HIV INTEGRASE INHIBITORS

INHIBITEURS DE VIH INTEGRASE

English Abstract

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

French Abstract

Cette invention a trait à des dérivés d'acide dioxo-butyrique hétéro-aryle contenant du soufre, agissant en tant qu'inhibiteurs de VIH intégrase et de la réplication du VIH. Ces composés sont utilisés dans le cadre de la prévention et du traitement des infections par le VIH et du sida, que ce soit sous forme de composés, de sels acceptables du point de vue pharmaceutique ou d'ingrédients de composition pharmaceutique, seuls ou associés à d'autres antiviraux, immunorégulateurs, antibiotiques ou vaccins. L'invention concerne également des méthodes de traitement du sida ainsi que des méthodes de prévention et de traitement des infections par VIH.

Claims

1. The compound of structural formula (I):
<IMG>
and tautomers and pharmaceutically acceptable salts thereof, wherein:
A is selected from:
(1) thienyl,
(2) thiazolyl,
(3) <IMG>
(4) <IMG>
(5) <IMG>
R1 is selected from:
(1) -H,
(2) -CH3,
(3) -CF3,
(4) -halo,
(5) -NO2,
(6)~-N(R4)(R5),
(7)~-phenyl,
-108-

(8) substituted phenyl substituted with 1 or 2 substituents independently
selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) -OCF3,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with l, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1-6 alkyl,
(iii) -CF3, and
(iv) hydroxy;
(9) phenyl C1-3 alkyl-,
(10) substituted phenyl C1-3 alkyl- substituted with 1 or 2 substituents
independently selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) -OCF3,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1-6 alkyl,
(iii) -CF3, and
(iv) hydroxy;
(11) -C2-5 alkenyl-R3,
-109-

(12) -C2-5 alkynyl-R3, and
(13) -C(O)CH2C(O)C(O)OR7;
R2 is selected from:
(1) -H,
(2) -R3,
(3) -C1-6 alkyl,
(4) -C1-6 alkyl substituted with R3,
(5) -O-R6,
(6) -O-C1-6 alkyl-OR6,
(7) -S(O)n-R6,
(8) -C1-6 alkyl (OR6)(R4),
(9) -C1-6 alkyl (OR4)(R6),
(10) -C0-6 alkyl-N(R4)(R6),
(11) -C1-6 alkyl S(O)n-R6,
(12) -C0-6 alkyl C(O)-R6,
(13) -C0-6 alkyl C(S)-R6,
(14) -C0-6 alkyl NR4C(O)-R6, and
(15) -C0-6 alkyl-C(O)N(R4)(R5);
each R3 is independently selected from:
(1) phenyl;
(2) substituted phenyl with 1, 2, or 3 substituents independently
selected
from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) phenyl,
-110-

(e) -CF3,
(f) -OCF3,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1-6 alkyl,
(iii) -CF3, and
(iv) hydroxy;
(3) thienyl;
(4) substituted thienyl substituted on a carbon atom with one or two
substituents independently selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) -OCF3,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1-6 alkyl,
(iii) -CF3, and
(iv) hydroxy;
(5) pyridyl;
(6) substituted pyridyl substituted on a carbon atom with one or two
substituents independently selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) phenyl,
-111-

(e) -CF3,
(f) -OCF3,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1-6 alkyl,
(iii) -CF3, and
(iv) hydroxy;
(7) imidazolyl;
(8) substituted imidazolyl substituted on a carbon atom with one or two
substituents independently selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) -OCF3,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1-6 alkyl,
(iii) -CF3, and
(iv) hydroxy;
(9) pyrrolyl;
(10) substituted pyrrolyl substituted on a carbon atom with one or two
substituents independently selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) phenyl,
-112-

(e) -CF3,
(f) -OCF3,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1-6 alkyl,
(iii) -CF3, and
(iv) hydroxy;
(11) pyrazolyl;
(12) substituted pyrazolyl substituted on a carbon atom with one or two
substituents independently selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) -OCF3,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1-6 alkyl,
(iii) -CF3, and
(iv) hydroxy;
(13) cycloalkyl;
(14) substituted C3-6 cycloalkyl with 1 or 2 substituents independently
selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) -CF3,
-113-

(e) -OCF3,
(f) -CN,
(g) =O, and
(h) hydroxy;
(15) piperidinyl;
(16) substituted piperidinyl substituted on a carbon atom with one or two
substituents independently selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) -CF3,
(e) -OCF3,
(f) -CN,
(g) =O, and
(h) hydroxy;
(17) morpholinyl;
(18) substituted morpholinyl substituted at a carbon or nitrogen atom with 1
or 2 substituents independently selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) -CF3,
(e) -OCF3,
(f) -CN,
(g) =O, and
(h) hydroxy;
(19) naphthyl,
(20) substituted naphthyl with 1, 2, or 3 substituents independently selected
from:
(a) -halogen,
(b) -C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) -CF3,
(e) -OCF3,
-114-

(f) -CN, and
(g) -hydroxy;
(21) indolyl;
(22) substituted indolyl substituted on a carbon atom with one or two
substituents independently selected from:
(a) -halogen,
(b) -C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) -CF3,
(e) -OCF3,
(f) -CN, and
(g) -hydroxy;
(23) C3-6 cycloalkyl fused with a phenyl ring
(24) substituted C3-6 cycloalkyl fused with a phenyl ring substituted on a
carbon atom with one or two substituents independently selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) -CF3,
(e) -OCF3,
(f) -CN,
(g) =O, and
(h) hydroxy;
each R4 is independently selected from:
(1) -H,
(2) -C1-3 alkyl,
(3) -CF3,
(4) -R3,
(5) -C2-3 alkenyl,
(6) -C1-3 alkyl-R3,
(7) -C2-3 alkenyl-R3,
-115-

(8) -S(O)n-R3, and
(9) -C(O)-R3;
each R5 is independently selected from:
(1) -H,
(2) -C1-3 alkyl,
(3) -CF3,
(4) -R3,
(5) -C2-3 alkenyl,
(6) -C1-3 alkyl-R3,
(7) -C2-3 alkenyl-R3,
(8) -S(O)n-R3, and
(9) -C(O)-R3;
each R6 is independently selected from:
(1) -C1-3 alkyl-R3, and
(2) -R3;
R8 is selected from hydrogen, methyl and methoxy;
each n is independently selected from 0, 1 and 2, and
each m is independently selected from 0, 1, and 2;
and provided that
(A) when A is thienyl or thiazolyl and R2 is -H or -C1-6 alkyl, then R1 is
not
(1) -H,
(2) -CH3, or
(7) -phenyl;
-116-

(B) when A is thienyl or thiazolyl and R2 is -R3 wherein R3 is
unsubstituted phenyl, then R1 is not
(1) -H or
(2) -CH3;
(C) when A is thienyl and R2 is -H or -C1-6 alkyl, then R1 is not
(4) -halo,
(5) -NO2, or
(6) -N(R4)(R5) when R4 and R5 are both -H; and
(D) when A is thienyl and R2 is -R3 wherein R3 is (7) imidiazolyl
or (17) morpholinyl, then R1 is not
(1) -H,
(2) -CH3,
(4) -halo,
(5) -NO2, or
(6) -N(R4)(R5) when R4 and R5 are both -H.
2. The compound according to Claim 1, and tautomers and
pharmaceutically acceptable salts thereof, wherein:
A is selected from:
(1) thienyl,
(2) thiazolyl,
(3) <IMG>, and
(4)<IMG>;
R1 is selected from:
(1) -H,
(2) -CH3,
(3) -CF3,
-117-

(4) -halo,
(5) -NO2,
(6) -N(R4)(R5),
(7) -phenyl,
(8) substituted phenyl substituted with 1 or 2 substituents independently
selected from:
(a) halo,
(b) methyl, and
(c) methoxy,
(9) phenyl C1-3 alkyl-,
(10) substituted phenyl C1-3 alkyl- substituted with 1 or 2 substituents
independently selected from:
(a) halo,
(b) methyl, and
(c) methoxy, and
(11) -C2-5 alkenyl-R3;
R2 is selected from:
(1) -H,
(2) -R3,
(3) -C1-6 alkyl,
(4) -C1-6 alkyl substituted with R3,
(5) -O-R6,
(6) -S(O)n-R6,
(7) -C1-6 alkyl(OR6)(R4),
(8) -C1-6 alkyl(OR6)(R4),
(9) -CO-6 alkyl-N(R4)(R6),
(10) -C1-6 alkyl S(O)n-R6,
(11) -CO-6 alkyl C(O)-R6,
-118-

(12) -C0-6 alkyl NR4C(O)-R6, and
(13) -C0-6 alkyl-C(O)N(R4)(R5);
each R3 is independently selected from:
(1) phenyl;
(2) substituted phenyl with 1, 2, or 3 substituents independently selected
from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) -OCF3,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1-6 alkyl,
(iii) -CF3, and
(iv) hydroxy;
(3) thienyl;
(4) substituted thienyl substituted on a carbon atom with one or two
substituents independently selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) -OCF3,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
-119-

(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1-6 alkyl,
(iii) -CF3, and
(iv) hydroxy;
(5) pyridyl;
(6) substituted pyridyl substituted on a carbon atom with one or two
substituents independently selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) -OCF3,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1-6 alkyl,
(iii) -CF3, and
(iv) hydroxy;
(7) imidazolyl;
(8) pyrrolyl;
(9) pyrazolyl;
(10) C3-6 cycloalkyl,
(11) substituted C3-6 cycloalkyl with 1 or 2 substituents independently
selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) -CF3,
(e) -OCF3,
(f) -CN,
-120-

(g) =O, and
(h) hydroxy;
(12) piperidinyl;
(13) substituted piperidinyl substituted on a carbon atom with one or two
substituents independently selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) -CF3,
(e) -OCF3,
(f) -CN,
(g) =O, and
(h) hydroxy;
(14) morpholinyl;
(15) naphthyl;
(16) indolyl; and
(17) C3-6 cycloalkyl fused with a phenyl ring;
each R4 is independently selected from:
(1) -H,
(2) -C1-3 alkyl,
(3) -CF3,
(4) -R3,
(5) -C2-3 alkenyl,
(6) -C1-3 alkyl-R3, and
(7) -S(O)n -R3; and
each R5 is independently selected from:
(1) -H,
(2) -C1-3 alkyl,
(3) -CF3,
(4) -R3,
-121-

(5) -C2-3 alkenyl,
(6) -C1-3 alkyl-R3,
(7) -C2-3 alkenyl-R3, and
(8) -S(O)n -R3;
each R6 is independently selected from:
(1) -C1-3 alkyl-R3, and
(2) -R3;
R8 is H; and
each n is independently selected from 0, 1 and 2;
and provided that
(A) when A is thienyl or thiazolyl and R2 is -H or -C1-6 alkyl, then
R1 is not
(1) -H,
(2) -CH3, or
(7) -phenyl;
(B) when A is thienyl or thiazolyl and R2 is -R3 wherein R3 is
unsubstituted phenyl, then R1 is not
(1) -H or
(2) -CH3; and
(C) when A is thienyl and R2 is -H or -C1-6 alkyl, then R1 is not
(4) -halo,
(5) -NO2, or
(6) -N(R4)(R5) when R4 and R5 are both -H; and
(D) when A is thienyl and R2 is -R3 wherein R3 is (7) imidiazolyl
or (17) morpholinyl, then R1 is not
(1) -H,
(2) -CH3,
(4) -halo,
(5) -NO2, or
-122-

(6) -N(R4)(R5) when R4 and R5 are both -H.
3. The compound according to Claim 1 of structural formula:
<IMG>
and tautomers and pharmaceutically acceptable salts thereof, wherein:
R2 is selected from:
(1) -R3,
(2) -C1-6 alkyl substituted with R3,
(3) -O-R6,
(4) -S(O)n -R6,
(5) -C1-6 alkyl (OR6)(R4),
(6) -C1-6 alkyl (OR4)(R6),
(7) -C0-6 alkyl-N(R4)(R6),
(8) -C1-6 alkyl S(O)n -R6,
(9) -C0-6 alkyl C(O)-R6,
(10) -C0-6 alkyl NR4C(O)-R6, and
(11) -C0-6 alkyl-C(O)N(R4)(R5);
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, and -Br,
(b) CH3,
-123-

(c) methoxy-,
(d) phenyl,
(e) -CF3,
(f) -OCF3,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen selected from -F, -Cl, and -Br,
(ii) -CH3,
(iii) -CF3, and
(iv) hydroxy;
(3) thienyl,
(4) pyridyl,
(5) imidazolyl,
(6) pyrrolyl,
(7) pyrazolyl,
(8) C3-6 cycloalkyl,
(9) piperidinyl,
(10) morpholinyl,
(11) naphthyl,
(12) indolyl, and
(13) C3-6 cycloalkyl fused with a phenyl ring;
each R4 is independently selected from:
(1) -H,
(2) -C1-3 alkyl,
(3) -CF3,
(4) -R3,
(5) -C2-3 alkenyl,
(6) -C1-3 alkyl-R3, and
(7) -S(O)n -R3,
-124-

each R5 is independently selected from:
(1) -H,
(2) -C1-3 alkyl,
(3) -CF3,
(4) -R3,
(5) -C2-3 alkenyl,
(6) -C1-3 alkyl-R3,
(7) -C2-3 alkenyl-R3, and
(8) -S(O)n -R3,
each R6 is independently selected from:
(1) -C1-3 alkyl-R3, and
(2) -R3; and
each n is independently selected from 0, 1 and 2;
and provided that when R2 is -R3, then R3 is not unsubstituted phenyl,
unsubstituted
imidazolyl, or unsubstituted morpholinyl.
4. The compound according to Claim 3 selected from:
(1)
<IMG> ,
-125-

(2)
<IMG> ,
(3)~
<IMG> ,
(4)
<IMG> ,
(5)~
<IMG> ,
(6)
<IMG> ,
-126-

(7)
<IMG>
(8)
<IMG>
(9)
<IMG>
(10)
<IMG>
(11)
<IMG>
-127-

(12) <IMG> ,
(13) <IMG> ,
(14) <IMG> ,
(15) <IMG> ,
-128-

(16) <IMG> ,
(17) <IMG> ,
(18) <IMG> ,
(19) <IMG> ,
-129-

(20) <IMG> ,
(21) <IMG> ,
(22) <IMG> ,
(23) <IMG> ,
(24) <IMG> ,
-130-

(25) <IMG> ,
(26) <IMG> ,
(27) <IMG> , and
(28) <IMG> ,
and tautomers and pharmaceutically acceptable salts thereof.
5. The compound according to Claim 1 of structural formula:
-131-

<IMG>
and tautomers and pharmaceutically acceptable salts thereof, wherein:
R2 is selected from:
(1) -R3,
(2) -C1-6 alkyl substituted with R3,
(3) -O-R6,
(4) -S(O)n -R6,
(5) -C1-6 alkyl (OR6)(R4),
(6) -C1-6 alkyl (OR4)(R6),
(7) -C0-6 alkyl-N(R4)(R6),
(8) -C1-6 alkyl S(O)n -R6,
(9) -C0-6 alkyl C(O)-R6,
(10) -C0-6 alkyl NR4C(O)-R6, and
(11) -C0-6 alkyl-C(O)N(R4)(R5);
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, and -Br,
(b) CH3,
(c) methoxy-,
(d) phenyl,
(e) -CF3,
-132-

(f) -OCF3,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen selected from -F, -Cl, and -Br,
(ii) -CH3,
(iii) -CF3, and
(iv) hydroxy;
(3) thienyl,
(4) pyridyl,
(5) imidazolyl,
(6) pyrrolyl,
(7) pyrazolyl,
(8) C3-6 cycloalkyl,
(9) piperidinyl,
(10) morpholinyl,
(11) naphthyl,
(12) indolyl, and
(13) C3-6 cycloalkyl fused with a phenyl ring;
each R4 is independently selected from:
(1) -H,
(2) -C1-3 alkyl,
(3) -CF3,
(4) -R3,
(5) -C2-3 alkenyl,
(6) -C1-3 alkyl-R3, and
(7) -S(O)n -R3,
each R5 is independently selected from:
(1) -H,
(2) -C1-3 alkyl,
-133-

(3)-CF3,
(4)-R3,
(5)-C2-3 alkenyl,
(6)-C1-3 alkyl-R3,
(7)-C2-3 alkenyl-R3, and
(8)-S(O)n -R3,
each R6 is independently selected from:
(1) -C1-3 alkyl-R3, and
(2) -R3;
R8 is selected from methyl and hydrogen; and
each n is independently selected from 0, 1 and 2;
and provided that when R2 is -R3, then R3 is not unsubstituted phenyl,
unsubstituted
imidazolyl, or unsubstituted morpholinyl.
6. The compound according to Claim 5 selected from:
(1)
<IMG> ,
-134-

(2) <IMG> ,
(3) <IMG> ,
(4) <IMG> ,
(5) <IMG> , and
(6) <IMG>
-135-

and tautomers and pharmaceutically acceptable salts thereof.
7. The compound according to Claim 1 of structural formula:
<IMG>
and tautomers and pharmaceutically acceptable salts thereof, wherein:
R2 is selected from:
(1) -R3,
(2) -C1-6 alkyl substituted with R3,
(3) -O-R6,
(4) -S(O)n -R6,
(5) -C1-6 alkyl (OR6)(R4),
(6) -C1-6 alkyl (OR4)(R6),
(7) -C0-6 alkyl-N(R4)(R6),
(8) -C1-6 alkyl S(O)n -R6,
(9) -C0-6 alkyl C(O)-R6,
(10) -C0-6 alkyl NR4C(O)-R6, and
(11) -C0-6 alkyl-C(O)N(R4)(R5);
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, and -Br,
(b) CH3,
(c) methoxy-,
-136-

(d) phenyl,
(e) -CF3,
(f) -OCF3,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen selected from -F, -Cl, and -Br,
(ii) -CH3,
(iii) -CF3, and
(iv) hydroxy;
(3)thienyl,
(4)pyridyl,
(5)imidazolyl,
(6)pyrrolyl,
(7)pyrazolyl,
(8)C3-6 cycloalkyl,
(9) piperidinyl,
(10) morpholinyl,
(11) naphthyl,
(12) indolyl, and
(13) C3-6 cycloalkyl fused with a phenyl ring;
each R4 is independently selected from:
(1) -H,
(2) -C1-3 alkyl,
(3) -CF3,
(4) -R3,
(5) -C2-3 alkenyl,
(6) -C1-3 alkyl-R3, and
(7) -S(O)n -R3,
each R5 is independently selected from:
-137-

(1) -H,
(2) -C1-3 alkyl,
(3) -CF3,
(4) -R3,
(5) -C2-3 alkenyl,
(6) -C1-3 alkyl-R3,
(7) -C2-3 alkenyl-R3, and
(8) -S(O)n -R3,
each R6 is independently selected from:
(1) -C1-3 alkyl-R3, and
(2) -R3; and
each n is independently selected from 0, 1 and 2;
and provided that when R2 is -R3, then R3 is not unsubstituted phenyl,
unsubstituted
imidazolyl, or unsubstituted morpholinyl.
8. The compound according to Claim 7 selected from:
(1) <IMG>,
-138-

(2)
<IMG>
(3)
<IMG>
(4)
<IMG>
(5)
<IMG>
and tautomers and pharmaceutically acceptable salts thereof.
9. The compound according to Claim 1 of structural formula:
<IMG>
-139-

and tautomers and pharmaceutically acceptable salts thereof, wherein:
R2 is selected from:
(1) -R3,
(2) -C1-6 alkyl substituted with R3,
(3) -O-R6,
(4) -S(O)n-R6,
(5) -C1-6 alkyl (OR6)(R4),
(6) -C1-6 alkyl (OR4)(R6),
(7) -C0-6 alkyl-N(R4)(R6),
(8) -C1-6 alkyl S(O)n-R6,
(9) -C0-6 alkyl C(O)-R6,
(10)-C0-6 alkyl NR4 C(O)-R6, and
(11)-C0-6 alkyl-C(O)N(R4)(R5);
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, and -Br,
(b) CH3,
(c) methoxy-,
(d) phenyl,
(e) -CF3,
(f) -OCF3,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
-140-

(i) halogen selected from -F, -Cl, and -Br,
(ii) -CH3,
(iii) -CF3, and
(iv) hydroxy;
(3)thienyl,
(4)pyridyl,
(5)imidazolyl,
(6)pyrrolyl,
(7)pyrazolyl,
(8)C3-6 cycloalkyl,
(9) piperidinyl,
(10) morpholinyl,
(11) naphthyl,
(12) indolyl, and
(13) C3-6 cycloalkyl fused with a phenyl ring;
each R is independently selected from:
(1) -H,
(2) -C1-3 alkyl,
(3) -CF3,
(4) -R3,
(5) -C2-3 alkenyl,
(6) -C1-3 alkyl-R3,and
(7) -S(O)n-R3,
each R5 is independently selected from:
(1) -H,
(2) -C1-3 alkyl,
(~) -CF3,
(4) -R3,
(5) -C2-3 alkenyl,
(6) -C1-3 alkyl-R3,
-141-

(7) -C2-3 alkenyl-R3, and
(8) -S(O)n-R3, ~
each R6is independently selected from:
(1)~-C1-3 alkyl-R3, and
(2) -R3; and
each n is independently selected from 0, 1 and 2;
and provided that when R2 is -R3, then R3 is not unsubstituted phenyl.
10. The compound according to Claim 9 selected from:
(1)
<IMG>
(2)
<IMG>
-142-

<IMGS>
-143-

(7)
<IMG>
and tautomers and pharmaceutically acceptable salts thereof.
11. The compound according to Claim 1 selected from:
(1)
<IMG>
(2)
<IMG>
(3)
<IMG>
-144-

(4)
<IMG>
(5)
<IMG>
(6)
<IMG>
(7)
<IMG>
(8)
<IMG>
and tautomers and pharmaceutically acceptable salts thereof.
-145-

12. The compound according to Claim 1 selected from:
(1) 2,4-dioxo-4-(5-phenethylthiophen-2-yl)butanoic acid,
(2) ethyl 2,4-dioxo-4-(5-phenethylthiophen-2-yl)butanoate,
(3) 2,4-dioxo-4-(5-benzyloxythiophen-2-yl)butanoic acid,
(4) 2,4-dioxo-4-[5-(3-fluorobenzyloxy)thiophen-2-yl]butanoic acid,
(5) 2,4-dioxo-4-(5-(4-fluorobenzyloxy)thiophen-2-yl]butanoic acid,
(6) 2,4-dioxo-4-[5-(3,4-difluorobenzyloxy)thiophen-2-yl]butanoic acid,
(7) 2,4-dioxo-4-[5-(pyridin-2-ylmethyloxy)thiophen-2-yl]butanoic acid,
(8) 2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-2-yl]butanoic acid,
(9) ethyl 2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-2-yl]butanoate,
(10) 2,4-dioxo-4-[5-(4-fluorobenzyl)thiophen-2-yl]butanoic acid,
(11) 2,4-dioxo-4-[5-(3-chlorobenzyl)thiophen-2-yl]butanoic acid,
(12) 2,4-dioxo-4-(5-benzylthiophen-2-yl)butanoic acid,
(13) 2,4-dioxo-4-(5-phenylsulfanylthiophen-2-yl)butanoic acid,
(14) 2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-3-yl]butanoic acid,
(15) 2,4-dioxo-4-[5-(4-fluorobenzyl)thiophen-3-yl]butanoic acid,
(16) 2,4-dioxo-4-[5-(3-chlorobenzyl)thiophen-3-yl]butanoic acid,
(17) 2,4-dioxo-4-(5-benzylthiophen-3-yl)butanoic acid,
(18) 2,4-dioxo-4-(2-phenylsulfanylthiophen-4-yl)butanoic acid,
(19) 2,4-dioxo-4-[2-(3-fluorobenzyl)thiophen-3-yl]butanoic acid,
(20) 2,4-dioxo-4-[2-(4-fluorobenzyl)thiophen-3-yl]butanoic acid,
(21) 2,4-dioxo-4-[2-(3-chlorobenzyl)thiophen-3-yl]butanoic acid,
(22) 2,4-dioxo-4-[5-(benzyloxy-phenylmethyl)thiophen-2-yl]butanoic acid,
(23) 2,4-dioxo-4-[5-(phenoxy-phenylmethyl)thiophen 2-yl]butanoic acid,
(24) 2,4-dioxo-4-[5-(methoxy-phenylmethyl)thiophen-2-yl]butanoic acid,
(25) 2,4-dioxo-4-(5-dibenzylaminothiophen-2-yl)butanoic acid,
(26) 2,4-dioxo-4-(5-benzylaminothiophen-2-yl)butanoic acid,
(27) 2,4-dioxo-4-(5-diallylaminothiophen-2-yl)butanoic acid,
(28) 2,4-dioxo-4-(5-di-n-propylaminothiophen-2-yl)butanoic acid,
(29) 2,4-dioxo-4-[5-(di-4-fluorobenzylamino)thiophen-2-yl]butanoic acid,
(30) 2,4-dioxo-4-[5-(N-benzyl-N-methylamino)thiophen-2-yl]butanoic
acid,
(31) 2,4-dioxo-4-(5-piperidin-1-yl-thiophen-2-yl)butanoic acid,
-146-

(32) 2,4-dioxo-4-[5-(benzylbenzenesulfonylamino)thiophen-2-yl]butanoic
acid,
(33) 2,4-dioxo-4-(2-dibenzylaminothiazol-5-yl)butanoic acid,
(34) 2,4-dioxo-4-(2-benzylaminothiazol-5-yl)butanoic acid,
(35) 2,4-dioxo-4-(2-N-benzyl-N-methylaminothiazol-5-yl)butanoic acid,
(36) 2,4-dioxo-4-(2-dibenzylaminothiazol-4-yl)butanoic acid,
and tautomers and pharmaceutically acceptable salts thereof.
13. The compound according to Claim 12 selected from:
(1) 2,4-dioxo-4-(5-phenethylthiophen-2-yl)butanoic acid,
(2) 2,4-dioxo-4-(5-benzyloxythiophen-2-yl)butanoic acid,
(3) 2,4-dioxo-4-[5-(3-fluorobenzyloxy)thiophen-2-yl]butanoic acid,
(4) 2,4-dioxo-4-[5-(4-fluorobenzyloxy)thiophen-2-yl]butanoic acid,
(5) 2,4-dioxo-4-[5-(3,4-difluorobenzyloxy)thiophen-2-yl]butanoic acid,
(6) 2,4-dioxo-4-[5-(pyridin-2-ylmethyloxy)thiophen-2-yl]butanoic acid,
(7) 2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-2-yl]butanoic acid,
(8) 2,4-dioxo-4-[5-(4-fluorobenzyl)thiophen-2-yl]butanoic acid,
(9) 2,4-dioxo-4-[5-(3-chlorobenzyl)thiophen-2-yl]butanoic acid,
(10) 2,4-dioxo-4-(5-benzylthiophen-2-yl)butanoic acid,
(11) 2,4-dioxo-4-(5-phenylsulfanylthiophen-2-yl)butanoic acid,
(12) 2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-3-yl]butanoic acid,
(13) 2,4-dioxo-4-[5-(4-fluorobenzyl)thiophen-3-yl]butanoic acid,
(14) 2,4-dioxo-4-[5-(3-chlorobenzyl)thiophen-3-yl]butanoic acid,
(15) 2,4-dioxo-4-(5-benzylthiophen-3-yl)butanoic acid,
(16) 2,4-dioxo-4-(2-phenylsulfanylthiophen-4-yl)butanoic acid,
(17) 2,4-dioxo-4-[2-(3-fluorobenzyl)thiophen-3-yl]butanoic acid,
(18) 2,4-dioxo-4-[2-(4-fluorobenzyl)thiophen-3-yl]butanoic acid,
(19) 2,4-dioxo-4-[2-(3-chlorobenzyl)thiophen-3-yl]butanoic acid,
(20) 2,4-dioxo-4-[5-(benzyloxy-phenylmethyl)thiophen-2-yl]butanoic acid,
(21) 2,4-dioxo-4-[5-(phenoxy-phenylmethyl)thiophen-2-yl]butanoic acid,
(22) 2,4-dioxo-4-[5-(methoxy-phenylmethyl)thiophen-2-yl]butanoic acid,
(23) 2,4-dioxo-4-(5-dibenzylaminothiophen-2-yl)butanoic acid,
(24) 2,4-dioxo-4-(5-benzylaminothiophen-2-yl)butanoic acid,
(25) 2,4-dioxo-4-(5-diallylaminothiophen-2-yl)butanoic acid,
-147-

(26) 2,4-dioxo-4-(5-di-n-propylaminothiophen-2-yl)butanoic acid,
(27) 2,4-dioxo-4-[5-(di-4-fluorobenzylamino)thiophen-2-yl]butanoic acid,
(28) 2,4-dioxo-4-[5-(N-benzyl-N-methylamino)thiophen-2-yl]butanoic
acid,
(29) 2,4-dioxo-4-(5-piperidin-1-yl-thiophen-2-yl)butanoic acid,
(30) 2,4-dioxo-4-[5-(benzylbenzenesulfonylamino)thiophen-2-yl)butanoic
acid,
(31) 2,4-dioxo-4-(2-dibenzylaminothiazol-5-yl)butanoic acid,
(32) 2,4-dioxo-4-(2-benzylaminothiazol-5-yl)butanoic acid,
(33) 2,4-dioxo-4-(2-N-benzyl-N-methylaminothiazol-5-yl)butanoic acid,
(34) 2,4-dioxo-4-(2-dibenzylaminothiazol-4-yl)butanoic acid,
and tautomers and pharmaceutically acceptable salts thereof.
14. The compound according to Claim 13 selected from:
(1) 2,4-dioxo-4-[5-(3-chlorobenzyl)thiophen-2-yl]butanoic acid,
(2) 2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-3-yl]butanoic acid,
(3) 2,4-dioxo-4-[5-(4-fluorobenzyl)thiophen-3-yl]butanoic acid,
(4) 2,4-dioxo-4-[5-(3-chlorobenzyl)thiophen-3-yl]butanoic acid,
(5) 2,4-dioxo-4-(5-benzylthiophen-3-yl)butanoic acid,
(6) 2,4-dioxo-4-(2-phenylsulfanylthiophen-4-yl)butanoic acid, CII(4)
(7) 2,4-dioxo-4-[2-(3-chlorobenzyl)thiophen-3-yl)butanoic acid,
(8) 2,4-dioxo-4-[5-(benzyloxy-phenylmethyl)thiophen-2-yl]butanoic acid,
(9) 2,4-dioxo-4-[5-(phenoxy-phenylmethyl)thiophen-2-yl]butanoic acid,
(10) 2,4-dioxo-4-(5-dibenzylaminothiophen-2-yl)butanoic acid,
(11) 2,4-dioxo-4-(5-diallylaminothiophen-2-yl)butanoic acid,
(12) 2,4-dioxo-4-[5-(di-4-fluorobenzylamino)thiophen-2-yl]butanoic acid,
(13) 2,4-dioxo-4-[5-(N-benzyl-N-methylamino)thiophen-2-yl]butanoic
acid,
(14) 2,4-dioxo-4-(2-dibenzylaminothiazol-5-yl)butanoic acid, and
(15) 2,4-dioxo-4-(2-N-benzyl-N-methylaminothiazol-5-yl)butanoic acid,
and tautomers and pharmaceutically acceptable salts thereof.
-148-

15. A pharmaceutical composition useful for inhibiting HIV
integrase, comprising an effective amount of a compound according to Claim 1
and a
pharmaceutically acceptable carrier.
16. The pharmaceutical composition of Claim 15, useful for
treating infection by HIV, or for treating AIDS or ARC.
17. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of structural formula (I):
<IMG>
or tautomers or pharmaceutically acceptable salts thereof,
in combination with a therapeutically effective amount of an AIDS treatment
agent
selected from
(1) an AIDS antiviral agent,
(2) an anti-infective agent, and
(3) an immunomodulator; wherein
A is a five-membered heteroaromatic ring containing l sulfur atom and 0 or 1
nitrogen atoms and substituted on carbon by R1, R2 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:
<IMG>
R1 is selected from:
(1) -H,
(2) -C1-5 alkyl,
(3) -CF3,
(4) -halo,
(5) -NO2,
-149-

(6) -N(R4)(R5),
(7) -R6,
(8) -C2-5 alkenyl-R3,
(9) -C2-5 alkynyl-R3,
(10) -O-R6,
(11) -O-C1-6 alkyl,and
(12) -C(O)CH2C(O)C(O)OR7;
R2is selected from:
(1) -H,
(2) -R3,
(3) -C1-6 alkyl,
(4) -C1-6 alkyl substituted with R3,
(5) -O-R6,
(6) -O-C1-6 alkyl-OR6,
(7) -S(O)n-R6,
(8) -C1-6 alkyl (OR6)(R4),
(9) -C1-6 alkyl (OR4)(R6),
(10) -C0-6 alkyl-N(R4)(R6),
(11) -C1-6 alkyl S(O)n-R6,
(12)-C0-6 alkyl C(O)-R6,
(13)-C0-6 alkyl C(S)-R6,
(14)-C0-6 alkyl NR4 C(O)-R6, and
(15)-C0-6 alkyl-C(O)N(R4)(R5);
each R3 is independently selected from:
-150-

(1) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0,1,2,
3, or 4 heteroatoms selected from oxygen.nitrogen and sulfur,
unsubstituted or substituted on a nitrogen or carbon atom by 1 to5
substituents selected from:¦
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) -OCF3,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1-6 alkyl,
(iii) -CF3, and
(iv) hydroxy;
(2) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms
selected from oxygen, nitrogen or sulfur, unsubstituted or substituted
with 0 to 5 substituents selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) -CF3,
(e) -OCF3,
(f) -CN,
(g) =O, and
(h) hydroxy;
(3) unsubstituted or substituted hexahydrothieno[3,4-d]imidazolyl with
one or two substituents selected from:
(a) oxo,
-151-

(b) halogen,
(c) C1-6 alkyl,
(d) C1-6 alkyloxy-,
(e) -CF3,
(f) -OCF3,
(g) -CN, and
(h) hydroxy;
(4) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, or
2 heteroatoms selected from oxygen, nitrogen and sulfur, fused with a
phenyl ring; wherein the ring system is unsubstituted or substituted on
a nitrogen or carbon atom by 1 to 3 substituents selected from:
(a) -halogen,
(b) -C1-6 alkyl,
(c) -C1-6 alkyloxy-,
(d) -CF3,
(e) -OCF3,
(f) -CN, and
(g) -hydroxy;
(5) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms
selected from oxygen, nitrogen or sulfur, fused with a phenyl ring,
unsubstituted or substituted withl or 2 substituents selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) -CF3,
(e) -OCF3,
(f) -CN,
(g) =O, and
(h) hydroxy;
(6) a 5 to 6 membered ring containing 0, 1 or 2 heteroatoms selected from
oxygen, nitrogen or sulfur, containing 2 or 3 double bonds,
unsubstituted or substituted with 1 or 2 substituents selected from:
- 152-

(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) -CF3,
(e) -OCF3,
(f) -CN,
(g) =O, and
(h) hydroxy;
each R4 is independently selected from:
(1) -H,
(2) -C1-3 alkyl,
(3) -CF3,
(4) -R3,
(5) -C2-3 alkenyl,
(6) -C1-3 alkyl-R3,
(7) -C2-3 alkenyl-R3,
(8) -S(O)n-R3, and
(9) -C(O)-R3;
each R5 is independently selected from:
(1) -H,
(2) -C1-3 alkyl,
(3) -CF3,
(4) -R3,
(5) -C2-3 alkenyl,
(6) -C1-3 alkyl-R3,
(7) -C2-3 alkenyl-R3,
(8) -S(O)n-R3, and
(9) -C(O)-R3;
153

each R6 is independently selected from:
(1) -C1-3 alkyl-R3, and
(2) -R3;
R7 is selected from:
(1) -H, and
(2) C1-6 alkyl;
R8 is selected from:
(1) -H, and
(2) C1-6 alkyl-oxy-, and
(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.
18. The composition of Claim 17 wherein the antiviral agent is an
HIV protease inhibitor.
19. The composition of Claim 18 wherein the HIV 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.
20. A pharmaceutical composition made by combining the
compound of Claim 1 and a pharmaceutically acceptable carrier.
21. A process for making a pharmaceutical composition
comprising combining a compound of Claim 1 and a pharmaceutically acceptable
carrier.
154

22. A method of inhibiting HIV integrase, comprising the
administration to a mammal in need of such treatment a therapeutically
effective
amount of a compound of structural formula (I):
<IMG>
or tautomers or pharmaceutically acceptable salts thereof,
wherein:
A is a five-membered heteroaromatic ring containing 1 sulfur atom and 0 or 1
nitrogen atoms and substituted on carbon by R1, R2 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:
<IMG>
R1 is selected from:
(1) -H,
(2) -C1-5 alkyl,
(3) -CF3,
(4) -halo,
(5) -NO2,
(6) -N(R4)(R5),
(7) -R6,
(8) -C2-5 alkenyl-R3,
(9) -C2-5 alkynyl-R3,
(10) -O-R6,
(11) -O-C1-6 alkyl, and
(12) -C(O)CH2C(O)C(O)OR7;
155

2
R2 is selected from:
(1) -H,
(2) -R3,
(3) -C1-6 alkyl,
(4) -C1-6 alkyl substituted with R3,
(5) -O-R6,
(6) -O-C1-6 alkyl-OR6,
(7) -S(O)n-R6,
(8) -C1-6 alkyl (OR6)(R4),
(9) -C1-6 alkyl (OR4)(R6),
(10) -C0-6 alkyl-N(R4)(R6),
(11) -C1-6 alkyl S(O)n-R6
(12) -C0-6 alkyl C(O)-R6,
(13) -C0-6 alkyl C(S)-R6,
(14) -C0-6 alkyl NR4C(O)-R6, and
(15) -C0-6 alkyl-C(O)N(R4)(R5);
each R3 is independently selected from:
(1) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1,
2,
3, or 4 heteroatoms selected from oxygen, nitrogen and sulfur,
unsubstituted or substituted on a nitrogen or carbon atom by 1 to 5
substituents selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) -OCF3,
156

(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1-6 alkyl,
(iii) -CF3, and
(iv) hydroxy;
(2) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms
selected from oxygen, nitrogen or sulfur, unsubstituted or substituted
with 0 to 5 substituents selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) -CF3,
(e) -OCF3,
(f) -CN,
(g) =O, and
(h) hydroxy;
(3) unsubstituted or substituted hexahydrothieno[3,4-d]imidazolyl with
one or two substituents selected from:
(a) oxo,
(b) halogen,
(c) C1-6 alkyl,
(d) C1-6 alkyloxy-,
(e) -CF3,
(f) -OCF3,
(g) -CN, and
(h) hydroxy;
(4) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, or
2 heteroatoms selected from oxygen, nitrogen and sulfur, fused with a
157

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,
(c) -C1-6 alkyloxy-,
(d) -CF3,
(e) -OCF3,
(f) -CN, and
(g) -hydroxy;
(5) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms
selected from oxygen, nitrogen or sulfur, fused with a phenyl ring,
unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) -CF3,
(e) -OCF3,
(f) -CN,
(g) =O, and
(h) hydroxy;
(6) a 5 to 6 membered ring containing 0, 1 or 2 heteroatoms selected from
oxygen, nitrogen or sulfur, containing 2 or 3 double bonds,
unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) -CF3,
(e) -OCF3,
(f) -CN,
(g) =O, and
(h) hydroxy;
158

each R4 is independently selected from:
(1) -H,
(2) -C1-3 alkyl,
(3) -CF3,
(4) -R,
(5) -C2-3 alkenyl,
(6) -C1-3 alkyl-R3,
(7) -C2-3 alkenyl-R3,
(8) -S(O)n-R3, and
(9) -C(O)-R3;
each R5 is independently selected from:
(1) -H,
(2) -C1-3 alkyl,
(3) -CF3,
(4) -R3,
(5) -C2-3 alkenyl,
(6) -C1-3 alkyl-R3,
(7) -C2-3 alkenyl-R3,
(8) -S(O)n-R3, and
(9) -C(O)-R3; ~
each R6 is independently selected from:
(1) -C1-3 alkyl-R3, and
(2) -R3;
R7 is selected from:
(1) -H, and
(2) C1-6 alkyl;
159

R8 is selected from:
(1) -H, and
(2) C1-6 alkyl-oxy-, and
(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.
23. A method of treating infection by HIV, or of treating AIDS or
ARC, comprising the administration to a mammal in need of such treatment a
therapeutically effective amount of a compound of structural formula (I):
<IMG>
or tautomers or pharmaceutically acceptable salts thereof,
wherein:
A is a five-membered heteroaromatic ring containing 1 sulfur atom and 0 or 1
nitrogen atoms and substituted on carbon by R1, R2 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:
<IMG>
R1 is selected from:
(1) -H,
(2) -C1-5 alkyl,
(3) -CF3,
(4) -halo,
(5) -NO2,
160

(6) -N(R4)(R5),
(7) -R6,
(8) -C2-5 alkenyl-R3
(9) -C2-5 alkynyl-R3
(10) -O-R6,
(11) -O-C1-6 alkyl, and
(12) -C(O)CH2C(O)C(O)OR7;
R2 is selected from:
(1) -H,
(2) -R3,
(3) -C1-6 alkyl,
(4) -C1-6 alkyl substituted
(5) -O-R6,
(6) -O-C1-6 alkyl-OR6,
(7) -S(O)n-R6,
(8) -C1-6 alkyl (OR6)(R4),
(9) -C1-6 alkyl (OR4)(R6),
(10) -C0-6 alkyl-N(R4)(R6),
(11) -C1-6 alkyl S(O)n-R6,
(12) -C0-6 alkyl C(O)-R6,
(13) -C0-6 alkyl C(S)-R6,
(14) -C0-6 alkyl NR4C(O)-R6, and
(15) -C0-6 alkyl-C(O)N(R6, and
each R3 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,
161

unsubstituted or substituted on a nitrogen or carbon atom by 1 to 5
substituents selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) -OCF3,
(g) -CN,
(h) hydroxy,
(i) phenyloxy. and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1-6 alkyl,
(iii) -CF3, and
(iv) hydroxy;
(2) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms
selected from oxygen, nitrogen or sulfur, unsubstituted or substituted
with 0 to 5 substituents selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) -CF3,
(e) -OCF3,
(f) -CN,
(g) =O, and
(h) hydroxy;
(3) unsubstituted or substituted hexahydrothieno[3,4-d]imidazolyl with
one or two substituents selected from:
(a) oxo,
(b) halogen,
(c) C1-6 alkyl,
162

(d) C1-6 alkyloxy-,
(e) -CF3,
(f) -OCF3,
(g) -CN, and
(h) hydroxy;
(4) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, or
2 heteroatoms selected from oxygen, nitrogen and sulfur, fused with a
phenyl ring; wherein the ring system is unsubstituted or substituted on
a nitrogen or carbon atom by 1 to 3 substituents selected from:
(a) -halogen,
(b) -C1-6 alkyl,
(c) -C1-6 alkyloxy-,
(d) -CF3,
(e) -OCF3,
(f) -CN, and
(g) -hydroxy;
(5) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms
selected from oxygen, nitrogen or sulfur, fused with a phenyl ring,
unsubstituted or substituted with1 or 2 substituents selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) -CF3,
(e) -OCF3,
(f) -CN,
(g) =O, and
(h) hydroxy;
(6) a 5 to 6 membered ring containing 0, 1 or 2 heteroatoms selected from
oxygen, nitrogen or sulfur, containing 2 or 3 double bonds,
unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen,
163

(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) -CF3,
(e) -OCF3,
(f) -CN,
(g) =O, and
(h) hydroxy;
each R4 is independently selected from:
(1) -H,
(2) -C1-3 alkyl,
(3) -CF3,
(4) -R3,
(5) -C2-3 alkenyl,
(6) -C1-3 alkyl-R3,
(7) -C2-3 alkenyl-R3,
(8) -S(O)n-R3, and
(9) -C(O)-R3;
each R5 is independently selected from:
(1) -H,
(2) -C1-3 alkyl,
(3) -CF3,
(4) -R3,
(5) -C2-3 alkenyl,
(6) -C1-3 alkyl-R3,
(7) -C2-3 alkenyl-R3,
(8) -S(O)n-R3, and
(9) -C(O)-R3;
164

each R6 is independently selected from:
(1) -C1-3 alkyl-R3, and
(2) -R3;
R7 is selected from:
(1) -H, and
(2) C1-6 alkyl;
R8 is selected from:
(1) -H, and
(2) C1-6 alkyl-oxy-, and
(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.
165
~ ~S

Description

CA 02333771 2000-11-30
WO 99/62897 PCT/US99/12094
TITLE OF THE INVENTION
HIV INTEGRASE INHIBITORS
CROSS-REFERENCE TO RELATED APPLICATIONS
The present application claims priority of U.S. provisional
application Serial No. 60/087,846, filed June 3, 1998.
BACKGROUND OF THE INVENTION
A retrovirus designated human immunodeficiency virus
(HIV) is the etiological agent of the complex disease that includes
progressive destruction of the immune system (acquired immune
deficiency syndrome; AIDS) and degeneration of the central and
peripheral nervous system. This virus was previously known as
LAV, HTLV-III, or ARV. A common feature of retrovirus
replication is the insertion by virally-encoded integrase of proviral
DNA into the host cell genome, a required step in HIV replication in
human T-lymphoid and monocytoid cells. Integration is believed to
be mediated by integrase in three steps: assembly of a stable
nucleoprotein complex with viral DNA sequences; cleavage of two
nucleotides from the 3' termini of the linear proviral DNA; covalent
joining of the recessed 3' OH termini of the proviral DNA at a
staggered cut made at the host target site. The fourth step in the
process, repair synthesis of the resultant gap, may be accomplished
by cellular enzymes.
Nucleotide sequencing of HIV shows the presence of a
pol gene in one open reading frame [Ratner, L. et al., Nature, 313,
277(1985)]. Amino acid sequence homology provides evidence that the
pol sequence encodes reverse transcriptase, integrase and an HIV
protease [Toh, H. et aL, EMBO J. 4, 1267 (1985); Power, M.D. et al.,
Science, 231, 1567 (1986); Pearl, L.H. et al., Nature, 329, 351 (1987)].
All three enzymes have been shown to be essential for the replication
of HIV.
It is known that some antiviral compounds which act as
inhibitors of HIV replication are effective agents in the treatment of
AIDS and similar diseases, e.g., azidothymidine or AZT. Applicants
-1-

CA 02333771 2000-11-30
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demonstrate that the compounds of this invention are inhibitors of
HIV integrase and inhibitors of HIV replication. The applicants
additionally demonstrate that inhibition of integrase in vitro and HIV
replication in cells is a direct result of inhibiting the strand transfer
reaction catalyzed by the recombinant integrase in vitro and
integrase as a component of the preintegration complex in HIV
infected cells. The particular advantage of the present invention is
highly specific inhibition of HIV integrase and HIV replication. The
compounds of the present invention inhibit integrases of closely
related lentiviruses such as HIV 2 and SIV, but not integrases from
more distantly related retroviruses, for example RSV. These
compounds do not inhibit binding or catalysis of other nucleic acid
binding proteins, including enzymatic reactions such as those
catalyzed by HIV reverse transcriptase, HIV Rnase H, Influenza
transcriptase, Hepatitis C polymerase, Yeast DNA polymerase,
DNase I, Eco RI endonuclease, or mammalian polymerase II.
Zhao et al., (J. Med Chem. vol. 40, pp. 937-941 and 1186-
1194 (1997)) describe hydrazide and arylamide HIV integrase
inhibitors. Bis-catechols useful for inhibiting HIV integrase are
described in LaFemina et a1. (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
intreating urinary tract calcium oxalate lithiasis. 4-substituted 2,4-
dioxobutanoic acid compounds useful for inhibiting an influenza
virus endonuclease are described in Tomassini et al. (Antimicrobial
Agents & Chemotherapy, vol. 38, no. 12, pp. 2827-2837, December,
1994).
Applicants have discovered that certain 5-membered sulfur
containing heteroaromatic diketo acid derivatives are potent inhibitors of
HIV integrase. These compounds are useful in the treatment of AIDS
or HIV infection.
SUMMARY OF THE INVENTION
-2-

CA 02333771 2000-11-30
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,
pharmaceutically acceptable salts or hydrates (when appropriate),
pharmaceutical composition ingredients, whether or not in combination
with other antivirals, anti-infectives, immunomodulators, antibiotics or
vaccines. Methods of treating AIDS, methods of preventing infection by
HIV, and methods of treating infection by HIV are also disclosed.
DETAILED DESCRIPTION OF THE INVENTION
This invention is concerned with compounds of formula I,
combinations thereof, or pharmaceutically acceptable salts thereof, in
the inhibition of HIV integrase, the prevention or treatment of infection
by HIV and in the treatment of the resulting acquired immune
deficiency syndrome (AIDS). Compounds of formula I are defined as
follows:
/'~ R~ O
'ORS
R8 O O
and tautomers or pharmaceutically acceptable salts thereof,
wherein:
A is a five-membered heteroaromatic ring containing 1 sulfur atom and
0 or 1 nitrogen atoms and substituted on carbon by Rl ,R2 and Rg; 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 \
S~ s / S~
-3-

CA 02333771 2000-11-30
WO 99/62897 PCT/US99/12094
Rl is selected from:
(1) -H,
(2) -C1-~ alkyl,
(3) -CF3,
(4) -halo,
(5) -N02,
(6) -N(R4)(R5)
,
(7) -R6,
(8) -C2_5 alkenyl-R3,
{9) -C2-5 alkynyl-R3,
(10) -O-R6,
(11) -O-C1-6 alkyl, and
(12) -C(O)CH2C(O)C(O)OR7;
R2 is selected from:
(1) -H,
(2) -R3,
(3) -C1~ alkyl,
(4) -C1~ alkyl substituted
with R3,
(5) -O-R6,
(6) -O-Cl-g alkyl-ORs,
(7) -S(O)n-Rs,
(8) -C1-g alkyl (OR6)(R4)
,
(9) -C1~ alkyl (OR4KR6) ,
(10) -Cpl alkyl-N(R4 XRs )
,
(11) -C1-g alkyl S(O)n-R6,
{12) -Cpl alkyl C(O)-R6,
(13) -Cpl alkyl C(S)-R6,
(14) -Cp-s alkyl NR4C{O)-R6,
and
(15) -C
alkyl-C(O)N(R4 )(R~ );
pl
-4-

CA 02333771 2000-11-30
WO 99/62897 PCT/US99/12094
each R3 is independently selected from:
(1) a 5 or 6 membered aromatic or heteroaromatic ring,
containing 0, 1, 2, 3, or 4 heteroatoms selected from oxygen,
nitrogen and sulfur, unsubstituted or substituted on a
nitrogen or carbon atom by 1 to 5 substituents selected from:
(a) halogen,
(b) C1_6 alkyl,
(c) Cl-6 alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) -OCFg,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents
selected from:
(i) halogen,
(ii) C1-g alkyl,
(iii) -CF3, and
(iv) hydroxy;
(2) a 3 to 6 membered saturated ring containing 0 or 1
heteroatoms selected from oxygen, nitrogen or sulfur,
unsubstituted or substituted with 0 to 5 substituents selected
from:
(a) halogen,
(b) Cl_g alkyl,
(c) C1~ alkyloxy-,
(d) -CFg,
(e) -OCF3,
(f) -CN,
(g) =O,
(h) hydroxy;
-5-

CA 02333771 2000-11-30
WO 99/62897 PCT/US99/12094
(3) unsubstituted or substituted hexahydrothieno[3,4-
d]imidazolyl with one or two substituents selected from:
(a) oxo,
(b) halogen,
(c) C1"6 alkyl,
(d) C1~ alkyloxy-,
(e) -CF3,
(fj -OCF3,
(g) -CN, and
(h) hydroxy;
(4) a 5 or 6 membered aromatic or heteroaromatic ring,
containing 0, 1, or 2 heteroatoms selected from oxygen,
nitrogen and sulfur, fused with a phenyl ring; wherein the
ring system is unsubstituted or substituted on a nitrogen or
carbon atom by 1 to 3 substituents selected from:
(a) -halogen,
(b) -C1_g alkyl,
(c) -C1~ alkyloxy-,
(d) -CF3,
(e) -OCF3,
(f) -CN, and
(g) -hydroxy;
(5) a 3 to 6 membered saturated ring containing 0 or 1
heteroatoms selected from oxygen, nitrogen or sulfur, fused
with a phenyl ring, unsubstituted or substituted withl or 2
substituents selected from:
(a) halogen,
(b) C1~ alkyl,
(c) Cl_6 alkyloxy-,
(d) -CF3,
-6-

CA 02333771 2000-11-30
WO 99/62897 PCT/US99/12094
(e) -OCF3,
(f) -CN,
(g) =O
(h) hydroxy;
(6) a 5 to 6 membered ring containing 0, 1 or 2 heteroatoms
selected from oxygen, nitrogen or sulfur, containing 2 or 3
double bonds, unsubstituted or substituted with 1 or 2
substituents selected from:
(a) halogen,
(b) C1-g alkyl,
(c) C1-6 alkyloxy-,
(d) -CF3,
(e) -OCF3,
(f) -CN,
(g) =O
(h) hydroxy;
each R4 is independently selected from:
(1) -H,
(2) -C1~ alkyl,
(3) -CF3,
-R3
(5) -C2-3 alkenyl,
-C 1-3 amyl-R3
(7) -C2_g alkenyl-R3,
(8) -S(O)ri R3, and
(9) -C(O)-R3;
each R5 independently selected
is from:
(1) -H,
(2) -Cl-3 alkyl,
_7_

CA 02333771 2000-11-30
WO 99/62897 PCT/US99/12094
(3) -CF3,
-R3
(5) -C2-3 alkenyl,
(6) g alkyl-R3 ,
-C 1
(7) -
-C2~ alkenyl-R3,
(8) -S(O)ri R3,
and
(9) -C(O)-R3;
each R6 is independently selected from:
( 1 ) -C 1-3 alkyl-R3 , and
(2) -R3;
R7 is selected from:
(1) -H, and
(2) C1-g alkyl;
R8 is selected from:
(1) -H, and
(2) C1_6 alkY1_oxY_;
(3) C1-g alkyl-;
each n is independently selected from 0, 1 and 2, and
each m is independently selected from 0, 1, and 2.
Particular compounds of structural formula I include:
(1)
O
~S
OH
O O ,
(2)
_g_

CA 02333771 2000-11-30
WO 99/62897 PCT/US99/12094
(3)
(4)
(5)
(6)
(7)
(8)
O / ~ O
/ \ s off
0 0 ,
O / ~ O
/ \ S OH
O O
F
O / ~ O
F / \ S OH
O O
O / ~ O
F / \ S OH
O O
F
O
/ S OH
O O
/ I O
OH
F \ / O O
O
OH
/ O O
F
_g_

CA 02333771 2000-11-30
WO 99/62897 PCT/US99/12094
(9)
(10)
(11)
(12)
O
S ~~~OH
CI \ ~ O O
O
S OH
\ ~ O O
S / ~ O
OH
\ ~ O O
OH
(13)
\ O
O
OH
\ / O O
(14)
H3C0 / O
S ~~~OH
\ / O O
-10-

CA 02333771 2000-11-30
WO 99/62897 PCT/US99/12094
(15)
~I
OH
O O
(16)
0
H S OH
O O
(1?)
O
~I
OH
O O
(18)
~I
OH
O O
(19)
F
I O
OH
O O
F
(20)
-11-

CA 02333771 2000-11-30
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/ \
N / I o
H3C~ S OH
O O
(21)
(22)
(23)
(24)
(25)
(26)
/I o
N
S ~~~OH
O O
/ \
N / ~ O
02S S OH
\ O O
S / I o
/ \ S off
0 0 ,
o.o / I o
/ \ s off
0 0
/ I O
/ \ S OH
O O O
N / I o
/ \ S;o s
off
0 0 0
-12-

CA 02333771 2000-11-30
WO 99/62897 PCT/US99/12094
(27)
(28)
(29)
(30)
(31)
O ~ ~ O
S OH
\ / O O
O
S OH
\ ~ O O
CI
\ S O
~OH
O O
S O
\
O o OH
F
OH
F
(32)
(33)
S O
~OH
CI \ ~ O O
-13-

CA 02333771 2000-11-30
WO 99/62897 PCT/US99/12094
(34)
(35)
CI
(36)
OH
OH
F
(37)
O
S
~OH
O O
F
,
(38)
S O
~OH
\ / O O
S O
S \
OH
\ / O O
CI
OH
- 14-

CA 02333771 2000-11-30
WO 99/62897 PCT/US99/12094
(39)
(40)
(41)
(42)
(43)
O
S
~OH
O O
CI -
O
S
I S ~ ~ ~OH
/ O O
N
N ~~ I O
S OH
O O
N
N ~~ ( O
H S OH
O O
N
N~~ I O
HsC~ S OH
O O
(44)
-15-

CA 02333771 2000-11-30
WO 99/62897 PCT/US99/12094
N
N ~~ I O
S OH
O O
(45)
(46)
(47)
(48)
(49)
N
N ~~ I O
H S OH
O O
N
N~~ I O
H3C S OH
O O
S
N~ ~ O
N OH
O O
S
N--~ ~ o
N OH
O O
-16-

CA 02333771 2000-11-30
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(50)
(51)
(52)
(53)
(54)
(55)
/~S O
i
OH
o O O
S O
~OH
S O O
CI
~~S O
OH
O O O
w
F
S O
1f 1f -oH
0 0
O
S ~ ~ ~OH
O O
/ off
il II
S O O , and
- 17-

CA 02333771 2000-11-30
WO 99/62897 PCT/US99/1Z094
' S O
-OH
O O
and tautomers and pharmaceutically acceptable salts thereof.
In one embodiment of the present invention, structural
formula (I) is:
O
R2
S OH
O O ,
In another embodiment of the present invention, structural
formula (I) is:
R8
S ' O
R ~ OH
O O
In still another embodiment of the present invention,
lp structural formula (I) is:
O
S
OH
R2 O O
In yet another embodiment of the present invention,
structural formula (I) is;
R~ ~ O
S ~ ~ ~OH
O O
In one class of compounds of the present invention, A is
selected from:
-18-

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(1) thienyl,
(2) thiazolyl,
(3)
(4)
S
S
and
(5)
m ~ ~~
S
In another class of compounds of the present invention, A is
selected from:
(1) thienyl,
(2) thiazolyl,
(3)
S , and
(4)
S~
In one class of compounds of the present invention, R1 is
selected from:
(1) -H,
(2) -CH3,
(3) -CF3,
(4) -halo,
(5) -N02,
-19-

CA 02333771 2000-11-30
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-N(R4 XR5 )
(7) -phenyl,
($) substituted phenyl substituted with 1 or
2 substituents
independently selected from:
(a) halogen,
(b) C1_g alkyl,
(c) C1_s alkyloxy-,
(d) phenyl,
(e) -CFg,
(f) -OCF3,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3
substituents
selected from:
(i) halogen,
(ii) Cl~ alkyl,
(iii) -CF3, and
(iv) hydroxy;
(9) phenyl C1_3 alkyl-,
(10) substituted phenyl C1_3 alkyl- substituted
with i or 2
substituents independently selected from:
(a) halogen,
(b) Cl~ alkyl,
(c) C1_6 alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) -OCF3,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
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CA 02333771 2000-11-30
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(j) substituted phenyloxy with 1, 2, or 3 substituents
selected from:
(i) halogen,
(ii) C1~ alkyl,
(iii) -CF3, and
(iv) hydroxy;
(11) -C2_5 alkenyl-R3,
(12) -C2_5 alkynyl-R3, and
(13) -C(O)CH2C(O)C(O)OR7.
In another class of compounds of the present invention,
R1
is selectedfrom:
(1) -H,
(2) -CH3,
(3) -CF3,
(4) -halo,
(5) -NO2,
(6) -N(R4 )(R5 )
,
(7) -phenyl,
(8) substituted phenyl substituted with 1 or 2 substituents
independently selected from:
(a) halo,
(b) methyl, and
(c) methoxy,
(9) phenyl Cl_3 alkyl-,
(10) substituted phenyl C1_3 alkyl- substituted with
1 or 2
substituents independently selected from:
(a) halo,
(b) methyl, and
(c) methoxy, and
(11) -C2_5 alkenyl-R3.
In still another class of compounds of the present
invention,
R1 is
hydrogen.
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CA 02333771 2000-11-30
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In one class of compounds of the present invention, R2 is
selected from:
(1) -H,
(2) -R3,
(3) -C1_6 alkyl,
(4) -C1_6 alkyl substituted with R3,
(5) -O-R6,
(6) -O-C1_g alkyl-ORs,
(7) -S(O)n-R6,
(8) -C1_g alkyl (OR6)(R4) ,
(9) -C 1~ alkyl (OR4 )(Rs ) ,
( 10) -Cp_6 alkyl-N(R4 KR6 ) ,
(11) -C1~ alkyl S(O)n-R6,
(12) -C~~ alkyl C(O)-R6,
(13) -Cpl alkyl C(S)-R6,
(14) -Cpl alkyl NR4C(O)-R6, and
(15) -C~",6 alkyl-C(O)N(R4)(R,5).
In another class of compounds of the present
invention, R2
is selected from:
(1) -H,
(2) -R3,
(3) -C1~ alkyl,
(4) -C1~ alkyl substituted with R3,
(5) -O-R6
,
(6) -S(O)n-Rs,
(7) -C1..6 alkyl (OR6)(R4) ,
(8) -C 1-s alkyl (OR4 )(R6 ) ,
-CO-6 ~yl-N(R4 )(Rs ) ,
(10) -C1~ alkyl S(O)n-R6,
(11) -Co-g alkyl C(O)-Rs,
(12) -Cpl alkyl NR4C(O)-Rs, and
- 22 -

CA 02333771 2000-11-30
WO 99/62897 PCT/US99/12094
(13) -Cog alkyl-C(O)N(R4)(R5).
In one class of compounds of the present invention, R3 is
selected from:
(1) phenyl;
(2) substituted phenyl with 1, 2, or 3 substituents independently
selected from:
(a) halogen,
(b) C1_g alkyl,
(c) Cl-6 alkyloxy-,
(d) phenyl,
(e) -CF3,
-OCF3 ,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j ) substituted phenyloxy with '1, 2, or 3 substituents
selected from:
(i) halogen,
(ii) Cl-g alkyl,
(iii) -CF3, and
(iv) hydroxy;
(3) thienyl;
(4) substituted thienyl substituted on a carbon atom with one or
two substituents independently selected from:
(a) halogen,
(b) C1~ alkyl,
(c) Cl_6 alkyloxy-,
(d) phenyl,
(e) -CF3,
(~ -OCF3,
(g) -CN,
(h) hydroxy,
-23-

CA 02333771 2000-11-30
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(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents
selected from:
(i) halogen,
(ii) Cl~ alkyl,
(iii) -CF3, and
(iv) hydroxy;
(5) pyridyl;
(6) substituted pyridyl substituted on a carbon atom with one or
two substituents independently selected from:
(a) halogen,
(b) C1-g alkyl,
(c) C1~ alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) -OCFg,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents
selected from:
(i) halogen,
(ii) Cl_g alkyl,
(iii) -CF3, and
(iv) hydroxy;
(?) imidazolyl;
(8) substituted imidazolyl substituted on a carbon atom with
one or two substituents independently selected from:
(a) halogen,
(b) C1~ alkyl,
(c) Cl-s alkyloxy-,
(d) phenyl,
(e) -CF3,

CA 02333771 2000-11-30
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(f) -OCFg,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents
selected from:
(i) halogen,
(ii) C1~ alkyl,
(iii) -CF3, and
(iv) hydroxy;
(9) pyrrolyl;
(10) substituted pyrrolyl substituted on a carbon atom with one
or two substituents independently selected from:
(a) halogen,
(b) C1~ alkyl,
(c) C1~ alkyloxy-,
(d) phenyl,
(e) -CF3
(f) -OCF3,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents
selected from:
(i) halogen,
(ii) C1~ alkyl,
(iii) -CF3, and
(iv) hydroxy;
(11) pyrazolyl;
(12) substituted pyrazolyl substituted on a carbon atom with one
or two substituents independently selected from:
(a) halogen,
(b) Cl_g alkyl,
-25-

CA 02333771 2000-11-30
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(c) C1_g alkyloxy-,
(d) phenyl,
(e) -CF3>
(f) -OCF3,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents
selected from:
(i) halogen,
(ii) C1_s alkyl,
(iii) -CF3, and
(iv) hydroxy;
(13) C~6 cycloalkyl;
(14) substituted C3_g cycloalkyl with 1 or 2 substituents
independently selected from:
(a) halogen,
(b) C1_g alkyl,
(c) C1~ alkyloxy-,
(d) -CF3,
(e) -OCF3,
-CN,
(g) =O,and
(h) hydroxy;
(15) piperidinyl;
(16) substituted piperidinyl substituted on a carbon atom with
one or two substituents independently selected from:
(a) halogen,
(b) C1"~ alkyl,
(c) C1~ alkyloxy-,
(d) -CF3,
(e) -OCF3,
-26-

CA 02333771 2000-11-30
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(f) -CN,
(g) =O, and
(h) hydroxy;
(17) morpholinyl;
(18) substituted morpholinyl substituted at a carbon
or nitrogen
atom with 1 or 2 independently selected from:
(a) halogen,
(b) Cl-g alkyl,
(c) C~-6 alkyloxy-,
(d) -CF3,
(e) -OCF3,
(f) -CN,
(g) =O, and
(h) hydroxy;
(19) naphthyl,
(20) substituted naphthyl with 1, 2, or 3 substituents
independently selected from:
(a) -halogen,
(b) -C1~ alkyl,
(c) -C1~ alkyloxy-,
(d) -CFg,
(e) -OCF3,
(f) -CN, and
(g) -hydroxy;
(21) indolyl;
(22) substituted indolyl substituted on a carbon atom
with one or
two substituents independently selected from:
(a) -halogen,
(b) -C1~ alkyl,
(c) -C1-6 alkyloxy-,
(d) -CF3,
(e) -OCF3,
(f) -CN, and
-2?-

CA 02333771 2000-11-30
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(g) -hydroxy;
(23) Cog cycloalkyl fused with a phenyl ring
(24) substituted C3-6 cycloalkyl fused with a phenyl ring
substituted on a carbon atom with one or two substituents
independently selected from:
(a) halogen,
(b) C1~ alkyl,
(c) C1-s alkyloxy-,
(d) -CFg,
(e) -OCF3,
(f) -CN,
(g) =0, and
(h) hydroxy.
In another class of compounds of the present invention, R3
is selected from:
(1) phenyl;
(2) substituted phenyl with 1, 2, or 3 substituents independently
selected from:
(a) halogen,
(b) C1-g alkyl,
(c) C1~ alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) -OCFg,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents
selected from:
(i) halogen,
(ii) C1_s alkyl,
(iii) -CF3, and
(iv) hydroxy;
-28-

CA 02333771 2000-11-30
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(3) thienyl;
(4) substituted thienyl substituted on a carbon atom with one or
two substituents independently selected from:
(a) halogen,
(b) Cl~ alkyl,
(c) C1~ alkylaxy-,
(d) phenyl,
(e) -CF3,
(f) -OCF3,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents
selected from:
(i) halogen,
(ii) C1~ alkyl,
(iii) -CF3, and
(iv) hydroxy;
(5) pyridyl;
(6) substituted pyridyl substituted on a carbon atom with one or
two substituents independently selected from:
(a) halogen,
(b) C1~ alkyl,
(c) C1-g alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) -OCF3,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents
selected from:
(i) halogen,
-29-

CA 02333771 2000-11-30
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(ii) Cl~ alkyl,
(iii) -CF3, and
(iv) hydroxy;
(7) imidazolyl;
(8) pyrrolyl;
(9) pyrazolyl;
(10) Cog cycloalkyl,
(11) substituted C3_6 cycloalkyl with 1 or 2 substituents
independently selected from:
(a) halogen,
(b) C1~ alkyl,
(c) C1~ alkyloxy-,
(d) -CF3,
(e) -OCF3,
(f) -CN,
(g) =O, and
(h) hydroxy;
(12) piperidinyl;
(13) substituted piperidinyl substituted on a carbon
atom with
one or two substituents independently selected
from:
(a) halogen,
(b) Cl_g alkyl,
(c) C1_6 alkyloxy-,
(d) -CFg,
(e) -OCF3,
(f~ -CN,
(g) =O, and
(h) hydroxy;
(14) morpholinyl;
(15) naphthyl;
(16) indolyl, and
(17) C3_g cycloalkyl fused with a phenyl ring.
-30-

CA 02333771 2000-11-30
WO 99/62897 PCT/US99/12094
In still another class of compounds of the present
invention,
R3 is
selected
from:
(1) phenyl,
(2) substituted phenyl with 1, 2, or 3 substituents
independently
selected from:
(a) halogen selected from -F, -Cl, -Br"
(b) CH3,
(c) methoxy-,
(d) phenyl,
(e) -CFg,
(f) -OCFg,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents
selected from:
(i) halogen selected from -F, -Cl, -Br,
(ii) -CH3,
(iii) -CF3, and
(iv) hydroxy;
(3) thienyl,
(5) pyridyl,
(7) imidazolyl,
(8) pyrrolyl,
(9) pyrazolyl,
(10) C~s cycloalkyl,
(12) piperidinyl,
(14) morpholinyl,
(15) naphthyl,
(16) indolyl, and
(17) C~ cycloalkyl fused with a phenyl ring.
In one class of compounds of the present invention,
R4 is
selected from:
-31-

CA 02333771 2000-11-30
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(1) -H,
(2) -C1_3 alkyl,
{3) -CF3,
{4) -R3
,
(5) -C2_3 alkenyl,
(6) -C1_g alkyl-R3,
(7) -C2~ alkenyl-R3,
(8) -S(O)ri R3, and
(9) -C(O)-R3.
In another class of compounds of the present
invention, R4
is selectedfrom:
(1) -H,
(2) -C1~ alkyl,
(3) -CF3,
(4) -R3,
(5 ) -C2_3 alkenyl,
(6) -C1_3 alkyl-R3, and
(7) -S(O)ri R3.
In one class of compounds of the present invention,
R5 is
selected
from:
(1) -H,
(2) -C1_3 alkyl,
(3) -CFg,
-R3
~
(5) -C2_g alkenyl,
{6) -C1~ alkyl-R3,
(7) -C2~ alkenyl-R3,
(8) -S(0)n R3, and
(9) -C(0)-R3.
In another class of compounds of the present
invention, R5
is selectedfrom:
-32-

CA 02333771 2000-11-30
WO 99/62897 PCT/US99/12094
(1) -H,
(2) -C1_3 alkyl,
(3) -CF3,
-R3
(5) -C2_3 alkenyl,
(6) -C1~ alkyl-R3,
(7) -CZ_3 alkenyl-R3, and
(8) -S(O)ri R3.
In one class of compounds of the present invention, R7 is
hydrogen.
In one class of compounds of the present invention, R8 is
selected from: hydrogen, methyl and methoxy.
Also included within the present invention are
pharmaceutical compositions useful for inhibiting HIV integrase,
comprising an effective amount of a compound of this invention, and a
pharmaceutically acceptable carrier. Pharmaceutical compositions
useful for treating infection by HIV, or for treating AIDS or ARC, are
also encompassed by the present invention, as well as a method of
inhibiting HIV integrase, and a method of treating infection by HIV, or
of treating AIDS or ARC. Additionally, the present invention is directed
to a pharmaceutical composition comprising a therapeutically effective
amount of a compound of the present invention in combination with a
therapeutically effective amount of an AIDS treatment agent selected
from:
(1) an AIDS antiviral agent,
(2) an anti-infective agent, and
(3) an immunomodulator.
The compounds of the present invention may have
asymmetric centers and may occur, except when specifically noted, as
mixtures of stereoisomers or as individual diastereomers, or
enantiomers, with all isomeric forms being included in the present
invention.
-33-

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As is recognized by one of ordinary skill in the art, the
diketo-acid/ester compounds of the present invention exist as tautomers,
and thus by using the phrase "and tautomers thereof' in describing
compounds of structural formula (I), Applicants also intend the
following tautomeric forms of the same compound (Ia) and (Ib):
z-L. 1R 1 O z~R 1 O
R A ORS R ' A \ ORS
R8 O O Rs O OH
(I) (la)
R~
~ O
Rz
~~~OR~
R$ 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),
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, R4, etc.) occurs more than one
time in any constituent or in formula I, its definition on each occurrence
is independent of its definition at every other occurrence. Also,
combinations of substituents and/or variables are permissible only if
such combinations result in stable compounds.
The compounds of the present inventions are useful in the
inhibition of HIV integrase, the prevention or treatment of infection by
human immunodeficiency virus (HIV) and the treatment of consequent
pathological conditions such as AIDS. Treating AIDS or preventing or
treating infection by HIV is defined as including, but not limited to,
treating a wide range of states of HIV infection: AIDS, ARC (AIDS

CA 02333771 2000-11-30
WO 99/62897 PCT/US99/12094
related complex), both symptomatic and asymptomatic, and actual or
potential exposure to HIV. For example, the compounds of this
invention are useful in treating infection by H1V after suspected past
exposure to HIV by e.g., blood transfusion, exchange of body fluids, bites,
accidental needle stick, or exposure to patient blood during surgery.
The compounds of this invention are useful in the
preparation and execution of screening assays for antiviral
compounds. For example, the compounds of this invention are
useful for isolating enzyme mutants, which are excellent screening
tools for more powerful antiviral compounds. Furthermore, the
compounds of this invention are useful in establishing or
determining the binding site of other antivirals to HIV integrase,
e.g., by competitive inhibition. Thus the compounds of this invention
are commercial products to be sold for these purposes.
The present invention also provides for the use of a
compound of structural formula (I) to make a pharmaceutical
composition useful for inhibiting HIV integrase and in the treatment of
AIDS or ARC.
Compounds of structural formula (I) wherein A is thienyl
may be made according to the procedures in Schemes AI, AII, 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.
O
~S
OEt
O O
AI(3)
-35-

CA 02333771 2000-11-30
WO 99/62897 PCT/US99/12094
i. NaOH, MeOH-H20-THF
ii.HCl
O
~S
OH
O O
AI (4)
Scheme All
s
O AII(1)
X - CH , N X OH
R - H, F, F2 ~ \
NaH , DMSO
R
~ I
s
R O
AII(2a-e)
- 36 -

CA 02333771 2000-11-30
WO 99/62897 PCT/US99/12094
O
Et0 OEt NaOEt , THF
O
X O ~ ~ O
O Et
R
O O
AII(3a-e)
i. NaOH; MeOH-H20-THF
ii.HCl
X O ~ ( O
OH
R
O O
AII(4a-e)
-37-

CA 02333771 2000-11-30
WO 99/62897 PCT/US99/12094
Scheme BI
Br
Br
BI(1)
O
n-BuLi, Et20,
R~~H
HO
S~ Br
R
BI ( 2a--d)
BF3 . Et20, Et3SiH, CH2C1~
-38-

CA 02333771 2000-11-30
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S Br
R~
BI(3a-d)
n-BuLi , Et20, CH3CONCH3 ( OCH3 )
S
R% / O
BI ( 4a-d)
O
Et0 OEt LDA, THF
O
- 39 -

CA 02333771 2000-11-30
WO 99/62897 PCT/US99/12094
O
S OEt
j~ O O
BI ( 5<~-d)
i. NaOH, MeOH-H20-THF
ii.HCl
O
S OH
O O
BI(6a-d)
Scheme BII
Br
S
O BII(1)
~~ SNa acetone
R~
-40-

CA 02333771 2000-11-30
WO 99/62897 PCT/US99/I2094
S
0
BII(2)
Et0 OEt NaOEt , THF
O
s / l o
OEt
O O
BII(:3)
i . NaOH, MeOH-H20-THF
ii.HCl
/~ O
s OH
j ~ O O
BI I ( 4 )
-41-

CA 02333771 2000-11-30
WO 99/62897 PCT/US99/12094
Scheme CI
S
Br
Br
CI (1)
O
n-BuLi, Et20,
R~~H
HO S
- -Br
R~
CI (2a-d)
BF3 . Et20, Et3SiH (xs ) , CH2C12
-42-

CA 02333771 2000-11-30
WO 99/62897 PCT/US99/12094
S
Br
R~
CI (3a-d)
n-BuLi , Et20, CH3CONCH3 ( OCH3 )
S
O
R
CI(4a-d)
-43-

CA 02333771 2000-11-30
WO 99/62897 PCT/US99/12094
Scheme CI (continue)
S
j / O
R
CI ( 4a-d)
O
Et0 OEt LDA, THF
O
S O
- ~ ~ -oEt
R~~ / O O
CI(5a-d)
i. NaOH, MeOH-H20-THF
ii.HCl
S O
- ~ ~ ~OH
R j~ O O
CI ( 6a-d)

CA 02333771 2000-11-30
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Scheme CII
S
Br
Br
CI(1)
n-BuLi, Et20, ~~ S-S ~
R
S
S
Br CII(1)
R
n-BuLi, Et20, CH3CONCH3 (OCH3)
S
S ~
O CII(2)
R
O
Et0 LDA, THF
OEt
O
-45-

CA 02333771 2000-11-30
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S O
OEt CII(3)
O O
i. NaOH, MeOH-H20-THF
ii.HCl
S O
S
OH
O O CII (4)
Scheme DI
w
S
Br
gr DI(1) _
\ O
n-BuLi, Et20, R/~H
-46-

CA 02333771 2000-11-30
WO 99/62897 PCT/US99/12094
S
i
Br
R~~ ~O H
DI(2a-c)
BF3 . Et20, Et3SiH, CH2C1~
S
Br
R/'
DI(3a-c)
n-BuLi, Et20, CH3CONCH3 ( OCH3 )
S
O
R
DI ( 4a-c )
-47-

CA 02333771 2000-11-30
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Scheme DI (continue)
S
O
R
DI:(4a-c)
O
Et0 LDA, THF
OEt
O
S ~ O
-OEt
O O
R
DI(5a-c)
i. NaOH, MeOH-H20-THF
ii.HCl
S ~ O
O ~ OH
r
R
DI(6a-c)
-48-

CA 02333771 2000-11-30
WO 99/62897 PCTNS99/12094
Scheme EI
Br
Br
BI(1)
O
n-BuLi, Et20, ~ ~C
R /'_' H
HO
S~ Br
BI (2d)
NaH, DMSO, RX
-49-

CA 02333771 2000-11-30
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RO
R - Bn, Ph, Me
S~ Br
EI(1a-c)
n-BuLi , Et20, CH3CONC
RO
S
\ / O
EI (2a-c)
-50-

CA 02333771 2000-11-30
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Scheme EI (continue)
RO
S
\ / O
EI ( 3a-c )
O
Et0 OEt LDA, THF
O
RO ~ O
~~~OEt
\ / O O
EI(4a-c)
i. NaOH, MeOH-H20-THF
ii.HCl
RO / O
OH
\ / O O
EI(5a-c)
-51-

CA 02333771 2000-11-30
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Scheme FI
OzN ~ ~ F I ( 1 )
S
O
i. H2, Pt2S/C, MeOH
ii.HCl
HCLH2N
S FI(2~
O
RX, iPr2NEt, MeCN or
RX, Cs2C03 , DMF
-52-

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R'= H, R
R - Bn, n-Pr, allyl, Me
R
R,' S FI (3a-e)
O
O
Et0
OEt NaOEt, THF
O
R ~ O
N I
R' S OEt FI ( 4a-a )
O O
i. NaOH, MeOH-H20-THF
ii.HCl
O
N
R' S OH FI(5a-e)
O O
-53-

CA 02333771 2000-11-30
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Scheme FII
C~ / I AI I ( 1 )
S
O
R
'NH Cs2C03. DMF
R'
R
,N /
R'~ S FII ( 1a-b)
O
-54-

CA 02333771 2000-11-30
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O
Et0
OEt NaOEt, THF
O
R / O
N
R' S OEt FII (2a-b)
O O
i. NaOH, MeGH-H20-THF
ii.HCl
R, / O
N I
R' S OH FII ( 3a-b)
O O
Scheme FIII
HCLH2N / I
S FI ( 2 )
O
RS02C1, pyridine
- 55 -

CA 02333771 2000-11-30
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RS02HN
S FIII(1)
O
NaHMDS, DMSO, R~X
RS02R'N
S FIII(2)
O
O
Et0
OEt NaOEt, THF
O
RS02R'N ~ ~ O
S ~~~OEt FI I I ( 3 )
O O
i. NaOH, MeOH-H20-THF
ii.HCl
RS02R'N ~ ~ O
S OH FIII(4)
O O
-56-

CA 02333771 2000-11-30
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Scheme GI
R
'N-H
,
R'
R - Bn, R' - Bn i. S=C =N ,hexane
R - Bn, R' - H
R - Bn, R' - CH3 ii. c. HC1
R, NHZ
N~ GI(1a-c)
R' ~ S
CH30, CH3
~.- N
CH30 CH3
R, N~N(CH3)2
N
R'~ S GI ( 2a-c )
Br~
IIO
R N
GI(3a-c)
R' S
O
-57-

CA 02333771 2000-11-30
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O
Et0
OEt NaOEt, THF
O
R N O
N
-< I
R'~ S OEt GI ( 4a-c )
O O
i. NaOH, MeOH-H20-THF
ii.HCl
R N O
N-~~ I
R' S OH GI(5a-c)
O O
Scheme GII
R
~N- H
R'
i . S=C =N , hexane
ii. c. HCl
-58-

CA 02333771 2000-11-30
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R S
GI (1)
R' N H2
Br
O
O
R S
I
R' N G I I ( 3 )
O
O
Et0
OEt NaOEt, THF
O
R S O
N-~~ I
R N OEt GII ( 4 )
O O
i . NaOH, MeOH-H20-THF
ii.HCl
-59-

CA 02333771 2000-11-30
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R S O
N-<v
R'~ N OH GI I ( S )
O O
The compounds of the present invention may be
administered in the form of pharmaceutically acceptable salts. The
term "pharmaceutically acceptable salt" is intended to include all
acceptable salts such as acetate, lactobionate, benzenesulfonate, laurate,
benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate,
mesylate, borate, methylbromide, bromide, methylnitrate, calcium
edetate, methylsulfate, camsylate, mutate, carbonate, napsylate,
chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium
salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate
(embonate), estolate, palmitate, esylate, pantothenate, fumarate,
phosphate/diphosphate, gluceptate, polygalacturonate, gluconate,
salicylate, glutamate, stearate, glycollylarsanilate, sulfate,
hexylresorcinate, subacetate, hydrabamine, succinate, hydrobromide,
tannate, hydrochloride, tartrate, hydroxynaphthoate, teoclate, iodide,
tosylate, isothionate, triethiodide, lactate, panoate, valerate, and the like
which can be used as a dosage form for modifying the solubility or
hydrolysis characteristics or can be used in sustained release or pro-
drug formulations. Depending on the particular functionality of the
compound of the present invention, pharmaceutically acceptable salts of
the compounds of this invention include those formed from cations such
as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc,
and from bases such as ammonia, ethylenediamine, N-methyl-
glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylene-
diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethyl-
amine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane,
and tetramethylammonium hydroxide. These salts may be prepared by
standard procedures, e.g. by reacting a free acid with a suitable organic
or inorganic base. Where a basic group is present, such as amino, an
acidic salt, i.e. hydrochloride, hydrobromide, acetate, pamoate, and the
like, can be used as the dosage form.
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Also, in the case of an acid (-COOH) or alcohol group being
present, pharmaceutically acceptable esters can be employed, e.g.
acetate, maleate, pivaloyloxymethyl, and the like, and those esters
known in the art for modifying solubility or hydrolysis characteristics for
use as sustained release or prodrug formulations.
For these purposes, the compounds of the present invention
may be administered orally, parenterally (including subcutaneous
injections, intravenous, intramuscular, intrasternal injection or
infusion techniques), by inhalation spray, or rectally, in dosage unit
formulations containing conventional non-toxic pharmaceutically-
acceptable carriers, adjuvants and vehicles.
The terms "administration of and or "administering a"
compound should be understood to mean providing a compound of the
invention or a prodrug of a compound of the invention to the individual
in need of treatment.
Thus, in accordance with the present invention there is
further provided a method of treating and a pharmaceutical composition
for treating HIV infection and AIDS. The treatment involves
administering to a patient in need of such treatment a pharmaceutical
composition comprising a pharmaceutical carrier and a
therapeutically-effective amount of a compound of the present invention.
As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly or
indirectly, from combination of the specified ingredients in the specified
amounts.
By "pharmaceutically acceptable" it is meant the carrier,
diluent or excipient must be compatible with the other ingredients of the
formulation and not deleterious to the recipient thereof.
These pharmaceutical compositions may be in the form of
orally-administrable suspensions or tablets, nasal sprays, sterile
injectible preparations, for example, as sterile injectible aqueous or
oleagenous suspensions or suppositories.
When administered orally as a suspension, these
compositions are prepared according to techniques well-known in the
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art of pharmaceutical formulation and may contain microcrystalline
cellulose for imparting bulk, alginic acid or sodium alginate as a
suspending agent, methylcellulose as a viscosity enhancer, and
sweeteners/flavoring agents known in the art. As immediate release
tablets, these compositions may contain microcrystalline cellulose,
dicalcium phosphate, starch, magnesium stearate and lactose and/or
other excipients, binders, extenders, disintegrants, diluents and
lubricants known in the art.
When administered by nasal aerosol or inhalation, these
compositions are prepared according to techniques well-known in the
art of pharmaceutical formulation and may be prepared as solutions in
saline, employing benzyl alcohol or other suitable preservatives,
absorption promoters to enhance bioavailability, fluorocarbons, and/or
other solubilizing or dispersing agents known in the art.
The injectible solutions or suspensions may be formulated
according to known art, using suitable non-toxic, parenterally-
acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water,
Ringer's solution or isotonic sodium chloride solution, or suitable
dispersing or wetting and suspending agents, such as sterile, bland,
fixed oils, including synthetic mono- or diglycerides, and fatty acids,
including oleic acid.
When rectally administered in the form of suppositories,
these compositions may be prepared by mixing the drug with a suitable
non-irritating excipient, such as cocoa butter, synthetic glyceride esters
of polyethylene glycols, which are solid at ordinary temperatures, but
liquefy and/or dissolve in the rectal cavity to release the drug.
The compounds of this invention can be administered orally
to humans in a dosage range of 1 to 1000 mg/kg body weight in divided
doses. One preferred dosage range is 0.1 to 200 mg/kg body weight orally
in divided doses. Another preferred dosage range is 0.5 to 100 mg/kg
body weight orally in divided doses. For oral administration, the
compositions are preferably provided in the form of tablets containing 1.0
to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0,
15Ø 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0,
600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient
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for the symptomatic adjustment of the dosage to the patient to be' treated.
It will be understood, however, that the specific dose level and frequency
of dosage for any particular patient may be varied and will depend upon
a variety of factors including the activity of the specific compound
employed, the metabolic stability and length of action of that compound,
the age, body weight, general health, sex, diet, mode and time of
administration, rate of excretion, drug combination, the severity of the
particular condition, and the host undergoing therapy.
The present invention is also directed to combinations of the
HIV integrase inhibitor compounds with one or more agents useful in
the treatment of AIDS. For example, the compounds of this invention
may be effectively administered, whether at periods of pre-exposure
and/or post-exposure, in combination with effective amounts of the AIDS
antivirals, imunomodulators, antiinfectives, or vaccines, such as those
in the following table.
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ANTIVIRALS
Drug Name Manufacturer Indication
Q97 HoechstJBayer 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 dipivoxilGilead 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/R,etrovir

CA 02333771 2000-11-30
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Ansamycin Adria Laboratories ARC
LM 427 (Dublin, OH)
Erbamont
(Stamford, CT)
Antibody which Advanced BiotherapyAIDS, ARC
neutralizes pH Concepts
labile alpha aberrant (Rockville, MD)
Interferon
AR177 Aronex Pharm HIV infection, AIDS,
ARC
beta-fluoro-ddA Nat'1 Cancer InstituteAIDS-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 immuneMedImmune CMV retinitis
globin
Cytovene Syntex sight threatening
Ganciclovir CMV
peripheral CMV
retiniti s
Delaviridine Pharmacia-Upjohn HIV infection,
AIDS, ARC
(RT inhibitor)
Dextran Sulfate Ueno Fine Chem. AIDS, ARC, HIV
Ind. Ltd. (Osaka, positive asymptomatic
Japan)
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ddC Hoffman-La Roche HIV infection, AIDS,
Dideoxycytidine ARC
ddI Bristol-Myers SquibbHIV 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 HIV infection
(Gainesville, GA)
Famciclovir Smith HIine herpes zoster,
herpes simplex
FTC Emory University HIV infection,
AIDS, ARC
(reverse transcriptase
inhibitor)
GS 840 Gilead HIV infection,
AIDS, ARC
(reverse transcriptase
inhibitor)
HBY097 Hoechst Marion HIV infection,
Roussel AIDS, ARC
(non-nucleoside
reverse transcriptase
inhibitor)
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Hypericin VIMRx 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
HIV positive, also
in
combination with
AZT/ddI/ddC
ISIS 2922 ISIS Pharmaceuticals CMV retinitis
KNI-272 Nat'1 Cancer InstituteHIV-assoc.
diseases
Lamivudine, 3TC Glaxo Wellcome HIV infection,
AIDS, ARC
(reverse
transcriptase
inhibitor); also
with
AZT
Lobucavir Bristol-Myers Squibb CMV infection
Nelfinavir Agouron HIV infection,
Pharmaceuticals AIDS, ARC
(protease inhibitor)
Nevirapine Boeheringer HIV 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
Phosphonoformate Products, Inc infection, other
CMV
infections
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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-I01 Wyeth-Ayerst AID S
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Bropirimine Pharmacia Upjohn advanced AIDS
Acemannan Carrington Labs, AIDS, ARC
Inc.
(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 ColonySandoz
Stimulating
Factor
Granulocyte Hoeschst-Roussel AIDS
Macrophage ColonyImmunex
Stimulating
Factor
Granulocyte Schering-Plough AIDS, combination
Macrophage Colony w/AZT
Stimulating Factor
HIV Core ParticleRorer 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)
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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
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Thymopentin Immunobiology HIV infection
Research Institute
(Annandale, NJ)
Tumor Necrosis Genentech ARC, in combination
Factor; TNF w/gamma Interferon
ANTI-INFECTIVES
Drub Name Manufacturer Indication
Clindamycin withPharmacia 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 (Rosemont, IL)
& IV)
Trimethoprim antibacterial
Trimethoprim/sulfa antibacterial
Piritrexim Burroughs WellcomePCP treatment
Pentamidine Fisons CorporationPCP prophylaxis
isethionate for
inhalation
Spiramycin Rhone-Poulenc cryptosporidial
diarrhea
Intraconazole- Janssen Pharm. histoplasmosis;
851211 cryptococcal
meningitis
Trimetrexate Warner-Lambert PCP
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OTHER
Drug Name Manufacturer Indication
Daunorubicin NeXstar, Sequus Karposi's sarcoma
Recombinant Human Ortho Pharm. Corp.severe anemia
Erythropoietin assoc. with AZT
therapy
Recombinant Human Serono AIDS-related wasting,
Growth Hormone cachexia
Megestrol Acetate Bristol-Myers Squibbtreatment of
anorexia assoc.
w/AIDS
Testosterone Alza, Smith Kline AIDS-related wasting
Total Enteral Norwich Eaton diarrhea and
Nutrition Pharmaceuticals malabsorption
related to AIDS
It will be understood that the scope of combinations of the
compounds of this invention with AIDS antivirals, immunomodulators,
anti-infectives or vaccines is not limited to the list in the above Table, but
includes in principle any combination with any pharmaceutical
composition useful for the treatment of AIDS.
Preferred combinations are simultaneous or alternating
treatments of with a compound of the present invention and an inhibitor
of HIV protease and/or a non-nucleoside inhibitor of HIV reverse
transcriptase. An optional fourth component in the combination is a
nucleoside inhibitor of HIV reverse transcriptase, such as AZT, 3TC,
ddC or ddI. A preferred inhibitor of HIV protease is indinavir, which 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. Indinavir is generally administered at a dosage of 800
mg three times a day. Other preferred protease inhibitors are nelfinavir
and ritonavir. Another preferred inhibitor of HIV protease is saquinavir
which is administered in a dosage of 600 or 1200 mg tid. Preferred non-
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nucleoside inhibitors of HIV reverse transcriptase include efavirenz.
The preparation of ddC, ddI and AZT are also described in EPO
0,484,071. These combinations may have unexpected effects on limiting
the spread and degree of infection of HIV. Preferred combinations
include those with the following (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
Iamivudine.
In such combinations the compound of the present
invention and other active agents may be administered separately or in
conjunction. In addition, the administration of one element may be
prior to, concurrent to, or subsequent to the administration of other
agent(s).
It will be understood that the scope of combinations of the
compounds of this invention with AIDS antivirals, immunomodulators,
anti-infectives or vaccines is not limited to the list in the above Table, but
includes in principle any combination with any pharmaceutical
composition useful for the treatment of AIDS.
Indinavir is an inhibitor of HIV protease and is the sulfate
salt of N-(2(R)-hydroxy-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.
The following examples are provided to further illustrate
details for the perparation and use of the compounds of the present
invention. The examples are not intended to be limitations on the scope
of the instant invention in any way, and they should not be so construed.
Furthermore, the compounds described in the following examples are
not to be construed as forming the only genus that is considered as the
invention, and any combination of the ocmpounds or their moieties may
itself form a genus. Those skilled in the art will readily understand that
known variatioons of the conditions and processes of the following
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preparative procedures can be used to prepare these compounds. All
temperatures are in degrees Celsius unless noted otherwise.
Abbreviations: aq is aqueous; Ac represents acetyl; ACN is
acetonitrile; Bn represents benzyl; DMF is dimethyl formamide; DMSO
is dimethyl sulfoxide; Et represents ethyl; IPA is isopropyl alcohol; Me
represents methyl; NaHMDS represents sodium hexamethyl disilamide;
rt, RT both represent room temperature; sat represents saturated; THF
is tetrahydrofuran; TLC is thin layer (Si02) chromatography.
EXAMPLE 1
2,4-dioxo-4-(5-phenethylthiophen-2-yl)butanoic acid
Step A: Preparation of ethyl 2,4-dioxo-4-(5-phenethynylthiophen-2-
yl)butanoate AI(2)
O
OEt
O O
A mixture of 2-acetyl-5-(phenylethynyl)thiophene (1.81 g, 8.02 mmol),
diethyl oxalate (2.17 mL, 16 mmol}, and sodium ethoxide (1.09 g, 16
mmol) in anhydrous THF (25 mL) was stirred at rt under an atmosphere
of argon for 5 hr. The resultant mixture was diluted with
dichloromethane, and washed successively with dilute HCl, and brine.
The organic extract was dried over anhydrous magnesium sulfate,
filtered, and concentrated under vacuum to provide yellow solid.
Recrystallization of the solid from a mixture dichloromethane and
hexane provided the title compound.
Step B: Preparation of ethyl 2,4-dioxo-4-(5-phenethylthiophen-2-
yl)butanoate AI(3)
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O
OEt
O O
A mixture of ethyl 2,4-dioxo-4-(5-phenethynylthiophen-2-yl)butanoate
(195 mg, 0.597 mmol), 10% Pd/C (95 mg), and THF (5 mL) in absolute
ethanol (40 mL) was stirred under a balloon of hydrogen for 2 h. The
resulting mixture was filtered through a pad of CeliteTM, diatomaceous
earth. The filtrate was concentrated under vacuum to provide the title
compound.
Step C: Preparation of 2,4-dioxo-4-(5-phenethylthiophen-2-
yl)butanoic acid AI(4)
O
OH
O O
A solution of ethyl 2,4-dioxo-4-(5-phenethylthiophen-2-yl)butanoate ( 125
mg, 0.378 mmol), aqueous sodium hydroxide (1.2 mL, 1M, 1.2 mmol),
and THF (5 mL) in methanol (5 mL) was stirred at rt overnight. The
resultant mixture was treated with aq 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
o~=white solid. Recrystallization of the solid from a mixture
dichloromethane and hexane provided the title compound. 1H NMR
(CDC13) 8 7.72 (d, J =3.1 Hz, 1H), 7.35-?.15 (m, 5H), 6.94 (s, 1H), 6.86 (d, J
=3.1 Hz, 1H), 3.22 (d, J =8.1 Hz, 2H), 3.03 (d, J =8.1 Hz, 2H).
EXAMPLE 2
2,4-dioxo-4-(5-benzyloxythiophen-2-yl)butanoic acid
Step A: Preparation of 2-acetyl-5-(benzyloxy)thiophene AII(2a)
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/ \
0
A suspension of sodium hydride (538 mg, 22.4 mmol) in anhydrous
DMSO (30 mL) was stirred at 60 °C under an atmosphere of argon for
1
hr. The resultant mixture was cooled to rt, benzyl alcohol (2.32 mL,
22.40 mmol) and 2-acetyl-5-chlorothiophene (3.01 g, 18.74 mmol) was
added. The mixture was heated under an atmosphere of argon at 85 °C
overnight. The product mixture was concentrated under vacuum, and
the residue partitioned between ethyl acetate and dilute aqueous HCl.
The organic extract was washed with brine, dried over anhydrous
magnesium sulfate, filtered and concentrated under vacuum. The
residue was subjected to column chromatography on silica gel eluting
with 3% methanol in chloroform. Collection and concentration of
appropriate fractions provided the title ketone.
Step B: Preparation of 2,4-dioxo-4-(5-benzyloxythiophen-2-
yl)butanoic acid AII(4a)
O / ~ O
/ ~ S OH
O 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-acetyl-5-(benzyloxy)thiophene in Step A. 1H NMR
(CDC13) S 7.75 (d, J =4.6 Hz, 1H), 7.5-7.3 (m, 5H), 6.85 (s, 1H), 6.42 (d, J
=4.6 Hz, 1H), 5.21 (s, 2H).
EXAMPLE 3
2,4-dioxo-4-[5-(3-fluorobenzyloxy)thiophen-2-yl]butanoic acid
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o / ~ O
/ ~ s off
0 0
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-
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
o / ~ o
F / \ S OH
O O
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) b 8.0 (br s 1H), 7.54
(m, 2H), 7.25 (m, 2H), 6.85 (brs, 1H), 6.6 (br s, 1.H), 5.3 (br s, 2H}.
EXAMPLE 5
2,4-dioxo-4-[5-(3,4-difluorobenzyloxy)thiophen-2-yl]butanoic acid
o / I o
F / \ S OH
O O
F
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) 8 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).
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EXAMPLE 6
2,4-dioxo-4-[5-(pyridin-2-ylmethyloxy)thiophen-2-yl]butanoic acid
O
N O
OH
O O
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-dg) 8 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
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
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
F
To a cold (-78 °C) solution of n-butyl lithium (20.8 mL, 2.5 M in
hexane, 52
mmol) in anhydrous diethyl ether ( 100 mL) under an atmosphere of
argon, 2,5-dibromothiophene (5.63 mL, 50 mmol) was added dropwise
over a period of 30 min. After the reaction mixture was stirred at -78
°C
for an additional 90 min, 3-fluorobenzaldehyde (5.5 mL, 52 mmol) was
added over a period of 15 min. The resultant mixture was allowed to
warm to rt over a period of 2.5 h. The resultant solution was diluted with
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dichloromethane, and neutralized with dilute HCl. The organic extract
was washed with brine, dried over anhydrous magnesium sulfate,
filtered, and concentrated under vacuum to provide the title compound
as brown oil. The oil was used in the following step without further
purification.
Step B: Preparation of 2-bromo-5-(3-fluorobenzyl)thiophene BI(3a)
Br
F \ /
To a cold (0 °C) solution of (5-bromothiophen-2-yl)-(3-
fluorophenyl)-
methanol (4.35 g, 15.2 mmol) and triethylsilane (3.60 mL, 22.7 mmol) in
dichloromethane (30 mL), boron trifluoride etherate (2.90 mL, 22.9
mmol) was added. The resultant mixture was stirred at rt for 3 h, and
treated with sat. aq. sodium bicarbonate. The organic extract was
washed with brine, dried over anhydrous ma~,mesium sulfate, filtered,
and concentrated under vacuum. The residue was subjected to column
chromatography on silica gel eluting with hexane. Collection and
concentration of appropriate fractions provide the title compound as
clear colorless oil. The product was stored under argon in a freezer.
Step C: Preparation of 2-acetyl-5-(3-fluorobenzyl)thiophene BI(4a)
S
F \ / o
To a cold (-78 °C) solution of 2-bromo-5-(3-fluorobenzyl)thiophene
(2.0 g,
7.38 mmol) in anhydrous diethyl ether (20 mL) under an atmosphere of
argon, n-butyl lithium (4.8 mL, 1.6 M in hexane, 7.68 mmol) was added
dropwise over a period of 15 min. After the reaction mixture was stirred
at -78 °C for an additional 1 h, N-methoxy-N-methylacetamide (0.91 mL,
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8.86 mmol) was added over a period of 10 min. The resultant mixture
was allowed to warm to rt and stirred overnight. The resultant solution
was diluted with ether, and neutralized with dilute HCl. The organic
extract was washed with brine, dried over anhydrous magnesium
sulfate, filtered, and concentrated under vacuum. The residue was
subjected to column chromatography on silica gel eluting with 20% ethyl
acetate in hexane. Collection and concentration of appropriate fractions
provide the title compound as clear pale yellow oil.
Step D: Preparation of ethyl 2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-
2-yl]butanoate BI(5a)
O
OEt
O O
To a cold (-78 °C} solution of 2-acetyl-5-(3-fluorobenzyl)thiophene
(315 mg,
1.34 mmol) in anhydrous THF (5 mL) under an atmosphere of argon,
LDA (0.7 mL, 2 M in a mixture of heptane, THF and ethylbenzene, 1.40
mmol) was added dropwise over a period of 10 min. After the reaction
mixture was stirred at -78 °C for an additional 40 min, diethyl oxalate
(0.26 mL, 1.91 mmol) was added over a period of 5 min. The resultant
mixture was allowed to warm to rt and stirred overnight. The resultant
solution was diluted with ethyl acetate, and neutralized with dilute HCl.
The organic extract was washed with brine, dried over anhydrous
magnesium sulfate, filtered, and concentrated under vacuum. The
residue was triturated with hexane. The precipitate was filtered to
provide the title compound as yellow solid.
Step E: Preparation of 2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-2-
yl]butanoic acid BI(6a)
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0
OH
F \ / O O
The title compound was prepared using the protocol described in
Example AI(4), Step C substituting ethyl 2,4-dioxo-4-(5-
phenethylthiophen-2-yl)butanoate with ethyl 2,4-dioxo-4-[5-(3-
fluorobenzyl)thiophen-2-yl]butanoate. The product was recrystallized
from a mixture of ether and hexane. 1H NMR (CDC13) b 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
2,4-dioxo-4-[5-(4-fluorobenzyl)thiophen-2-yl]butanoic acid
O
OH
O O
F
The title compound was prepared using the protocol described in
Example BI(6a), Step A - E substituting 3-fluorobenzaldehyde with 4-
fluoro-benzaldehyde in Step A. 1H NMR (CDC13) 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
2,4-dioxo-4-[5-(3-chlorobenzyl)thiophen-2-yl]butanoic acid
O
OH
CI \ ~ O O
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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 (CDC13) 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).
EXAMPLE 10
2,4-dioxo-4-(5-benzylthiophen-2-yl)butanoic acid
O
OH
O O
The title compound was prepared using the protocol described in
Example BI(6a), Step A - E substituting 3-fluorobenzaldehyde with
benzaldehyde in Step A. 1H NMR (CDC13) 8 7.74 (d, J =3.9 Hz, 1H), 7.38-
7.22 (m, 5H), 6.91 (m, 2H), 4.21 (s, 2H).
EXAMPLE 11
2,4-dioxo-4-(5-phenylsulfanylthiophen-2-yl)butanoic acid
Step A: Preparation of 2-acetyl-5-phenylsufanylthiophene BII(2)
S ~
S
O
A mixture of thiophenol, sodium salt (718 mg, 5,43 mmol) and 2-acetyl-5-
bromothiophene (1.0 g, 4.88 mmol) in acetone (10 mL) was stirred at rt
under an atmosphere of argon overnight. The resultant mixture was
concentrated under vacuum. The residue was subjected to column
chromatography on silica gel eluting with chloroform. Collection and
concentration of appropriate fractions provided the title ketone.
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Step B: Preparation of 2,4-dioxo-4-(5-phenylsulfanylthiophen-2-
yl)butanoic acid BII(4)
s / I o
S OH
O 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-acetyl-5-phenylsufanylthiophene in Step A. The
product was recrystallized from a mixture of ether and hexane. 1H
NMR (CDC13) 8 7.73 (d, J =4.0 Hz, 1H), 7.48 (m, 2H), 7.38 (m, 3H), 7.08 (d,
J =4.0 Hz, 1H), 6.88 (s, 1H).
EXAMPLE 12
2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-3-yl]butanoic acid
S O
~OH
F ~ O O
\
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
Example BI(6a), Step A substituting 2,5-dibromothiophene with 2,4-
dibromothiophene.
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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
dichloromethane (60 mL), boron trifluoride etherate (2.49 mL, 19.8
mmol) was added. The resultant mixture was stirred at rt for 2 h, and
treated with sat. aq. sodium bicarbonate. The organic extract was
washed with brine, dried over anhydrous magnesium sulfate, filtered,
and concentrated under vacuum. The residue was subjected to column
chromatography on silica gel eluting with hexane. Collection and
concentration of appropriate fractions provide the title compound as
clear colorless oil. The product was stored under argon in a freezer.
Step C: Preparation of 2,4-dioxo-4-[5-(3-fluorobenzyl)thiophen-3-
yl]butanoic acid CI(6a)
S O
~' ~ -OH
F ~ ~ O O
The title compound was prepared using the protocol described in
Example BI(6a), Step C - E substituting 2-bromo-5-(3-fluorobenzyl)-
thiophene with 4-bromo-2-(3-fluorobenzyl)thiophene in Step C. 1H NMR
(CDC13) b 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
2,4-dioxo-4-[5-(4-fluorobenzyl)thiophen-3-yl]butanoic acid
_ g4 _

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OH
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 (CDC13) 8 8.07 (d, J =1.5 Hz,
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 O
~OH
CI ~ Q O
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 (CDC13) 8 8.09 (br s, 1H), 7.28-
7.22 (m, 4H), 7.14 (m, 1H), 6.90 (s, 1H), 4.13 (s, 2H).
EXAMPLE 15
2,4-dioxo-4-(5-benzylthiophen-3-yl)butanoic acid
S O
~oH
/ 0 0
The title compound was prepared using the protocol described in
Example CI(6a), Step A - C substituting 3-fluorobenzaldehyde with
85 _

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benzaldehyde in Step A. 1H NMR (CDC13) 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
2,4-dioxo-4-(2-phenylsulfanylthiophen-4-yl)butanoic acid
Step A: Preparation of 2-phenylsulfanyl-4-bromothiophene CII(1)
S
S
Br
To a cold (-78 °C) solution of n-butyl lithium (10.4 mL, 2.5 M in
hexane, 26
mmol) in anhydrous diethyl ether (100 mL) under an atmosphere of
argon, 2,4-dibromothiophene (2.81 mL, 25 mmol) was added dropwise
over a period of 15 min. After the reaction mixture was stirred at -78
°C
for an additional 15 min, a solution of diphenyl disulfide (5.68 g, 52
mmol) in ether (50 mL) was added over a period of I5 min. The resultant
mixture was allowed to warm to rt and stirred at rt overnight. The
resultant solution was diluted with ether, and washed successively with
aq. NaOH, and brine. The organic extract was dried over anhydrous
magnesium sulfate, filtered, and concentrated under vacuum. The
residue was subjected to column chromatography on silica gel eluting
with hexane. Collection and concentration of appropriate fractions
provided the title compound.
Step B: Preparation of 4-acetyl-2-phenylsulfanylthiophene CII(2)
S
O
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To a cold (-78 °C) solution of 2-phenylsulfanyl-4-bromothiophene
(2.28 g,
8.4 mmol) in anhydrous diethyl ether (20 mL) under an atmosphere of
argon, n-butyl lithium (5.78 mL, 1.6 M in hexane, 9.25 mmol) was added
dropwise over a period of 5 min. After the reaction mixture was stirred
at -78 °C for an additional 1 h, N-methoxy-N-methylacetamide (1.03 mL,
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.
Step C: 2,4-dioxo-4-(2-phenylsulfanylthiophen-4-yl)butanoic acid
CII(4)
S O
S \
OH
O 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 4-acetyl-2-phenylsulfanylthiophene in Step A. The
product was recrystallized from a mixture of ether and hexane. 1H
NMR, (CDCl3) 8 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).
EXAMPLE 17
2,4-dioxo-4-[2-(3-fluorobenzyl)thiophen-3-yl]butanoic acid
_87_

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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 (CDC13:) 8 7.42 (d, J =5.5 Hz, 1H),
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
2,4-dioxo-4-[2-(4-fluorobenzyl)thiophen-3-yl]butanoic acid
O
o a
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, and 3-fluorobenzaldehyde with 4-fluorobenzaldehyde
in Step A. 1H NMR (DMSO-d6) 8 7.62 (br d, 1H), 7.47 (br d, 1H), 7.35 (m,
2H), 7.15 (m, 2H), 6.83 (br s, 1H), 4.55 (s, 2H).
EXAMPLE 19
2,4-dioxo-4-[2-(3-chlorobenzyl)thiophen-3-yl]butanoic acid
_88_

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OH
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
in Step A. 1H 1VMR (DMSO-dg) 8 7.42 (br d, 1H), 7.3-7.1 (m, 5H), 6.92 (br
s, 1H), 4.55 (s, 2H).
EXAMPLE 20
2,4-dioxo-4-[5-(benzyloxy-phenylmethyl)thiophen-2-yl]butanoic acid
Step A: Preparation of (5-bromothiophen-2-yl)-(phenyl)methanol
CI(2d)
HO
S- _ Br
The title compound was prepared using the protocol described in
Example BI(6a), Step A substituting 3-fluorobenzaldehyde with
benzaldehyde. Without further purification, the alcohol was used in the
following step.
Step B: Preparation of 5-(benzyloxy-phenylmethyl)-2-
bromothiophene EI(la)
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O
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)-
methanol (1.5 g, 5.57 mmol) was added. After stirring for IO min.,
benzyl bromide (0.8 mL, 6.68 mmol) was added. The mixture was stirred
at rt under an atmosphere of argon overnight. The product mixture was
concentrated under vacuum, and the residue partitioned between ethyl
ether and dilute aqueous HCl. The organic extract was washed with
brine, dried over anhydrous magnesium sulfate, filtered and
concentrated under vacuum. The residue was subjected to column
chromatography on silica gel eluting with 5% ethyl acetate in hexane.
Collection and concentration of appropriate fractions provided the title
compound.
I5
Step C: Preparation of 2,4-dioxo-4-[5-(benzyloxy-
phenylmethyl)thiophen-2-yl]butanoic acid EI(5a)
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 5-(benzyloxy-phenylmethyl)-2-bromothiophene in Step C.
_g0_

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1H NMR (CDCl3) 8 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 =1.2.1 Hz, 1H), 4.53 (d, J
=12.1
Hz, 1H).
EXAMPLE 21
OH
2,4-dioxo-4-[5-(phenoxy-phenylmethyl)thiophen-2-yl]butanoic acid
The title compound was prepared using the protocol described in
Example EI(5a), Step A - C substituting benzy:l bromide with diphenyl
iodonium chloride in Step B. 1H NMR (CDC13) 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).
EXAMPLE 22
2,4-dioxo-4-[5-(methoxy-phenylmethyl)thiophen-2-yl]butanoic acid
H3C0 ~ O
OOH
\ / O O
The title compound was prepared using the protocol described in
Example EI{5a), Step A - C substituting benzyl bromide with methyl
iodide in Step B. 1H NMR (CDC13) b 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
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2,4-dioxo-4-(5-dibenzylaminothiophen-2-yl)butanoic acid
Step A: Preparation of 2-acetyl-5-aminothiophene hydrochloride
FI(2)
HCL H2N
S
O
A mixture of 2-acetyl-5-nitrothiophene (5.00 g, 29.2 mmol), and 5%
Pt2S/C (3 g) in methanol (120 mL) was stirred under a balloon of
hydrogen overnight at rt. To the resulting mixture, an ethanolic
solution of hydrogen chloride gas was added (final pH ~ 2), and the
solution was filtered through a pad of Celite. The filtrate was
concentrated under vacuum to provide the title compound.
Step B: Preparation of 2-acetyl-5-dibenzylaminothiophene FI(3a)
/ \
N ~ I
s o
/ \
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, I3.8 mmol) in acetonitrile (15 mL) was stirred at 60 °C for 7
days. The resulting mixture was concentrated under vacuum. The
residue was subjected to column chromatography on silica gel eluting
with chloroform - chloroform saturated with. ammonia gradient.
Collection and concentration of appropriate fractions provided the title
compound as red oil.
Step C: Preparation of 2,4-dioxo-4-(5-dibenzylaminothiophen-2-
yl)butanoic acid FI(5a)
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O
S OH
O 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-acetyl-5-dibenzylaminothiophene in Step A. The
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, lOH), 6.79 (s, 1H), 6.27
(d, J =4.8 Hz, 1H), 4.81 (s, 4H).
EXAMPLE 24
2,4-dioxo-4-(5-benzylaminothiophen-2-yl)butanoic acid
Step A: Preparation of 2-acetyl-5-benzylaminothiophene FI(3b)
/ \
N ~ I
H S
O
A mixture of 2-acetyl-5-aminothiophene hydrochloride (700 mg, 3.94
mmol), benzyl bromide (0.47 mL, 3.94 mmol), and diisopropylethylamine
(1.72 mL, 9.85 mmol) in acetonitrile (15 mL) was stirred at 60 °C for 4
days. The resulting mixture was concentrated under vacuum. The
residue was subjected to column chromatography on silica gel eluting
with chloroform - chloroform saturated with ammonia gradient.
Collection and concentration of appropriate fractions provided the title
compound.
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Step B: Preparation of 2,4-dioxo-4-(5-benzylaminothiophen-2-
yl)butanoic acid FI(5b)
O
H S OH
O 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-acetyl-5-benzylaminothiophene in Step A. The product
was purified by HPLC on C-18 stationary phase. 1H NMR (CD30D) 8 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).
EXAMPLE 25
2,4-dioxa-4-(5-diallylaminothiophen-2-yl)butanoic acid
Step A: Preparation of 2-acetyl-5-diallylaminothiophene FI(3c)
o
A mixture of 2-acetyl-5-aminothiophene hydrochloride (1.5 g, 8.44
mmol), allyl bromide (7.30 mL, 84.4 mmol), and diisopropylethylamine
(6.5 mL, 37.3 mmol) in acetonitrile (10 mL) was stirred at 60 °C for 3
days. The resulting mixture was concentrated under vacuum. The
residue was subjected to column chromatography on silica gel eluting
with 40% ethyl acetate in hexane. Collection and concentration of
appropriate fractions provided the title compound as orange oil.

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Step B: Preparation of 2,4-dioxo-4-(5-diallylaminothiophen-2-
yl)butanoic acidFI(5c)
O
N ~
OH
O 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-acetyl-5-diallylaminothiophene in Step A. The product
was purified by HPLC on C-18 stationary phase. 1H NMR (CDC13) 8 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).
EXAMPLE 26
2,4-dioxo-4-(5-di-n-propylaminothiophen-2-yl)butanoic acid
Step A: Preparation of 2-acetyl-5-di-n-propylaminothiophene FI(3d)
si
0
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
CeliteT"', 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)
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fl
~I
S OH
O 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-acetyl-5-di-n-propylaminothiophene in Step A. The
product was purified by HPLC on C-18 stationary phase. IH NMR
(DMSO-dg) 8 7.95 (d, J =4.8 Hz, IH), 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
2,4-dioxo-4-[5-(di-4-fluorobenzylamino)thiophen-2-yl]butanoic acid
Step A: Preparation of 2-acetyl-5-(di-4-fluorobenzylamino)thiophene
FI(3e)
F
~I
S
O
F
A mixture of 2-acetyl-5-aminothiophene hydrochloride (600 mg, 3.38
mmol), 4-fluorobenzyl bromide (0.92 mL, 7.43 mmol), and Cs2C03 (2.42 g,
7.43 mmol) in DMF (10 mL) was stirred at rt for 2 days. The resulting
mixture was concentrated under vacuum. The residue was treated with
a mixture of chloroform and aq HCl. After stirring at rt for I 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
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silica gel eluting with 40% ethyl acetate in hexane. Collection and
concentration of appropriate fractions provided the title compound.
Step B: Preparation of 2,4-dioxo-4-[5-(di-4-
fluorobenzylamino)thiophen-2-yl]butanoic acid FI(5e)
F
O
O 0
F
OH
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.
1H NMR (CDC13) 8 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
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(1a)
~I
C
O
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
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aqueous HCl. After stirring at rt for 1 h, pH of the solution was adjusted
to ~8 with sat. aq. NaHCOg, and organic extract was washed with brine,
dried over anhydrous sodium sulfate, filtered and concentrated under
vacuum. The residue was subjected to column chromatography on
silica gel eluting with 30% ethyl acetate in hexane. Collection and
concentration of appropriate fractions provided the title ketone.
Step B: Preparation of 2,4-dioxo-4-[5-(N-benzyl-N-
methylamino)thiophen-2-yl]butanoic acid FII(3a)
N / ~ O
HsC S OH
O 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-acetyl-5-(benzylmethylamino)thiophene in Step A. 1H
NMR (CDClg) b 7.70 (d, J =4.6 Hz, 1H), 7.4-7.2 (m, 5H), 6.77 (br s, 1H), 6.10
(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
Step A: Preparation of 2-acetyl-5-piperidin-1-yl-thiophene FII(2b)
\N
S
'IO
The title compound was prepared using the protocol described in
Example FII(3a), Step A and C substituting N-methyl-N-benzylamine
with piperidine in Step A, and using DMSO as solvent.
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Step B: Preparation of 2,4-dioxo-4-(5-piperidin-1-yl-thiophen-2-
yl)butanoic acid FII(3b)
O
N
S ~ ~ ~OH
O 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-acetyl-5-piperidin-1-yl-thiophene in Step A. 1H NMR
(CDC13) b 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).
EXAMPLE 30
2,4-dioxo-4-[5-(benzylbenzenesulfonylamino)thiophen-2-yl]butanoic acid
Step A: Preparation of 2-acetyl-5-(benzenesulfonylamino)thiophene
FIII(1)
H
N
02S S
/\ O
A solution of 2-amino-5-acetylthiophene hydrochloride (0.75 g, 4.22
mmol), benzenesulfonyl chloride (0.7 mL, 5.49 mmol) in pyridine (15 mL)
was stirred at 70 °C under an atmosphere of argon for 1.5 h. The
product
mixture was concentrated under vacuum, and the residue was
partitioned between ethyl acetate and aq. HCl. The organic extract was
washed with brine, dried over anhydrous sodium sulfate, filtered and
concentrated under vacuum. The residue was subjected to column
chromatography on silica gel eluting with 50°lo ethyl acetate in
hexane.
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Collection and concentration of appropriate fractions provided the title
sulfonamide.
Step B: Preparation of 2-acetyl-5-
(benzylbenzenesulfonylamino)thiophene FIII(2)
~I
O
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
h, and treated with benzyl bromide (89.2 ~.L, 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 MgS04,
filtered and concentrated under vacuum. The residue was subjected to
column chromatography on silica gel eluting with 40% ethyl acetate in
hexane. Collection and concentration of appropriate fractions provided
the title ketone.
Step C: Preparation of 2,4-dioxo-4-[5-
(benzylbenzenesulfonylamino)thiophen-2-yl]butanoic acid
FIII(4)
O
~I
02S S II II \OH
O O
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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 (CDC13) 8 7.76 (d, J =4.5 Hz, 1H), 7.7-7.5 (m, 5H), 7.3 (m,
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
Step A: Preparation of 1,1-dibenzylthiourea GI(la)
NH2
N-
S
A mixture of dibenzylamine (9.6 mL, 50 mmol) and tert-butyl
isothiocyanate (6.34 mL, 50 mmol) in hexane (50 mL) was stirred at rt
overnight. The white precipitate was isolated by filtration, and was
treated with concentrated hydrochloric acid (25 mL) at 100 °C for 1.5
h.
The product mixture was concentrated under vacuum. The residue was
treated with 10% aq. NaHC03. The white solid precipitated was obtained
by filtration, and recrystallized from a mixture of chloroform and
hexane. Filtration provided the title compound as white powder.
Step B: Preparation of 1,1-dibenzyl-3-
dimethylaminomethylenethiourea GI(2a)
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/ ~ N=-~
,N-
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
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
N---~~ I
S
/ ~ O
A solution of 1,1-dibenzyl-3-dimethylaminomethylenethiourea (1.8 g, 5.78
mmol) and bromoacetone (0.93 g, 5.78 mmol) in acetone (25 mL) was
stirred in the dark for 3 days. The resultant mixture was concentrated
under vacuum, and the residue partitioned between toluene and aq.
sodium bicarbonate. The organic extract was washed with brine, dried
over Na2S04, filtered and concentrated under vacuum. The residue was
recrystallized from a mixture ethyl acetate and hexane to provide the
title compound as light yellow solid.
Step D: Preparation of 2,4-dioxo-4-(2-dibenzylaminothiazol-5-
yl)butanoic acid GI(5a)
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N
N~~ I O
S OH
O 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
was purified by recrystallization from toluene. 1H NMR (CDC13) 8 8.19
(s, 1H), 7.40-7.20 (m, lOH), 6.81 (s, 1H), 4.76 (s, 4H).
EXAMPLE 32
2,4-dioxo-4-(2-benzylaminothiazol-5-yl)butanoic acid
Step A: Preparation of 1-benzyl-3-dimethylaminomethylenethiourea
GI(2b)
N=J
N--
H~ S
A mixture of 1-benzylthiourea (8.3 g, 50 mmol) and N,N-dimethyl-
formamide dimethyl acetal (25 mL) was heated at 100 °C for 1 h. The
reaction mixture was concentrated, and the residue was recrystallized
from a mixture of chloroform and hexane. Filtration of the white solid
provide the title compound.
Step B: Preparation of 2-benzylamino-5-acetylthiazole GI(3b)
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N
N-~~ I
H S
I
O
A solution of 1-benzyl-3-dimethylaminomethylenethiourea (4.0 g, 18
mmol) and bromoacetone (2.5 g, 18.3 mmol) in acetone (75 mL) was
stirred in the dark for 3 days. The white precipitated was isolated by
filtration and dissolved in chloroform. The organic solution was washed
successively with aq. NaHC03~ brine, dried over Na2S04, filtered and
concentrated under vacuum. The residue was recrystallized from a
mixture dichloromethane and hexane to provide the title compound.
Step C: Preparation of 2,4-dioxo-4-(2-benzylaminothiazol-5-
yl)butanoic acid GI(5b)
N O
N--~~ I
H S OH
O 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-benzylamino-5-acetylthiazole in Step A. The product
was purified by recrystallization from a mixture of THF and hexane. 1H
NMR (DMSO-dg) b 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).
EXAMPLE 33
2,4-dioxo-4-(2-N-benzyl-N-methylaminothiazol-5-yl)butanoic acid
Step A: Preparation of 2-N-benzyl-N-methylamino-5-acetylthiazole
GI(3c)
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N
N~/
HsC S
O
The title compound was prepared using the protocol described in
Example GI(5a), Step A - C substituting N,N-dibenzylamine with N-
benzyl-N-methylamine in Step A.
Step B: Preparation of 2,4-dioxo-4-(2-N-benzyl-N-
methylaminothiazol-5-yl)butanoic acid GI(5c)
N
N~~ ( O
S OOH
O 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-N-benzyl-N-methylamino-5-acetylthiazole in Step A.
The product was purified by recrystallization from toluene. 1H NMR
(CDC13) b 8.01 (s, 1H), 7.40-7.20 (m, 5H), 6.78 (s, 1H), 4.82 (s, 2H), 3.15
(s,
3H).
EXAMPLE 34
2,4-dioxo-4-(2-dibenzylaminothiazol-4-yl)butanoic acid
Step A: Preparation of 2-dibenzylamino-4-acetylthiazole GII(3)
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N-<v
N
O
A suspension of 1,1-dibenzylthiourea (3.05 g, 11.9 mmol) in absolute
ethanol (40 mL) was treated with 1-bromo-2,3-butanedione (2.06 g, 12.5
mmol). The mixture was heated under reflux for 2 h. The resultant
mixture was cooled to 0 °C, and white solid precipitated. The white
solid
was dissolved in ethyl acetate, and washed with sat. aq. NaHC03. The
organic extract was washed with brine, dried aver Na2S04, filtered and
concentrated under vacuum. The residue solidified upon standing to
provide the title compound.
Step D: Preparation of 2,4-dioxo-4-(2-dibenzylaminothiazol-4-
yl)butanoic acid GII(5)
S
Ny I O
N OH
O 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-4-acetylthiazole in Step A. The product
was purified by recrystallization from a mixture of ether and hexane as
orange needles. 1H NMR (CDC13) 8 ?.56 (s, 1H), 7.40-7.20 (m, 11H), 4.70
(s, 4H).
EXAMPLE 35
HIV Integrase Assay: Strand Transfer Catalyzed by Recombinant
Integrase and Preintegration Complexes
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Assays for the strand transfer activity of integrase were
conducted according to Wolfe, A.L. et al., J. Virol. 70, 1424 (1996), and
Farnet, C.M. and Bushman F.D. (1997) Cell; 88, 483 for recombinant
integrase and preintegration complexes, respectively, hereby
incorporated by reference for these purposes.
Representative compounds tested in the integrase assay
demonstrated IC50's less than 1 micromolar. Further, representative
compounds tested in the preintegration complex assay also
demonstrated IC50's of less than 1 micromolar.
EXAMPLE 36
Assay for inhibition of HIV replication
Assays for the inhibition of acute HIV infection of T-
lymphoid cells was conducted according to Vacca, J.P.et al., (1994),
Proc. Natl. Acad. Sci. USA 91, 4906, herein incorporated by reference for
these purposes.
Representative compounds tested in the present assay
demonstrated ICgSs of less than 10 micromolar.
EXAMPLE 37
Oral Composition
As a specific embodiment of an oral composition of a
compound of this invention, 50 mg of a compound of the present
invention is formatted with sufficient finely divided lactose to provide a
total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.
While the foregoing specification teaches the principles of
the present invention, with examples provided for the purpose of
illustration, it will be understood that the practice of the invention
encompasses all of the usual variations, adoptions, or modifications, as
come within the scope of the following claims and their equivalents.
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