AU2003302382B2 - 8-hydroxy-1-oxo-tetrahydropyrrolopyrazine compounds useful as HIV integrase inhibitors - Google Patents

Description

8-HYDROXY-l-OXO-TETRAHYDROPYRROLOPYRAZINE COMPOUNDS USEFUL AS HIN INTEGRASE INHIBITORS

This application claims the benefit of U.S. Provisional Application No.

60/409,745, filed September 11, 2002, the disclosure of which is hereby incorporated by reference in its entirety.

FIELD OF THE INNENTION The present invention is directed to 8-hydroxy-l-oxo-teiτahyckopyrrolopyrazine compounds and pharmaceutically acceptable salts thereof, their synthesis, and their use as inhibitors of the HIN integrase enzyme. The compounds of the present invention and their pharmaceutically acceptable salts are useful for preventing or treating infection by HIN and for treating, delaying the onset of, or preventing AIDS.

BACKGROUND OF THE INVENTION

A retrovirus designated human immunodeficiency virus (HTV) is the etiological agent of the complex disease that mcludes 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, HTLN-ITI, or ARN. A common feature of retrovirus replication is the insertion by virally-encoded integrase of proviral DΝA into the host cell genome, a required step in HIN 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 DΝA sequences; cleavage of two nucleotides from the 3' termini of the linear proviral DΝA; covalent joining of the recessed 3' OH termini of the proviral DΝA 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 cellul r enzymes.

ΝucleoLide sequencing of HIN shows the presence of a pol gene in one open reading frame [Ratner et al., Nature 1985, 313: 277]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, integrase and an HIN protease [Toh et al., EMBO J. 1985, 4: 1267; Power et al., Science 1986, 231: 1567; Pearl et al„ Nature 1987, 329: 351]. All three enzymes have been shown to be essential for the replication of HIN. It is known that some antiviral compounds which act as inhibitors of HIN replication are effective agents in the treatment of AIDS and similar diseases, including reverse transcriptase inhibitors such as azidoώymtdiiie (AZT) and efavirenz and protease inhbitors such as indfnavir an nelfinavir. The compounds of this invention are inhibitors of H N integrase and inhibitors of HIN replication. The inhibition of integrase in vitro and of HIN replication in cells is a direct result of inliibiting the strand transfer reaction catalyzed by the recombinant integrase in vitro in HIN infected cells. A particular advantage of the present invention is highly specific inhibition of HTV integrase and HIN replication.

The following references are of interest as background: Chemical Abstracts No.33-2525 discloses the preparation of 5-chloro-8-hydroxy-

1 ,6-naphthyridine-7-carboxyljc acid amide from the corresponding methyl ester.

US 5,294,620 discloses certain l,6-naphthvridin-2-one derivatives having aπgiotensin II antagonist activity.

US 2003/0055071 (Publication of U.S. Application Serial No.09/973,853, filed October 10, 2001) and WO 02/30930 (Publication of International Application No. PCT/TJS 01/31456, filed October 9, 2001) each disclose certain 8-hydroxy-l,6-naphthyridine-7- carboxarnides as HTN integrase inhibitors, wherein the carboxamido nitrogen is directly or indirectly attached to phenyl or phenyl fused to a carbocycle. The carboxamides are disclosed to be useful, inter alia, for treating HIN infection and AIDS. WO 02/30426 discloses another group of 8-hydroxy-l,6-naphmyridine-7-carboxaraides as HTV integrase inhibitors, wherein the carboxamido nitrogen is directly or indirectly attached to a heterocycle. WO 02/055079 discloses still another group of 8-hydroxy-l,6-naphthyridine-7-carboxamides as HIN integrase inhibitors, wherein the carboxamido nitrogen is part of a heterocyclic ring system.

WO 02/036734 discloses certain aza- and polyaza-naphthalenyl ketones to be HIN integrase inhbitors. The ketones include certain l-aryl-l-(poly)azanaphthylenyl methanones and H eterocyclyl-l-(poly)azanaph ylerryl methanones. Quinoliny], πaphthyridinyl, and quinoxalinyl are disclosed as suitable (poly)azaπaphthalenyl groups in the ketones.

WO 03/35076 discloses certain 5,6-dihydroxypyrimidine- -carboxamides as HIN integrase inhibitors, and WO 03/35077 discloses certain Ν-substituted 5-hydroxy-6-oxb-l,6- dihydropyrimidine-4-carboxamides as HIN integrase inhibitors. SUMMARY OF THE INVENTION

The present invention is directed to novel 8-hydroxy-l-oxo- tetrahydropyrrolopyrazine compounds. These compounds and their pharmaceutically acceptable salts are useful in the inhibition of HIN integrase, the prevention of infection by HIN, the treatment of infection by HIN and in the prevention, treatment, and delay in the onset of AIDS, either as compounds or their pharmaceutically acceptable salts, or as pharmaceutical composition ingredients, whether or not in combination with other HTN/AIDS antivirals, anti-infectives, i munornodulators, antibiotics or vaccines. More particularly, the present invention includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof:

wherein

Rl is -H, -Ci-6 alkyl, -C3-.6 cycloalkyl, or -C1-6 alkyl which is substituted with 1 or 2 substituents each of which is independently: (1) C3_8 cycloalkyl,

(2) aryl,

(3) a 5- or 6-membered saturated or mono-unsamrated heterocyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S,

(4) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, or

(5) a 9- or 10-membered fused bicyclic heterocycle containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein at least one of the rings is aromatic; wherein (A) each cycloalkyl is optionally substituted with from 1 to 3 substituents, each of which is independently halo, -C\~6 alkyl, or -O-Ci-g alkyl;

(B) each aryl is optionally substituted with from 1 to 5 substituents each of which is independently (1) -Cχ_6 alkyl, optionally substituted with from 1 to 3 substituents each of which is independently -OH, -O-Ci-6 alkyl, -0-Cι_6 haloalkyl, -CN, -NO2, -N(RaRb), -C(=O)N(RaRb), -C(=O)Ra, -Cθ2 ^c, -S(O)_nR^c, -SO2N(RaRb), -N(Ra)C(=O)Rb, -N(R )CO2RC, -N(Ra)SO2Rc -N(Ra)SO₂N(RaRb),

-OC(=O)N(RaRb), or -N(Ra)C(=O)N(RaRb),

(2) -O-Ci-6 alkyl, optionally substituted with from 1 to 3 substituents each of which is independently -OH, -O-Ci-6 alkyl, -O-Ci-<5 haloalkyl, -S(O)_nRc, -C(=O)N(RaRb), -SO₂N(RaRb), -N(Ra)C(--.θ)Rb -N(R )Cθ2 ^c, -N(Ra)Sθ2R^c,

-N(Ra)C(=O)N(RaRb),

(3) -Ci-6 haloalkyl,

(4) -O-Ci-6 haloalkyl, (5) -OH,

(6) halo,

(7) -CN,

(8) -NO2,

(9) -N(RaRb), (10) -C(=O)N(RaRb),

(11) -C(=O)Ra

(13) -SRC,

(14) -S(=O)Rc, (15) -S02R^C,

(17) -SO₂N(RaRb

(18) -N(Ra)C(=O)Rb, or

(19) -N(R^a)CO2R^c; (C) each saturated or moπo-unsaturated heterocyclic ring is

(i) optionally substituted with from 1 to 5 substituents each of which is independently halogen, -Cι_6 alkyl, -Ci-6 haloalkyl, -O-Ci-6 alkyl, -O-Cl-6 haloalkyl, or oxo; and (ii) optionally substituted with 1 or 2 substituents each of which is independently aryl or a 5- or 6-rπeιabered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S; and (D) each heteroaromatic ring or each fused bicyclic heterocycle is

(i) optionally substituted with from 1 to 7 substituents each of which is independently halogen, -Ci-g alkyl, -Cj_._6 haloalkyl, -O-Cl-6 alkyl, -O-Ci-g haloalkyl, or oxo; and

(ii) optionally substituted with 1 or 2 substituents each of which is independently aryl or -Ci-6 alkyl-aryl;

R2 is -H or -Cl-6 alkyl;

R3 is -H, -Ci-6 alkyl, -Ci-g haloalkyl, or -Cι_6 alkyl substituted with one of -OH, -O-Ci-6 alkyl, -O-Cι _6 haloalkyl, -CN, -Nθ2, -N(RaRb), -C(=0)N(RaRb), -C(=0)Ra, -CO2R^c,

-S(O)_nR^c, -SO2N(RaRb), -N(Ra)C(=O)Rb, -N(Ra)C0₂Rc -N(Ra)SO₂Rc, -N(Ra)Sθ2N(RaRb), -OC(=O)N(RaRb), or -N(Ra)C(=0)N(RaRb);

R4 .S: (1) -H,

(2) -Ci- alkyl optionally substituted with one of -OH, -O-Cl-6 alkyl, -O-Ci-6 haloalkyl, -CN, -NO2, -N(RaRb), -C(=O)N(RaRb), -C(=0)Ra, -CO2 ^c, -S(O)nRc, -S0 N(RaRb), -N(Ra)-C(Rb)=0, -N(Ra)Sθ2Rc -N(Ra)S0₂N(RaRb), -OC(=0)N(RaRb), -N(Ra)C(=0)N(RaRb), -O-C1-_.6 alkyl-C(=O)NCRaRb)_ι

-N(S0₂R^c)-Ci-6 alkyl-C(=O)N(RaRb),

(3) -Cχ_6 haloalkyl,

(4) -C(=0)Ra, (6) -C(=0)N(RaRb),

(8) -C2-6 alkenyl,

(9) -C2-6 alkenyl-C(=0)-N(Ra)₂,

(10) -C₂-5 alkynyl, (11) -C2-5 alkynyl-CH₂N(Ra)₂,

(12) -C2-5 alkynyl-CH20Ra

(13) -C2-5 alkynyl-CH2S(O)_nRc, or

(14) -Rk (15) -Cι_6 alkyl substituted with Rk

(16) -Cι„6 haloalkyl substituted with Rk,

(17) -Cι_6 alkyl-O-R

(15) -Ci-6 alkyl-O-Cι.6 alkyl-Rk (19) -Ci_6 alkyl-S(O)n-Rk (20) -Ci-6 alkyl-S(0)n-Cι.6 alkyl-Rk

(21) -Ci-6 a!kyl-N(Ra)-Rk_>

(22) -Cl-6 alkyl-N(Ra)-Cl.6 alkyl-Rk

(23) -Cι_6 alkyl-ORk with the proviso that the -N(Ra)- moiety and the -ORk moiety are not both attached to the same carbon of the -Cχ_6 alkyl- moiety,

(24) -Cι_g alkyl-C(=O)-Rk,

(25) -Cl-6 alkyμC(=O)N(Ra)-Rk

(26) -Cι„6 aIkyl-N(Ra)C(=O)-Rk

(27) -Ci-6 alkyl-Rk, ₀r (28) -Ci-6 alkyl-N(Ra)-Co-6 alkyl-S(0)_nRk; wherein Rk is

(i) aryl, which is optionally substituted with from 1 to 5 substituents each of which is independently -Ci- alkyl, -Cj-6 alkyl-OH, -Ci-6 alkyl-O-Ci-6 alkyl, -Ci-6 alkyl-O-Ci-6 haloalkyl, -Ci-6 alkyl-N(RaRb), -Cι_6 alkyl-C(^O)N(RaRb), -Cι_₆ alkyl-C(= )Ra -Cι „6 alkyl-C02R^c, -Cι_₆ alkyl-S(O)_nR^c, -O-Cl-6 alkyl, -Cl-6 haloalkyl, -O-Ci-β haloalkyl, -OH, halo, -N(RaRb)_; ~C(=0)N(RaRb), -C(=0)Ra, -CO2R^c, -S(0)_nRc, or

(ii) a 4- to 7-membered saturated or mon o-unsaturated heterocyclic ring containing at least one carbon atom and from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heterocyclic ring is: (a) optionally substituted with from 1 to 5 substituents each of which is independently halogen, -Cl-6 alkyl, -C1-.6 haloalkyl, -O-Cl-6 alkyl, -O-Cl-6 haloalkyl, or oxo; and (b) optionally mono-substituted with aryl or HetA; wherein HetA is a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heteroaromatic ting is optionally fused with a benzene ring, and HetA is optionally substituted with from 1 to 4 substituents each of which is independently -Ci_6 alkyl, -Cl-6 haloalkyl, -0-Cι_6 alkyl, -O-Ci-6 haloalkyl, or oxo; or (iii) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heteroaromatic ring is optionally substituted with from optionally substituted with from 1 to 4 substituents each of which is independently -Cl-6 alkyl, -Ci-6 haloalkyl, -O-Ci-6 alkyl, -O-Cι_6 haloalkyl, or oxo;

R5 is -H or -Cl-6 alkyl;

Rό is:

(1) -OH,

(2) -O-Ci-6 alkyl, (4) -O-Cl-6 haloalkyl,

(5) -O-Ci-6 alkyl-aryl

(6) -O-Cl-6 alkyl-HetB, or

(7) -O-Ci-6 alkyl-HetC, wherein Ru is -H or -Cl-6 alkyl;

Rv independently has the same definition as R ;

HetB is a 5- or 6-membered saturated or ono-unsaturated ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein the ring is optionally substituted with from 1 to 5 substituents each of which is independently halogen, -Cι_6 alkyl, -Cχ_6 haloalkyl, -O-Cl-6 alkyl, -0-Cι_6 haloalkyl, or oxo; and

HetC is a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heteroaromatic ring is optionally substituted with from 1 to 4 substituents each of which is independently -Cι_6 alkyl, -Ci-6 haloalkyl, -O-Cl-6 alkyl, -O-Cj-6 haloalkyl, or oxo;

each R^a and Rb is independently -H or -Cl-6 alkyl;

each R is independently a -Cj .-6 alkyl; and

each n is independently an integer equal to 0, 1 or 2.

The present invention also includes pharmaceutical compositions containing a compound of the present invention and methods of preparing such pharmaceutical compositions. The present invention further includes methods of treating AIDS, methods of delaying the onset of AIDS, methods of preventing AIDS, methods of preventing infection by HIN, and methods of treating infection by HIN. Other embodiments - aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples and appended claims.

DETAILED DESCRIPTION OF THE -Q NENTION The present invention includes the 8-hydroxy-l-oxo-tetrahydropyrroloρyrazines of

Formula (I) above. These compounds and pharmaceutically acceptable salts thereof are HIV integrase inhibitors.

A first embodiment of the present invention is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Rl is -C1-4 alkyl mono-substituted with aryl; wherein the aryl is optionally substituted with from 1 to 4 substituents each of which is independently

(1) -Cχ_4 alkyl, optionally mono-substituted with -OH, -O-Cι_4 alkyl, -O-C1-4 haloalkyl, -CN, -N(RaRb), -C(=0)N(RaRb), -C(=0)Ra -.Cθ₂R^c, -S(0)_nRc, -S0₂N(RaRb)₃ -N(Ra)C(=0)Rb -N(Ra)C0₂Rc, -N(Ra)S0₂Rc_s

(2) -O-Ci- alkyl, optionally mono-substituted with -OH, -O-C1-4 alkyl, -O-C1-4 haloalkyl, -S(O)_πRc -N(Ra)-CO2R^c, -C(=O)N(RaRb), -Sθ₂NCR^aRb), -N(Ra)C(=O)Rb -N(Ra)C02R^c, -N(Ra)S0₂Rc, -N(Ra)Sθ2N(RaRb), -OC(=0)N(RaRb), _or -N(Ra)C(=0)N(RaRb), (3) -C J-4 haloalkyl,

(4) -O-Cι_4 haloalkyl,

(5) -OH,

(6) halo,

(7) -CN,

(8) -NO2,

(9) -N(RaRb),

(10) -SRc,

(ID -S(=O)Rc,

(12) -SO₂R^c,

(13) -N(Ra)SO2R^c,

(14) -SO2N(RaRb),

(15) -N(Ra)C(=0)Rb, or

and all other variables are as originally defined above.

An aspect of the first embodiment is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein

Rl is as defined in the first embodiment;

Rό is:

(1) -OH,

(2) -0-C1..6 alkyl,

(4) -O-Cl-6 haloalkyl,

(5) -O-Ci-6 alkyl-aryl

(6) -0-Cι_6 alkyl-Hefβ, or

(7) -O-Ci-6 alkyl-HetC, wherein

Ru is -H or -Ci-6 alkyl;

Rv is -H, -Cl-6 alkyl, -C3-.6 cycloalkyl, or independently has the same definition as Rl above; HetB is a 5- or 6-membered saturated or mono-unsaturated ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein the ring is optionally substituted with from 1 to 5 substituents each of which is independently halogen, -Cι_6 alkyl, -C1..6 haloalkyl, -O-Ci-6 alkyl, -O-Ci-6 haloalkyl, or oxo; and

HetC is a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heteroaromatic ring is optionally substituted with from 1 to 4 substituents each of which is independently -Cι_6 alkyl, -Ci-6 haloalkyl, -O-C1-.6 alkyl, -O-C1.6 haloalkyl, or oxo;

and all other variables are as originally defined.

In the foregoing aspect, the reference to RV having "the same definition as Rl above" means that Rl in the definition of Rv is as defined in the instant embodiment, here the first embodiment, instead of as originally defined.

A second embodiment of the present invention is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Rl is -(CH2)ι-4-phenyl, wherein the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently

(1) -C 1.4 alkyl, optionally mono-substituted with -OH, -O-Ci-4 alkyl, -O-C1-4 haloalkyl, -CN, -N(RaRb), -C(=0)N(RaRb), -C(=0)Ra -C0₂R^c. -S(O)_πRc, or -SO2N(R^a ),

(2) -O-C1-4 alkyl, (3) -C1.4 haloalkyl,

(4) - Cl haloalkyl,

(5) -OH,

(6) halo,

(7) -CN, (8) -NO2,

(9) -N(RaRb),

(10) -SRc,

(11) -S(=0)RC,

(12) -Sθ2R^c,

(14) -SO2N(RaRb)_s

(15) -N(Ra)C(-O)Rb or

and all other variables are as originally defined above.

An aspect of the second embodiment is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Rl is as defined in the second embodiment, R⁶ is as defined in the foregoing aspect of the first embodiment except that Rl in the definition of R is as defined in the second embodiment; and all other variables are as originally defined.

A third embodiment of the present invention is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Rl is

wherein Xl and χ2 are each independently

(1) -H,

(2) methyl,

(3) ethyl,

(4) methoxy,

(5) ethoxy,

(6) -CF₃,

(7) fluoro,

(8) bromo, or

(9) chloro;

and all other variables are as originally defined above. In an aspect of the third embodiment, Rl is 4-fluorobenzyl. Another aspect of the third embodiment is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Rl is as defined in the third embodiment, R6 is as defined in the foregoing aspect of the first embodiment except that Rl in the definition of Rv is as defined in the third embodiment; and all other variables are as originally defined. In a feature of this aspect, Rl is 4-fluorobenzyl.

A fourth embodiment of the present invention is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R is is -H or -C 1-4 alkyl; and all other variables are as originally defined or as defined in any of the preceding embodiments or aspects. hi an aspect of this embodiment, R² is -H.

A fifth embodiment of the present invention is a compound of Formula (J), or a pharmaceutically acceptable salt thereof, wherem R3 is -H or -Ci-4 alkyl; and all other variables are as originally defined or as defined in any of the preceding embodiments or aspects thereof. In an aspect of this embodiment, R3 is -H.

A sixth embodiment of the present invention is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R4 is: (1) -H, (2) -Ci-4 alkyl optionally substituted with one of -OH, -O-Cl,4 alkyl, -O-Ci-4 haloalkyl, -CN, -N(RaRb), -C(=0)N(R^aRb), -C(=0)Ra -CO2RC, -S(0)_nRC -Sθ2N(RaRb), -N(R3)-C(Rb)=O, -N(R^a)Sθ2Rb or -N(R^a)SO2N(RaRb),

(3) -C(=0)N(RaRb),

(4) -Rk, (5) -C1-4 alkyl substituted with Rk

(6) -C1-4 alkyl-O-Rk ₀r

(7) -C1.4 alkyl-O-Ci-4 alkyl-Rk;

and all other variables are as originally defined or as defined in any of the preceding embodiments or aspects thereof.

A seventh embodiment of the present invention is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R4 is: (1) -H, (2) -Ci-4 alkyl optionally substituted with one of -OH, -N(RaRb), ₀r -C(=O)N(RaRb),

(3) -C(=O)N(RaRb).

(4) -(CH2)l-3-R , (5) -(CH2)i-3-O-Rk or

(6) -(CH2)l.3'0-(CH₂)l-3-R^k;

and all other variables are as originally defined or as defined in any of the first five embodiments or aspects thereof.

An eighth embodiment of the present invention is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Rk is;

(i) phenyl, which is optionally substituted with from 1 to 3 substituents each of which is independently -Ci- alkyl, -C1-4 alkyl-OH, -C1-4 alkyl-Q-Ci. 4 alkyl, -C1.4 alkyl-O-Ci-4 haloalkyl, -C1 al yl-N(RaRb), -Cι_₄ alkyl-C(=O)N(RaRb)_> -C1.-4 alkyl-C(=0)Ra _Q_4 alkyl-Cθ2Rc -Cl-4 alkyl-S(O)_nR^C -O-Cl^ alkyl, -C1.4 haloalkyl, -O-C1-4 haloalkyl, -OH, halo, -N(RaRb), -C(=0)N(RaRb), -C(=0)Ra -CO2RC, -S(0)_nRc or -SO₂N(RaRb); (ii) a 4- to 7-membered saturated heterocyclic ring containing at least one carbon atom and a total of from 1 to 4 heteroatoms independently selected from 1 to 4 N atoms, from 0 to 2 O atoms, and from 0 to 2 S atoms, wherein the heterocyclic ring is:

(a) optionally substituted with from 1 to 4 substituents each of which is independently halogen, -Cl-4 alkyl, -Cj_.-4 haloalkyl, -O-C1.4 alkyl, -O-Cl-4 haloalkyl, or oxo; and

(b) optionally mono-substituted with phenyl or HetA; wherein HetA is a 5- or 6-membered heteroaromatic ring containing a Lotal of from 1 to 4 heteroatoms independently selected from 1 to 4 N atoms, from 0 to 2 O atoms, and from 0 to 2

S atoms, wherein HetA is optionally substituted with from 1 to 3 substituents each of which is independently -C1-.4 alkyl, -Cl-4 haloalkyl, -O-C1-4 alkyl, -O-Ci-4 haloalkyl, or oxo; or (iii) a 5- or 6-membered heteroaromatic ring containing a total of from 1 to 4 heteroatoms independently selected from 1 to 4 N atoms, from 0 to 2 O atoms, and from 0 to 2 S atoms, wherein the heteroaromatic ring is optionally substituted with from optionally substituted with from 1 to 3 substituents each of which is independently -Ci-6 alky], -Cl-6 haloalkyl, -O-Cl-6 alkyl, -O-Ci-6 haloalkyl, or oxo;

and all other variables are as originally defined or as defined in any of the preceding embodiments or aspects thereof.

In an aspect of the eighth embodiment, HetA is a 5- or 6-membered heteroaromatic ring containing 1 or 2 N atoms, wherein HetA is optionally substituted with from 1 to 3 substituents each of which is independently -Cl-4 alkyl, -Cl-4 haloalkyl, -O-C1-4 alkyl, -O-Cχ_4 haloalkyl, or oxo. In another aspect of the eighth embodiment, HetA is pyrrolyl, pyrazolyl, imidazolyl, pyridyl, or pyrazinyl; which is optionally substituted with from 1 to 3 substituents each of which is independently -Cl-4 alkyl (e.g., methyl), -Ci-4 haloalkyl (e.g., trifluoromethyl) , -O-CI-.4 alkyl (e.g., methoxy), -O-C1-4 haloalkyl (e.g., -OCF3), or oxo.

A ninth embodiment of the present invention is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Rk is:

(i) phenyl, which is optionally substituted with from 1 to 3 substituents each of which is independently -Cl-4 alkyl, -C1-4 alkyl-OH, -Cl-4 alkyl-Q-Ci- 4 alkyl, -C1. alkyl-O-Cl-4 haloalkyl, -C1 alkyl~N(RaRb), -C1-4 alkyl-C(=0)N(RaRb)₇ -C1-.4 alkyl-C(=0)Ra .C_j-4 alkyl-Cθ2Rc, -Cl-4 alkyl-S(0)_nRc, -O-C1 alkyl, -C1.4 haloalkyl, -O-C1-4 haloalkyl, -OH, halo, -N(RaRb), -C(=0)N(RaRb), -C(=0)Ra -CO2 ⁰, -S(0)_nRc, or -Sθ2N(RaRb)-₅ or

(ii) a saturated heterocyclic ring selected from the group consisting of piperidinyl, morpholinyl, thiomorpholinyl, tbiazolidinyl, isothiazolidinyl, oxazolidinyl, isooxazolidinyl, pyrrolidinyl, imidazolidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, hexahydropyrimidinyl, t'hiazinanyl, thia2epanyl, thiadiazepanyl, dithiazepanyl, azepanyl, diazepanyl, thiadiazinanyl, and dioxanyl; wherein the saturated heterocyclic ring is: (a) optionally substituted with from 1 to 4 substituents each of which is independently halogen, -Cl- alkyl, -Cl-4 haloalkyl, -O-C1-4 alkyl, -O- -4 haloalkyl, or oxo; and

(b) optionally mono-substituted with phenyl or HetA; wherein HetA is a heteroaromatic ring selected from the group consisting of pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, oxatriazolyl, thiazolyl, isothiazolyl, and thiadiazolyl; wherein the heteroaromatic ring is optionally substituted with from 1 to 3 substituents each of which is independently -C1-4 alkyl, "C1-4 haloalkyl, -O-Ci-4 alkyl, -O-Ci- 4 haloalkyl, or oxo;

and all other variables are as originally defined or as defined in any of the first seven embodiments or aspects thereof.

A tenth embodiment of the present invention is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R5 j$ -H; and all other variables are as originally defined or as defined in any of the preceding embodiments or aspects thereof.

An eleventh embodiment of the present invention is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein 6 is:

(1) -OH,

(2) -O-C1.4 alkyl, (3) -NCRURV),

(4) -O-C1.4 haloalkyl,

(5) -O-Cι,4 alkyl-aryl

(6) -O-C1.4 alkyl-HetB, or

(7) -O-C1-4 alkyl-HetC. wherein

R^u is -H or -Ci-4 alkyl; Rv is -I-I, -C1 alkyl, or cyclopropyl;

HetB is a 5- or 6-membered saturated ring containing a total of from 1 to 4 heteroatoms independently selected from 1 to 4 N atoms, from 0 to 2 O atoms, and from 0 to 2 S atoms, wherein the saturated ring is optionally substituted with from 1 to 4 substituents each of which is independently halogen, -C1.4 alkyl, -Ci-4 haloalkyl, -O-C14 alkyl, -O-Cμ4 haloalkyl, or oxo; and

HetC is a 5- or 6-membered heteroaromatic ring containing a total of from 1 to 4 heteroatoms independently selected from 1 to 4 N atoms, from 0 to 2 O atoms, and from 0 to 2 S atoms, wherein the heteroaromatic ring is optionally substituted with from 1 to 3 substituents each of which is independently -C14 alkyl, -C1.4 haloalkyl, -O-Ci-4 alkyl, -O-C1-4 haloalkyl, or oxo;

and all other variables are as originally defined or as defined in any of the first ten embodiments or aspects thereof.

A twelfth embodiment of the present invention is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Rό is: (1) -OH,

(2) -O-C1-4 alkyl,

(3) -NfRURv),

(4) -O-C 1 -4 hal oalkyl, or

(5) -O-Ci-4 alkyl-HetC, wherein

R js -H or -Ci^ alkyl;

Rv is -Ci-4 alkyl or cyclopropyl;

HetC is a 5- or 6-membered heteroaromatic ring containing a total of from 1 to 4 heteroatoms independently selected from 1 to 4 N atoms, from 0 to 2 O atoms, and from 0 to 2 S atoms, wherein the ring is attached to the remainder of the compound via a ring carbon atom and a ring N atom is alpha to the ring carbon attached to the remainder of the compound; and wherein the heteroaromatic ring is optionally substituted with from 1 to 3 substituents each of which is independently -C1 alkyl, -C1 haloalkyl, -O-C1.4 alkyl, -O-Cι_4 haloalkyl, or oxo;

and all other variables are as originally defined or as defined in any of the first ten embodiments or aspects thereof. A first class of the present invention includes compounds of Formula (H), or a pharmaceutically acceptable salt thereof:

wherein:

wherein l' and χ2' are each independently:

(1) -H,

(2) Cl-4 alkyl,

(2) -O-Ci-4 alkyl,

(3) -C 14- haloalkyl,

(4) -O-Cl-4 haloalkyl, or

(5) halo; and

R6' is:

(1) -OH,

(2) -Q-Cι-4 alkyl, or

(3) -N(RuRv)_; wherein

Ru is -H or -Cl-4 alkyl; and

R^v is -Cl-4 alkyl or cyclopropyl

A sub-class of the first class includes compounds of Formula (E), or a pharmaceutically acceptable salt thereof, wherein:

Xl ' and X²' are each independently:

(1) -H,

(2) methyl,

(2) -OCH3,

(3) "CF₃, (4) -OCF3,

(5) chloro,

(6) fluoro, or

(7) bromo; and

'' is:

(1) -OH,

(2) methoxy

(3) ethoxy

(4) -N(RURV); wherein

Ru is -H; and v is methyl, ethyl, or cyclopropyl,

A second class of the present invention includes compounds of Formula (ffl), or a pharmaceutically acceptable salt thereof:

wherein χl' and χ2' are each independently -H or halo; and

R6' is:

(1) -OH,

(2) -O-C1-4 alkyl, or

(3) -NCR Rv); wherein Ru is -H or -C ι_4 alkyl; and

R^v is -Cι_4 alkyl or cyclopropyl.

A sub-class of the second class includes compounds of Fomiula (III), or a pharmaceutically acceptable salt thereof, wherein: Xl' and χ2' are each independently -H, fluoro, chloro, or bromo; and

Rό' is:

(1) -OH,

(2) rαethoxy

(3) ethoxy

(4) -N(RURV); wherein

Ru is -H; and

R^v is methyl, ethyl, or cyclopropyl.

A thirteenth embodiment of the present invention is a compound of Formula (IN), or a pharmaceutically acceptable salt thereof:

wherein

Ru is -H or -Ci-6 alkyl;

Rv is Ci-6 alkyl which is substituted with 1 or 2 substituents each of which is independently: (1) C3-.8 cycloalkyl,

(2) aryl,

(3) a 5- or 6-membered saturated or mono-unsaturated heterocyclic ring containing from 1 to 4 heteroatoms independently selected from Ν, O and S,

(4) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from Ν, O and S, or

(5) a 9- or 10-membered fused bicyclic heterocycle containing from 1 to 4 heteroatoms independently selected from Ν, O and S, wherein at least one of the rings is aromatic; wherein (A) each cycloalkyl is optionally substituted with from 1 to 3 substituents, each of which is independently halo, -Cι_6 alkyl, or -O-Cχ-6 alkyl;

(B) each aryl is optionally substituted with from 1 to 5 substituents each of which is independently (1) -Cl-6 alkyl, optionally substituted with from 1 to 3 substituents each of which is independently -OH, -O-Cl-6 alkyl, -O-Cχ.6 haloalkyl, -CN, -NO₂, -N(R^aRb), -C(=O)N(RaRb), -C(=0)Ra, -CO2RC, -S(0)_nRc, -SO2N(RaRb), -N(Ra)C(=0)Rb -N(Ra)CO2R , -N(Ra)Sθ2R^c, -N(R^a)Sθ2N(R^aRb), -OC(=0)N(RaRb), or -N(Ra)C(=0)N(RaRb),

(2) -O-Cχ-6 alkyl, optionally substituted with from 1 tp 3 substituents each of which is independently -OH, -0-Cχ_6 alkyl, -0-Cχ_6 haloalkyl, -S(O)_nRc, -C(^0)N(RaRb), -SO2N(RaRb), -N(Ra)C(=0)Rb, -N(Ra)CO2R^c, -N(R^a)Sθ2RC,

-N(Ra)C(=O)N(RaRb),

(3) -Cl-6 haloalkyl,

(4) -O-Cl-6 haloalkyl,

(5) -OH, (6) halo,

(7) -CN,

(8) -NO2,

(9) -N(RaRb),

(10) -C(=0)N(R^aRb), (11) -C(=0)Ra,

(12) -C0₂R^c, •

(13) -SRc,

(14) -S(=O)Rc₉

(15) -S0₂Rc,

(17) -S0₂N(R^aRb)_]

(18) -N(Ra)C(=O)Rb, or

(C) each saturated or mono-unsaturated heterocyclic ring i s (i) optionally substituted with from 1 to 5 substituents each of which is independently halogen, -Cχ.6 alkyl, -Cχ_6 haloalkyl, -O-Cχ_6 alkyl, -O-Cχ-6 haloalkyl, or oxo; and (ii) optionally substituted with 1 or 2 substituents each of which is independently aryl or a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S; and (D) each heteroaromatic ring or each fused bicyclic heterocycle is

(i) optionally substituted with from 1 to 7 substituents each of which is independently halogen, -C .6 alkyl, -Cχ_6 haloalkyl, -O-Cl-6 alkyl, -O-Cχ-6 haloalkyl, or oxo; and

(ii) optionally substituted with 1 or 2 substituents each of which is independently aryl or -Cχ- alkyl-aryl;

Rl is -H or -Cχ_6 alkyl;

and all other variables are as originally defined above or as defined in any of the previous embodiments or aspects thereof.

A fourteenth embodiment of the present invention is a compound of Formula

(TV), or a phaπnaceutically acceptable salt thereof, wherein Rv is -Cχ-4 alkyl mono-substituted with aryl; wherein the aryl is optionally substituted with from 1 to 4 substituents each of which is independently

(1) -Cχ-4 alkyl, optionally mono-substituted with -OH, -O-C 1.4 alkyl, -O-Cl-4 haloalkyl, -CN, -N(RaRb), -C(=0)N(R^aRb), -C(=O)Ra -CO2RC, -S(0)_nRc,

-S0₂N(RaRb)_j -N(R^a)C(=O)Rb, -N(Ra)CO2R^c, -N(Ra)SO2R^c, -N(Ra)SO2N(RaRb), ~OC(=O)N(RaRb), or -N(Ra)C(=O)N(RaRb),

(2) -O-Cχ-4 alkyl, optionally mono-substituted with -OH, -O-Cχ-4 alkyl, -O-Ci-4 haloalkyl, -S(0)_nRc, -N(Ra)-Cθ2Rc -C(=0)N(RaRb), -Sθ2N(RaRb), -N(Ra)C(=0)Rb -N(Ra)C0₂Rc, -N(Ra)S0₂Rc, -N(Ra)Sθ2N(RaRb₎,

-OC(=0)N(R^aRb), or -N(R^a)C(=O)N(R^aRb),

(3) -Cχ-4 haloalkyl,

(4) -0-Cχ4 haloalkyl,

(5) -OH, (6) halo,

(7) -CN,

(8) -NO2,

(9) -N(RaRb), (10) -SRc,

(11) -S(=O)Rc

(12) -SO₂Rc,

(13) -N(Ra)S0₂Rc, (15) -N(Ra)C(=0)Rb, or

(16) -N(R^a)C02R^c;

and all other variables are as first defined above for Formula (IN).

A fifteenth embodiment of the present invention is a compound of Formula (IN), or a pharmaceutically acceptable salt thereof, wherein R^v is -(CH2)l-4-phenyl, wherein the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently

(1) -Cχ-4 alkyl, optionally mono-substituted with -OH, -O-Cχ-4 alkyl, -O-C14 haloalkyl, -CΝ, -Ν(RaRb). -C(=O)N(RaRb). -C(=0)Ra, -C0₂Rc, -S(O)_nRC, or -Sθ2N(RaRb),

(2) -O-C14 alkyl,

(3) -Cχ4 haloalkyl,

(4) -O-Cχ-4 haloalkyl,

(5) -OH, (6) halo,

(7) -CN,

(8) -NO₂₎

(9) -NCRaRb),

(10) -SRc, (11) -S(=0)Rc,

(13) -N(R^a)S0₂Rc,

(14) -SO2N(RaRb),

(15) -N(Ra)C(=0)Rb, or

and all other variables are as first defined above in Formula (IV).

A sixteenth embodiment of the present invention is a compound of Formula (IN), or a pharmaceutically acceptable salt thereof, wherem R^v is:

χl and X² are each independently

(1) -H,

(2) methyl,

( ) ethyl,

(4) methoxy,

(5) ethoxy,

(6) -CF3,

(7) fluoro,

(8) bromo, or

(9) chloro;

and all other variables are as first defined above in Formula (IN).

In an aspect of the sixteenth embodiment, R^v is 4-fluorobenzyl.

A seventeenth embodiment of the present invention is a compound of Formula (IN), or a phaπnaceutically acceptable salt thereof, wherein is -H; and all other variables are as first defined in Formula (IN) or as defined in the preceding embodiments or aspects thereof.

An eighteenth embodiment of the present invention is a compound of Formula (IN), or a pharmaceutically acceptable salt thereof, wherein R⁵ is -H; and all other variables are as first defined in Formula (IN) or as defined in the preceding embodiments or aspects thereof. A nineteenth embodiment of the present invention is a compound of Formula (IN), or a pharmaceutically acceptable salt thereof, wherein R4 is: (1) -H, (2) -Cχ-4 alkyl optionally substituted with one of -OH, -Ν(RaRb)_s or

-C(=0)N(RaRb),

(3) -C(=0)N(RaRb),

(4) -(CH₂)i-3-Rk,

(5) -(CH2)l-3-0-Rk or (6) -(CH₂)l->0-(CH2)l-3-Rk;

and all other variables are as first defined in Formula (IV) or as defined in the preceding embodiments or aspects thereof.

A twentieth embodiment of the present invention is a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein Rk is the same as defined above in the eighth embodiment for compounds of Formula (I); and all other variables are as originally defined in Formula (IN) or as defined in any of the preceding embodiments or aspects thereof.

In an aspect of the twentieth embodiment, HetA is a 5- or 6-membered heteroaromatic ring containing 1 or 2 Ν atoms, wherein HetA is optionally substituted with from I to 3 substituents each of which is independently -Cχ4 alkyl, -Cχ_4 haloalkyl, -O-Cχ-4 alkyl, -0-Cχ4 haloalkyl, or oxo. In another aspect of the eighth embodiment, HetA is pyrrolyl, pyrazolyl, imidazolyl, pyridyl, or pyrazinyl; which is optionally substituted with from 1 to 3 substituents each of which is independently -Cχ alkyl (e.g., methyl), -Cχ-4 haloalkyl (e.g., trifluoromethyl) , -O-Cχ.4 alkyl (e.g., methoxy), -O-Cχ^ haloalkyl (e.g., -OCF3), or oxo.

A twenty first embodiment of the present invention is a compound of Formula (IN), or a pharmaceutically acceptable salt thereof, wherein Rk is the same as defined above in the ninth embodiment for compounds of Formula (I); and all other variables are as originally defined in Formula (IN) or as defined in any of the preceding embodiments or aspects thereof. A twenty-second embodiment of the present invention is a compound of Formula (TV), or a pharmaceutically acceptable salt thereof, wherein R² is -H; and all other variables are as originally defined or as defined in the preceding embodiments or aspects thereof.

A twenty third embodiment of the present invention is a compound of Formula

(IV), or a pharmaceutically acceptable salt thereof, wherein Rl is -Cl-4 alkyl; and all other variables are as originally defined or as defined in the preceding embodiments or aspects thereof, h an aspect of this embodiment, Rl is methyl or ethyl.

A twenty fourth embodiment of the present invention is a compound of Formula

(TV), or a pharmaceutically acceptable salt thereof, wherein Rl is -H, methyl, or ethyl; and all other variables are as originally defined or as defined in the preceding embodiments or aspects thereof.

A twenty-fifth embodiment of the present invention is a compound selected from the group consisting of:

ethyl 2-ben₂^1-8-hydroxy-l-oxo-l,2,3,4-tetiahydroρyrrolo[l,2-α]pyrazine-7-carboxylate;

2-benzyl-8-hydroxy-l-oxo-l,2,3,4-tetiahydropyrrolo[l,2-α]pyrazine-7-carboxylic acid;

emyI 2-(4-fluoroberizyI)-8-hydroxy-l^ carboxylate;

2-(4-fluorobenzyl)-8-hydroxy-l-oxo-l,2,3,4-tefrahydropyrxolo[l,2-a]pyrazine-7-carboxylic acid;

2-(4-fluoroben2yl)-8-hyc-roxy-N-mem^^ carboxarnide;

2-(4-fluorobenzy])-8-hydroxy-N-ethyl-l-oxo-l,2,3,4-tetrahydroρyιτolo[l_J2-ώ]ρyrai;ine-7- carboxamide;

2-(4-fluorobenzyl)-8-hydroxy-N-cyclopropyl-l-oxo-l_J2,3,4-tetrahydropyrrolo[l,2-β]pyrazine-7- carboxarnide; ethyl 2-(3-chlorobenzyl)-8-hyα^oxy-l-oxo-l,2,3,4-tetrahydropyrτolo[l,2-α]p azine-7- carboxylate;

2-(3-chlorobenzyl)-8-hychoxy-l-oxo-l,2,3,4-te^

N-(4-fluorobenzyl)-8-hydroxy-2-methyl-l-oxo-l,2,3,4-teiτ3hyo^opyrrolo[l,2--z]pyrazine-7- carboxamide;

ethyl 2-(3-fluorobenzyl)-8-hydroxy-l-oxo-l ,2,3,4-tetrahydropyrrolo[l ,2--z]ρyrazine-7- carboxylate;

ethyl 2-(3,4-fluorobenzyl)-8-hydroxy-l-oxo-l,2,3,4-tetiahydrop rrolo[l,2--ϊ]pyrazine-7- carboxylate;

emyl 2-(4-chlorobenzyl)-8-hydroxy-l-oxo-l,2,3,4-tefrahydτopyrrolo[l,2-α]pyrazme-^ carboxylate;

ethyl 2-(3-chloro-4-fiuoiObenzyl)-8-hydroxy-l-oxo-l,2,3,4-tetrahydropyrrolo[l_!2-α]ρyrazine-7- carboxylate;

ethyl 2-(3,4-chcmorobenzyl)~8-hyάroxy-l-oxo-l,2,3,4-tetι^y⁽lropyrrolo[l,2-β]pyrazine-7- carboxylate;

2-(4-chlorobenzyl)-8-hydroxy-N-methyl-l-oxo-l,2,3,4-tetrahydropyrrolo[l,2-a]pyra2ine-7- carboxamide;

2-(3,4-difluorobenzyI)-8-hydroxy-N-methyl-l-oxo-l,2,3,4-tetiahydr pyrrolo[l,2-α]pyrazine-7- carboxamide;

2-(3,4-dichloroberⁱzyl)-8-hyclroxy-N-methyl-l-oxo-l,2,3,4-tefrahydropyrrolo[l,2-a]pyrazine-7- carboxarnide;

and pharmaceutically acceptable salts thereof. Other embodiments of the present invention include compounds of Formula (I) and (IN) respectively, wherein each R^a and Rb is independently -H or -Cχ alkyl; each R is independently a -Cχ-4 alkyl; and all other variables are as originally defined or as defined in any of the foregoing embodiments or aspects thereof.

Still other embodiments of the present invention include compounds of Formula (I) and (TV) respectively, wherein each R^a and Rb is independently -H, methyl, or ethyl; each R is independently methyl or ethyl; and all other variables are as originally defined or as defined in any of the foregoing embodiments or aspects thereof.

Other embodiments of the present invention include the following:

(a) A pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention (e.g., a compound of Formula (I) or Formula (H.) or Formula (TIT) or Formula (TV) or any of the specific compounds set forth above) and a pharmaceutically acceptable carrier.

(b) A pharmaceutical composition which comprises the product prepared by combining (e.g., mixing) a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. (c) The pharmaceutical composition of (a) or (b), further comprising a therapeutically effective amount of an HIN infection/AIDS treatment agent selected from the group consisting of HIN/AIDS antiviral agents, immunomodulators, and anti-infective agents.

(d) The pharmaceutical composition of (c), wherein the HIV infection/AIDS treatment agent is an antiviral selected from the group consisting of HIN protease inhibitors, non- nucleoside HIN reverse transcriptase inhibitors, and nucleoside HIN reverse transcriptase inhibitors.

(e) A combination useful for inhibiting HIN integrase, for treating or preventing infection by HIN, or for preventing, treating or delaying the onset of AIDS, which is a therapeutically effective amount of a compound of the invention and a therapeutically effective amount of an HIN infection/AIDS treatment agent selected from the group consisting of HTN/ATDS antiviral agents, immunomodulators, and anti-infective agents.

(f) The combination of (e), wherein the HIN infection/AIDS treatment agent is an antiviral selected from the group consisting of HIV protease inhibitors, non-nucleoside HJN reverse transcriptase inhibitors and nucleoside HIN reverse transcriptase inhibitors. (g) A method of inhibiting HIN integrase in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of the invention.

(h) A method of preventing or treating infection by HTV in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of the invention.

(i) The method of (h), wherein the compound of the invention is administered in combination with a therapeutically effective amount of at least one antiviral selected-from the group consisting of HTV protease inhibitors, non-nucleoside HIN reverse transcriptase inhibitors, and nucleoside HIN reverse transcriptase inhibitors.

(j) A method of preventing, treating or delaying the onset of AIDS in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of the invention.

(k) The method of (j), wherein the compound is administered in combination with a therapeutically effective amount of at least one antiviral selected from the group consisting of HIN protease inhibitors, non-nucleoside HTN reverse transcriptase inhibitors, and nucleoside HIN reverse transcriptase inhibitors

(I) A method of inhibiting HIV integrase in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b), (c) or (d) or the combination of (e) or (f).

(m) A method of preventing or treating infection by HIN in a subject in need thereof which comprises administering to the subject the ph rmaceutical composition of (a), (b), (c) or (d) or the combination of (e) or (f).

(n) A method of preventing, treating or delaying the onset of AIDS in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b), (c) or (d) or the combination of (e) or (f).

The present invention also includes a compound of the present invention (i) for use in, (ii) for use as a medicament for, or (iii) for use in the preparation of a medicament for: (a) inhibiting HIN protease, (b) preventing or treating infection by HIN, or (c) preventing, treating or delaying the onset of AIDS. In these uses, the compounds of the present invention can optionally be employed in combination with one or more HTWAIDS treatment agents selected from HIN/AIDS antiviral agents, anti-infective agents, and immunomodulators.

Additional embodiments of the invention include the pharmaceutical compositions, combinations and methods set forth in (a)-(n) above and the uses set forth in the preceding paragraph, wherein the compound of the present invention employed therein is a compound of one of the embodiments, or an aspect or feature or sub-feature thereof, described above.

In all of the foregoing embodiments describing compositions, combinations and methods, the compound may optionally be used in the form of a pharmaceutically acceptable salt. As used herein, the term "Cχ_6 alkyl" (or "Cχ-C6 alkyl") means a linear or branched chain alkyl group having from 1 to 6 carbon atoms and includes all of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. "Cχ.4 alkyl" means n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. The term "Co" as employed in expressions such as "-Cθ-6 alkyl-⁷' means a direct covalent bond. For example, in the group -Cl- alkyl-N(Ra)-Crj-6 alkyl-S(0)_nRk when the second alkylene group is "Co", then the group is -Cχ_6 alkyl-N(Ra)-S(0)_nRk.

The term "-Cχ.6 alkyl-" refers to a Cl to C linear or branched alkyl group as just defined which is bivalent. It can alternatively be referred to as "Cχ_6 alkylene" or "Cι_6 alkanediyl". A class of alkylenes of particular interest with respect to the invention is -(CH2)l- 6-, and sub-classes of particular interest include -(CH2)l-4~, -(CH2)l-3-, -(CH2)i-2-, and -CH2-.

The term "C2-6 alkenyl" (or "C2-C alkenyl") means a linear or branched chain alkenyl group having from 2 to 6 carbon atoms and includes all of the hexenyl and pentenyl isomers as well as 1-butenyl, 2-butenyL 3-buteny], isobutenyl, 1-propenyl, 2-propenyl, and ethenyl (or vinyl). Similar terms such as "C2-4 alkenyl" have an analogous meaning. A class of alkenyls of particular interest with respect to the invention is -CH2=CH-(CH2^')0-4H, and subclasses of particular interest include -CH=CH-(CH2)χ-2H, -CH=CH-CH3, and-CH=CH2. Another class of alkenyls of particular interest with respect to the invention is alkenyls selected from -(CH2)2-CH=CH-(CH2)0-2H and -CH₂-CH=CH-(CH₂)θ-3H. The term "C2-5 alkynyl" (or "C2-C5 alkynyl") means a linear or branched chain alkynyl group having from 2 to 5 carbon atoms and includes all of the pentynyl isomers as well as 1-butynyl, 2-butynyl, 3-butynyl, 1-propynyl, 2-ρropynyl, and ethynyl (or acetylenyl). Similar terms such as "C2-4 alkynyl" have an analogous meaning. A class of alkynyls of particular interest with respect to the invention is C=C— (CH₂)ι- H ^^ C≡C-CH₃^ another class of alkynyls of particular interest with respect to the invention is alkynyls selected from

The term "C3_s cycloalkyl" (or "C3-C8 cycloalkyl") means a cyclic ring of an alkane having three to eight total carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl). Similar terms such as "C3..6 cycloalkyl" have an analogous meaning.

The term "halogen" (or "halo") refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro, chloro, bromo, and iodo). The term "Cχ-6 haloalkyl" (which may alternatively be referred to as "Cχ-C6 haloalkyl" or "halogenated Cχ-C6 alkyl") means a Ci to C6 linear or branched alkyl group as defined above with one or more halogen substituents. The term "Cχ-4 haloalkyl" has an analogous meaning. The term "Cχ-6 fluoroalkyl" has an analogous meaning except that the halogen substituents are restricted to fluoro. A class of fluoroalkyls of particular interest with respect to the invention is the series (CH2)θ-4CF (i.e., trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-n-propyl, etc.).

The term "oxo" means a divalent oxygen substituent; i.e., =O. An oxo substituent on a carbon atom in a heteroaromatic ring refers to the keto form of the keto-enol tautomer, as exemplified here for an oxαpyridinyl substituent:

Compounds of the present invention having an oxo substituent on a carbon atom of a heteroaromatic ring are understood to include compounds in which only the keto form is present, compounds in which only the enol form is present, and compounds in which the keto and enol forms are both present. The term "aryl" as used herein refers to an aromatic carbocychc ring or an aromatic carbocychc fused ring system. The fused ring system contains two or more carbocyclic rings hi which each ring shares two adjacent carbon atoms with at least one other ring. The aryl group may be attached to the rest of the molecule at any carbon atom which results in a stable compound. A subset of aryl groups particularly suitable for use in the present invention (e.g., in the definition of R^k) includes those selected from phenyl, naphthyl, anthryl, and phenanthryl. Another particularly suitable subset of aryl groups is phenyl and naphthyl. Still another particularly suitable subset of aryl groups is phenyl per se.

The teπn "heterocyclic ring" refers to a 4- to 8-membered, saturated or unsaturated monocyclic ring that contains one or more heteroatoms (e.g., from 1 to 6 heteroatoms, from 1 to 5 heteroatoms, from 1 to 4 heteroatoms, from 1 to 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom) independently selected from N, O and S and a balance of carbon atoms (the ring typically contains at least one carbon atom); and wherein any one or more of the nitrogen and sulfur heteroatoms is optionally oxidized, and any one or more of the nitrogen heteroatoms is optionally quatemized. The heterocyclic ring may be attached to the rest of the molecule via any heteroatom or carbon atom in the ring, provided that attachment results in the creation of a stable structure. WThen the heterocyclic ring has substituents, it is understood that the substituents may be attached to any atom in the ring, whether a heteroatom or a carbon atom, provided that a stable chemical structure results. A subset of the heterocyclic rings useful in the present invention (e.g., in the definition of Rk) includes any 4- to 7-membered saturated or mono-unsaturated heterocyclic ring, wherein the ring contains at least one carbon atom and from 1 to 4 heteroatoms independently selected from N, O and S. A subgroup of this subset includes any 4- to 7-membered saturated or mono-unsaturated heterocyclic ring in which the ring contains at least one carbon atom and a total of from 1 to 4 heteroatoms independently selected from 1 to 4 N atoms, from 0 to 2 O atoms, and from 0 to 2 S atoms. Representative examples of saturated heterocyclic rings include piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidiπyl, oxazolidiny], isσoxazolidinyl, pyirolidinyl, imidazolidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl,

pyrazolidinyl, hexal ydropyrimidinyl, thiazmauyl [ e.g., 1,2-thiazinanyl ^N j₇ thiazepanyl,

thiadiazepanyl, dithiazepanyl, azepanyl (i.e., N-⁷ ), diazepanyl, thiadiazinanyl (e.g., 1,2,6-

thiadiazinanyl s "^N J , and dioxanyl. Representative examples of mono-unsaturated rings are the same as the saturated rings listed in the preceding sentence except that each ring contains a double bond.

Another subset of the heterocycHc rings useful in the present invention (e.g., in the definition of HetB) includes any 5- or 6-membered saturated or mono-unsaturated ring containing from 1 to 4 heteroatoms independently selected from N, O and S. A useful subgroup of this subset includes any 5- or 6-membered saturated or mono-unsaturated heterocyclic ring in which the ring contains at least one carbon atom and a total of from 1 to 4 heteroatoms independentiy selected from 1 to 4 N atoms, from 0 to 2 O atoms, and from 0 to 2 S atoms. Another useful subgroup is identical to the preceding subgroup, except that it is limited to saturated heterocyclic rings. Still another subgroup of this subset of heterocyclic rings suitable for use in the present invention includes any 5- or 6-membered saturated ring containing 1 or 2 N atoms and carbon atoms. Representative examples of this subgroup include piperidinyl, pyrazolidinyl, imidazolidinyl, piperazinyl, piperidinyl, andhexahydropyrimidinyl.

Still another subset of the heterocyclic rings useful in the present invention are the heteroaromatic rings. The term "heteroaromatic ring" (alternatively "heteroaryl ring") generally refers to a heterocyclic ring as defined above in which the ring is an aromatic ring. A useful subgroup of this subset (e.g., in the definition of Rk, HetA, or HetC) includes any 5- or 6- rnembered monocyelic aromatic ring which consist of carbon atoms and from 1 to 4 heteroatoms independently selected from N, O and S, Representative examples of this subgroup include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, tiiazinyl, thienyl (or thiophenyl), thiazolyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, oxatriazolyl, thiazolyl, isothiazolyl, and thiadiazolyl. Another useful subgroup of this subset includes any 5- or 6-membered heteroaromatic ring in which the ring contains a total of from 1 to 4 heteroatoms independently selected from 1 to 4 N atoms, from 0 to 2 O atoms, and from 0 to 2 S atoms. Another useful subgroup includes any 5- or 6-membered heteroaromatic ring containing 1 or 2 N atoms and carbon atoms.

The term "fused bicyclic hetcrocycle" refers to any 8- to 12-membered bicyclic ring system containing one or more heteroatoms (e.g., from 1 to 6 heteroatoms, from 1 to 5 heteroatoms, from 1 to 4 heteroatoms, from 1 to 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom) independently selected from N, O and S, in which one ring contains all of the heteroatoms or each ring contains at least one of the heteroatoms, and wherein each ring is saturated or unsaturated, and two adjacent ring atoms are shared by each of the rings in the ring system and each of the two shared atoms is independently a carbon atom or a heteroatom. Any one or more of the nitrogen and sulfur heteroatoms in the ring system is optionally oxidized, and any one or more of the nitrogen heteroatoms is optionally quaternized. The fused bicyclic heterocycle may be attached to the rest of the molecule via any heteroatom or carbon atom in the ring, provided that attachment results in the creation of a stable structure. When the bicyclic heterocycle has substituents, it is understood that the substituents may be attached to any atom in the ring, whether a heteroatom or a carbon atom, provided that a stable chemical structure results. A subset of the fused bicyclic heterocycles useful in the present invention (e.g., in the definition of Rl) includes any 9- or 10-membered fused bicyclic heterocycle containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein at least one of the rings is aromatic. Representative examples of bicyclic heterocycles in this subset include bcnzotria-joiyl, indolyl, isoindolyl, indazolyl, indolinyl, isomdolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, isochromanyl, tetrahydroquinolinyl, quinolinyl, tetraliydroisoquinolinyl,

isoquinolinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo-l,4-dioxinyl (i.e., ^ r ), and

benzo-l,3-dioxolyl {i.e., ^=^0 J .

Unless expressly stated to the contrary, an "unsaturated" ring is a partially or fully unsaturated ring.

Unless expressly stated to the contrary, all ranges cited herein are inclusive. For example, a heterocyclic ring described as containing from "1 to 4 heteroatoms" means the ring can contain 1, 2, 3 or 4 heteroatoms.

When any variable (e.g., Ra, Rb₅ o Rc) occurs more than one time in any constituent or in Formula (I) or in any other formula depicting and describing compounds of the invention, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The term "substituted" (e.g., as in "each aryl is optionally substituted with from 1 to 5 substituents ...") includes mono- and poly-substitution by a named substituent to the extent such single and multiple substitution (including multiple substitution at the same site) is chemically allowed.

The symbol " '^w^ " in front of an open bond in the structural formula of a group marks the point of attachment of the group to the rest of the molecule. The compounds of the present invention may have asymmetric centers and may occur, except when specifically noted, as mixtures of stereoisomers or as individual diastereomers, or enantiomers, with all isomeric forms being included in the present invention.

As would be recognized by one of ordinary skill in the art, all of the compounds of the present invention can exist as tautomers such as the following:

It is to be understood for the purposes of the present invention that a reference herein to a compound of Formula (I) is a reference to compound I per se, or to any one of its tautomers per se (e.g., IA or IB), or to mixtures of two or more of the tautomers (e.g., two or more of I, IA, and IB).

The compounds of the present invention are useful in the inhibition of HTV integrase, the prevention or treatment of infection by human immunodeficiency virus (HIN) and the prevention, treatment or the delay in the onset of consequent pathological conditions such as AIDS. Preventing AIDS, treating AIDS, delaying the onset of AIDS, or preventing or treating infection by HIN is defined as including, but not limited to, treatment of a wide range of states of HTV infection: AIDS, ARC (AIDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIN. For example, the compounds of this invention are useful in treating infection by HIN after suspected past exposure to HIN by such means as 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 estabhshing or determining the binding site of other antivirals to HIN integrase, e.g., by competitive inhibition. Thus the compounds of this invention are commercial products to be sold for these purposes. The compounds of the present invention can be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a salt which possesses the effectiveness of the parent compound and which is not biologically or otherwise undesirable (e.g., is neither toxic nor otherwise deleterious to the recipient thereof). Suitable salts include acid addition salts which may, for example, be formed by mixing a solution of the compound of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid. When the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof can include alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and salts formed with suitable organic ligands such as quaternary ammonium salts. Also, in the case of an acid (-COOH) or alcohol group being present, pharmaceutically acceptable esters can be employed to modify the solubility or hydrolysis characteristics of the compound.

For the purpose of preventing or treating HIN infection or preventing, treating or delaying the onset of AIDS, the compounds of the present invention can be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrastemal injection or infusion techniques), by inhalation spray, or rectally, in the form of a unit dosage of a pharmaceutical composition containing a therapeutically effective amount of the compound and conventional non-toxic pharmaceuticaily-acceptable carriers, adjuvants and vehicles. The term "administration" and variants thereof (e.g., " administering" a compound) in reference to a compound of the invention mean providing the compound to the individual in need of treatment. When a compound of the invention is provided in combination with one or more other active agents (e.g., antiviral agents useful for treating HIN infection or AIDS), "administration" and its variants are each understood to include concurrent and sequential provision of the compound and other agents.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combining the specified ingredients in the specified amounts. By "pharmaceutically acceptable" is meant that the ingredients of the pharmaceutical composition must be compatible with each other and not deleterious to the recipient thereof.

The term "subject" (which may be alternatively referred to herein as "patient") as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. The term "therapeutically effective amount" as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tⁱssue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which mcludes alleviation of the symptoms of the disease being treated When the active compound (i.e., active ingredient) is administered as the salt, references to the amount of active ingredient are to the free acid or free base form of the compound.

The pharmaceutical compositions can be in the form of orally-admimstrable suspensions or tablets or capsules, nasal sprays, sterile iπjectible preparations, for example, as sterile mjectible aqueous or oleagenous suspensions or suppositories. These compositions can be prepared by methods and contain excipients which are well known in the art. Suitable methods and ingredients are described in Remington's Pharmaceutical Sciences. 18^th edition, edited by A R. Gennaro, Mack Publishing Co., 1990, which is herein incorporated by reference in its entirety. The compounds of this invention can be administered orally in a dosage range of 0.001 to 1000 mg/kg of mammal (e.g., human) body weight per day in a single dose or in divided doses. One preferred dosage range is 0.01 to 500 mg/kg body weight per day orally in a single dose or in divided doses. Another preferred dosage range is 0.1 to 100 mg/kg body weight per day orally in single or divided doses. For oral administration, the compositions can be provided in the form of tablets or capsules containing 1.0 to 500 milligrams of the active ingredient, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, and 500 milhgrams of _the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The specific dose level and frequency of dosage for any particular patient may be vaπed and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

As noted above, the present invention is also directed to use of the HTV integrase inhibitor compounds of the present invention with one or more agents useful in the treatment of HTV infection or 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 one or more of the HIN/AIDS antivirals, imunomodulators, antiinfectives, or vaccines useful for treating HTV infection or AIDS. Suitable antiviral agents include those listed in the following Table. DΓUΞ Name Manufacturer Indication (Activity. (Tradename and/or Location) abacavir Glaxo Welcome HIN infection, AIDS, ARC GW 1592 (ZIAGEN®) (nRTI) 1592U89 abacavir + lamivudiπe + GlaxoSmithKIine HTV infection, AIDS, ARC zidovudine (TRIZrVIR®) (nRTIs) acemannan Carrington Labs ARC (Irving, TX)

ACH 126443 Achillion Pharm, HIV infections, AIDS, ARC (nRTI) acyclovir Burroughs Wellcome HTV infection, AIDS, ARC, in combination with AZT

AD439 Tanox Biosystems HIV infection, AIDS, ARC

AD-519 Tanox Biosystems HIV infection, AIDS, ARC adefovir dipivoxil Gilead HIN infection, AIDS, ARC GS 840 (reverse transcriptase inhibitor)

AL-721 Ethigen ARC, PGL, HTV positive,

(Los Angeles, CA) AIDS alpha interferon GlaxoSmithKhne Kaposi's sarcoma, HTV, in combination w Retrovir

AMD3100 AnorMed HIN infection, AIDS,

ARC

(CXCR4 antagonist) amprenavir GlaxoSmithKIine HIN infection, AIDS, 141 W94 (AGENERASE®) ARC (PI) G 141 VX478 (Vertex) ansamycin Adria Laboratories ARC LM 427 (Dublin, OH)

Erbamont (Stamford, CT) antibody which neutralizes Advanced Bi otherapy AIDS, ARC pH labile alpha aberrant Concepts (Rockville, interferon MD)

AR177 Aronex Pharm HTV infection, AIDS, ARC atazanavir (BMS 232632) Bristol-Myers Squibb HIN infection, AIDS, ARC (REYATAZ™) (PI) beta-fluoro-ddA Nat'l Cancer Institute AIDS-associated diseases

BMS-232623 Bristol-Myers Squibb/ HIV infection, AIDS, (CGP-73547) Novartis ARC (PI)

BMS-234475 Bristol-Myers Squibb/ HTV infection, AIDS, (CGP-61755) Novartis ARC (PI) capravirine Pfizer HIV infection, AIDS, (AG-1549. S-1153) ARC (nnRTI)

CI-1012 Warner-Lambert HIN-1 infection cidofovir Gilead Science CMN retinitis, herpes, papillomavirus curdlan sulfate AJI Pharm USA HIN inf ction cytomegalovirus immune Medlmrnune CMN retinitis globin cytovene Syntex sight threatening CMV ganciclovii^* peripheral CMV retinitis delavirdine Pharmacia-Upjohn HIV infection, AIDS, ORESCRIPTOR®) ARC (nnRTI) dextran Sulfate Ueno Fine Chem. h d. AIDS, ARC, HTV Ltd. (Osaka, Japan) positive asymptomatic ddC Hoffman-La Roche HIN infection, AIDS, ARC

(zalcitabine, (HINID®) (nuclesodie reverse dideoxycytidine) transcriptase inhibitor) ddl Bristol-Myers Squibb HIN infection, AIDS, ARC;

(didanosine, (VTDEX®) combination with AZT/d4T dideoxyinosine) (nRTI)

DPC 681 & DPC 684 DuPont HTV infection, AIDS, ARC (Pis)

DPC 961 & DPC 083 Bristol-Myers Squibb HIV infection AIDS, ARC (from DuPont Pharma) (nnRTIs)

EL10 Elan Corp, PLC HIN infection (Gainesville, GA) efavirenz Bristol-Myers Squibb HTV infection, AIDS, (DMP 266) (SUSTINA®) ARC (non-nucleoside RT Merck (STOCRIΝ®) inhibitor) famciclovir Novartis herpes zoster, herpes (FAMVIR®) simplex emtricitabine Gilead (from Triangle HIN infection, AIDS, ARC FTC Pharmaceuticals) (nRTI) (CONIRACIL®) Emory University emvirine Gilead (from Triangle HIN infection, AIDS, ARC

Pharmaceuticals) (nnRTL)

(COACTIΝOΝ®) enfuvirtide Trimeris & Roche HTV infection, AIDS, ARC T-20 (FUZEOΝ®) (fusion inhibitor)

HBY097 Hoechst Marion Roussel HIV infection, AIDS, ARC (nnRTI) fosamprenavir Glaxo Smith Kline HIV infection, AIDS, ARC (prodrug of amprenavir) hypericin NIMRx Pharm. HIN infection, AIDS, ARC recombinant human Triton Biosciences AIDS, Kaposi's sarcoma, interferon beta (Almeda, CA) ARC interferon alfa-n3 Interferon Sciences ARC, AIDS indinavir Merck (CRTXINAΝ®) HIN infection, AIDS, ARC, asymptomatic HTV positive, (PD

ISIS 2922 ISIS Pharmaceuticals CMV retinitis

JE2147/AG1776 Agouron HIN infection, AIDS, ARC (PI)

KNI-272 Νafl Cancer Institute HtN-assoc. diseases lamivudine, 3TC GlaxoSmithKIine BQN infection, AIDS,

(EPIVΓR®) ARC (nRTI) lamivudine + zidovudine GlaxoSmithKIine HTV infection, AIDS, (COMBINIR®) ARC (nRTI) lobucavir Bristol-Myers Squibb CMN infection lopinavir (ABT-3 S) Abbott HIN infection, AIDS, ARC (PI)

Iopinavir + ritonavir Abbott (KALETR A®) HTV infection, AIDS, ARC (ABT-378/r) (PD mozenavir AVID (Camdcn, ΝJ) HTV infection, ADDS, ARC (DMP-450) (PI) nelfinavir Agouron HTV infection, AIDS, (VIRACEPT®) ARC (PI) nevirapine Boeheringer HIN infection, AIDS,

Ingleheim ARC (nnRTT)

(VIRAMUNE®) novapren Novaferoπ Labs, Inc. HIN inhibitor (Akron, OH) peptide T Peninsula Labs AIDS octapeptide (Belmont, CA) sequence

PRO 140 Progenies HIN infection, AIDS, ARC (CCR5 co-receptor inhibitor)

PRO 542 Progenies HIN infection, AIDS, ARC (attachment inhibitor) trisodium Astra Pharm. Products, CMN retinitis, HIN infection, phosphonofoπnate Inc other CMN infections

PNU-140690 Pharmacia Upjohn HIN infection, AIDS, ARC (PI) probucol Nyrex HTV infection, AIDS

RBC-CD4 Sheffield Med. Tech HIV infection, AIDS, (Houston TX) ARC ritonavir Abbott (ΝORNIR®) HIN infection, AIDS, (ABT-538) ARC (PI) saquinavir Hoffmann-LaRoche HIN infection, AIDS, (FORTOVASE®) ARC (PI) stavudine; d4T Bristol-Myers Squibb HIN infection, AIDS, ARC didehydrodeoxy- (ZERIT®) (riRTT) thymidine

T-1249 Trimeris HTV infection, AIDS, ARC (fusion inhibitor)

TAK-779 Takeda HIV infection, AIDS, ARC

(injectable CCR5 receptor antagonist) tenofovir Gilead (VIREAD®) HTV infection, AIDS, ARC (nucleotide reverse transcriptase inhibitor) opranavir (PNU-140690) Boehringer Ingelheim HIN infection, AIDS, ARC (PI)

TMC-120 & TMC-125 Tibotec HIN infections, AIDS, ARC (nnRTIs)

TMC-126 Tibotec HIN infection, AIDS, ARC ⁽PD valaciciovir GlaxoSmithKIine genital HSN & CMN infections virazole Viratek ICN (Costa asymptomatic HIV positive, ribavirin Mesa, CA) LAS, ARC zidovudiπe; AZT GlaxoSmithKIine HIN infection, AIDS, ARC, (RETROVTR®) Kaposi's sarcoma in combination with other therapies (nRTD

PI = protease inhibitor nnRTI = non-nucleoside reverse transcriptase inhibitor nRTI - nucleoside reverse transcriptase inhibitor

A compound of the present invention can also be administered in combination with an HIV integrase inhibitor such as a compound described in WO 99/625l3,WO 99/62520, or WO 99/62897. A compound of the present invention can also be adtrjinistered in combination with a CCR5 receptor antagonist, such as a compound described in WO 99/04794, WO 99/09984, WO 99/38514, WO 00/59497, WO 00/59498, WO 00/59502, WO 00/59503, WO 00/76511, WO 00/76512, WO 00/76513, WO 00/76514 , WO 00/76792, or WO 00/76793. The compounds of this invention may be effectively adr nistered, whether at periods of pre- exposure and/or post-exposure, in combination with effective amounts of one or more HIV/AIDS antivirals, immunomodulators, antiinfectives, υr vaccines useful for treating HTV infection or AIDS disclosed in the Table in WO 02/30930, which is herein incorporated by reference in its entirety.

It will be understood that the scope of combinations of the compounds of this invention with HIN/AIDS antivirals, immunomodulators, anti-infectives or vaccines is not limited to those described or referenced above, but includes in principle any combination with any pharmaceutical composition useful for the treatment of AIDS. The HJN/AIDS antivirals and other agents wi II typically be employed in these combinations in their conventional dosage ranges and regimens as reported in the art, including the dosages described in the Physicians' Desk Reference, 54^& edition, Medical Irteonornics Company, 2000. The dosage ranges for a compound of the invention in these combinations are the same as those set forth above.

Abbreviations used in the instant specification, particularly the Schemes and Examples, include the following: AIDS = acquired nmunodeficiency syndrome

ARC = AIDS related complex

Bn =; benzyl

DMF = dimethylf omiarnide

DMSO = dimethyl sulfoxide ES-MS = eletron spray mass spectroscopy

Et = ethyl

HIV = human immunodeficiency virus

HPLC = high performance liquid chromatography

LC = liquid chromatography LiHMDS = lithium hexamethyldisilazide

Me = methyl

MS = mass spectroscopy

NaHMDS = sodium hexamethyldisilazide

NMR = nuclear magnetic resonance TFA =s trifluoroacetic acid

THF = tetrahydrofuran

The compounds of the present invention can be readily prepared according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Furthermore, other methods for preparing compounds of the invention will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above.

A general method for the preparation of compounds of the present invention embraced by Formula (I) is shown, in Scheme 1, wherein piperazin-2-one 1-3 is treated with dialkylalkoxymethylenemalonate 1-4 and then with a deprotonating agent (e.g., Li or Na bis(trimethylsilyl)aτnide or Na hydride) at low temperature (e.g., from about 0 to about 25°C) in an anhydrous non-protic solvent (e.g., DMF or THF) to give alkyl S-hydroχy-l-oxo-1,2,3,4- tefrahydropyrrolopyrazine-7-carboxylate 1-6. The carboxylate 1-6 can be hydrolyzed to give the 7-carboxylic acid 1-7. Carboxylate 1-6 can also be treated with amine to give the 7-carboχamide 1-8. The piperazin-2-one 1-3 reactant can be obtained by alkylation of amine-protected piperazin-2-one 1-1 followed by deprotection to afford 1-3, as depicted in Scheme 1. Compound 1-1 can be prepared using methods described in Choi et al., /. Med. Chem. 1999, 3647; Najman- Broπzewska et al., Pharmazie 1997, 198; Fryer et al., /. Org. Chem. 1991, 3715, Dinsmore et al, Organic Prep. & Procedures International. 2002, 369, or routine variations thereof. An alternative method for preparing piρerazin-2-one 1-3 is described in Bemotas et al., Tetrahedron Lett. 1996, 7339; Saari et al, J. Med. Chem. 1990, 2590; Sugihara et al., /. Med. Chem. 1998, 489, Dinsmore et al, Organic Prep. & Procedures International. 2002, 369, or routine variations thereof.

Some of the suitable dialkylalkoxymethylenemalonates 1-4 are commercially available (e.g., diethylethoxymethylenemalonate or dimethylmethoxy-methylenemalonate). Others can be obtained by preparative methods known in the art; e.g., heterocyclylalkyloxymethylcne malonates can be prepared by the method described in Boger et al., J. Org. Chem 1988, 3408, or routine variations thereof.

The protection and deprotection of the amine in the piperazin-2-one can be accomplished using conventional amine protecting groups, such as those described in Protective Groups in Organi Chemistry, ed, J.F.W. McOmie, Plenum Press, 1973 and in T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sous, 1991.

SCHEME 1 arnine ^dΘP^rotecti^orι

deprotonating agent

Scheme 2 exemplifies the same approach as set forth in Scheme 1 for the preparation of compounds embraced by Formula (II). In Scheme 2, 4-((aryl- or alkyl- oxy)carbonyl)piperazin-2-one 2-1 is alkylated with benzyl bromide 2-2 in the presence of a base (e.g., LiHMDS, NaHMDS, or NaH) to afford l-benzyI-4-((aryl- or alkyl-oxy)carbonyl)piperazm- 2-one 2-3, which can be deprotected by standard methods (e.g., treatment with hydrogen) to afford l-benzylpiperazin-2-one 2-4. Benzylpiperazinone 2-4 can then be reacted with dialkylethoxymethylenemalonate -5 in a suitable solvent (e.g., a hydrocarbon such as toluene) at elevated temperature (e.g., from about 60 to about 90°C) to afford the

2,2-dialkyloxycarbonylethenyl-substituted product 2-6. Compound 2-6 can then be treated with a deprotonatmg agent (e.g., LiHMDS) in an aprotic solvent (e.g., DMF) to provide the alkyl 2- benzyl-8-hydroxy-l-oxo-l,2,3_s4-tetrahydropyπolopyrazme-7-carboxylate 2-7. Carboxylate 2-7 can be converted to the corresponding acid 2-8 by hydrolysis (e.g., with NaOH) and to the corresponding amide by treatment with an amine in the presence of a Lewis base (e.g., AlC-3).

SCHEME 2

alkyl or Bπ] ^UHMDS

Scheme 3 illustrates a method for preparing compounds of Formula (IN).

SCHEME 3

Scheme 4 is a variation of Scheme 3 and exemplifies the preparation of compounds of Formula (TV) with R^z = H. In Scheme 4, the piperazin-2-oπe 4-2 can be obtained by treatment of amine-protected piρerazin-2-one 4-1 with base (e.g., DHMDS, NaHMDS, or NaH) in DMF, followed by addition of methoxymethyl chloride or similar aroide protecting group. Selective deprotection of the amine protecting group by hydrogenolysis provides piρerazin-2-one 4-3. Treatment of piperazin-2-one 4-3 with dialkylalkoxymethylenemalonate 1- 4 and then with a deprotonating agent provides 8-hydroxy-l-oxo-l,2,3,4- tetrahydropyrroloρyrazine-7-carboxylate 4-5. The carboxylate 4-5 can be hydrolyzed to give the 7-caτboxylic acid 4-6, and deprotected to provide 4-7. Carboxylate 4-5 can also be treated with amine to give the 7-carboxamide 4-8, and deprotected to provide 4-9.

SCHEME 4

BBr_n

In the processes for preparing compounds of the present invention set forth in the foregoing schemes, functional groups in various moieties and substituents may be sensitive or reactive under the reaction conditions employed and/or in the presence of the reagents employed. Such sensitivity/reactivity can interfere with the progress of the desired reaction to reduce the yield of the desired product, or possibly even preclude its formation. Accordingly, it may be necessary or desirable to protect sensitive or reactive groups on any of the molecules concerned. Protection can be achieved by means of conventional protecting groups, such as those described i Protective Groups in Or^ganic Chemistry, ed. TRW. McOmie, Plenum Press, 1973 and in T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis. John Wiley & Sons, 1991. The protective groups may be removed at a convenient subsequent stage using methods known in the art. The use of protective groups is illustrated in Scheme 4.

The following examples serve only to illustrate the invention and its practice. The examples are not to be construed as lirnitations on the scope or spirit of the invention.

EXAMPLE 1 Ethyl 2-beιιzyl-8-hyclroxy-l-oxo-l,2,3,4-tetrahydropyιτolo[l,2--z]ρyrazine'7-carboxylate

Step 1: Benzyl 4-benzyl-3-oxopiρerazine-I-carboxylate

To a cold (0 °C) solution of benzyl 3-oxopiperazine-l-carboxylate (4.7 g, 20 mmol) in DMF (75 mL) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide in THF (24 mL, 24 mmol) was added and stirred at the temperature for 30 min. The resultant solution was treated with benzyl bromide (2.9 mL, 24 mmol), and stirred at room temperature overnight. The product mixture was concentrated under vacuum, and the residue partitioned between aqueous HC1 and ethyl acetate. The organic extracted 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 a 50-50 mixture of ethyl acetate and hexane. Collection and concentration of appropriate fractions provided the benzylated product.

1H NMR (400 MHz, CDC1₃) δ 7.4-7.2 (m, 10H), 5.15 (s, 2H), 4.63 (s, 2H), 4.25 (s, 2H), 3.66 (br t, J= 5.3 Hz, 2H), 3.27 (br s, 2H). ES MS M+1 = 325 Step 2: l-Benzylpiperazin-2-one

A mixture of benzyl 4-benzyl-3-oxopiperazine-l-carboxylate (4.7 g, 14.5 mmol) and 10% Pd C (0.47 g) in ethanol (150 mL) was stirred under an atmosphere of hydrogen (1 atm) at room temperature overnight. The product mixture was filtered through a pad of Celite, and concentrated under vacuum to provide l-benzylρiperazin-2-one. H NMR (400 MHz, CDC1₃) δ 7.4-7.2 ( , 5H), 4.61 (s, 2H), 3.60 (s, 2H)₇3.22 (t, 7 = 5.3 Hz, 2H), 3.03 (t, 7= 5.3 Hz, 2H). ES MS M+l = 191

Step 3: E yl 2-benzyl-8-hyάroxy-l-oxo-l,2,3,4-tetιr^ydroρyrtθlo[l,2-fl]-pyrazine-7- carboxylate

A mixture of l-benzylpiperazin-2-one (0.29 g, 1.54 mmol) and diethyl ethoxymethylenemalonate (0.35 g, 1.63 mmol) in toluene was heated in a sealed tube at 80 °C for 4 hours. The resultant mixture was concentrated under vacuum. The residue was dissolved in anhydrous DMF (10 mL), cooled to 0 °C under an atmosphere of nitrogen, and treated with a solution of lithium bis(trimethylsilyl)arnide in THF (1 M, 2,0 mL, 2.0 mmol). The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was partitioned between ethyl acetate and dilute aqueous HC1. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, Filtered, and concentrated under vacuum. The residue was triturated with diethyl ether, and the solid precipitated was filtered to provide the title compound. ²H NMR (400 MHz, CDC1₃) δ 8.39 (br s, IH), 7.36-7.27 (m, 5H), 7.03 (s, IH), 4.67 (s, 2H), 4.31 (q, 7- 7-1 Hz, 2H), 4.00 (t, 7 = 5.8 Hz, 2H), 3.51 (t, 7 = 5.8 Hz, 2H), 1.35 (t, 7= 7,1 Hz, 3H). ES MS M+l = 315

EXAMPLE 2 2-Benzyl-8-hyάro^χy-l-oxo-l,2,3,4-tetrahydropyrrolo[l,2- ]ρyrazine-7-carboxylic cid

A mixture of ethyl 2-benzyl-8-hydroxy-l-oxo-l,2,3,4-tetrahydropyrroIo-[I,2- α]ρyrazme-7-carboxylate (0.30 g; see Example 1) and aqueous sodium hydroxide (1 M, 2 mL) in ethanol (20 mL) was heated in a sealed tube at 100 °C overnight. The product mixture was acidified with addition of TFA and concentrated under vacuum. The residue was subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/ TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound. 1H NMR (400 MHz, DMSO-d₆) δ 7.37-7.25 (m, 6H), 4.62 (s, 2H), 4.09 (t, 7= 5.7 Hz, 2H), 3.52 (t, J= 5.7 Hz, 2H). ES MS M+l =287

EXAMPLE 3

Ethyl 2-(4-fluorobenzyl)-8-hydroxy-l-oxo-l,2,3,4-tetrahydropyrrolo[l,2- ]pyrazϊne-7- carboxylate

The title compound was prepared using a procedure similar to that described in Example 1, except that benzyl bromide (Step 1) was substituted with 4-fluorobenzyl bromide. 1H NMR (400 MHz, DMSO-d₆) δ 8.54 (s, IH), 7.40 (dd, 7 = 8.3, 5.8 Hz, 2H), 7.36 (s, IH), 7.17 (t, 7= 8.3 Hz, 2H), 4.59 (s, 2H), 4.18 (q, 7= 7.1 Hz, 2H), 4.01 (t, 7^ 5-3 Hz, 2H), 3.53 (t.7= 5.3 Hz, 2H), 1.24 (t, 7 = 7.1 Hz, 3H). ES MS M+l = 333

EXAMPLE 4 2-(4-Fluorobenzyl)-8-hydroxy-l-oxo-l,2,3,4-tetrahydropyrrolo[l,2-Λ]pyrazine-7-carboxylic acid

The title compound was prepared using a procedure similar to that described in Example 2, except that ethyl 2-berιzyl-8-hydroxy-l-oxo-l₇2,3,4-tetrahydroρyrrolo-[l,2- β]ρyrazine-7-carboxylate was substituted with ethyl 2-(4-fluorobenzyl)-8-hydroxy-l-oxo-l,2,3,4- terrahydropyrrolo[l,2-α]pyraziπe-7-carboxylate.

1H NMR (400 MHz, DMSO-ds) δ 8.6 (br s, IH), 7.40 (dd, 7 = 8.3, 5.8 Hz, 2H), 7.31 (s, IH), 7.36 (s, IH), 7.17 (t, J= 8.3 Hz, 2H), 4,59 (s, 2H), 4.09 (t, 7 = 5.5 Hz, 2H), 3.52 (t, 7= 5.5 Hz, 2H). ES MS M+l = 305

EXAMPLE 5

2-(4-Hnorobeιιzyl)-8-hy(lroxy-N-methyl-l-oxo-l,2,3,4-tetrahydropyrrolo[l,2-α]pyrazine-7- carboxarnide

Anhydrous methylarnme gas was bubbled through a mixture of ethyl 2-(4- fluoroben2yl)-8-hydroxy-l-oxo-l,2,3,4-tetrahydropyrrolo[l,2-z]pyrazine-7-carboxylate (200 mg) and anhydrous aluminum chloride (200 mg) in anhydrous chloroform at 0 °C for 5 minutes. The resultant mixture was heated in a seal tube at 70 "C overnight and concentrated under vacuum. The residue was dissolved in DMSO and acidified with TFA. The solution was subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/ TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound. *H NMR (400 MHz, DMSO-d₆) 87.71 (br q, 7= 4.6, IH), 7.35 (dd, 7 = 8.6, 5.7 Hz, 2H), 7.24 (s, IH), 7.17 (t, 7= 8.6 Hz, 2H), 4.59 (s, 2H), 4.07 (t, /= 5.3 Hz, 2H), 3.50 (t, 7 = 5.3 Hz, 2H), 2.74 (s, 3H). ES MS M+l - 318 EXAMPLE 6

2-(4-Fluorobenzyl)-8-hydVoxy-N-ethyl-l-oxo-l,2,3,4-terralιydropyτrolo[l,2-α3pyrazine-7^» carboxarnide

The title compound was prepared using a procedure similar to that described in Example 5, except that methylamine was substituted with ethylamjne.

^!H NMR (400 MHz, DMSO-d₆) δ 7.76 (br t, 7 = 5.3, IH), 7.35 (dd, 7 = 8.7, 5.6 Hz, 2H), 7.27 (s, IH), 7.17 (t, 7= 8.8 Hz, 2H), 4.59 (s, 2H), 4.07 (t, 7 = 5.9 Hz, 2H), 3.50 (t, 7= 5.9 Hz, 2H), 3.25 (m, 2H), 1.09 (t, 7 = 7.1 Hz, 3H). ES MS M+l = 332

EXAMPLE 7

2-(4-Fluorobcnzyl)-8-hyάroxy-N-cycloproρyl-l-oxo-l,2,3,4-tetrahyάropyrrolo[l,2-α]pyrazine-7- carboxarnide

The title compound was prepared using a procedure similar to that described in Example 5, except that methylamine was substituted with cyclopropyl arnine. *H NMR (400 MHz, DMSO-de) δ 7.76 (br d, 7 = 3.2, IH), 7.35 (dd, 7 = 8.2, 5.6 Hz, 2H), 7.26 (s, IH), 7.17 (t, 7 = 8.9 Hz, 2H), 4.59 (s, 2H), 4.06 (t, 7 = 5.9 Hz, 2H), 3.50 (t, 7 = 5.9 Hz, 2H), 2.75 (m, IH), 0.69 (m, 2H), 0.49 (ra, 2H). ^■ ES MS M+l = 344

EXAMPLE 8 Eihyl 2-(3-chlorobenzyI)-8-hydroxy-l-oxo-l,2,3,4-tetrahydropyrroIo[l,2--ιjpyrazine-7- carboxylate

Step l: l-(3-chlorobenzyI)ρiperazin-2-one

To a cold (0 °C) solution of 4-[(terf-butoxy)carbonyl]-piperazm-2-one (4.0 g, 20 mmol) in DMF (175 mL) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide in THF (22 mL, 22 mmol) was added and stirred at the temperature for 30 min. The resultant solution was treated with 3-chIorobenzyl bromide (2.6 mL, 20 mmol), and stirred at room temperature overnight. The product mixture was concentrated under vacuum, and the residue partitioned between 0.1 M aqueous HCl and ethyl acetate. The organic extracted 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 a 50-50 mixture of ethyl acetate and hexane. Collection and concentration of appropriate fractions provided the benzylated product- The product was dissolved in ethyl acetate (150 mL) and cooled to 0 °C. A steady stream of anhydrous HCl gas was bubbled through for 10 minutes. The resultant mixture was capped and stirred at the same temperature for 1 hour. The product mixture was concentrated under vacuum. The residue was treated with chloroform saturated with ammonia, and the resultant suspension was filtered through a pad of Celite. The filtrate was concentrated under vacuum provided the title amine. Residual ammonia was removed by concentrating the residue three time with toluene under vacuum. ES MS M+l = 225

Step 2: Ethyl 2-(3-chlorobenzyl)-8-hydroxy-l-oxo-l,2,3,4-tetralιydroρyrrolo[l,2-^β]- pyrazine-7-carboxylate

A mixture of I-(3-chloroben2yl)piperazin-2-onc (3.97 g, 17.67 mmol) and diethyl ethoxymethylenemalonate (4.01 g, 18.55 mmol) in toluene (60 mL) was heated in a sealed tube at 80 °C overnight. The resultant mixture was concentrated under vacuum. The residue was dissolved in anhydrous DMF (200 mL), cooled to 0 °C under an atmosphere of nitrogen, and treated with a solution of lithium bis(trimethylsilyl)amide in THF (1 M, 21.2 mL, 21.2 mmol).

The reaction mixture was stirred at room temperature overnight and concentrated under vacuum.

The residue was 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 triturated with diethyl ether, and the solid precipitated was filtered to provide the title compound.

1H MR (400 MHz, DMSO-dg) δ 8.60 (s, IH), 7.41-7.28 (m, 5H), 4.62 (s, 2H), 4.19 (q, 7= 7.2

Hz, 2H), 4.11 (t, 7 = 5,7 Hz, 2H), 3,57 (t, 7= 5.7 Hz, 2H), 1.25 (t, 7= 7.2 Hz, 3H). ES MS M+l = 349

EXAMPLE 9 2-(3-Chlorobenzyl)-8-hyc--roxy-l-oxo-l,2,3,4-te1τahy(iropyrrolo[l,2-α]pyrazme-7-carboxylic cid

The title compound was prepared using a procedure similar to that described in

Example 2, except that ethyl 2-benzyl-8-hydroxy-l-oxo-l,2,3,4-tetrahydropyrrolo-[l,2- a]pyrazine-7-carboxylate was substituted with ethyl 2-(3-chlorobenzyI)-8-hydroxy-l-oxo-l, 2,3,4- tetrahydropyrrolo[I,2--ι]pvrazine-7-carboxylate. Η NMR (400 MHz, DMSO-d₆) δ 12.33 (br s, IH), 8.69 (br β, IH), 7.41-7.27 (m, 5H), 4.61 (s, 2H), 4.10 (t, J = 5.3 Hz, 2H), 3.55 (t, / = 5.3 Hz, 2H). ES MS M+l = 322

EXAMPLE 10

N-(4-Fluorobenzyl)-8-hyolroxy-2-methyl-l-oxo-l,2,3,4-tetrahydropyrrolo[l,2-α]pyrazine-7- carboxarnide

Step 1: l-Methylρiperazin-2-one

The title compound was prepared using a procedure similar to that described in Example 1 (Step 1 & 2), except that benzyl bromide (Step 1) was substituted with methyl iodide. ES MS M+l = 115

Step 2: Ethyl S-hydroxy-2-methyl-l-oxo ,2,3,4-tetrahydiOpyrroIo[l,2-α]pyrazine-7- carboxyl te

The title compound was prepared using a procedure similar to that described in Example 1 (Step 3), except that l-benzylpiperazin-2-one was substituted with l-methylpiperazin- 2-one.

ES MS M+l = 238

Step_3: N"(4-Fluorobenzyl)-8-hydroxy-2-methyl-l-oxo-l,2,3,4-tetrahydro-pyrrolo[l,2- fl]pyrazine-7-cafboxamide

The title compound was prepared using a procedure similar to that described in Example 5, except that methylamine was substituted with 4-fluorobεnyl-amine.

ES MS M+l = 318

EXAMPLE 11

Ethyl 2-(3-fluorobenzyl)-8-hyclroxy-l-oxo-l,2,3-4-tetrahydroρyιτolo[l,2-βJρyrazine-7- carboxylate

The title compound was prepared using a procedure similar to that described in Example 1, except that benzyl bromide (Step 1) was substituted with 3-fluorobenzyl bromide. H NMR (400 MHz, DMSO-ds) δ 7.36 (dd, 7 = 8, 8 Hz, IH), 7.2-6.8 ( , 5 H), 4.57 (s, 2H), 4.05 (q, 7= 7.1 Hz, 2H), 4.01 (t, 7= 5.3 Hz, 2H), 3.53 (t, 7= 5.3 Hz, 2H), 1.18 (t, 7= 7.1 Hz, 3H). ES MS M+l = 333

EXAMPLE 12

Ethyl 2-(3,4-fluorobenzyl)-8-hydiOxy-l-oxo-l,2,3,4-tetrahydropyrrolo[l,2-α]pyrazine-7- carboxylate

The title compound was prepared using a procedure similar to that described in Example 1, except that benzyl bromide (Step 1) was substituted with 3,4-difluoi'obenzy] bromide. ^lTΪ NMR (400 MHz, DMSO-d ) δ 7.43 - 6.82 (m, 5H), 4.58 (s, 2H), 4.18 (q, 7 = 7.0 Hz, 2H), 4.02 (t, 7 = 5.3 Hz, 2H), 3.52 (t, 7 = 5.3 Hz, 2H), 1.23 (t, 7 = 7.0 Hz, 3H). ES MS M+l 351

EXAMPLE 13 Ethyl 2-(4-chlorobenzyl)-8-hydroxy-l-oxo-l,2,3,4-tetrahydropyrrolo[l,2-β]pyrazine-7- carboxylate

Step 1: ført-Butyl 4-(4-chlorobenzyl)-3-oxopiperazine-l -carboxylate

To a cold (0 °C) solution of tert-butyl 3-oχopipera.dne-l-carboxylate (2.0 g, 9.9 mmol) in DMF (100 mL) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide in THF (10.9 mL, 10.9 mmol) was added and stirred at the temperature for 30 min. The resultant solution was treated with 4-chlorobenzyl bromide (2.1, 10.5 mmol), and stirred at room temperature overnight. The product mixture was concentrated under vacuum, and the residue partitioned between aqueous HCl and ethyl acetate. The organic extracted was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to colu n chromatography on silica gel eluting with a mixture of ethyl acetate and dichloro-methane (0 to 50% gradient). Collection and concentration of appropriate fractions provided the benzylated product.

Η NMR (400 MHz, CDC1₃) 67.31 (br d, 7= 8.5 Hz, 2H), 7.20 (br d, 7= 8.5 Hz, 2H), 4.58 (s, 2H), 4.15 (s, 2H), 3.59 (br t, 7= 5.3 Hz, 2H), 3.25 (br t, 2H). ES MS M+l = 325

Step 2: l-(4-Chlorobenzyl)-piperazin-2-one

A cold. (0 °C) solution of tent-Butyl 4-(4-chlorobenzyl)-3-oxopiperazine-l- carboxylate (3.2 g, 9.9 mmol) in ethyl acetate (100 mL) was saturated with HCl gas. The resultant mixture was stirred at 0 °C for 1 h. The product mixture was concentrated under vacuum. The residue was treated with dichloromethane saturated with arnmonia gas. The resultant chalky mixture was filtered, and the filtrate concentrated inder vaccu . The residue was diluted with benzene and concentrated under vacuum to provide l-(4-chlorobenzyl)- piperazin-2-one. ES MS M+l = 225

Ste^p 3: Ethyl 2-(4-cMorobenzyl)-8-hy*oxy-l-oxo-l,2,3,4-teiτahydropyrrolo[l,2-

«]pyrazine-7-carboxylate

A mixture of l-(4-chlorobenzyl)-ρiρerazm-2-one (1.94 g, 8.63 mmol) and diethyl ethoxymethylenemalonate (1.87 g, 8.63 mmol) in toluene (40 L) was heated in a sealed tube at 80 °C overnight. The resultant mixture was concentrated under vacuum. The residue was dissolved in anhydrous DMF (50 mL), cooled to 0 °C under an atmosphere of nitrogen, and treated with a solution of lithium bi$(trimethylsilyl)anιide in THF (1 M, 12 mL, 12 mmol). The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was 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 HPLC purification on C-18 stationary phase eluted with water/acetonitrile/ TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound.

1H NMR (400 MHz, DMSO-d₆) δ 7.37 (d, 7= 8.3, 2H), 7.30 (d, 7= 8.3, 2H), 7.09 (s, IH), 4.55 (s, 2H), 4.05 (q, 7 = 7.1 Hz, 2H), 4.01 (br t, 2H), 3.53 (br t, 2H), 1.19 (t, 7 = 7.1 Hz, 3H). ES MS M+l = 349

EXAMPLE 14

Ethyl 2-(3-chloro^-fluorobenzyl)--8-hydroxy- 1 -oxo- 1 ,2,3 ,4-tetrahydroρyrrol o[ 1 ,2-α]pyrazine-7- carboxylate

The title compound was prepared using a procedure similar to that described in Example 13, except that 4-chlorobenzyl bromide (Step 1) was substituted with 3-chloro-4- fJuorobenzyl bromide.

1H MR (400 MHz, DMSO-ds) 6 8.58 (s, IH), 7.4-7.3 (m, 4 H), 4.59 (s, 2H), 4.18 (q, 7= 7.1 Hz, 2H), 4.11 (t.7 = 5-3 Hz, 2H), 3.56 (t, 7= 5.3 Hz, 2H). 1.24 (t, 7 = 7.1 Hz, 31-1). ES MS M+l = 367

EXAMPLE 15

Ethyl 2-(3,4-dichlorobeιιzyl)-8-hydroxy-l-oxo-l,2,3,4-tetrahydroρyπ-olo[l,2--z]ρyrazine-7- carboxylate

The title compound was prepared using a procedure similar to that described in Example 13, except that 4-chlorobenzyl bromide (Step I) was substituted with 3,4- dichlorobenzyl bromide. 1H NMR (400 MHz, DMSO-d₆) δ 8.59 (s, IH), 7.61 (d, 7 = 8.4 Hz, IH), 7.58 (d, 7 = 1.8 Hz, IH), 7.37 (s, IH), 7.31 (dd, 7= 8.4, 1.8 Hz, IH), 4.60 (s, 2H), 4.18 (q, /= 7.0 Hz, 2H), 4.11 (t, 7 = 5.8 Hz, 2H), 3.57 (t, 7= 5-8 Hz, 2H), 1.24 (t, 7 = 7.0 Hz, 3H). ES MS M+l = 383

EXAMPLE 16

2-(4-Chlorobenzyl)-8-hydroxy-N-methyI-l^ carboxarnide

The title compound was prepared using a procedure similar to that described in

Example 5, except that ethyl 2-(4-fluorobenzyI)-8-hydroxy-l-oxo-l,2,3_]4-ietrahyάropyrrolo[l,2- α]pyrazine-7-carboxylate was subsituted with ethyl 2-(4-chlorobenzyl)-8-hydroxy-l-oxo-l,2,3,4- tetrahydropyrrolo[l,2-<7]ρyrazine-7-carboxylate (Example 13).

1H NMR (400 MHz, CDC1₃) δ 7.33 (d, 7= 8.2, IH), 7.27 - 7.21 (m), 7.18 (s, IH), 4.65 (s, 2H), 4.03 (t, 7= 6.3 Hz, 2H), 3.53 (t, 7= 6.3 Hz, 2H), 2.99 (d, 7= 4.8 Hz, 3H). ES MS M+l = 334

EXAMPLE 17

2-(3,4-Difluorobenzyl)-8-hychoxy-N-methyl-l-oxo-l,2,3,4-tetiahydropyπOlo[l,2-α]pyrazine-7- carboxarnide

The title compound was prepared using a procedure similar to that described in Example 5, except that ethyl 2-(4'fluorobenzyl)-8-hydroxy-l-oxo-l,2,3,4-tetrahydropyrTolo[l,2- α]pyrazine-7-carboxylate was subsituted with ethyl 2-(3,4-difluorobenzyl)-8-hydroxy-l-oxo- l,2,3,4-tetiahydroρyrrolo[l,2-α]pyrazine-7-carboxylate (Example 12). 1H NMR (400 MHz, CDC1₃) δ 7.34 - 7.05 (m), 6.74 (br s, IH), 4.64 (s, 2H), 4.05 (t, 7 = 5.7 Hz, 2H), 3.54 (t, 7 = 5.7 Hz, 2H), 2.99 (d, 7 = 4.6 Hz, 3H). ES MS M+l = 336

EXAMPLE 18 2-(3,4-Dichlorobenzyl)-8-hyd^oxy-N-methyl-l-oxo-l,2,3,4-tetι^ydropyrrolo[l,2- ]pyrazine-7- carboxarnide

The title compound was prepared using a procedure similar to that described in Example 5, except that ethyl 2-(4-fluorobenzyl)-8-hydroxy-l-oxo-l,2,3,4-tetrahydropyrroIo[l,2" ]pyrazine-7-carboxylate was subsituted with ethyl 2-(3,4-dichlorobenzyl)-8-hydroxy- 1-oxo- l,2,3,4-tetrahydroρyrrolo[l,2-β]ρyrazine-7-carboxylate (Example 15). ^]H NMR (400 MHz, CDC1₃) δ 7,43 (d, 7 = 8.4 Hz, IH), 7.40 (d, 7 = 1.8 Hz, IH), 7.19 (s, IH),

7.16 (dd, 7= 8.4, 1.8 Hz, IH), 4-64 (s, 2H), 4.05 (t, 7= 5.7 Hz, 2H), 3.54 (t, 7= 5.7 Hz, 2H), 2.99

(d, 7= 4.6 Hz, 3H).

ES MS M+l = 368

EXAMPLE 19

Oral Compositions

As a specific embodiment of an oral composition of a compound of this invention, 50 mg of compound of Example 1 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule. Encapsulated oral compositions containing any one of the compounds of Examples 2-18 can be similarly prepared.

EXAMPLE 20 HEN Integrase Assay: Strand Transfer Catalyzed by Recombinant Integrase Assays for the strand transfer activity of integrase were conducted in accordance with WO 02/30930 for recombinant integrase. Representative compounds of the present invention exhibit inhibition of strand transfer activity in this assay. For example, the compounds prepared in Examples 1-18 were tested in the integrase assay and all were found to have IC50's less than 1.5 micromolar- In particular, the compounds prepared in Examples 1-10 were all found to have ICso's less than 0.7 micromolar in the integrase assay.

Further description on conducting the assay using preasse bled complexes is found in Wolfe, AX. et al, 7. Virol 1996, 70: 14244432, Hazuda et al„ 7. Virol. 1997, 71: 7005-7011; Hazuda et al., Drug Design and Discovery 1997, 15: 17-24; and Hazuda et al., Science 2000, 287: 646-650.

EXAMPLE 21 Assay for inhibition of HIN replication

Assays for the inhibition of acute HIV infection of T-lymphoid cells were conducted in accordance with Nacca, J.P. et al, Proc Natl. Acad. Sci. USA 1994, 91: 4096- Representative compounds of the present invention exhibit inhibition of HIN repUcation in this assay. For example, the compounds prepared in Examples 1, 3, 5-8, 10, 16 and 17 were found to have IC95's at or less than 20 micromolar in the present assay. While the foregoing specification teaches the principles of the present invention, with ex mples provided for the purpose of illustration, the practice of the invention encompasses all of the usual variations, adaptations and/or modifications that come within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (T), or a pharmaceutically acceptable salt thereof:

wherein

Rl is -H, -Cχ-.g alkyl, -C3-6 cycloalkyl, or -Cχ-6 alkyl which is substituted with 1 or 2 substituents each of which is independently: (1) C3-8 cycloalkyl, (2) aryl,

(3) a 5- or 6-membered saturated or mono-unsaturated heterocyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S,

(4) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, or (5) a 9- or 10-membered fused bicyclic heterocycle containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein at least one of the rings is aromatic; wherein

(A) each cycloalkyl is optionally substituted with from 1 to 3 substituents, each of which is independently halo, -Cl-6 alkyl, or -O-Cl-6 alkyl;

(B) each aryl is optionally substituted with from 1 to 5 substituents each of which is independently

(1) -Cχ_6 alkyl, optionally substituted with from 1 to 3 substituents each of which is independently -OH, -O-Cl-6 alkyl, -0-Cχ_6 haloalkyl, -CN, -NO₂, -N(RaRb), -C(=O)N(RaRb), -C(=O)Ra,

-CO2RC, -S(O)_nRc -SO2N(RaRb), -N(Ra)C(=0)Rb, -N(Ra)Cθ2Rc, -N Ra)Sθ2Rc, -N(Ra)S02N(RaRb), -OC(=O)N(RaRb), or -N(Ra)C(=0)N(RaRb), (2) -O-Cχ-6 alkyl, optionally substituted with from 1 to 3 substituents each of which is independently -OH, -O-Cl-6 alkyl, -O-Cl-6 haloalkyl, -S(0)_nRc, -C(=O)N(RaRb), -Sθ2N(R*R ), -N(Ra)C(=0)Rb, -N(Ra)CO2R^c, -N(Ra)Sθ2R^c,

-N(Ra)C(=O)N(R^aR ),

(3) -Cχ.6 haloalkyl,

(4) -O-Ci-6 haloalkyl,

(5) -OH, (6) halo,

(7) -CN,

(8) -N02,

(9) -N(RaRb),

(10) -C(=0)N(RaRb), (11) -C(=0)Ra

(13) -SRc,

(14) -S(=0)RC,

(15) -SO2 ^C, (16) -N(Ra)Sθ2R^c,

(17) -S0₂N(RaRb),

(IS) -N(Ra)C(=0)Rb, or

(C) each saturated or mono-unsaturated heterocyclic ring is (i) optionally substituted with from 1 to 5 substituents each of which is independently halogen, -Cχ-,6 alkyl, -Cl-6 haloalkyl, -O-Cl-6 alkyl, -O-Cχ.6 haloalkyl, or oxo; and (ii) optionally substituted with 1 or 2 substituents each of which is independently aryl or a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N,

O and S; and

(D) each heteroaromatic ring or each fused bicyclic heterocycle is (i) optionally substituted with from 1 to 7 substituents each of which is independently halogen, -Cχ-6 alkyl, -Cχ_6 haloalkyl, -O-Cχ_6 alkyl, -0-Cl_6 haloalkyl, or oxo; and

(ii) optionally substituted with 1 or 2 substituents each of which is independently aryl or -Cl-6 alkyl-aryl;

R2 is -H or -Cχ_6 lkyl;

R3 is -H, -Cχ-6 alkyl, -Cl-6 haloalkyl, or -Cχ.g alkyl substituted with one of -OH, -O-Cl-6 alkyl, -O-Cl-6 haloalkyl, -CN, -Nθ2, -N(RaRb), -C(=O)N(RaRb), -C(=O)Ra, -C02R^C,

-S(O)_nR^c, -SO2N(RaRb), -N(Ra)C(=0)Rb, -N(Ra)C02R^c, -N(Ra)SO2R^c, -N(Ra)SO2N(RaRb), -OC(=0)N(RaRb), or -N(Ra)C(=0)N(RaRb)_;

R is: (1) -H,

(2) -Cχ_6 alkyl optionally substituted with one of -OH, -O-Cχ.6 alkyl, -0-Cχ-.6 haloalkyl, -CN, -NO2, -Cθ2R^c, -S(O)nRC, -SO2N(RaRb), -N(Ra)Sθ2R^c, -N(Ra)SO2N(RaRb)₃ -OC(=O)N(RaRb), -N(Ra)C(=O)N(RaRb), -O^Ci-6 alkyl-C(=O)N(RaRb), -S-C1-6 alkyl-C(=O)N(RaRb), -N(Ra)-Ci_6 alkyl-C(=O)N(RaRb), or

-N(SO2R^c)-Ci-6 alkyl-C(=O)N(RaRb),

(3) -Cl-6 haloalkyl,

(4) -C(=O)Ra,

(5) -CO₂R^c, (6) -C(=O)N(RaRb),

(7) -S0₂N(RaRb),

(8) -C2-6 alkenyl,

(9) -C2-6 alkenyl-C(=0)-N(Ra)₂,

(10) -C2,5 alkynyl, (11) -C2-5 alkynyl-CH2N(Ra)₂,

(12) -C2-5 aιkynyl-CH₂ORa

(13) -C2-5 alkynyl-CH2S(0)_nRc, or

(14) -Rk

(15) -Cχ_6 alkyl substituted with Rk, (16) -Ci-6 haloalkyl substituted with Rk

(17) -Cl-6 alkyl-O-Rk

(18) -Ci-6 alkyl-O-Ci-6 alkyl-Rk

(19) -C .6 alkyl-S(O)n-Rk, (20) -Cχ-6 alkyl-S(0)ij-Ci-6 alkyl-Rk,

(21) -Cχ-6 alkyl-N(Ra)-Rk

(22) -Ci-6 alkyμN(Ra)-Ci_6 alkyl-Rk

(23) -Cl-6 alkyI-N(Ra)-C ι_6 alkyl-ORk with the proviso that the -N(Ra)- moiety and the -ORk moiety are not both attached to the same carbon of the -Cl-6 alkyl- moiety,

(24) -Cl-6 alkyl-C(=0)-Rk

(25) -Cl-6 alkyl-C(=0)N(Ra)-Rk

(26) -Cl-6 alkyl-N(Ra)C(=O)-Rk,

(27) -Cl-6 alkyl-C(=0)N(Ra)-Ci_6 alkyl-Rk, or (28) -Cχ-6 alkyl-N(Ra)-Co-6 alkyl-S(O)_nRk; wherein Rk is

(i) aryl, which is optionally substituted with from 1 to 5 substituents each of which is independently -Cl- alkyl, -Cχ.6 alkyl-OH, -Ci-6 alkyl-O-Cχ-6 alkyl, -Cχ.6 alkyl-O-Ci-6 haloalkyl, -Cχ.6 alkyl-N(RaRb), -Cχ_6 alkyl-C(=0)N(RaRb), -Cχ_6 alkyl-C(=O)Ra, -C .6 alkyl-C02R^c, -Cχ-6 alkyl-S(O)_nRc, -O-Cl-6 alkyl, -Cχ.g haloalkyl, -O-Cχ-6 haloalkyl, -OH, halo, -N(RaRb), -C(=O)N(RaRb), -C(=0)Ra, -CO2RC, -S(0)_nRc, or

(ii) a 4- to 7-membered saturated or mono-unsaturated heterocyclic ring containing at least one carbon atom and from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heterocychc ring is: (a) optionally substituted with from 1 to 5 substituents each of which is independently halogen, -Ci-6 alkyl, -Cχ_6 haloalkyl, -Q-Cχ_6 alkyl, -O-Ci_6 haloalkyl, or oxo; and (b) optionally mono-substituted with aryl or HetA", wherein HetA is a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heteroaromatic ring is optionally fused with a benzene ring, and HetA is optionally substituted with from 1 to 4 substituents each of which is independently -Cl-6 alkyl, -Cχ-6 haloalkyl, -O-Cχ_6 alkyl, -O-Cj-6 haloalkyl, or oxo; or (iii) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heteroaromatic ring is optionally substituted with from optionally substituted with from 1 to 4 substituents each of which is independently -Cl-6 alkyl, -Cχ_6 haloalkyl, -0-Cχ_6 alkyl, -O-Cl-6 haloalkyl, or oxo;

R5 is -H or -Cl-6 alkyl;

R<5 is:

(1) -OH,

(2) -O-Cl-6 alkyl, (4) -0-Cχ,6 haloalkyl,

(5) -O-Cl-6 alkyl aryl

(6) -O-Cχ-6 alkyl-HetB, or

(7) -O-Cl-6 alkyl-HetC, wherein Ru is -H or -Cχ_6 alkyl;

R^v independently has the same definition as Rl;

HetB is a 5- or 6-membered saturated or mono-unsaturated ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein the ring is optionally substituted with from 1 to 5 substituents each of which is independently halogen, -Cχ.6 alkyl, -Cl-6 haloalkyl, -O-C .6 alkyl, -O-Ci_6 haloalkyl, or oxo; and

HetC is a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heteroaromatic ring is optionally substituted with from 1 to 4 substituents each of which is independently -Cl-6 alkyl, -Cχ_6 haloalkyl, -O-Cχ_6 alkyl, -O-Cχ-6 haloalkyl, or oxo;

each R^a and Rb is independently -H or -Cl_^6 alkyl; each Rc is independently a -Cχ_6 alkyl; and

each n is independently an integer equal to 0, 1 or 2.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:

Rl is -Cχ-4 alkyl mono-substimted with aryl; wherein the aryl is optionally substituted with from

1 to 4 substituents each of which is independently (1) -Ci_4 alkyl, optionally mono-substituted with -OH, -O-Cχ.4 alkyl, -O-Cχ.4 haloalkyl, -CN, -N(R*Rb), -C(=O)N(RaRb), -C(=0)Ra -Cθ2R^c, -S(O)_ΩRc, -Sθ2N(RaRb), -N(Ra)C(=0)Rb -N(Ra)CO2Rc, -N(Ra)SO2Rc,

(2) -O-Cχ- alkyl, optionally mono-substituted with -OH, -O-Cχ-4 alkyl, -O-C1-4 haloalkyl, -S(O)_nR^c, -N(Ra)-CO2R^c, -C(=O)N(RaRb), -SO2N(RaRb),

-N(Ra)C(=O)Rb, -N(Ra)Cθ2Rc, -N(Ra)Sθ2R^c, -N(R )S02N(R Rb), -OC(=O)N(RaRb), or -N(Ra)C(=0)N(RaRb),

(3) -Cχ-4 haloalkyl,

(4) -O-Cχ- haloalkyl, (5) -OH,

(6) halo,

(7) -CN,

(8) -Nθ2,

(9) -NCRaRb), (10) -SRC,

(11) -S(=0)Rc,

(12) -SO2RC,

(14) -SO2N(RaRb), (15) -N(Ra)C(=O)Rb, or

R is:

(1) -OH, (2) -O-Cχ-6 alkyl,

(4) -O-Cl-6 haloalkyl,

(5) -O-Cl-6 alkyl-aryl (6) -O-Cχ.6 alkyl-HetB, or

(7) -O-Cl-6 alkyl-HetC, wherein

Ru is -H or -Cl-6 alkyl;

Rv is -H, -Ci-6 alkyl, -C3-6 cycloalkyl, or independently has the same definition as Rl above;

HetB is a 5- or 6-membered saturated or mono-unsaturated ring containing from 1 to 4 heteroatoms independently selected fro N, O and S, wherein the ring is optionally substituted with from 1 to 5 substituents each of which is independently halogen, -Cχ_6 alkyl, -Cl-6 haloalkyl, -O-Cl-6 alkyl, -O-Cl-6 haloalkyl, or oxo; and

HetC is a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heteroaromatic ring is optionally substituted with from 1 to 4 substituents each of which is independently -Ci_6 alkyl, -Cl-6 haloalkyl, -O-Cl-6 alkyl, -0-Cχ-.6 haloalkyl, or oxo.

3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein in is -(CH2)l_^Φ-phenyl, wherein the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently (1) -Cl-4 alkyl, optionally mono-substituted with -OH, -O-Cχ- alkyl, -O-Cχ-4 haloalkyl, -CN, -N(RaRb), -C(=O)N(RaRb), -C(=O)Ra, -CO2RC, -S(O)_nR^c, or

(2) -O-Ci-4 alkyl,

(3) -Cχ-4 haloalkyl, (4) -O-Cχ_4 haloalkyl,

(5) -OH,

(6) halo,

(7) -CN,

(8) -NO2, (9) -N(RaRb),

(10) -SRc,

(11) -S(=O)Rc,

(12) -SO2R^c,

(13) -N(Ra)SO2R^c.

(15) -N(Ra)C(=O)Rb, or

4. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein Rl is:

wherein Xl and χ are each independently

(1) -H,

(2) methyl,

(3) ethyl,

(4) methoxy,

(5) ethoxy,

(6) -CF3,

(7) fluoro,

(8) bromo, or

(9) chloro.

5. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein Rl is 4-fluorobenzyl.

6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: R2 is -H or -Cχ„4 lkyl;

R3 is -H or -Cl-4 alkyl;

R4 is:

(1) -H,

(2) -Cl-4 alkyl optionally substituted with one of -OH, -O-Cχ.4 alkyl, -O-Cχ.4 haloalkyl, -CN, -N(RaRb). -C(=0)N(RaRb), -C(=0)Ra -C0₂RC, -S(0)_nR^c, -SO2N(RaRb), -N(Ra)-C(Rb)=O, -N(Ra)SO2 ^b, or -N(Ra)SO2N(RaRb), (3) -C(=O)N(RaRb),

(4) -Rk,

(5) -Cl-4 alkyl substituted with R

(6) -Cχ-4 alkyl-O-Rk or

(7) -Cχ-4 alkyl-O-Cχ-4 alkyl-Rk; and

R5 is -H.

7. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R6 is: (1) -OH,

(2) -O-Cχ-4 alkyl,

(3) -N(R^UR^V),

(4) -O-C1-4 haloalkyl,

(5) -O-Cχ-4 alkyl-aryl (6) -O-Cχ„4 alkyl-HetB, or

(7) -O-C1-4 alkyl-HetC, wherein

Ru is -H or -Cχ.4 alkyl; Rv is -H, -Cχ-4 alkyl, or cyclopropyl; HetB is a 5- or 6-membered saturated ring containing a total of from 1 to 4 heteroatoms independently selected from 1 to 4 N atoms, from 0 to 2 O atoms, and from 0 to 2 S atoms, wherein the saturated ring is optionally substituted with from 1 to 4 substituents each of which is independently halogen, -Cχ_4 alkyl, -Cχ_4 haloalkyl, -O-Cχ-4 alkyl, -0-Cχ„4 haloalkyl, or oxo; and HetC is a 5- or 6-membered heteroaromatic ring containing a total of from 1 to 4 heteroatoms independently selected from 1 to 4 N atoms, from 0 to 2 O atoms, and from 0 to 2 S atoms, wherein the heteroaromatic ring is optionally substituted with from 1 to 3 substituents each of which is independently -Cχ.4 alkyl, -Cl-4 haloalkyl, -O-C1.4 alkyl, -O-Cχ-4 haloalkyl, or oxo.

8. A compound of Formula (H), or a pharmaceutically acceptable salt thereof:

wherein:

Xl' and X ' are each independently:

(1) -H,

(2) C1.4 alkyl,

(2) -O-Cχ.4 alkyl,

(3) -Cχ-4 haloalkyl,

(4) -O-Cχ-4 haloalkyl, or

(5) halo; and

R6' IS:

(1) -OH,

(2) -O-Ci-4 alkyl, or wherein

Ru is -H or -Cχ.4 alkyl; and R^v is -Cχ_4 alkyl or cyclopropyl.

9. A compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein: wherein Xl' and ' ai'e each independently:

(1) -H,

(2) methyl,

(2) -OCH3,

(3) -CF3,

(4) -OCF3,

(5) chloro,

(6) fluoro, or

(7) bromo; and

R6^' is:

(1) -OH,

(2) methoxy

(3) ethoxy

(4) -N(RURV); wherein

Ru is -H; and

R^v is methyl, ethyl, or cyclopropyl

10. The compound according to claim 8, which is a compound of Formula

(in), or a pharmaceutically acceptable salt thereof:

wherein χl' and X2' are each independently -H or halo.

11. The compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein

XT and X2^" are each independently -H, fluoro, chloro, or bromo; and

' is: (1) -OH,

(2) methoxy

(3) ethoxy wherein

Ru is -H; and

Rv is methyl, ι ethyl, or cyclopropyl.

12. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is a compound of Formula (IN):

wherein

Ru is -H or -Ci-6 alkyl;

Rv is Cχ-6 alkyl which is substituted with 1 or 2 substituents each of which is independently:

(1) C3-S cycloalkyl,

(2) aryl,

(3) a 5- or 6-membered saturated or mono-unsaturated heterocyclic ring containing from 1 to 4 heteroatoms independently selected from Ν, O and S,

(4) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from Ν, O and S, or

(5) a 9- or 10-membered fused bicyclic heterocycle containing from 1 to 4 heteroatoms independently selected from Ν, O and S, wherein at least one of the rings is aromatic; wherein

(A) each cycloalkyl is optionally substituted with from 1 to 3 substituents, each of which is independently halo, -Cj-6 alkyl, or -O-Cχ-6 alkyl; (B) each aryl is optionally substituted with from 1 to 5 substituents each of which is independently

(1) -Cχ-6 alkyl, optionally substituted with from 1 to 3 substituents each of which is independently -OH, -O-Cl- alkyl, -O-Cχ-6 haloalkyl, -CN, -NO2, -N(RaRb), -C(=O)N(RaRb), -C(=0)Ra

-CO2R , -S(O)_πRc, -SO2N(RaRb), -N(Ra)C(=O)Rb -N(Ra)Cθ2R^c, -N(Ra)SO2R^c, -N(Ra)SO2N(RaRb), -OC(=0)N(RaRb), or -N(Ra)C(=O)N(RaRb),

(2) -O-Ci-6 alkyl, optionally substituted with from 1 to 3 substituents each of which is independently -OH, -O-Cχ-6 alkyl, -0-Cχ . haloalkyl, -S(0)_nR^c, -C(=0)N(RaRb)_s -Sθ2N(RaRb), -N(Ra)C(=0)Rb, -N(Ra)CO2R^c, -N(Ra)SO2R^c,

-N(Ra)C(=0)N(RaRb), (3) -Cl-6 haloalkyl,

(4) -0-Cχ_6 haloalkyl,

(5) -OH,

(6) halo,

(7) -CN, (8) -NO2,

(9) -NCRaRb),

(10) -C(=O)N(RaRb),

(11) -C(=0)Ra (13) -SRc,

(15) -SO₂Rc,

(17) -SO2N(RaRb), (18) -N(Ra)C(=0)Rb₃ or

(C) each samrated or mono-unsaturated heterocyclic ring is (i) optionally substituted with from 1 to 5 substituents each of which is independently halogen, -Cι_6 alkyl, -Cχ_6 haloalkyl, -O-Cχ-6 alkyl, -O-Cl-6 haloalkyl, or oxo; and (ii) optionally substituted with 1 or 2 substituents each of which is independently aryl or a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S; and (P) each heteroaromatic ring or each fused bicyclic heterocycle is

(i) optionally substituted with from 1 to 7 substituents each of which is independently halogen, -Cχ.6 alkyl, -Cχ-6 haloalkyl, -O-Cχ-6 alkyl, -O-Cl-6 haloalkyl, or oxo; and

(ii) optionally substituted with 1 or 2 substituents each of which is independently aryl or-Cχ.6 alkyl-aryl; and

Rl is -H or -C χ-6 alkyl.

13. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein Rv is -Cl-4 alkyl mono-substituted with aryl; wherein the aryl is optionally substituted with from 1 to 4 substituents each of which is independently (1) -Cχ-4 alkyl, optionally mono-substituted with -OH, -O-Ci-4 alkyl, -O-Cχ-4 haloalkyl, -CN, -N(RaRb). -C(=O)N(RaRb), -C(=0)Ra, -CO2RC, -S(0)_nRc, -SO2N(R^aRb), -N(Ra)C(=0)Rb -N(Ra)Cθ2R^c, -N(Ra)Sθ2R^c,

(2) -0-Cχ_4 alkyl, optionally mono-substituted with -OH, -O-Cχ.4 alkyl, -O-Cχ.4 haloalkyl, -S(O)_nRC, -N(Ra)-CO2R^c, -C(=O)N(RaRb), -Sθ2N(RaRb),

-N(Ra)C(0)Rb, - ( a Cθ2 , -N(Ra)SO2Rc, -N(Ra)SO2N(RaRb),

-OC(=O)N(RaRb), or -N(Ra)C(=O)N(RaRb),

(3) -Cχ-4 haloalkyl,

(4) -O-C1-4 haloalkyl, (5) -OH,

(6) halo,

(7) -CN,

(8) -NO2,

(9) -N(RaRb), (10) -SRc,

(11) -S(=O)Rc,

(12) -S0₂RC, (14) -SO2N(RaRb),

(15) -N(Ra)C(=O)Rb, or

14, The compound according to claim 13, or a pharmaceutically acceptable salt thereof, wherein R^v is:

wherein Xl and 2 are each independently

(1) -H,

(2) methyl,

(3) ethyl,

(4) methoxy,

(5) ethoxy,

(6) -CF3.

(7) fluoro,

(8) bromo, or

(9) chloro-

15. The compound according to claim 14, or a phaimaceutically acceptable salt thereof, wherein R^v is 4-fluorobeπzyl.

16. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein:

R is -H; R5 is -H;

R is:

(1) -H,

(2) -Cl-4 alkyl optionally substituted with one of -OH, -N(RaRb), or

-C(=Q)N(RaRb),

(3) -C(=O)N(RaRb),

(4) -(CH₂)l-3-Rk,

(5) -(CH2)l_^3-0-Rk, or

(6) -(CH2)l-3-O-(CH2)l-3-Rk;

R2 is -H; and

Rl is -Cχ-4 alkyl.

17. A compound selected from the group consisting of:

10

Cl XXJCQ OH-C

10

^axxo^χζ HN-CH₃

O OH

O OH .

and pharmaceutically acceptable salts thereof.

18. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

19. A method of inhibiting HEN integrase in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

20. A method for preventing or treating infection by HIN or for preventing, treating or delaying the onset of AIDS in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition which comprises the product prepared by combining an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

22. A combination useful for inhibiting HIN integrase, for treating or preventing infection by HIN, or for preventing, treating or delaying the onset of AIDS, which is a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of an HIN infection/AIDS antiviial agent selected from the group consisting of HIN protease inhibitors, non-nucleoside HIN reverse transcriptase inhibitors and nucleoside HIN reverse transcriptase inhibitors.