (4) -R3, 5 (5) -C 2
-
3 alkenyl, (6) -C 1
-
3 alkyl-R3 (7) -C 2
-
3 alkenyl-R , and 3 (8) -S(O)n-R In one class of compounds of the present invention, R7 is 10 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, 15 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 20 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: 25 (1) an AIDS antiviral agent, (2) an anti-infective agent, and (3) an immunomodulator. The compounds of the present invention may have asymmetric centers and may occur, except when specifically noted, as 30 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 (I), Applicants also intend the 5 following tautomeric forms of the same compound (Ia) and (Ib):
R
2 A OR R AOR
R
8 0 0 R8 0 OH (I) (la) R1 R2- OR 7
R
8 OH O (Ib) By naming or referring to compound (I) 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), 10 it is understood for the purposes of the present application that the tautomers (I) and (Ib) are also intended. The same holds true for references to tautomer (Ib). When any variable (e.g., R3, R 4 , etc.) occurs more than one time in any constituent or in formula I, its definition on each occurrence 15 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 20 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 PCTIUS99/12094 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 e.g., blood transfusion, exchange of body fluids, bites, 5 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 10 tools for more powerful antiviral compounds. Furthermore, the compounds of this invention are useful in establishing or determining the binding site of other antivirals to HIV integrase, e.g., by competitive inhibition. Thus the compounds of this invention are commercial products to be sold for these purposes. 15 The present invention also provides for the use of a compound of structural formula (I) to make a pharmaceutical composition useful for inhibiting HIV integrase and in the treatment of AIDS or ARC. Compounds of structural formula (I) wherein A is thienyl 20 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. 0 S OEt 0 0 25 AI (3) -35- WO 99/62897 PCT/US99/12094 i. NaOH, MeOH-H 2 0-THF ii.HC1 0 OH AI(4) Scheme AII Cl 0 AII(l) X CH, N X OH R H, F, F 2 R NaH, DMSO R R- 0 AII(2a-e) -36- WO 99/62897 PCT/US99/12094 0 EtO OEt NaOEt, THF 0 x 0
-
I S OEt O 0 AII (3a-e) i. NaOH, MeOH-H 2 0-THF ii.HCl x 0 -1 S OH O 0 AII(4a-e) - 37- WO 99/62897 PCT/US99/12094 Scheme BI Br S Br BI (1) n-BuLi, Et 2 O, R HO - S Br BI(2a-d)
BF
3 .Et 2 O, Et 3 SiH, CH 2 Cl 2 -38- WO 99/62897 PCT/US99/12094 - S Br BI (3a-d) n-BuLi, Et 2 O, CH 3
CONCH
3
(OCH
3 ) - S R<0 BI (4a-d) 0 EO EtO OEt LDA, THF 0 -39- WO 99/62897 PCT/US99/12094 R OEt BI (5a-d) i. NaOH, MeOH-H 2 0-THF ii.HC1 R OH BI(6a-d) Scheme BII Br BII(1) / SNa acetone -40- WO 99/62897 PCT/US99/12094 S - S R0 BII (2) EtO OEt NaOEt, THF 0 s - OEt R00 BIT (3) i. NaOH, MeOH-H 2 0-THF ii.HC1 - OH R"'\0 0 BII (4) -41- WO 99/62897 PCT/US99/12094 Scheme CI S Br Br CI (1) n-BuLi, Et 2 O, R H R H HO S Br R CI (2a-d)
BF
3 .Et 2 O, Et 3 SiH(xs) , CH 2 Cl 2 -42- WO 99/62897 PCT/US99/12094 S Br R~< CI (3a-d) n-BuLi, Et 2 O, CH 3
CONCH
3
(OCH
3 ) S R0 CI (4a-d) -43- WO 99/62897 PCT/US99/12094 Scheme CI (continue) S
R<
7 0 CI (4a-d) 0 EtO OEt LDA, THF 0 O~ R CI(5a-d) i. NaOH, MeOH-H 2 0-THF ii.HC1 R OH CI(6a-d) -44- WO 99/62897 PCT/US99/12094 Scheme CII S Br Br CI(1) n-BuLi, Et20,R S S RBr CII(1) n-BuLi, Et 2 O, CH 3
CONCH
3
(OCH
3 ) S R~ OCII(2) 00 EO EtO OEt LDA, THF 0 -45- WO 99/62897 PCT/US99/12094 OEt CII(3) RO 0 i. NaOH, MeOH-H 2 0-THF ii.HCl S OH R / O 0 CII(4) Scheme DI S 'Br Br DI (1) n-BuLi, Et 2 0, Rj H -46- WO 99/62897 PCT/US99/12094 S Br O H R DI (2a-c)
BF
3 .Et 2 O, Et 3 SiH, CH 2 Cl 2 S Br R DI (3a-c) n-BuLi, Et 2 0, CH 3
CONCH
3
(OCH
3 ) S 0 R/ \ o R DI (4a-c) -47- WO 99/62897 PCTIUS99/12094 Scheme DI (continue) S 0 R DI (4a-c) 0 EtO OEt LDA, THF 0 OEt DI (5a-c) i. NaOH, MeOH-H 2 0-THF ii.HC1 Y--- OH DI(6a-c) -48- WO 99/62897 PCT/US99/12094 Scheme EI Br S Br BI (1) 0 n-BuLi, Et 2 0, R H HO - S Br \s / BI(2d) NaH, DMSO, RX -49- WO 99/62897 PCT/US99/12094 RO R Bn, Ph, Me - S EI(la-c) n-BuLi, Et 2 0, CH 3 CONC RO - S 0 EI (2a-c) -50- WO 99/62897 PCT/US99/12094 Scheme EI (continue) RO s 0 El (3a-c) 0 EtO OEt LDA, THF 0 O0 s OEt EI(4a-c) i. NaOH, MeOH-H 2 0-THF ii.HC1 OH EI(5a-c) -51- WO 99/62897 PCT/US99/12094 Scheme FI 0 2 N FI(1) 0 i. H 2 , Pt 2 S/C, MeOH ii.HCl
HCI.H
2 N FI(2) 0 RX, iPr 2 NEt, MeCN or RX, Cs 2
CO
3 , DMF -52- WO 99/62897 PCT/US99/12094 R'= H, R R Bn, n-Pr, allyl, Me /N S FI(3a-e) 0 0 EO EtO OEt NaOEt, THF 0 N e R S OEt FI(4a-e) 0 0 i. NaOH, MeOH-H 2 0-THF ii.HC1 Ne R' S OH FI(5a-e) 0 0 - 53- WO 99/62897 PCT/US99/12094 Scheme FII C / I AII(1) O 0 R NH Cs 2
CO
3 , DMF R' NH FII(la-b) 0 -54- WO 99/62897 PCT/US99/12094 0 EO EtO OEt NaOEt, THF 0 RN R' S OEt FII(2a-b) 0 0 i. NaOH, MeOH-H 2 0-THF ii.HC1 R, N 0 R' S OH FII(3a-b) 0 0 Scheme FIII
HCI.H
2 N FI(2) 0
RSO
2 Cl, pyridine -55- WO 99/62897 PCT/US99/12094
RSO
2 HN FIII (1) S O 0 NaHMDS, DMSO, R'X
RSO
2 R'N FIII(2) S 0 0 EO EtO OEt NaOEt, THF 0
RSO
2 R'N / I S OEt FIII(3) 0 0 i. NaOH, MeOH-H 2 0-THF ii.HC1
RSO
2R'N /I( Sir OH FIIT(4) 0 0 - 56- WO 99/62897 PCTIUS99/12094 Scheme GI R N-H R' R = Bn, R' = Bn i. S=C=N ,hexane R = Bn, R' = H R = Bn, R' = CH 3 ii- c. HCl RN
NH
2 GI(la-c) R'S
CH
3 0 CH 3 N'
CH
3 O CH 3 R, N N N(C H3) 2
,N
R' S GI(2a-c) Br 0 R N S GI(3a-c) 0 -57 - WO 99/62897 PCT/US99/12094 0 EtO OEt NaOEt, THF 0 R N R'N S OEt GI(4a-c) 0 0 i. NaOH, MeOH-H 2 0-THF ii.HC1 R N R'NS OH GI(5a-c) 0 0 Scheme GII R N-H R' i. S=C=N ,hexane ii. c. HC1 -58- WO 99/62897 PCT/US99/12094 R S N4 sGI (1) R'
NH
2 Br 0 R S /N-< R' N GII(3) 0 0 EO EtO OEt NaOEt, THF 0 R S R' N OEt GIT(4) 0 0 i. NaOH, MeOH-H 2 0-THF ii.HC1 -59- WO 99/62897 PCT/US99/12094 R S R' N OH GII(5) 0 0 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 5 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 10 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, 15 tannate, hydrochloride, tartrate, hydroxynaphthoate, teoclate, iodide, tosylate, isothionate, triethiodide, lactate, panoate, valerate, and the like which can be used as a dosage form for modifying the solubility or hydrolysis characteristics or can be used in sustained release or pro drug formulations. Depending on the particular functionality of the 20 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-methyl glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylene 25 diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethyl amine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide. These salts may be prepared by standard procedures, e.g. by reacting a free acid with a suitable organic or inorganic base. Where a basic group is present, such as amino, an 30 acidic salt, i.e. hydrochloride, hydrobromide, acetate, pamoate, and the like, can be used as the dosage form. -60- 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 5 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 10 formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The terms "administration of' and or "administering a" compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual 15 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 20 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 25 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. 30 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 35 compositions are prepared according to techniques well-known in the -61- WO 99/62897 PCTIUS99/12094 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 5 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 10 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. 15 The injectible solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, 20 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 25 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 30 in divided doses. Another preferred dosage range is 0.5 to 100 mg/kg body weight orally in divided doses. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 35 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient - 62 - WO 99/62897 PCTIUS99/12094 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 5 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 10 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 15 in the following table. -63 - WO 99/62897 PCT/US99/12094 ANTIVIRALS DruL, Name Manufacturer Indication 097 Hoechst/Bayer HIV infection, AIDS, ARC (non-nucleoside reverse transcriptase (RT) inhibitor) Amprenivir Glaxo Wellcome HIV infection, 141 W94 AIDS, ARC GW141 (protease inhibitor) Abacavir (1592U89) Glaxo Wellcome HIV infection, AIDS, ARC (RT inhibitor) Acemannan Carrington Labs ARC (Irving, TX) Acyclovir Burroughs Wellcome HIV infection, AIDS, ARC, in combination with AZT AD-439 Tanox Biosystems HIV infection, AIDS, ARC AD-519 Tanox Biosystems HIV infection, AIDS, ARC Adefovir dipivoxil Gilead Sciences HIV infection AL-721 Ethigen ARC, PGL (Los Angeles, CA) HIV positive, AIDS Alpha Interferon Glaxo Wellcome Kaposi's sarcoma, HIV in combination w/Retrovir -64- WO 99/62897 PCT/US99/12094 Ansamycin Adria Laboratories ARC LM 427 (Dublin, OH) Erbamont (Stamford, CT) Antibody which Advanced Biotherapy AIDS, ARC neutralizes pH Concepts labile alpha aberrant (Rockville, MD) Interferon AR177 Aronex Pharm HIV infection, AIDS, ARC beta-fluoro-ddA Nat'l Cancer Institute AIDS-associated diseases BMS-232623 Bristol-Myers Squibb! HIV infection, (CGP-73547) Novartis AIDS, ARC (protease inhibitor) BMS-234475 Bristol-Myers Squibb! HIV infection, (CGP-61755) Novartis AIDS, ARC (protease inhibitor) CI-1012 Warner-Lambert HIV-1 infection Cidofovir Gilead Science CMV retinitis, herpes, papillomavirus Curdlan sulfate AJI Pharma USA HIV infection Cytomegalovirus immune Medlmmune CMV retinitis globin Cytovene Syntex sight threatening Ganciclovir CMV peripheral CMV retinitis Delaviridine Pharmacia-Upjohn HIV infection, AIDS, ARC (RT inhibitor) Dextran Sulfate Ueno Fine Chem. AIDS, ARC, HIV Ind. Ltd. (Osaka, positive asymptomatic Japan) - 65 - WO 99/62897 PCTIUS99/12094 ddC Hoffman-La Roche HIV infection, AIDS, Dideoxycytidine ARC ddl Bristol-Myers Squibb HIV infection, AIDS, Dideoxyinosine ARC; combination with AZT/d4T DMP-450 AVID HIV infection, (Camden, NJ) AIDS, ARC (protease inhibitor) Efavirenz DuPont Merck HIV infection, (DMP 266) AIDS, ARC ((-) 6-Chloro-4(S)- (non-nucleoside RT cyclopropylethynyl-4(S)- inhibitor) trifluoro-methyl-1,4 dihydro-2H-3,1 benzoxazin-2-one) STOCRIN, EL10 Elan Corp, PLC HlV infection (Gainesville, GA) Famciclovir Smith Kine herpes zoster, herpes simplex FTC Emory University HIV infection, AIDS, ARC (reverse transcriptase inhibitor) GS 840 Gilead HIV infection, AIDS, ARC (reverse transcriptase inhibitor) HBYD97 Hoechst Marion HIV infection, Roussel AIDS, ARC (non-nucleoside reverse transcriptase inhibitor) - 66- WO 99/62897 PCT/US99/12094 Hypericin VJMRx Pharm. HIV infection, AIDS, ARC Recombinant Human Triton Biosciences AIDS, Kaposi's Interferon Beta (Almeda, CA) sarcoma, ARC Interferon alfa-n3 Interferon Sciences ARC, AIDS Indinavir Merck HIV infection, AIDS, ARC, asymptomatic HlV positive, also in combination with AZT/ddl/ddC ISIS 2922 ISIS Pharmaceuticals CMV retinitis KNI-272 Natl Cancer Institute HIV-assoc. diseases Lamivudine, 3TC Glaxo Wellcome HIV infection, AIDS, ARC (reverse transcriptase inhibitor); also with AZT Lobucavir Bristol-Myers Squibb CMV infection Nelfinavir Agouron HlV infection, Pharmaceuticals AIDS, ARC (protease inhibitor) Nevirapine Boeheringer HV infection, Ingleheim AIDS, ARC (RT inhibitor) Novapren Novaferon Labs, Inc. HIV inhibitor (Akron, OH) Peptide T Peninsula Labs AIDS Octapeptide (Belmont, CA) Sequence Trisodium Astra Pharm. CMV retinitis, HIV PhoHsphonoformate Products, Inc infection, other CMV infections - 67 - WO 99/62897 PCT/US99/12094 PNU-140690 Pharmacia Upjohn HIV infection, AIDS, ARC (protease inhibitor) Probucol Vyrex HIV infection, AIDS RBC-CD4 Sheffield Med. Tech HIV infection, (Houston TX) AIDS, ARC Ritonavir Abbott HIV infection, AIDS, ARC (protease inhibitor) Saquinavir Hoffmann-LaRoche HIV infection, AIDS, ARC (protease inhibitor) Stavudine; d4T Bristol-Myers Squibb HIV infection, AIDS, Didehydrodeoxy- ARC thymidine Valaciclovir Glaxo Wellcome genital HSV & CMV infections Virazole Viratek/ICN asymptomatic HIV Ribavirin (Costa Mesa, CA) positive, LAS, ARC VX-478 Vertex HIV infection, AIDS, ARC Zalcitabine Hoffmann-La Roche HIV infection, AIDS, ARC, with AZT Zidovudine; AZT Glaxo Wellcome HIV infection, AIDS, ARC, Kaposi's sarcoma, in combination with other therapies IMMUNO-MODULATORS Drug Name Manufacturer Indication AS-101 Wyeth-Ayerst AIDS - 68- WO 99/62897 PCT/US99/12094 Bropirimine Pharmacia Upjohn advanced AIDS Acemannan Carrington Labs, Inc. AIDS, ARC (Irving, TX) CL246,738 American Cyanamid AIDS, Kaposi's Lederle Labs sarcoma EL10 Elan Corp, PLC HIV infection (Gainesville, GA) FP-21399 Fuki ImmunoPharm blocks HIV fusion with CD4+ cells Gamma Interferon Genentech ARC, in combination w/TNF (tumor necrosis factor) Granulocyte Genetics Institute AIDS Macrophage Colony Sandoz Stimulating Factor Granulocyte Hoeschst-Roussel AIDS Macrophage Colony Immunex Stimulating Factor Granulocyte Schering-Plough AIDS, combination Macrophage Colony w/AZT Stimulating Factor HIV Core Particle Rorer seropositive HIV Immunostimulant IL-2 Cetus AIDS, in combination Interleukin-2 w/AZT IL-2 Hoffman-La Roche AIDS, ARC, HIV, in Interleukin-2 Immunex combination w/AZT IL-2 Chiron AIDS, increase in CD4 Interleukin-2 cell counts (aldeslukin) -69- WO 99/62897 PCT/US99/12094 Immune Globulin Cutter Biological pediatric AIDS, in Intravenous (Berkeley, CA) combination w/AZT (human) IMREG-1 Imreg AIDS, Kaposi's (New Orleans, LA) sarcoma, ARC, PGL IMREG-2 Imreg AIDS, Kaposi's (New Orleans, LA) sarcoma, ARC, PGL Imuthiol Diethyl Merieux Institute AIDS, ARC Dithio Carbamate Alpha-2 Schering Plough Kaposi's sarcoma Interferon w!AZT, AIDS Methionine- TNI Pharmaceutical AIDS, ARC Enkephalin (Chicago, IL) MTP-PE Ciba-Geigy Corp. Kaposi's sarcoma Muramyl-Tripeptide Granulocyte Amgen AIDS, in combination Colony Stimulating w/AZT Factor Remune Immune Response immunotherapeutic Corp. rCD4 Genentech AIDS, ARC Recombinant Soluble Human CD4 rCD4-IgG AIDS, ARC hybrids Recombinant Biogen AIDS, ARC Soluble Human CD4 Interferon Hoffman-La Roche Kaposi's sarcoma Alfa 2a AIDS, ARC, in combination w/AZT SK&F106528 Smith Kline HIV infection Soluble T4 - 70 - WO 99/62897 PCT/US99/12094 Thymopentin Immunobiology HIV infection Research Institute (Annandale, NJ) Tumor Necrosis Genentech ARC, in combination Factor; TNF w/gamma Interferon ANTI-INFECTIVES Drug Name Manufacturer Indication Clindamycin with Pharmacia Upjohn PCP Primaquine Fluconazole Pfizer cryptococcal meningitis, candidiasis Pastille Squibb Corp. prevention of Nystatin Pastille oral candidiasis Ornidyl Merrell Dow PCP Eflornithine Pentamidine LyphoMed PCP treatment Isethionate (IM & IV) (Rosemont, IL) Trimethoprim antibacterial Trimethoprim/sulfa antibacterial Piritrexim Burroughs Wellcome PCP treatment Pentamidine Fisons Corporation PCP prophylaxis isethionate for inhalation Spiramycin Rhone-Poulenc cryptosporidial diarrhea Intraconazole- Janssen Pharm. histoplasmosis; R51211 cryptococcal meningitis Trimetrexate Warner-Lambert PCP -71- WO 99/62897 PCT/US99/12094 OTHER Druiz Name Manufacturer Indication Daunorubicin NeXstar, Sequus Karposi's sarcoma Recombinant Human Ortho Pharm. Corp. severe anemia Erythropoietin assoc. with AZT therapy Recombinant Human Serono AIDS-related wasting, Growth Hormone cachexia Megestrol Acetate Bristol-Myers Squibb treatment of anorexia assoc. w/AIDS Testosterone Alza, Smith Kline AIDS-related wasting Total Enteral Norwich Eaton diarrhea and Nutrition Pharmaceuticals malabsorption related to AIDS It will be understood that the scope of combinations of the 5 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 10 treatments of with a compound of the present invention and an inhibitor of HdV 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 15 the sulfate salt of N-(2(R)-hydroxy- 1(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 nefinavir 20 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 PCTIUS99/12094 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 5 include those with the following (1) indinavir with efavirenz, and, optionally, AZT and/or 3TC and/or ddI and/or ddC; (2) indinavir, and any of AZT and/or ddI and/or ddC and/or 3TC, in particular, indinavir and AZT and 3TC; (3) stavudine and 3TC and/or zidovudine; (4) zidovudine and lamivudine and 141W94 and 1592U89; (5) zidovudine and 10 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 15 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 20 composition useful for the treatment of AIDS. Indinavir is an inhibitor of HIV protease and is the sulfate salt of N-(2(R)-hydroxy-1(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. 25 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 30 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 35 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 5 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 10 2,4-dioxo-4-(5-phenethylthiophen-2-yl)butanoic acid Step A: Preparation of ethyl 2,4-dioxo-4-(5-phenethynylthiophen-2 yl)butanoate AI(2) _ 0 S JOEt 15 0 0 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 20 dichloromethane, and washed successively with dilute HCl, and brine. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide yellow solid. Recrystallization of the solid from a mixture dichloromethane and hexane provided the title compound. 25 Step B: Preparation of ethyl 2,4-dioxo-4-(5-phenethylthiophen-2 yl)butanoate AI(3) - 74- WO 99/62897 PCT/US99/12094 0 S OEt 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 5 resulting mixture was filtered through a pad of Celite T M , diatomaceous earth. The filtrate was concentrated under vacuum to provide the title compound. Step C: Preparation of 2,4-dioxo-4-(5-phenethylthiophen-2 10 yl)butanoic acid AI(4) 0 S OH 0 0 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), 15 and THF (5 mL) in methanol (5 mL) was stirred at rt overnight. The resultant mixture was treated with aq HCl (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 20 off-white solid. Recrystallization of the solid from a mixture dichloromethane and hexane provided the title compound. 1H NMR (CDCl3) 8 7.72 (d, J =3.1 Hz, 1H), 7.35-7.15 (m, 5H), 6.94 (s, 1H), 6.86 (d, J =3.1 Hz, 1H), 3.22 (d, J =8.1 Hz, 2H), 3.03 (d, J =8.1 Hz, 2H). 25 EXAMPLE 2 2,4-dioxo-4-(5-benzyloxythiophen-2-yl)butanoic acid Step A: Preparation of 2-acetyl-5-(benzyloxy)thiophene AJJ(2a) - 75- WO 99/62897 PCT/US99/12094 0 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 5 hr. The resultant mixture was cooled to rt, benzyl alcohol (2.32 mL, 22.40 mmol) and 2-acetyl-5-chlorothiophene (3.01 g, 18.74 mmol) was added. The mixture was heated under an atmosphere of argon at 85 *C overnight. The product mixture was concentrated under vacuum, and the residue partitioned between ethyl acetate and dilute aqueous HCl. 10 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. 15 Step B: Preparation of 2,4-dioxo-4-(5-benzyloxythiophen-2 yl)butanoic acid AII(4a) S~ OH 0 0 The title compound was prepared using the protocol described in 20 Example AI(4), Step A and C substituting 2-acetyl-5-(phenylethynyl) thiophene with 2-acetyl-5-(benzyloxy)thiophene in Step A. 1H NMR (CDCl3) 6 7.75 (d, J =4.6 Hz, 1H), 7.5-7.3 (m, 5H), 6.85 (s, 1H), 6.42 (d, J =4.6 Hz, 1H), 5.21 (s, 2H). 25 EXAMPLE 3 2,4-dioxo-4-[5-(3-fluorobenzyloxy)thiophen-2-yl]butanoic acid - 76- WO 99/62897 PCT/US99/12094 S OH F The title compound was prepared using the protocol described in Example AII(4a), Step A - B substituting benzyl alcohol with 3 fluorobenzyl alcohol in Step A. 1H NMR (DMSO-d6) 8 8.0 (br s 1H), 7.5 5 7.15 (m, 4H), 6.85 (brs, 1H), 6.6 (br s, 1H), 5.3 (br s, 2H). EXAMPLE 4 2,4-dioxo-4-[5-(4-fluorobenzyloxy)thiophen-2-yl]butanoic acid F OH 10 0 0 The title compound was prepared using the protocol described in Example AII(4a), Step A - B substituting benzyl alcohol with 4 fluorobenzyl alcohol in Step A. 1H NMR (DMSO-d6) 5 8.0 (br s 1H), 7.54 (m, 2H), 7.25 (m, 2H), 6.85 (brs, 1H), 6.6 (br s, 1H), 5.3 (br s, 2H). 15 EXAMPLE 5 2,4-dioxo-4-[5-(3,4-difluorobenzyloxy)thiophen-2-yl]butanoic acid 0 0 F 20 The title compound was prepared using the protocol described in Example AII(4a), Step A - B substituting benzyl alcohol with 3,4 difluorobenzyl alcohol in Step A. 1H NMR (CD30D) 6 7.79 (d, J =4.4 Hz, 1H), 7.45-7.25 (m, 3H), 6.92 (s, 1H), 6.53 (d, J =4.4 Hz, 1H), 5.24 (s, 2H). - 77 - WO 99/62897 PCT/US99/12094 EXAMPLE 6 2,4-dioxo-4-[5-(pyridin-2-ylmethyloxy)thiophen-2-yl]butanoic acid X OH 5 0 0 The title compound was prepared using the protocol described in Example AII(4a), Step A - B substituting benzyl alcohol with 2 pyridylcarbinol in Step A. 1H NMR (DMSO-d6) 6 8.60 (d, J =4.6 Hz, 1H), 8.07 (d, J =4.6 Hz, 1H), 7.87 (ddd, J =7.7, 7.7, 1.7 Hz, 1H), 7.56 (d, J =7.7 10 Hz, 1H), 7.40 (dd, J =7.7, 4.7 Hz, 1H), 6.95 (s, 1H), 6.67 (d, J =4.6 Hz, 1H), 5.39 (s, 2H). EXAMPLE 7 15 2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-2-yl]butanoic acid Step A: Preparation of (5-bromothiophen-2-yl)-(3 fluorophenyl)methanol BI(2a) HO
-
S Br Fd 20 To a cold (-78 *C) solution of n-butyl lithium (20.8 mL, 2.5 M in hexane, 52 mmol) in anhydrous diethyl ether (100 mL) under an atmosphere of argon, 2,5-dibromothiophene (5.63 mL, 50 mmol) was added dropwise over a period of 30 min. After the reaction mixture was stirred at -78 *C for an additional 90 min, 3-fluorobenzaldehyde (5.5 mL, 52 mmol) was 25 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 HCl. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the title compound as brown oil. The oil was used in the following step without further 5 purification. Step B: Preparation of 2-bromo-5-(3-fluorobenzyl)thiophene BI(3a) .- S Br To a cold (0 'C) solution of (5-bromothiophen-2-yl)-(3-fluorophenyl) 10 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, 15 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. 20 Step C: Preparation of 2-acetyl-5-(3-fluorobenzyl)thiophene BI(4a) -..-. S To a cold (-78 *C) solution of 2-bromo-5-(3-fluorobenzyl)thiophene (2.0 g, 7.38 mmol) in anhydrous diethyl ether (20 mL) under an atmosphere of argon, n-butyl lithium (4.8 mL, 1.6 M in hexane, 7.68 mmol) was added 25 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 HCl. The organic extract was washed with brine, dried over anhydrous magnesium 5 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. 10 Step D: Preparation of ethyl 2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen 2-yl]butanoate BI(5a) / | 0 -C S OEt To a cold (-78 *C) solution of 2-acetyl-5-(3-fluorobenzyl)thiophene (315 mg, 1.34 mmol) in anhydrous THF (5 mL) under an atmosphere of argon, 15 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 20 solution was diluted with ethyl acetate, and neutralized with dilute HCl. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was triturated with hexane. The precipitate was filtered to provide the title compound as yellow solid. 25 Step E: Preparation of 2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-2 yl]butanoic acid BI(6a) - 80- WO 99/62897 PCT/US99/12094 / | 0 F- S OH The title compound was prepared using the protocol described in Example AI(4), Step C substituting ethyl 2,4-dioxo-4-(5 phenethylthiophen-2-yl)butanoate with ethyl 2,4-dioxo-4-[5-(3 5 fluorobenzyl)thiophen-2-yl]butanoate. The product was recrystallized from a mixture of ether and hexane. 1H NMR (CDCl3) 5 7.75 (d, J =4.1 Hz, 1H), 7.35-7.25 (m, 2H), 7.05-6.90 (m, 4H), 4.20 (s, 2H). EXAMPLE 8 10 2,4-dioxo-4-[5-(4-fluorobenzyl)thiophen-2-yl]butanoic acid /1 0 -S OH \ / 0 0 F The title compound was prepared using the protocol described in Example BI(6a), Step A - E substituting 3-fluorobenzaldehyde with 4 15 fluoro-benzaldehyde in Step A. 1H NMR (CDCl3) 8 7.74 (d, J =3.8 Hz, 1H), 7.21 (m, 2H), 7.03 (m, 2H), 6.91 (m, 2H), 4.18 (s, 2H). EXAMPLE 9 20 2,4-dioxo-4-[5-(3-chlorobenzyl)thiophen-2-yl]butanoic acid /-|10 - S OH -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 3 chloro-benzaldehyde in Step A. 1H NMR (CDCl3) 8 7.74 (d, J =4.0 Hz, 1H), 7.3-7.2 (m, 3H), 7.14 (m, 1H), 6.92 (m, 2H), 4.18 (s, 2H). 5 EXAMPLE 10 2,4-dioxo-4-(5-benzylthiophen-2-yl)butanoic acid 0 C S OH 10 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 (CDCl3) 6 7.74 (d, J =3.9 Hz, 1H), 7.38 7.22 (m, 5H), 6.91 (m, 2H), 4.21 (s, 2H). 15 EXAMPLE 11 2,4-dioxo-4-(5-phenylsulfanylthiophen-2-yl)butanoic acid Step A: Preparation of 2-acetyl-5-phenylsufanylthiophene BII(2)
--
S 20 A mixture of thiophenol, sodium salt (718 mg, 5,43 mmol) and 2-acetyl-5 bromothiophene (1.0 g, 4.88 mmol) in acetone (10 mL) was stirred at rt under an atmosphere of argon overnight. The resultant mixture was concentrated under vacuum. The residue was subjected to column 25 chromatography on silica gel eluting with chloroform. Collection and concentration of appropriate fractions provided the title ketone. -82 - WO 99/62897 PCT/US99/12094 Step B: Preparation of 2,4-dioxo-4-(5-phenylsulfanylthiophen-2 yl)butanoic acid BII(4) -- S OH 0 0 5 The title compound was prepared using the protocol described in Example AI(4), Step A and C substituting 2-acetyl-5-(phenylethynyl) thiophene with 2-acetyl-5-phenylsufanylthiophene in Step A. The product was recrystallized from a mixture of ether and hexane. 1H NMR (CDCl3) 6 7.73 (d, J =4.0 Hz, 1H), 7.48 (m, 2H), 7.38 (m, 3H), 7.08 (d, 10 J =4.0 Hz, 1H), 6.88 (s, 1H). EXAMPLE 12 2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-3-yl]butanoic acid - OH 15 Step A: Preparation of (4-bromothiophen-2-yl)-(3 fluorophenyl)methanol CI(2a) HO S - Br F The title compound was prepared using the protocol described in 20 Example BI(6a), Step A substituting 2,5-dibromothiophene with 2,4 dibromothiophene. -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 *C) solution of (5-bromothiophen-2-yl)-(3-fluorophenyl) methanol (3.78 g, 13.2 mmol) and triethylsilane (8.4 mL, 52.7 mmol) in 5 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 10 chromatography on silica gel eluting with hexane. Collection and concentration of appropriate fractions provide the title compound as clear colorless oil. The product was stored under argon in a freezer. Step C: Preparation of 2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-3 15 yl]butanoic acid CI(6a) F-6 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 20 (CDCl3) 8 8.08 (d, J =1.5 Hz, 1H), 7.35-7.25 (m, 3H), 7.05-6.92 (m, 2H), 6.90 (s, 1H), 4.15 (s, 2H). EXAMPLE 13 25 2,4-dioxo-4-[5-(4-fluorobenzyl)thiophen-3-yl]butanoic acid -84- WO 99/62897 PCT/US99/12094 S 0 - OH \ / 0 0 F The title compound was prepared using the protocol described in Example CI(6a), Step A - C substituting 3-fluorobenzaldehyde with 4 fluoro-benzaldehyde in Step A. 1H NMR (CDCl3) 8 8.07 (d, J =1.5 Hz, 5 1H), 7.26-7.18 (m, 3H), 7.05-6.92 (m, 2H), 6.89 (s, 1H), 4.13 (s, 2H). EXAMPLE 14 2,4-dioxo-4-[5-(3-chlorobenzyl)thiophen-3-yl]butanoic acid S 0 - OH 10 CI The title compound was prepared using the protocol described in Example CI(6a), Step A - C substituting 3-fluorobenzaldehyde with 3 chloro-benzaldehyde in Step A. 1H NMR (CDCl3) 8 8.09 (br s, 1H), 7.28 7.22 (m, 4H), 7.14 (m, 1H), 6.90 (s, 1H), 4.13 (s, 2H). 15 EXAMPLE 15 2,4-dioxo-4-(5-benzylthiophen-3-yl)butanoic acid S 0 -0- OH 20 The title compound was prepared using the protocol described in Example CI(6a), Step A - C substituting 3-fluorobenzaldehyde with -85 - WO 99/62897 PCT/US99/12094 benzaldehyde in Step A. 1H NMR (CDCl3) 8 8.07 (d, J =1.3 Hz, 1H), 7.36 7.22 (m, 6H), 6.89 (s, 1H), 4.16 (s, 2H). EXAMPLE 16 5 2,4-dioxo-4-(2-phenylsulfanylthiophen-4-yl)butanoic acid Step A: Preparation of 2-phenylsulfanyl-4-bromothiophene CII(1) S S Br 10 To a cold (-78 'C) solution of n-butyl lithium (10.4 mL, 2.5 M in hexane, 26 mmol) in anhydrous diethyl ether (100 mL) under an atmosphere of argon, 2,4-dibromothiophene (2.81 mL, 25 mmol) was added dropwise over a period of 15 min. After the reaction mixture was stirred at -78 "C for an additional 15 min, a solution of diphenyl disulfide (5.68 g, 52 15 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 20 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 25 - 86- WO 99/62897 PCTIUS99/12094 To a cold (-78 "C) solution of 2-phenylsulfanyl-4-bromothiophene (2.28 g, 8.4 mmol) in anhydrous diethyl ether (20 mL) under an atmosphere of argon, n-butyl lithium (5.78 mL, 1.6 M in hexane, 9.25 mmol) was added dropwise over a period of 5 min. After the reaction mixture was stirred 5 at -78 *C for an additional 1 h, N-methoxy-N-methylacetamide (1.03 mL, 10 mmol) was added over a period of 5 min. The resultant mixture was allowed to warm to rt and stirred overnight. The resultant solution was diluted with ether, and neutralized with dilute HCl. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, 10 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. 15 Step C: 2,4-dioxo-4-(2-phenylsulfanylthiophen-4-yl)butanoic acid CII(4) S 0 O OH 0 0 The title compound was prepared using the protocol described in Example AI(4), Step A and C substituting 2-acetyl-5-(phenylethynyl) 20 thiophene with 4-acetyl-2-phenylsulfanylthiophene in Step A. The product was recrystallized from a mixture of ether and hexane. 1H NMR (CDCl3) 6 8.27 (d, J =1.5 Hz, 1H), 7.68 (d, J =1.5 Hz, 1H), 7.34-7.24 (m, 5H), 6.93 (s, 1H). 25 EXAMPLE 17 2,4-dioxo-4-[2-(3-fluorobenzyl)thiophen-3-yl]butanoic acid - 87 - WO 99/62897 PCTIUS99/12094 s OH F The title compound was prepared using the protocol described in Example BI(6a), Step A - E substituting 2,5-dibromothiophene with 1,2 dibromothiophene in Step A. 1H NMR (CDCl3) 6 7.42 (d, J =5.5 Hz, 1H), 5 7.32-7.24 (m, 1H), 7.20 (dd, J =5.5, 1.1 Hz, 1H), 7.05 (br d, J =7.5 Hz, 1H), 6.98-6.92 (m, 3H), 4.57 (s, 2H). EXAMPLE 18 10 2,4-dioxo-4-[2-(4-fluorobenzyl)thiophen-3-yl]butanoic acid S0 OH FO O O The title compound was prepared using the protocol described in Example BI(6a), Step A - E substituting 2,5-dibromothiophene with 1,2 dibromothiophene, and 3-fluorobenzaldehyde with 4-fluorobenzaldehyde 15 in Step A. 1H NMR (DMSO-d6) 5 7.62 (br d, 1H), 7.47 (br d, IH), 7.35 (m, 2H), 7.15 (m, 2H), 6.83 (br s, 1H), 4.55 (s, 2H). EXAMPLE 19 20 2,4-dioxo-4-[2-(3-chlorobenzyl)thiophen-3-yl]butanoic acid - 88- WO 99/62897 PCTIUS99/12094 S / \ o oOH CI The title compound was prepared using the protocol described in Example BI(6a), Step A - E substituting 2,5-dibromothiophene with 1,2 dibromothiophene, and 3-fluorobenzaldehyde with 3-chlorobenzaldehyde 5 in Step A. 1H NMR (DMSO-d6) 8 7.42 (br d, 1H), 7.3-7.1 (m, 5H), 6.92 (br s, 1H), 4.55 (s, 2H). EXAMPLE 20 10 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 15 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. 20 Step B: Preparation of 5-(benzyloxy-phenylmethyl)-2 bromothiophene EI(la) - 89- WO 99/62897 PCTIUS99/12094 \ 0 S S Br A suspension of sodium hydride (147 mg, 6 mmol) in anhydrous DMSO (20 mL) was stirred at 60 *C under an atmosphere of argon for 1 hr. The resultant mixture was cooled to rt, (5-bromothiophen-2-yl)-(phenyl) 5 methanol (1.5 g, 5.57 mmol) was added. After stirring for 10 min., benzyl bromide (0.8 mL, 6.68 mmol) was added. The mixture was stirred at rt under an atmosphere of argon overnight. The product mixture was concentrated under vacuum, and the residue partitioned between ethyl ether and dilute aqueous HCl. The organic extract was washed with 10 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. 15 Step C: Preparation of 2,4-dioxo-4-[5-(benzyloxy phenylmethyl)thiophen-2-yl]butanoic acid EI(5a) \0 /
-
00 OH The title compound was prepared using the protocol described in 20 Example BI(6a), Step C - E substituting 2-bromo-5-(3-fluorobenzyl) thiophene with 5-(benzyloxy-phenylmethyl)-2-bromothiophene in Step C. -90- WO 99/62897 PCT/US99/12094 1H NMR (CDCl3) 5 7.71 (d, J =4.0 Hz, 1H), 7.5-7.3 (m, 9H), 6.94 (s, 1H), 6.86 (d, J =4.0 Hz, 1H), 5.62 (s, 2H), 4.63 (d, J =12.1 Hz, 1H), 4.53 (d, J =12.1 Hz, 1H). 5 EXAMPLE 21 -- -- OH \ 0 0 2,4-dioxo-4-[5-(phenoxy-phenylmethyl)thiophen-2-yl]butanoic acid The title compound was prepared using the protocol described in 10 Example EI(5a), Step A - C substituting benzyl bromide with diphenyl iodonium chloride in Step B. 1H NMR (CDCl3) 8 7.73 (d, J =4.0 Hz, 1H), 7.5-7.2 (m, 7H), 7.01 (d, J =4.0 Hz, 1H), 6.94 (s, 1H), 7.00-6.95 (m, 3H), 6.41 (s, 1H). 15 EXAMPLE 22 2,4-dioxo-4-[5-(methoxy-phenylmethyl)thiophen-2-yl]butanoic acid H3CO0 - 8 OH \ / 0 0 The title compound was prepared using the protocol described in 20 Example EI(5a), Step A - C substituting benzyl bromide with methyl iodide in Step B. 1H NMR (CDCl3) 6 7.71 (d, J =4.0 Hz, 1H), 7.42 (m, 7H), 6.94 (s, 1H), 6.92 (d, J =4.0 Hz, 1H), 3.42 (s, 3H). EXAMPLE 23 25 - 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 5 0 A mixture of 2-acetyl-5-nitrothiophene (5.00 g, 29.2 mmol), and 5% Pt2S/C (3 g) in methanol (120 mL) was stirred under a balloon of hydrogen overnight at rt. To the resulting mixture, an ethanolic solution of hydrogen chloride gas was added (final pH ~ 2), and the 10 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) - NI 0 15 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 20 with chloroform - chloroform saturated with ammonia gradient. Collection and concentration of appropriate fractions provided the title compound as red oil. Step C: Preparation of 2,4-dioxo-4-(5-dibenzylaminothiophen-2 25 yl)butanoic acid FI(5a) -92- WO 99/62897 PCTIUS99/12094 N OH 0 0 The title compound was prepared using the protocol described in Example AI(4), Step A and C substituting 2-acetyl-5-(phenylethynyl) thiophene with 2-acetyl-5-dibenzylaminothiophene in Step A. The 5 product was purified by HPLC on C-18 stationary phase. 1H NMR (DMSO-d6) 8 7.93 (d, J =4.8 Hz, 1H), 7.40-7.25 (m, 10H), 6.79 (s, 1H), 6.27 (d, J =4.8 Hz, 1H), 4.81 (s, 4H). EXAMPLE 24 10 2,4-dioxo-4-(5-benzylaminothiophen-2-yl)butanoic acid Step A: Preparation of 2-acetyl-5-benzylaminothiophene FI(3b) - ~N I H S 0 15 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 20 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-2 yl)butanoic acid FI(5b) - 0 H SOH 0 0 The title compound was prepared using the protocol described in 5 Example AI(4), Step A and C substituting 2-acetyl-5-(phenylethynyl) thiophene with 2-acetyl-5-benzylaminothiophene in Step A. The product was purified by HPLC on C-18 stationary phase. 1H NMR (CD30D) 6 7.70 (d, J =4.6 Hz, 1H), 7.40-7.25 (m, 5H), 6.79 (s, 1H), 6.14 (d, J =4.6 Hz, 1H), 4.86 (s, 2H). 10 EXAMPLE 25 2,4-dioxo-4-(5-diallylaminothiophen-2-yl)butanoic acid 15 Step A: Preparation of 2-acetyl-5-diallylaminothiophene FI(3c) N A mixture of 2-acetyl-5-aminothiophene hydrochloride (1.5 g, 8.44 mmol), allyl bromide (7.30 mL, 84.4 mmol), and diisopropylethylamine (6.5 mL, 37.3 mmol) in acetonitrile (10 mL) was stirred at 60 *C for 3 20 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 PCT/US99/12094 Step B: Preparation of 2,4-dioxo-4-(5-diallylaminothiophen-2 yl)butanoic acidFI(5c) N-1 0 N SOH O 0 The title compound was prepared using the protocol described in 5 Example AI(4), Step A and C substituting 2-acetyl-5-(phenylethynyl) thiophene with 2-acetyl-5-diallylaminothiophene in Step A. The product was purified by HPLC on C-18 stationary phase. 1H NMR (CDCl3) 5 7.67 (d, J =4.6 Hz, 1H), 6.76 (s, 1H), 6.06 (d, J =4.6 Hz, 1H), 5.85 (m, 2H), 5.3 (m, 4H), 4.05 (m, 4H). 10 EXAMPLE 26 2,4-dioxo-4-(5-di-n-propylaminothiophen-2-yl)butanoic acid 15 Step A: Preparation of 2-acetyl-5-di-n-propylaminothiophene FI(3d) N $0O A mixture of 2-acetyl-5-diallylaminothiophene (200 mg, 0.904 mmol) and 5% Pd/C (200 mg) in methanol (10 mL) was stirred under a balloon of hydrogen for 3 h. The resulting mixture was filtered through a pad of of 20 Celite
TM
, diatomaceous earth. The filtrate was concentrated under vacuum to provide the title compound. Step B: Preparation of 2,4-dioxo-4-(5-di-n-propylaminothiophen-2 yl)butanoic acid FI(5d) - 95 - WO 99/62897 PCT/US99/12094 N 0 OH ;~I0 0 The title compound was prepared using the protocol described in Example AI(4), Step A and C substituting 2-acetyl-5-(phenylethynyl) thiophene with 2-acetyl-5-di-n-propylaminothiophene in Step A. The 5 product was purified by HPLC on C-18 stationary phase. 1H NMR (DMSO-d6) 6 7.95 (d, J =4.8 Hz, 1H), 6.81 (s, 1H), 6.19 (d, J =4.8 Hz, 1H), 3.38 (t, J =7.5 Hz, 4H), 1.62 (h, J =7.5 Hz, 4H), 0.89 (d, J =7.5 Hz, 6H), EXAMPLE 27 10 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) FN S 0 15 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
3 (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 20 a mixture of chloroform and aq HCl. After stirring at rt for 1 h, the pH of the mixture was adjusted to -8. The organic extract was washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was subjected to column chromatography on - 96- WO 99/62897 PCT/US99/12094 silica gel eluting with 40% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title compound. Step B: Preparation of 2,4-dioxo-4-[5-(di-4 5 fluorobenzylamino)thiophen-2-yl]butanoic acid FI(5e) F N0 S OH 0 0 F The title compound was prepared using the protocol described in Example AI(4), Step A and C substituting 2-acetyl-5-(phenylethynyl) thiophene with 2-acetyl-5-(di-4-fluorobenzylamino)thiophene in Step A. 10 1H NMR (CDCl3) 6 7.66 (d, J =4.6 Hz, 1H), 7.2-7.0 (m, 8H), 6.78 (s, 1H), 6.14 (d, J =4.6 Hz, 1H), 4.59 (s, 4H). EXAMPLE 28 15 2,4-dioxo-4-[5-(N-benzyl-N-methylamino)thiophen-2-yl]butanoic acid Step A: Preparation of 2-acetyl-5-(N-benzyl-N methylamino)thiophene FII(la) - ~N1
H
3 0/ S 0 20 A solution of cesium carbonate (3.25 g, 10 mmol), N-methyl-N benzylamine (2.58 mL, 20 mmol) and 2-acetyl-5-chlorothiophene (1.61 g, 10 mmol) in DMF (20 mL) was stirred at 60 *C under an atmosphere of argon for 9 days. The product mixture was concentrated under vacuum, and the residue was treated with a mixture of ethyl ether and dilute - 97- WO 99/62897 PCTIUS99/12094 aqueous HCl. After stirring at rt for 1 h, pH of the solution was adjusted to -8 with sat. aq. NaHCO3, 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 5 silica gel eluting with 30% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title ketone. Step B: Preparation of 2,4-dioxo-4-[5-(N-benzyl-N methylamino)thiophen-2-yl]butanoic acid FII(3a)
H
3 C S OH 10 0 0 The title compound was prepared using the protocol described in Example AI(4), Step A and C substituting 2-acetyl-5-(phenylethynyl) thiophene with 2-acetyl-5-(benzylmethylamino)thiophene in Step A. 1H NMR (CDCl3) 5 7.70 (d, J =4.6 Hz, 1H), 7.4-7.2 (m, 5H), 6.77 (br s, 1H), 6.10 15 (d, J =4.6 Hz, 1H), 4.62 (s, 2H), 3.15 (s, 3H). EXAMPLE 29 2,4-dioxo-4-(5-piperidin-1-yl-thiophen-2-yl)butanoic acid 20 Step A: Preparation of 2-acetyl-5-piperidin-1-yl-thiophene FII(2b) CN SD 0 The title compound was prepared using the protocol described in Example FII(3a), Step A and C substituting N-methyl-N-benzylamine 25 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-1-yl-thiophen-2 yl)butanoic acid FII(3b) S OH 0 0 The title compound was prepared using the protocol described in 5 Example AI(4), Step A and C substituting 2-acetyl-5-(phenylethynyl) thiophene with 2-acetyl-5-piperidin-1-yl-thiophene in Step A. 1H NMR (CDCl3) 6 7.70 (d, J =4.8 Hz, 1H), 6.77 (br s, 1H), 6.13 (d, J =4.6 Hz, 1H), 3.41 (t, J =5.7 Hz, 4H), 1.7 (m, 6H). 10 EXAMPLE 30 2,4-dioxo-4-[5-(benzylbenzenesulfonylamino)thiophen-2-yl]butanoic acid Step A: Preparation of 2-acetyl-5-(benzenesulfonylamino)thiophene 15 FIII(1) H / O N 0 2 S S 0 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 20 mixture was concentrated under vacuum, and the residue was partitioned between ethyl acetate and aq. HCl. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 50% ethyl acetate in hexane. -99- WO 99/62897 PCT/US99/12094 Collection and concentration of appropriate fractions provided the title sulfonamide. Step B: Preparation of 2-acetyl-5 5 (benzylbenzenesulfonylamino)thiophene FIII(2) a-\N I 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 2.5 10 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. HCl. The organic extract was washed with brine, dried over anhydrous MgSO4, filtered and concentrated under vacuum. The residue was subjected to 15 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 20 (benzylbenzenesulfonylamino)thiophen-2-yl]butanoic acid FIII(4) 0 2 S OH 0 0 - 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 2-acetyl-5-(phenylethynyl) thiophene with 2-acetyl-5-(benzylbenzenesulfonylamino)thiophene in Step A. 1H NMR (CDCl3) 8 7.76 (d, J =4.5 Hz, 1H), 7.7-7.5 (m, 5H), 7.3 (m, 5 5H), 6.83 (br s, 1H), 6.82 (d, J =4.5 Hz, 1H), 4.83 (s, 4H). EXAMPLE 31 2,4-dioxo-4-(2-dibenzylaminothiazol-5-yl)butanoic acid 10 Step A: Preparation of 1,1-dibenzylthiourea GI(la)
NH
2 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 15 overnight. The white precipitate was isolated by filtration, and was treated with concentrated hydrochloric acid (25 mL) at 100 *C for 1.5 h. The product mixture was concentrated under vacuum. The residue was treated with 10% aq. NaHCO 3 . The white solid precipitated was obtained by filtration, and recrystallized from a mixture of chloroform and 20 hexane. Filtration provided the title compound as white powder. Step B: Preparation of 1,1-dibenzyl-3 dimethylaminomethylenethiourea GI(2a) -101- WO 99/62897 PCT/US99/12094
N
-N-K S A mixture of 1,1-dibenzylthiourea (4.0 g, 15.6 mmol) and N,N dimethylformamide dimethyl acetal (20 mL) was heated at 100 *C for 1 h. The reaction mixture was concentrated, and the residue was 5 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 / \ 0 10 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 15 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-5 20 yl)butanoic acid GI(5a) - 102 - WO 99/62897 PCT/US99/12094 N O - N-I S O The title compound was prepared using the protocol described in Example AI(4), Step A and C substituting 2-acetyl-5-(phenylethynyl) thiophene with 2-dibenzylamino-5-acetylthiazole in Step A. The product 5 was purified by recrystallization from toluene. 1H NMR (CDCl3) 6 8.19 (s, 1H), 7.40-7.20 (m, 10H), 6.81 (s, 1H), 4.76 (s, 4H). EXAMPLE 32 10 2,4-dioxo-4-(2-benzylaminothiazol-5-yl)butanoic acid Step A: Preparation of 1-benzyl-3-dimethylaminomethylenethiourea GI(2b)
N
N H S 15 A mixture of 1-benzylthiourea (8.3 g, 50 mmol) and N,N-dimethyl formamide dimethyl acetal (25 mL) was heated at 100 *C for 1 h. The reaction mixture was concentrated, and the residue was recrystallized from a mixture of chloroform and hexane. Filtration of the white solid provide the title compound. 20 Step B: Preparation of 2-benzylamino-5-acetylthiazole GI(3b) - 103 - WO 99/62897 PCT/US99/12094 N 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 5 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. 10 Step C: Preparation of 2,4-dioxo-4-(2-benzylaminothiazol-5 yl)butanoic acid GI(5b) N O .N-</ H S O H 0 The title compound was prepared using the protocol described in Example AI(4), Step A and C substituting 2-acetyl-5-(phenylethynyl) 15 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 (s, 1H), 7.40-7.20 (m, 5H), 6.88 (s, 1H), 4.57 (d, J=5.4 Hz, 2H). 20 EXAMPLE 33 2,4-dioxo-4-(2-N-benzyl-N-methylaminothiazol-5-yl)butanoic acid Step A: Preparation of 2-N-benzyl-N-methylamino-5-acetylthiazole 25 GI(3c) - 104 - WO 99/62897 PCTIUS99/12094 N
H
3 C S 0 The title compound was prepared using the protocol described in Example GI(5a), Step A - C substituting N,N-dibenzylamine with N benzyl-N-methylamine in Step A. 5 Step B: Preparation of 2,4-dioxo-4-(2-N-benzyl-N methylaminothiazol-5-yl)butanoic acid GI(5c) N0 - N-<I
H
3 N S OH 0 0 The title compound was prepared using the protocol described in 10 Example AI(4), Step A and C substituting 2-acetyl-5-(phenylethynyl) thiophene with 2-N-benzyl-N-methylamino-5-acetylthiazole in Step A. The product was purified by recrystallization from toluene. 1H NMR (CDCl3) 8 8.01 (s, 1H), 7.40-7.20 (m, 5H), 6.78 (s, 1H), 4.82 (s, 2H), 3.15 (s, 3H). 15 EXAMPLE 34 2,4-dioxo-4-(2-dibenzylaminothiazol-4-yl)butanoic acid 20 Step A: Preparation of 2-dibenzylamino-4-acetylthiazole GII(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 5 mixture was cooled to 0 *C, 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. 10 Step D: Preparation of 2,4-dioxo-4-(2-dibenzylaminothiazol-4 yl)butanoic acid GII(5) - ~ N-<\I N N OH 0 0 The title compound was prepared using the protocol described in 15 Example AI(4), Step A and C substituting 2-acetyl-5-(phenylethynyl) thiophene with 2-dibenzylamino-4-acetylthiazole in Step A. The product was purified by recrystallization from a mixture of ether and hexane as orange needles. 1H NMR (CDCl3) 8 7.56 (s, 1H), 7.40-7.20 (m, 11H), 4.70 (s, 4H). 20 EXAMPLE 35 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 5 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. 10 EXAMPLE 36 Assay for inhibition of HIV replication Assays for the inhibition of acute HIV infection of T lymphoid cells was conducted according to Vacca, J.P.et al., (1994), 15 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. 20 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 25 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 30 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 (24)
1. A compound of structural formula (I): R10 OR 7 R 8 0 0 (I) or tautomers or pharmaceutically acceptable salts thereof, 5 wherein: A is a five-membered heteroaromatic ring containing 1 sulfur atom and 1 2 8 0 or 1 nitrogen atoms and substituted on carbon by R , R and R ; the heteroaromatic ring may optionally be fused with a phenyl ring or a C4-6 cycloalkyl ring, or with two six membered rings to form: or S or 10 R is selected from: (1) -H, (2) -C 1 - 5 alkyl, (3) -CF 3 > 15 (4) -halo, (5) -NO 2 , (6) -N(R')(R5 (7) -R 6 , 3 (8) -C 2 - 5 alkenyl-R3 3 20 (9) -C 2 - 5 alkynyl-R3 (10) -O-R 6 , (11) -0-C1-6 alkyl, and (12) -C(O)CH2C(O)C(O)OR7; - 108 - WO 99/62897 PCT/US99/12094 R2 is selected from: (1) -H, (2) -R3 (3) -C 1 - 6 alkyl, 5 (4) -C 1 - 6 alkyl substituted with R (5) -O-R6 6 (6) -0-C 1 - 6 alkyl-OR 6 (7) -S(O)n-R (8) -C 1 - 6 alkyl (OR 6)(R ) , 10 (9) -C1- 6 alkyl (OR )(R6 , (10) -C 0 - 6 alkyl-N(R )(R 6), 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 15 (14) -C 0 - 6 alkyl NR C(O)-R , and (15) -C 0 - 6 alkyl-C(O)N(R )(R 5); each R 3 is independently selected from: (1) a 5 or 6 membered aromatic or heteroaromatic ring, 20 containing 0, 1, 2, 3, or 4 heteroatoms selected from oxygen, nitrogen and sulfur, unsubstituted or substituted on a nitrogen or carbon atom by 1 to 5 substituents selected from: (a) halogen, (b) C 1 - 6 alkyl, 25 (c) C 1 - 6 alkyloxy-, (d) phenyl, (e) -CF 3 , (f) -OCF 3 , (g) -CN, 30 (h) hydroxy, (i) phenyloxy, and - 109 - WO 99/62897 PCT/US99/12094 (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C 1 - 6 alkyl, 5 (iii) -CF3, and (iv) hydroxy; (2) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms selected from oxygen, nitrogen or sulfur, 10 unsubstituted or substituted with 0 to 5 substituents selected from: (a) halogen, (b) C 1 - 6 alkyl, (c) C 1 - 6 alkyloxy-, 15 (d) -CF 3 , (e) -OCF 3 , (f) -CN, (g) =0, and (h) hydroxy; 20 (3) unsubstituted or substituted hexahydrothieno[3,4 d]imidazolyl with one or two substituents selected from: (a) oxo, (b) halogen, 25 (c) C 1 - 6 alkyl, (d) C 1 - 6 alkyloxy-, (e) -CF 3 , (f) -OCF 3 ' (g) -CN, and 30 (h) hydroxy; (4) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, or 2 heteroatoms selected from oxygen, -110- WO 99/62897 PCT/US99/12094 nitrogen and sulfur, fused with a phenyl ring; wherein the ring system is unsubstituted or substituted on a nitrogen or carbon atom by 1 to 3 substituents selected from: (a) -halogen, 5 (b) -C1- 6 alkyl, (c) -C 1 - 6 alkyloxy-, (d) -CF 3 , (e) -OCF 3 , (f) -CN, and 10 (g) -hydroxy; (5) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms selected from oxygen, nitrogen or sulfur, fused with a phenyl ring, unsubstituted or substituted with or 2 15 substituents selected from: (a) halogen, (b) C 1 - 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) -CF 3 , 20 (e) -OCF 3 , (f) -CN, (g) =0, and (h) hydroxy; 25 (6) a 5 to 6 membered ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, containing 2 or 3 double bonds, unsubstituted or substituted with 1 or 2 substituents selected from: (a) halogen, 30 (b) C1- 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) -CF 3 , (e) -OCF 3 , - 111 - WO 99/62897 PCTIUS99/12094 (f) -CN, (g) =0, and (h) hydroxy; 5 each R4 is independently selected from: (1) -H, (2) -C1- 3 alkyl, (3) -CF 3 , (4) -R 10 (5) -C 2 - 3 alkenyl, 3 (6) -C 1 - 3 alkyl-R 3 (7) -C 2 - 3 alkenyl-R (8) -S(0)n-R 3, and 3 (9) -C(O)-R 15 each R5 is independently selected from: (1) -H, (2) -C 1 - 3 alkyl, (3) -CF 3 ' 3 20 (4) -R3 (5) -C 2 - 3 alkenyl, (6) -C 1 - 3 alkyl-R3 (7) -C 2 - 3 alkenyl-R3 3 (8) -S(O)n-R, and 3 25 (9) -C(O)-R each R6 is independently selected from: 3 (1) -C 1 - 3 alkyl-R , and 3 (2) -R3 30 R 7 is selected from: -112- WO 99/62897 PCT/US99/12094 (1) -H, and (2) C1-6 alkyl; R 8 is selected from: 5 (1) -H, and (2) C1-6 alkyl-oxy-, and (3) C1-6 alkyl-; each n is independently selected from 0, 1 and 2, and 10 each m is independently selected from 0, 1, and 2.
2. The compound according to Claim 1, and tautomers and pharmaceutically acceptable salts thereof, wherein: 15 A is selected from: (1) thienyl, (2) thiazolyl, (3) S 20 (4) /\ ,and (5) R is selected from: 25 (1) -H, (2) -CH 3 , (3) -CF 3 ' (4) -halo, -113- WO 99/62897 PCT/US99/12094 (5) -NO 2 , (6) -N(R )(R 5), (7) -phenyl, (8) substituted phenyl substituted with 1 or 2 substituents 5 independently selected from: (a) halogen, (b) C 1 - 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) phenyl, 10 (e) -CF 3 > (f) -OCF 3 , (g) -CN, (h) hydroxy, (i) phenyloxy, and 15 (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C 1 - 6 alkyl, (iii) -CF 3 , and 20 (iv) hydroxy; (9) phenyl C 1 - 3 alkyl-, (10) substituted phenyl C1- 3 alkyl- substituted with 1 or 2 substituents independently selected from: (a) halogen, 25 (b) C 1 - 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) phenyl, (e) -CF 3 , (f) -OCF 3 , 30 (g) -CN, (h) hydroxy, (i) phenyloxy, and -114- WO 99/62897 PCT/US99/12094 (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C 1 - 6 alkyl, 5 (iii) -CF3, and (iv) hydroxy; 3 (11) -C 2 - 5 alkenyl-R3 3 (12) -C 2 - 5 alkynyl-R , and (13) -C(O)CH2C(O)C(O)OR 7 ; 10 R2 is selected from: (1) -H, (2) -R3, (3) -C1- 6 alkyl, 15 (4) -C 1 - 6 alkyl substituted with R (5) -O-R 6 (6) -0-C 1 - 6 alkyl-OR (7) -S(O)n-R6 (8) -C 1 - 6 alkyl (OR6 )(R) , 20 (9) -C 1 - 6 alkyl (OR )(R 6), (10) -C 0 - 6 alkyl-N(R )(R6), (11) -C 1 - 6 alkyl S(O)n-R6 6 (12) -C 0 - 6 alkyl C(O)-R 6 (13) -C 0 .. 6 alkyl C(S)-R 25 (14) -C 0 - 6 alkyl NR C(O)-R , and (15) -C 0 - 6 alkyl-C(O)N(R )(R 5); each R 3 is independently selected from: (1) phenyl; 30 (2) substituted phenyl with 1, 2, or 3 substituents independently selected from: (a) halogen, -115- WO 99/62897 PCT/US99/12094 (b) C 1 - 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) phenyl, (e) -CF 3 ' 5 (f) -OCF 3 , (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents 10 selected from: (i) halogen, (ii) C 1 - 6 alkyl, (iii) -CF3, and (iv) hydroxy; 15 (3) thienyl; (4) substituted thienyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, (b) C 1 - 6 alkyl, 20 (c) C 1 - 6 alkyloxy-, (d) phenyl, (e) -CF 3 , (f) -OCF 3 , (g) -CN, 25 (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, 30 (ii) C 1 - 6 alkyl, (iii) -CF 3 , and (iv) hydroxy; -116- WO 99/62897 PCT/US99/12094 (5) pyridyl; (6) substituted pyridyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, 5 (b) C 1 - 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) phenyl, (e) -CF 3 , (f) -OCF 3 , 10 (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: 15 (i) halogen, (ii) C 1 - 6 alkyl, (iii) -CF 3 , and (iv) hydroxy; (7) imidazolyl; 20 (8) substituted imidazolyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, (b) C 1 - 6 alkyl, (c) C 1 - 6 alkyloxy-, 25 (d) phenyl, (e) -CF 3 , (f) -OCF 3 ' (g) -CN, (h) hydroxy, 30 (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, -117- WO 99/62897 PCT/US99/12094 (ii) C 1 - 6 alkyl, (iii) -CF 3 , and (iv) hydroxy; (9) pyrrolyl; 5 (10) substituted pyrrolyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, (b) C 1 - 6 alkyl, (c) C 1 - 6 alkyloxy-, 10 (d) phenyl, (e) -CF 3 ' (f) -OCF 3 , (g) -CN, (h) hydroxy, 15 (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C 1 - 6 alkyl, 20 (iii) -CF 3 , and (iv) hydroxy; (11) pyrazolyl; (12) substituted pyrazolyl substituted on a carbon atom with one or two substituents independently selected from: 25 (a) halogen, (b) C 1 - 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) phenyl, (e) -CF 3 ' 30 (f) -OCF 3 , (g) -CN, (h) hydroxy, -118- WO 99/62897 PCTIUS99/12094 (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, 5 (ii) C 1 - 6 alkyl, (iii) -CF3, and (iv) hydroxy; (13) C 3 - 6 cycloalkyl; (14) substituted C 3 - 6 cycloalkyl with 1 or 2 substituents 10 independently selected from: (a) halogen, (b) C1- 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) -CF 3 , 15 (e) -OCF 3 ' (f) -CN, (g) =0, and (h) hydroxy; (15) piperidinyl; 20 (16) substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, (b) C 1 - 6 alkyl, (c) C 1 - 6 alkyloxy-, 25 (d) -CF 3 , (e) -OCF 3 ' (f) -CN, (g) =0, and (h) hydroxy; 30 (17) morpholinyl; (18) substituted morpholinyl substituted at a carbon or nitrogen atom with 1 or 2 independently selected from: (a) halogen, -119- WO 99/62897 PCT/US99/12094 (b) C 1 - 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) -CF 3 > (e) -OCF 3 , 5 (f) -CN, (g) =0, and (h) hydroxy; (19) naphthyl, (20) substituted naphthyl with 1, 2, or 3 substituents 10 independently selected from: (a) -halogen, (b) -C1- 6 alkyl, (c) -C 1 - 6 alkyloxy-, (d) -CF 3 , 15 (e) -OCF 3 , (f) -CN, and (g) -hydroxy; (21) indolyl; (22) substituted indolyl substituted on a carbon atom with one or 20 two substituents independently selected from: (a) -halogen, (b) -C 1 - 6 alkyl, (c) -C1- 6 alkyloxy-, (d) -CF 3 > 25 (e) -OCF 3 , (f) -CN, and (g) -hydroxy; (23) C 3 - 6 cycloalkyl fused with a phenyl ring (24) substituted C 3 - 6 cycloalkyl fused with a phenyl ring 30 substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, -120- WO 99/62897 PCT/US99/12094 (b) C1- 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) -CF 3 ' (e) -OCF 3 , 5 (f) -CN, (g) =0, and (h) hydroxy; each R4 is independently selected from: 10 (1) -H, (2) -C 1 - 3 alkyl, (3) -CF 3 , (4) -R3, (5) -C 2 - 3 alkenyl, 3 15 (6) -C 1 - 3 alkyl-R (7) -C2- 3 alkenyl-R3 3 (8) -S(0)n-R3, and (9) -C(0)-R 20 each R5 is independently selected from: (1) -H, (2) -C1- 3 alkyl, (3) -CF 3 , (4) -R3, 25 (5) -C 2 - 3 alkenyl, 3 (6) -C 1 - 3 alkyl-R (7) -C 2 - 3 alkenyl-R3 3 (8) -S(O)n-R3, and (9) -C(O)-R 3 . 30 each R6 is independently selected from: -121- WO 99/62897 PCT/US99/12094 (1) -C 1 - 3 alkyl-R 3, and (2) -R R 7 is H; 5 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. 10
3. The compound according to Claim 2 , and tautomers and pharmaceutically acceptable salts thereof, wherein: 15 A is selected from: (1) thienyl, (2) thiazolyl, (3) S ,and 20
(4) S R is selected from: (1) -H, (2) -CH 3 , 25 (3) -CF3, (4) -halo, (5) -NO 2 , (6) -N(R 4)(R 5 (7) -phenyl, - 122 - WO 99/62897 PCT/US99/12094 (8) substituted phenyl substituted with 1 or 2 substituents independently selected from: (a) halo, (b) methyl, and 5 (c) methoxy, (9) phenyl C 1 - 3 alkyl-, (10) substituted phenyl C 1 - 3 alkyl- substituted with 1 or 2 substituents independently selected from: (a) halo, 10 (b) methyl, and (c) methoxy, and (11) -C 2 - 5 alkenyl-R3 R2 is selected from: 15 (1) -H, 3 (2) -R, (3) -C1- 6 alkyl, (4) -C 1 - 6 alkyl substituted with R3 (5) -O-R6 6 20 (6) -S(O)n-R (7) -C 1 - 6 alkyl (OR 6)(R4), (8) -C 1 - 6 alkyl (OR )(R 6), (9) -C 0 - 6 alkyl-N(R )(R 6), (10) -C 1 - 6 alkyl S(O)n-R6 25 (11) -C 0 - 6 alkyl C(O)-R6 (12) -C 0 - 6 alkyl NR C(O)-R 6, and (13) -C 0 - 6 alkyl-C(O)N(R4)(R 5); each R 3 is independently selected from: 30 (1) phenyl; (2) substituted phenyl with 1, 2, or 3 substituents independently selected from: - 123 - WO 99/62897 PCT/US99/12094 (a) halogen, (b) C 1 - 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) phenyl, 5 (e) -CF 3 , (f) -OCF 3 ' (g) -CN, (h) hydroxy, (i) phenyloxy, and 10 (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C 1 - 6 alkyl, (iii) -CF 3 , and 15 (iv) hydroxy; (3) thienyl; (4) substituted thienyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, 20 (b) C 1 - 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) phenyl, (e) -CF 3 , (f) -OCF 3 ' 25 (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: 30 (i) halogen, (ii) C 1 - 6 alkyl, (iii) -CF 3 , and (iv) hydroxy; - 124 - WO 99/62897 PCT/US99/12094 (5) pyridyl; (6) substituted pyridyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, 5 (b) C 1 - 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) phenyl, (e) -CF 3 , (f) -OCF 3 ' 10 (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: 15 (i) halogen, (ii) C 1 - 6 alkyl, (iii) -CF3, and (iv) hydroxy; (7) imidazolyl; 20 (8) pyrrolyl; (9) pyrazolyl; (10) C 3 - 6 cycloalkyl, (11) substituted C 3 - 6 cycloalkyl with 1 or 2 substituents independently selected from: 25 (a) halogen, (b) C 1 - 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) -CF 3 , (e) -OCF 3 > 30 (f) -CN, (g) =0, and (h) hydroxy; (12) piperidinyl; -125 - WO 99/62897 PCT/US99/12094 (13) substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, (b) C.1- 6 alkyl, 5 (c) C 1 - 6 alkyloxy-, (d) -CF 3 , (e) -OCF 3 ' (f) -CN, (g) =0, and 10 (h) hydroxy; (14) morpholinyl; (15) naphthyl; (16) indolyl; and (17) C 3 - 6 cycloalkyl fused with a phenyl ring; 15 each R4 is independently selected from: (1) -H, (2) -C1- 3 alkyl, (3) -CF 3 ' 20 (4) -R3, (5) -C 2 - 3 alkenyl, 3 (6) -C 1 - 3 alkyl-R , and (7) -S(O)n-R 3; and 25 each R5 is independently selected from: (1) -H, (2) -C 1 - 3 alkyl, (3) -CF 3 , 3 (4) -R, 30 (5) -C 2 - 3 alkenyl, (6) -C 1 - 3 alkyl-R3 - 126 - WO 99/62897 PCTIUS99/12094 (7) -C 2 - 3 alkenyl-R 3, and (8) -S(O)n-R3 each R6 is independently selected from: 5 (1) -C 1 - 3 alkyl-R 3, and 3 (2) -R; R 7 is H; 10 R 8 is H; and each n is independently selected from 0, 1 and 2. 15 4. The compound according to Claim 1 of structural formula: R2 S OH 0 0 and tautomers and pharmaceutically acceptable salts thereof, wherein: R2 is selected from: 20 (1) -H, 3 (2) -R, (3) -C1- 6 alkyl, (4) -C 1 - 6 alkyl substituted with R 3 (5) -O-R 6 25 (6) -S(O)n-R (7) -C1-6 alkyl (OR6)(R ) , (8) -C 1 - 6 alkyl (OR )(R 6), (9) -C 0 - 6 alkyl-N(R )(R 6), (10) -C 1 - 6 alkyl S(O)n-R6 - 127 - WO 99/62897 PCT/US99/12094 (11) -C 0 - 6 alkyl C(O)-R6 (12) -C 0 - 6 alkyl NR C(O)-R 6, and (13) -C 0 - 6 alkyl-C(O)N(R )(R5); 5 each R3 is independently selected from: (1) phenyl, (2) substituted phenyl with 1, 2, or 3 substituents independently selected from: (a) halogen selected from -F, -Cl, -Br, 10 (b) CH 3 ' (c) methoxy-, (d) phenyl, (e) -CF 3 , (f) -OCF 3 , 15 (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: 20 (i) halogen selected from -F, -Cl, -Br, (ii) -CH 3 , (iii) -CF 3 , and (iv) hydroxy; (3) thienyl, 25 (5) pyridyl, (7) imidazolyl, (8) pyrrolyl, (9) pyrazolyl, (10) C 3 - 6 cycloalkyl, 30 (12) piperidinyl, (14) morpholinyl, (15) naphthyl, (16) indolyl, and - 128 - WO 99/62897 PCT/US99/12094 (17) C 3 - 6 cycloalkyl fused with a phenyl ring; each R4 is independently selected from: (1) -H, 5 (2) -C1- 3 alkyl, (3) -CF 3 , (4) -R3, (5) -C 2 - 3 alkenyl, (6) -C1- 3 alkyl-R 3, and 10 (7) -S(O)n-R 3 each R5 is independently selected from: (1) -H, (2) -C 1 - 3 alkyl, 15 (3) -CF 3 , 3 (4) -R, (5) -C2- 3 alkenyl, (6) -C 1 - 3 alkyl-R3 (7) -C 2 - 3 alkenyl-R 3, and 3 20 (8) -S(O)n-R each R6 is independently selected from: 3 (1) -C 1 - 3 alkyl-R , and (2) -R 3 ; and 25 each n is independently selected from 0, 1 and 2. - 129 - WO 99/62897 PCT/US99/12094
5. The compound according to Claim 4 selected from: (1) 0 OH 0 0 (2) OH 5 0 0 (3) OH S 0 0 F (4) F S OH 0 0 10 (5) F S OH F (6) S O 0 0 (7) 15 - 130 - WO 99/62897 PCT/US99/12094 (8) s OH F (9) 5 (10) OH (11) - S OH 0 0 (12) 5O 100 10 OH (13) OH - 131 - WO 99/62897 PCTIUS99/12094 (14) H OH (15) S OH 00 5 (16) H OH 0 0 (17) N OH -I O OH 00 (18) OH 10 0 (19) - 132 - WO 99/62897 PCTIUS99/12094 F N OH O OH 0 0 F (20) H 3 0 s- OH O 0 (21) CN-0 S OH 5 0 0 (22) S OH 0 0 (23) S OH 0 0 10 (24) 00 S OH 0 0 (25) - 133 - WO 99/62897 PCT/US99/12094 S OH (26) Hj~ 0 O OH 0-:ZO 0 0 (27) 0-0 S-1 OH O O 5 ,and (28) -S OH CI and tautomers and pharmaceutically acceptable salts thereof. 10
6. The compound according to Claim 1 of structural formula: R 8 S 0 R2 OH 0 0 and tautomers and pharmaceutically acceptable salts thereof, wherein: 15 R2 is selected from: (1) -H, (2) -R3 - 134 - WO 99/62897 PCT/US99/12094 (3) -C 1 - 6 alkyl, (4) -C 1 - 6 alkyl substituted with R (5) -O-R 6 (6) -S(O)n-R 5 (7) -C 1 - 6 alkyl (OR 6)(R ), (8) -C 1 - 6 alkyl (OR)(R 6), (9) -C 0 - 6 alkyl-N(R )(R 6), 6 (10) -C 1 - 6 alkyl S(O)n-R 6 (11) -C 0 - 6 alkyl C(O)-R 10 (12) -C 0 - 6 alkyl NR4 C(O)-R , and (13) -C 0 - 6 alkyl-C(O)N(R4)(R5); each R 3 is independently selected from: (1) phenyl; 15 (2) substituted phenyl with 1, 2, or 3 substituents independently selected from: (a) halogen selected from -F, -Cl, -Br, (b) CH 3 ' (c) methoxy-, 20 (d) phenyl, (e) -CF 3 , (f) -OCF 3 ' (g) -CN, (h) hydroxy, 25 (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen selected from -F, -Cl, -Br, (ii) -CH 3 ' 30 (iii) -CF 3 , and (iv) hydroxy; (3) thienyl, -135- WO 99/62897 PCT/US99/12094 (5) pyridyl, (7) imidazolyl, (8) pyrrolyl, (9) pyrazolyl, 5 (10) C 3 - 6 cycloalkyl, (12) piperidinyl, (14) morpholinyl, (15) naphthyl, (16) indolyl, and 10 (17) C 3 - 6 cycloalkyl fused with a phenyl ring; each R 4 is independently selected from: (1) -H, (2) -C 1 - 3 alkyl, 15 (3) -CF 3 , (4) -R3, (5) -C 2 - 3 alkenyl, 3 (6) -C 1 -. 3 alkyl-R3, and (7) -S(O)n-R 3 20 each R5 is independently selected from: (1) -H, (2) -C 1 - 3 alkyl, (3) -CF 3 , 25 (4) -R3, (5) -C2- 3 alkenyl, (6) -C 1 - 3 alkyl-R3 3 (7) -C 2 - 3 alkenyl-R3, and 3 (8) -S(O)n-R 30 each R6 is independently selected from: - 136 - WO 99/62897 PCT/US99/12094 3 (1) -C 1 - 3 alkyl-R , and (2) -R R 8 is selected from methyl and hydrogen; and 5 each n is independently selected from 0, 1 and 2.
7. The compound according to Claim 6 selected from: (1) S 0 OH 10 0 0 (2) F- OH (3) S0 - OH F 15 (4) CI-0 OH (5) OH -137 - WO 99/62897 PCT/US99/12094 (6) S 0 O OH ,and (7) - OH CI 5 and tautomers and pharmaceutically acceptable salts thereof.
8. The compound according to Claim 1 of structural formula: OH 10 R 2 0 0 and tautomers and pharmaceutically acceptable salts thereof, wherein: R2 is selected from: (1) -H, (2) -R3 15 (3) -C 1 - 6 alkyl, (4) -C 1 - 6 alkyl substituted with R 3 (5) -O-R (6) -S(O)n-R6 (7) -C 1 - 6 alkyl (OR 6)(R ), 20 (8) -C 1 - 6 alkyl (OR )(R 6), (9) -C 0 - 6 alkyl-N(R )(R6 , (10) -C 1 - 6 alkyl S(O)n-R 6 - 138 - WO 99/62897 PCT/US99/12094 6 (11) -C 0 - 6 alkyl C(O)-R (12) -C 0 - 6 alkyl NR4 C(O)-R 6, and (13) -C 0 - 6 alkyl-C(O)N(R 4)(R 5); 5 each R3 is independently selected from: (1) phenyl, (2) substituted phenyl with 1, 2, or 3 substituents independently selected from: (a) halogen selected from -F, -Cl, -Br, 10 (b) CH 3 > (c) methoxy-, (d) phenyl, (e) -CF 3 , (f) -OCF 3 , 15 (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: 20 (i) halogen selected from -F, -Cl, -Br, (ii) -CH 3 , (iii) -CF3, and (iv) hydroxy; (3) thienyl, 25 (5) pyridyl, (7) imidazolyl, (8) pyrrolyl, (9) pyrazolyl, (10) C 3 - 6 cycloalkyl, 30 (12) piperidinyl, (14) morpholinyl, (15) naphthyl, (16) indolyl, and - 139 - WO 99/62897 PCT/US99/12094 (17) C 3 - 6 cycloalkyl fused with a phenyl ring; each R4 is independently selected from: (1) -H, 5 (2) -C 1 - 3 alkyl, (3) -CF 3 , (4) -R (5) -C 2 - 3 alkenyl, (6) -C 1 - 3 alkyl-R 3, and 10 (7) -S(O)n-R each R5 is independently selected from: (1) -H, (2) -C 1 - 3 alkyl, 15 (3) -CF 3 , (4) -R3, (5) -C 2 - 3 alkenyl, 3 (6) -C1- 3 alkyl-R 3 (7) -C 2 - 3 alkenyl-R3, and 3 20 (8) -S(O)n-R each R6 is independently selected from: (1) -C 1 - 3 alkyl-R 3, and (2) -R 3 ; and 25 each n is independently selected from 0, 1 and 2. - 140 - WO 99/62897 PCTIUS99/12094
9. The compound according to Claim 8 selected from: (1) OH F (2) 5 (3) S0 OH CI (4) CI OH 10 (5) IS OH and tautomers and pharmaceutically acceptable salts thereof. -141- WO 99/62897 PCT/US99/12094
10. The compound according to Claim 1 of structural formula: N 0 R~K S OH 0 0 and tautomers and pharmaceutically acceptable salts thereof, wherein: 5 R2 is selected from: (1) -H, (2) -R3 (3) -C 1 - 6 alkyl, (4) -C 1 - 6 alkyl substituted with R 10 (5) -O-R 6 (6) -S(O)n-R (7) -C 1 - 6 alkyl (OR6)(R ) , (8) -C 1 - 6 alkyl (OR )(R 6), (9) -C 0 - 6 alkyl-N(R4)(R6), 6 15 (10) -C 1 - 6 alkyl S(O)n-R 6 (11) -C 0 - 6 alkyl C(O)-R (12) -C 0 - 6 alkyl NR C(O)-R , and (13) -C 0 - 6 alkyl-C(O)N(R )(R 5); 20 each R 3 is independently selected from: (1) phenyl, (2) substituted phenyl with 1, 2, or 3 substituents independently selected from: (a) halogen selected from -F, -Cl, -Br, 25 (b) CH3, (c) methoxy-, (d) phenyl, (e) -CF 3 > - 142 - WO 99/62897 PCT/US99/12094 (f) -OCF 3 , (g) -CN, (h) hydroxy, (i) phenyloxy, and 5 (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen selected from -F, -Cl, -Br, (ii) -CH 3 , (iii) -CF 3 , and 10 (iv) hydroxy; (3) thienyl, (5) pyridyl, (7) imidazolyl, (8) pyrrolyl, 15 (9) pyrazolyl, (10) C 3 - 6 cycloalkyl, (12) piperidinyl, (14) morpholinyl, (15) naphthyl, 20 (16) indolyl, and (17) C 3 - 6 cycloalkyl fused with a phenyl ring each R4 is independently selected from: (1) -H, 25 (2) -C1- 3 alkyl, (3) -CF 3 , (4) -R3 (5) -C 2 - 3 alkenyl, (6) -C1- 3 alkyl-R 3, and 3 30 (7) -S(O)n-R each R5 is independently selected from: - 143 - WO 99/62897 PCT/US99/12094 (1) -H, (2) -C 1 - 3 alkyl, (3) -CF 3 , (4) -R3, 5 (5) -C 2 - 3 alkenyl, (6) -C 1 - 3 alkyl-R3 3 (7) -C 2 - 3 alkenyl-R3, and 3 (8) -S(O)n-R 10 each R6 is independently selected from: (1) -C 1 - 3 alkyl-R 3, and (2) -R 3 ; and each n is independently selected from 0, 1 and 2. 15
11. The compound according to Claim 10 selected from: (1) N Sl " OH 0 0 (2) No H S OH 20 0 0 (3) - 144 - WO 99/62897 PCTIUS99/12094 N- 0 H 3 N S OH 0 0 (4) NS OH 00 0 (5) N -~ N-<I S OH 5 0 0 (6) N H 3 N S OH O 0 , and (7) So N OH 0 0 10 and tautomers and pharmaceutically acceptable salts thereof. - 145 - WO 99/62897 PCT/US99/12094
12. The compound according to Claim 1 selected from: (1) N OH 0 0 5 (2) S 0 OH 0 0 (3) <S 0 OH C1- S 0 0 (4) S s 0 OH 0 0 0 10 F (5) S 0 OH 0 0 (6) - 146 - WO 99/62897 PCT/US99/12094 0 S OH 0 0 (6) OH S 0 0 ,and (7) S 0 Qj- OH 5 0 0 and tautomers and pharmaceutically acceptable salts thereof.
13. The compound according to Claim 1 selected from: (1) 2,4-dioxo-4-(5-phenethylthiophen-2-yl)butanoic acid, 10 (2) ethyl 2,4-dioxo-4-(5-phenethylthiophen-2-yl)butanoate, (3) 2,4-dioxo-4-(5-benzyloxythiophen-2-yl)butanoic acid, (4) 2,4-dioxo-4-[5-(3-fluorobenzyloxy)thiophen-2-yl]butanoic acid, (5) 2,4-dioxo-4-[5-(4-fluorobenzyloxy)thiophen-2-yl]butanoic 15 acid, (6) 2,4-dioxo-4-[5-(3,4-difluorobenzyloxy)thiophen-2-yl]butanoic acid, (7) 2,4-dioxo-4-[5-(pyridin-2-ylmethyloxy)thiophen-2-yl]butanoic acid, 20 (8) 2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-2-yl]butanoic acid, (9) ethyl 2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-2-yllbutanoate, (10) 2,4-dioxo-4-[5-(4-fluorobenzyl)thiophen-2-yl]butanoic 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, 25 (13) 2,4-dioxo-4-(5-phenylsulfanylthiophen-2-yl)butanoic acid, (14) 2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-3-yl]butanoic acid, - 147 - WO 99/62897 PCTIUS99/12094 (15) 2,4-dioxo-4-[5-(4-fluorobenzyl)thiophen-3-yl]butanoic acid, (16) 2,4-dioxo-4-[5-(3-chlorobenzyl)thiophen-3-yl]butanoic acid, (17) 2,4-dioxo-4-(5-benzylthiophen-3-yl)butanoic acid, (18) 2,4-dioxo-4-(2-phenylsulfanylthiophen-4-yl)butanoic acid, 5 (19) 2,4-dioxo-4-[2-(3-fluorobenzyl)thiophen-3-yl]butanoic acid, (20) 2,4-dioxo-4-[2-(4-fluorobenzyl)thiophen-3-yl]butanoic acid, (21) 2,4-dioxo-4-[2-(3-chlorobenzyl)thiophen-3-yl]butanoic acid, (22) 2,4-dioxo-4-[5-(benzyloxy-phenylmethyl)thiophen-2 yl]butanoic acid, 10 (23) 2,4-dioxo-4-[5-(phenoxy-phenylmethyl)thiophen-2 yl]butanoic acid, (24) 2,4-dioxo-4-[5-(methoxy-phenylmethyl)thiophen-2 yl]butanoic acid, (25) 2,4-dioxo-4-(5-dibenzylaminothiophen-2-yl)butanoic acid, 15 (26) 2,4-dioxo-4-(5-benzylaminothiophen-2-yl)butanoic acid, (27) 2,4-dioxo-4-(5-diallylaminothiophen-2-yl)butanoic acid, (28) 2,4-dioxo-4-(5-di-n-propylaminothiophen-2-yl)butanoic acid, (29) 2,4-dioxo-4-[5-(di-4-fluorobenzylamino)thiophen-2 yl]butanoic acid, 20 (30) 2,4-dioxo-4-[5-(N-benzyl-N-methylamino)thiophen-2 yl]butanoic acid, (31) 2,4-dioxo-4-(5-piperidin-1-yl-thiophen-2-yl)butanoic acid, (32) 2,4-dioxo-4-[5-(benzylbenzenesulfonylamino)thiophen-2 yl]butanoic acid, 25 (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-methylaninothiazol-5-yl)butanoic acid, (36) 2,4-dioxo-4-(2-dibenzylaminothiazol-4-yl)butanoic acid, 30 and tautomers and pharmaceutically acceptable salts thereof.
14. The compound according to Claim 13 selected from: (1) 2,4-dioxo-4-(5-phenethylthiophen-2-yl)butanoic acid, (2) 2,4-dioxo-4-(5-benzyloxythiophen-2-yl)butanoic acid, - 148 - WO 99/62897 PCTIUS99/12094 (3) 2,4-dioxo-4-[5-(3-fluorobenzyloxy)thiophen-2-yllbutanoic acid, (4) 2,4-dioxo-4-[5-(4-fluorobenzyloxy)thiophen-2-yl]butanoic acid, 5 (5) 2,4-dioxo-4-[5-(3,4-difluorobenzyloxy)thiophen-2-yl]butanoic acid, (6) 2,4-dioxo-4-[5-(pyridin-2-ylmethyloxy)thiophen-2-yl]butanoic acid, (7) 2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-2-yl]butanoic acid, 10 (8) 2,4-dioxo-4-[5-(4-fluorobenzyl)thiophen-2-yl]butanoic acid, (9) 2,4-dioxo-4-[5-(3-chlorobenzyl)thiophen-2-yl]butanoic acid, (10) 2,4-dioxo-4-(5-benzylthiophen-2-yl)butanoic acid, (11) 2,4-dioxo-4-(5-phenylsulfanylthiophen-2-yl)butanoic acid, (12) 2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-3-yl]butanoic acid, 15 (13) 2,4-dioxo-4-[5-(4-fluorobenzyl)thiophen-3-yl]butanoic acid, (14) 2,4-dioxo-4-[5-(3-chlorobenzyl)thiophen-3-yl]butanoic acid, (15) 2,4-dioxo-4-(5-benzylthiophen-3-yl)butanoic acid, (16) 2,4-dioxo-4-(2-phenylsulfanylthiophen-4-yl)butanoic acid, (17) 2,4-dioxo-4-[2-(3-fluorobenzyl)thiophen-3-yl]butanoic acid, 20 (18) 2,4-dioxo-4-[2-(4-fluorobenzyl)thiophen-3-yl]butanoic acid, (19) 2,4-dioxo-4-[2-(3-chlorobenzyl)thiophen-3-yl]butanoic acid, (20) 2,4-dioxo-4-[5-(benzyloxy-phenylmethyl)thiophen-2 yl]butanoic acid, (21) 2,4-dioxo-4-[5-(phenoxy-phenylmethyl)thiophen-2 25 yl]butanoic acid, (22) 2,4-dioxo-4-[5-(methoxy-phenylmethyl)thiophen-2 yl]butanoic acid, (23) 2,4-dioxo-4-(5-dibenzylaminothiophen-2-yl)butanoic acid, (24) 2,4-dioxo-4-(5-benzylaminothiophen-2-yl)butanoic acid, 30 (25) 2,4-dioxo-4-(5-diallylaminothiophen-2-yl)butanoic acid, (26) 2,4-dioxo-4-(5-di-n-propylaminothiophen-2-yl)butanoic acid, (27) 2,4-dioxo-4-[5-(di-4-fluorobenzylamino)thiophen-2 yl]butanoic acid, (28) 2,4-dioxo-4-[5-(N-benzyl-N-methylamino)thiophen-2 35 yl]butanoic acid, - 149 - WO 99/62897 PCT/US99/12094 (29) 2,4-dioxo-4-(5-piperidin-1-yl-thiophen-2-yl)butanoic acid, (30) 2,4-dioxo-4-[5-(benzylbenzenesulfonylamino)thiophen- 2 yl]butanoic acid, (31) 2,4-dioxo-4-(2-dibenzylaminothiazol-5-yl)butanoic acid, 5 (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. 10
15. The compound according to Claim 14 selected from: (1) 2,4-dioxo-4-[5-(3-chlorobenzyl)thiophen-2-yl]butanoic acid, (2) 2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-3-yl]butanoic acid, (3) 2,4-dioxo-4-[5-(4-fluorobenzyl)thiophen-3-yl]butanoic acid, 15 (4) 2,4-dioxo-4-[5-(3-chlorobenzyl)thiophen-3-yl]butanoic acid, (5) 2,4-dioxo-4-(5-benzylthiophen-3-yl)butanoic acid, (6) 2,4-dioxo-4-(2-phenylsulfanylthiophen-4-yl)butanoic acid, XII(4) (7) 2,4-dioxo-4-[2-(3-chlorobenzyl)thiophen-3-yl]butanoic acid, 20 (8) 2,4-dioxo-4-[5-(benzyloxy-phenylmethyl)thiophen-2 yl]butanoic acid, (9) 2,4-dioxo-4-[5-(phenoxy-phenylmethyl)thiophen-2 yl]butanoic acid, (10) 2,4-dioxo-4-(5-dibenzylaminothiophen-2-yl)butanoic acid, 25 (11) 2,4-dioxo-4-(5-diallylaminothiophen-2-yl)butanoic acid, (12) 2,4-dioxo-4-[5-(di-4-fluorobenzylamino)thiophen-2 yl]butanoic acid, (13) 2,4-dioxo-4-[5-(N-benzyl-N-methylamino)thiophen-2 yl]butanoic acid, 30 (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 -150 - WO 99/62897 PCT/US99/12094
16. A pharmaceutical composition useful for inhibiting HIV integrase, comprising an effective amount of a compound according to Claim 1 and a pharmaceutically acceptable carrier. 5
17. The pharmaceutical composition of Claim 16, useful for treating infection by HIV, or for treating AIDS or ARC.
18. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Claim 1 in 10 combination with a therapeutically effective amount of an AIDS treatment agent selected from (1) an AIDS antiviral agent, (2) an anti-infective agent, and (3) an immunomodulator. 15
19. The composition of Claim 18 wherein the antiviral agent is an HIV protease inhibitor.
20. The composition of Claim 19 wherein the HIV 20 protease inhibitor is N-(2(R)-hydroxy-1-(S)-indanyl)-2(R)-phenylmethyl 4(S)-hydroxy-5-(1-(4-(3-pyridylmethyl)-2(S)-N'-(t-butylcarboxamido) piperazinyl))-pentaneamide or a pharmaceutically acceptable salt thereof. 25
21. A pharmaceutical composition made by combining the compound of Claim 1 and a pharmaceutically acceptable carrier.
22. A process for making a pharmaceutical composition comprising combining a compound of Claim 1 and a pharmaceutically 30 acceptable carrier.
23. A method of inhibiting HIV integrase, comprising the administration to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1. 35 -151- WO 99/62897 PCT/US99/12094
24. A method of treating infection by HIV, or of treating AIDS or ARC, comprising the administration to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1. 5 - 152 -
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US8784698P | 1998-06-03 | 1998-06-03 | |
| US60/087846 | 1998-06-03 | ||
| GBGB9814925.5A GB9814925D0 (en) | 1998-07-09 | 1998-07-09 | HIV integrase inhibitors |
| GB9814925 | 1998-07-09 | ||
| PCT/US1999/012094 WO1999062897A1 (en) | 1998-06-03 | 1999-06-01 | Hiv integrase inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU4225599A true AU4225599A (en) | 1999-12-20 |
| AU757409B2 AU757409B2 (en) | 2003-02-20 |
Family
ID=26314001
Family Applications (1)
| 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 |
|---|---|---|---|---|
| ID26031A (en) | 1998-03-26 | 2000-11-16 | Shionogi & Co | INDOL DAMAGES THAT HAVE AN ANTIVIRAL ACTIVITY |
| JP2003525200A (en) | 1998-07-27 | 2003-08-26 | イスティトゥト ディ リチェルケ ディ ビオロジア モレコラーレ ピー．アンジェレッティ ソチエタ ペル アツィオニ | Diketoacid derivatives as polymerase inhibitors |
| KR20010089708A (en) | 1998-12-25 | 2001-10-08 | 시오노 요시히코 | Aromatic heterocycle compounds having hiv integrase inhibiting activities |
| BR0207809A (en) | 2001-03-01 | 2004-03-09 | Shionogi & Co | Nitrogen-containing heteroaryl compounds having inhibitory activity against hiv integrase |
| DK2266958T1 (en) | 2001-08-10 | 2016-04-04 | Shionogi & Co | antiviral |
| MXPA04003932A (en) | 2001-10-26 | 2004-06-18 | Angeletti P Ist Richerche Bio | N-substituted hydroxypyrimidinone carboxamide inhibitors of hiv integrase. |
| WO2003035076A1 (en) | 2001-10-26 | 2003-05-01 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa | Dihydroxypyrimidine carboxamide inhibitors of hiv integrase |
| DE60323743D1 (en) | 2002-03-15 | 2008-11-06 | Merck & Co Inc | N-(substituierte benzyl)-8-hydroxy-1,6-naphthyridin-7- carbonsäureamide als hiv-integrase-hemmer |
| US7358249B2 (en) | 2002-08-13 | 2008-04-15 | Shionogi & Co., Ltd. | Heterocyclic compounds having inhibitory activity against HIV integrase |
| 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) |
| EP2046328A4 (en) | 2006-07-19 | 2009-10-28 | Univ Georgia Res Found | Pyridinone diketo acids: inhibitors of hiv replication in combination therapy |
| WO2010047774A2 (en) * | 2008-10-20 | 2010-04-29 | The Texas A & M University System | Inhibitors of mycobacterium tuberculosis malate synthase, methods of marking and uses thereof |
| KR20120094098A (en) | 2009-12-07 | 2012-08-23 | 유니버시티 오브 조지아 리서치 파운데이션, 인코포레이티드 | Pyridinone hydroxycyclopentyl carboxamides: hiv integrase inhibitors with therapeutic applications |
| RS62410B1 (en) | 2016-10-04 | 2021-10-29 | Merck Sharp & Dohme | Benzo[b]thiophene compounds as sting agonists |
| US11312772B2 (en) | 2017-08-04 | 2022-04-26 | Merck Sharp & Dohme Corp. | Combinations of PD-1 antagonists and benzo [b] thiophene STING agonists for cancer treatment |
| EP3661498A4 (en) | 2017-08-04 | 2021-04-21 | Merck Sharp & Dohme Corp. | BENZO[b]THIOPHENE STING AGONISTS FOR CANCER TREATMENT |
| US10793557B2 (en) | 2018-04-03 | 2020-10-06 | Merck Sharp & Dohme Corp. | Sting agonist compounds |
| US11702430B2 (en) | 2018-04-03 | 2023-07-18 | Merck Sharp & Dohme Llc | Aza-benzothiophene compounds as STING agonists |
Family Cites Families (5)
| 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 |
| ID26031A (en) * | 1998-03-26 | 2000-11-16 | Shionogi & Co | INDOL DAMAGES THAT HAVE AN ANTIVIRAL ACTIVITY |
-
1999
- 1999-06-01 JP JP2000552109A patent/JP2002517390A/en not_active Withdrawn
- 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
- 1999-06-01 CA CA002333771A patent/CA2333771A1/en not_active Abandoned
- 1999-06-01 AU AU42255/99A patent/AU757409B2/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| JP2002517390A (en) | 2002-06-18 |
| EP1086091A4 (en) | 2001-10-10 |
| WO1999062897A1 (en) | 1999-12-09 |
| CA2333771A1 (en) | 1999-12-09 |
| AU757409B2 (en) | 2003-02-20 |
| EP1086091A1 (en) | 2001-03-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6262055B1 (en) | HIV integrase inhibitors | |
| AU757409B2 (en) | Hiv integrase inhibitors | |
| US6306891B1 (en) | HIV integrase inhibitors | |
| CA2391643C (en) | Gamma-hydroxy-2-(fluoroalkylaminocarbonyl)-1-piperazinepentanamides as hiv protease inhibitors | |
| CA2425440C (en) | Aza- and polyaza-naphthalenyl carboxamides useful as hiv integrase inhibitors | |
| EP1326611B1 (en) | Aza- and polyaza-naphthalenyl-carboxamides useful as hiv integrase inhibitors | |
| US7135467B2 (en) | HIV integrase inhibitors | |
| AU756826C (en) | HIV integrase inhibitors | |
| EP1943221B1 (en) | Piperazine amidines as antiviral agents | |
| US7087610B2 (en) | Benzothiazole antiviral agents | |
| AU2014340110B2 (en) | Inhibitors of human immunodeficiency virus replication | |
| US7601715B2 (en) | Process for preparing triazole substituted azaindoleoxoacetic piperazine derivatives and novel salt forms produced therein | |
| AU4225499A (en) | Hiv integrase inhibitors | |
| US20070287712A1 (en) | Piperazine Enamines as Antiviral Agents | |
| AU2015355839A1 (en) | Heterocyclic derivatives and use thereof | |
| US6635636B1 (en) | Substituted 6-benzyl-4-oxopyrimidines, process for their preparation and pharmaceutical compositions containing them | |
| KR20070112121A (en) | Diketo acids with nucleobase scaffolds: anti-hiv replication inhibitors targeted at hiv integrase | |
| EP2013170B1 (en) | 4-squarylpiperazine derivatives as antiviral agents | |
| US6890942B2 (en) | Acyl sulfonamides as inhibitors of HIV integrase | |
| US20060223834A1 (en) | Diketo acids on nucleobase scaffolds as inhibitors of Flaviviridae | |
| US8980938B2 (en) | CXCR2 inhibitors | |
| US20030125336A1 (en) | Hydrohalide salts of an HIV protease inhibitor | |
| US6589962B1 (en) | Alpha-hydroxy-gamma-[[(carbocyclic-or heterocyclic-substituted)amino]carbonyl]alkanamide derivatives and uses thereof | |
| AU6109500A (en) | Alpha-hydroxy-gamma-(((carbocyclic-or heterocyclic-substituted)amino)carbonyl)alkanamide derivatives and uses thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FGA | Letters patent sealed or granted (standard patent) |