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WO2009154870A1 - Hiv integrase inhibitors - Google Patents

Hiv integrase inhibitors Download PDF

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Publication number
WO2009154870A1
WO2009154870A1 PCT/US2009/041598 US2009041598W WO2009154870A1 WO 2009154870 A1 WO2009154870 A1 WO 2009154870A1 US 2009041598 W US2009041598 W US 2009041598W WO 2009154870 A1 WO2009154870 A1 WO 2009154870A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
independently
haloalkyl
substituents
pharmaceutically acceptable
Prior art date
Application number
PCT/US2009/041598
Other languages
French (fr)
Inventor
Richard C. A. Isaacs
John S. Wai
Thorsten E. Fisher
Original Assignee
Merck & Co., Inc.
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Filing date
Publication date
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Publication of WO2009154870A1 publication Critical patent/WO2009154870A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention is directed to hydroxy substituted polyhydropyridazinopyridodiazocine trione compounds and hydroxy substituted polyhydropyrimidopyridodiazocine trione compounds (including hydrates and solvates thereof) and pharmaceutically acceptable salts thereof, their synthesis, and their use as inhibitors of the HIV integrase enzyme.
  • the compounds and hydrates, solvates and pharmaceutically acceptable salts thereof of the present invention are useful for preventing or treating infection by HIV and for preventing or treating or delaying the onset or progression of AIDS.
  • HIV human immunodeficiency virus
  • HIV-I HIV type-1
  • HIV-2 HIV-2
  • AIDS immunosuppressive disease
  • HIV seropositive individuals are initially asymptomatic but typically develop AIDS related complex (ARC) followed by AIDS.
  • Affected individuals exhibit severe immunosuppression which makes them highly susceptible to debilitating and ultimately fatal opportunistic infections.
  • a common feature of retrovirus replication is the insertion by virally-encoded integrase of +proviral DNA into the host cell genome, a required step in HIV replication in human T-lymphoid and monocytoid cells.
  • Integration is believed to be mediated by integrase in three steps: assembly of a stable nucleoprotein complex with viral DNA sequences; cleavage of two nucleotides from the 3' termini of the linear proviral DNA; covalent joining of the recessed 3' OH termini of the. proviral DNA at a staggered cut made at the host target site.
  • the fourth step in the process, repair synthesis of the resultant gap may be accomplished by cellular enzymes.
  • Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al, Nature, 313, 277(1985)].
  • Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, integrase and an HIV protease [Toh, H. et al., EMBO J. 4, 1267 (1985); Power, M.D. et al., Science, 231, 1567 (1986); Pearl, L.H. et al., Nature, 329, 351 (1987)]. All three enzymes have been shown to be essential for the replication of HIV.
  • ⁇ transcriptase inhibitors such as azidothymldine (AZT) and efavirenz, protease inhibitors such as indinavir and nelfinavir, and integrase inhibitors such as raltegravir.
  • the compounds of this invention are inhibitors of HIV integrase and inhibitors of HIV replication.
  • the inhibition of integrase in vitro and HIV replication in cells is a direct result of inhibiting the strand transfer reaction catalyzed by the recombinant integrase in vitro in HIV infected cells.
  • An advantage of the present invention is highly specific inhibition of HIV integrase and HIV replication. Another advantage is the inhibition of mutant strains of HIV integrase and the inhibition of the replication of the corresponding HIV.
  • US 7169780 and US 7217713 disclose certain N-substituted 5-hydroxy-6-oxo- l J 6-dihydro ⁇ yrimidine-4-carboxamides as HIV integrase inhibitors.
  • US 7211572 discloses nitrogen-containing fused ring compounds suitable for use as HIV integrase inhibitors.
  • US 7232819 discloses certain 5,6-dihydroxypyrimidine-4-carboxamides as HIV integrase inhibitors.
  • US 2006/0046985 discloses tetrahydro-4H-pyrido[l,2-a]pyrimidines and related compounds as HFV integrase inhibitors.
  • US 2007/0179196 discloses hydroxy tetrahydro-2,6-naphthyridine dione and hydroxy hexahydro-2,6-naphthyridine dione compounds as HIV integrase inhibitors useful , for example, in the treatment of infection by HIV.
  • WO 2005/110414 discloses hydroxy-substituted pyrazinopyrrolopyridazine dione compounds as HIV integrase inhibitors useful , for example, in the treatment of infection by HIV.
  • WO 2006/121831 discloses tricyclic analogs of hydroxy polyhydro-2, 6- naphthyridine dione compounds.
  • the compounds are inhibitors of HIV integrase and are useful, for example, in the treatment of infection by HIV.
  • the present invention is directed to hydroxy polyhydropyridazinopyridodiazocine triones and hydroxy polyhydropyrimidopyridodiazocine triones. These compounds are useful in the inhibition of HFV integrase, the prophylaxis of infection by HIV, the treatment of infection by HIV and in the prophylaxis, treatment, and delay in the onset or progression of AIDS and/or ARC, either as compounds or their pharmaceutically acceptable salts, or as pharmaceutical composition ingredients, whether or not in combination with other HIV/ AIDS antivirals, anti- infectives, immunomodulators, antibiotics or vaccines. More particularly, the present invention includes compounds of Formula I (including hydrates and solvates thereof) and pharmaceutically acceptable salts thereof:
  • Rl is C 1-6 alkyl, R J, or Cl -6 alkyl substituted with RJ, wherein RJ is CycA, AryA, HetA, or
  • HetP; R2 is:
  • R3A ; R3B ; R6A and R6B are each independently selected from the group consisting of: (1) H 5
  • N(RA)SO2R B N(RA)SO2N(RA)RB ⁇ N(RA)C(O)N(RA)RB, 0C(0)N(RA)RB S or OC(O)RA,
  • CO2RA; R4A, R4B, R5A and R5B are as defined in (A), (B), or (C) as follows:
  • R4A s R4B 5 R5A and R5B each independently selected from the group consisting of: (1) H,
  • Ci-6 alkyl (4) Ci-6 haloalkyl
  • OC(O)N(RA)RB each RA is independently H or Ci-6 alkyl; each RB is independently H or Cl .5 alkyl; CycA is a C3-8 cycloalkyl which is optionally substituted with a total of from 1 to 6 substituents, wherein:
  • V is an aryl which is optionally substituted with a total of from 1 to 5 substituents, wherein:
  • N(RA)RB 5 C(O)N(RA)RB, C(O)RA C ⁇ 2R A , SRA, S(O)RA 5
  • HetA is a heteroaryl which is optionally substituted with a total of from 1 to 5 substituents, wherein:
  • HetP is (i) 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
  • each S is optionally oxidized to S(O) or S(0)2 or (ii) a 6- to 10-membered saturated or mono-unsaturated, bridged or fused heterobicyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, where each S is optionally oxidized to S(O) or S(0)2; and wherein the saturated or mono-unsaturated heterocyclic or heterobicyclic ring is optionally substituted with a total of from 1 to 4 substituents, wherein:
  • substituents are each independently halogen, C 1-6 alkyl, Cl -5 haloalkyl, O-Ci-6 alkyl, O-Ci-6 haloalkyl, oxo, C(O)N(RA)RB 5 C(O)C(O)N(RA)RB, C(O)RA C02RA, SRA, S(O)RA, SO2RA or 802N(RA)RB, and
  • substituents are each independently CycD, AryD, HetD, or Ci_6 alkyl substituted with CycD, AryD, HetD; HetS independently has the same definition as HetP; each CycD is independently a C3-8 cycloalkyl which is optionally substituted with from 1 to 4 substituents each of which is independently halogen, Cj.g alkyl, OH, O-Ci_6 alkyl, or
  • each AryD is independently phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with from 1 to 5 substituents each of which is independently any one of the substituents (1) to (25) as set forth above in part (i) of the definition of AryA
  • each HetD is independently 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 any one of the substituents (1) to (25) as set forth above in part (i) of the definition of HetA
  • HetE is a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S 5 wherein the heteroaromatic ring is optionally substituted with from 1 to 4 substituents each of which is independently any one of the substituents (1) to (25) as set
  • each aryl is independently (i) phenyl, (ii) a 9- or 10-membered bicyclic, fused carbocyclic ring system in which at least one ring is aromatic, or (iii) an 11- to 14-membered tricyclic, fused carbocyclic ring system in which at least one ring is aromatic; and each heteroaryl is independently (i) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein each N is optionally in the form of an oxide, (ii) a 9- or 10-membered bicyclic, fused ring system, or (iii) an 11- to 14-membered tricyclic, fused ring system, wherein the fused ring system in (ii) or (iii) contains from 1 to 4 heteroatoms independently selected from N, O and S, and wherein in the
  • the present invention also includes pharmaceutical compositions containing a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • the present invention further includes methods for the treatment of AIDS, the delay in the onset or progression of AIDS, the prophylaxis of AIDS, the prophylaxis of infection by HIV, and the treatment of infection by HIV.
  • the present invention includes compounds of Formula I above (including hydrates and solvates thereof), and pharmaceutically acceptable salts thereof. These compounds are HIV integrase inhibitors (e.g., HIV-I integrase inhibitors).
  • a first embodiment of the present invention is a compound of Formula I (alternatively and more simply referred to as “Compound I”), or a pharmaceutically acceptable salt thereof, wherein R ⁇ is: (1) H,
  • a third embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein RJ is AryA or HetA; and all other variables are as originally defined or as defined in Embodiment El.
  • a fourth embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein RJ is AryA; and all other variables are as originally defined or as defined in Embodiment El.
  • a fifth embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein RJ is HetA; and all other variables are as originally defined or as defined in Embodiment El.
  • a sixth embodiment of the present invention is a compound of
  • Vl and V2 are each independently:
  • HetD is a 5- or ⁇ -membered heteroaromatic ring containing a total of from 1 to 3 heteroatoms independently selected from 1 to 3 N atoms, from zero to 1 O atom, and from zero to 1 S atom, wherein the heteroaromatic ring is optionally substituted with from 1 to 3 substituents each of which is independently Ci_4 alkyl, OH, O-Q-4 alkyl, halogen, CN 5 C(O)N(RA)RB, C(O)RA, C(O)ORA, O r SO 2 RA 5
  • HetZ is a 5- or 6-membered saturated heterocyclic ring containing a total of from 1 to 2 heteroatoms selected from 1 to 2 N atoms, zero to 1 O atom, and zero to 1 S atom, wherein the S atom is optionally S(O) or SO 2 , wherein the saturated heterocyclic ring is optionally substituted with from 1 to 2 substituents each of which is independently Cl -4 alkyl, oxo, C(O)N(RA)RB 5 C(O)RA 5 CO 2 RA, or SO 2 RA, and with the proviso that when HetZ is attached to the rest of the compound via the C(O) moiety, then HetZ is attached to the C(O) via a ring N atom; or alternatively V 1 and V2 are respectively located on adjacent carbons in the phenyl ring and together form methylenedioxy or ethylenedioxy; and V3 is: (1) H,
  • a seventh embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Rl is: wherein Vl and V2 are each independently:
  • V3 is H, Cl, Br 5 F, CH 3 , or OCH 3 ; and all other variables are as originally defined or as defined in Embodiment El .
  • An eighth embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Rl is 4-fluorobenzyl,
  • a ninth embodiment of the present invention is a compound of
  • Ci-4 haloalkyl or (4) Cl -4 alkyl substituted with C(O)N(RA)RB 5 C(O)RA C ⁇ 2R A , S(O)RA, S ⁇ 2R A ,
  • HetE is a 5- or 6-membered heteroaromatic ring containing a total of from 1 to 3 heteroatoms independently selected from 1 to 3 N atoms, from zero to 1 O atom, and from zero to 1 S atom, wherein the heteroaromatic ring is optionally substituted with from 1 to 3 substituents each of which is independently Ci_4 alkyl, OH, O-Ci-4 alkyl, halogen, CN, C(O)N(RA)RB 5 C(O)RA 5 C(O)ORA or S ⁇ 2R A .
  • a tenth embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R2 is: (1) H, (2) Ci- 4 alkyl,
  • An eleventh embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R2 is:
  • V is C(O)N(RA)RB 1 C(O)RA, CO 2 RA S(O)RA, SO 2 RA, SO 2 N(RA)RB, ORA, or Het E; and all other variables are as originally defined or as defined in any one of the foregoing embodiments.
  • HetE is heteroaromatic ring selected from the group consisting of pyrazolyl, im ⁇ dazolyl, oxazolyl, isooxazolyl, thiazolyl, triazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein the ring is optionally substituted with CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , or CH(CH 3 )2.
  • a twelfth embodiment of the present invention is a compound of Formula I 5 or a pharmaceutically acceptable salt thereof, wherein R2 is: (D CH 3 , (2) CH 2 CH 3 , (3) CH 2 CH 2 CH 3 ,
  • V is C(O)N(RA)RB 5 C(O)RA C ⁇ 2R A , S(O)RA S ⁇ 2R A , and ail other variables are as originally defined or as defined in any one of the foregoing embodiments.
  • a thirteenth embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R3A and R3B are both H; R4A is H 5 C 1-4 alkyl, OH or HetS; wherein HetS is a 5 ⁇ or 6-membered saturated heterocyclic ring containing a total of from 1 to 2 heteroatoms selected from 1 to 2 N atoms, zero to 1 O atom, and zero to 1 S atom, wherein the S atom is optionally S(O) or SO2, wherein the saturated heterocyclic ring is optionally substituted with from 1 to 3 substituents each of which is independently C 1.4 alkyl, oxo, C(O)N(RA)RB, C(O)RA CO2RA, or S ⁇ 2R A ; R4B is H or C 1-4 alkyl; alternatively, R4A and R4B together form oxo; R5 A is H, C 1.4 alkyl, or OH
  • R5B is H or Ci -4 alkyl; alternatively, R5A and R5B together form oxo; provided that one, not both, of (a) R4A and R4B and (b) R5A and R5B are oxo;
  • R6A is H, C 1-4 alkyl, or Cl .4 alkyl substituted with OH;
  • R6B is H or Cl ⁇ t alkyl; and provided that:
  • a fourteenth embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R7 is H or C 1-4 alkyl; and all other variables are as originally defined or as defined in any one of the foregoing embodiments.
  • a fifteenth embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R? is H or C 1 -3 alkyl; and all other variables are as originally defined or as defined in any one of the foregoing embodiments.
  • a sixteenth embodiment of the present invention (Embodiment El 6) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R? is H or CH3; and all other variables are as originally defined or as defined in any one of the foregoing embodiments.
  • a seventeenth embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein RA and RB are each independently H or Cl -4 alkyl; and all other variables are as originally defined or as defined in any of the preceding embodiments.
  • An eighteenth embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein RA and RB are each independently H or Cl -3 alkyl; and all other variables are as originally defined or as defined in any of the preceding embodiments.
  • a nineteenth embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R A and RB are each independently H or CH3 ; and all other variables are as originally defined or as defined in any of the preceding embodiments.
  • a first class of compounds of the present invention includes compounds, and pharmaceutically acceptable salts thereof, selected I, wherein:
  • Vl and V2 are each independently:
  • HetD is a 5- or 6-membered heteroaromatic ring containing a total of from 1 to 3 heteroatoms independently selected from 1 to 3 N atoms, from zero to 1 O atom, and from zero to 1 S atom, wherein the heteroaromatic ring is optionally substituted with 1 to 3 substituents each of which is independently Cj -4 alkyl, OH 5 O-Ci-4 alkyl, halogen, CN 5 C(O)N(RA)RB, C(O)RA, C(O)ORA, O r SO2RA
  • HetZ is a 5- or 6-membered saturated heterocyclic ring containing a total of from 1 to 2 heteroatoms selected from 1 to 2 N atoms, zero to 1 O atom, and zero to 1 S atom, wherein the S atom is optionally S(O) or SO2, wherein the saturated heterocyclic ring is optionally substituted with from 1 to 2 substituents each of which is independently Cl .4 alkyl, oxo, C(O)N(RA)RB, C(O)RA 5 and with the proviso that when HetZ is attached to the rest of the compound via the C(O) moiety, then HetZ is attached to the C(O) via a ring N atom; or alternatively Vl and V2 are respectively located on adjacent carbons in the phenyl ring and together form methylenedioxy or ethylenedioxy; and V3 is:
  • R2 is:
  • R4A is H, C 1-4 alkyl, OH or HetS; wherein HetS is a 5- or 6-membered saturated heterocyclic ring containing a total of from 1 to 2 heteroatoms selected from 1 to 2 N atoms, zero to 1 O atom, and zero to 1 S atom, wherein the S atom is optionally S(O) or SO2, wherein the saturated heterocyclic ring is optionally substituted with from 1 to 3 substituents each of which is independently Cl .4 alkyl, oxo, C(O)N(RA)RB 5 C(O)RA 5 C ⁇ 2R A , or S ⁇ 2R A ;
  • R.4B is H or C 1-4 alkyl; alternatively, R4A and R4B together form oxo; R5A is H, C 1-4 alkyl, or OH; R5B is H or C i_4 alkyl; alternatively, R5A and R5B together form oxo; provided that one, not both, of (a) R4A and R4B and (b) R5A and R5B are oxo;
  • R6A is H, C 1-4 alkyl, or Cl .4 alkyl substituted with OH;
  • R6B is H or C 1-4 alkyl; and provided that:
  • R5A is not OH.
  • a second class of compounds of the present invention includes compounds, and pharmaceutically acceptable salts thereof, selected from compounds of Formula I, wherein:
  • Vl and V2 are each independently:
  • V is C(O)N(RA)RB 5 C(O)RA CO 2 RA 5 S(O)RA, SO 2 RA, or SO 2 N(RA)RB;
  • R3A and R3B are bolh H; R4A is H, CH 3 , or OH; R4B is H or CH 3 ; alternatively, R4A and R4B together form oxo;
  • R5A is H, CH 3 , or OH
  • R5B is H or CH 3 ; alternatively, R5A and R5B together form oxo; provided that one, not both, of (a) R4A and R4B and (b) R5A and R5B are oxo; R6A ls H or CH3;
  • R6B is H or CH3; and provided that:
  • a third class of compounds of the present invention includes compounds, and pharmaceutically acceptable salts thereof, selected from compounds of Formula
  • Rl is 4-fluorobenzyl, 3-chloro-4-fluorobenzyl, or 4-fluoro-3-methylbenzyl; one of G and T is N, and the other of G and T is CH; R2 is CH 3 ;
  • R3A and R3B are both H;
  • R4A is H, CH 3 , or OH;
  • R4B is H or CH 3 ; alternatively,, R.4A and R4B together form oxo;
  • R6A and R6B ⁇ 6 both H.
  • Another embodiment of the present invention is a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the compounds set forth in Examples 1 to 2.
  • Another embodiment of the present invention is Compound I, or a pharmaceutically acceptable salt thereof, as defined in any of the foregoing embodiments, aspects, classes, or sub-classes, wherein the compound or its salt is in a substantially pure form.
  • substantially pure means suitably at least about 60 wt.%, typically at least about 70 wt.%, preferably at least about 80 wt.%, more preferably at least about 90 wt.% (e.g., from about 90 wt.% to about 99 wt.%), even more preferably at least about 95 wt.% (e.g., from about 95 wt.% to about 99 wt.%, or from about 98 wt.% to 100 wt.%), and most preferably at least about 99 wt.% (e.g., 100 wt.%) of a product containing a compound Formula I or its salt (e.g., the product isolated from a reaction mixture affording the compound or salt) consists of the compound or salt.
  • a product containing a compound Formula I or its salt e.g., the product isolated from a reaction mixture affording the compound or salt
  • the level of purity of the compounds and salts can be determined using a standard method of analysis such as thin layer chromatography, gel electrophoresis, high performance liquid chromatography, and/or mass spectrometry. If more than one method of analysis is employed and the methods provide experimentally significant differences in the level of purity determined in a given sample, then the method providing the highest purity level governs.
  • a compound or salt of 100% purity is one which is free of detectable impurities as determined by a standard method of analysis.
  • a substantially pure compound can be either a substantially pure mixture of the stereoisomers or a substantially pure individual diastereomer or enantiomer.
  • compositions comprising an effective amount of
  • Compound I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition which comprises the product prepared by combining (e.g., mixing) an effective amount of Compound I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • anti-HIV agent selected from the group consisting of HFV antiviral agents, immunomodulators, and anti-infective agents.
  • anti-HIV agent is an antiviral selected from the group consisting of HIV protease inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, nucleoside HIV reverse transcriptase inhibitors, HIV integrase inhibitors other than a compound of Formula I, HIV fusion inhibitors, and HIV entry inhibitors.
  • a combination which is (i) Compound I, or a pharmaceutically acceptable salt thereof, and (ii) an anti-HIV agent selected from the group consisting of HIV antiviral agents, immunomodulators, and anti-infective agents; wherein the compound of Formula I and the anti- HIV agent are each employed in an amount that renders the combination effective for the inhibition of HIV integrase, for the treatment or prophylaxis of infection by HIV, or for the treatment, prophylaxis or delay in the onset or progression of AIDS.
  • anti-HIV agent is an antiviral selected from the group consisting of HIV protease inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, nucleoside HIV reverse transcriptase inhibitors, HIV integrase inhibitors other than Compound I, HIV fusion inhibitors, and HIV entry inhibitors.
  • a method of inhibiting HIV integrase in a subject in need thereof which comprises administering to the subject an effective amount of Compound I, or a pharmaceutically acceptable salt thereof.
  • (k) The method of (j), wherein the compound is administered in combination with an effective amount of at least one antiviral selected from the group consisting of HIV protease inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, nucleoside HIV reverse transcriptase inhibitors, HIY integrase inhibitors other than Compound I, HIV fusion inhibitors, and HIV entry inhibitors.
  • at least one antiviral selected from the group consisting of HIV protease inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, nucleoside HIV reverse transcriptase inhibitors, HIY integrase inhibitors other than Compound I, HIV fusion inhibitors, and HIV entry inhibitors.
  • a method of inhibiting HFV integrase e.g., HIV-I integrase
  • a method for the treatment or prophylaxis of infection by HIV e.g., HIV-I
  • a method for the treatment or prophylaxis of infection by HIV e.g., HIV-I
  • a method for the treatment or prophylaxis of infection by HIV e.g., HIV-I
  • a method for the treatment or prophylaxis of infection by HIV e.g., HIV-I
  • a method for the treatment or prophylaxis of infection by HIV e.g., HIV-I
  • a method for the treatment, prophylaxis, or delay in the onset or progression of AIDS e.g., AIDS due to HIV-I
  • Additional embodiments of the invention include the pharmaceutical compositions, combinations and methods set forth in (a)-(n) above and the uses (i)(a)-(e) through (iii)(a)-(e) set forth in the preceding paragraph, wherein the compound of the present invention employed therein is a compound of one of the embodiments, classes or sub-classes described above. In all of these embodiments etc., the compound may optionally be used in the form of a pharmaceutically acceptable salt.
  • Additional embodiments of the present invention include each of the pharmaceutical compositions, combinations, methods and uses set forth in the preceding paragraphs, wherein the compound of the present invention or its salt employed therein is substantially pure.
  • a pharmaceutical composition comprising Compound I or its salt and a pharmaceutically acceptable carrier and optionally one or more excipients, it is understood that the term “substantially pure” is in reference to a compound of Formula I or its salt per se.
  • Still additional embodiments of the present invention include the pharmaceutical compositions, combinations and methods set forth in (a)-(n) above and the uses (i)(a)-(e) through (iii)(a) ⁇ (e) set forth above, wherein the HIV of interest is HIV-I.
  • the compound of Formula I is employed in an amount effective against HIV-I and the anti-HIV agent is an HIV-I antiviral selected from the group consisting of HIV-I protease inhibitors, HIV-I reverse transcriptase inhibitors, HIV-I integrase inhibitors other than a compound of Formula I, HIV-I entry inhibitors and HIV-I fusion inhibitors.
  • alkyl refers to any monovalent straight or branched chain, saturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range.
  • Ci -6 alkyl (or “Ci-Cg atkyl”) refers to any of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n ⁇ and iso- propyl, ethyl and methyl.
  • C i_4 alkyl refers to n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.
  • alkylene refers to any divalent linear or branched chain aliphatic hydrocarbon radical (alternatively referred to as “alkanediyl”) having a number of carbon atoms in the specified range.
  • alkanediyl an alkanediyl
  • -Ci -6 alkylene- refers to any of the Cl to C ⁇ linear or branched alkylenes
  • -C1-.4 alkylene- refers to any of the C] to C4 linear or branched alkylenes.
  • a class of alkylenes of interest with respect to the invention is -(CH2)l-6 ⁇ ?
  • subclasses of particular interest include ⁇ (CH2)l-4- 5 -(CH2)2-4-» -(CH2)l-3-, -(CH2)2-3- > -(CH2) 1-2-j and -CH2-.
  • Another sub-class of interest is an alkylene selected from the group consisting of -CH2-, -CH(CH3>, and -C(CH3)2--
  • haloalkyl refers to an alkyl group as defined above in which one or more of the hydrogen atoms have been replaced with a halogen (i.e., F, Cl, Br and/or I).
  • a halogen i.e., F, Cl, Br and/or I.
  • Ci- ⁇ haloalkyl or “Ci-Cg haloalkyl” refers to a Cj to Ce linear or branched alkyl group as defined above with one or more halogen substituents.
  • fluoroalkyl has an analogous meaning except that the halogen substituents are restricted to fluoro.
  • Suitable fluoroalkyls include the series (CH2) ⁇ -4CF3 (i.e., trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3- trifluoro-n-propyl, etc.).
  • a fluoroalkyl of particular interest is CF3.
  • C(O) refers to carbonyl.
  • S(O)2 and “SO2” each refer to sulfonyl.
  • S(O) refers to sulfinyl.
  • cycloalkyl refers to any cyclic ring of an alkane having a number of carbon atoms in the specified range.
  • C3-8 cycloalkyl refers to any of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • halogen refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro, chloro, bromo, and iodo).
  • aryl refers to (i) phenyl, (ii) a 9- or 10-membered bicycHc, fused carbocyclic ring system in which at least one ring is aromatic, or (iii) an 11- to 14-membered tricyclic, fused carbocyclic ring system in which at least one ring is aromatic.
  • Suitable aryls include, for example, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indenyl, indanyl, acenaphthenyl and fluorenyl.
  • a class of aryls suitable for use in the present invention is phenyl, naphthyl, and indenyl.
  • Another class of suitable aryls is phenyl and naphthyl.
  • a particularly suitable aryl is phenyl.
  • a class of heteroaryls suitable for use in the present invention consists of 5- and 6-membered heteroaromatic rings containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein each N is optionally in the form of an oxide.
  • Heteroaryls belonging to this class include pyridinyl. pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, and oxadiazolyl.
  • a sub-class of heteroaryls suitable for use in the present invention consists of * , , , ,
  • saturated or mono-unsaturated heterocyclic ring refers to (i) 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, where each S is optionally oxidized to S(O) or S(O)2 or (ii) a 6- to 10-membered saturated or mono-unsaturated, bridged or fused heterobicyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, where each S is optionally oxidized to S(O) or S(O)2-
  • Suitable saturated heterocycles include, for example, azetidinyl, pyrrolidinyl, imidazolinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl,
  • Suitable mono-unsaturated heterocyclic rings include those corresponding to the saturated heterocyclic rings listed in. the preceding sentence in which a single bond is replaced with a double bond (e.g., a carbon-carbon single bond is replaced with a carbon-carbon double bond).
  • a class of saturated heterocycles suitable for use in the present invention consists of 4- to 7-membered saturated heterocyclic rings containing from 1 to 3 heteroatoms independently selected from 1 to 3 N atoms, zero or 1 O atom, and zero or 1 S atom.
  • a sub-class of saturated heterocycles suitable for use in the present invention consists of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl.
  • a heterocyclic ring described as containing from “1 to 4 heteroatoms” means the ring can contain 1, 2, 3 or 4 heteroatoms. It is also to be understood that any range cited herein includes within its scope all of the sub-ranges within that range. Thus, for example, a heterocyclic ring described as containing from “1 to 4 heteroatoms” is intended to include as aspects thereof, heterocyclic rings containing 2 to 4 heteroatoms, 3 or 4 heteroatoms, 1 to 3 heteroatoms, 2 or 3 heteroatoms, 1 or 2 heteroatoms, 1 heteroatom, 2 heteroatoms, 3 heteroatoms and 4 heteroatoms.
  • substituted 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 and results in a stable compound.
  • substitution by a named substituent is permitted on any atom in a ring (e.g., aryl, a heteroaromatic ring, or a saturated or mono-unsaturated heterocyclic ring) provided such ring substitution is chemically allowed and results in a stable compound.
  • any of the various carbocyclic and heterocyclic rings and ring systems defined herein may be attached to the rest of the compound at any ring atom (i.e., any carbon atom or any heteroatom) provided that a stable compound results.
  • a “stable” compound is a compound which can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic or prophylactic administration to a subject).
  • R.2 in Formula I can be Ci-6 alkyl substituted with C(O)-N(RA)-C2-6 alkylene-ORB. It is understood that the N(RA) and the OR ⁇ are typically not both attached to the same carbon of the C2-6 alkylene because typically the resulting hemlaminal is not chemically stable.
  • certain of the compounds of the present invention can have asymmetric centers and can occur as mixtures of stereoisomers, or as individual diastereomers or enantiomers. All isomeric forms of these compounds, whether isolated or in mixtures, are within the scope of the present invention.
  • Compounds of the present invention having a hydroxy substituent susceptible to keto-enol tautomerism on a carbon atom of a heteroaromatic ring are understood to include compounds in which only the hydroxy is present, compounds in which only the tautomeric keto form (i.e., an oxo substitutent) is present, and compounds in which the keto and enol forms are both present. Certain of the compounds of the present invention can exhibit a chirality resulting from the presence of bulky substituents that hinder the otherwise free rotation about a bond.
  • rotational enantiomers are named atropisomers, and the interconversion can be sufficiently slow to allow for their separation and characterization. See, e.g., J. March, Advanced Organic Chemistry. 4th Edition, John Wiley & Sons, 1992, pp. 101-102; and Ahmed et al, Tetrahedron 1998, 13277.
  • certain of the compounds of the present invention as exemplified with structure A below in which there could be sufficient hindrance to rotation along the bond indicated with an arrow to permit separation of the enantiomers using, e.g., column chromatography on a chiral stationary phase.
  • the present invention includes atropisomers of compounds embraced by Formula I, singly and in mixtures.
  • the compounds of the present inventions are useful in the inhibition of HIV integrase (e.g., HIV-I integrase), the prophylaxis or treatment of infection by HIV and the prophylaxis, treatment or the delay in the onset or progression of consequent pathological conditions such as AIDS.
  • HIV integrase e.g., HIV-I integrase
  • the prophylaxis of AIDS, treating AIDS 5 delaying the onset or progression of AIDS, the prophylaxis of infection by HIV 5 or treating infection by HIV is defined as including, but not limited to, treatment of a wide range of states of HIV infection: AIDS, ARC (AIDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV.
  • the compounds of this invention are useful in treating infection by HIV after suspected past exposure to HIV 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.
  • the compounds of this invention are useful for isolating enzyme mutants, which are excellent screening tools for more powerful antiviral compounds.
  • the compounds of this invention are useful in establishing or determining the binding site of other antivirals to HIV integrase, e.g., by competitive inhibition.
  • the compounds of this invention can be commercial products to be sold for these purposes.
  • the compounds of the present invention can be administered in the form of pharmaceutically acceptable salts.
  • 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, or benzoic acid.
  • a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, or benzoic acid.
  • Compounds of the invention carry an acidic moiety and thus 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.
  • suitable organic ligands such as quaternary ammonium salts.
  • pharmaceutically acceptable esters can be employed to modify the solubility or hydrolysis characteristics of the compound.
  • administration and variants thereof (e.g., "administered” or
  • administering in reference to a compound of the invention mean providing the compound or its salt (or a hydrate, solvate, or individual stereoisomer thereof) to the individual in need of treatment or prophylaxis.
  • active agents e.g., antiviral agents useful for the prophylaxis or treatment of HFV infection or AIDS
  • administration and its variants are each understood to include provision of the compound and other agents at the same time or at different times.
  • the agents of a combination are administered at the same time, they can be administered together in a single composition or they can be administered separately.
  • the terra "composition” is intended to encompass a product comprising the specified ingredients, as well as any product which results, directly or indirectly, from combining the specified ingredients.
  • the term "subject” refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
  • the term "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.
  • the effective amount is a "therapeutically effective amount” for the alleviation of the symptoms of the disease or condition being treated.
  • the effective amount is a "prophylactically effective amount” for prophylaxis of the symptoms of the disease or condition being prevented.
  • the term also includes herein the amount of active compound sufficient to inhibit HIV integrase and thereby elicit the response being sought (i.e., an "inhibition effective amount").
  • an “inhibition effective amount” 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 compounds of the present invention can be administered by any means that produces contact of the active agent with the agent's site of action. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but typically are administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
  • the compounds of the invention can, for example, be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectaliy, in the form of a unit dosage of a pharmaceutical composition containing an effective amount of the compound and conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles.
  • Liquid preparations suitable for oral administration e.g., suspensions, syrups, elixirs and the like
  • Solid preparations suitable for oral administration can be prepared according to techniques known in the art and can employ such solid excipients as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like.
  • Parenteral compositions can be prepared according to techniques known in the art and typically employ sterile water as a carrier and optionally other ingredients, such as a solubility aid.
  • injectable solutions can be prepared according to methods known in the art wherein the carrier comprises a saline solution, a glucose solution or a solution containing a mixture of saline and glucose.
  • compositions of the present invention are described in detail in Remington's Pharmaceutical Sciences, 18 th edition, edited by A. R. Gennaro, Mack Publishing Co., 1990 and in Remington - The Science and Practice of Pharmacy, 21 st edtion, Lippincott Williams & Wilkins, 2005.
  • the compounds of this invention can be administered orally in a dosage range of about 0.001 to about 1000 mg/kg of mammal (e.g., human) body weight per day in a single dose or in divided doses.
  • mammal e.g., human
  • One preferred dosage range is about 0.01 to about 500 mg/kg body weight per day orally in a single dose or in divided doses.
  • compositions can be provided in the form of tablets or capsules containing about 1.0 to about 500 milligrams of the active ingredient, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, and 500 milligrams 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 varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
  • an anti-HIV agent is any agent which is directly or indirectly effective in the inhibition of HIV integrase or another enzyme required for HTV replication or infection, the treatment or prophylaxis of HIV infection, and/or the treatment, prophylaxis or delay in the onset or progression of AIDS. It is understood that an anti-HIV agent is effective in treating, preventing, or delaying the onset or progression of HIV infection or AIDS and/or diseases or conditions arising therefrom or associated therewith.
  • 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 HIV antivirals, imunomodulators, antiinfectives, or vaccines useful for treating HIV infection or AIDS, such as those disclosed in Table 1 of WO 01/38332 or in the Table in WO 02/30930.
  • Suitable HIV antivirals for use in combination with the compounds of the present invention include, for example, those listed in Table A as follows: Table A
  • Some of the drugs listed in the table are used in a salt form; e.g., abacavir sulfate, indinavir sulfate, atazanavir sulfate, nelfinavir mesylate.
  • HIV antiviral agents and other agents will typically be employed in these combinations in their conventional dosage ranges and regimens as reported in the art, including, for example, the dosages described in the Physicians' Desk Reference, Thomson PDR, Thomson PDR 1 57 th edition (2003), the 58 th edition (2004), the 59 th edition (2005), and subsequent editions thereof.
  • the dosage ranges for a compound of the invention in these combinations are the same as those set forth above.
  • 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.
  • Scheme 1 depicts a method for preparing 5-(alkyloxy)-3-halo-4- (alkyloxycarbonyl)-6-oxo-l ,6-dihydropyridine-2-carboxylic acids 1-F, which is a key intermediate for the preparation of 5-hydroxy-9,10,l l ? 12-tetrahydro-3H- pyridazino[4 ! ) 5 t :3 ! 4] ⁇ yrido[l,2-a][l,4]diazocme-4,6,13(8H)-triones 3-D 5 from dialkyl 2- hydroxybut-2-enedioates.
  • Scheme 2 depicts a method for preparing an alkyl 9-(alkyloxy)-l l-bromo-1,8- dioxo-1 ,3,4,5,6 ; ,8-hexahydro-2H-pyrido[ 1 ,2-a][l ,4]diazocine ⁇ 10-carboxylate of formula 2-C from 5-(alkyloxy)-3-halo-4-(alkyloxycarbonyl)-6-oxo-l,6-dihydropyridine-2-carboxylic acid 1-F 5 wherein the intermediate 1-F is treated with a suitable substituted aminoalcohol and an amide coupling reagent (e.g., EDC or BOP) to provide the amide product 2- A.
  • a suitable substituted aminoalcohol e.g., EDC or BOP
  • Scheme 4 depicts a method for preparing a 5 -aIkoxy-4 5 6-dioxo-3 ,4,6,7- tetrahydropyrido[3 j 4-d]pyrimidine-8 ⁇ carboxylic acid of formula 4-1, a key intermediate for the preparation of 5 -hydroxy-9, 10,11,12-tetrahydro-3 H-pyrimido[4',5 ' : 3 ,4]pyrido [1,2- a][l,4]diazocine-4,6,13(8H)-trione 5-C.
  • the 8-carboxyl group can be installed through a sequence of oxidation, acetylation, rearrangement, sulfonylation, and palladium(O) catalyzed carbonylation.
  • the intermediate 4-E can be treated with a suitable oxidizing agent (e.g., hydrogen peroxide or m-chloroperbenzoic acid) as described in Sharpless et al., J Org. Chem. 1998 > 1740 and Caron et al., Tet, Letters 2000, 2299 and references cited therein, to obtain the corresponding N-oxide, which can then be treated as described in Suzuki et ai., J Med. Chem.
  • a suitable oxidizing agent e.g., hydrogen peroxide or m-chloroperbenzoic acid
  • Scheme 4a depicts an alternative, though less efficient, route to 4-1 via a cyano analog, wherein 4-E is treated with a suitable oxidizing agent to provide the N-oxide which can then be treated with a cyanating agent (e.g., trimethylsilyl cyanide in the presence of TEA) at elevated temperature (e.g., about 90°C) in an appropriate solvent mixture such as acetonitrile/- dichloroethane/dioxane to provide nitrile 4al.
  • a cyanating agent e.g., trimethylsilyl cyanide in the presence of TEA
  • a cyanating agent e.g., trimethylsilyl cyanide in the presence of TEA
  • a cyanating agent e.g., trimethylsilyl cyanide in the presence of TEA
  • elevated temperature e.g., about 90°C
  • an appropriate solvent mixture such as acetonitrile/- dichloroethane/
  • Scheme 5 depicts a sequence of reactions, similar to that illustrated in Scheme 2, in which 4-1 is coupled with appropriately substituted aminoalcohols, the resultant alcohol 5-A is sulfonylated and cyclized in the presence of base (e.g., K2CO3 or CS2CO3) to provide the
  • the protecting groups may be removed at a convenient subsequent stage using methods known in the art.
  • the interfering group can be introduced into the molecule subsequent to the reaction step of concern.
  • ammonia gas was bubbled vigorously through a cold (3 0 C 5 ice bath) mixture of diethyl oxalacetate (50.0 g, 0.265 mol) and chloroacetone (29.5 g, 0319 mol) in anhydrous THF (1 L) stirred with a mechanical stirrer. The solution turned dark orange and the temperature increased to 12 0 C and then dropped to 5°C. Ammonium acetate (40.9 g, 0.531 mol) was added and the reaction mixture was heated at reflux for 3 hours. The resultant bright yellow product mixture was cooled to room temperature and then slowly cooled to 5 0 C using an ice bath.
  • Step 3 Ethyl 3 -(benzyloxy)-6-methyl -2-oxo- 1 ,2-dihydropyridine-4-carboxylate
  • Step 5 Ethyl-3 -(benzyloxy)-5 -bromo-6-formyl-2-oxo- 1 ,2-dmydropyridine-4 ⁇ carboxylate
  • Step 6 5-(Benzyloxy)-3 ⁇ bromo-4-(ethoxycarbonyl)-6-oxo- 1 ,6-dihydropyridine-2- carboxylic acid
  • Step 8 2-(Benzyloxy)-4-hydroxy-N,3 ,3 -trimethylbutanamide
  • Step 10 Ethyl 3 -(benzy ⁇ oxy>6- ⁇ [[2-(benzyloxy) ⁇ 4-hydroxy-3 ,3 -dimethylbutyl] (methyl- amino]carbonyl ⁇ -5-bromo-2-oxo-l,2-dihydropyridine-4-carboxylate
  • Step 11 Ethyl-3-(benzyloxy)-6- ⁇ [ ⁇ 2-(benzyloxy)-3,3-dimethyl-4-
  • Step 12 Ethyl-4,9-bis(benzyloxy)-l l-bromo-2,5 J 5-trimethyl-l,8-dioxo-l,3,4,5,6,8- hexahydro-2H-pyrido[l ,2-a] [1 ,4]diazocine-l O-carboxylate
  • Step 13 Ethyl ⁇ -bis ⁇ enzyloxy ⁇ -trimethyl-l ⁇ -dioxo-l l-vinyl-l ⁇ - hexahydro-2H-pyrido[ 1 ,2-a] [ 1 ,4]diazocine- 1 O-carboxylate
  • Step 16 5,10-bis(benzyloxy) ⁇ 3-(4-fluorobenzyl)-9,9, 12-trimethyl-9, 10, 11 , 12-tetrahydro-
  • Step 17 3-(4-Fluorobenzyl)-5, 10-dihydroxy-9,9, 12-trimethyl-9,l 0,11 ,12-tetrahydro-3H- pyridazino[4',5':3,4]pyrido[l 5 2-a] [1 ,4]diazocine-4,6, 13(8H)-trione
  • Step l 7er/-butyl (5-methoxypyridin-3-yl)carbarnate
  • Step 5 3-(3-Chloro-4-fiuorobenzyl)-5-methoxypyrido[3 ,4-d]pvrimidin-4(3H)-one-7- oxide
  • Step 6 3-(3-Chloro-4-fiuorobenzyl)-5-methoxy-4-oxo-3,4-dihydropyrido[3,4- d] ⁇ yrimidin-8-yl acetate
  • Step 7 3-(3 ⁇ Chloro-4-fluorobenzyl)-8-hydroxy-5-methoxypyrido[3,4-d]pyrimidin-4(3H)- one
  • Step 8 3 -(3 -Chloro-4-fiuorobenzyl)-5 -methoxy-4-oxo-3 ,4-dihydropyrido [3,4- d] pyrimidin-8 -yl trifluoromethanesulfonate
  • Step 9 Methyl-3 -(3 -chloro-4-fluorobenzyl)- 5-methoxy-4-oxo-3 ,4-dihydropyrido [3 ,4- d] pyrimidine-8-carboxyIate
  • Step 11 Methyl 6-(acetyloxy)-3 -(3 -chloro-4-fluorobenzyl)-5-metho ⁇ y-4-oxo-3 ,4- dihydropyrido [3 ,4-d]pyrimidine-8 -carboxylate
  • Step 12 3-(3-Chloro-4-fluorobenzyl)-6-hydroxy-5-methoxy-4-oxo-3 5 4-dihydropyrido[3,4- d]pyrimidine-8-carboxylic acid
  • Step 13 3 -(3 -Chloro-4-fluorobenzyl)-6-hydroxy-N-(4-hydroxybutyl)- 5 -methoxy-N- methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-8-carboxamide
  • Step 14 3-(3-Chloro-4-fluorobenzyl)-5-methoxy-8-[(methyl ⁇ 4- [(methylsulfonyl)oxy] butyl ⁇ amino)carbonyl] -4-oxo-3 ,4-dihydropyrido [3 ,4- d]pyrimidin-6-yl methanesulfonate
  • Step 15 3-(3 -Chloro-4-fluorobenzyl)-5-methoxy- 12-methyl-9, 10,11,12-tetrahydro-3H- pyrimido[4 ! ,5':3,4]pyrido[l,2-a][l > 4]diazocine-4,6,13(8H)-trione
  • Step 16 3-(3-Chloro-4-fluorobenzyl)-5-hydroxy-12-methyl-9 ; 10 5 l l 5 12-tetrahydro-3H- pyr ⁇ mido[4 t ,5':3,4]pyrido[l,2-a][l,4]diazocine-4 : ,6 > 13(8H)-trione
  • 3-(3-chloro-4-fluorobenzyl)-5-methoxy-12-methyI- 9,10,11 J 12-tetrahydro-3H-pyrimido[4 1 s 5':3 s 4]pyrido[l,2-a][l ; 4]diazocine-4,6,13(8H)-trione (30 mg, 0.067 mmol) in CH2CI2 (500 ⁇ L), a solution of boron tribromide in CH2CI2 (201 ⁇ L, IM,
  • Cytotoxicity was determined by microscopic examination of the cells in each well in the spread assay, wherein a trained analyst observed each culture for any of the following morphological changes as compared to the control cultures: pH imbalance, cell abnormality, cytostatic, cytopathic, or crystallization (i.e., the compound is not soluble or forms crystals in the well).
  • the toxicity value assigned to a given compound is the lowest concentration of the compound at which one of the above changes is observed.
  • the compounds set forth in Examples 1 and 2 exhibited no cytotoxicity at concentrations up to 10 micromolar.

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Abstract

Tricyclic compounds of Formula I are inhibitors of HIV integrase and inhibitors of HIV replication: (I) wherein G, T, R1, R2, R3A, R3B, R4A, R4B, R5A, R5B, R6A and R6B are defined herein. The compounds are useful for the prophylaxis or treatment of infection by HIV and the prophylaxis, treatment, or delay in the onset or progression of AIDS. The compounds are employed against HIV infection and AIDS as compounds per se (or as hydrates or solvates thereof) or in the form of pharmaceutically acceptable salts. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines.

Description

TITLE OF THE INVENTION HIV JNTEGRASE INHIBITORS
CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No.
61/126,430 (filed May 5, 2008), the disclosure of which is hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION The present invention is directed to hydroxy substituted polyhydropyridazinopyridodiazocine trione compounds and hydroxy substituted polyhydropyrimidopyridodiazocine trione compounds (including hydrates and solvates thereof) and pharmaceutically acceptable salts thereof, their synthesis, and their use as inhibitors of the HIV integrase enzyme. The compounds and hydrates, solvates and pharmaceutically acceptable salts thereof of the present invention are useful for preventing or treating infection by HIV and for preventing or treating or delaying the onset or progression of AIDS.
BACKGROUND OF THE INVENTION
The retrovirus designated human immunodeficiency virus (HIV), particularly the strains known as HIV type-1 (HIV-I ) and type-2 (HIV-2) viruses, have been etiologically linked to the immunosuppressive disease known as acquired immunodeficiency syndrome (AIDS). HIV seropositive individuals are initially asymptomatic but typically develop AIDS related complex (ARC) followed by AIDS. Affected individuals exhibit severe immunosuppression which makes them highly susceptible to debilitating and ultimately fatal opportunistic infections. A common feature of retrovirus replication is the insertion by virally-encoded integrase of +proviral DNA into the host cell genome, a required step in HIV replication in human T-lymphoid and monocytoid cells. Integration is believed to be mediated by integrase in three steps: assembly of a stable nucleoprotein complex with viral DNA sequences; cleavage of two nucleotides from the 3' termini of the linear proviral DNA; covalent joining of the recessed 3' OH termini of the. proviral DNA at a staggered cut made at the host target site. The fourth step in the process, repair synthesis of the resultant gap, may be accomplished by cellular enzymes.
Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al, Nature, 313, 277(1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, integrase and an HIV protease [Toh, H. et al., EMBO J. 4, 1267 (1985); Power, M.D. et al., Science, 231, 1567 (1986); Pearl, L.H. et al., Nature, 329, 351 (1987)]. All three enzymes have been shown to be essential for the replication of HIV.
It is known that some antiviral compounds which act as inhibitors of HIV replication are effective agents in the treatment of AIDS and similar diseases, including reverse
\ transcriptase inhibitors such as azidothymldine (AZT) and efavirenz, protease inhibitors such as indinavir and nelfinavir, and integrase inhibitors such as raltegravir. The compounds of this invention are inhibitors of HIV integrase and inhibitors of HIV replication. The inhibition of integrase in vitro and HIV replication in cells is a direct result of inhibiting the strand transfer reaction catalyzed by the recombinant integrase in vitro in HIV infected cells. An advantage of the present invention is highly specific inhibition of HIV integrase and HIV replication. Another advantage is the inhibition of mutant strains of HIV integrase and the inhibition of the replication of the corresponding HIV.
The following references are of interest as background: US 6921759, US 2005/0176718, US 6919351 and US 6841558 disclose aza- and polyaza-naphthalenyl carboxamides (including l,6-naphthyridine-7~carboxamides) as HIV integrase inhibitors useful, for example, in the treatment of infection by HFV.
US 7169780 and US 7217713 disclose certain N-substituted 5-hydroxy-6-oxo- lJ6-dihydroρyrimidine-4-carboxamides as HIV integrase inhibitors. US 7211572 discloses nitrogen-containing fused ring compounds suitable for use as HIV integrase inhibitors.
US 7232819 discloses certain 5,6-dihydroxypyrimidine-4-carboxamides as HIV integrase inhibitors.
US 2006/0046985 discloses tetrahydro-4H-pyrido[l,2-a]pyrimidines and related compounds as HFV integrase inhibitors.
US 2007/0179196 discloses hydroxy tetrahydro-2,6-naphthyridine dione and hydroxy hexahydro-2,6-naphthyridine dione compounds as HIV integrase inhibitors useful , for example, in the treatment of infection by HIV.
WO 2005/110414 discloses hydroxy-substituted pyrazinopyrrolopyridazine dione compounds as HIV integrase inhibitors useful , for example, in the treatment of infection by HIV.
WO 2006/121831 discloses tricyclic analogs of hydroxy polyhydro-2, 6- naphthyridine dione compounds. The compounds are inhibitors of HIV integrase and are useful, for example, in the treatment of infection by HIV.
SUMMARY OF THE INVENTION
The present invention is directed to hydroxy polyhydropyridazinopyridodiazocine triones and hydroxy polyhydropyrimidopyridodiazocine triones. These compounds are useful in the inhibition of HFV integrase, the prophylaxis of infection by HIV, the treatment of infection by HIV and in the prophylaxis, treatment, and delay in the onset or progression of AIDS and/or ARC, either as compounds or their pharmaceutically acceptable salts, or as pharmaceutical composition ingredients, whether or not in combination with other HIV/ AIDS antivirals, anti- infectives, immunomodulators, antibiotics or vaccines. More particularly, the present invention includes compounds of Formula I (including hydrates and solvates thereof) and pharmaceutically acceptable salts thereof:
Figure imgf000004_0001
wherein:
Rl is C 1-6 alkyl, R J, or Cl -6 alkyl substituted with RJ, wherein RJ is CycA, AryA, HetA, or
HetP; R2 is:
(1) H, (2) C 1-6 alkyl,
(3) Ci-6 haloalkyl, or
(4) C i _6 alkyl substituted with C(O)N(RA)RB, C(O)RA, Cθ2RA, C(O)-N(RA)-C2-6 alkylene-ORB, S(O)RA, Sθ2RA, Sθ2N(RA)RB? ORA, or HetE;
R3A; R3B; R6A and R6B are each independently selected from the group consisting of: (1) H5
(2) Ci-6 alkyl,
(3) C i_6 haloalkyl,
(4) Ci-6 alkyl substituted with OH, O-Ci-6 alkyl, O-Ci-6 haloalkyl, CN, N(RA)RB5 C(O)N(RA)RB, C(O)RA CO2RA, C(O)-N(RA)-C2-6 alkylene-ORB, SRA, S(O)RA, SO2RA, SO2N(RA)RB9 N(RA)C(O)RB, N(RA)C02RB ?
N(RA)SO2RB, N(RA)SO2N(RA)RB} N(RA)C(O)N(RA)RB, 0C(0)N(RA)RBS or OC(O)RA,
(5) C(O)N(RA)RB,
(6) C(O)C(O)N(RA)RB, (7) C(O)RA, and
(8) CO2RA; R4A, R4B, R5A and R5B are as defined in (A), (B), or (C) as follows:
(A) R4As R4B5 R5A and R5B each independently selected from the group consisting of: (1) H,
(2) halogen,
(3) Ci-6 alkyl, (4) Ci-6 haloalkyl,
(5) C i -6 alkyl substituted with OH, O-C i _6 alkyl, O-Ci _6 haloalkyl, CN5 N(RA)RB, C(O)N(RA)RB5 C(O)RA, Cθ2RA, C(O)-N(RA)-C2-6 alkylene-ORB, SRA, S(O)RA, SO2RA, S02N(RA)RB, N(RA)C(O)RB, N(RA)C02RB, N(RA)Sθ2RB, N(RA)S02N(RA)RBS
N(RA)C(O)N(RA)RB; OC(O)N(RA)RB, or OC(O)RA,
(6) O-C 1-6 alkyl,
(7) O-Ci_6 haloalkyl,
(8) C(O)N(RA)RB, (9) C(O)C(O)N(RA)RB,
Figure imgf000005_0001
(12) SRA
(13) S(O)RA, (14) Sθ2RA,
Figure imgf000005_0002
(16) OH, and
(17) HetS;
(B) R4A and R4B together form oxo or =C(RA)RB; and R5 A and R5B are as defined in (A); or
(C) R5A and R5B together form oxo or =C(RA)RB? and R4A and R4B are as defined in (A); one of G and T is N, and the other of G and T is C-R?, wherein R? is:
(1) H5 (2) Ci -6 alkyl,
(3) Ci-g fluoroalkyL or
(4) C 1.6 alkyl substituted with OH, O-C 1 -6 alkyl, O-C 1 -6 haloalkyl, CN, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO2RA C(O)-N(RA)-C2-6 alkylene-ORB, SRA, S(O)RA SO2RA, S02N(RA)RB, N(RA)C(O)RB, N(RA)C02RB, N(RA)S02RB, N(RA)SO2N(RA)RB, N(RA)C(O)N(RA)RBS Or
OC(O)N(RA)RB; each RA is independently H or Ci-6 alkyl; each RB is independently H or Cl .5 alkyl; CycA is a C3-8 cycloalkyl which is optionally substituted with a total of from 1 to 6 substituents, wherein:
(i) from zero to 6 substituents are each independently:
(1) halogen,
(2) CN (3) Q -6 alkyl,
(4) OH5
(5) O-Ci-6 aIkyl,
(6) C 1-6 haloalkyl, or
(7) OC 1-6 haloalkyl, and
(ϋ) from zero to 2 substituents are each independently:
(D CycD,
(2) AryD,
(3) HetD,
(4) HetZ,
(5) C 1-6 alkyl substituted with CycD, AryD, HetD, or HetZ, or
(6) C(O)-HeIZ or C(O)C(O)-HetZ;
V is an aryl which is optionally substituted with a total of from 1 to 5 substituents, wherein:
C) from zero to 5 substituents are each independently:
(1) Ci-6 alkyl,
(2) Ci-6 alkyl substituted with OH, O-Cj-6 alkyl, O-Ci-6 haloalkyl, CN,
NO2, N(RA)RB5 C(O)N(RA)RB, C(O)RA Cθ2RA, SRA, S(O)RA5
SO2RA, Sθ2N(RA)RB, N(RA)C(O)RB, N(RA)C02RB, N(RA)Sθ2RB,
N(RA)S02N(RA)RB, OC(O)N(RA)RB, N(RA)C(O)N(RA)RB5 or
N(RA)C(O)C(O)N(RA)RB5
(3) O-Ci-6 alkyl,
(4) C 1-6 haloalkyl,
(5) 0-C i_6 haloalkyl,
(6) OH,
(7) halogen,
(8) CN,
(9) NO2,
(10) N(RA)RB5
(H) C(O)N(RA)RB,
(12) C(O)RA,
(B) C(O)-Ci.6 haloalkyl,
(14) C(O)ORA
(15) OC(O)N(RA)RB5
(16) SRA,
(17) S(O)RA,
(18) SO2RA,
(19) SO2N(RA)RB5
Figure imgf000006_0001
(21) N(RA)SO2N(RA)RB,
(22) N(RA)C(O)RB,
(23) N(RA)C(O)N(RA)RB5
(24) N(RA)C(O)C(O)N(RA)RB5 or
(25) N(RA)C02RB, and
(ii) from zero to 2 substituents are each independently:
(1) CycD5
(2) AryD,
(3) HetD,
(4) HetZ,
(5) C i_6 alkyl substituted with CycD, AryD, HetD, or HetZ, or
(6) C(O)-HetZ or C(0)C(O)-HetZ;
HetA is a heteroaryl which is optionally substituted with a total of from 1 to 5 substituents, wherein:
(i) from zero to 5 substituents are each independently:
(1) Ci-6 alkyl,
(2) C 1-6 alkyl substituted with OH, O-Q-6 alkyl, O-Ci-6 haloalkyl, CN,
NO2, N(RA)RB, C(O)N(RA)RB5 C(O)RA CO2RA, SRA5 S(O)RA5
SO2RA, Sθ2N(RA)RB, N(RA)C(O)RB, N(RA)C02RB, N(RA)SO2RB,
N(RA)SO2N(RA)RB, OC(O)N(RA)RB5 N(RA)C(O)N(RA)RB5 or
N(RA)C(O)C(O)N(RA)RB5
(3) O-Ci-6 alkyl,
(4) C 1-6 haloalkyl,
(5) 0-C 1-6 haloalkyl,
(6) OH,
(7) halogen,
(8) CN,
(9) NO2,
(10) N(RA)RB,
(11) C(O)N(RA)RB5
(12) C(O)RA
(13) C(O)-C 1-6 haloalkyl,
(14) C(O)ORA
(15) OC(O)N(RA)RB5
(16) SRA,
(17) S(O)RA
(18) SO2RA,
(19) SO2N(RA)RB5
Figure imgf000008_0001
(22) N(RA)C(O)RB,
(23) N(RA)C(O)N(RA)RB, (24) N(RA)C(O)C(O)N(RA)RB5 Or
Figure imgf000008_0002
(ii) from zero to 2 substituents are each independently:
(1) CycD,
(2) AryD, (3) HeID,
(4) HetZ,
(5) C i -6 alkyl substituted with CycD, AryD, HetD, or HetZ, or
(6) C(O)-HetZ or C(O)C(O)-HeIZ;
HetP is (i) 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
S5 where each S is optionally oxidized to S(O) or S(0)2 or (ii) a 6- to 10-membered saturated or mono-unsaturated, bridged or fused heterobicyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, where each S is optionally oxidized to S(O) or S(0)2; and wherein the saturated or mono-unsaturated heterocyclic or heterobicyclic ring is optionally substituted with a total of from 1 to 4 substituents, wherein:
(i) from zero to 4 substituents are each independently halogen, C 1-6 alkyl, Cl -5 haloalkyl, O-Ci-6 alkyl, O-Ci-6 haloalkyl, oxo, C(O)N(RA)RB5 C(O)C(O)N(RA)RB, C(O)RA C02RA, SRA, S(O)RA, SO2RA or 802N(RA)RB, and
(ii) from zero to 2 substituents are each independently CycD, AryD, HetD, or Ci_6 alkyl substituted with CycD, AryD, HetD; HetS independently has the same definition as HetP; each CycD is independently a C3-8 cycloalkyl which is optionally substituted with from 1 to 4 substituents each of which is independently halogen, Cj.g alkyl, OH, O-Ci_6 alkyl, or
C 1-6 haloalkyl; each AryD is independently phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with from 1 to 5 substituents each of which is independently any one of the substituents (1) to (25) as set forth above in part (i) of the definition of AryA; each HetD is independently 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 any one of the substituents (1) to (25) as set forth above in part (i) of the definition of HetA; HetE is a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S5 wherein the heteroaromatic ring is optionally substituted with from 1 to 4 substituents each of which is independently any one of the substituents (1) to (25) as set forth above in part (i) of the definition of HetA; each HetZ is independently 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, where each S is optionally oxidized to S(O) or S(O)2, wherein the saturated or mono-unsaturated heterocyclic ring is optionally substituted with from 1 to 4 substituents each of which is independently halogen, Cl -β alkyl, C\,β haloalkyl, O-Ci-6 alkyl, O-C i _6 haloalkyl, oxo, C(O)N(RA)RB5 C(O)C(O)N(RA)RB, C(O)RA, Cθ2RA 5
SRA, S(O)RA, SO2RA, or SO2N(RA)RB; each aryl is independently (i) phenyl, (ii) a 9- or 10-membered bicyclic, fused carbocyclic ring system in which at least one ring is aromatic, or (iii) an 11- to 14-membered tricyclic, fused carbocyclic ring system in which at least one ring is aromatic; and each heteroaryl is independently (i) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein each N is optionally in the form of an oxide, (ii) a 9- or 10-membered bicyclic, fused ring system, or (iii) an 11- to 14-membered tricyclic, fused ring system, wherein the fused ring system in (ii) or (iii) contains from 1 to 4 heteroatoms independently selected from N, O and S, and wherein in the fused ring system of (ii) or (iii) any one or more of the rings contain one or more of the heteroatoms, at least one ring is aromatic, each N in a ring is optionally in the form of an oxide, and each S is optionally S(O) or S(0)2-
The present invention also includes pharmaceutical compositions containing a compound of Formula I or a pharmaceutically acceptable salt thereof. The present invention further includes methods for the treatment of AIDS, the delay in the onset or progression of AIDS, the prophylaxis of AIDS, the prophylaxis of infection by HIV, and the treatment of infection by HIV.
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 INVENTION
The present invention includes compounds of Formula I above (including hydrates and solvates thereof), and pharmaceutically acceptable salts thereof. These compounds are HIV integrase inhibitors (e.g., HIV-I integrase inhibitors).
A first embodiment of the present invention (alternatively referred to herein as "Embodiment El") is a compound of Formula I (alternatively and more simply referred to as "Compound I"), or a pharmaceutically acceptable salt thereof, wherein R^ is: (1) H,
(2) Ci-6 alkyl,
(3) Ci-β haloalkyL or
(4) C l -6 alkyl substituted with C(O)N(RA)RB5 C(O)RA, Cθ2RA, C(O)-N(RA)-C2-O alkylene-ORB, S(O)RA, Sθ2RA 5 or Sθ2N(RA)RB; and all other variables are as originally defined (i.e., as defined in the Summary of the Invention).
A second embodiment of the present invention (Embodiment E2) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Rl is Cl -6 alkyl substituted with RJ; and all other variables are as originally defined or as defined in Embodiment El .
A third embodiment of the present invention (Embodiment E3) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein RJ is AryA or HetA; and all other variables are as originally defined or as defined in Embodiment El.
A fourth embodiment of the present invention (Embodiment E4) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein RJ is AryA; and all other variables are as originally defined or as defined in Embodiment El.
A fifth embodiment of the present invention (Embodiment E5) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein RJ is HetA; and all other variables are as originally defined or as defined in Embodiment El. A sixth embodiment of the present invention (Embodiment E6) is a compound of
Formula I, or a pharmaceutically acceptable salt thereof, wherein Rl is:
Figure imgf000010_0001
the asterisk * denotes the point of attachment of Rl to the rest of the compound;
Vl and V2 are each independently:
(D H,
(2) CM alkyl,
(3) OH,
(4) O-Ci-4 alkyl,
(5) C 1-4 haloalkyl,
(6) O-Ci-4 haloalkyl,
(7) halogen,
(8) CN,
(9) N(RA)RB5
(10) C(O)N(RA)RB5
(11) C(O)RA5 (12) C(O)ORA5
(13) SRA,
(14) S(O)RA,
(15) SO2RA,
Figure imgf000011_0001
(17) N(RA)SO2N(RA)RB,
(18) N(RA)C(O)RB5
(19) N(RA)C(O)C(O)N(RA)RB?
(20) HetD, (21) HetZ, or
(22) C(O>HetZ, wherein:
HetD is a 5- or ό-membered heteroaromatic ring containing a total of from 1 to 3 heteroatoms independently selected from 1 to 3 N atoms, from zero to 1 O atom, and from zero to 1 S atom, wherein the heteroaromatic ring is optionally substituted with from 1 to 3 substituents each of which is independently Ci_4 alkyl, OH, O-Q-4 alkyl, halogen, CN5 C(O)N(RA)RB, C(O)RA, C(O)ORA, Or SO2RA5
HetZ is a 5- or 6-membered saturated heterocyclic ring containing a total of from 1 to 2 heteroatoms selected from 1 to 2 N atoms, zero to 1 O atom, and zero to 1 S atom, wherein the S atom is optionally S(O) or SO2, wherein the saturated heterocyclic ring is optionally substituted with from 1 to 2 substituents each of which is independently Cl -4 alkyl, oxo, C(O)N(RA)RB5 C(O)RA5 CO2RA, or SO2RA, and with the proviso that when HetZ is attached to the rest of the compound via the C(O) moiety, then HetZ is attached to the C(O) via a ring N atom; or alternatively V 1 and V2 are respectively located on adjacent carbons in the phenyl ring and together form methylenedioxy or ethylenedioxy; and V3 is: (1) H,
(2) Cl-4 alkyl,
(3) O-Cl-4 alkyl,
(4) C 1-4 haloalkyl,
(5) O-Ci-4 haloalkyl, or (6) halogen; and all other variables are as originally defined or as defined in Embodiment El.
A seventh embodiment of the present invention (Embodiment E7) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Rl is:
Figure imgf000012_0001
wherein Vl and V2 are each independently:
(D H, (2) CH3, (3) CF3,
(4) OH,
(5) OCH3,
(6) Cl, Br, or F,
(7) CN, (8) C(0)NH2,
(9) C(O)NH(CH3),
(10) C(O)N(CH3)2, or
(11) SO2CH3;
V3 is H, Cl, Br5 F, CH3, or OCH3 ; and all other variables are as originally defined or as defined in Embodiment El .
An eighth embodiment of the present invention (Embodiment E8) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Rl is 4-fluorobenzyl,
3-chloro-4-fiuorobenzyl, or 4-fluoro-3-methylbenzyl; and all other variables are as originally defined or as defined in Embodiment El. A ninth embodiment of the present invention (Embodiment E9) is a compound of
Formula I, or a pharmaceutically acceptable salt thereof, wherein R2 is:
(D H,
(2) Ci-4 alkyl,
(3) Ci-4 haloalkyl, or (4) Cl -4 alkyl substituted with C(O)N(RA)RB5 C(O)RA Cθ2RA, S(O)RA, Sθ2RA,
Sθ2N(RA)RB, ORA5 or HetE; and all other variables are as originally defined or as defined in any one of the foregoing embodiments, hi an aspect of this embodiment, HetE is a 5- or 6-membered heteroaromatic ring containing a total of from 1 to 3 heteroatoms independently selected from 1 to 3 N atoms, from zero to 1 O atom, and from zero to 1 S atom, wherein the heteroaromatic ring is optionally substituted with from 1 to 3 substituents each of which is independently Ci_4 alkyl, OH, O-Ci-4 alkyl, halogen, CN, C(O)N(RA)RB5 C(O)RA5 C(O)ORA or Sθ2RA.
A tenth embodiment of the present invention (Embodiment ElO) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R2 is: (1) H, (2) Ci-4 alkyl,
(3 ) C l -4 haloalkyl, or
(4) Cl „4 alkyl substituted with C(O)N(RA)RB, C(O)RA Cθ2RA, S(O)RA SO2RA, or SO2N(RA)RB; and all other variables are as originally defined or as defined in any one of the foregoing embodiments.
An eleventh embodiment of the present invention (Embodiment El 1) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R2 is:
(D CH3, (2) CH2CH3,
(3) CH2CH2CH3,
(4) CH(CH3)2,
(5) CH2CH2CH2CH3,
(6) C(CH3)3, (7) CH2CH(CH3)Z
(8) CH(CH3)CH2CH3,
(9) CF3,
(10) CH2CF3, or
(11) (CH2)i-4~V, wherein V is C(O)N(RA)RB1 C(O)RA, CO2RA S(O)RA, SO2RA, SO2N(RA)RB, ORA, or Het E; and all other variables are as originally defined or as defined in any one of the foregoing embodiments. In an aspect of this embodiment, HetE is heteroaromatic ring selected from the group consisting of pyrazolyl, imϊdazolyl, oxazolyl, isooxazolyl, thiazolyl, triazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein the ring is optionally substituted with CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2.
A twelfth embodiment of the present invention (Embodiment El 2) is a compound of Formula I5 or a pharmaceutically acceptable salt thereof, wherein R2 is: (D CH3, (2) CH2CH3, (3) CH2CH2CH3,
(4) CH(CH3)2,
(5) CH2CH2CH2CH3,
(6) C(CH3)3,
(7) CH2CH(CH3)2j (8) CH(CH3)CH2CH3,
(9) CF3,
(10) CH2CF3, or (11) (CH2) 1 -4- V, wherein V is C(O)N(RA)RB5 C(O)RA Cθ2RA, S(O)RA Sθ2RA,
Figure imgf000014_0001
and ail other variables are as originally defined or as defined in any one of the foregoing embodiments. A thirteenth embodiment of the present invention (Embodiment El 3) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R3A and R3B are both H; R4A is H5 C 1-4 alkyl, OH or HetS; wherein HetS is a 5~ or 6-membered saturated heterocyclic ring containing a total of from 1 to 2 heteroatoms selected from 1 to 2 N atoms, zero to 1 O atom, and zero to 1 S atom, wherein the S atom is optionally S(O) or SO2, wherein the saturated heterocyclic ring is optionally substituted with from 1 to 3 substituents each of which is independently C 1.4 alkyl, oxo, C(O)N(RA)RB, C(O)RA CO2RA, or Sθ2RA; R4B is H or C 1-4 alkyl; alternatively, R4A and R4B together form oxo; R5 A is H, C 1.4 alkyl, or OH;
R5B is H or Ci -4 alkyl; alternatively, R5A and R5B together form oxo; provided that one, not both, of (a) R4A and R4B and (b) R5A and R5B are oxo;
R6A is H, C 1-4 alkyl, or Cl .4 alkyl substituted with OH; R6B is H or Cl^t alkyl; and provided that:
(i) when R4A is OH or HetS, then R5 A is not OH and R6A is not C 1.4 alkyl substituted with OH; (ii) when R5 A is OH, then R4A is not OH or HetS and R6A is not C 1.4 alkyl substituted with OH;
(iii) when RoA is C 1.4 alkyl substituted with OH, then R4A 1S not OH or HetS and
R5A is not OH; and all other variables are as originally defined or as defined in any one of the foregoing embodiments. A fourteenth embodiment of the present invention (Embodiment E 14) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R7 is H or C 1-4 alkyl; and all other variables are as originally defined or as defined in any one of the foregoing embodiments.
A fifteenth embodiment of the present invention (Embodiment E15) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R? is H or C 1 -3 alkyl; and all other variables are as originally defined or as defined in any one of the foregoing embodiments. A sixteenth embodiment of the present invention (Embodiment El 6) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R? is H or CH3; and all other variables are as originally defined or as defined in any one of the foregoing embodiments. A seventeenth embodiment of the present invention (Embodiment E 17) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein RA and RB are each independently H or Cl -4 alkyl; and all other variables are as originally defined or as defined in any of the preceding embodiments.
An eighteenth embodiment of the present invention (Embodiment El 8) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein RA and RB are each independently H or Cl -3 alkyl; and all other variables are as originally defined or as defined in any of the preceding embodiments.
A nineteenth embodiment of the present invention (Embodiment E 19) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R A and RB are each independently H or CH3 ; and all other variables are as originally defined or as defined in any of the preceding embodiments.
A first class of compounds of the present invention (alternatively referred to herein as Class Cl) includes compounds, and pharmaceutically acceptable salts thereof, selected I, wherein:
Figure imgf000015_0001
Vl and V2 are each independently:
(D
(2) Ci-4 alkyl,
(3) OH,
(4) O-C 1-4 alkyl,
(5) C 1-4 haloalkyl,
(6) O-Ci-4 haloalkyl,
(7) halogen,
(8) CN,
(9) N(RA)RB,
(10) C(O)N(RA)RB5
(H) C(O)RA,
(12) C(O)ORA,
(13) SRA,
(14) S(O)RA,
(15) SO2RA (16) N(RA)Sθ2RB >
(17) N(RA)SO2N(RA)RB?
(18) N(RA)C(O)RB,
(19) N(RA)C(O)C(O)N(RA)RB5 (20) HetD,
(21) HetZ, or
(22) C(O)-HeIZ, wherein:
HetD is a 5- or 6-membered heteroaromatic ring containing a total of from 1 to 3 heteroatoms independently selected from 1 to 3 N atoms, from zero to 1 O atom, and from zero to 1 S atom, wherein the heteroaromatic ring is optionally substituted with 1 to 3 substituents each of which is independently Cj -4 alkyl, OH5 O-Ci-4 alkyl, halogen, CN5 C(O)N(RA)RB, C(O)RA, C(O)ORA, Or SO2RA
HetZ is a 5- or 6-membered saturated heterocyclic ring containing a total of from 1 to 2 heteroatoms selected from 1 to 2 N atoms, zero to 1 O atom, and zero to 1 S atom, wherein the S atom is optionally S(O) or SO2, wherein the saturated heterocyclic ring is optionally substituted with from 1 to 2 substituents each of which is independently Cl .4 alkyl, oxo, C(O)N(RA)RB, C(O)RA5
Figure imgf000016_0001
and with the proviso that when HetZ is attached to the rest of the compound via the C(O) moiety, then HetZ is attached to the C(O) via a ring N atom; or alternatively Vl and V2 are respectively located on adjacent carbons in the phenyl ring and together form methylenedioxy or ethylenedioxy; and V3 is:
(1) H5
(2) C1.4 alkyl,
(3) O-C1-.4 alkyl,
(4) C 1.4 haloalkyl, (5) O-Ci-4 haloalkyl, or
(6) halogen; one of G and T is N, and the other of G and T is C-R7, wherein R? is H or Cl -4 alkyl;
R2 is:
O) H, (2) C 1-4 alkyl,
(3) C i-4 haloalkyl, or
(4) C 1.4 alkyl substituted with C(O)N(RA)RB, C(O)RA, CO2RA, S(O)RA Sθ2RA, or S02N(RA)RB; R3A and R3B are both H;
R4A is H, C 1-4 alkyl, OH or HetS; wherein HetS is a 5- or 6-membered saturated heterocyclic ring containing a total of from 1 to 2 heteroatoms selected from 1 to 2 N atoms, zero to 1 O atom, and zero to 1 S atom, wherein the S atom is optionally S(O) or SO2, wherein the saturated heterocyclic ring is optionally substituted with from 1 to 3 substituents each of which is independently Cl .4 alkyl, oxo, C(O)N(RA)RB5 C(O)RA5 Cθ2RA, or Sθ2RA;
R.4B is H or C 1-4 alkyl; alternatively, R4A and R4B together form oxo; R5A is H, C 1-4 alkyl, or OH; R5B is H or C i_4 alkyl; alternatively, R5A and R5B together form oxo; provided that one, not both, of (a) R4A and R4B and (b) R5A and R5B are oxo;
R6A is H, C 1-4 alkyl, or Cl .4 alkyl substituted with OH;
R6B is H or C 1-4 alkyl; and provided that:
(i) when R4A [S OH or HetS, then R5 A is not OH and R6A is not C 1.4 alkyl substituted with OH; (ii) when R5 A is OH, then R4 A is not OH or HetS and R6A is not C 1.4 alkyl substituted with OH; (iii) when R^ A is C 1 -4 alkyl substituted with OH, then R4 A is not OH or HetS and
R5A is not OH.
A second class of compounds of the present invention (Class C2) includes compounds, and pharmaceutically acceptable salts thereof, selected from compounds of Formula I, wherein:
Figure imgf000017_0001
Vl and V2 are each independently:
(D H5
(2) CH3,
(3) CF3, (4) OH,
(5) OCH3,
(6) Cl, Br, or F,
(7) CN,
(8) C(O)NH2, (9) C(O)NH(CH3),
(10) C(O)N(CH3)2, or (11) SO2CH3; and V3 is H, Cl, Br, F, CH3, or OCH3; one of G and T is N, and the other of G and T is C-R7, wherein R7 is H or CH3; R2 is: (1) CH3,
(2) CH2CH3,
(3) CH2CH2CH3,
(4) CH(CH3)2,
(5) CH2CH2CH2CHs, (6) C(CH3)3,
(7) CH2CH(CH3)2)
(8) CH(CH3)CH2CH3,
(9) CF3,
(10) CH2CF35 Or (11) (CH2) 1 _4-V, wherein V is C(O)N(RA)RB5 C(O)RA CO2RA5 S(O)RA, SO2RA, or SO2N(RA)RB;
R3A and R3B are bolh H; R4A is H, CH3, or OH; R4B is H or CH3; alternatively, R4A and R4B together form oxo;
R5A is H, CH3, or OH;
R5B is H or CH3; alternatively, R5A and R5B together form oxo; provided that one, not both, of (a) R4A and R4B and (b) R5A and R5B are oxo; R6A ls H or CH3;
R6B is H or CH3; and provided that:
(i) when R4A js OH, then R5A is not OH;
(11) when R5A js OH, then R4A is not OH. A third class of compounds of the present invention (Class C3) includes compounds, and pharmaceutically acceptable salts thereof, selected from compounds of Formula
I5 wherein:
Rl is 4-fluorobenzyl, 3-chloro-4-fluorobenzyl, or 4-fluoro-3-methylbenzyl; one of G and T is N, and the other of G and T is CH; R2 is CH3;
R3A and R3B are both H; R4A is H, CH3, or OH; R4B is H or CH3; alternatively,, R.4A and R4B together form oxo;
R5A is H, CH3, or OH;
R5B is H or CH3; alternatively, R5 A and R5B together form oxo; provided that one, not both, of (a) R4A and R4B and (b) R5A and R5B are oxo; and
R6A and R6B ^6 both H.
Another embodiment of the present invention is a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the compounds set forth in Examples 1 to 2. Another embodiment of the present invention is Compound I, or a pharmaceutically acceptable salt thereof, as defined in any of the foregoing embodiments, aspects, classes, or sub-classes, wherein the compound or its salt is in a substantially pure form. As used herein "substantially pure" means suitably at least about 60 wt.%, typically at least about 70 wt.%, preferably at least about 80 wt.%, more preferably at least about 90 wt.% (e.g., from about 90 wt.% to about 99 wt.%), even more preferably at least about 95 wt.% (e.g., from about 95 wt.% to about 99 wt.%, or from about 98 wt.% to 100 wt.%), and most preferably at least about 99 wt.% (e.g., 100 wt.%) of a product containing a compound Formula I or its salt (e.g., the product isolated from a reaction mixture affording the compound or salt) consists of the compound or salt. The level of purity of the compounds and salts can be determined using a standard method of analysis such as thin layer chromatography, gel electrophoresis, high performance liquid chromatography, and/or mass spectrometry. If more than one method of analysis is employed and the methods provide experimentally significant differences in the level of purity determined in a given sample, then the method providing the highest purity level governs. A compound or salt of 100% purity is one which is free of detectable impurities as determined by a standard method of analysis. With respect to a compound of the invention which has one or more asymmetric centers and can occur as mixtures of stereoisomers, a substantially pure compound can be either a substantially pure mixture of the stereoisomers or a substantially pure individual diastereomer or enantiomer.
Other embodiments of the present invention include the following: (a) A pharmaceutical composition comprising an effective amount of
Compound I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
(b) A pharmaceutical composition which comprises the product prepared by combining (e.g., mixing) an effective amount of Compound I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
(c) The pharmaceutical composition of (a) or (b), further comprising an effective amount of an anti-HIV agent selected from the group consisting of HFV antiviral agents, immunomodulators, and anti-infective agents. (d) The pharmaceutical composition of (c), wherein the anti-HIV agent is an antiviral selected from the group consisting of HIV protease inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, nucleoside HIV reverse transcriptase inhibitors, HIV integrase inhibitors other than a compound of Formula I, HIV fusion inhibitors, and HIV entry inhibitors. (e) A combination which is (i) Compound I, or a pharmaceutically acceptable salt thereof, and (ii) an anti-HIV agent selected from the group consisting of HIV antiviral agents, immunomodulators, and anti-infective agents; wherein the compound of Formula I and the anti- HIV agent are each employed in an amount that renders the combination effective for the inhibition of HIV integrase, for the treatment or prophylaxis of infection by HIV, or for the treatment, prophylaxis or delay in the onset or progression of AIDS.
(f) The combination of (e), wherein the anti-HIV agent is an antiviral selected from the group consisting of HIV protease inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, nucleoside HIV reverse transcriptase inhibitors, HIV integrase inhibitors other than Compound I, HIV fusion inhibitors, and HIV entry inhibitors. (g) A method of inhibiting HIV integrase in a subject in need thereof which comprises administering to the subject an effective amount of Compound I, or a pharmaceutically acceptable salt thereof.
(h) A method for the treatment or prophylaxis of infection by HIV in a subject in. need thereof which comprises administering to the subject an effective amount of Compound I, or a pharmaceutically acceptable salt thereof.
(i) The method of (h), wherein the compound of Formula I is administered in combination with an effective amount of at least one antiviral selected from the group consisting of HIV protease inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, nucleoside HIV reverse transcriptase inhibitors, HIV integrase inhibitors other than Compound I, HFV fusion inhibitors, and HIV entry inhibitors.
(j) A method for the treatment, prophylaxis, or delay in the onset or progression of AIDS in a subject in need thereof which comprises administering to the subject an effective amount of Compound I, or a pharmaceutically acceptable salt thereof.
(k) The method of (j), wherein the compound is administered in combination with an effective amount of at least one antiviral selected from the group consisting of HIV protease inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, nucleoside HIV reverse transcriptase inhibitors, HIY integrase inhibitors other than Compound I, HIV fusion inhibitors, and HIV entry inhibitors.
(1) A method of inhibiting HFV integrase (e.g., HIV-I 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 for the treatment or prophylaxis of infection by HIV (e.g., HIV-I) 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).
(n) A method for the treatment, prophylaxis, or delay in the onset or progression of AIDS (e.g., AIDS due to HIV-I) 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 or pharmaceutically acceptable salt thereof, (i) for use in, (ii) for use as a medicament for, or (iii) for use in the preparation or manufacture of a medicament for: (a) therapy (e.g., of the human body), (b) medicine, (c) inhibition of HIV integrase, (d) treatment or prophylaxis of infection by HIV, or (e) treatment, prophylaxis of, or delay in the onset or progression of AIDS. In these uses, the compounds of the present invention can optionally be employed in combination with one or more anti-HIV agents selected from HIV 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 (i)(a)-(e) through (iii)(a)-(e) set forth in the preceding paragraph, wherein the compound of the present invention employed therein is a compound of one of the embodiments, classes or sub-classes described above. In all of these embodiments etc., the compound may optionally be used in the form of a pharmaceutically acceptable salt.
Additional embodiments of the present invention include each of the pharmaceutical compositions, combinations, methods and uses set forth in the preceding paragraphs, wherein the compound of the present invention or its salt employed therein is substantially pure. With respect to a pharmaceutical composition comprising Compound I or its salt and a pharmaceutically acceptable carrier and optionally one or more excipients, it is understood that the term "substantially pure" is in reference to a compound of Formula I or its salt per se.
Still additional embodiments of the present invention include the pharmaceutical compositions, combinations and methods set forth in (a)-(n) above and the uses (i)(a)-(e) through (iii)(a)~(e) set forth above, wherein the HIV of interest is HIV-I. Thus, for example, in the pharmaceutical composition (d), the compound of Formula I is employed in an amount effective against HIV-I and the anti-HIV agent is an HIV-I antiviral selected from the group consisting of HIV-I protease inhibitors, HIV-I reverse transcriptase inhibitors, HIV-I integrase inhibitors other than a compound of Formula I, HIV-I entry inhibitors and HIV-I fusion inhibitors.
As used herein, the term "alkyl" refers to any monovalent straight or branched chain, saturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range. Thus, for example, "Ci -6 alkyl" (or "Ci-Cg atkyl") refers to any of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n~ and iso- propyl, ethyl and methyl. As another example, "C i_4 alkyl" refers to n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.
The term "alkylene" refers to any divalent linear or branched chain aliphatic hydrocarbon radical (alternatively referred to as "alkanediyl") having a number of carbon atoms in the specified range. Thus, for example, "-Ci -6 alkylene-" refers to any of the Cl to Cβ linear or branched alkylenes, and "-C1-.4 alkylene-" refers to any of the C] to C4 linear or branched alkylenes. A class of alkylenes of interest with respect to the invention is -(CH2)l-6~? and subclasses of particular interest include ~(CH2)l-4-5 -(CH2)2-4-» -(CH2)l-3-, -(CH2)2-3-> -(CH2) 1-2-j and -CH2-. Another sub-class of interest is an alkylene selected from the group consisting of -CH2-, -CH(CH3>, and -C(CH3)2--
The term "haloalkyl" refers to an alkyl group as defined above in which one or more of the hydrogen atoms have been replaced with a halogen (i.e., F, Cl, Br and/or I). Thus, for example, "Ci-ό haloalkyl" (or "Ci-Cg haloalkyl") refers to a Cj to Ce linear or branched alkyl group as defined above with one or more halogen substituents. The term "fluoroalkyl" has an analogous meaning except that the halogen substituents are restricted to fluoro. Suitable fluoroalkyls include the series (CH2)θ-4CF3 (i.e., trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3- trifluoro-n-propyl, etc.). A fluoroalkyl of particular interest is CF3.
The term "C(O)" refers to carbonyl. The terms "S(O)2" and "SO2" each refer to sulfonyl. The term "S(O)" refers to sulfinyl.
The symbol "*" at the end of a bond refers to the point of attachment of a functional group or other chemical moiety to the rest of the molecule of which it is a part.
The terms "cycloalkyl" refers to any cyclic ring of an alkane having a number of carbon atoms in the specified range. Thus, for example, "C3-8 cycloalkyl" (or "C3-C8 cycloalkyl") refers to any of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
The term "halogen" (or "halo") refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro, chloro, bromo, and iodo).
The term "aryl" refers to (i) phenyl, (ii) a 9- or 10-membered bicycHc, fused carbocyclic ring system in which at least one ring is aromatic, or (iii) an 11- to 14-membered tricyclic, fused carbocyclic ring system in which at least one ring is aromatic. Suitable aryls include, for example, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indenyl, indanyl, acenaphthenyl and fluorenyl. A class of aryls suitable for use in the present invention is phenyl, naphthyl, and indenyl. Another class of suitable aryls is phenyl and naphthyl. A particularly suitable aryl is phenyl.
The term "heteroaryl" refers to (i) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein each N is optionally in the form of an oxide, (ii) a 9- or 10-membered bicyclic, fused ring system, or (iii) an 11- Io 14-membered tricyclic, fused ring system, wherein the fused ring system in (ii) or (iii) contains from 1 to 4 heteroatoms independently selected from N, O and S, and wherein in the fused ring system of (ii) or (iii) any one or more of the rings contain one or more of the heteroatoms, at least one ring is aromatic, each N in a ring is optionally in the form of an oxide, and each S is optionally S(O) or S(O)2- Suitable heteroaryls include, for example, pyridinyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzodioxolyl, benzopiperidinyl, benzisoxazolyl, benzoxazolyl, chromenyl, chromanyl. isochromanyl, cinnolinyl, quinazolinyl, benzothienyl, benzofuranyl, imidazo [ 1 ,2-a]pyridinyl, benzotriazolyl, dihydroindolyl , dihydroisoindolyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl, quinazolinyl,
2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo-l,4-dioxinyl ( ■i.e., Q ^ O°) ); benzo-l,3-dioxolyl
(i.e., ^^O )5 thiazolyl, and isothiazolyl.
A class of heteroaryls suitable for use in the present invention consists of 5- and 6-membered heteroaromatic rings containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein each N is optionally in the form of an oxide. Heteroaryls belonging to this class include pyridinyl. pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, and oxadiazolyl. A sub-class of
Figure imgf000023_0001
heteroaryls suitable for use in the present invention consists of * , , ,
Figure imgf000023_0002
The term "saturated or mono-unsaturated heterocyclic ring" refers to (i) 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, where each S is optionally oxidized to S(O) or S(O)2 or (ii) a 6- to 10-membered saturated or mono-unsaturated, bridged or fused heterobicyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, where each S is optionally oxidized to S(O) or S(O)2- Suitable saturated heterocycles include, for example, azetidinyl, pyrrolidinyl, imidazolinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, thiazinanyl, azepanyl, diazepanyl, thiazepanyl, and thiadiazepanyl. Suitable mono-unsaturated heterocyclic rings include those corresponding to the saturated heterocyclic rings listed in. the preceding sentence in which a single bond is replaced with a double bond (e.g., a carbon-carbon single bond is replaced with a carbon-carbon double bond). A class of saturated heterocycles suitable for use in the present invention consists of 4- to 7-membered saturated heterocyclic rings containing from 1 to 3 heteroatoms independently selected from 1 to 3 N atoms, zero or 1 O atom, and zero or 1 S atom. A sub-class of saturated heterocycles suitable for use in the present invention consists of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl.
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. It is also to be understood that any range cited herein includes within its scope all of the sub-ranges within that range. Thus, for example, a heterocyclic ring described as containing from "1 to 4 heteroatoms" is intended to include as aspects thereof, heterocyclic rings containing 2 to 4 heteroatoms, 3 or 4 heteroatoms, 1 to 3 heteroatoms, 2 or 3 heteroatoms, 1 or 2 heteroatoms, 1 heteroatom, 2 heteroatoms, 3 heteroatoms and 4 heteroatoms.
When any variable (e.g., RA5 RB? Or AryD) 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 substiluents and/or variables are permissible only if such combinations result in stable compounds.
The term "substituted" (e.g., as in "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 and results in a stable compound. Unless expressly stated to the contrary, substitution by a named substituent is permitted on any atom in a ring (e.g., aryl, a heteroaromatic ring, or a saturated or mono-unsaturated heterocyclic ring) provided such ring substitution is chemically allowed and results in a stable compound.
Any of the various carbocyclic and heterocyclic rings and ring systems defined herein may be attached to the rest of the compound at any ring atom (i.e., any carbon atom or any heteroatom) provided that a stable compound results.
A "stable" compound is a compound which can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic or prophylactic administration to a subject). As an example, R.2 in Formula I can be Ci-6 alkyl substituted with C(O)-N(RA)-C2-6 alkylene-ORB. It is understood that the N(RA) and the ORβ are typically not both attached to the same carbon of the C2-6 alkylene because typically the resulting hemlaminal is not chemically stable.
As a result of the selection of substituents and substituent patterns, certain of the compounds of the present invention can have asymmetric centers and can occur as mixtures of stereoisomers, or as individual diastereomers or enantiomers. All isomeric forms of these compounds, whether isolated or in mixtures, are within the scope of the present invention.
As would be recognized by one of ordinary skill in the art, certain of the compounds of the present invention can exist as tautomers. All tautomeric forms of these compounds, whether isolated or in mixtures, are within the scope of the present invention.
The person of ordinary skill in the art would also understand that compounds of the invention can form hydrates and/or solvates. Chemically stable hydrates and solvates of compounds encompassed by Formula I and their pharmaceutically acceptable salts are within the scope of the present invention. In instances where a hydroxy (-OH) substituent is permitted on a heteroaromatic ring and keto-enol tautomerism is possible, it is understood that the substituent might in fact be present, in whole or in part, in the keto form, as exemplified here for a hydroxypyridinyl substituent:
Figure imgf000025_0001
Compounds of the present invention having a hydroxy substituent susceptible to keto-enol tautomerism on a carbon atom of a heteroaromatic ring are understood to include compounds in which only the hydroxy is present, compounds in which only the tautomeric keto form (i.e., an oxo substitutent) is present, and compounds in which the keto and enol forms are both present. Certain of the compounds of the present invention can exhibit a chirality resulting from the presence of bulky substituents that hinder the otherwise free rotation about a bond.
These rotational enantiomers are named atropisomers, and the interconversion can be sufficiently slow to allow for their separation and characterization. See, e.g., J. March, Advanced Organic Chemistry. 4th Edition, John Wiley & Sons, 1992, pp. 101-102; and Ahmed et al, Tetrahedron 1998, 13277. For example, certain of the compounds of the present invention as exemplified with structure A below in which there could be sufficient hindrance to rotation along the bond indicated with an arrow to permit separation of the enantiomers using, e.g., column chromatography on a chiral stationary phase. The present invention includes atropisomers of compounds embraced by Formula I, singly and in mixtures.
Figure imgf000025_0002
The compounds of the present inventions are useful in the inhibition of HIV integrase (e.g., HIV-I integrase), the prophylaxis or treatment of infection by HIV and the prophylaxis, treatment or the delay in the onset or progression of consequent pathological conditions such as AIDS. The prophylaxis of AIDS, treating AIDS5 delaying the onset or progression of AIDS, the prophylaxis of infection by HIV5 or treating infection by HIV is defined as including, but not limited to, treatment of a wide range of states of HIV infection: AIDS, ARC (AIDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV. For example, the compounds of this invention are useful in treating infection by HIV after suspected past exposure to HIV by 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 establishing or determining the binding site of other antivirals to HIV integrase, e.g., by competitive inhibition. Thus the compounds of this invention can be 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, or benzoic acid. Compounds of the invention carry an acidic moiety and thus 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. The term "administration" and variants thereof (e.g., "administered" or
"administering") in reference to a compound of the invention mean providing the compound or its salt (or a hydrate, solvate, or individual stereoisomer thereof) to the individual in need of treatment or prophylaxis. When a compound of the invention is provided in combination with one or more other active agents (e.g., antiviral agents useful for the prophylaxis or treatment of HFV infection or AIDS), "administration" and its variants are each understood to include provision of the compound and other agents at the same time or at different times. When the agents of a combination are administered at the same time, they can be administered together in a single composition or they can be administered separately. As used herein, the terra "composition" is intended to encompass a product comprising the specified ingredients, as well as any product which results, directly or indirectly, from combining the specified ingredients.
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" (or, alternatively, "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 "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. In one embodiment, the effective amount is a "therapeutically effective amount" for the alleviation of the symptoms of the disease or condition being treated. In another embodiment, the effective amount is a "prophylactically effective amount" for prophylaxis of the symptoms of the disease or condition being prevented. The term also includes herein the amount of active compound sufficient to inhibit HIV integrase and thereby elicit the response being sought (i.e., an "inhibition effective amount"). 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.
For the purpose of the inhibition of HIV integrase, the prophylaxis or treatment of HIV infection, or the prophylaxis or treatment or delay in the onset or progression of AIDS, the compounds of the present invention, optionally in the form of a salt (or hydrate, solvate, or individual stereoisomer), can be administered by any means that produces contact of the active agent with the agent's site of action. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but typically are administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. The compounds of the invention can, for example, be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectaliy, in the form of a unit dosage of a pharmaceutical composition containing an effective amount of the compound and conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles. Liquid preparations suitable for oral administration (e.g., suspensions, syrups, elixirs and the like) can be prepared according to techniques known in the art and can employ any of the usual media such as water, glycols, oils, alcohols and the like. Solid preparations suitable for oral administration (e.g., powders, pills, capsules and tablets) can be prepared according to techniques known in the art and can employ such solid excipients as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like. Parenteral compositions can be prepared according to techniques known in the art and typically employ sterile water as a carrier and optionally other ingredients, such as a solubility aid. Injectable solutions can be prepared according to methods known in the art wherein the carrier comprises a saline solution, a glucose solution or a solution containing a mixture of saline and glucose. Further description of methods suitable for use in preparing pharmaceutical compositions of the present invention and of ingredients suitable for use in said compositions is provided in Remington's Pharmaceutical Sciences, 18th edition, edited by A. R. Gennaro, Mack Publishing Co., 1990 and in Remington - The Science and Practice of Pharmacy, 21st edtion, Lippincott Williams & Wilkins, 2005. The compounds of this invention can be administered orally in a dosage range of about 0.001 to about 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 about 0.01 to about 500 mg/kg body weight per day orally in a single dose or in divided doses. Another preferred dosage range is about 0.1 to about 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 about 1.0 to about 500 milligrams of the active ingredient, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, and 500 milligrams 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 varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
As noted above, the present invention is also directed to use of the HIV integrase inhibitor compounds of the present invention with one or more anti-HIV agents useful in the treatment of HIV infection or AIDS. An "anti-HIV agent" is any agent which is directly or indirectly effective in the inhibition of HIV integrase or another enzyme required for HTV replication or infection, the treatment or prophylaxis of HIV infection, and/or the treatment, prophylaxis or delay in the onset or progression of AIDS. It is understood that an anti-HIV agent is effective in treating, preventing, or delaying the onset or progression of HIV infection or AIDS and/or diseases or conditions arising therefrom or associated therewith. 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 HIV antivirals, imunomodulators, antiinfectives, or vaccines useful for treating HIV infection or AIDS, such as those disclosed in Table 1 of WO 01/38332 or in the Table in WO 02/30930. Suitable HIV antivirals for use in combination with the compounds of the present invention include, for example, those listed in Table A as follows: Table A
Figure imgf000029_0001
EI = entry inhibitor; FI = fusion inhibitor; InI = integrase inhibitor; PI - protease inhibitor; nRTI = nucleoside reverse transcriptase inhibitor; nnRTI = non-nucleoside reverse transcriptase inhibitor. Some of the drugs listed in the table are used in a salt form; e.g., abacavir sulfate, indinavir sulfate, atazanavir sulfate, nelfinavir mesylate.
It is understood that the scope of combinations of the compounds of this invention with anti-HIV agents is not limited to the HIV antivirals listed in Table A and/or listed in the above-referenced Tables in WO 01/38332 and WO 02/30930, but includes in principle any combination with any pharmaceutical composition useful for the treatment or prophylaxis of HIV infection or AIDS. The HIV antiviral agents and other agents will typically be employed in these combinations in their conventional dosage ranges and regimens as reported in the art, including, for example, the dosages described in the Physicians' Desk Reference, Thomson PDR, Thomson PDR1 57th edition (2003), the 58th edition (2004), the 59th edition (2005), and subsequent editions thereof. The dosage ranges for a compound of the invention in these combinations are the same as those set forth above.
Abbreviations employed herein include the following: Boc = t-butyloxycarbonyl; DIPEA = diisopropylethylamine (or Hunig's base); DMAP = 4-dimethylaminopyridine; DMF = N,N- dimethylformarnide; DMSO = dimethyl sulfoxide; dppp = l,3-bis(diphenylphosphino)-propane; EDC = l-ethyl-3-(3-dimethylaminopropyl) carbodiimide; ES MS = electrospray mass spectroscopy; Et = ethyl; EtOAc = ethyl acetate; EtOH = ethanol; Et2θ = ethyl ether; HOAt = l-hydroxy-7-azabenzotriazole; HPLC = high-performance liquid chromatography; LC-MS = liquid chromatography mass spectroscopy; MeOH = methanol; NBS = N-bromosuccinϊmide; NMR = nuclear magnetic resonance; Ph = phenyl; TEA = triethylamine; Tf2θ = trifiic anhydride; TFA = 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.
Scheme 1 depicts a method for preparing 5-(alkyloxy)-3-halo-4- (alkyloxycarbonyl)-6-oxo-l ,6-dihydropyridine-2-carboxylic acids 1-F, which is a key intermediate for the preparation of 5-hydroxy-9,10,l l?12-tetrahydro-3H- pyridazino[4! )5t:3!4]ρyrido[l,2-a][l,4]diazocme-4,6,13(8H)-triones 3-D5 from dialkyl 2- hydroxybut-2-enedioates. Treatment of dialkyl 2-hydroxybut-2-enedioate 1-A and haloacetone with a mixture of ammonia and ammonium acetate in a suitable solvent (e.g., THF) provides alkyl 3-hydroxy-6-methyl-2-oxo-l,2-dihydroρyridine-4-carboxylate 1-B. In the preparation of compounds of the present invention that require the protection of phenolic hydroxyl group, the intermediate 1-B can be treated with a suitable protecting group; e.g., I-B can be treated with a benzyl halide such as benzyl bromide to provide the O-benzyl ether 1-C. The protecting group can be removed in a later step to provide the desired final products. Alkyl 3-hydroxy-6-methyl~ 2-oxo-l,2-dihydropyridine-4-carboxylate 1-C can be transformed to the corresponding
5-(alkyloxy)-3-halo-4-(alkyloxycarbonyl)-6-oxo-l,6-dihydropyridme-2-carboxylic acid 1-F via a sequence of oxidation/bromination (e.g., with NBS)/oxidation to adjust the oxidation state of the 6-methyl group to carboxylic group for a subsequent amide coupling reaction, and functionalization at the 5 position for later construction of the pyridazino ring.
Scheme 1
[R == alkyl; Xl, χ2 = halogen; R! = OH protecting group (e.g., benzyl]
Figure imgf000031_0001
1-A 1-B 1-C
Figure imgf000031_0002
1-D 1-E
1-F
Scheme 2 depicts a method for preparing an alkyl 9-(alkyloxy)-l l-bromo-1,8- dioxo-1 ,3,4,5,6;,8-hexahydro-2H-pyrido[ 1 ,2-a][l ,4]diazocine~10-carboxylate of formula 2-C from 5-(alkyloxy)-3-halo-4-(alkyloxycarbonyl)-6-oxo-l,6-dihydropyridine-2-carboxylic acid 1-F5 wherein the intermediate 1-F is treated with a suitable substituted aminoalcohol and an amide coupling reagent (e.g., EDC or BOP) to provide the amide product 2- A. Sequential treatment of 2-A with alkyl or aryl sulfonic anhydride (e.g., methanesulfonic anhydride) followed by a suitable base (e.g., cesium carbonate) in the presence of a small quantity of water, wherein the water liberates one of the sulfonyl groups on 2-B to provide the corresponding alkoxypyrimidinone which then undergoes an intramolecular cyclization to provide the bicyclic pyridinone derivative 2-C. Further standard functional group interconversion of R^ - R6 at an appropriate stage of the synthesis can provide required substitution on the 8-membered ring. Scheme 2
[R" - alkyl or aiyl]
Figure imgf000032_0001
1-F
Figure imgf000032_0002
Scheme 3 depicts a method for preparing a 5-hydroxy-9,l 0, 11,12-tetrahydro-3H- pyridazino^'^'^^Jpyridotl^-alEl^ldiazocine^^jBCS^-trione of formula 3-D from alkyl 9- (alkyloxy)- 11 -bromo- 1 ,8-dioxo- 1 ,3 ,4,5,6,8-hexahydro-2H-pyrido[ 1 ,2-a] [ 1 ,4]diazocine- 10- carboxylate 2-C. In this sequence, bromide 2-C is converted to corresponding carbonyl derivative 3-B. Illustrated here is a two-step sequence in which 2-C is treated sequentially with trialkylvinyltin and palladium(O) catalyst (e.g., bis(tri-t-butylphosphine)palladium(0)) and a mixture of osmium tetraoxide and sodium periodate to provide the carbonyl derivative 3-B. Treatment of this intermediate with a mono-substituted hydrazine provided the tricyclic pyridazinopyridodiazocine analog 3-C. Removal of the protecting group on the phenolic hydroxyl group (e.g., via H2 in the presence of Pd/C or by treatment with HBr in acetic acid) in a manner similar to the conditions described in T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley& Sons, 1999, provides the target compound 3-D. Scheme 3
Figure imgf000033_0001
deprotection
Figure imgf000033_0002
Figure imgf000033_0003
Figure imgf000033_0004
Scheme 4 depicts a method for preparing a 5 -aIkoxy-456-dioxo-3 ,4,6,7- tetrahydropyrido[3 j4-d]pyrimidine-8~carboxylic acid of formula 4-1, a key intermediate for the preparation of 5 -hydroxy-9, 10,11,12-tetrahydro-3 H-pyrimido[4',5 ' : 3 ,4]pyrido [1,2- a][l,4]diazocine-4,6,13(8H)-trione 5-C. Treatment of 3-bromo-5~alkoxypyridine 4-A with tert- butylcarbamate in the presence of a palladium(O) catalyst provides tøt-butyl (5-alkoxypyridin-3- yl)carbamate 4-B, which is lithiated and then treated with alkyl chloroformate to provide alkyl 3-[(/er/-butoxycarbonyl)amino]-5-alkoxyisonicotinate 4-C. Removal of the Boc protecting group by treatment with acid (e.g., HCl or TFA), followed by reaction with formamidine or alkylamidine provides the 5-alkoxypyrido[354-d]pyrimidin-4(3H)-one 4-D as the core of the targeted inhibitors. The 5-alkoxypyrido[3,4-d]pyrimidin-4(3H)-one 4-D can then be N-alkylated with various alkylating reagents in the presence of a suitable base (e.g., cesium carbonate, or potassium carbonate) to provide 4-E. The 8-carboxyl group can be installed through a sequence of oxidation, acetylation, rearrangement, sulfonylation, and palladium(O) catalyzed carbonylation. The intermediate 4-E can be treated with a suitable oxidizing agent (e.g., hydrogen peroxide or m-chloroperbenzoic acid) as described in Sharpless et al., J Org. Chem. 1998> 1740 and Caron et al., Tet, Letters 2000, 2299 and references cited therein, to obtain the corresponding N-oxide, which can then be treated as described in Suzuki et ai., J Med. Chem. 1992, 35, 4045-4053 with acetic anhydride to effect the rearrangement to the O-acylated intermediate 4-F5 which can then be hydrolyzed to the corresponding 5-alkoxy-8-hydroxy-4-oxo- 3,4-dihydropyrido[3,4-d]pyrimidine 4-G. O-sulfonylation and palladium catalyzed carbonylation of 4-G provides alkyl 5-alkoxy-4-oxo-354-dihydropyrido[3,4-d]pyrimidine-8-carboxylate 4-H. Further transformation using a sequence of oxidation, acetylation, rearrangement, and hydrolysis, similar to the sequence that can be employed to convert 4-E to 4-F, provides the key intermediate 5~alkoxy-4,6-dioxo-354,6,7-tetrahydropyrido[3t4-d]-pyrimidine-8-carboxylate 4-I.
Scheme 4
[R*, RΛ = alkyl]
Figure imgf000034_0001
Scheme 4a depicts an alternative, though less efficient, route to 4-1 via a cyano analog, wherein 4-E is treated with a suitable oxidizing agent to provide the N-oxide which can then be treated with a cyanating agent (e.g., trimethylsilyl cyanide in the presence of TEA) at elevated temperature (e.g., about 90°C) in an appropriate solvent mixture such as acetonitrile/- dichloroethane/dioxane to provide nitrile 4al. Oxidation, acetylation and thermal rearrangement of 4al provides 4a2, which can be hydrolyzed with a base (e.g., NaOH in ethanol) to provide 4-1, Scheme 4a
2. cyanation
Figure imgf000035_0002
Scheme 5 depicts a sequence of reactions, similar to that illustrated in Scheme 2, in which 4-1 is coupled with appropriately substituted aminoalcohols, the resultant alcohol 5-A is sulfonylated and cyclized in the presence of base (e.g., K2CO3 or CS2CO3) to provide the
9,10, 11, 12-tetrahydro-3H-ρyrimido[4',5':3,4]pyrido[ 1 ,2-a] [1 ,4]diazocϊne-456, 13(8H)-trione core. Removal of the protecting group on the phenolic hydroxyl group provides the target molecule 5-C.
Scheme 5
Figure imgf000035_0003
4-1
Figure imgf000035_0004
In the methods for preparing compounds of the present invention set forth in the foregoing schemes, functional groups in various moieties and substituents (in addition to those already explicitly noted in the foregoing schemes) 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 in Protective Groups in Organic 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 & Sons, 3rd edition, 1999, and 2nd edition, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known in the art. Alternatively the interfering group can be introduced into the molecule subsequent to the reaction step of concern.
The following examples serve only to illustrate the invention and its practice. The examples are not to be construed as limitations on the scope or spirit of the invention.
EXAMPLE 1
3-(4-Fluorobenzyl)-5.10-dihydroxy-9,9, 12-trimethyl-9, 10,11,12-tetrahydro-3H-pyridazino- ^'^'^^ipyridotl^-aJtl^Jdiazocine^^^StSHHrione
Figure imgf000036_0001
Stepl : Diethyl (2Z)-2-hydroxybut-2-enedioate
Figure imgf000036_0002
Diethyl oxalacetate, sodium salt (12O g, 0.571 mol) was partitioned between aqueous HCl (1.5 L adjusted to pH ~3) and CH2CI2 (500 mL). The layers were stirred at room temperature for 2.5 hours until completely homogenous. The organic extract was separated and the aqueous layer was extracted twice more with CH2CI2 (2X250 mL). The organic extracts were combined, dried over Na2SO4, filtered and concentrated under vacuum. The resultant yellow oil was used in the following step without further purification. Step 2 : Ethyl 3 -hydroxy-β-methyl-^-oxo- 1 ,2-dihydropyridine-4-carboxyIate
Figure imgf000037_0001
For 30 minutes ammonia gas was bubbled vigorously through a cold (30C5 ice bath) mixture of diethyl oxalacetate (50.0 g, 0.265 mol) and chloroacetone (29.5 g, 0319 mol) in anhydrous THF (1 L) stirred with a mechanical stirrer. The solution turned dark orange and the temperature increased to 120C and then dropped to 5°C. Ammonium acetate (40.9 g, 0.531 mol) was added and the reaction mixture was heated at reflux for 3 hours. The resultant bright yellow product mixture was cooled to room temperature and then slowly cooled to 50C using an ice bath. The yellow precipitate was collected by vacuum filtration, washing with THF, and stirred in aqueous HCl (1 M, 300 mL) for 30 minutes. The solid was then collected by filtration and dried under vacuum over night with heating to provide the title product as an off white solid. 1 H NMR (400 MHz, CDCI3) 6 12.0 (br s, IH), 9.90 (br s, IH), 6.14 (s, IH), 4.30 (q, J- 7.1 Hz,
2H), 2.14 (s, 3H), 1.31 (t, J= 7.1 Hz5 3H). ES MS M+l - 198.3.
Step 3 : Ethyl 3 -(benzyloxy)-6-methyl -2-oxo- 1 ,2-dihydropyridine-4-carboxylate
Figure imgf000037_0002
Ethyl 3-hydroxy-6-methyl-2-oxo-l52-dihydropyridine-4-carboxylate (11.9 g, 60.3 mmol) and potassium carbonate (9.17 g, 66.4 mmol) were suspended in water (650 mL) and then aged in an ultrasonic bath for 40 minutes to aid in the dissolution of the solids. This mixture was then added to a solution of benzyl bromide (7.9 mL , 66.4 mmol) in CH2CI2 (500 mL). The reaction mixture was then treated with cetylpyridinium chloride monohydrate (10.74 g, 30 mmol) and stirred vigorously at reflux for 24 hours. The reaction mixture was cooled to room temperature and the layers were separated. The aqueous layer was extracted with CH2CI2 (3 X, 200 mL). The organic extracts were combined, dried over Na2SO4, filtered and concentrated. The residue was subjected to column chromatography on silica gel eluting with EtOAc/hexane gradient to provide title compound as an off white solid. ^H NMR (400 MHz, CDCI3) δ 12.34
(br S5 IH)5 7.51 (d, J= 7.1 Hz, 2H), 7.33 (m, 3H), 6.16 (s, IH), 5.28 (s, 2H), 4.29 (q, J= 7.1 Hz, 2H), 2.33 (s, 3H), 1.29 (t, J= 7.1 Hz, 3H). ES MS M+l - 288.14. Step 4: Ethyl 3 -(benzyloxy)-6-formyl-2-oxo- 1 ,2-dihydropyridme~4-carboxylate
Figure imgf000038_0001
A mixture of ethyl 3-(benzyloxy)-6-methyl-2-oso-l;2-dihydroρyridine-4- carboxylate (5.83 g, 20.29 mmol) and selenium dioxide (9.01 g, 81 mmol) in anhydrous dioxane (50.7 niL) was heated in a pressure vessel at 100°C for 6 hours. The resultant suspension was filtered. The filtrate was concentrated and the residue purified by silica gel chromatography eluting with 0-5% MeOH/CHCl3 gradient to give the title product. Impure fractions were combined and re-purified eluting with 30-100% EtOAc/hexane to provide additional amount of product. IH NMR (400 MHz, CDCI3) δ 9.44 (s, IH), 9.31 (br s, IH), 7.47 (d, J = 6.6 Hz, 2H), 7.34 (m, 3H), 7.08 (s, IH), 5.63 (s, 2H), 4.33 (q, J - 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz5 3H).
Step 5 : Ethyl-3 -(benzyloxy)-5 -bromo-6-formyl-2-oxo- 1 ,2-dmydropyridine-4~carboxylate
Figure imgf000038_0002
A mixture of ethyl 3-(benzyloxy)-6-formyl-2-oxo-l,2-dihydropyridine-4- carboxylate (4.6 g, 15.27 mmol) and N-bromosuccimmide (2.72 gs 15.27 mmol) in CH2CI2 (76 niL) was stirred at room temperature for 12 hours. The product mixture was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 0-5% MeOH/CHCl3. Collection and concentration of appropriate fractions provided a gummy residue. Concentration of this residue from CH2CI2 provided title product as off-white solid. lH NMR (400 MHz, CDCI3) δ 9.81 (s, IH), 9.32 (br s, IH), 7.35(m, 5H), 5.64 (s, 2H), 4.35 (q, J= 7.1 Hz, 2H), 1.30 (dt, J= 7.1, 0.7 Hz, 3H).
Step 6: 5-(Benzyloxy)-3~bromo-4-(ethoxycarbonyl)-6-oxo- 1 ,6-dihydropyridine-2- carboxylic acid
Figure imgf000039_0001
A solution of ethyl-3~(benzyloxy)-5-bromo-6-formyl-2-oxo-l,2-dihydropyridine- 4-carboxylate (3.13 g, 8.23 mmol) and oxone (5.57 g, 9.06 mmol) in DMF (41.2 niL) was stirred at room temperature for 15 hours. The product mixture was diluted with CH2CI2 (70 mL) and aqueous HCl (0.5 M, 50 mL), then was stirred vigorously for 20 minutes/ The organic layer was separated, and the aqueous layer was extracted with CH2CI2 (3X, 80 mL). The organic extracts were combined, dried over MgSθ4, filtered and concentrated to provide the title compound as yellow solid. IH NMR (400 MHz, CDCI3) δ 12.73 (br s, IH), 7.36 (m, 5H), 5.51 (s, 2H), 4.37 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H). ES MS M - 395.91, M+2 - 397.
Step 7: 3-(Benzyloxy)-4,4-dimethyldihydrofuran-2(3H)-one
Figure imgf000039_0002
A mixture of 3-hydroxy-4,4-dimethyldihydrofuran-2(3H)-one (25 g, 192 mmol; racemic pantolactone), cesium carbonate (68.8 g, 211 mmol), and benzyl chloride (19.7 mL, 211 mmol) in anhydrous DMF (192 mL) was stirred at room temperature for 12 hours. The product mixture was diluted with Et2θ and extracted with water. The organic layer was washed successively with 5% aqueous KHSO4 (3X) and brine (2X), then dried over MgSθ4, filtered and concentrated to give a 2:1 mixture of title product and benzyl chloride as colorless oil. lH NMR (400 MHz, CDCI3) δ 7.33 (m, 5H), 5.04 (d, J= 12.1 Hz1 IH), 4.75 (d, J= 12.1Hz, IH), 4.58 (s,
IH), 4.0 (d, J= 8.7 Hz5 IH), 3.86 (d, J= 8.7 Hz, IH), 1.14 (s, 3H), 1.10 (s, 3H).
Step 8: 2-(Benzyloxy)-4-hydroxy-N,3 ,3 -trimethylbutanamide
Figure imgf000039_0003
A biphasic mixture 3-(benzyloxy)-4,4-dimethyldihydrofuran-2(3H)-one (28.7 g, 130 mmol) in MeOH (130 mL) and 40% aqueous methylamine (35.2 rriL, 391 mmol) was stirred at room temperature for 12 hours. The reaction was concentrated in vacuo and the residue was dissolved and re-concentrated twice from toluene. The residue was subjected to column chromatography on silica gel eluting with 20-100% EtOAc/hexane gradient to give the title compound as colorless, viscous oil. IH NMR (400 MHz, CDCI3) δ 7.37 (m, 5H), 6.60 (br S5
IH), 4.55 (d, J = 11.4 Hz, IH)5 4.48 (d, J= 11.4 Hz, IH), 3.80 (s, IH)3 3.37 (m, 3H), 2.85 (d, J- 5 Hz, 3H), 1.06 (s, 3H)5 0.85 (s, 3H).
Step 9: 3-(Benzyloxy)-2,2-dimethyl-4~(methylamino)butan-l-ol
Figure imgf000040_0001
To a cold (ice bath) solution of 2-(benzyloxy)-4-hydroxy~N,3,3- trimethylbutanamide (10.4 g, 41.4 mraol) in anhydrous THF (145 mL) under Drierite®, a solution of L1AIH4 in THF (2M, 62.1 mL, 124 mmol) was added over 10 minutes. After the addition of UAIH4 was complete, the reaction mixture was refluxed for 36 hours. The product mixture was cooled with an ice-water bath and treated successively with H2O (4.7 mL) over 7 minutes, 15% aqueous NaOH (4.7 mL) over 5 minutes, and H2O (14.1 mL). The mixture was stirred at 00C for 10 minutes. The ice bath was then removed and the mixture was allowed to warm to room temperature and stirred for 45 minutes. The slurry was filtered through Celite®, and the solid filtered washed with fresh THF (3 X, 30 mL). The filtrate was combined and concentrated under vacuum. The residue was dissolved and re-concentrated twice from benzene to afford a yellow oil. lH NMR (400 MHz, CDCI3) δ 7.31 (m, 5H)5 4.59 (d5 J= 11.7 Hz9 IH)5 4.50 (d, J= 11.7 Hz, IH), 3.68 (d, J= 11.6 Hz, IH), 3.17 (d, J= 5.1 Hz, IH), 2.97 (d, J= 11.7 Hz5 IH), 2.82 (dd, J= 12.6, 5.3 Hz, IH), 2.62 (d, J- 12.5 Hz, IH), 2.38 (s, 3H), 1.06 (br s, IH), 0.98 (s, 3H), 0.92 (s, 3H).
Step 10: Ethyl 3 -(benzyϊoxy>6- { [[2-(benzyloxy)~4-hydroxy-3 ,3 -dimethylbutyl] (methyl- amino]carbonyl}-5-bromo-2-oxo-l,2-dihydropyridine-4-carboxylate
Figure imgf000040_0002
To a solution of 5~(benzyloxy)-3-bromo-4-(ethoxycarbonyl)-6-oxo-l,6- dihydropyridine-2-carboxylic acid (500 mg, 1.262 mmol) in CH2CI2 (12.6 mL)5 HOAt (17.18 mg, 0.126 mmol), 3-(benzyloxy)-2,2-dimethyl-4-(methylamino)butan-l-ol (329 mgs 1.388 mmol), N-methylmorpholine (694 μL, 6.31 mmol) and EDC (266 mg, 1.388 mmol) were added. The reaction mixture was stirred at room temperature for 12 hours and then diluted with CH2CI2 (5 mL) and 5% aqueous KHSO4 (15 mL). The layers were separated and the aqueous layer was extracted with CH2CI2 (2X, 1 OmL). The organic extracts were combined and washed with brine (15 mL), dried over MgSθ4, filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 0-5% MeOH/ CHCI3 gradient to give the title compound as a colorless syrup. Proton NMR indicates an approximate 2: 1 mixture of rotational isomers. lH NMR (400 MHz, CDCI3) δ 1 Al -125 (m, ~10H), 5.39 (d, J= 11.2 Hz, -2/3H), 5.33( s, -2/3H), 5.24 (d, J- 11.2 Hz, -2/3H), 4.83 (d, J= 10.4 Hz, -2/3H), 4.69 (dds J - 13.6, 11.6 Hz, -2/3H), 4.54 (d, J- 10.5 Hz, -2/3H), 4.21-4.36 (m, ~2H), 4.12 (d, J= 14.0 Hz, -1/3H), 3.81 (m, -IH), 3.39-3.60 (m, ~3H), 3.23 (d, J- 12.6 Hz, -2/3H), 3.05 (s, ~2H), 3.03 (s, ~1H), 1.26 (m, ~3H), 1.02 (s, ~1H), 0.95 (s, ~1H), 0.93 (s, ~2H), 0.91 (s, ~2H). ES MS M+1 = 615, 617
Step 11 : Ethyl-3-(benzyloxy)-6-{ [{2-(benzyloxy)-3,3-dimethyl-4-
[(methylsulfonyl)oxy]butyl } (methyl)amino] carbonyl } -5-bromo-2- [(methylsulfonyl)oxy]- 1 ,2-dihydropyridine-4-carboxylate
Figure imgf000041_0001
To a cold (0 0C) solution of ethyl 3-(benzyloxy)-6-{[[2-(benzyloxy)-4-hydroxy-
3,3-dimethylbutyl](methyl)amino]carbonyl}-5-bromo-2-oxo-l,2-dihydroρyridine-4-carboxylate (450 mg, 0.731 mmol) and diisopropylethylamine (281 μL, 1.61 mmol) in anhydrous CH2CI2
(7.3 mL), methanesulfonic anhydride (267 mg, 1.53 mmol) was added. The reaction was then stirred at room temperature for 30 minutes. The product mixture was diluted with CH2CI2 (10 mL) and washed with 0.5 M aqueous NaHCO3 (IX, 10 mL) and brine (2X, 1OmL). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was dissolved and re- concentrated from a mixture of anhydrous CH2CI2 and benzene to provide a pale yellow foamy solid. LC-MS indicated the solid was an 85:15 mixture of the titled compound and mono- mesylated analog. ES MS M+l = 772.92. Step 12: Ethyl-4,9-bis(benzyloxy)-l l-bromo-2,5J5-trimethyl-l,8-dioxo-l,3,4,5,6,8- hexahydro-2H-pyrido[l ,2-a] [1 ,4]diazocine-l O-carboxylate
Figure imgf000042_0001
A mixture of ethyl-3-(benzyloxy)-6-{[{2-(benzyloxy)-3,3-dimethyl-4-
[(methylsulfonyl)oxy] butyl } (methyl)amino] carbonyl } -5 -bromo-2- [(methylsulfonyl)oxy] -1,2- dihydropyridine-4-carboxylate (490 mg, 0.635 mmol) and CS2CO3 (621 rag, 1.905 mmol) in anhydrous DMF (63 mL) was heated at 1000C with stirring for 27 hours. The product mixture was concentrated in vacuo and the residue was partitioned between EtOAc and brine. The aqueous layer was extracted twice with EtOAc. The organic extracts were combined, dried over Na2SO4, filtered, and concentrated. The residue was subjected to column chromatography on silica gel eluting with 0-70% EtOAc/hexane gradient to provide the titled product as a 7:2 mixture of two diastereoisomers (atropisomeric with the 8 membered lactam and racemic at the protected secondary alcohol). Proton NMR appears as an approximate 7:2 mixture of atropic diastereomers. IH NMR (400 MHz, CDCI3) δ 7.52-7.25 (m, -10H), 5.35 (m, -IH), 5.21( d, J =
11.0 Hz -7/9H), 5.16 (d, J = 11.0 Hz, -2/9H), 4.84 (d, J = 14.8 Hz, -7/9H), 4.71-4.52 (m, -20/9H), 4.32 (m, -2H), 3.77-3.43 (m, ~2H), 3.18-3.0 (m, ~5H), 1.28 (ra, ~3H), 1.16 (s, -2/3H), 1.15 (s, -7/3 H), 0.88 (s, -7/3 H), 0.77 (s, -2/3 H). ES MS M+l - 598.85
Step 13: Ethyl^^-bisφenzyloxy^^^-trimethyl-l^-dioxo-l l-vinyl-l^^^^^- hexahydro-2H-pyrido[ 1 ,2-a] [ 1 ,4]diazocine- 1 O-carboxylate
Figure imgf000042_0002
A solution of ethyl-4,9-bis(benzyloxy)~l l-bromo-2,5,5-trimethyHs8-dioxo- l,3,4,5?6,8-hexahydro-2H-pyrido[l52-a][l,4]diazocine-10-carboxylate in anhydrous dioxane (1.5 mL) was purged with argon for 5 minutes. Bis(tri-t-butylphosphine)palladium(0) (7.53 nig, 0.015 mmol), CsF (98 mg, 0.648 mmol), and vinyl tri-n-butyltin (95 μL, 0.324 mmol) were added and the solution was purged with argon for additional 5 minutes. The vessel was then sealed and heated at 1000C for 19 hours. The product mixture was cooled to room temperature, diluted with dioxane (1.5 mL), and filtered. The filtrate was concentrated, and the residue was subjected to column chromatography on silica gel eluting with 0-50% EtOAc/hexane gradient to afford the title compound as white foamy gum which appears to be an approximate 5:1 mixture of atopic diastereoisomers. IH NMR (400 MHz, CDCI3) δ 7.52-7.21 (m, -10H)5 6.35 (m,
-IH), 5.37-5.06( m, -4H), 4.84 (d, J - 14.8 Hz5 -IH)5 4.62 (m, -2H), 4.24 (m, ~2H), 3.83-3.36 (m, -2H), 3.20-3.01 (m, ~5H), 1.23 (t, J = 7.14 Hz, -3H), 1.17 (s, -3H), 0.93 (s, -15/6H), 0.88 (S5 -1/2H). ES MS M+l - 545.
Step 14: Ethyl-4,9-bis(benzyloxy)-l l-formyl-2,5,5-trimethyl-l58-dioxo-l5354s556J8- hexahydro-2H-pyrido [ 1 ,2-a] [ 1 ,4] diazocine- 10-carboxylate
Figure imgf000043_0001
A mixture of ethyl-4,9-bis(benzyloxy)-2,5,5-trimethyl-l,8-dioxo-l 1-vinyl- l,3,4,5,6,8-hexahydro-2H-pyrido[l,2-a][l,4]diazocine-10-carboxylate (110 mg, 0.202 mmol), 2,6-lutidine (47 μL, 0.404 mmol), Nalθ4 (173 mg, 0.808 mmol), and a catalytic amount of Osθ4 (32 μL, 4.04 μmol) in THF (2 mL) and H2O (750 μL) was stirred at room temperature for 12 hours. The product mixture was diluted with THF (20 mL) and filtered through a pad of Celite. The filtrate was concentrated in vacuo to give the titled compound as a pale gray gum, and was used in the step 16 without further purification. The crude NMR analysis is consistent with an approximate 4:1 mixture of atropic diastereomeric aldehydes. IH NMR (400 MHz, CDCI3) δ
9.51 (s, IH), 7.47-7.29 (m, -10H), 5.33-5.10 (m, -2H), 4.83 (d, J - 14.8 Hz5 -4/5H) 4.72-4.54 (m, -2H), 4.36 (m, -2H), 3.78-3.57 (m, -2H)5 3.23-3.02 (m, -5H), 1.29 (t, J - 7.1 Hz , 3H), 1.19 (s, 3H), 0.89 (s, -12/5H), 0.77 (s, -3/5H).
Step 15: (4-Fluorobenzyl)hydrazine
Figure imgf000043_0002
A solution of 4-fluorobenzyl chloride (5.35 g5 37 mmol) in anhydrous EtOH (30 mL) was added drop- wise over 1 hour to a stirring solution of hydrazine hydrate (17.98 mL, 370 mmol) in EtOH (40 mL). Upon complete addition, the reaction was stirred at room temperature for 12 hours. The reaction was then concentrated under vacuum and the residue was partitioned between 50% aqueous NaOH (40 niL) and Et2θ (50 mL). The layers were separated and the aqueous layer was extracted with Et2θ (3X, 10OmL). The organic extracts were combined, dried over Na2SO4, filtered, and concentrated in vacuo to give the titled product as yellow oil. The hydrazine was used in step 16 without further purification. IH NMR (400 MHz, CDCI3) δ 7.3 (m, 2H), 7.04 (m, 2H), 3.89 (s, 2H), 2.90 (br s, 3H).
Step 16: 5,10-bis(benzyloxy)~3-(4-fluorobenzyl)-9,9, 12-trimethyl-9, 10, 11 , 12-tetrahydro-
3H-pyridazmo[4',5':3,4]pyrido[l ,2-a] [1 ,4]diazocine-4,6, 13(8H)-trione
Figure imgf000044_0001
A solution of ethyl-459-bis(benzyloxy)-l l-formyl-2,5,5-trimethyl-l,8-dioxo- l?3,4,5,6P8-hexahydro-2H-pyrido[l,2-a][l,4]diazocine-10-carboxylate (110 mg, 0.201 mmol) and (4-fluorobenzyl)hydrazine (113 mg, 0.805 mmol) in MeOH (2 mL) was heated in a microwave reactor at 1000C for 15 minutes. The product mixture was concentrated under vacuum. The resultant brown residue was subjected to column chromatography on silica gel eluting with 10- 100% EtOAc/hexane. LC-MS analysis of the fractions indicated that a mixture of the titled product and intermediate hydrazone co-eluted. The mixture fractions were collected and concentrated under vacuum and dissolved in glacial acetic acid (3 mL) and heated in a microwave reactor at 8O0C for a total of 20 minutes. The product mixture was concentrated under vacuum to provide titled product as a 5:2 mixture of diastereroisomers. The residue was dissolved and concentrated twice from toluene, and was used in the following step without further purification. ES MS M+l = 623.11.
Step 17: 3-(4-Fluorobenzyl)-5, 10-dihydroxy-9,9, 12-trimethyl-9,l 0,11 ,12-tetrahydro-3H- pyridazino[4',5':3,4]pyrido[l 52-a] [1 ,4]diazocine-4,6, 13(8H)-trione
To a cold (O0C) solution of 5f10-bis(benzyloxy)-3-(4-fluorobenzyl)-9,9,12- trimethyl-9!10,l l,12-tetrahydro-3H-pyridazino[41,5':3,43pyrido[l,2-a][l,43diazocine-4,6,13(8H)- trione (80 mg, 0.128 mmol) in anhydrous CH2CI2 (2.5 mL), a solution of boron tribromide in dichloromethane (IM, 385 μL, 0.385 mmol) was added. The reacting mixture was stirred at 00C for 5 minutes for an additional hour at room temperature. The reaction was then cooled to O0C and treated with MeOH (2mL) and stirred for one-half hour at room temperature. The reaction was concentrated and the residue was re-concentrated twice more from MeOH to a brownish yellow gum. The material is subjected to reverse phase column chromatography on Cl 8 stationary phase eluting with 5-95% CH3CN/H2O gradient. The fractions of the major diastereoisomer were collected and dried under vacuum. The residue was concentrated from CH3CN (3X) and dried in vacuo to provide a yellow oil. This oil was triturated with Et2θ to provide a solid which was collected by filtration and dried in vacuo to give the title compound as a yellow solid. ^H NMR (400 MHz, CDCI3) δ 12.40 (s, IH), 7.76 (s, IH), 7.43 (m, 2H), 7-02
(m, 2H)5 5.20 (d, J - 14 Hz, IH), 5.05 (d, J = 14 Hz, IH), 4.97 (d, J - 14 Hz, IH), 3.59 (m, IH)5 3.48 (m, IH), 3.33 (m, IH), 3.25 (s, 3H), 3.06 (m, IH), 1.25 (s, 3H), 0.91 (s, 3H). ES MS exact mass M+l = 443.1752.
EXAMPLE 2
3 -(3 -Chloro-4-fluorobenzyl)-5-hydroxy- 12-methy 1-9, 10, 11 , 12-tetrahydro-3H- pyrimido[4',5':3,4]pyrido[l,2-a][l,4]diazocine-4,6,13(8H)~trione
Figure imgf000045_0001
Step l : 7er/-butyl (5-methoxypyridin-3-yl)carbarnate
Figure imgf000045_0002
A mixture of 3-bromo-5-methoxypyridine (23 g, 122 mmol), tert-butyl carbamate (17.2 g, 147 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (3.19 g, 5.50 mmol), CS2CO3 (55.8 g, 171 mmol) and tris(dibenzylideneacetone)dipalladium (0) (1.68 g, 1.84 mmol) in dioxane (122 mL) was heated at 900C for 72 hours. The reaction was cooled to room temperature, filtered, and concentrated under vacuum. The residue was dissolved in ether and treated with pentane. The white solid precipitated was filtered, washed with pentane, and dried under vacuum. The filtrate was concentrated and the residue subjected to column chromatography on silica gel eluting with 2% MeOH/CH2Cl2 to give additional product as a white solid. lH NMR (300 MHz, CDCI3) δ 7.99 (s, IH), 7.45 (s, IH), 7.26 (s, IH), 3.84 (s, 3H), 3.73 (d, IH), 1.52 (s, 9H). ES MS M+l = 225.0. Step 2: Ethyl 3-[(fer^butoxycarbonyl)amino]-5~methoxyisonicotinate
Figure imgf000046_0001
To a stirred solution of tert-butyl (5-methoxypyridin-3-yl)carbamate (2Jg, 12.1 mmol) in THF (35 mL) at -78°C, a solution of w-butyl lithium in hexane (12 raL, 2.5 M, 30.2 mmol) was added drop- wise. The reaction mixture was stirred at -250C for 1 hour, cooled back to -780C, and was treated drop- wise with a solution of ClCOOEt (1.4 mL, 14.4 mmol) in THF (10 mL). The reaction was allowed to stir at -780C for 30 minutes and was then quenched with saturated aqueous NH4CI. The product mixture was extracted with EtOAc (3x40mL). The combined organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified column chromatography on silica gel eluting with 20% EtOAc/pentane to give the title product as a white solid. lH NMR (400 MHz, CDCI3) δ 9.09 (s,
IH)5 8.08 (s, IH), 4.39-4.44 (m, IH), 3.92 (s, 3H)5 1.49 (s, 9H)5 1.38 (t, J= 8.2 Hz, 3H). ES MS M+l = 297.0.
Step 3: 5-Methoxypyrido[3,4-d]ρyrimidin-4(3H)-one
Figure imgf000046_0002
To a solution of ethyl 3-[(tert-butoxycarbonyl)amino]-5-methoxyisonicotinate (4 g, 13.5 mmol) in CH2CI2 (10 mL) at room temperature, TFA (10 mL) was added. The reaction was stirred for 3 hours at room temperature and was concentrated under vacuum. The residue was diluted with CH2CI2 and basified with aqueous Na2CO3 solution. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. Without further purification, the resultant crude aminopyridine intermediate and formamidine acetate (2.3 g, 20.25 mmol) was dissolved in EtOH (50 mL)5 heated under reflux for 48 hours, and cooled. The solid precipitated was filtered, washed with cold EtOH5 air dried to provide the title compound as a brown crystalline solid. IH NMR (400 MHz5 CDC13) δ 8.57 (s, IH), 8.34 (s, IH)5 8.11 (s, IH)5 3.95 (s5 3H). ES MS M+l = 178.0. Step 4: 3-(3-Chloro-4-fluoroben2yl)-5-methoxypyrido[3,4-d]pyrimidin-4(3H)-one
Figure imgf000047_0001
A mixture of 5-methoxyρyrido[3,4-d]pyrimidin-4(3H)-one (5 g, 28.2 mmol), 4- (bromomethyl)-2-chloro-l-fluorobenzene (6.31 g, 28.2 mmol), and CS2CO3 (18.4 g, 56.4 mmol) in DMF (50 mL) was stirred at room temperature for 4 hours. The product mixture was filtered and the filtrate was concentrated under vacuum. The residue was diluted with EtOAc (50 mL) and washed subsequently with H2O (40 mL) and brine (40 mL). The organic layer was dried over MgSθ4, filtered, and concentrated to provide title compound. lH NMR (400 MHz, CDCI3) δ 8.76 (s, IH), 8.35 (s, IH), 8.17 (s, IH), 7.45 (dd, J= 2,7 Hz, IH), 7.29 (m, IH)5 7.12 (t, J- 8.6 Hz5 IH), 5.08 (s, 2H)S 4.11 (s, 3H). ES MS M+l = 520.0.
Step 5 : 3-(3-Chloro-4-fiuorobenzyl)-5-methoxypyrido[3 ,4-d]pvrimidin-4(3H)-one-7- oxide
Figure imgf000047_0002
A solution of 3-(3-chloro-4-fluorobenzyl)-5-methoxypyrido[3,4-d3pyrimidin- 4(3H)-one, peracetic acid (10.9 mL), and sodium acetate (1.08 g, 13.166 mmol) in acetic acid (50 mL) was stirred at room temperature for 12 hours. Half of the solvent was removed under vacuum. The product mixture was treated portion- wise with 10% aqueous Na2SO3 until the solution no longer turned starch KI strip blue, diluted with water, and extracted with three times with CH2CI2. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo to give title compound as a solid. lH NMR (400 MHz5 CDCI3) δ 8.28 (s, IH), 8.16 (s, IH), 8.02 (s, IH), 7.45 (d, J= 7 Hz, IH), 7.27 (m5 IH), 7.14 (t, J= 8.6 Hz, IH),
5.05 (s5 2H), 4.02 (s, 3H). ES MS M = 335.8.
Step 6: 3-(3-Chloro-4-fiuorobenzyl)-5-methoxy-4-oxo-3,4-dihydropyrido[3,4- d]ρyrimidin-8-yl acetate
Figure imgf000048_0001
A solution of 3-(3-chloro-4-fluorobenzyl)-5-methoxypyrido[3,4-d]pyrimidin- 4(3H)-one-7-oxide (9 g, 26.81 mmol) in acetic anhydride (50 niL) was heated in a microwave oven at 1300C for 20 minutes. After removal of solvent, the residue was dissolved in CH2CI2 (75 niL). The organic solution was washed subsequently with 10% aqueous Na2Cθ3 (50 ml), water (50 mL). and brine (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product as a solid. lH NMR (400 MHz, CDCI3) δ 8.16 (s, IH), 8.02 (s, IH), 7.45 (dd, J= 2, 7 Hz, IH), 7.27 (m, IH), 7.12 (t, J- 8.6 Hz, IH), 5.06 (s, 2H), 4.09 (s, 3H), 2.43 (s, 3H). ES MS M = 377.8.
Step 7: 3-(3~Chloro-4-fluorobenzyl)-8-hydroxy-5-methoxypyrido[3,4-d]pyrimidin-4(3H)- one
Figure imgf000048_0002
A solution of 3-(3-chloro-4-fluorobenzyl)-5-methoxy-4-oxo-354- dihydropyrido[3,4-d]ρyrimidin-8-yl acetate (13 g, 34.4 mmol) and aqueous NaOH (2N, 35 mL) in a mixture of water (35 mL) and MeOH (250 mL) was stirred at room temperature for 2 hours. The product mixture was acidified with IN HCl (70 mL), concentrated under vacuum, and diluted with water. The solids precipitated were filtered and dried in vacuo to give the titled product. lH NMR (400 MHz, DMSO) δ 11.74 ( br s, IH), 8.65 (s, IH), 7.66 (d, J= 7 Hz, IH), 7.40 (d, J= 7 Hz5 IH), 6.94 (s, IH), 5.10 (s, 2H), 3.64 (s, 3H). ES MS M = 336.0.
Step 8 : 3 -(3 -Chloro-4-fiuorobenzyl)-5 -methoxy-4-oxo-3 ,4-dihydropyrido [3,4- d] pyrimidin-8 -yl trifluoromethanesulfonate
Figure imgf000048_0003
A solution of 3-(3-chloro-4-fluorobenzyl)-8-hydroxy-5-methoxypyrido[3,4- d]pyrimidm-4(3H)-one (3 g, 8.94 mmol), DMAP (109 mg, 0.894 mmol), and 2,6-lutidine (1.6 mL, 13.40 mmol) in CH2CI2 (150 mL) was treated with Tf2θ (1.7 mL, 9.83 mmol). The reaction mixture was stirred at room temperature for 12 hours. An additional amount of Tf2θ
(326 μL) was added and stirred for additional 2 hours. The product mixture was diluted with CH2CI2 (50 mL), washed with successively with water (75 mL) and brine (75 mL). The organic phase was separated, dried over Na2SOzj., filtered, and concentrated under vacuum. The residual oil was subjected to column chromatography on silica gel eluting with 0-40% EtOAc/hexane to give the title product as a solid. lH NMR (400 MHz, CDCI3) δ 8.30 (s, IH), 7.97 (s, IH), 7.47
(dd, J= 2, 7 Hz, IH), 7.30 (m, IH), 7.14 (t, J- 9 Hz, IH), 5.10 (s, 2H), 4.13 (s, 3H). ES MS M+l = 468.0.
Step 9: Methyl-3 -(3 -chloro-4-fluorobenzyl)- 5-methoxy-4-oxo-3 ,4-dihydropyrido [3 ,4- d] pyrimidine-8-carboxyIate
Figure imgf000049_0001
A mixture of 3-(3-chloro-4-fluorobenzyl)-5-methoxy-4-oxo-3 ,4-dihydropyrido- [3,4-d]pyrimidin-8-yl trifluoromethanesulfonate (2.97 g, 6.35 mmol), DIPEA (2.8 mL, 15.87 mmol), dppp (262 mg, 0.635 mmol), Pd(OAc)2 (143 mg, 0.635 mmol) and MeOH (1 mL) in DMSO (4 mL) was purged successively with argon for 5 minutes and then with CO for 3 minutes. The mixture was sealed and pressurized with CO (300 psi). The reaction mixture was stirred at 8O0C for 24 hours. The reaction was cooled and diluted with water. The solids precipitated were filtered, washed with water, and the dissolved in CH2CI2. The resultant mixture was dried over Na2SO4 , filtered, and concentrated under vacuum. The residual solid was subjected to column chromatography eluting with 0-10% MeOH:CHCl3 to give the title product as a solid. lH NMR (400 MHz, CDCI3) δ 8.36 (s, IH), 8.26 (s, IH), 7.45 (dd, J- 2, 7
Hz, IH), 7.26 (m, IH), 7.12 (t, J- 9 Hz, IH), 5.07 (s, 2H), 4.16 (s, 3H), 4.04 (s, 3H). ES MS M
- 377.8. Step 10: Methyl-3-(3-cUoro^-flvιoroberi-^l)-5-methoxy-4-oxo-3}4κlihydropyrido[3,4- d]pyrimidine-8-carboxylate 7-oxide
Figure imgf000050_0001
A cold solution of methyltrioxorhenium (37 mg, 0.149 mmol) and urearhydrogen peroxide (701 mg, 7.45 mmol) in methanol (5 mL) was added to a solution of methyl 3-(3- chloro-4-fiuorobenzyl)-5-methoxy-4-oxo-354-dihydropyήdo[3,4-d]pyrimidme-8-carboxylate (565 mg, 1.49 mmol) in chloroform (15 mL). The reaction mixture was stirred at room temperature for 7 days and concentrated under vacuum. The residual was dissolved in CH2CI2. The solution was washed with saturated NaHCθ3 and brine, dried over Na2SO4, and concentrated in vacuo to provide the title product. lH NMR (400 MHz, CDCI3) δ 8.14 (s, IH), 7.87 (s, IH), 7.44 (d, J= 2.2 Hz, IH), 7.27 (m, IH), 7.13 (t, J= 8.6 Hz, IH)5 5.03 (s, 2H), 4.05 (s, 3H), 4.02 (s 3H). ES MS M - 393.8.
Step 11: Methyl 6-(acetyloxy)-3 -(3 -chloro-4-fluorobenzyl)-5-methoχy-4-oxo-3 ,4- dihydropyrido [3 ,4-d]pyrimidine-8 -carboxylate
Figure imgf000050_0002
A solution of methyl 3-(3-chloro-4-fiuorobenzyi)-5-methoxy-4-oxo-3,4- dihydropyrido-[3,4-d]pyrimidine-8-carboxylate 7-oxide (470 mg, 1.19 mmol) in acetic anhydride (10 mL) was heated at 1300C for 2 hours. The solvent was removed under vacuum and the residue dissolved in CH2CI2 (40 mL). The organic mixture was washed with water (25 mL) and brine (25 mL). The organic extract was dried over Na2SO4, filtered, and concentrated under vacuum. The residual oil was subjected to column chromatography on silica gel eluting with 0- 10% MeOH: CHCI3 to give the product as a foamy solid. lH NMR (400 MHz5 CDCI3) δ 8.18
(s, IH), 7.44 (dd, J- 2.2, 6.8 Hz, IH), 7.27 (m, IH)5 7.14 (t, J= 8.4 Hz5 IH), 5.09 (s, 2H), 4.022 (s, 3H), 4.018 (s, 3H), 2.40 (s, 3H). ES MS M = 435.9.
Step 12: 3-(3-Chloro-4-fluorobenzyl)-6-hydroxy-5-methoxy-4-oxo-354-dihydropyrido[3,4- d]pyrimidine-8-carboxylic acid
Figure imgf000051_0001
A mixture of methyl 6-(acetyloxy)-3-(3-chloro-4-fluorobenzyl)-5-methoxy-4-oxo- 3,4-dihydropyrido[3,4-d]pyrimidme-8-carboxylate (367 mg, 0.842 mmol) and 2N NaOH (1.26 mL, 2.53 mmol) in methanol (5 mL) was heated at 40°C for 3 hours. The product mixture was neutralized with IN HCl (2.53 mL, 2.53 mmol) and concentrated under vacuum. The residue was dissolved with DMF and concentrated under vacuum to dryness to give the title product as a solid. lH NMR (400 MHz, DMSO) δ 7.95 (s, IH)5 7.68 (m, IH)5 7.38-7.44 (m, 2H), 5.08 (s, 2H), 3.89 (s, 3H). ES MS M = 379.9.
Step 13: 3 -(3 -Chloro-4-fluorobenzyl)-6-hydroxy-N-(4-hydroxybutyl)- 5 -methoxy-N- methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-8-carboxamide
Figure imgf000051_0002
A solution of 3-(3-chloro-4-fluorobenzyl)-5-methoxy-4-oxo-3,4-dihydropyrido- [3,4-d]-pyrimidine-8-carboxylic acid (350 mg, 0.842 mmol), N-methyl-4-hydroxybutylamine (148 mg, 1.44 mmol), EDC (194 mg, 1.01 mmol), HOAt (5.7 mg, 0.042 mmol), N- methylmorpholine (464 μL, 4.21 mmol) in DMF (4 mL) was stirred at room temperature overnight. The solvent was removed and the residue was dissolved in CH2CI2 (40 mL). The organic solution was washed with water (25 mL) and brine (25 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residual oil was subjected to column chromatography on silica gel eluting with 0-10% MeOH: CHCI3 to give the titled product as an oil. ^H NMR (400 MHz, CDCI3) δ 7.86 (d, J=17.6 Hz5 IH)5 7.45 (m, IH), 7.26 (m, IH), 7.11 (t, J=8.0 Hz, IH), 5.00 (d, 3.8 Hz, 2H)5 4.05 (d5 12.8 Hz5 3H)5 3.68 (m, IH), 3.60 (m, IH), 3.47 (m, IH)5 3.14 (m, IH)5 3.11 (s, 1.5H)5 2.86 (s5 1.5H), 1.76 (m, IH), 1.66 (m, IH), 1.41 (m, 1H)1.21 (m, IH). ES MS M = 465.0. Step 14: 3-(3-Chloro-4-fluorobenzyl)-5-methoxy-8-[(methyl{4- [(methylsulfonyl)oxy] butyl } amino)carbonyl] -4-oxo-3 ,4-dihydropyrido [3 ,4- d]pyrimidin-6-yl methanesulfonate
Figure imgf000052_0001
To a cold (O0C) solution of 3-(3-chloro-4-fluorobenzyl)-6-hydroxy-N-(4- hydroxybutyl)-5-methoxy-N-methyl-4-oxo-3f4-dihydropyrido[3,4-d]pyrimidine-8~carboxamide (53 mg, 0.114 mmol) and TEA (39.7 μL, 0.285 mmol) in CH2CI2 (1 niL), a solution of methanesulfonyl chloride (19.6 μL, 0.251 mmol) in CH2CI2 (200 μL) was added drop-wise. The resulting solution was stirred at O0C for 2 hours. The product solution was washed with water (5 mL) and brine (5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to give the titled product as a solid. ES MS M = 621.0.
Step 15: 3-(3 -Chloro-4-fluorobenzyl)-5-methoxy- 12-methyl-9, 10,11,12-tetrahydro-3H- pyrimido[4!,5':3,4]pyrido[l,2-a][l>4]diazocine-4,6,13(8H)-trione
Figure imgf000052_0002
A mixture of 3-(3-chloro-4-fluorobenzyl)-5-methoxy-8-[(methyl{4-
[(methylsulfonyl)oxy]butyl } amino)carbonyl] -4-oxo-3 ,4-dihydropyrido[3 ,4-d]pyrimidin-6-yl methanesulfonate (65 mg, 0.105 mmol) and CS2CO3 (102 mg, 0.314 mmol) in DMF (5 mL) was heated at 1000C for 3 hours. The product mixture was concentrated under vacuum. The residual was dissolved in CH2CI2. The organic solution was washed with water (5 mL) and brine (5 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residual oil was subjected to column chromatography on silica gel eluting with 0-10% MeOH: CHCI3 to give the titled product as an oil. lH NMR (400 MHz, CDCI3) δ 7.63 (s, IH), 7.41 (dd, J=2.1, 6.8 Hz, IH), 7.25 (m, IH), 7.11 (t, J=8.5 Hz, IH), 4.96 (d, J=5.9 Hz, IH), 4.92 (d, J=6.5 Hz, 2H), 4.16 (s, 3H), 3.37-3.51 (m, 2H), 3.26-3.31 (m, IH), 3.21 (s, 3H), 2.16 (m, IH)5 1.77-1.84 (m, 3H). ES MS M
= 447.5.
Step 16: 3-(3-Chloro-4-fluorobenzyl)-5-hydroxy-12-methyl-9;105l l512-tetrahydro-3H- pyrϊmido[4t,5':3,4]pyrido[l,2-a][l,4]diazocine-4:,6>13(8H)-trione To a cold (00C) solution of 3-(3-chloro-4-fluorobenzyl)-5-methoxy-12-methyI- 9,10,11 J12-tetrahydro-3H-pyrimido[41 s5':3s4]pyrido[l,2-a][l;4]diazocine-4,6,13(8H)-trione (30 mg, 0.067 mmol) in CH2CI2 (500 μL), a solution of boron tribromide in CH2CI2 (201 μL, IM,
0.201 mmol) was added and the reaction was stirred for 10 minutes in an ice bath. The reaction was quenched with methanol (2 mL) and the solvent removed to give the product as a glass. The residual was purified by preparative reverse phase HPLC. Collection and lyophilization of appropriate fractions provided the titled compound. lH NMR (400 MHz, DMSO) δ 7.99 (s, IH), 7.66 (d, J=7.5 Hz, IH), 7.41 (m, 2H)5 6.68 (bs, IH), 5.00 (m, 2H), 4.65 (m, IH), 3.35-3.37 (m, 2H), 3.17-3.22 (m, IH), 3.02 (s, 3H), 1.96-1.99 <m, IH), 1.76-1.83 (m, IH) 1.55-1.61 (m, 2H). ES MS M = 433-0. Exact mass m/z = 433.1068
EXAMPLE 3 HFV Integrase Assay: Strand Transfer Catalyzed bv Recombinant Integrase
Assays for the strand transfer activity of integrase were conducted in accordance with WO 02/30930 for recombinant integrase. Further description on conducting the assay using preassembled complexes is found in Wolfe, AX. et al., J Virol. 1996, 70: 1424-1432, Hazuda et al., J 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.
The compounds of Examples 1 and 2 were tested in the integrase assay and found to have the following IC50 values:
Figure imgf000053_0001
EXAMPLE 4 Assay for inhibition of HIV replication
Assays for the inhibition of acute HIV-I infection of T-lymphoid cells were conducted in accordance with Vacca, J.P. et al.s Proc. Natl. Acad. ScI USA 1994, 91: 4096. The compounds of Examples 1 and 2 were tested in this assay and found to have the following IC95 values:
Figure imgf000054_0001
EXAMPLE 5 Cytotoxicity
Cytotoxicity was determined by microscopic examination of the cells in each well in the spread assay, wherein a trained analyst observed each culture for any of the following morphological changes as compared to the control cultures: pH imbalance, cell abnormality, cytostatic, cytopathic, or crystallization (i.e., the compound is not soluble or forms crystals in the well). The toxicity value assigned to a given compound is the lowest concentration of the compound at which one of the above changes is observed. The compounds set forth in Examples 1 and 2 exhibited no cytotoxicity at concentrations up to 10 micromolar.
While the foregoing specification teaches the principles of the present invention, with examples 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 I5 or a pharmaceutically acceptable salt thereof:
Figure imgf000055_0001
wherein:
Rl is Cl -6 alkyl, RJ, or Cl -6 alkyl substituted with RJ, wherein RJ is CycA, AryA, HetA, or HetP;
R2 is:
(1) H,
(2) Ci^ alkyl,
(3) Ci_6 haloalkyl, or
(4) C i .6 alkyl substituted with C(O)N(RA)RB , C(O)RA, Cθ2RA, C(O)-N(RA)-C2-O alkylene-ORB, S(O)RA, SO2RA, SO2N(RA)RB, ORA, or HetE;
R3 A5 R3B5 R6A and R6B are each independently selected from the group consisting of:
(1) H,
(2) Ci-6 alkyl, (3) Ci.6 haloalkyl,
(4) Cl _6 alkyl substituted with OH, O-C i -6 alkyl, 0-Q -6 haloalkyl, CN, N(RA)RB, C(O)N(RA)RB, C(O)RA5 Cθ2RA 5 C(O)-N(RA)-C2-6 alkylene-ORB, SRA S(O)RA SO2RA, SO2N(RA)RB5 N(RA)C(O)RB, N(RA)Cθ2RB, N(RA)SO2RB, N(RA)SO2N(RA)RB5 N(RA)C(O)N(RA)RB5 OC(O)N(RA)RB, or OC(O)RA,
(5) C(O)N(RA)RB,
(6) C(O)C(O)N(RA)RB,
(7) C(O)RA5 and
(8) CO2RA;
R4A5 R4B, R5A and R5B are as defined in (A)5 (B), or (C) as follows: (A) R.4As R4B} R5A and R5B each independently selected from the group consisting of:
(1) H,
(2) halogen, (3) Cμ6 alkyl,
(4) Ci-6 haloalkyl,
(5) C i -6 alkyl substituted with OH, OC l -6 alkyl, 0-C l -6 haloalkyl, CN, N(RA)RB5 C(O)N(RA)RB5 C(O)RA5 Cθ2RA, C(O)-N(RA)-C2-6 alkylene-ORB, SRA, S(O)RA, Sθ2RA, SO2N(RA)RB, N(RA)C(O)RB5 N(RA)Cθ2RB, N(RA)S02RB, N(RA)SO2N(RA)RB,
N(RA)C(O)N(RA)RB5 OC(O)N(RA)RB, Or OC(O)RA5
(6) O-Ci-6 alkyl,
(7) O-Ci-6 haloalkyl,
(8) C(O)N(RA)RB5 (9) C(O)C(O)N(RA)RB5
Figure imgf000056_0001
(12) SRA,
(13) S(O)RA,
Figure imgf000056_0002
(16) OH5 and
(17) HetS;
(B) R4A and R4B together form oxo or =C(RA)RB5 and R5A and R5B are as defined in (A); or
(C) R5A and R5B together form oxo or ^=C(RA)RB1 and R4A and R4B are as defined in (A);
one of G and T is N, and the other of G and T is C-R?, wherein R? is: (1) H,
(2) Ci-6 alkyl,
(3) C 1 _6 fluoroalkyl, or
(4) Ci-6 alkyl substituted with OH, O-Ci-6 alkyl, 0-Cμ6 haloalkyl, CN, N(RA)RB? C(O)N(RA)RB5 C(O)RA CO2RA. C(O>N(RA)-C2-6 alkylene-ORBs SRA, S(O)RA5 S02RA, 802N(RA)RB, N(RA)C(O)RB, N(RA)C02RB,
N(RA)S02RB, N(RA)SO2N(RA)RB5 N(RA)C(O)N(RA)RB5 or OC(O)N(RA)RB; each RA is independently H or Cl -6 alkyl;
each RB is independently H or C]. g alkyl;
CycA is a C3-8 cycloalkyl which is optionally substituted with a total of from 1 to 6 substituents, wherein:
(i) from zero to 6 substituents are each independently:
(1) halogen,
(2) CN
(3) C 1-6 alkyl
(4) OH,
(5) O-C1-6 alkyl,
(6) Ci-6 haloalkyl, or
(7) O-Ci-6 haloalkyl, and
(ii) from zero to 2 substituents are each independently:
(1) CycD,
(2) AryD,
(3) HetD,
(4) HetZ,
(5) C 1-6 alkyl substituted with CycD, AryD, HetD, or HetZ, or
(6) C(O)-HeIZ or C(O)C (O)-HetZ;
AryA is an aryl which is optionally substituted with a total of from 1 to 5 substituents, wherein:
(i) from zero to 5 substituents are each independently: (1) Ci-6 alkyl,
(2) C 1 -6 alkyl substituted with OH, O-C 1 -6 alkyl, O-C 1 -6 haloalkyl, CN, NO2, N(RA)RB, C(O)N(RA)RB, C(O)RA, Cθ2RA, SRA, S(O)RA, SO2RA, Sθ2N(RA)RB, N(RA)C(O)RB, N(RA)C02RB, N(RA)S02RB, N(RA)S02N(RA)RB, OC(O)N(RA)RB, N(RA)C(O)N(RA)RB, or N(RA)C(O)C(O)N(RA)RB,
(3) O-C1-6 alkyl,
(4) C 1-6 haloalkyl,
(5) O-C 1-6 haloalkyl,
(6) OH, (7) halogen,
(8) CN,
(9) NO2,
(10) N(RA)RB, (11) C(O)N(RA)RB5
(12) C(O)RA
(13) C(O)-C l -6 haloalkyl,
(14) C(O)ORA5
(15) OC(O)N(RA)RB,
(16) SRA,
(17) S(O)RA,
(18) SO2RA
Figure imgf000058_0001
(20) N(RA)Sθ2RB>
(21) N(RA)SO2N(RA)RB5
(22) N(RA)C(O)RB,
(23) N(RA)C(O)N(RA)RB5
(24) N(RA)C(O)C(O)N(RA)RB, Or
(25) N(RA)CO2RB > and
(ii) from zero to 2 substituents are each independently:
(1) CycD,
(2) AryD,
(3) HetD,
(4) HetZ,
(5) C] -6 alkyl substituted with CycD, AryD, HetD, or HetZ, or
(6) QOVHetZ or C(O)C(O)-HetZ;
HetA is a heteroaryl which is optionally substituted with a total of from 1 to 5 substituents, wherein:
(i) from zero to 5 substituents are each independently:
(1) Ci-6 alkyl,
(2) C 1 _6 alkyl substituted with OH, 0-C 1 _6 alkyl, 0-C 1.5 haloalkyl, CN5 NO2, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO2RA BRA S(O)RA SO2RA Sθ2N(RA)RB, N(RA)C(O)RB, N(RA)C02RB, N(RA)S02RB,
N(RA)SO2N(RA)RB9 OC(O)N(RA)RB5 N(RA)C(O)N(RA)RB, or
N(RA)C(O)C(O)N(RA)RB,
(3) O-Ci-6 alkyl,
(4) Ci-6 haloalkyl, (5) O-Ci-6 haloalkyl,
(6) OH,
(7) halogen,
(8) CN? (9) NO2,
(10) N(RA)RB,
(11) C(O)N(RA)RB,
(12) C(O)RA,
(13) C(O)-C 1-6 haloalkyl,
(14) C(O)ORA,
(15) OC(O)N(RA)RB,
(16) SRA,
(17) S(O)RA5
(18) Sθ2RA,
Figure imgf000059_0001
(22) N(RA)C(O)RB,
(23) N(RA)C(O)N(RA)RB,
(24) N(RA)C(O)C(O)N(RA)RB5 Or
Figure imgf000059_0002
(ii) from zero to 2 substituents are each independently:
(D CycD,
(2) AryD,
(3) HetD,
(4) HetZ,
(5) C 1-6 alkyl substituted with CycD, AryD, HetD, or HetZ, or
(6) C(O)-HetZ or C(O)C(O)-HetZ;
HetP is (i) 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, where each S is optionally oxidized to S(O) or S (0)2 or (ii) a 6- to 10-membered saturated or mono-unsaturated, bridged or fused heterobicyclic ring containing from 1 to 4 heteroatoms independently selected from N5 O and S, where each S is optionally oxidized to S(O) or S(0)2; and wherein the saturated or mono-unsaturated heterocyclic or heterobicyclic ring is optionally substituted with a total of from 1 to 4 substituents, wherein:
(i) from zero to 4 substituents are each independently halogen, Ci -6 alkyl, Ci -6 haloalkyl, O-Ci-6 alkyl, O-Q-6 haloalkyl, oxo, C(O)N(RA)RB5 C(O)C(O)N(RA)RB, C(O)RA, Cθ2RA, SRA, S(O)RA5 SO2RA, or
Figure imgf000059_0003
(ii) from zero to 2 substituents are each independently CycD, AryD, HetD, or Ci-g alkyl substituted with CycD, AryD, HetD; HetS independently has the same definition as HetP;
each CycD is independently a C3-8 cycloalkyl which is optionally substituted with from 1 to 4 substituents each of which is independently halogen, C \ ~6 alkyl, OH, O-C 1 -6 alkyl, or C 1.5 haloalkyl;
each AryD is independently phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with from 1 to 5 substituents each of which is independently any one of the substituents (1) to (25) as set forth above in part (i) of the definition of AryA;
each HetD is independently 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 any one of the substituents ( 1 ) to (25) as set forth above in part (i) of the definition of HetA;
HetE 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 any one of the substituents (1) to (25) as set forth above in part (i) of the definition of HetA;
each HetZ is independently 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 N5 O and S, where each S is optionally oxidized to S(O) or S(O)2, wherein the saturated or mono- unsaturated heterocyclic ring is optionally substituted with from 1 to 4 substituents each of which is independently halogen, C 1-6 alkyl, Ci_6 haloalkyl, O-Ci-6 alkyl, O-Cj.g haloalkyl, oxo, C(O)N(RA)RBs C(O)C(O)N(RA)RB, C(O)RA, CO2RA SRA, S(O)RA, SO2RA, or
Figure imgf000060_0001
each aryl is independently (i) phenyl, (ii) a 9- or 10-membered bicyclic, fused carbocyclic ring system in which at least one ring is aromatic, or (iii) an 11- to 14-membered tricyclic, fused carbocyclic ring system in which at least one ring is aromatic; and
each heteroaryl is independently (i) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein each N is optionally in the form of an oxide, (ii) a 9- or 10-membered bicyclic, fused ring system, or (iii) an 11- to 14-membered tricyclic, fused ring system, wherein the fused ring system in (ii) or (iii) contains from 1 to 4 heteroatoms independently selected from N, O and S5 and wherein in the fused ring system of (ii) or (iii) any one or more of the rings contain one or more of the heteroatoms, at least one ring is aromatic, each N in a ring is optionally in the form of an oxide, and each S is optionally S(O) or S(O)2-
2. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Rl is C}_6 alkyl substituted with RJ.
3. A compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein RJ is AryA or HetA.
4. A compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein Rl is:
Figure imgf000061_0001
the asterisk * denotes the point of attachment of Rl to the rest of the compound;
Vl and V2 are each independently:
(D H,
(2) CM alkyl,
(3) OH,
(4) O-C 1-4 alkyl,
(5) Ci-4 haloalkyl,
(6) O-Ci-4 haloalkyl>
(7) halogen,
(8) CN,
(9) N(RA)RB9
(10) C(O)N(RA)RB,
(H) C(O)RA,
(12) C(O)ORA,
(13) SRA,
(14) S(O)RA
(15) SO2RA,
(16) N(RA)SO2RB,
(17) N(RA)SO2N(RA)RB5
(18) N(RA)C(O)RB,
(19) N(RA)C(O)C(O)N(RA)RB, (20) HetD,
(21) HetZ, or
(22) C(O)-HetZ, wherein:
HetD is a 5- or 6-membered heteroaromatic ring containing a total of from 1 to 3 heteroatoms independently selected from 1 to 3 N atoms, from zero to 1 O atom, and from zero to 1 S atom, wherein the heteroaromatic ring is optionally substituted with from 1 to 3 substituents each of which is independently Cl -.4 alkyl, OH, O-Ci-4 alkyl, halogen, CN5 C(O)N(RA)RB, C(O)RA5 C(O)ORA, or
HetZ is a 5- or 6-membered saturated heterocyclic ring containing a total of from 1 to 2 heteroatoms selected from 1 to 2 N atoms, zero to 1 O atom, and zero to 1 S atom, wherein the S atom is optionally S(O) or SO2, wherein the saturated heterocyclic ring is optionally substituted with from 1 to 2 substituents each of which is independently Ci-4 alkyl, oxo, C(O)N(RA)RB5 C(O)RA,
Figure imgf000062_0001
and with the proviso that when HetZ is attached to the rest of the compound via the C(O) moiety, then HetZ is attached to the C(O) via a ring N atom;
or alternatively V 1 and V^ are respectively located on adjacent carbons in the phenyl ring and together form methylenedioxy or ethylenedioxy; and
V3 is:
(1) H,
(2) C i_4 alkyl,
(3) 0-C 1-4 alkyl,
(4) C 1-4 haloalkyl,
(5) O-Ci-4 haloalkyl, or
(6) halogen.
5. A compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein Vl and V2 are each independently:
(D H,
(2) CH3, (3) CF3,
(4) OH5
(5) OCH3,
(6) Cl5 Br, or F, (7) CN,
(8) C(O)NH2,
(9) C(O)NH(CH3),
(10) C(O)N(CH3)2, or (11) Sθ2CH3; and
V3 is H, Cl, Br, F, CH3, or OCH3.
6. A compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein Rl is 4-fluorobenzyl, 3-chloro-4-fluorobenzyl, or 4-fIuoro-3-methylbenzyl.
7. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R.2 is:
(D H, (2) Ci_4 alkyl,
(3) C 1-4 haloalkyl, or
(4) Ci-4 alkyl substituted with C(O)N(RA)RB5 C(O)RA, CO2RA S(O)RA, SO2RA, SO2N(RA)RB5 ORA, or HetE; and
HetE is a 5- or 6-membered heteroaromatic ring containing a total of from 1 to 3 heteroatoms independently selected from 1 to 3 N atoms, from zero to 1 O atom, and from zero to 1 S atom, wherein the heteroaromatic ring is optionally substituted with from 1 to 3 substituents each of which is independently C 1.4 alkyl, OH, O-C1.4 alkyl, halogen, CN5 C(O)N(RA)RB, C(O)RA, C(O)ORA or SO2RA.
8. A compound according to claim 7. or a pharmaceutically acceptable salt thereof, wherein R2 is:
(1) CH3,
(2) CH2CH3, (3) CH2CH2CH3,
(4) CH(CH3)2,
(5) CH2CH2CH2CH3S
(6) C(CH3)3,
(7) CH2CH(CH3)Z (8) CH(CH3)CH2CH3,
(9) CF3,
(10) CH2CF3, or (11) (CH2)l-4-V, wherein V is C(O)N(RA)RB, C(O)RA Cθ2RA, S(O)RA, Sθ2RA, Sθ2N(RA)RB? ORA, or Het E; and
HetE is heteroaromatic ring selected from the group consisting of pyrazolyl, imidazolyl, oxazolyl, isooxazolyl, thiazolyl, triazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein the ring is optionally substituted with CH3, CH2CH3, CH2CH2CH3, or
CH(CH3)2-
9. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:
R3A and R3B are both H;
R4A is H, C 1-4 alkyl, OH or HetS; wherein HetS is a 5- or 6-membered saturated heterocyclic ring containing a total of from 1 to 2 heteroatoms selected from 1 to 2 N atoms, zero to 1 O atom, and zero to 1 S atom, wherein the S atom is optionally S(O) or SO2, wherein the saturated heterocyclic ring is optionally substituted with from 1 to 3 substituents each of which is independently C 1.4 alkyl, oxo, C(O)N(RA)RB, C(O)RA, CO2RA, or SO2RA;
R4B is H or C 1.4 alkyl;
alternatively, R4A and R4B together form oxo;
R5A is H, C1-4 alkyl, or OH;
R5B is H or C i_4 alkyl;
alternatively. R5A and R5B together form oxo; provided that one, not both, of (a) R4A and R4B and (b) R5A and R5B are oxo;
R6A is H5 C 1-4 alkyl, or Ci_4 alkyl substituted with OH;
R6B is H or Cl -4 alkyl;
and provided that:
(i) when R4A is OH or HetS, then R5A is not OH and R6A is not Ci-4 alkyl substituted with OH; (ii) when R5 A is OH, then R4A is not OH or HetS and R6 A is not C 1.4 alkyl substituted with OH;
(iii) when R6A is C] .4 alkyl substituted with OH, then R4A }S not OH or HetS and R5A is not OH.
10. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R? is H or C 1.4 alkyl.
1 1. A compound according to claim 105 or a pharmaceutically acceptable salt thereof, wherein R? is H or Ci -3 alkyl.
12. A compound according to claim 11 , or a pharmaceutically acceptable salt thereof, wherein R? is H or CH3.
13. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
Rl is:
Figure imgf000065_0001
the asterisk * denotes the point of attachment of Rl to the rest of the compound;
Vl and V2 are each independently:
(1) H,
(2) Ci-4 alkyl, (3) OH,
(4) 0-Ci-4 alkyL
(5) Ci-4 haloalkyl,
(6) O-C1-4 haloalkyl,
(7) halogen, (8) CN5
(9) N(RA)RB9
(10) C(O)N(RA)RB,
(11) C(O)RA
(12) C(O)ORA, (13) SRA,
(14) S(O)RA,
(15) SO2RA
(16) N(RA)Sθ2RB,
Figure imgf000066_0001
(18) N(RA)C(O)RB,
(19) N(RA)C(O)C(O)N(RA)RB,
(20) HetD,
(21) HetZ, or (22) C(O)-HetZ, wherein:
HetD is a 5- or 6-membered heteroaromatic ring containing a total of from 1 to 3 heteroatoms independently selected from 1 to 3 N atoms, from zero to 1 O atom, and from zero to 1 S atom, wherein the heteroaromatic ring is optionally substituted with 1 to 3 substituents each of which is independently C 1-4 alkyl, OH, O-C i -4 alkyl, halogen, CN5 C(O)N(RA)RB, C(O)RA, C(O)ORA5 or
HetZ is a 5- or 6-membered saturated heterocyclic ring containing a total of from 1 to 2 heteroatoms selected from 1 to 2 N atoms, zero to 1 O atom, and zero to 1 S atom, wherein the S atom is optionally S(O) or SO2, wherein the saturated heterocyclic ring is optionally substituted with from 1 to 2 substituents each of which is independently Ci .4 alkyl. oxo, C(O)N(RA)RB, C(O)RA,
Figure imgf000066_0002
and with the proviso that when HetZ is attached to the rest of the compound via the C(O) moiety, then HetZ is attached to the C(O) via a ring N atom;
or alternatively Vl and V^ are respectively located on adjacent carbons in the phenyl ring and together form methylenedioxy or ethylenedioxy; and
V3 is:
(1) H5
(2) CM alkyl,
(3) O-C 1-4 alkyl,
(4) Ci-4 haloalkyl, (5) O-C 1.4 haloalkyl, or
(6) halogen;
one of G and T is N, and the other of G and T is C-R7, wherein R7 is H or Cl .4 alkyl; R2 is:
(1) H,
(2) CM alkyl, (3) Ci_4 haloalkyl, or
(4) C i -4 alkyl substituted with C(O)N(RA)RB, C(O)RA, CO2RA, S(O)RA, Sθ2RA,
Figure imgf000067_0001
R3A and R3B are both H;
R4A is H5 C 1-4 alkyl, OH or HetS; wherein HetS is a 5- or 6-membered saturated heterocyclic ring containing a total of from 1 to 2 heteroatoms selected from 1 to 2 N atoms, zero to 1 O atom, and zero to 1 S atom, wherein the S atom is optionally S(O) or S02, wherein the saturated heterocyclic ring is optionally substituted with from 1 to 3 substituents each of which is independently C 1.4 alkyl, oxo, C(O)N(RA)RB, C(O)RA, CO2RA or SO2RA;
R4B is H or C 1-4 alkyl;
alternatively, R4A and R4B together form oxo;
R5A is H5 C 1-4 alkyl, or OH;
R5B is H or C 1-4 alkyl;
alternatively, R5A and R5B together form oxo; provided that one, not both, of (a) R4A and R4B and (b) R5A and R5B are oxo;
R6A is H, C 1-4 alkyl, or C 1.4 alkyl substituted with OH;
R6B is H or Cl -4 alkyl;
and provided that:
(i) when R4A is OH or HetS, then R5A is not OH and R6A is not C 1 „4 alkyl substituted with OH; (ii) when R5 A 1S OH, then R4 A is not OH or HetS and R6 A is not C 1.4 alkyl substituted with OH;
(iii) when R6A is C 1 -4 alkyl substituted with OH, then R4A is not OH or HetS and R5A is not OH.
14. A compound according Io claim 13, or a pharmaceutically acceptable salt thereof, wherein:
Rl is:
Figure imgf000068_0001
Vl and V2 are each independently:
(D H,
(2) CH3, (3) CF3,
(4) OH,
(5) OCH3,
(6) Cl, Br, or F,
(7) CN, (8) C(O)NH2,
(9) C(O)NH(CH3),
(10) C(O)N(CH3)2, or
(1 1) SO2CH3; and
V3 is H, Cl, Br, F5 CH3, or OCH3;
one of G and T is N, and the other of G and T is C-R?, wherein R7 is H or CH3;
R2 is: (1) CH3,
(2) CH2CH3,
(3) CH2CH2CH3,
(4) CH(CH3)2,
(5) CH2CH2CH2CH35 (6) C(CH3)3,
(7) CH2CH(CH3)2,
(8) CH(CH3)CH2CH3,
(9) CF3,
(10) CH2CF3, or (11) (CH2)l-4-V, wherein V is C(O)N(RA)RB5 C(O)RA5 Cθ2RA, S(O)RA, Sθ2RA, or Sθ2N(RA)RB;
R3A and R3B are both H;
Figure imgf000069_0001
R4B ls H or CH3;
alternatively, R4A and R4B together form oxo;
Figure imgf000069_0002
R5B is H or CH3;
alternatively, R5A and R5B together form oxo; provided that one, not both, of (a) R4A and R4B and (b) Rβ A and R5B are oxo;
R6A is H or CH3;
R6B is H or CH3;
and provided that:
(i) when R4A 1S OH, then R5A JS not OH; (ii) when R5A 1S OH, then R4A js not OH.
15. A compound according to claim 14, or a pharmaceutically acceptable salt thereof, wherein:
Rl is 4-fluorobenzyl, 3-chloro-4-fluorobenzyl, or 4-fluoro-3-methylbenzyl;
one of G and T is N, and the other of G and T is CH;
R2 is CH3;
R3 A and R3B are both H;
R4A is H, CH3, or OH; R4B is H or CH3;
alternatively, R.4A and R4B together form oxo;
R5A is H, CH3, or OH;
R5B is H or CH3;
alternatively, R5A and R5B together form oxo; provided that one, not both, of (a) R4A and R4B and (b) R5A and R5B are oxo; and
R6A and R6B are both H.
16. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, which is a compound selected from the group consisting of:
Figure imgf000070_0001
pharmaceutically acceptable salts thereof.
17. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
18. A method for the inhibition of HIV integrase in a subject in need thereof which comprises administering to the subject an effective amount of the compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof.
19. A method for the treatment or prophylaxis of infection by HIV or for the treatment, prophylaxis, or delay in the onset or progression of AIDS in a subject in need thereof, which comprises administering to the subject an effective amount of the compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof.
20. A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, for use in therapy.
21. A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for the inhibition of HIV integrase, for the treatment or prophylaxis of infection by HIV, or for the treatment, prophylaxis, or delay in the onset or progression of AIDS in a subject in need thereof.
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WO2019160783A1 (en) * 2018-02-15 2019-08-22 Merck Sharp & Dohme Corp. Tricyclic heterocycle compounds useful as hiv integrase inhibitors
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US11548902B1 (en) 2019-03-22 2023-01-10 Gilead Sciences, Inc. Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical use
US11084832B2 (en) 2019-03-22 2021-08-10 Gilead Sciences, Inc. Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical use
US11697652B2 (en) 2020-02-24 2023-07-11 Gilead Sciences, Inc. Tetracyclic compounds and uses thereof
US12122776B2 (en) 2020-02-24 2024-10-22 Gilead Sciences, Inc. Tetracyclic compounds and uses thereof
US11613546B2 (en) 2021-01-19 2023-03-28 Gilead Sciences, Inc. Substituted pyridotriazine compounds and uses thereof
US11897892B2 (en) 2021-01-19 2024-02-13 Gilead Sciences, Inc. Substituted pyridotriazine compounds and uses thereof
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